+4<5
definitions 6.3.1

Evaluable for toxicity: All patients will be evaluable for toxicity from the time of their first treatment with tremelimumab and durvalumab.  
Evaluable for objective response: Only those patients who have measurable disease present at baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for response. These patients will have their response classified according to the definitions stated below. (Note: Patients who exhibit objective disease progression prior to the end of cycle 1 will also be considered evaluable.)
"\#$%&$'%(
)*+,-$./(0
123($3(
4(35*+3(6
7$02(+03
89*
9$\#(
%(32*+3
5.(3(+0
$0
'$3(%2+(
09$0
$.( (\#$%&$'%(
'&0
:*
+*0
;((0
09(
:(<2+202*+3
*<
;($3&.$'%(
:23($3(=
9$\#(
.(>(2\#(:
$0
%($30
*+(
>?>%( *<
09(.$5?=
$+:
9$\#(
9$:
09(2.
:23($3(
.(,(\#$%&$0(:
82%%
'(
>*+32:(.(:
(\#$%&$'%(
<*.
+*+,0$./(0 :23($3(@
-9(
.(35*+3(
$33(33;(+0
23
'$3(:
*+
09(
5.(3(+>(=
$'3(+>(=
*.
&+(A&2\#*>$%
5.*/.(332*+ *<
09(
%(32*+3@ B@C@D 123($3(
7$.$;(0(.3 E($3&.$'%(
:23($3(6
E($3&.$'%(
%(32*+3
$.(
:(<2+(:
$3
09*3(
09$0
>$+
'(
$>>&.$0(%?
;($3&.(:
2+
$0
%($30
*+(
:2;(+32*+
F%*+/(30
:2$;(0(.
0*
'(
.(>*.:(:G
$3
HDI
;;
'?
>9(30
J,.$?=
$3
HKI
;; 8209
L3>$+=
*.
HKI
;;
8209
>$%25(.3
'?
>%2+2>$%
(J$;@
M%%
0&;*.
;($3&.(;(+03
;&30
'(
.(>*.:(:
2+
;2%%2;(0(.3
F*.
:(>2;$%
<.$>02*+3
*<
>(+02;(0(.3G@ E$%2/+$+0
%?;59
+*:(3@
-*
'(
>*+32:(.(:
5$09*%*/2>$%%?
(+%$./(:
$+:
;($3&.$'%(=
$
%?;59
+*:( ;&30
'(
HK!
;;
2+
39*.0
$J23
89(+
$33(33(:
'?
L3>$+
FL3>$+
3%2>(
092>N+(33
.(>*;;(+:(: 0*
'(
+*
/.($0(.
09$+
!
;;G@
M0
'$3(%2+(
$+:
2+
<*%%*8,&5=
*+%?
09(
39*.0
$J23
82%%
'(
;($3&.(: $+:
<*%%*8(:@ )*+,;($3&.$'%(
:23($3(@
M%%
*09(.
%(32*+3
F*.
320(3
*<
:23($3(G=
2+>%&:2+/
3;$%%
%(32*+3
F%*+/(30 :2$;(0(.
OKI
;;
*.
5$09*%*/2>$%
%?;59
+*:(3
8209
PQR
0*
OK!
;;
39*.0
$J23G=
$.(
>*+32:(.(: +*+,;($3&.$'%(
:23($3(@
S*+(
%(32*+3=
%(50*;(+2+/($%
:23($3(=
$3>20(3=
5%(&.$%T5(.2>$.:2$% (<<&32*+3=
%?;59$+/2023
>&023T5&%;*+2023=
2+<%$;;$0*.?
'.($30
:23($3(=
$+:
$':*;2+$%
;$33(3 F+*0
<*%%*8(:
'?
L*.
E4UG=
$.(
>*+32:(.(:
$3
+*+,;($3&.$'%(@ )*0(6
L?302>
%(32*+3
09$0
;((0
09(
>.20(.2$
<*.
.$:2*/.$592>$%%?
:(<2+(:
32;5%(
>?303
39*&%:
+*0
'( >*+32:(.(:
$3
;$%2/+$+0
%(32*+3
F+(209(.
;($3&.$'%(
+*.
+*+,;($3&.$'%(G
32+>(
09(?
$.(=
'? :(<2+202*+=
32;5%(
>?303@ VL?302>
%(32*+3W
09*&/90
0*
.(5.(3(+0
>?302>
;(0$30$3(3
>$+
'(
>*+32:(.(:
$3
;($3&.$'%(
%(32*+3= 2<
09(?
;((0
09(
:(<2+202*+
*<
;($3&.$'2%20?
:(3>.2'(:
$'*\#(@
X*8(\#(.=
2<
+*+,>?302>
%(32*+3
$.( 5.(3(+0
2+
09(
3$;(
5$02(+0=
09(3(
$.(
5.(<(..(:
<*.
3(%(>02*+
$3
0$./(0
%(32*+3@ -$./(0
%(32*+3@
M%%
;($3&.$'%(
%(32*+3
&5
0*
$
;$J2;&;
*<
D
%(32*+3
5(.
*./$+
$+:
!
%(32*+3
2+ 0*0$%=
.(5.(3(+0$02\#(
*<
$%%
2+\#*%\#(:
*./$+3=
39*&%:
'(
2:(+02<2(:
$3
YZ[\]Y
^]_`ab_
$+:
.(>*.:(: $+:
;($3&.(:
$0
'$3(%2+(@
-$./(0
%(32*+3
39*&%:
'(
3(%(>0(:
*+
09(
'$323
*<
09(2.
32c(
F%(32*+3 8209
09(
%*+/(30
:2$;(0(.G=
'(
.(5.(3(+0$02\#(
*<
$%%
2+\#*%\#(:
*./$+3=
'&0
2+
$::202*+
39*&%:
'( 09*3(
09$0
%(+:
09(;3(%\#(3
0*
.(5.*:&>2'%(
.(5($0(:
;($3&.(;(+03@
U0
;$?
'(
09(
>$3(
09$0=
*+ *>>$32*+=
09(
%$./(30
%(32*+
:*(3
+*0
%(+:
203(%<
0*
.(5.*:&>2'%(
;($3&.(;(+0
2+
892>9 >2.>&;30$+>(
09(
+(J0
%$./(30
%(32*+
892>9
>$+
'(
;($3&.(:
.(5.*:&>2'%?
39*&%:
'(
3(%(>0(:@
M 3&;
*<
09(
:2$;(0(.3
F%*+/(30
<*.
+*+,+*:$%
%(32*+3=
39*.0
$J23
<*.
+*:$%
%(32*+3G
<*.
$%%
0$./(0 %(32*+3
82%%
'(
>$%>&%$0(:
$+:
.(5*.0(:
$3
09(
'$3(%2+(
3&;
:2$;(0(.3@
U<
%?;59
+*:(3
$.(
0*
'( 2+>%&:(:
2+
09(
3&;=
09(+
*+%?
09(
39*.0
$J23
23
$::(:
2+0*
09(
3&;@
-9(
'$3(%2+(
3&;
:2$;(0(.3 82%%
'(
&3(:
$3
.(<(.(+>(
0*
<&.09(.
>9$.$>0(.2c(
$+?
*'d(>02\#(
0&;*.
.(/.(332*+
2+
09(
;($3&.$'%( :2;(+32*+
*<
09(
:23($3(@ )*+,0$./(0
%(32*+3@
M%%
*09(.
%(32*+3
F*.
320(3
*<
:23($3(G
2+>%&:2+/
$+?
;($3&.$'%(
%(32*+3
*\#(. $+:
$'*\#(
09(
!
0$./(0
%(32*+3
39*&%:
'(
2:(+02<2(:
$3
babeYZ[\]Y
^]_`ab_
$+:
39*&%:
$%3*
'( .(>*.:(:
$0
'$3(%2+(@
E($3&.(;(+03
*<
09(3(
%(32*+3
$.(
+*0
.(A&2.(:=
'&0
09(
5.(3(+>(=
$'3(+>(= *.
2+
.$.(
>$3(3
&+(A&2\#*>$%
5.*/.(332*+
*<
($>9
39*&%:
'(
+*0(:
09.*&/9*&0
<*%%*8,&5@ "\#$\#$ %&'()*+
,)./0120'3)4
),
%&0+2-051&
63+&0+& 711
8&0+2-&8&4'+
+()21*
5&
'09&4
04*
-&:)-*&*
34
8&'-3:
4)'0'3)4
2+34;
0
-21&):013<&-+\#
711 50+&134&
&/0120'3)4+
+()21*
5&
<&-,)-8&*
0+
:1)+&1=
0+
<)++351&
')
'(&
5&;34434;
),
'-&0'8&4'
04* 4&/&8)-&
'(04
>
?&&9+
5&,)-&
'(&
5&;34434;
),
'(&
'-&0'8&4'\# @(&
+08&
8&'()*
),
0++&++8&4'
04*
'(&
+08&
'&:(43A2&
+()21*
5&
2+&*
')
:(0-0:'&-3B&
&0:( 3*&4'3,3&*
04*
-&<)-'&*
1&+3)4
0'
50+&134&
04*
*2-34;
,)11)?C2<\#
D80;34;C50+&*
&/0120'3)4
3+ <-&,&--&*
')
&/0120'3)4
5=
:1343:01
&E08340'3)4
241&++
'(&
1&+3)4F+G
5&34;
,)11)?&*
:044)'
5& 380;&*
52'
0-&
0++&++051&
5=
:1343:01
&E08\# H1343:01
1&+3)4+I
H1343:01
1&+3)4+
?311
)41=
5&
:)4+3*&-&*
8&0+2-051&
?(&4
'(&=
0-&
+2<&-,3:301 F&\#;\#J
+934
4)*21&+
04*
<01<051&
1=8<(
4)*&+G
04*
KLM
88
*308&'&0+
0++&++&*
2+34;
:013<&-+ F&\#;\#J
+934
4)*21&+G\#
D4
'(&
:0+&
),
+934
1&+3)4+J
*):28&4'0'3)4
5=
:)1)<()');-0<(=J
34:12*34;
0
-21&')
&+'380'&
'(&
+3B&
),
'(&
1&+3)4J
3+
-&:)88&4*&*\#
H(&+'
EC-0=I
N&+3)4+
)4
:(&+'
EC-0=
0-&
0::&<'051&
0+
8&0+2-051&
1&+3)4+
?(&4
'(&=
0-&
:1&0-1= *&,34&*
04*
+2--)24*&*
5=
0&-0'&*
124;\#
O)?&/&-J
H@
3+
<-&,&-051&\# H)4/&4'3)401
H@
04*
%PDI
@(3+
;23*&134&
(0+
*&,34&*
8&0+2-05313'=
),
1&+3)4+
)4
H@
+:04
50+&* )4
'(&
0++28<'3)4
'(0'
H@
+13:&
'(3:94&++
3+
!
88
)1&++\#
D,
H@
+:04+
(0/&
+13:&
'(3:94&++ ;-&0'&'(04
!
88J
'(&
8343828
+3B&
,)0
8&0+2-051&
1&+3)4
+()21*
5&
'?3:&
'(&
+13:&
'(3:94&++\# %PD
3+
01+)
0::&<'051&
34
:&-'034
+3'20'3)4+
F&\#;\#
,)5)*=
+:04+G\# Q+&
),
%PD
-&8034+
0
:)8<1&E
3++2&\#
%PD
(0+
&E:&11&4'
:)4'-0+'J
+<0'301J
04*
'&8<)-01 -&+)12'3)4R
()?&/&-J
'(&-&
0-&
804=
380;&
0:A23+3'3)4
/0-3051&+
34/)1/&*
34
%PDJ
?(3:(
;-&0'1= 38<0:'
380;&
A2013'=J
1&+3)4
:)4+<3:23'=J
04*
8&0+2-&8&4'\#
S2-'(&-8)-&J
'(&
0/03105313'=
),
%PD 3+
/0-3051&
;1)5011=\#
7+
?3'(
H@J
3,
04
%PD
3+
<&-,)-8&*J
'(&
'&:(43:01
+<&:3,3:0'3)4+
),
'(& +:04434;
+&A2&4:&+
2+&*
+()21*
5&
)<'383B&*
,)'(&
&/0120'3)4
),
'(&
'=<&
04*
+3'&
),
*3+&0+&\# S2-'(&-8)-&J
0+
?3'(
H@J
'(&
8)*013'=
2+&*
0'
,)11)?C2<
+()21*
5&
'(&
+08&
0+
?0+
2+&*
0' 50+&134&
04*
'(&
1&+3)4+
+()21*
5&
8&0+2-&*T0++&++&*
)4
'(&
+08&
<21+&
+&A2&4:&\#
D'
3+
5&=)4* '(&
+:)<&
),
'(&
P.HDU@
;23*&134&+
')
<-&+:-35&
+<&:3,3:
%PD
<21+&
+&A2&4:&
<0-08&'&-+
,)011 +:044&-+J
5)*=
<0-'+J
04*
*3+&0+&+\#
D*&011=J
'(&
+08&
'=<&
),
+:044&+()21*
5&
2+&*
04*
'(& 380;&
0:A23+3'3)4
<-)'):)1
+()21*
5&
,)11)?&*
0+
:1)+&1=
0+
<)++351&
')
<-3)+:04+\#
V)*=
+:04+ +()21*
5&
<&-,)-8&*
?3'(
5-&0'(C()1*
+:04434;
'&:(43A2&+J
3,
<)++351&\# W.@CH@I
7'
<-&+&4'J
'(&
1)?
*)+&
)0''&420'3)4
:)--&:'3)4
H@
<)-'3)4
),
0
:)8534&*
W.@CH@
3+ 4)'
01?0=+
),
)<'3801
*30;4)+'3:
H@
A2013'=
,)2+&
?3'(
P.HDU@
8&0+2-&8&4'+\#
O)?&/&-J
3, '(&
+3'&
:04
*):28&4'
'(0'
'(&
H@
<&-,)-8&*
0+
<0-'
),
0
W.@CH@
3+
),
3*&4'3:01
*30;4)+'3: A2013'=
')
0
*30;4)+'3:
H@
F?3'(
DX
04*
)-01
:)4'-0+'GJ
'(&4
'(&
H@
<)-'3)4
),
'(&
W.@CH@
:04
5& 2+&*
,)P.HDU@
8&0+2-&8&4'+
04*
:04
5&
2+&*
34'&-:(04;&051=
?3'(
:)4/&4'3)401
H@
34 0::2-0'&1=
8&0+2-34;
:04:&1&+3)4+
)/&'38&\#
Y)'&J
()?&/&-J
'(0'
'(&
W.@
<)-'3)4
),
'(&
H@ 34'-)*2:&+
0**3'3)401
*0'0
?(3:(
80=
530+
04
34/&+'3;0')3,
3'
3+
4)'
-)2'34&1=
)+&-3011= <&-,)-8&*\# Q1'-0+)24*I
Q1'-0+)24*
3+
4)'
2+&,21
34
0++&++8&4'
),
1&+3)4
+3B&
04*
+()21*
4)'
5&
2+&*
0+
0 8&'()*
),
8&0+2-&8&4'\#
Q1'-0+)24*
&E08340'3)4+
:044)'
5&
-&<-)*2:&*
34
'(&3&4'3-&'=
,)- 34*&<&4*&4'
-&/3&?
0'
0
10'&*0'&
04*J
5&:02+&
'(&=
0-&
)<&-0')*&<&4*&4'J
3'
:044)'
5& ;20-04'&&*
'(0'
'(&
+08&
'&:(43A2&
04*
8&0+2-&8&4'+
?311
5&
'09&4
,-)8
)4&
0++&++8&4'
')
'(& 4&E'\#
D,
4&?
1&+3)4+
0-&
3*&4'3,3&*
5=
21'-0+)24*
34
'(&
:)2-+&
),
'(&
+'2*=J
:)4,3-80'3)4
5=
H@
)- \#$%
&'
()*&'+),
%./+0+
&'
1231+03
(425.
0()&(.&23
+672'50+
(.
89:
\#$%
;(<
4+
5'+)
&3'.+()
289
&3
'+=+1.+)
&3'.(31+', >3)2'127<:
?(7(02'127<@
9/+
5.&=&A(.&23
2./+'+
.+1/3&B5+'
-20
24C+1.&*+
.5;20
+*(=5(.&23
&' 32.
()*&'+),
D2E+*+0:
'51/
.+1/3&B5+'
;(<
4+
5'+-5=
.2
123-&0;
12;7=+.+
7(./2=2F&1(=
0+'723'+ E/+3
4&27'&+'
(0+
24.(&3+)
20
.2
)+.+0;&3+
0+=(7'+
&3
.0&(='
E/+0+
0+1500+31+
-2==2E&3F
12;7=+.+ 0+'723'+
G8$H
20
'50F&1(=
0+'+1.&23
&'
(3
+3)72&3., 95;20
;(0I+0'@
95;20
;(0I+0'
(=23+
1(332.
4+
5'+)
.2
(''+''
0+'723'+,
%;(0I+0'
(0+
&3&.&(==< (42*+
./+
577+0
320;(=
=&;&.:
./+<
;5'.
320;(=&A+
-20
(
7(.&+3.
.2
4+
123'&)+0+)
&3
12;7=+.+ 1=&3&1(=
0+'723'+,
J7+1&-&1
F5&)+=&3+'
-20
42./
8KLMN!
0+'723'+
G&3
0+1500+3.
2*(0&(3
1(31+0H
(3) OJK
0+'723'+
G&3
0+1500+3.
702'.(.+
1(31+0H
/(*+
4++3
754=&'/+)PQRS
PQTS
PUVS,
%3
())&.&23:
./+ W<3+12=2F&1
8(31+0
%3.+0F0257
/('
)+*+=27+)
8KLMN!
702F0+''&23
10&.+0&(
E/&1/
(0+
.2
4+ &3.+F0(.+)
E&./
24C+1.&*+
.5;20
(''+'';+3.
-20
5'+
&3
-&0'.L=&3+
.0&(='
&3
2*(0&(3
1(31+0PUMS, 8<.2=2F<:
D&'.2=2F<@
9/+'+
.+1/3&B5+'
1(3
4+
5'+)
.2
)&--+0+3.&(.+
4+.E++3
7(0.&(=
0+'723'+' GO$H
(3)
12;7=+.+
0+'723'+'
G8$H
&3
0(0+
1('+'
G+,F,:
0+'&)5(=
=+'&23'
&3
.5;20
.<7+':
'51/
(' F+0;
1+==
.5;20':
E/+0+
I32E3
0+'&)5(=
4+3&F3
.5;20'
1(3
0+;(&3H, 9/+
1<.2=2F&1(=
123-&0;(.&23
2./+
3+27=('.&1
20&F&3
2(3<
+--5'&23
./(.
(77+(0'
20
E20'+3' )50&3F
.0+(.;+3.
E/+3
./+
;+('50(4=+
.5;20
/('
;+.
10&.+0&(
-20
0+'723'+
20
'.(4=+
)&'+('+
&' ;(3)(.20<
.2
)&--+0+3.&(.+
4+.E++3
0+'723'+
20
'.(4=+
)&'+('+
G(3
+--5'&23
;(<
4+
(
'&)+
+--+1.
2- ./+
.0+(.;+3.H
(3)
702F0+''&*+
)&'+('+, XYWLO>9@
Z/&=+
XYWLO>9
0+'723'+
(''+'';+3.'
3++)
())&.&23(=
'.5)<:
&.
&'
'2;+.&;+' 0+('23(4=+
.2
&3120720(.+
./+
5'+
2XYWLO>9
'1(33&3F
.2
12;7=+;+3.
89
'1(33&3F
&3 (''+'';+3.
2702F0+''&23
G7(0.&15=(0=<
72''&4=+
[3+E[
)&'+('+H,
\+E
=+'&23'
23
./+
4('&'
2XYWL O>9
&;(F&3F
1(3
4+
&)+3.&-&+)
(1120)&3F
.2
./+
-2==2E&3F
(=F20&./;@  
(,\+F(.&*+
XYWLO>9
(.
4('+=&3+:
E&./
(
72'&.&*+
XYWLO>9
(.
-2==2EL57
&'
(
'&F3
2OY
4('+)
23
(
3+E
=+'&23, 4,\2
XYWLO>9
(.
4('+=&3+
(3)
(
72'&.&*+
XYWLO>9
(.
-2==2EL57@
%./+
72'&.&*+
XYWLO>9
(.
-2==2EL57
1200+'723)'
.2
(
3+E
'&.+
2)&'+('+
123-&0;+)
4<
89:
./&'
&'
OY,
%./+ 72'&.&*+
XYWLO>9
(.
-2==2EL57
&'
32.
123-&0;+)
('
(
3+E
'&.+
2)&'+('+
23
89: ())&.&23(=
-2==2EL57
89
'1(3'
(0+
3++)+)
.2
)+.+0;&3+
&./+0+
&'
.05=<
702F0+''&23 211500&3F
(.
./(.
'&.+
G&'2:
./+
)(.+
2OY
E&==
4+
./+
)(.+
2./+
&3&.&(=
(4320;(=
XYWL O>9
'1(3H,
%./+
72'&.&*+
XYWLO>9
(.
-2==2EL57
1200+'723)'
.2
(
70+L+6&'.&3F
'&.+
2- )&'+('+
23
89
./(.
&'
32.
702F0+''&3F
23
./+
4('&'
2./+
(3(.2;&1
&;(F+':
./&'
&'
32.
OY,
1,XYWLO>9
;(<
4+
5'+)
.2
57F0()+
(
0+'723'+
.2
(
8$
&3
(
;(33+0
'&;&=(0
.2
(
4&27'<
&3 1('+'
E/+0+
(
0+'&)5(=
0()&2F0(7/&1
(4320;(=&.<
&'
./25F/.
.2
0+70+'+3.
-&402'&'
20 '1(00&3F,
9/+
5'+
2XYWLO>9
&3
./&'
1&015;'.(31+
'/25=)
4+
702'7+1.&*+=<
)+'10&4+)
&3 ./+
702.212=
(3)
'57720.+)
4<
)&'+('+L'7+1&-&1
;+)&1(=
=&.+0(.50+
-20
./+
&3)&1(.&23, D2E+*+0:
&.
;5'.
4+
(1I32E=+)F+)
./(.
42./
(7702(1/+'
;(<
=+()
.2
-(='+
72'&.&*+
8$ )5+
.2
=&;&.(.&23'
2XYWLO>9
(3)
4&27'<
0+'2=5.&23]'+3'&.&*&.<,  
\2.+@
K
^72'&.&*+_
XYWLO>9
'1(3
=+'&23
;+(3'
23+
E/&1/
&'
XYW
(*&)
E&./
(3
57.(I+
F0+(.+0 ./(3
.E&1+
./(.
2./+
'500253)&3F
.&''5+
23
./+
(..+35(.&23
1200+1.+)
&;(F+, \#$%$& '()*+,)(
-./0(./1 \#$%$&$23415610/+,
+7
81.9(0
:()/+,)
-+;*5(0(
'()*+,)(
<-'=>
?/)1**(1.1,@(
+7
155
01.9(0
5()/+,)$
A,B
*10C+5+9/@15
5B;*C
,+D()
<EC(0C(.
01.9(0
+.
,+,F01.9(0=
;6)0
C14(
.(D6@0/+,
/,
)C+.0
1G/)
0+
H2I
;;$ J1.0/15
'()*+,)(
<J'=>
A0
5(1)0
1
%IK
D(@.(1)(
/,
0C(
)6;
+7
0C(
D/1;(0(.)
+7
01.9(0
5()/+,)L 01M/,9
1)
.(7(.(,@(
0C(
N1)(5/,(
)6;
+7
D/1;(0(.)$ J.+9.())/4(
?/)(1)(
<J?=>
A0
5(1)0
1
OIK
/,@.(1)(
/,
0C(
)6;
+7
0C(
D/1;(0(.)
+7
01.9(0
5()/+,)L 01M/,9
1)
.(7(.(,@(
0C(
);155()0
)6;
+,
)06DB
<0C/)
/,@56D()
0C(
N1)(5/,(
)6;
/7
0C10
/)
0C( );155()0
+,
)06DB=$
P,
1DD/0/+,
0+
0C(
.(510/4(
/,@.(1)(
+7
OIKL
0C(
)6;
;6)0
15)+
D(;+,)0.10(
1, 1N)+560(
/,@.(1)(
+7
10
5(1)0
!
;;$
<Q+0(>
0C(
1**(1.1,@(
+7
+,(
+.
;+.(
,(E
5()/+,)
/)
15)+ @+,)/D(.(D
*.+9.())/+,)=$ R01N5(
?/)(1)(
<R?=>Q(/0C(.
)677/@/(,0
)C./,M19(
0+
S615/7B
7+.
J'
,+.
)677/@/(,0
/,@.(1)(
0+ S615/7B
7+.
J?L
01M/,9
1)
.(7(.(,@(
0C(
);155()0
)6;
+7
D/1;(0(.)
EC/5(
+,
)06DB$ \#$%$&$O3415610/+,
+7
Q+,F81.9(0
:()/+,) -+;*5(0(
'()*+,)(
<-'=>
?/)1**(1.1,@(
+7
155
,+,F01.9(0
5()/+,)
1,D
,+.;15/T10/+,
+7
06;+. ;1.M(.
5(4(5$
A55
5B;*C
,+D()
;6)0
N(
,+,F*10C+5+9/@15
/,
)/T(
<H2I
;;
)C+.0
1G/)=$ Q+0(>
P7
06;+.
;1.M(.)
1.(
/,/0/155B
1N+4(
0C(
6**(.
,+.;15
5/;/0L
0C(B
;6)0
,+.;15/T(
7+.
1 *10/(,0
0+
N(
@+,)/D(.(D
/,
@+;*5(0(
@5/,/@15
.()*+,)($ Q+,F-'UQ+,FJ?>
J(.)/)0(,@(
+7
+,(
+.
;+.(
,+,F01.9(0
5()/+,<)=
1,DU+.
;1/,0(,1,@(
+7
06;+. ;1.M(.
5(4(5
1N+4(
0C(
,+.;15
5/;/0)$ J.+9.())/4(
?/)(1)(
<J?=>
A**(1.1,@(
+7
+,(
+.
;+.(
,(E
5()/+,)
1,DU+.
VWXYVZ[\]^_ `a\baXccZ\W
+7
(G/)0/,9
,+,F01.9(0
5()/+,)$
dWXYVZ[\]^_
`a\baXccZ\W
)C+65D
,+0
,+.;155B
0.6;* 01.9(0
5()/+,
)0106)$
P0
;6)0
N(
.(*.()(,010/4(
+7
+4(.155
D/)(1)(
)0106)
@C1,9(L
,+0
1
)/,95(
5()/+, /,@.(1)($ A50C+69C
1
@5(1.
*.+9.())/+,
+7
e,+,F01.9(0f
5()/+,)
+,5B
/)
(G@(*0/+,15L
0C(
+*/,/+,
+7
0C( 0.(10/,9
*CB)/@/1,
)C+65D
*.(41/5
/,
)6@C
@/.@6;)01,@()L
1,D
0C(
*.+9.())/+,
)0106)
)C+65D
N( @+,7/.;(D
10
1
510(.
0/;(
NB
0C(
.(4/(E
*1,(5
<+.
J./,@/*15
P,4()0/910+.=$ \#$%$&$%3415610/+,
+7
g()0
h4(.155
'()*+,)( 8C(
N()0
+4(.155
.()*+,)(
/)
0C(
N()0
.()*+,)(
.(@+.D(D
7.+;
0C(
)01.0
+7
0C(
0.(10;(,0
6,0/5 D/)(1)(
*.+9.())/+,U.(@6..(,@(
<01M/,9
1)
.(7(.(,@(
7+.
*.+9.())/4(
D/)(1)(
0C(
);155()0 ;(1)6.(;(,0)
.(@+.D(D
)/,@(
0C(
0.(10;(,0
)01.0(D=$
8C(
*10/(,0i)
N()0
.()*+,)(
1))/9,;(,0
E/55 D(*(,D
+,
0C(
1@C/(4(;(,0
+7
N+0C
;(1)6.(;(,0
1,D
@+,7/.;10/+,
@./0(./1$  
| ~nlqo 'krƒ~nlqo    | 'qt    | "…qlnyy    | ˆqso "…qlnyy †qs‡krsq tuqr    |    |
|----|----|----|----|----|
| qspkrs    | qspkrs    | qspkrs †qs‡krsq    | ‰krŠpl‹nopkr ps †qŒwplqŽ    |    |
| -' | -' | Q+ | -' | & EM)$ -+,7/.;10/+,    |  
| #$%&'( .,-/#$%&'(        | .'0                                                                                                                                                                                                                                                                                                                       | 12'%$33          | 6'*( 12'%$33 4'*5,-*' 07'-                       |
|--------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------|--------------------------------------------------|
| )'*+,-*                  | )'*+,-*                                                                                                                                                                                                                                                                                                                   | )'*+,-* 4'*5,-*' | 8,-9+%:$(+,- +* 4';<+%'=>                        |
| ?@                       | ABCD                                                                                                                                                                                                                                                                                                                      | AB               | F@                                               |
| ?@EABCDFG                |                                                                                                                                                                                                                                                                                                                           |                  |                                                  |
| ?@                       | ABH                                                                                                                                                                                                                                                                                                                       | AB               | F@                                               |
| IJKLMKHIN                | OP QRST ?BCUVWXKHVBCYY                                                                                                                                                                                                                                                                                                    |                  |                                                  |
| F@                       | ABCD                                                                                                                                                                                                                                                                                                                      |                  |                                                  |
| ?@EABCD FGECBH IJKLMKHIN | AB                                                                                                                                                                                                                                                                                                                        | F@               |                                                  |
| ZG                       | ABCD                                                                                                                                                                                                                                                                                                                      |                  |                                                  |
| ?@EABCD FGECBH IJKLMKHIN | AB                                                                                                                                                                                                                                                                                                                        | ZG               | GB[MXICHIN KH LIKSH BC[I OP QRST UWBX \KSILVCIYY |
| FG                       | ]C^                                                                                                                                                                                                                                                                                                                       | _IS BW           | FG                                               |
| AB                       |                                                                                                                                                                                                                                                                                                                           |                  |                                                  |
| ]C^                      | FGYYY                                                                                                                                                                                                                                                                                                                     | _IS BW           | FG                                               |
| AB                       | CB `WVBW ZGa F@ BW ?@                                                                                                                                                                                                                                                                                                     |                  |                                                  |
| ]C^                      | ]C^                                                                                                                                                                                                                                                                                                                       | _IS              | FG                                               |
| Y                        | ZII @b?cZd eTe XKCMS[WV`H UBW UMWHfIW NIHKVLS BC QfKH VS IJVNIC[I BU K CIQ LISVBCT                                                                                                                                                                                                                                        |                  |                                                  |
| YY                       | gCL^ UBW CBCDWKCNBXVhIN HWVKLS QVHf WIS`BCSI KS `WVXKW^ ICN`BVCHT                                                                                                                                                                                                                                                         |                  |                                                  |
| YYY                      | cC Ii[I`HVBCKL [VW[MXSHKC[ISa MCIjMVJB[KL `WBkWISSVBC VC CBCDHKWkIH LISVBCS XK^ \I K[[I`HIN KS NVSIKSI `WBkWISSVBCT                                                                                                                                                                                                       |                  |                                                  |
| ABHIl                    | FKHVICHS QVHf K kLB\KL NIHIWVBWKHVBC BU fIKLHf SHKHMS WIjMVWVCk NVS[BCHVCMKHVBC BU HWIKHXICH QVHfBMH B\mI[HVJI IJVNIC[I BU NVSIKSI `WBkWISSVBC KH HfKH HVXI SfBMLN \I WI`BWHIN KS nopqrstqusvw xysyzvtzusvt{|} bJIW^ IUUBWH SfBMLN \I XKNI HB NB[MXICH HfI B\mI[HVJI `WBkWISSVBC IJIC KUHIW NVS[BCHVCMKHVBC BU HWIKHXICHT |                  |                                                  |
+4<5
~%

$(+'-(*
0+(7
.,-/'$*<%$3'
+*'$*'
+'
.,-/#$%&'(
+*'$*'  
| .,-/#$%&'( )'*+,-*   | .'0 )'*+,-*   | 12'%$33 4'*5,-*'   |
|----------------------|---------------|--------------------|
| ?@                   | AB            | ?@                 |
| ABCD?@ECBCDFG        | AB            | ABCD?@ECBCDFGY     |  
| o,* )55 04)5')*08   | o,        | -,* 04)5')*08   |
|---------------------|-----------|-----------------|
| v-0w'+4,:)5 <&      | x01 ,( o, | <&              |
| p-C                 | x01       | <&              |  
y
zo,-^;/s-,-^<&{
+1
2(0.0((08
,40(
z1*)A50
8+10)10{
.,(
-,-^*)(@0*
8+10)10
1+-:0
F&
+1
+-:(0)1+-@5C
'108
)1
)0-82,+-*
.,(
)1101190-*
,.
0..+:):C
+1,90
*(+)51
1,
*,
)11+@*7+1
:)*0@,(C
>70-,
501+,-1
:)A0 90)1'(08
+1
-,*
)84+108
+4<5
!##% &'()+.

/012,-10 !#$#%#3&'()*+,,.
,40()55
(012,-10  
670
8'()*+,,.
,40()55
(012,-10
+1
90)1'(08
.(,9
*70
*+90
90)1'(090-*
:(+*0(+)
)(0
90*
.,(
;/ ,(
</
=>7+:7040(
+1
.+(1*
(0:,(808?
'-*+5
*70
.+(1*
8)*0
*7)*
(0:'((0-*
,(
2(,@(011+40
8+10)10
+1 ,AB0:*+405C
8,:'90-*08
=*)D+-@
)1
(0.0(0-:0
.,(
2(,@(011+40
8+10)10
*70
19)5501*
90)1'(090-*1 (0:,(808
1+-:0
*70
*(0)*90-*
1*)(*08?\# 670
8'()*+,,.
,40()55
;/
+1
90)1'(08
.(,9
*70
*+90
90)1'(090-*
:(+*0(+)
)(0
.+(1*
90*
.,(
;/ '-*+5
*70
.+(1*
8)*0
*7)*
2(,@(011+40
8+10)10
+1
,AB0:*+405C
8,:'90-*08\# !\#$\#%\#E&'()*+,,.
1*)A50
8+10)10 F*)A50
8+10)10
+1
90)1'(08
.(,9
*70
1*)(*
,.
*70
*(0)*90-*
'-*+5
*70
:(+*0(+)
.,(
2(,@(011+,)(0 90*G
*)D+-@
)1
(0.0(0-:0
*70
19)5501*
90)1'(090-*1
(0:,(808
1+-:0
*70
*(0)*90-*
1*)(*08G +-:5'8+-@
*70
A)105+-0
90)1'(090-*1\#
%&
hil wlmnznwn

'()*'+%$,
'(-.%'(/($+0123+3
3$2
034(+5
/*$%+*'%$,
)63$ #78 2(4%$%+%*$0
9:;<=;
>;?;>
@A
B;?CDC@CAD=
E>AFCB;B
CD
9A:CGH
IJ"K
L;EA>@CDM
L;=;<>GN
OF;D@=
?APDB
N;>;Q  
#7R *&0')
*44%S(
*4
S*/)6%3$S(
3$2
+'3%$%$,
1
%'T
'()*'+%$, UQVQ" OWE;BC@;B
L;EA>@CDM
9:;<=;
>;?;>
@A
@N;
>;EA>@CDM
>;XPC>;Y;D@=
CD
9A:CGH
IJ"K
L;EA>@CDM
L;=;<>GN
OF;D@=
<DB
9A:CGH IJV
ZAD[\AYE:C<DG;
]PY<D
^P_`;G@=
L;=;<>GN
?APDB
N;>;Q
ZA@;K
aD:H
bZc
^<?;@H
L;EA>@=
@N<@ Y;;@
@N;
B;?CDC@CAD
A?
<D
PD<D@CGCE<@;B
E>A_:;Y
dC::
D;;B
@A
_;
>;EA>@;B
E;>
@N;=;
EA:CGC;=Q UQVQV bLe
L;XPC>;Y;D@=
?A>
9b
L;EA>@CDM
<@
\AD@CDPCDM
L;FC;d 9:;<=;
>;?;>
@A
@N;
>;EA>@CDM
>;XPC>;Y;D@=
CD
9A:CGH
IJ"K
L;EA>@CDM
L;=;<>GN
OF;D@=
?APDB
N;>;Q  
#7f $S%
S6%$%S36
2%'(S+*'
'()*'+%$,
9>A_:;Y=
;WE;BC@CAP=:H
>;EA>@;B
@A
@N;
a]^L9
CD
CLb^
dC::
<:=A
_;
>;EA>@;B
@A
@N;
Z\b
\:CDCG<: cC>;G@A>Q  
g
=;E<><@;
=P_YC==CAD
C=
DA@
D;G;==<>H
<=
>;EA>@=
CD
CLb^
dC::
_;
<F<C:<_:;
@A
@N; \:CDCG<:
cC>;G@A>Q bD
<BBC@CAD
@A
@NA=;
>;EA>@=h
<::
B;<@N=
@N<@
AGGP>
dC@NCD
iJ
B<H=
<?@;>
>;G;CFCDM
<
>;=;<>GN CD@;>F;D@CAD
jNAP:B
_;
>;EA>@;B
FC<
;Y<C:
@A
@N;
\:CDCG<:
cC>;G@A>
PD:;==
@N;H
<>;
BP;
@A E>AM>;==CF;
BC=;<=;Q kA
>;EA>@
@N;=;
B;<@N=h
E:;<=;
=;DB
<D
;Y<C:
B;=G>C_CDM
@N;
GC>GPY=@<DG;=
A?
@N;
B;<@N
@A
c>Q c<NP@
<@
Z\b\\LlgmY<C:QDCNQMAF
dC@NCD
AD;
_P=CD;==
B<H
A?
:;<>DCDM
A?
@N;
B;<@NQ  
#7n $%&
'(-.%'(2
23+3
3$2
034(+5
/*$%+*'%$,
)63$ UQoQ" 9>CDGCE<:
bDF;=@CM<@A>pL;=;<>GN
k;<Y
kN;
G:CDCG<:
>;=;<>GN
@;<Y
dC::
Y;;@
AD
<
d;;q:H
_<=C=
dN;D
E<@C;D@=
<>;
_;CDM
<G@CF;:H
@>;<@;B AD
@N;
@>C<:
@A
BC=GP==
;<GN
E<@C;D@Q
c;GC=CAD=
<_AP@
BA=;
:;F;:
;D>A::Y;D@
<DB
BA=;
;=G<:<@CAD
C? <EE:CG<_:;
dC::
_;
Y<B;
_<=;B
AD
@N;
@AWCGC@H
B<@<
?>AY
E>CA>
E<@C;D@=Q g::
B<@<
dC::
_;
GA::;G@;B
CD
<
@CY;:H
Y<DD;>
<DB
>;FC;d;B
_H
@N;
E>CDGCE<:
CDF;=@CM<@A>
A>
<
:;<B <==AGC<@;
CDF;=@CM<@A>Q
OF;D@=
Y;;@CDM
>;XPC>;Y;D@=
?A>
;WE;BC@;B
>;EA>@CDM
<=
B;=G>C_;B
CD =;G@CAD
\#7R78
dC::
_;
=P_YC@@;B
dC@NCD
@N;
<EE>AE>C<@;
@CY;:CD;=Q kN;
E>CDGCE<:
CDF;=@CM<@A>
dC::
>;FC;d
<BF;>=;
;F;D@
<DB
>;=EAD=;
B<@<
AD
;<GN
E<@C;D@
@A
;D=P>; =<?;@H
<DB
B<@<
<GGP><GHQ
kN;
E>CDGCE<:
CDF;=@CM<@A>
dC::
E;>=AD<::H
GADBPG@
A>
=PE;>FC=;
@N; CDF;=@CM<@CAD
<DB
E>AFCB;
<EE>AE>C<@;
B;:;M<@CAD
A?
>;=EAD=C_C:C@C;=
@A
A@N;>
Y;Y_;>=
A?
@N; >;=;<>GN
=@<??Q
%&
r 0)0'

)'*+*S*61034(+5
'()*'+%$, R78 2(4%$%+%*$0 Iq"Q" Gbf;>=;
Of;D@  
gDH
PD@Ad<>B
Y;BCG<:
AGGP>>;DG;
CD
<
E<@C;D@
A>
G:CDCG<:
CDF;=@CM<@CAD
=P_`;G@
<BYCDC=@;>;B
< EN<>Y<G;P@CG<:
E>ABPG@
<DB
dNCGN
BA;=
DA@
D;G;==<>C:H
N<F;
<
G<P=<:
>;:<@CAD=NCE
dC@N
@NC= \#$%&\#'%(\#)
*(
&+,%$-%
%,%(\#
.*/0
1&(
\#2%$%34$%
5%
&(6
7(3&,4$&58%
&(+
7(9(\#%(+%+
-9:( .9(187+9(:
&(
&5(4$'&8
8&54$&\#4$6
39(+9(:0;
-6'<\#4';
4$
+9-%&-%
\#%'<4$&886
&--419&\#%+
=9\#2
\#2% 7-%
43
&
'%+919(&8
.9(,%-\#9:&\#94(&80
<$4+71\#;
=2%\#2%$
4$
(4\#
$%8&\#%+
\#4
\#2%
'%+919(&8 .9(,%-\#9:&\#94(&80
<$4+71\#
.>?@
/!
.A"00 B)C)" D%$947*+,%$-%
/,%(\#
.D*/0 *(
&+,%$-%
%,%(\#
4$
-7-<%1\#%+
&+,%$-%
$%&1\#94(
914(-9+%$%+
-%$94793
9(
\#2%
,9%=
43
\#2% 9(,%-\#9:&\#4$
4$
\#2%
-<4(-4$;
9\#
$%-78\#9(
&(6
43
\#2%
34884=9(:E
F G%  
F *
893%H\#2$%&\#%(9(:
&+,%$-%
%,%(\#
.-%%
-%1\#94(
IJKJL0 F >(<&\#9%(\#
24-<9\#&89M&\#94(
4$
<$484(:&\#94(
43
%N9-\#9(:
24-<9\#&89M&\#94( O *
24-<9\#&89M&\#94(P&+'9--94(
\#2&\#
9<$%H<8&((%+
.9)%);
%8%1\#9,%
4$
-12%+78%+
-7$:%$6
&$$&(:%+
<$94$
\#4
\#2%
-\#&$\#
43
\#2%
-\#7+60;
&
<8&((%+
24-<9\#&89M&\#94(
34$
<$%H%N9-\#9(: 14(+9\#94(;
4$
&
<$41%+7$%
$%Q79$%+
56
\#2%
<$4\#4148;
=9\#247\#
&
-%$947+%\#%$94$&\#94(
9( 2%&8\#2;
9(4\#
14(-9+%$%+
&
-%$947&+,%$-%
%,%(\#)
O *
24-<9\#&89M&\#94(P&+'9--94(
\#2&\#
9-48%86
+$9,%(
56
(4(H'%+91&8
$%&-4(.%):);
24-<9\#&89M&\#94(
34$
<&\#9%(\#
4$
-75R%1\#
14(,%(9%(1%0
9(4\#
14(-9+%$%+
&
-%$947&+,%$-% %,%(\#)
O /'%$:%(16
$44'
,9-9\#4$
-\#&69(
45-%$,&\#94(
7(9\#\#2&\#
+4
(4\#
$%-78\#
9(
&+'9--94(
\#4
\#2%
24-<9\#&8
=478+
(4\#
5%
14(-9+%$%+
&
-%$947&+,%$-%
%,%(\#)
S2%
$%&-4(
34$
-%%T9(: '%+91&8
1&$%
-2478+
5%
%,&87&\#%+
34$
'%%\#9(:
4(%
43
\#2%
4\#2%$
-%$9471$9\#%$9&
F U%$-9-\#%(\#
4$
-9:(9391&(\#
9(1&<&19\#6
4$
-75-\#&(\#9&8
+9-$7<\#94(
43
\#2%
&5989\#6
\#4
14(+71\#
(4$'&8
893%
37(1\#94(-
F *
14(:%(9\#&8
&(4'&86P59$\#2
+%3%1\#) F >'<4$\#&(\#
'%+91&8
%,%(\#\#2&\#
'&6
(4\#
$%-78\#
9(
+%&\#2;
5%
893%H\#2$%&\#%(9(:;
4$
$%Q79$%
24-<9\#&89M&\#94(
'&6
5%
14(-9+%$%+
&
-%$947&+,%$-%
+$7:
%N<%$9%(1%
=2%(;
5&-%+
7<4( &<<$4<$9&\#%
'%+91&8
R7+:'%(\#;
\#2%6
'&6
R%4<&$+9M%
\#2%
<&\#9%(\#
4$
-75R%1\#
&(+
'&6
$%Q79$% '%+91&8
4$
-7$:91&8
9(\#%$,%(\#94(
\#4
<$%,%(\#
4(%
43
\#2%
47\#14'%89-\#%+
9(
\#29+%39(9\#94()
B)C)V W93%H\#2$%&\#%(9(:
*(
&+,%$-%
%,%(\#
4$
-7-<%1\#%+
&+,%$-%
$%&1\#94(
914(-9+%$%+
X893%H\#2$%&\#%(9(:X
93;
9(
\#2%
,9%=
43 %9\#2%$
\#2%
9(,%-\#9:&\#4$
4$
-<4(-4$;
9\#4117$$%(1%
<8&1%\#2%
<&\#9%(\#
4$
-75R%1\#
&\#
9''%+9&\#%
$9-T
43 +%&\#2)
>\#
+4%(4\#
9(187+%
&(
&+,%$-%
%,%(\#
4$
-7-<%1\#%+
&+,%$-%
$%&1\#94(
\#2&\#;
2&+
9\#
4117$$%+
9(
& '4$%
-%,%$%
34$';
'9:2\#
2&,%
1&7-%+
+%&\#2)
."C?YAVC")V"0 B)C)Z D%,%$9\#6 S2%
-%,%$9\#6
43
%&12
*+,%$-%
/,%(\#
=988
5%
&--%--%+
7\#989M9(:
\#2%
?S?*/
,%$-94(
Z)[) B)C)\ A%8&\#94(-29<
\#4
D\#7+6
U$4+71\# *88
*/=988
2&,%
\#2%9$
$%8&\#94(-29<
\#4
-\#7+6
<$4+71\#
&--%--%+
7-9(:
\#2%
\#%$'-E  
$%8&\#%+
4$
(4\# $%8&\#%+)  
\# $%&'(%)
*
+,%-%
./
'
-%'/01'2&%
30//.2.&.(4
(,'(
(,%
/(5)4
3-0)56(
6'5/%)
(,%
')7%-/%
%7%1(8
$%'/01'2&%
30//.2.&.(4
9%'1/
(,'(
(,%-%
./
%7.)%16%
(0
/5::%/(
'
6'5/'&
-%&'(.01/,.3 2%(;%%1
(,%
/(5)4
3-0)56(
'1)
(,%
')7%-/%
%7%1(8
\# <0(
$%&'(%)
*
+,%-%
./
10(
'
-%'/01'2&%
30//.2.&.(4
(,'(
(,%
')9.1./(-'(.01
0=
(,%
/(5)4 3-0)56(
6'5/%)
(,%
%7%1(8
>8?8! @)7%-/%
A7%1(/
0=
B3%6.'&
C1(%-%/(
D@ABCE
B%%
B%6(.01
FGHGIG
%&
jgi kllmllnmop

Qr
Lkrmps
Mtmopl  
@A
.1=0-9'(.01
60&&%6(%)
;.&&
.16&5)%
%7%1(
)%/6-.3(.01U
)'(%
0=
01/%(U
'//%//9%1(
0=
/%7%-.(4 '1)
-%&'(.01/,.3
(0
/(5)4
3-0)56(
'1)
'&(%-1'(%
%(.0&0:4
D.=
10(
-%&'(%)
(0
/(5)4
3-0)56(EU
)'(%
0=
-%/0&5(.01
0=
(,%
%7%1(U
/%-.05/1%//
'1)
05(609%8
+,%
'//%//9%1(
0=
/%7%-.(4
'1)
-%&'(.01/,.3
(0
(,%
/(5)4
3-0)56(
;.&&
2%
)01%
01&4
24
(,0/%
;.(,
(,%
(-'.1.1:
'1)
'5(,0-.(4
(0
9'V%
'
).':10/./ '1)
&./(%)
01
(,%
W0-9
WX@
?YZ[
'/
(,%
/.(%
3-.16.3'&
.17%/(.:'(00/52\.17%/(.:'(0-8  
@A/ 0665--.1:
)5-.1:
(,%
60&&%6(.01
'1)
-%30-(.1:
3%-.0)
;.&&
2%
)0659%1(%)
'33-03-.'(%&4
-%:'-)&%// 0=
-%&'(.01/,.38  
@A/
;.&&
2%
=0&&0;%)
(,-05:,
-%/0&5(.018 B@A/
;.&&
2%]  
\# @//%//%)
=0/%7%-.(4
'1)
-%&'(.01/,.3
(0
/(5)4
3-0)56(
'1)
'&(%-1'(%
%(.0&0:4
D.=
10(
-%&'(%)
(0
/(5)4
3-0)56(E
24
'
&.6%1/%)
/(5)4
3,4/.6.'1
&./(%)
01
(,%
W0-9
WX@
?YZ[
'/ (,%
/.(%
3-.16.3'&
.17%/(.:'(00/52\.17%/(.:'(0-8
\# $%60-)%)
01
(,%
'33-03-.'(%
B@A
-%30-(
=0-9U
(,%
9%).6'&
-%60-)
'1)
6'3(5-%)
.1
(,%
6&.1.6'&
)'('2'/%8
\# W0&&0;%)
(,-05:,
-%/0&5(.01
24
'
&.6%1/%)
/(5)4
3,4/.6.'1
&./(%)
01
(,%
W0-9
WX@
?YZ[
'/
(,%
/.(%
3-.16.3'&
.17%/(.:'(00/52\.17%/(.:'(0-8
W0(.9%=-'9%
0=
-%60-).1:
')7%-/%
%7%1(/U
3&%'/%
-%=%(0
/%6(.01
^G_8
@&&
/%-.05/
')7%-/%
%7%1(/ -%60-)%)
=-09
(,%
(.9%
0=
=.-/(
.17%/(.:'(.01'&
3-0)56(
')9.1./(-'(.01
95/(
2%
-%30-(%)
(0
(,% /301/0;.(,
(,%
%`6%3(.01
0=
'14
&./(%)
.1
/%6(.01
JGH8
%&
jgf ambqapcod

Qr
Lmacqel
Kftmalm
Mtmopl  
@14
@A
(,'(
9%%(/
3-0(060&\)%=.1%)
/%-.05/
6-.(%-.'
09%%(/
(,%
)%=.1.(.01
0=
@)7%-/%
A7%1(
0= B3%6.'&
C1(%-%/(
(,'(
-%g5.-%
%`3%).(%)
-%30-(.1:
95/(
2%
/529.((%)
.99%).'(%&4
D;.(,.1
[h
,05-/ 0=
';'-%1%//E
(0
iB$i
B'=%(4
5/.1:
(,%
jj$
B@A
-%30-(
=0-98 @&&
B@A
-%30-(.1:
95/(
.16&5)%
(,%
%&%9%1(/
)%/6-.2%)
.1
/%6(.01
JGI8 B@A
-%30-(/
;.&&
2%
/529.((%)
(0
(,%
j%1(%=0j'16%$%/%'-6,
Djj$E
'(]
iB$iB'=%(4k9'.&81.,8:07
'1)
(0
(,%
jj$
lC
'1)
/(5)4
600-).1'(0-8  
jj$
B@A
-%30-(
=0-9 '1) .1/(-56(.01/
6'1
2%
=051) '(]
,((3/]mm66-0)86'16%-8:07m601=&5%16%m)./3&'4mjj$j$imW0-9/n'1)nC1/(-56(.01/ W0&&0;.1:
(,%
'//%//9%1(
0=
(,%
B@A
24
iB$iU
0(,%/5330-(.1:
)0659%1('(.01
0=
(,%
%7%1( 9'4
2%
-%g5%/(%)
24
(,%
iB$i
B'=%(4
'1)
/,05&)
2%
3-07.)%)
'/
/001
'/
30//.2&%8  
#$% &'()*+
,*./*0(1*0
+*/,+1(23
1,
44+
56
789:;
7<8
:=
7>68968
?@=A@866>=B
>6
?9@:
=C
:;8
6:<7D
=EF8G:>H86
IJKL
9B7
G9?:<@87
96
9B 8B7?=>B:
>B
:;>6
6:<7DM
789:;
7<8
:=
7>68968
?@=A@866>=B
N>OO
B=:
E8
@8?=@:87
>B
8P?87>:87
Q9BB8@ :=
:;8
K?=B6=@R
S=N8H8@M
>C
:;8@8
>6
8H>78BG8
6<AA86:>BA
9
G9<69O
@8O9:>=B6;>?
E8:N88B
:;8
6:<7D 7@<A
9B7
:;8
8H8B:M
@8?=@:
:;8
8H8B:
>B
9B
8P?87>:87
Q9BB8@
9GG=@7>BA
:=
68G:>=B
\#$T$ S=6?>:9O>U9:>=B
:;9:
>6
788Q87
:=
E8
7<8
:=
7>68968
?@=A@866>=BM
9B7
B=:
9::@>E<:9EO8
:=
:;8 >B:8@H8B:>=B
N>OO
B=:
E8
@8?=@:87
96
9B
K5VR
W;8
8H8B:M
9B7
:;8
966866Q8B:
:;9:
>:
N96
G9<687
ED 7>68968
?@=A@866>=B
N>OO
E8
7=G<Q8B:87
>B
:;8
Q87>G9O
@8G=@76R
W;8
G9<69O>:D
966866Q8B:
=C ;=6?>:9O>U9:>=B
N>OO
E8
@8X8H9O<9:87
9BD
:>Q8
N;8B
B8N
>BC=@Q9:>=B
>6
@8G8>H87R
YC
:;8
G9<69O>:D 966866Q8B:
G;9BA86
C@=Q
7>68968
?@=A@866>=B
:=
@8O9:87
:=
:;8
6:<7D
>B:8@H8B:>=BM
K5V
@8?=@:
N>OO E8
68B:
:=
:;8
K?=B6=@
>B
9B
8P?87>:87
Q9BB8@
9GG=@7>BA
:=
68G:>=B
\#$TR
YC
:;8@8
>6
9BD <BG8@:9>B:D
N;8:;8@
:;8
>B:8@H8B:>=B
>6
9
G=B:@>E<:>BA
C9G:=@
:=
:;8
8H8B:M
:;8
8H8B:
6;=<O7
E8
@8?=@:87
96
5V
=@
K5V
96
9??@=?@>9:8R  
#$Z +*/,+1(23
4+(1*+('
1,
1[*
/['+\'4*]1(4'^
4,^^'_,+'1,+`
5OO
8H8B:6
O>6:87
E8O=N
Q<6:
E8
@8?=@:87
>B
:;8
78C>B87
:>Q8O>B86
:=
JKaJ69C8:DbQ9>ORB>;RA=HR W;8
cca
JCC>G8
=C
a8A<O9:=@D
5CC9>@6
N>OO
68B7
9OO
@8?=@:6
:=
:;8
Q9B<C9G:<@8@
96
786G@>E87 E8O=NR dReRf VP?87>:87
57H8@68
VH8B:
a8?=@:>BA
c@>:8@>9
:=
:;8
Ygh
i9B<C9G:<@8@ 5OO
69C8:D
@8?=@:6
9B7
9BB<9O
@8?=@:6
:;9:
9@8
6<EQ>::87
:=
:;8
jh5
N>OO
E8
6<EQ>::87
:= 56:@9k8B8G9R 5
G=?D
=C
:;8
i87l9:G;
@8?=@:
=@
8m<>H9O8B:
C=@Q
Q<6:
E8
C9P87
:=
56:@9k8B8G9
9:
:;8
:>Q8
:;8 8H8B:
>6
@8?=@:87
:=
:;8
jh5R 5
G=H8@
?9A8
6;=<O7
9GG=Q?9BD
:;8
i87l9:G;
C=@Q
=@
8m<>H9O8B:
C=@Q
>B7>G9:>BA
:;8 C=OO=N>BAn o pg=:>C>G9:>=B
C@=Q
9B
YBH86:>A9:=@
K?=B6=@87
K:<7Dq  
o W;8
>BH86:>A9:=@
Ygh
B<QE8@
966>AB87
ED
:;8
jh5 o W;8
>BH86:>A9:=@r6
B9Q8
9B7
977@866 o W;8
:@>9O
B9Q8s:>:O8
9B7
56:@9k8B8G9
YKK
@8C8@8BG8
B<QE8@
IVKatf!tffuvwL
x
K?=B6=@
Q<6:
9O6=
>B7>G9:8M
8>:;8@
>B
:;8
K5V
@8?=@:
=@
:;8
G=H8@
?9A8M
:;8
G9<69O>:D
=C
8H8B:6 >B
@8O9:>=B
:=
9OO
6:<7D
Q87>G9:>=B6
9B7
>C
:;8
K5V
>6
@8O9:87
:=
7>68968
?@=A@866>=BM
96 78:8@Q>B87
ED
:;8
?@>BG>?9O
>BH86:>A9:=@R x
K8B7
K5V
@8?=@:
9B7
9GG=Q?9BD>BA
G=H8@
?9A8
ED
N9D
=C
8Q9>O
:=
56:@9k8B8G9r6
786>AB9:87 Q9>OE=Pn  
5Vi9>OE=PcO>B>G9OW@>9OWcKb96:@9U8B8G9RG=Q 5OO
K5V6
N>OO
E8
@8?=@:87M
N;8:;8@
=@
B=:
G=B6>78@87
G9<69OOD
@8O9:87
:=
:;8
>BH86:>A9:>=B9O ?@=7<G:M
=@
:=
:;8
6:<7D
?@=G87<@8I6LR
W;8
@8?=@:>BA
?8@>=7
C=@
K5V6
>6
:;8
?8@>=7
>QQ87>9:8OD C=OO=N>BA
:;8
:>Q8
:;9:
N@>::8B
>BC=@Q87
G=B68B:
>6
=E:9>B87
:;@=<A;
uy
79D6
9C:8@
:;8
O96:
7=68 =C
7<@H9O<Q9E
z
:@8Q8O>Q<Q9E
=@
<B:>O
:;8
>B>:>9:>=B
=C
9O:8@B9:>H8
9B:>G9BG8@
:;8@9?DR
W;8 >BH86:>A9:=@
9B7s=@
K?=B6=@
9@8
@86?=B6>EO8
C=@
>BC=@Q>BA
:;8
V:;>G6
c=QQ>::88
9B7s=@
:;8 a8A<O9:=@D
5<:;=@>:D
=C
:;8
K5V
96
?8@
O=G9O
@8m<>@8Q8B:6R \#$
%
&'&()*+,'-)
./
0*1'2*)
)*+,'-)3
45,)
%&6
'45*+
+*7*8%&4
$'77'9(-:
,&$'+2%4,'&
2-)4
%7)'
0* :+'8,6*6
4'
.)4+%;*&*1%< =*+,'-)
%68*+)*
*8*&4)
45%4
6'
&'4
+*>-,+*
*?:*6,4*6
+*:'+4,&@
4'
45*
AB.
)4,77
&**6
4'
0* +*:'+4*6
4'
.)4+%;*&*1%
:+*$*+%07C
-),&@
45*
D*6BE.
1'6,&@
7%&@-%@*
$'+
)*+,'-)
%68*+)* *8*&4)<
F5,)
,&$'+2%4,'&
)5'-76
0*
+*:'+4*6
'&
%
2'&457C
0%),)
%&6
-&6*+
&'
1,+1-2)4%&1*
7*)) $+*>-*&47C
45%&
>-%+4*+7C< F5*
):'&)'+
2-)4
,&$'+2
45*
AB.3
8,%
%
D*6G%415
$'+2
'+
*>-,8%7*&4
$'+23
'$
%&C
)*+,'-)
'+ -&*?:*14*6
%68*+)*
*8*&4)
45%4
'11-+
,&
%11'+6%&1*
9,45
45*
+*:'+4,&@
'07,@%4,'&)
'$
HI
JAE KIH<KH3
%&6
9,77
1'&1-++*&47C
$'+9%+6
%77
)-15
+*:'+4)
4'
.)4+%;*&*1%<
.
1':C
'$
45* D*6G%415L.6//E)
+*:'+4
'+
*>-,8%7*&4
$'+2
2-)4
0*
$%?*6
4'
.)4+%;*&*1%
%4
45*
4,2*
45* *8*&4
,)
+*:'+4*6
4'
45*
AB.<
\#4
,)
45*
+*):'&),0,7,4C
'$
45*
):'&)'+
4'
1'2:,7*
%77
&*1*))%+C ,&$'+2%4,'&
%&6
*&)-+*
45%4
45*
AB.
+*1*,8*)
%
+*:'+4
%11'+6,&@
4'
45*
AB.
+*:'+4,&@ +*>-,+*2*&4
4,2*7,&*)
%&6
4'
*&)-+*
45%4
45*)*
+*:'+4)
%+*
%7)'
)-02,44*6
4'
.)4+%;*&*1%
%4
45* )%2*
4,2*< M<"<H N45*+
*8*&4)
+*>-,+,&@
+*:'+4,&@
%&
m<"<h<in8+6')

.&C
'8*+6')*
'$
%
)4-6C
)-0O*14
9,45
6-+8%7-2%0
P
4+*2*7,2-2%03
9,45
'+
9,45'-4
%))'1,%4*6 ./)L=./)3
,)
+*>-,+*6
4'
0*
+*:'+4*6
9,45,&
HQ
5'-+)
'$
R&'97*6@*
'$
45*
*8*&4
4'
45*
):'&)'+ %&6
.)4+%;*&*1%LD*6\#22-&*
S%4,*&4
=%$*4C
'+
6*),@&**
-),&@
45*
6*),@&%4*6
=%$*4C
*(2%,70'? T)**
=*14,'&
UVWVX
$'+
1'&4%14
,&$'+2%4,'&Y<
\#$
45*
'8*+6')*
+*)-74)
,&
%&
./3
45*
./
2-)4
%7)'
0* +*1'+6*6
%)
%&
./
T)**
=*14,'&
XZVWY<
N8*+6')*
6'*)
&'4
%-4'2%4,1%77C
2%R*
%&
./
)*+,'-)3
0-4 ,$
45*
1'&)*>-*&1*)
'$
45*
'8*+6')*
%+*
)*+,'-)3
$'+
*?%2:7*
6*%45
'+
5'):,4%7,[%4,'&3
45*
*8*&4
,) )*+,'-)
%&6
2-)4
0*
+*1'+6*6
%&6
+*:'+4*6
%)
%&
=./
T)**
=*14,'&
XZVWY<
F5*+*
,)
1-++*&47C
&' ):*1,$,1
4+*%42*&4
,&
45*
*8*&4
'$
%&
'8*+6')*
'$
6-+8%7-2%0
'+
4+*2*7,2-2%0< M<"<H<H\*:%4,1
$-&14,'&
%0&'+2%7,4C \*:%4,1
$-&14,'&
%0&'+2%7,4C
T%)
6*$,&*6
,&
=*14,'&
]V^V_<Y
,&
%
)4-6C
)-0O*143
9,45
'+
9,45'-4 %))'1,%4*6
17,&,1%7
2%&,$*)4%4,'&)3
,)
+*>-,+*6
4'
0*
+*:'+4*6
%)
`5*:%4,1
$-&14,'&
%0&'+2%7a b  
c
bd
c  
4'
45*
):'&)'+
%&6
.)4+%;*&*1%LD*6\#22-&*
S%4,*&4 =%$*4C
-),&@
45*
6*),@&%4*6
=%$*4C
*(2%,70'?
T)**
=*14,'&
eV^
$'+
1'&4%14
,&$'+2%4,'&Y3
-&7*))
% 6*$,&,4,8*
-&6*+7C,&@
6,%@&'),)
$'+
45*
%0&'+2%7,4C
T*<@<3
15'7*7,45,%),)
'+
0,7*
6-14
'0)4+-14,'&Y 45%4
,)
-&+*7%4*6
4'
,&8*)4,@%4,'&%7
:+'6-14
5%)
0**&
1'&$,+2*6<  
f \#$
45*
6*$,&,4,8*
-&6*+7C,&@
6,%@&'),)
$'+
45*
%0&'+2%7,4C
5%)
0**&
*)4%07,)5*6
%&6
,)
-&+*7%4*6
4'
,&8*)4,@%4,'&%7
:+'6-143
45*
6*1,),'&
4'
1'&4,&-*
6'),&@
'$
45*
)4-6C
)-0O*14 9,77
0*
0%)*6
'&
45*
17,&,1%7
O-6@2*&4
'$
45*
,&8*)4,@%4'+<
f \#$
&'
6*$,&,4,8*
-&6*+7C,&@
6,%@&'),)
$'+
45*
%0&'+2%7,4C
,)
*)4%07,)5*63
6'),&@
'$
45*
)4-6C
)-0O*14
2-)4
0*
,&4*++-:4*6
,22*6,%4*7C<
A'77'9(-:
,&8*)4,@%4,'&)
%&6
,&>-,+,*) 2-)4
0*
,&,4,%4*6
0C
45*
,&8*)4,@%4,'&%7
),4*
9,45'-4
6*7%C<
/%15
+*:'+4*6
*8*&4
'$
5*:%4,1
$-&14,'&
%0&'+2%7,4C
9,77
0*
$'77'9*6
0C
45*
,&8*)4,@%4'+
%&6 *8%7-%4*6
0C
45*
):'&)'+
%&6
.)4+%;*&*1%LD*6\#22-&*<
%&
tl!lu v?321

3W8>@523  
QB
;
8;?63:?
H3<>I3@
8239:;:?
7526:9
?M3
<>52@3
>B
?M3
@?57=X
?M3
@?57=
?23;?I3:?
@M>517
H3 76@<>:?6:537
6II376;?31=X
;:7
?M3
8239:;:<=
238>2?37
?>
?M3
F8>:@>2
:>
1;?32
?M;:
YZ
M>52@
>B CM3:
?M3
Q:N3@?69;?>2
H3<>I3@
;C;23
>B
6?L
[M3
Q:N3@?69;?>2
@M>517
:>?6B=
?M3
F8>:@>2
:>
1;?32 ?M;:
YZ
M>52@
>B
CM3:
?M3
>5?<>I3
>B
?M3
P239:;:<=
H3<>I3
\:>C:X P239:;:<=
6?@31B
6@
:>?
239;2737
;@
;:
F0]L
^>C3N32X
<>:93:6?;1
;H:>2I;16?63@
>2
H62?M
73B3<?@ ;:7
@8>:?;:3>5@
I6@<;226;93@
?M;?
I33?
@326>5@
<26?326;
_@33
@3<?6>:
"\#`\#ab
@M>517
H3
238>2?37
;@ F0]@L [M3
>5?<>I3
>B
;11
8239:;:<63@
_@8>:?;:3>5@
I6@<;226;93X
313<?6N3
?32I6:;?6>:X
3<?>86< 8239:;:<=X
:>2I;1
H62?MX
>2
<>:93:6?;1
;H:>2I;16?=c
@M>517
H3
B>11>C37
58
;:7
7><5I3:?37L TL!LY P;?32:;1
3W8>@523 V;13
8;?63:?@
@M>517
23B2;6:
B2>I
B;?M326:9
;
<M617
>2
7>:;?6:9
@832I
7526:9
?M3
@?57=
;:7
B>2 UTd
7;=@
;B?32
?M3
1;@?
7>@3
>B
752N;15I;HS
?23I316I5I;H
<>IH6:37
?M32;8=
>2
ed
7;=@
;B?32 ?M3
1;@?
7>@3
>B
752N;15I;H
I>:>?M32;8=X
CM6<M3N32
6@
?M3
1>:932
?6I3
8326>7L P239:;:<=
>B
?M3
8;?63:?f@
8;2?:32
6@
:>?
<>:@673237
?>
H3
;:
0]L
^>C3N32X
?M3
>5?<>I3
>B
;11 8239:;:<63@
_@8>:?;:3>5@
I6@<;226;93X
313<?6N3
?32I6:;?6>:X
3<?>86<
8239:;:<=X
:>2I;1
H62?MX
>2 <>:93:6?;1
;H:>2I;16?=c
><<5226:9
B2>I
?M3
7;?3
>B
?M3
B62@?
7>@3
5:?61
UTd
7;=@
;B?32
?M3
1;@?
7>@3 >B
752N;15I;HS
?23I316I5I;H
<>IH6:37
?M32;8=
>2
ed
7;=@
;B?32
?M3
1;@?
7>@3
>B
752N;15I;H I>:>?M32;8=X
CM6<M3N32
6@
?M3
1>:932
?6I3
8326>7
;B?32
?M3
1;@?
7>@3
@M>517X
6B
8>@@6H13X
H3 B>11>C37
58
;:7
7><5I3:?37L
%&
"#g %&hi-)(%/

%&'(%)*+,
J(%
K)Hl*&K
.(+Lh.)&L
H+L&%
..%Mk'(+K(%&L
*+L  
R>11>C6:9
:>?6B6<;?6>:
B2>I
?M3
6:N3@?69;?>2X
OOGX
?M3
Qno
@8>:@>2X
C611
238>2?
;:=
@5@83<?37 ;7N32@3
23;<?6>:
?M;?
6@
H>?M
@326>5@
;:7
5:3W83<?37L  
OOG
C611
238>2?
;:
0]
;@
;
@5@83<?37 ;7N32@3
23;<?6>:
>:1=
6B
?M323
6@
3N673:<3
?>
@5993@?
;
<;5@;1
231;?6>:@M68
H3?C33:
?M3
@?57= 82>75<?
;:7
?M3
;7N32@3
3N3:?L  
OOG
C611
:>?6B=
Ro0
;:7
;11
8;2?6<68;?6:9
6:N3@?69;?>2@
_6L3LX
;11 6:N3@?69;?>2@
?>
CM>I
?M3
@8>:@>2
6@
82>N676:9
7259
5:732
6?@
Qno@
>2
5:732
;:=
6:N3@?69;?>2f@ Qnoc
6:
;:
Qno
@;B3?=
238>2?
>B
8>?3:?6;1
@326>5@
26@\@
B2>I
<16:6<;1
?26;1@
>2
;:=
>?M32
@>52<3X
;@ @>>:
;@
8>@@6H13X
6:
;<<>27;:<3
?>
YU
ORG
P;2?
pUYLpYL 011
@326>5@
3N3:?@
C611
H3
238>2?37
?>
?M3
Ro0
;?
13;@?
;::5;11=
6:
;
@5II;2=
B>2I;?L
%&
q .i+.-i

R(+*)(%*+,  
0@
;
@8>:@>2
B>2
<16:6<;1
?26;1@X
Ro0
23951;?6>:@
2345623
?M3
OOG
?>
I;6:?;6:
;
I>:6?>26:9 82>92;IL
[M3
OOGf@
82>92;I
;11>C@
B>2
<>:B62I;?6>:
>BJ
@?57=
7;?;X
@83<6B6<;11=
7;?;
?M;?
<>517 ;BB3<?
?M3
6:?32823?;?6>:
>B
826I;2=
;:7
@3<>:7;2=
@?57=
3:78>6:?@s
;7M323:<3
?>
?M3
82>?><>1X
regulations, ICH E6, and SOPs; and human subjects protection. This is done through independent verification of study data with source documentation focusing on:
.  
Informed consent process
.  
Eligibility confirmation
.  
Drug administration and accountability
.  
Adverse events monitoring
.  
Response assessment.
The monitoring program also extends to multi-site research when the CCR is the coordinating cnter.  
This trial will be monitored by personnel employed by a CCR contractor. Monitors are qualified by training and experience to monitor the progress of clinical trials. Personnel monitoring this study will not be affiliated in any way with the trial conduct.
%&
10 statistical considerations

The primary objective of this pilot trial is to preliminarily evaluate the efficacy of combining tremelimumab and durvalumab in patients with advanced HCC, either alone or with cryoablation, TACE, or RFA, and in patients with advanced biliary tract carcinoma (BTC), either alone or with cryoablation, or RFA.  
Cohorts A1 and A2 will enroll patients with advanced HCC, BCLC stage B/C and cohort B will enroll patients with intra/extra-hepatic cholangiocarcinoma. Cohort A1 will have 1 treatment Arm 1 (one without any ablative procedure) and Cohort A2 will have 3 separate treatment arms of 10 patients apiece (one a piece with TACE, RFA, or cryoablation). Cohort B will have 3 separate treatment arms of 10 patients apiece (one without any ablative procedure, one with RFA, and one with cryoablation). The initial 10 patients in cohorts A1 and B, the treatment arms without ablative procedure, must have satisfactory safety and feasibility outcomes in order to permit the treatment arms with ablation to open. This will likely mean that 7 or more of 10 are able to result in complete treatment for the patients. For this pilot, the assignment to specific method of ablation will be done by the multidisciplinary tumor board and thus will not be done randomly. As such, the results must be treated as preliminary and exploratory, requiring independent confirmation of any potentially positive findings. As each of these 7 treatment arms of 10 patients will be considered a small pilot, each will have same statistical objective, and each of these arms will be evaluated for efficacy as follows. For both HCC and BTC there is no standard second-line therapy in the advanced setting. Based on historical data of investigational agents for both these diseases and stage (i.e. post-sorafenib HCC and post-gem/cis BTC) the 6-month PFS would be not greater than 10-15%[ 42 , 43 ]. In each treatment arm of 10 patients in cohorts A1, A2 and B, the trial will have 82% power to rule out 15% as the proportion stable at 6 month in favor of 50% being stable at 6 months, with each evaluation assuming that a one-sided 0.10 significance level exact binomial test would be performed. If there are 3 patients in 10 who are able to have stable disease at a 6 month evaluation, then the lower one-sided 90% confidence bound for 3/10 is 11.6% (the two sided 80% confidence interval extends from 11.6% to 55.2%). Similarly, with 4 in 10 with stable disease at 6 months, the lower one-sided 90% confidence bound for 4/10 is 18.8% (the two sided
"\#$
%&'()*+'%+
)',+-./0
+1,+'*2
(-&3
4"5"$
,&
!65!$75
89:2;
)'
<&9&-,2
=4;
=>
&?;
@
&6 A/,)+',2
&:,
&(
4\#
/,,/)')'B
2,/C0+
*)2+/2+
/,
!
3&',92
)'
/'D
&(
,9+
E
,-+/,3+',
/-32
F&:0* ,+',/,).+0D
-:0+
&:,
4\#G4H$
/2
,9+
(-/%,)&'
F9&
F&:0*
*&
2&;
F),9
I\#$
&'+
2)*+*
%&'()*+'%+5 89+
-+2:0,2
(-&3
,9+
/C0/,)&'
,-+/,3+',
/-32
&(
%&9&-,
=>
J:2)'B
8=<K;
LM=;
&%-D&/C0/,)&'7 3/D
/02&
9/.+
,9+)-+2:0,2
%&3C)'+*
)'
/'
+1A0&-/,&-D
(/29)&'
,&
-+A&-,
,9+)&.+-/00
+(()%/%D5 N)3)0/-0D;
,9+
-+2:0,2
(-&3
,9+
/C0/,)&'
,-+/,3+',
/-32
&(
%&9&-,
?
J:2)'B
LM=
&%-D&/C0/,)&'7 3/D
/02&
9/.+
,9+)-+2:0,2
%&3C)'+*
)'
/'
+1A0&-/,&-D
(/29)&'
,&
-+A&-,
,9+)&.+-/00
+(()%/%D5 N9&:0*
A&2),).+
()'*)'B2
C+
)*+',)()+*
)'
/'D
&(
,9+
,-+/,3+',
/-3
&(
%&9&-,2
=4;
=>
&%&9&-,
?; ,9+'
/(,+,9)2
A)0&,
A9/2+
9/2
C++'
%&'%0:*+*;
2:C2+O:+',;
3&-+
*+()'),).+
+./0:/,)&'
3/D
C+ %&'*:%,+*
)'
,9+
/AA-&A-)/,+
2:CG%&9&-,2
:2)'B
0/-B+':3C+-2
&(
A/,)+',2;
/2
*+()'+*
CD /3+'*3+',2
J&2+A/-/,+
A-&,&%&02
)(
F/--/',+*7
:2+*
,&
*+2%-)C+
,9+
+1A/'2)&'
%&9&-,25 P,
)2
+1A+%,+*
,9/,
:A
,&
>
A/,)+',2
A+3&',9
3/D
C+
/C0+
,&
+'-&00
&',&
,9)2
,-)/05
<&9&-,
=4
F)00 -+O:)-+
4\#
+./0:/C0+
A/,)+',2;
<&9&-,
=>
3/D
-+O:)-+
:A
,&
@\#
+./0:/C0+
A/,)+',2
/'*
%&9&-,
? 3/D
-+O:)-+
:A
,&
@\#
+./0:/C0+
A/,)+',25
89+
/%%-:/0
%+)0)'B
(&,9+
A-&,&%&0
F)00
C+
2+,
/,
I\# A/,)+',2
,&
/00&F
(&/
23/00
':3C+&(
)'+./0:/C0+
A/,)+',2
,&
C+
+'-&00+*5
89:2;
),
)2
+1A+%,+* ,9/,
>6G@!
3&',92
3/D
C+
'++*+*
,&
/%%-:+
/00
A/,)+',2
&',&
,9)2
,-)/05 8&
/**-+22
2/(+,D
/'*
(+/2)C)0),D
&(
%&3C)')'B
,-+3+0)3:3/C
/'*
*:-./0:3/C
)'
J<&9&-,2
=4 /'*
=>7
A/,)+',2
F),9
/*./'%+*
Q<<
J+),9+/0&'+
&F),9
%-D&/C0/,)&';
8=<K
&LM=7
/'* J<&9&-,
?7
)'
A/,)+',2
F),9
/*./'%+*
C)0)/-D
,-/%,
%/-%)'&3/
J?8<7
J+),9+/0&'+
&F),9 %-D&/C0/,)&'
&LM=7;
/*.+-2+
+.+',2
F)00
C+
,/C:0/,+*
CD
B-/*+
A+<8<=K
6
/'*
/'/0DR+*
/'* -+A&-,+*
*+2%-)A,).+0D5
%&
sjbjywz[u'wv]

Kuy
Aoxp]Tz
A]V]Tz[U`  
N:Cv+%,2
,-+/,+*
&'
,9)2
2,:*D;
F)00
C+
)'*).)*:/02
F),9
/*./'%+*
9+A/,&%+00:0/%/-%)'&3/ JQ<<7
&C)0)/-D
,-/%,
%/-%)'&3/;
F9)%9
9/2
-+%:--+*
J&A+-2)2,+*7
/(,+/AA-&A-)/,+
2,/'*/-* ,-+/,3+',5
P'*).)*:/02
&(
/'D
-/%+
&+,9')%
B-&:A
F)00
C+
+0)B)C0+
(&,9)2
2,:*D5
K0)B)C)0),D /22+223+',
F)00
C+
C/2+*
2&0+0D
&'
,9+
A/,)+',w2
3+*)%/0
2,/,:25
L+%-:),3+',
&(
A/,)+',2
&',&
,9)2 2,:*D
F)00
C+
,9-&:B9
2,/'*/-*
<<L
3+%9/')2325
x&
2A+%)/0
-+%-:),3+',
+((&-,2
F)00
C+ %&'*:%,+*5  
#$%&'()*+,+'(*+-.
-/
,0+12)3.
45678769:;<
956=>
?@=
:A=
BC
DE
F7;;
5B?
G=
=;7A7G;=
?B
H:>?7I7H:?=
75
?@7<
<?96J
G=I:9<=
?@=J
:>= 95;7K=;J
?B
@:8=
@=H:?BI=;;9;:>
B>
G7;7:>J
?>:I?
I:>I75BL:M
:56
G=I:9<=
BC
95K5BF5
?BN7I7?7=<
75 H=67:?>7I
H:?7=5?<O  
#$%P'()*+,+'(*+-.
-/
QRST3,*Q
R.(S13
*U+V3
,-.Q3.*
W69;?<
95:G;=
?B
A78=
IB5<=5?
:>=
=NI;96=6
C>BL
=5>B;;75A
75
?@=
H>B?BIB;O
XBF=8=>
>=YIB5<=5? L:J
G=
5=I=<<:>J
:56
?@=>=
7<
:
HB<<7G7;7?JM
?@B9A@
95;7K=;JM
?@:?
<9GZ=I?<
IB9;6
G=IBL=
6=I7<7B5:;;J
7LH:7>=6O
[B>
?@7<
>=:<B5
:56
G=I:9<=
?@=>=
7<
:
H>B<H=I?
BC
67>=I?
G=5=C7?
C>BL >=<=:>I@
H:>?7I7H:?7B5
\<=I?7B5
\#$%]%&^M
:;;
<9GZ=I?<
F7;;
G=
BCC=>=6
?@=
BHHB>?957?J
?B
C7;;
75
?@=7>
F7<@=<
CB>
>=<=:>I@
:56
I:>=M
:56
:<<7A5
:
<9G<?7?9?=
6=I7<7B5
L:K=>
B5
?@=
_`4X
W68:5I= a7>=I?78=
CB>
X=:;?@
b:>=
:56
c=67I:;
d=<=:>I@
e:>?7I7H:?7B5f
CB>L
<B
?@:?
:5B?@=>
H=><B5
I:5 L:K=
6=I7<7B5<
:GB9?
?@=7>
L=67I:;
I:>=
75
?@=
=8=5?
?@:?
?@=J
G=IBL=
75I:H:I7?:?=6
B> IBA57?78=;J
7LH:7>=6
69>75A
?@=
IB9><=
BC
?@=
<?96JO
`B?=g
h@=
e4
B>
W4
F7;;
IB5?:I?
?@=
`4X WG7;7?J
?B
bB5<=5?
W<<=<<L=5?
h=:L
\WbWh^
CB>
=8:;9:?7B5
?B
:<<=<<
B5AB75A
I:H:I7?J
BC
?@= <9GZ=I?<
:56
?B
76=5?7CJ
:
iWdM
:<
5==6=6O e;=:<=
<==
<=I?7B5
\#$%j%\#
CB>
IB5<=5?
H>BI=69>=O  
#$%]3V(1R(*+-.
-/
S3.3/+*Q
(.2
)+QkQl2+Q,-m/-)*Q
/-)
(11
'()*+,+'(.*Q
DnOoODp5BF5
HB?=5?7:;
>7<K< h@=
H>7L:>J
>7<K
?B
H:?7=5?<
H:>?7I7H:?75A
75
?@7<
>=<=:>I@
<?96J
7<
C>BL
?@=
?BN7I7?J
BC 69>8:;9L:G
:56
?>=L=;7L9L:GO DnOoODODa9>8:;9L:Gg cB>=
?@:5
Dqr
H:>?7I7H:5?<
L:J
@:8=g s a7:>>@=:M s d:<@t6>J
7?I@J
<K75M s i78=>
H>BG;=L<g
45I>=:<=<
75
;78=>
=5uJL=<M
75C;:LL:?7B5
BC
?@=
;78=>
\@=H:?7?7<^v
@BF=8=>M
?@7<
7<
95IBLLB5O
s [:?7A9= s `:9<=: s wBL7?75A s WG6BL75:;
H:75 s WII9L9;:?7B5
BC
C;976
I:9<75A
<F=;;75A s xHH=>
>=<H7>:?B>J
?>:I?
75C=I?7B5< s a=I>=:<=6
:HH=?7?= s y@B>?5=<<
BC
G>=:?@  
s bB9A@
%&%'
sjbjywz[u'wv]

$'()
*
+(
*",
-.'+/0/-.1+2
).3
4.&%5  
\# 6178.)).+/(1
/1
+4%
891:2
;-1%9)(1/+/2<=
>'%8/)/1.'3
?.+.
29::%2+%?
+4.+
+4%'%
).3
@%
+4%
+%1?%103
(7
4/:4%'
7'%A9%103
.1?
2%&%'/+3
/1
B.-.1%2%
-.+/%1+2
0()-.'%?
C/+4
1(1D B.-.1%2%
-.+/%1+2=
\# E(C
+43'(/?
;F3-(+43'(/?/2)<=
G4%
0(1?/+/(1
0.1
@%
+'%.+%?
C/+4
'%-8.0%)%1+
+43'(/?  
4(')(1%=
\# F/:4
+43'(/?
;F3-%'+43'(/?/2)<=
H%-%1?/1:
(1
+4%
2%&%'/+3
(7
+4%
23)-+()2I
+'%.+)%1+
).3
/1089?%
J92+
)(1/+('/1:
+4%
23)-+()2I
+'%.+/1:
+4%
23)-+()2
+4%)2%8&%2
.1?K(' :/&/1:
)%?/0/1%
+(
@8(0L
+4%
+43'(/?
4(')(1%=
\# M/?1%3
-'(@8%)25
.1
/10'%.2%
(7
0'%.+/1/1%
8%&%82
/1
.
@8((?
+%2+=
N10())(183
.
-.+/%1+
).3
%O-%'/%10%
1%-4'/+/2
C4/04
/2
.1
/178.)).+/(1
(7
+4%
L/?1%32
+4.+
2+(-2
+4%
L/?1%32 7'()
C('L/1:
-'(-%'83=
\# P%'&(92
232+%)
-'(@8%)25
23)-+()2
0.1
/1089?%
91929.8
C%.L1%22
(7
8%:2I
.')2I
('
7.0%I
19)@1%22
('
+/1:8/1:
/1
4.1?2
('
7%%+=
61
'.'%
2/+9.+/(12
+4%'%
/2
+4%
-(+%1+/.8
7('
+4% /178.)).+/(1
(7
+4%
1%'&(92
232+%)
+(
@%
2%&%'%
.1?
0.92%
?.).:%
+(
+4%
1%'&%
0%882
(' @'%.L?(C1
/1
+4%
0())91/0.+/(1
@%+C%%1
1%'&%2
.1?
)9208%2=
\# 61792/(1
Q%8.+%?
Q%.0+/(12= \# 6178.)).+/(1
(7
+4%
/1+%2+/1%
;0(8/+/2<= \# R
4(.'2%
&(/0% \# >./1798
9'/1.+/(1 \# P/:4+
2C%.+2 \# >1%9)(1/. \# S'.8
+4'924 \# H%1+.8
.1?
('.8
2(7+
+/229%
/17%0+/(1 \# >./1
/1
)9208%2
.1?
J(/1+2
\# 61789%1T.=
E%22
+4.1
*,
-%(-8%
).3
4.&%5
\# 6178.)).+/(1
(7
+4%
-.10'%.2
;-.10'%.+/+/2<=  
\# R88%':/0
'%.0+/(12= \# >'(@8%)2
C/+4
.?'%1.8
:8.1?2
;R?'%1.8
612977/0/%103<=
G4%2%
0()-8/0.+/(12
).3
@%
-%').1%1+
.1?
).3
'%A9/'%
4(')(1%
'%-8.0%)%1+=
\# >'(@8%)2
C/+4
+4%
-/+9/+.'3
:8.1?
;43-(-/+9/+.'/2)<=
G4%2%
0()-8/0.+/(12
).3
@%
-%').1%1+
.1?
).3
'%A9/'%
4(')(1%
'%-8.0%)%1+=
\# 6178.)).+/(1
(7
+4%
)9208%2
('
.22(0/.+%?
+/229%2I
2904
.2
@8((?
&%22%82
+4.+
29--83
+4%
muscles (Myositis/polymyositis).  
.  
Type 1 Diabetes mellitus. Type 1 diabetes will require replacement of insulin through injection.
.  
Problems with the pituitary gland (hypopituitarism). These complications may be permanent and may require hormone replacement.
.  
Inflammation of the heart muscle (myocarditis).
.  
Inflammation of the membrane surrounding the heart.
.  
Growths of tiny collections of inflammatory cells in different parts of the body.  
.  
Inflammation of the middle layer of the eye and other events involving the eye (e.g.  
inflammation of the cornea and optic nerves).
.  
Inflammation of the brain or the membranes that cover the brain and spinal cord.
.  
Hardening and tightening of the skin and connective tissues and loss of skin color.
.  
Pemphigoid and hematological events (e.g., abnormal breakdown of the red blood cells and low levels of platelets).
.  
Inflammation of the blood vessels and rheumatological events (inflammatory disorder causing muscle pain and stiffness and autoimmune arthritis).
12.5.1.2 Tremelimumab The following are side effects that have been associated with Tremelimumab:
.  
Diarrhea
.  
Rash
.  
Pruritus (itching)
.  
Fatigue Nausea
.  
Vomiting
.  
.  
Anorexia Headache
.  
.  
Abdominal Pain
.  
Muscle pain
.  
Auto-immune changes to the pituitary gland leading to hormonal changes.  
.  
Inflammation of the part of the intestine (colitis).  
.  
Inflammation in the lungs (pneumonitis).
.  
Kidney problems: an increase of creatinine levels in a blood test.
.  
Inflammation of the pancreas (pancreatitis).
.  
Inflammation of the liver (hepatitis). In extreme cases this may result in liver failure and death.
.  
A skin rash related to the treatment and this can also result in severe and life-threatening symptoms.
.  
Problems related to tremelimumab infusion
.  
A serious allergic reaction (anaphylaxis)
There is a remote chance that participants may develop new allergies to previously exposed substances, other than durvalumab or tremelimumab. For example, it is possible that people could develop an allergy to shellfish or IV contrast while taking durvalumab or tremelimumab.  
These allergies may be severe and life threatening.  
All care will be taken to minimize study treatment side effects, but they can be unpredictable in nt to the control to monitor the treatment of patients will be recorded in the patient chart.
%&%'
12.5.1.3 risks of rfa

Subjects in Arm 3 additionally will have one protocol required RFA procedure. The risks from RFA include bleeding, injury to the normal liver tissue, re-growth of the tumor and infection.  
12.5.1.4 Risks of cryoablation Subjects in Arm 4 additionally will have one protocol required Cryo procedure. The risks from cryoablation procedure include bleeding, injury to the normal liver tissue, re-growth of the tumor and nerve damage.
%&%'
12.5.1.5 risk of optional biopsy

All care will be taken to minimize risks that may be incurred by tumor sampling. However, there are procedure-related risks (such as bleeding, infection and visceral injury) that will be explained fully during informed consent.
%&%'
12.5.1.6 risks of sedation

Potential side effects of sedation include headache, nausea and drowsiness. These side effects usually go away quickly.  
12.5.1.7 Risks of general anesthesia Risks of general anesthesia include temporary confusion and memory loss, although this is more common in the elderly, dizziness, difficulty passing urine, bruising or soreness from the IV drip, nausea and vomiting, shivering and feeling cold, sore throat due to the breathing tube 12.5.1.8 Risks of exposure to ionizing radiation The study will involve radiation from the following sources:
.  
Up to 6 CT scans per year for disease assessment (all subjects)
.  
Up to 3 CT scans for the collection of one mandatory and 2 optional biopsies (Arm A1 oly)
\# $%&
'()*
+,-.&/0,&
1(,2
(3
-%456  
\# 7+
89
)'
:.;%
8<0=/&
>?( \# 7+
89
)'
:.;%
8<0=/&
.,5-
@0AB&.8:
=%
(,2
9
2;5
C;D&
0+
8E
)'
:.;%:
;%/
"
)'
<0=/&/
A=-+:=&:
;%/
A&
&F+-:&/
8- ;++,-F=2;8&45
G
,&2
+&,
5&;,H
'C=:
;2-0%8
=:
2-,&
8C;%
I-04/
A&
&F+&.8&/
J,-2
&D&,5/;5 A;.K<,-0%/
,;/=;8=-%H
L&=%<
&F+-:&/
8&F.&::
,;/=;8=-%
.;%
=%.,&;:&
8C&
,=:K
-J
.;%.&,H
'C&
,=:K -J
<&88=%<
.;%.&,
J,-2
8C&
,;/=;8=-%
&F+-:0,&
=%
8C=:
:80/5
=:
MHG
-08
-J
9MM
1MHGN6
;%/
-J
<&88=%< ;
J;8;4
.;%.&,
=:
MHO
-08
-J
9MM
1MHON6H @0AB&.8:
=%
(,2
3
2;5
C;D&
0+
8E
)'
:.;%:P
3
)'
<0=/&/
A=-+:=&:
;%/
-%&
+,-8-.-4
,&Q0=,&/ '()*
+,-.&/0,&H
'C&
;.80;4
/-:&
-J
;
'()*
=:
C=<C45
D;,=;A4&P
/&+&%/=%<
-%
8C&
+;8=&%8H
L;:&/ -%
4=8&,;80,&
,&D=&I:
-%&
;D&,;<&
'()*
=:
;A-08
R
,&2H
@-P
:0AB&.8:
=%
(,2
3
2;5
A&
&F+-:&/
88-8;4
;2-0%8
-J
,;/=;8=-%
9EH3
,&2H
'C=:
;2-0%8
=:
2-,&
8C;%
I-04/
A&
&F+&.8&/
J,-2
&D&,5/;5 A;.K<,-0%/
,;/=;8=-%H
L&=%<
&F+-:&/
8&F.&::
,;/=;8=-%
.;%
=%.,&;:&
8C&
,=:K
-J
.;%.&,H
'C&
,=:K -J
<&88=%<
.;%.&,
J,-2
8C&
,;/=;8=-%
&F+-:0,&
=%
8C=:
:80/5
J-,
+;,8=.=+;%8:
=%
(,2
3
=:
9HE
-08
-J 9MM
19HEN6
;%/
-J
<&88=%<
;
J;8;4
.;%.&,
=:
MHR
-08
-J
9MM
1MHRN6H @0AB&.8:
=%
(,2
"
;%/
S
2;5
C;D&
0+
8E
)'
:.;%:P
3
)'
<0=/&/
A=-+:=&:P
9
)'
<0=/&/
>?(
-, .,5;%/
A&
&F+-:&/
8;++,-F=2;8&45
G
,&2
+&,
5&;,H
'C=:
;2-0%8
=:
2-,&
8C;%
I-04/
A& &F+&.8&/
J,-2
&D&,5/;5
A;.K<,-0%/
,;/=;8=-%H
L&=%<
&F+-:&/
8&F.&::
,;/=;8=-%
.;%
=%.,&;:& 8C&
,=:K
-J
.;%.&,H
'C&
,=:K
-J
<&88=%<
.;%.&,
J,-2
8C&
,;/=;8=-%
&F+-:0,&
=%
8C=:
:80/5
=:
MHG
-08 -J
9MM
1MHGN6
;%/
-J
<&88=%<
;
J;8;4
.;%.&,
=:
MHO
-08
-J
9MM
1MHON6H 93HOH9HG>=:K:
-J
)'
@.;%: T%
;//=8=-%
88C&
,;/=;8=-%
,=:K:
/=:.0::&/
;A-D&P
)'
:.;%:
2;5
=%.40/&
8C&
,=:K:
-J
;%
;44&,<=. ,&;.8=-%
88C&
.-%8,;:8H
U;,8=.=+;%8:
2=<C8
&F+&,=&%.&
C=D&:P
=8.C=%<P
C&;/;.C&P
/=JJ=.0485 A,&;8C=%<P
=%.,&;:&/
C&;,8,;8&
;%/
:I&44=%<H 93HOH9H9M >=:K
-J
4-:=%<
/;8; 'C=:
=%.40/&:
8C&
,=:K
8C;8
/;8;
-A8;=%&/
/0,=%<
8C=:
:80/5
.;%
A&
,&4&;:&/
82&2A&,:
-J
8C& +0A4=.P
=%:0,&,:P
&2+4-5&,:P
-,
4;I
&%J-,.&2&%8
;<&%.=&:H
(48C-0<C
8C&,&
;,&
%+4;%:
8,&4&;:& ,&:048:
88C&
+;8=&%8:P
J;2=45
2&2A&,:
-,
C&;48C
.;,&
+,-D=/&,:P
8C=:
,=:K
I=44
A&
=%.40/&/
=%
8C& =%J-,2&/
.-%:&%8
/-.02&%8H 93HOH9H99 L4--/
)-44&.8=-%
>=:K: >=:K:
-J
A4--/
/,;I:
=%.40/&
+;=%
;%/
A,0=:=%<
=%
8C&
;,&;
IC&,&
8C&
%&&/4&
=:
+4;.&/P 4=<C8C&;/&/%&::P
;%/
,;,&45P
J;=%8=%<H
VC&%
4;,<&
;2-0%8:
-J
A4--/
;,&
.-44&.8&/P
4-I
,&/
A4--/ .&44
.-0%8
1;%&2=;6
.;%
/&D&4-+H 93HOH9H93 >=:K:
-J
*WX >=:K:
=%.40/&
:-2&
2=%-,
:K=%
=,,=8;8=-%
J,-2
8C&
&4&.8,-/&: 93HOH9H9" 7,=%;45:=: 'C&,&
;,&
%+C5:=.;4
,=:K:
-J
0,=%;45:=:  
#$%&%$'()*(
+),-(,./0
1-(-2.,3
45+),-(,./0
1-(-2.,
,)
/
+/,.-(,
,5/,
6)-3
)(,)
3,789
.3
/
:-87;,.)(
.(
,5170<
)2
,5-.:
,7=): *5.;5
=/9
):
=/9
(),
5/>2/>):/10.=+/;,
)(
39=+,)=3
/(8?):
37:>.>/0%% \#$%&%@A.3<3?B-(-2.,3
C(/093.3 D):
+/,.-(,3
*.,5
5-+/,);-0070/:
;/:;.()=/
/(8
1.0./:9
;/(;-:E
=-8./(
37:>.>/0
.3
.(
,5:/(6)2 F
=)(,53%
G,
.3
+)33.10,5/,
,:-/,=-(,
)(
,5.3
+:),);)0
=/9
:-87;,7=):
17:8-(
):
0-33-( 39=+,)=3
;/73-8
19
,5;/(;-:%
H5.0,:-/,=-(,
)(
,5.3
+:),);)0
=/9
(),
.(8.>.87/009
1-(-2., 371I-;,3E
,5<()*0-866/.(-8
2:)=
,5.3
3,789
=/9
5-0+
),5-:3
.(
,527,7:*5)
5/>- 5-+/,);-0070/:
;/:;.()=/%  
J),-(,./0
:.3<3
.(;078,5+)33.10);;7::-(;)2
/(9
)2
/
:/(6)2 3.8-22-;,3
0.3,-8%
G2
+/,.-(,3
3722-:
/(9
+593.;/0
.(I7:9
/3
/
:-370,
)2
,51.)+3.-3E
.==-8./,- =-8.;/0
,:-/,=-(,
.3
/>/.0/10/,
,5KGLM3
N0.(.;/0
N-(,-:
.(
B-,5-38/E
O/:90/(8%
C0,5)765
() ;)=+-(3/,.)(
.3
/>/.0/10-E
/(9
.(I7:9
*.00
127009
->/07/,-8
/(8
,:-/,-8
.(
<--+.(6
*.,5
,51-(-2.,3
):
;/:,)
*5.;5
+/,.-(,3
/:-(,.,0-8
7(8-:
/++0.;/10:-670/,.)(3% 45:.3<3
/(8
1-(-2.,3
)2
+/:,.;.+/,.)(
2):
/870,3
*5)
1-;)=7(/10,)
;)(3-(,E
/:()
8.22-:-(, ,5/(
,5)38-3;:.1-8
2):
+/,.-(,3
*5)
/:0-33
>70(-:/10-%
%&%'
pqrstuvwxvy

Z[Utxww
\V]
]Ut^_Xvy\Y`Uv  
45.(2):=-8
;)(3-(,
8);7=-(,
*.00
1+:)>.8-8
,)
,5+/:,.;.+/(,
):
;)(3-(,
8-3.6(--a3b
a-%6%E 0-6/009
/7,5):.c-8
:-+:-3-(,/,.>deCAf
2):
:-;)(3-(,
+7:+)3-3
.2
+/:,.;.+/(,
.3
/(
/870,
7(/10,) ;)(3-(,b
2):
:->.-*
+:.):
,)
;)(3-(,.(6%
C
8-3.6(/,-8
3,789
.(>-3,.6/,):
*.00
;/:-27009
-g+0/.(
,5- +:);-87:-3
/(8
,-3,3
.(>)0>-8
.(
,5.3
3,789E
/(8
,5/33);./,-8
:.3<3E
8.3;)=2):,3
/(8
1-(-2.,3%
G( ):8-:
,)
=.(.=.c+),-(,./0
;)-:;.)(E
/3
=7;5
,.=/3
.3
(--8-8
,)
:->.-*
,58);7=-(,
*.00
16.>-(E
.(;078.(6
/(
)++):,7(.,9
,)
8.3;733
.,
*.,5
2:.-(83E
2/=.09
=-=1-:3
/(8?):
),5-:
/8>.3):3E /(8
,)
/3<
h7-3,.)(3
)2
/(9
8-3.6(/,-8
3,789
.(>-3,.6/,):%
C
3.6(-8
.(2):=-8
;)(3-(,
8);7=-(, *.00
1)1,/.(-8
+:.):
,)
-(,:9
)(,)
,53,789% 45.(.,./0
;)(3-(,
+:);-33
/3
*-00
/3
:-i;)(3-(,E
*5-(
:-h7.:-8E
=/9
,/<+0/;.(
+-:3)(
): :-=),-09
a-%6%E
>./
,-0-+5)():
),5-:
KGL
/++:)>-8
:-=),+0/,2):=3
73-8
.(
;)=+0./(;*.,5 0);/0
+)0.;9E
.(;078.(6
O$ji\#b
+-:
8.3;:-,.)(
)2
,58-3.6(/,-8
3,789
.(>-3,.6/,):
/(8
*.,5
,5- /6:--=-(,
)2
,5+/:,.;.+/(,?;)(3-(,
8-3.6(--a3b%
H5-,5-:
.(
+-:3)(
):
:-=),-E
,5+:.>/;9
)2
,5371I-;,
*.00
1=/.(,/.(-8%
N)(3-(,.(6
.(>-3,.6/,):3
a/(8
+/:,.;.+/(,?;)(3-(,
8-3.6(--a3bE
*5-( .(
+-:3)(b
*.00
10);/,-8
.(
/
+:.>/,/:-/
a-%6%E
;0.(.;
;)(370,
:))=b%
H5-(
;)(3-(,
.3
;)(87;,-8 :-=),-09E
,5+/:,.;.+/(,
*.00
1.(2):=-8
)2
,5+:.>/,(/,7:)2
,58.3;733.)(
/(8
*.00
1- -(;)7:/6-8
,)
:-0);/,,)
/
=):+:.>/,3-,,.(6
.2
(--8-8% D):
)+,.)(/0
1.)+3.-3
2):
:-3-/:;5
.(
,5+:),);)0E
,5+/,.-(,
*.00
;)(3-(,
/,
,5,.=)2
,5- +:);-87:-%
G2
,5+/,.-(,
:-273-3
,5)+,.)(/0
1.)+39
/,
,5/,
,.=-E
,5:-273/0
*.00
18);7=-(,-8 .(
,5=-8.;/0
:-;):8
/(8
.(
,5:-3-/:;5
:-;):8% \#$%F%\#N)(3-(,
J:);-33
2):
C870,3
H5)
e/;<
N/+/;.,9
,)
N)(3-(,
,)
A-3-/:;5
J/:,.;.+/,.)( D):
+/:,.;.+/(,3
/88:-33-8
.(
3-;,.)(
PQRkE
/(
eCA
*.00
1.8-(,.2.-8
;)(3.3,-(,
*.,5
J)0.;9
"j@ /(8
.(2):=-8
;)(3-(,
)1,/.(-8
2:)=
,5eCAE
/3
8-3;:.1-8
.(
l-;,.)(
PQRS%  
#$ %&'()*+,%*./
,0&%*+1,.*)
2,.31/&%*+1,.3 #$4#3+(//132,.+1.(*+1,.
*./
2),3(%&
5678
89:;<
=><
?@
9@=ABC>C7D<
8:8A@E;@;
BC
AC@=>9:C@D<
9@C=7E>9@;
7F
96@C@
78
8:FF7G7@E9 C@>8BE>?D@
G>:8@H
IC799@E
EB97F7G>97BEJ
;BG:=@E97EK
96@
C@>8BE
FBC
89:;<
8:8A@E87BE
BC 9@C=7E>97BEJ
L7DD
?@
ACBM7;@;
?<
96@
8:8A@E;7EK
BC
9@C=7E>97EK
A>C9<
9B
89:;<
A>C97G7A>E98J >88BG7>9@
7EM@897K>9BC8J
96@
NEM@897K>97BE>D
O@L
PC:K
QNOPR
8ABE8BC
>E;
C@K:D>9BC<
>:96BC797@8H NF
96@
89:;<
78
AC@=>9:C@D<
9@C=7E>9@;
BC
8:8A@E;@;J
96@
SC7EG7A>D
NEM@897K>9BC
QSNR
L7DD
ACB=A9D< 7EFBC=
89:;<
A>C97G7A>E98J
96@
NE8979:97BE>D
T@M7@L
UB>C;
QNTURJ
>E;
8ABE8BC
>E;
L7DD
ACBM7;@ 96@
C@>8BEQ8R
FBC
96@
9@C=7E>97BE
BC
8:8A@E87BEH
V9:;<
A>C97G7A>E98
L7DD
?@
GBE9>G9@;J
>8 >AAD7G>?D@J
>E;
?@
7EFBC=@;
BF
G6>EK@8
9B
89:;<
M7879
8G6@;:D@H W7CG:=89>EG@8
96>9
=><
L>CC>E9
9@C=7E>97BE
BC
8:8A@E87BE
7EGD:;@J
?:9
>C@
EB9
D7=79@;
9BX
Y P@9@C=7E>97BE
BF
:E@ZA@G9@;J
87KE7F7G>E9J
BC
:E>GG@A9>?D@
C78[
9B
A>C97G7A>E98  
Y P@=BE89C>97BE
BF
@FF7G>G<
96>9
LB:D;
L>CC>E9
89BAA7EK Y NE8:FF7G7@E9
GB=AD7>EG@
9B
ACB9BGBD
C@\:7C@=@E98 Y P>9>
96>9
>C@
EB9
8:FF7G7@E9D<
GB=AD@9@
>E;]BC
@M>D:>?D@ Y P@9@C=7E>97BE
96>9
96@
AC7=>C<
@E;AB7E9
6>8
?@@E
=@9 Y P@9@C=7E>97BE
BF
F:97D79<
V9:;<
=><
C@8:=@
BEG@
GBEG@CE8
>?B:9
8>F@9<J
ACB9BGBD
GB=AD7>EG@J
>E;
;>9>
\:>D79<
>C@ >;;C@88@;J
>E;
8>978F<
96@
8ABE8BCJ
NTU
>E;
>8
>AAD7G>?D@J
^BB;
>E;
PC:K
_;=7E789C>97BE
Q^P_RH  
#$4`a(*)1+*33(%*.2&
*./
a(*)1+2,.+%,)
56@
GD7E7G>D
879@
L7DD
A@CFBC=
7E9@CE>D
\:>D79<
=>E>K@=@E9
BF
89:;<
GBE;:G9J
;>9>
>E;
?7BDBK7G>D 8A@G7=@E
GBDD@G97BEJ
;BG:=@E9>97BE
>E;
GB=AD@97BEH
_E
7E;7M7;:>D7b@;
\:>D79<
=>E>K@=@E9
AD>E L7DD
?@
;@M@DBA@;
9B
;@8GC7?@
>
879@c8
\:>D79<
=>E>K@=@E9H d:>D79<
GBE9CBD
QdWR
ACBG@;:C@8
L7DD
?@
7=AD@=@E9@;
?@K7EE7EK
L796
96@
;>9>
@E9C<
8<89@=
>E; ;>9>
dW
G6@G[8
96>9
L7DD
?@
C:E
BE
96@
;>9>?>8@
L7DD
?@
K@E@C>9@;H
_E<
=7887EK
;>9>
BC
;>9> >EB=>D7@8
L7DD
?@
GB==:E7G>9@;
9B
96@
879@Q8R
FBC
GD>C7F7G>97BE]C@8BD:97BEH ^BDDBL7EK
LC799@E
V9>E;>C;
eA@C>97EK
SCBG@;:C@8
QVeS8RJ
96@
=BE79BC8
L7DD
M@C7F<
96>9
96@ GD7E7G>D
9C7>D
78
GBE;:G9@;
>E;
;>9>
>C@
K@E@C>9@;
>E;
?7BDBK7G>D
8A@G7=@E8
>C@
GBDD@G9@;J ;BG:=@E9@;
QC@GBC;@;RJ
>E;
C@ABC9@;
7E
GB=AD7>EG@
L796
96@
ACB9BGBDJ
NE9@CE>97BE>D
WBEF@C@EG@ BE
f>C=BE78>97BE
gBB;
WD7E7G>D
SC>G97G@
QNWf
gWSRJ
>E;
>AAD7G>?D@
C@K:D>9BC<
C@\:7C@=@E98 Q@HKHJ
gBB;
h>?BC>9BC<
SC>G97G@8
QghSRJ
gBB;
i>E:F>G9:C7EK
SC>G97G@8
QgiSRRH 56@
7EM@897K>97BE>D
879@
L7DD
ACBM7;@
;7C@G9
>GG@88
9B
>DD
9C7>D
C@D>9@;
879@8J
8B:CG@
;>9>];BG:=@E98J >E;
C@ABC98
FBC
96@
A:CAB8@
BF
=BE79BC7EK
>E;
>:;797EK
?<
96@
8ABE8BCJ
>E;
7E8A@G97BE
?<
DBG>D >E;
C@K:D>9BC<
>:96BC797@8H  
#$4$2,.j)12+
,j
1.+&%&3+
0,)12-
56@
7E;@A@E;@EG@
BF
9678
89:;<
FCB=
>E<
>G9:>D
BC
A@CG@7M@;
7EFD:@EG@J
8:G6
>8
?<
96@ A6>C=>G@:97G>D
7E;:89C<J
78
GC797G>DH
56@C@FBC@J
>E<
>G9:>D
GBEFD7G9
BF
7E9@C@89
BF
A@C8BE8
L6B
6>M@
a role in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, persons who have a perceived conflict of interest will be required to have such conflicts managed in a way that is appropriate to their participation in the design and conduct of this trial. The study leadership in conjunction with the NCI has established policies and procedures for all study group members to disclose all conflicts of interest and will establish a mechanism for the management of all reported dualities of interest.
%&%'
13.4 confidentiality and privacy

Participant confidentiality and privacy is strictly held in trust by the participating investigators, their staff, and the sponsor. This confidentiality is extended to cover testing of biological samples and genetic tests in addition to the clinical information relating to participants. Therefore, the study protocol, documentation, data, and all other information generated will be held in strict confidence. No information concerning the study or the data will be released to any unauthorized third party without prior written approval of the sponsor. All research activities will be conducted in as private a setting as possible.  
The study monitor, other authorized representatives of the sponsor, representatives of the Institutional Review Board (IRB), and/or regulatory agencies may inspect all documents and records required to be maintained by the investigator, including but not limited to, medical records (office, clinic, or hospital) and pharmacy records for the participants in this study. The clinical study site will permit access to such records.  
The study participant's contact information will be securely stored at each clinical site for internal use during the study. At the end of the study, all records will continue to be kept in a secure location for as long a period as dictated by the reviewing IRB, Institutional policies, or sponsor requirements.  
Study participant research data will not include the participant's contact or identifying information. Rather, individual participants and their research data will be identified by a unique study identification number. The study data entry and study management systems used by clinical sites will be secured and password protected. At the end of the study, all study databases will be archived at the NIH Clinical Center.  
To further protect the privacy of study participants, a Certificate of Confidentiality has been issued by the National Institutes of Health (NIH).  This certificate protects identifiable research information from forced disclosure. It allows the investigator and others who have access to research records to refuse to disclose identifying information on research participation in any civil, criminal, administrative, legislative, or other proceeding, whether at the federal, state, or local level. By protecting researchers and institutions from being compelled to disclose information that would identify research participants, Certificates of Confidentiality help achieve the research objectives and promote participation in studies by helping assure confidentiality and privacy to participants.
%&%'
"# %&'(&)+-)&.

-/01'(&,-1/ "#2",'*(*.-(+(&3  
456464789:;<
=:<><?@>9>AB
C@??
B<
D9EE?@<F
BG
HDI:AJ<K<;ALM<FN>>9K<O
NK;6 45646PQ8:>9?AI@8K
AKF
R:<EA:AI@8K =:<><?@>9>AB
@D
A
S9>AK
NTUP
AKI@VW=XHV5
>HB
ISAI
@D
B<@KT
F<Y<?8E<F
AD
AK @>>9K8IS<:AE<9I@;
AT<KI
Z8:
YA:@89D
;AK;<:D6  
| -[\]^_`ab_`c[bd (b[gibh_ge]e   | )c[h][_eb_`c[ b[f 0cejgdb_`c[ b^ kglld`]f   |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                |
|--------------------------------|---------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| $ecfgh_                        |                                             |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                |
| =:<><?@>9>AB                   | M<FN>>9K<                                   | =:<><?@>9>AB C@?? B< D9EE?@<F BG HDI:AJ<K<;A <@IS<: AD A 5mmV>T 8: A PnV>T Y@A? D8?9I@8K Z8: @KZ9D@8K AZI<: F@?9I@8K6 =S< D8?9I@8K ;8KIA@KD Pm >TL>X I:<><?@>9>ABO Pm >M S@DI@F@K<LS@DI@F@K< SGF:8;S?8:@F<O PPP >M I:<SA?8D< F@SGF:AI<O m6P! >M  F@D8F@9> <F<IAI< F@SGF:AI<O AKF m6mPo C<@TSILY8?9>< pCLYq E8?GD8:BAI< rms @I SAD A Et 8Z n6n AKF F<KD@IG 8Z 46mu5 TL>X6 =S< K8>@KA? Z@?? Y8?9>< @D Pm6m >X Z8: IS< 5mmV>T Y@A? AKF 46Pn >X Z8: IS< PnV>T Y@A?6 NKY<DI@TAI@8KA? E:8F9;I Y@A?D A:< DI8:<F AI PvW I8 rvW puwvQ I8 5wvQq AKF >9DI K8I B< Z:8x<K6 y:9T E:8F9;I DS89?F B< z<EI @K 8:@T@KA? ;8KIA@K<: 9KI@? 9D< I8 E:<Y<KI E:8?8KT<F ?@TSI <{E8D9:<6 |  
=S<
Pm
>TL>X
D8?9I@8K
C@??
B<
F@?9I<F
@KI8
A
DA?@K<
BAT
Z8:
N|
@KZ9D@8K6
|@A?D
;8KIA@K@KT I:<><?@>9>AB
>AG
B<
T<KI?G
@KY<:I<F
Z8:
>@{@KT
B9I
DS89?F
K8I
B<
DSAz<K6 Q8:
F8D<
E:<EA:AI@8K
DI<EDO
IS<
Z8??8C@KT
AK;@??A:G
@I<>D
A:<
:<}9@:<F~  
N|
@KZ9D@8K
BATD
8Z
m6o
D8F@9>
;S?8:@F<
@K<;I@8K
pPnm
>X
D@x<q6
7A?@K<
BATD
>9DI
B<
?AI<{VZ:<<
AKF
;AK
B<
>AF<
8Z
E8?GY@KG?
;S?8:@F<
pR|Wq
8:
E8?G8?<Z@KD
p<6T6O E8?G<ISG?<K<qO
>AK9ZA;I9:<F
C@IS
B@D
pPV<ISG?S<{G?q
ESISA?AI<
pytRq
8:
ytRVZ:<<6 N|
@KZ9D@8K
?@K<D
>AF<
8Z
R|WLytR
8:
R|WLI:@
8;IG?
I:@><??@IAI<
p==Mq
8:
E8?G<ISG?<K<
8:
E8?G9:<ISAK<6
H??
ytRV;8KIA@K@KT
8:
ytRVZ:<<
?@K<D
A:<
A;;<EIAB?<6 X@K<D
DS89?F
;8KIA@K
A
m6PP
8:
m6P  
@KV?@K<
Z@?I<:6
=S<
@KV?@K<
Z@?I<:
;AK
B<
>AF<
8Z E8?G<IS<:D9?Z8K<
pR7q
8:
E8?GY@KG?@F@K<
Z?98:@F<
yQ
pR|yQq6
X@K<D
;8KIA@K@KT ;<??9?8D<VBAD<F
Z@?I<:D
DS89?F
K8I
B<
9D<F
C@IS
I:<><?@>9>AB6 WAIS<I<:DL@KZ9D@8K
D<ID
>AF<
8Z
E8?G9:<ISAK<
8:
Z?98:8E8?G><:
C@IS
D@?@;8K<
AKF
DIA@K?<DD
DI<<?
AKFL8:
R|W
;8>E8K<KID6
\# $%&'()*+
,-.*
/0
1/2%1&/1%2*(*
-(.
2-3*450&**6
7/2%8-&9/(-3*
+%&'()*+
+:/;2.
(/3
9*
;+*.
<'3:
3&*,*2',;,-96
\# =**.2*+
,-.*
/0
+3-'(2*++
+3**26
>?6>6@A.,'('+3&-3'/(
7&/8*.;&*+
B&*,*2',;,-9
'+
3/
9*
-.,'('+3*&*.
-+
-(
CD
+/2;3'/(
/0
>E
,)FG)
-3
&-3*
/0
HIE
,JF:&K 0/22/<*.
9%
/9+*&L-3'/(
0/&
ME
,'(;3*+6 >?6>6?N/+*
O-28;2-3'/( PQRST
B:*
./+'()
0/&
3&*,*2',;,-9
<'22
9*
02-3
./+'()
/0
!I
,)6 B:*
8/&&*+1/(.'()
L/2;,*
/0
'(L*+3')-3'/(-2
1&/.;83
+:/;2.
9*
&/;(.*.
3/
3:*
(*-&*+3
3*(3:
/0
- ,J
UE6>
,JV6
W-8:
L'-2
8/(3-'(+
+,-22
-,/;(3
/0
/L*&-)*
-(.
3:*
/L*&-)*
+:/;2.
9*
;3'2'X*.
-+
,;8:
-+
1/++'92*
9*0/&*
;+'()
-(/3:*&
L'-26 B:*
(;,9*&
/0
L'-2+
&*Y;'&*.
0/&
./+*
1&*1-&-3'/(
'+
3:*
(*43
)&*-3*+3
<:/2*
(;,9*&
/0
L'-2+ 0&/,
3:*
0/22/<'()
0/&,;2-Z
=;,9*&
/0
L'-2+
[
N/+*
U,JV
\
HE
U,JFL'-2V >?6>6IC(L*+3')-3'/(-2
7&/.;83
C(+1*83'/( W-8:
L'-2
+*2*83*.
0/&
./+*
1&*1-&-3'/(
+:/;2.
9*
'(+1*83*.6 C0
3:*&*
-&*
-(%
.*0*83+
(/3*.
<'3:
3:*
'(L*+3')-3'/(-2
1&/.;83K
3:*
'(L*+3')-3/&
-(.
+'3*
,/('3/& +:/;2.
9*
(/3'0'*.
',,*.'-3*2%6
]*0*&
3/
3:*
7&/.;83
O/,12-'(3
+*83'/(
U^_`^`aV
0/&
0;&3:*& '(+3&;83'/(+6 N;&'()
3:*
'(+1*83'/(
'0
3:*
+/2;3'/(
'+
(/3
82*-&
/&
-(%
3;&9'.'3%K
.'+8/2/&-3'/(
/&
1-&3'8;2-3*+
-&* /9+*&L*.K
(/3'0%
%/;&
+'3*
,/('3/&
-(.
+3/&*
3:*
L'-2U+V
'(
bcA]A=BC=W
-3
&*0&')*&-3*.
UH5"dOV 3*,1*&-3;&*
0/&
.&;)
-88/;(3-9'2'3%
-(.
1/3*(3'-2
0;3;&*
'(+1*83'/(6 =/3'0%
3:*
Ce]$
3:-3
3:*
;(;+-92*
L'-2+
-&*
.-,-)*.6
B:*
Ce]$
<'22
'(.'8-3*
3:*
&*12-8*,*(3 L'-2+6
$*2*83
-11&/1&'-3*
&*12-8*,*(3
L'-2+
0/&
3:*
1&*1-&-3'/(
/0
3:*
+;9f*83g+
./+*
-(.
1*&0/&, 3:*
+-,*
'(+1*83'/(
/(
3:*
(*<2%
+*2*83*.
L'-2+6
h/&
-88/;(3-9'2'3%K
&*8/&.
3:*
3/3-2
(;,9*&
/0 L'-2+
&*,/L*.
0&/,
+'3*
'(L*(3/&%6
c+*.
L'-2+
+:/;2.
9*
:*2.
0/&
-88/;(3-9'2'3%
1;&1/+*+
-3 -,9'*(3
+3/&-)*
3*,1*&-3;&*6
%&%'
>?6>6mn/+

7&*1-&-3'/(
$3*1+  
B&*,*2',;,-9
./*+
(/3
8/(3-'(
1&*+*&L-3'L*+
-(.
-(%
;(;+*.
1/&3'/(
,;+3
9*
.'+8-&.*.6 7&*1-&-3'/(
/0
3&*,*2',;,-9
-(.
1&*1-&-3'/(
/0
3:*
CD
9-)
-&*
3/
9*
1*&0/&,*.
-+*13'8-22%6 B/3-2
'(5;+*
+3/&-)*
3',*
0/&
3:*
1&*1-&*.
0'(-2
CD
9-)
+:/;2.
(/3
*48**.
H?
:/;&+
-3
H5"iO
/&
? :/;&+
-3
&//,
3*,1*&-3;&*
UHIiOV6
j/<*L*&K
'3
'+
&*8/,,*(.*.
3:-3
3:*
1&*1-&*.
0'(-2
CD
9-)
9* +3/&*.
'(
3:*
.-&G
-3
H5"iO
;(3'2
(**.*.6
B:*
&*0&')*&-3*.
'(0;+'/(
+/2;3'/(+
'(
3:*
1&*1-&*.
0'(-2 CD
9-)
+:/;2.
9*
*Y;'2'9&-3*.
-3
&//,
3*,1*&-3;&*
0/&
-9/;3
H
:/;&+
1&'/&
3/
-.,'('+3&-3'/(6
C0 +3/&-)*
3',*
*48**.+
3:*+*
2','3+K
(*<
./+*
,;+3
9*
1&*1-&*.
0&/,
(*<
L'-2+6 B:*
'(L*+3')-3'/(-2
1&/.;83
,-(-)*&
/&
Y;-2'0'*.
1*&+/((*2
<'22
9*
&*+1/(+'92*
0/&
1&*1-&'()
3:* CD
./+*+
;+'()
3:*
0/22/<'()
+3*1+Z >V
$*2*83
3:*
Ce]$5-++')(*.
(;,9*&
/0
L'-2+
/0
'(L*+3')-3'/(-2
1&/.;83
&*Y;'&*.
3/
1&*1-&*
3:* +;9f*83g+
./+*6 \#$
%&&
'()*+,'-.,'/(.&
01/234,
)'.&+
+5/3&2
6*
*73'&'61.,*2
,/
1//8
,*80*1.,31*
9/1
:;
8'(3,*+ 01'/1
,/
2/+*
01*0.1.,'/(< :$
=/
01*0.1*
,5*
>?
6.-@
9'1+,@
4.&43&.,*
,5*
2/+*
)/&38*
/9
'()*+,'-.,'/(.&
01/234,
1*73'1*2< A*4/(2@
1*8/)*
,5*
)/&38*
/9
;<"B
+/2'38
45&/1'2*
>?
+/&3,'/(
*73').&*(,
,/
,5*
4.&43&.,*2 2/+*
)/&38*
/9
'()*+,'-.,'/(.&
01/234,
91/8
,5*
>?
6.-<
C.+,&D@
.22
,5*
4.&43&.,*2
2/+*
)/&38* /9
'()*+,'-.,'/(.&
01/234,
,/
,5*
>?
6.-<
E*(,&D
8'F
,5*
+/&3,'/(
'(
,5*
6.6D
'()*1,'(30
.(2 2/G(<
%)/'2
+5.H'(,5*
>?
6.,/
01*)*(,
9/.8'(-< C.6*&+
G'&&
6*
01*0.1*2
'(
.44/12.(4*
G',5
E//2
I.(39.4,31'(J1.4,'4*
KEIJ$< LM<L<!>()*+,'-.,'/(.&
J1/234,
%44/3(,.6'&',D =5*
'()*+,'-.,/1N+
/1
+',*N+
2*+'-(.,*2
'()*+,'-.,'/(.&
01/234,
8.(.-*1
'+
1*73'1*2
,/
8.'(,.'( .4431.,*
'()*+,'-.,'/(.&
01/234,
.44/3(,.6'&',D
1*4/12+<
O0/(
4/80&*,'/(
/9
,5*
+,32D@
4/0'*+
/9 '()*+,'-.,'/(.&
01/234,
.44/3(,.6'&',D
1*4/12+
G'&&
6*
1*,31(*2
,/
I*2>883(*<
%&&
3(3+*2 '()*+,'-.,'/(.&
01/234,
G'&&
6*
1*,31(*2
,/
.
I*2>883(*P.3,5/1'Q*2
2*0/,
/1
2'+0/+*2
/9
30/( .3,5/1'Q.,'/(
6D
I*2>883(*< LM<L<RS*0/1,'(J1/234,
T/80&.'(,+ %(D
2*9*4,+
G',5
,5*
'()*+,'-.,'/(.&
01/234,
83+,
6*
1*0/1,*2
UVVWXUYZW[\
,/
,5*
I*2>883(* J1/234,
T/80&.'(,
]*0.1,8*(,
6D
,5*
+',*
G',5
931,5*1
(/,'9'4.,'/(
,/
,5*
+',*
8/(',/1<
%&& 2*9*4,+
G'&&
6*
4/883('4.,*2
,/
I*2>883(*
.(2
'()*+,'-.,*2
931,5*1
G',5
,5*
J1/234, T/80&.'(,
]*0.1,8*(,<
]31'(,5*
'()*+,'-.,'/(
/9
,5*
01/234,
4/80&.'(,@
.&&
'()*+,'-.,'/(.& 01/234,+
83+,
6*
+,/1*2
.,
&.6*&*2
4/(2','/(+
3(&*++
/,5*1G'+*
'(+,134,*2< J1/234,
2*9*4,+
8.D
6*
1*&.,*2
,/
4/80/(*(,@
01/234,@
/1
0.4H.-'(.(2
&.6*&'('++3*+<
=5*
&'+, 6*&/G
'(4&32*+@
63,
'+
(/,
&'8',*2
,/@
2*+41'0,'/(+
/9
01/234,
4/80&.'(,+
,5.,
+5/3&2
6*
1*0/1,*2< ^_`a_bcbd
effgch
]*9*4,
'(
4/(,.'(*1
/1
2/+'(8*45.('+8
/9
,5*
'()*+,'-.,'/(.&
01/234,<
=5* 4/80/(*(,
2*9*4,
8.D
6*
2.8.-*2@
8'++'(-@
/1
61/H*(<
T/80/(*(,
*F.80&*+
'(4&32*
)'.&+@ +,/00*1+@
4.0+@
+01.D
6.11*&+@
+01.D
(/QQ&*+@
/1
0&3(-*1+< ij_kgld
effgch
]*9*4,
'(
,5*
01/234,
',+*&9<
=5*
01/234,
.00*.1.(4*
5.+
)'+3.&
'80*19*4,'/(+ +345
.+
9/1*'-(
0.1,'4&*+@
41D+,.&&'Q.,'/(@
2'+4/&/1.,'/(@
,316'2',D@
'(+399'4'*(,
)/&38*@
/1
.(D,5'(- ,5.,
2/*+
(/,
.00&D
,/
,5*
01/234,
2*+41'0,'/(< imlnmopboqrmsctpbo
effgch
]*9*4,
'(
,5*
0.4H.-'(/1
&.6*&'(/9
,5*
01/234,<
=5*
0.4H.-'(/1 &.6*&'(2*9*4,+
8.D
6*
2.8.-*2
/1
3(1*.2.6&*@
/1
,5*
&.6*&
8.D
6*
8'++'(-< u5*(
1*0/1,'(.
01/234,
4/80&.'(,@
+',*
+,.99
83+,
6*
01*0.1*2
,/
01/)'2*
,5*
9/&&/G'(- '(9/18.,'/(v L$
T3+,/8*1
'(9/18.,'/(v
1*0/1,*1
(.8*@
.221*++@
4/(,.4,
(386*1@
.(2
2.,*
/9
4/80&.'(, \#$
J1/234,
'(9/18.,'/(v
01/234,
(.8*@
0.4H.-'(H',
(386*1
/1
&/,
(386*1@
*F0'1D
2.,*@
.(2 4&'('4.&
01/,/4/&
(386*1 :$
T/80&.'(,
'(9/18.,'/(v
4/80&.'(,
'++3*
4.,*-/1D
.(2
2*+41'0,'/( I*2>883(*
4/(,.4,
'(9/18.,'/(
9/1
1*0/1,'(01/234,
4/80&.'(,+v w8.'&v
01/234,4/80&.'(,+x8*2'883(*<4/8 \#$%&'(
)*+,"*+,-!+.*"/
)*+!00+1234+5**
6)*+!00+7,,+55**8 9:;(
)*+,"*+,-!+!!""
1:<=(
1'>4??@&'A
BBC
DEE&(
\#F%>@GE
C%?H=:<&E
3'H:FE?'&E
I&'
1'>4??@&'
J:KA L:<E$'FMN@FOA
13
PQD
."!0!
%&%'
rstuvwxyz[wz]

*5^.^*Q%@FG' 3@F_:=@?:N
`<==
N'
M@HH=<'>
NK
DMEF:a'&'G:b1'>4??@&'
4&G^ *5^.^.9%F?@=:E<%&
:&>
\#F'H:F:E<%&  
3@F_:=@?:N
<M
:
$@?:&
?%&%G=%&:=
:&E<N%>K
%c
E$'
<??@&%O=%N@=<&
L*
d:HH:
efghijk M@NG=:MM^  
| M@NG=:MM^ lmnopqrstqrumtv wxuyz{q   | \tmz|t{qzxox   | }um{omqxtqrum tmy ~uxzvtqrum tp €zvroy   |
|-------------------------------------|----------------|---|
| 3@F_:=@?:N                          | 1'><??@&'      | 3@F_:=@?:N `<== N' M@HH=<'> :M : /"" ?O _<:= M%=@E<%& c%F <&c@M<%& :cE'F ><=@E<%&^ '$' M%=@E<%& G%&E:<&M /" ?Ob?B >@F_:=@?:NA .7 ?1  $<ME<><&'b$<ME<><&' $K>F%G$=%F<>'A .0/ ?1  EF'$:=%M' ><$K>F:E'A :&> "^".ƒ 6`'<O$Eb_%=@?'8 H%=KM%FN:E' !"" <E $:M : H… %c 7^"^ '$' &%?<&:= c<== _%=@?' <M *" ?B^ 4&_'ME<O:E<%&:= HF%>@GE _<:=M :F' ME%F'> :E .†C E% !†C 6,7†9 E% 57†98 :&> ?@ME &%E N' cF%‡'&^ 3@F_:=@?:N ?@ME N' @M'> `<E$<& E$' <&><_<>@:==K :MM<O&'> ';H<FK >:E' %& E$' =:N'=^   |
| *5^.^,QE:N<=<EK                     |                |   |  
$'
>%M'
%c
>@F_:=@?:N
c%F
:>?<&<MEF:E<%&
?@ME
N'
HF'H:F'>
NK
E$'
4&_'ME<O:E%FM
%F
M<E'M >'M<O&:E'>
4\#
?:&:O'F
@M<&O
:M'HE<G
E'G$&<@'^
%E:=
E<?'
cF%?
&''>='
H@&GE@F'
%c
E$' >@F_:=@?:N
_<:=
E%
E$'
ME:FE
%c
:>?<&<MEF:E<%&
M$%@=>
&%E
';G''>(
.5
$%@FM
:E
.C
E%
!C
6,79
E%
5798 5
$%@FM
:E
F%%?
E'?H'F:E@F'
If in-use storage time exceeds these limits, a new dose must be prepared from new vials. Infusion solutions must be allowed to equilibrate to room temperature prior to commencement of administration.  
No incompatibilities between durvalumab and polyvinylchloride or polyolefin IV bags have been observed. Dose of 1500mg durvalumab for patients >30 kg will be administered using an IV bag containing 0.9% (w/v) saline, with a final durvalumab concentration ranging from 1 to 20 mg/mL, and delivered through an IV administration set with a 0.2- or 0.22-µm in-line filter.  
Remove 30.0 mL of IV solution from the IV bag prior to addition of durvalumab. Next, 30.0 mL
of durvalumab (i.e., 1500 mg of durvalumab) is added to the IV bag such that final concentration is within 1 to 20 mg/mL (IV bag volumes 100 to 1000 mL). Mix the bag by gently inverting to ensure homogeneity of the dose in the bag.  
For patients <30kg, Calculate the dose volume of durvalumab and tremelimumab and number of vials needed for the subject to achieve the accurate dose.  
Durvalumab will be administered at room temperature (approximately 25°C) by controlled infusion via an infusion pump into a peripheral or central vein. Following preparation of durvalumab, the entire contents of the IV bag should be administered as an IV infusion over approximately 60 minutes (±5 minutes), using a 0.2, or 0.22-µm in-line filter. Less than 55 minutes is considered a deviation.  
The IV line will be flushed with a volume of IV solution (0.9% [w/v] saline equal to the priming volume of the infusion set used after the contents of the IV bag are fully administered, or complete the infusion according to institutional policy to ensure the full dose is administered and document if the line was not flushed.  
Standard infusion time is 1 hour. However, if there are interruptions during infusion, the total allowed time should not exceed 8 hours at room temperature. The table below summarizes time allowances and temperatures.  
Protect from light.  
14.2.4  Dose Calculation Note: The dosing for durvalumab will be a flat dosing of 1500mg. The corresponding volume of investigational product should be rounded to the nearest tenth of a mL (0.1 mL). Each vial contains a small amount of overage and the overage should be utilized as much as possible before using another vial. The number of vials required for dose preparation is the next greatest whole number of vials from the following formula: Number of vials = Dose (mL) ÷ 20 (mL/vial)
14.2.5 Investigational Product Preparation Steps The investigational product manager or qualified personnel will be responsible for preparing the IV doses using the following steps:  
1) Select the IXRS-assigned number of vials of investigational product required to prepare the subject's dose.  
2)
All investigational product vials should be equilibrated to room temperature for 30 minutes prior to dose preparation.  
\#$%&
'()'*()
+,)
-.
/*01
23(4+1
5*6576*+)
+,)
8&4)
9&67:)
&2
3;9)4+30*+3&;*6
'(&875+
()<73()8=
>)5&;81
():&9)
+,)
9&67:)
&2
?=@A
4&837:
5,6&(38)
-.
4&67+3&;
)<739*6);+
+& +,)
5*6576*+)8
8&4)
9&67:)
&2
3;9)4+30*+3&;*6
'(&875+
2(&:
+,)
-.
/*0=
B$
C*4+6D1
*88
+,)
5*6576*+)8
8&4)
9&67:)
&2
3;9)4+30*+3&;*6
'(&875+
+&
+,)
-.
/*0=
E);+6D
:3F
+,)
4&67+3&;
3;
+,)
/*0
/D
3;9)(+3;0
7'
*;8
8&G;=
H9&38
4,*I3;0
+,)
-.
/*0
+& '()9);+
2&*:3;0=
J$C*/)64
G366
/)
'()'*()8
3;
*55&(8*;5)
G3+,
E&&8
K*;72*5+7(3;0
L(*5+35)
MEKL$=
NB="=O-;9)4+30*+3&;*6
L(&875+
-;4')5+3&;
P*5,
93*6
4)6)5+)8
2&(
8&4)
'()'*(*+3&;
4,&768
/)
3;4')5+)8= -2
+,)()
*()
*;D
8)2)5+4
;&+)8
G3+,
+,)
3;9)4+30*+3&;*6
'(&875+1
+,)
3;9)4+30*+&(
*;8
43+)
:&;3+&( 4,&768
/)
;&+323)8
3::)83*+)6D=
Q)2)(
+&
+,)
L(&875+
R&:'6*3;+
4)5+3&;
MSTUVUW$
2&(
27(+,)( 3;4+(75+3&;4= X7(3;0
+,)
3;4')5+3&;
32
+,)
4&67+3&;
34
;&+
56)*(
&(
*;D
+7(/383+D1
8345&6&(*+3&;
&(
'*(+3576*+)4
*() &/4)(9)81
;&+32D
D&7(
43+)
:&;3+&(
*;8
4+&()
+,)
93*6M4$
3;
YZHQH[%-[P
*+
()2(30)(*+)8
M"\!]R$ +):')(*+7()
2&(
8(70
*55&7;+*/363+D
*;8
'&+);+3*6
27+7()
3;4')5+3&;= [&+32D
+,)
-^Q>
+,*+
+,)
7;74*/6)
93*64
*()
8*:*0)8=
%,)
-^Q>
G366
3;835*+)
+,)
()'6*5):);+
93*64=
>)6)5+
*''(&'(3*+)
()'6*5):);+
93*64
2&(
+,)
'()'*(*+3&;
&2
+,)
47/_)5+`4
8&4)1
*;8
')(2&(: +,)
4*:)
3;4')5+3&;
&;
+,)
;)G6D
4)6)5+)8
93*64=
a&(
*55&7;+*/363+D1
()5&(8
+,)
+&+*6
;7:/)(
&2 93*64
():&9)8
2(&:
43+)
3;9);+&(D=
Z4)8
93*64
4,&768
/)
,)68
2&(
*55&7;+*/363+D
'7('&4)4
*+ *:/3);+
4+&(*0)
+):')(*+7()= NB="=b-;9)4+30*+3&;*6
L(&875+
H55&7;+*/363+D %,)
3;9)4+30*+&(`4
&(
43+)`4
8)430;*+)8
3;9)4+30*+3&;*6
'(&875+
:*;*0)(
34
()<73()8
+&
:*3;+*3; *557(*+)
3;9)4+30*+3&;*6
'(&875+
*55&7;+*/363+D
()5&(84=
Z'&;
5&:'6)+3&;
&2
+,)
4+78D1
5&'3)4
&2 3;9)4+30*+3&;*6
'(&875+
*55&7;+*/363+D
()5&(84
G366
/)
()+7(;)8
+&
K)8-::7;)=
H66
7;74)8 3;9)4+30*+3&;*6
'(&875+
G366
/)
()+7(;)8
+&
*
K)8-::7;)\*7+,&(3c)8
8)'&+
&(
834'&4)8
&2
7'&; *7+,&(3c*+3&;
/D
K)8-::7;)= NB="=!Q)'&(+3;0
L(&875+
R&:'6*3;+4 H;D
8)2)5+4
G3+,
+,)
3;9)4+30*+3&;*6
'(&875+
:74+
/)
()'&(+)8
deefgdhifjk
+&
+,)
K)8-::7;) L(&875+
R&:'6*3;+
X)'*(+:);+
/D
+,)
43+)
G3+,
27(+,)(
;&+3235*+3&;
+&
+,)
43+)
:&;3+&(=
H66 8)2)5+4
G366
/)
5&::7;35*+)8
+&
K)8-::7;)
*;8
3;9)4+30*+)8
27(+,)(
G3+,
+,)
L(&875+ R&:'6*3;+
X)'*(+:);+=
X7(3;0
+,)
3;9)4+30*+3&;
&2
+,)
'(&875+
5&:'6*3;+1
*66
3;9)4+30*+3&;*6 '(&875+4
:74+
/)
4+&()8
*+
6*/)6)8
5&;83+3&;4
7;6)44
&+,)(G34)
3;4+(75+)8= L(&875+
8)2)5+4
:*D
/)
()6*+)8
+&
5&:'&;);+1
'(&875+1
&(
'*5I*03;0
*;8
6*/)63;0
3447)4=
%,)
634+ /)6&G
3;5678)41
/7+
34
;&+
63:3+)8
+&1
8)45(3'+3&;4
&2
'(&875+
5&:'6*3;+4
+,*+
4,&768
/)
()'&(+)8= lmnompqpr
sttuqv
X)2)5+
3;
5&;+*3;)(
&(
8&43;0
:)5,*;34:
&2
+,)
3;9)4+30*+3&;*6
'(&875+=
%,) 5&:'&;);+
8)2)5+
:*D
/)
8*:*0)81
:3443;01
&(
/(&I);=
R&:'&;);+
)F*:'6)4
3;5678)
93*641 4+&'')(41
5*'41
4'(*D
/*(()641
4'(*D
;&cc6)41
&(
'67;0)(4= wxmyuzr
sttuqv
X)2)5+
3;
+,)
'(&875+
3+4)62=
%,)
'(&875+
*'')*(*;5)
,*4
9347*6
3:')(2)5+3&;4 475,
*4
2&()30;
'*(+356)41
5(D4+*663c*+3&;1
8345&6&(*+3&;1
+7(/383+D1
3;4722353);+
9&67:)1
&(
*;D+,3;0 +,*+
8&)4
;&+
*''6D
+&
+,)
'(&875+
8)45(3'+3&;= \#$%&$'()'*+$,-.()'
/001-2
345467
89
7:4
;<6=<>89>
?@
A<B4A89>
?5
7:4
;@?CD67E
F:4
;<6=<>89>
?@ A<B4A89>
C45467G
H<I
B4
C<H<>4C
?@
D9@4<C<BA4J
?@
7:4
A<B4A
H<I
B4
H8GG89>E K:49
@4;?@789>
<
;@?CD67
6?H;A<897J
G874
G7<55
HDG7
B4
;@4;<@4C
7?
;@?L8C4
7:4
5?AA?M89> 895?@H<78?9N OP
QDG7?H4@
895?@H<78?9N
@4;?@74@
9<H4J
<CC@4GGJ
6?97<67
9DHB4@J
<9C
C<74
?5
6?H;A<897 RP
S@?CD67
895?@H<78?9N
;@?CD67
9<H4J
;<6=<>89>
=87
9DHB4@
?@
A?7
9DHB4@J
4T;8@I
C<74J
<9C 6A8986<A
;@?7?6?A
9DHB4@ "P
Q?H;A<897
895?@H<78?9N
6?H;A<897
8GGD4
6<74>?@I
<9C
C4G6@8;78?9 U4CVHHD94
6?97<67
895?@H<78?9
5?@
@4;?@789>
;@?CD67
6?H;A<897GN
WH<8AN
;@?CD676?H;A<897GXH4C8HHD94E6?H S:?94N
YOZ"[OZ"\!ZRO[]
YOZ!^^ZUW3VZ_OO
`YOZ!^^Za""Z__OOP
b<TN
YOZ"[OZ"\!Z!![[
U<8AN
U4CVHHD94J
ccQ
d779N
S@?CD67
Q?H;A<897
34;<@7H497
e94
U4CVHHD94
K<IJ f<87:4@GBD@>J
U3
ghd
R[!^!  
#$ %&'&%&()&*
+, -./0123
4,5,3
67
.8,3
9:;<=>;<?@
;AB
CDEFG
H>?HBE
IJEGB?K
LFDIDH>?
MNNNO
P27
Q
R.2S6/3 TUU+,
VWXTYZ
[,
+\]^_,
T, `8ab673
Q,5,3
67
.8,3
cB:<@?
>?G
B?GdD<?;:
De
HF<?<H>F
;E<>F:
<?
ABd>;DHBFFJF>E
H>EH<?D=>O
Q
f.78
R.2S6/
P2g73
TUU!,
\#hhX+UYZ
[,
_i!^j++,
], k.27all3
-,m,3
67
.8,3
n<dJFBJHBFop
<==J?D;ABE>dq
eDE
H>:;E>;<D?oEB:<:;>?;
dED:;>;B
H>?HBEO
f
r2s8
Q
56t3
TU+U,
uvuX\YZ
[,
"++^TT,
", wat13
x,y,3
67
.8,3
z=dED{BG
:JE{<{>F
C<;A
<d<F<=J=>I
<?
d>;<B?;:
C<;A
=B;>:;>;<H
=BF>?D=>O
f
r2s8
Q
56t3
TU+U,
uvuX!YZ
[,
j++^T],  
\, |a}6/73
R,3
67
.8,3
zd<F<=J=>I
dFJ:
G>H>EI>~<?B
eDE
dEB{<DJ:Fq
J?;EB>;BG
=B;>:;>;<H
=BF>?D=>O
f
r2s8
Q
56t3
TU++,
uvWXT_YZ
[,
T\+j^T_,
_, w.2..23
4,
.2t
|,,
m612}6/s3
>FF=>E:
De
H>?HBEK
;AB
?B;
@B?BE>;<D?O
R6883
TU++,
\#WWX\YZ
[,
_"_^j",
j, -./ta883
4,5,3
pAB
IFDH>GB
De
<==J?B
HABHdD<?;:
<?
H>?HBE
<==J?D;ABE>dqO
f.7
|6b R.2S6/3
TU+T,
\#X"YZ
[,
T\T^_",  
!, -ag7a3
5,,3
67
.8,3
z==J?DFD@<H
HDEEBF>;B:
De
;AB
>I:HDd>F
BeeBH;
<?
>
d>;<B?;
C<;A
=BF>?D=>O
f
r2s8
Q
56t,
uvvX+UYZ
[,
iT\^]+,
i, t62
/a03
5,w,3
67
.8,3
9ee<H<B?;
FD>G<?@
De
GB?GE<;<H
HBFF:
eDFFDC<?@
HEqD
>?G
E>G<DeEBJB?Hq
>IF>;<D?
<?
HD=I<?>;<D?
C<;A
<==J?B
=DGJF>;<D?
<?GJHB:
>?;<o;J=DJE <==J?<;qO
/
Q
R.2S6/3
TUU_,
V$XjYZ
[,
!i_^iU\,
+U, 6/}1213
,3
67
.8,3
>G<DeEBJB?Hq
;ABE=>F
>IF>;<D?
De
ABd>;DHBFFJF>E
H>EH<?D=>
F<{BE
?DGJFB:
H>?
>H;<{>;B
>?G
B?A>?HB
;J=DEo:dBH<e<H
poHBFF
EB:dD?:B:O
R.2S6/
|6g3
TUU_, vvXTYZ
[,
++]i^"_,
++, 6/}1213
,3
67
.8,3
z?HEB>:BG
<==J?D:;<=JF>;DEq
>H;<{<;q
HD?eBEEBG
;D
>?;<@B?odEB:B?;<?@
HBFF:
Iq
BdD:JEB
;D
>?;<@B?
B;E>H;
eED=
ABd>;DHBFFJF>E
H>EH<?D=>
>e;BE
E>G<DeEBJB?Hq ;ABE=>F
>IF>;<D?O
Q
P2a76/3
TUU!,
u\#X]YZ
[,
Tj+^!T,
+T, w.2g86/3
Q,3
67
.8,3
H;<{>;<D?
>?G
GE>=>;<H>FFq
<?HEB>:BG
Hq;DFq;<H
>H;<{<;q
De
;J=DE
:dBH<e<H
p
Fq=dADHq;B:
>e;BE
E>G<DoeEBJB?Hq
>IF>;<D?
<?
d>;<B?;:
C<;A
ABd>;DHBFFJF>E H>EH<?D=>
>?G
HDFDEBH;>F
F<{BE
=B;>:;>:B:O
ma/8t
Q
.g7/a6276/a83
TUU_,
\#XT]YZ
[,
]j+_^ T+,
+], w1/a1g13
k,3
67
.8,3
n;ED?@
c
poHBFF
EB:dD?:B:
>@><?:;
;J=DEo>::DH<>;BG
>?;<@B?:
dEDFD?@
;AB
EBHJEEB?HBoeEBB
<?;BE{>F
>e;BE
;J=DE
;EB>;=B?;
<?
d>;<B?;:
C<;A
ABd>;DHBFFJF>E H>EH<?D=>O
Q
.g7/a6276/a83
TU+U,
W$X"YZ
[,
"\+^!,
+", Qa2ga23
r,r,3
67
.8,3
>G<DeEBJB?Hq
>IF>;<D?
HD=I<?BG
C<;A
nozM
<==J?DHq;D<?B
9c
MN
EB:JF;:
<?
>?
B?A>?HBG
>?;<;J=DE
BeeBH;
>@><?:;
=JE<?B
HDFD? >GB?DH>EH<?D=>O
R812
R.2S6/
|6g3
TUUi,
\#$X+\YZ
[,
"!j\^!",
\#"$ %&'()*+,
-$.$,
/0
)1$,
23456789:;9<=>
3?@3A56<
67
=6@689=A3@
@5B98
C9A3DA3D9D
5<4;=9D
3<
5<7@3CC3A68>
89DE6<D9
5<
45DA3<A
F9E3A5=
C9A3DA3D9D
?;A
<6A
5<
@6=3@
3==9@983A94 6;AG86HAFI
J
KLMN
OPQR1,
ST\#T$
UVUWXYZ
+$
""\#[\$
\#\$ ]^)ML,
_$,
/0
)1$,
`<C3Da5<G
67
3@EF3b79A6E86A95<bDE9=575=
cdefgh
i
=9@@
89DE6<D9D
5<
F9E3A6=9@@;@38
=38=5<6C3
E3A59<AD
;<498G65<G
9C?6@5j3A56<I
J
k**LPR1,
STTX$
UlmWnYZ
+$ \#o\#p[SS$
\#X$ -&qL(Rrs&,
t$,
/0
)1$,
c6CE383A5B9
3<3@>D5D
67
B3856;D
A;C68b3DD6=53A94
3<A5G9<bDE9=575=
Ab=9@@
89DE6<D9D
5<
E3A59<AD
H5AF
F9E3A6=9@@;@38
=38=5<6C3I
u/+)0R1RN^,
ST\#\#$
vwWpYZ
+$ \#ST\[\#\$
\#!$ xMR*&,
K$]$,
/0
)1$,
23456789:;9<=>
3?@3A56<
5<4;=9D
3<A5G9<bE89D9<A5<G
=9@@
5<75@A83A56<
3<4
3CE@575=3A56<
67
H93a
A;C68b5<4;=94
5CC;<5A>I
y)z&R1RN^,
STTo$
{vUW\#YZ
+$
"![\\$
\#o$ KR)P/r,
.$]$,
y$J$
]|1&P,
)Pz
-$J$
}RPz/M,
29C5DD56<
67
C9A3DA3A5=
@9D56<D
76@@6H5<G
=8>6D;8G98>
5<
E86DA3A5=
=3<=98~
5CC;<6@6G5=
=6<D54983A56<DI
J
MR1,
\#oXT$
UVW\#YZ
+$ \#"p[o$
ST$ KR)P/r,
.$]$,
-$J$
}RPz/M,
)Pz
y$J$
]|1&P,  
E6DD5?@9
5CC;<6b=8>6AF98C5=
89DE6<D9
5<
E86DA3A5=
=3<=98I
1&P
y)z&R1,
\#oXT$
{UWnYZ
+$
S"n["$
S\#$ K)PQs/q[OM0&q,
y$$,
/0
)1$,
E6<A3<96;D
89G89DD56<
67
E;@C6<38>
C9A3DA3D9D
786C
89<3@
=9@@
=38=5<6C3
37A98
83456
789:;9<=>
3?@3A56<
67
E85C38>
A;C68~
3<
5<
D5A;
A;C68 B3==5<9
J
MR1,
STTn$
UlVW\#YZ
+$
\#X![o$
SS$ .)&0q,
y$,
/0
)1$,
6A9<A
5<4;=A56<
67
A;C68
5CC;<5A>
?>
=6C?5<5<G
A;C68
=8>63?@3A56<
H5AF
3<A5bcibe
AF983E>I
)PQ/M
y/r,
ST\#S$
l{WSYZ
+$
pnT[o$
Sn$ z/P
MR(,
-$u$,
/0
)1$,
><98G>
?9AH99<
5<
D5A;
=8>63?@3A56<
3<4
i2
DA5C;@3A56<
89D;@AD
5<
3
F5GF@>
9779=A5B9
5<
B5B6
49<485A5=
=9@@
B3==5<9I
)PQ/M
y/r,
STT\$
W\#pYZ
+$
XS!"[oS$
Sp$ -Q%//1,
x$}$,
/0
)1$,
F3D9  
A853@
67
A89C9@5C;C3?
5<
=6C?5<3A56<
H5AF
DF68AbA98C
3<486G9<
49E85B3A56<
5<
E3A59<AD
H5AF
b89=;889<A
E86DA3A9
=3<=98I
)PQ/M
k**LPR1 k**LPR0s/M,
ST\#S$
UWXYZ
+$
\#\#nX[pX$
S"$ )Ms&P&,
]$]$,
/0
)1$,
379A>
3<4
9775=3=>
67
=6C?5<3A56<
5CC;<6AF983E>
H5AF
5<A987986<
3@73b?
3<4
A89C9@5C;C3?
5<
E3A59<AD
H5AF
DA3G9  
C9@3<6C3I
J
1&P
OPQR1,
ST\#S$
wVWnYZ
+$
nSS[!$
S\$ ON)P/r^)P,
$,
/0
)1$,
A8;=A;83@
=F383=A985j3A56<
67
3
F;C3<
=
783GC9<A
9<G5<99894
768
@3=a
67
9779=A68
7;<=A56<DI
]Q0)
M^r0)11RNM)+s&Q)
K/Q0&RP
x[&R1RN&Q)1
M^r0)11RNM)+s^, STT!$
Z
+$
XTT[XTp$
SX$ K)PNMR,
$,
/0
)1$,  
=@5<5=3@
A853@
67
cibe
?@6=a349
H5AF
A89C9@5C;C3?
5<
E3A59<AD
H5AF
F9E3A6=9@@;@38
=38=5<6C3
3<4
=F86<5=
F9E3A5A5D
cI
J
u/+)0R1,
ST\#n$
vW\#YZ
+$
!\#[!$
S!$ /1/M,
$,
/0
)1$,
=A5B5A>
3<4
D379A>
67
cibe
?@6=a349
=6C?5<94
H5AF
B3==5<9D
5<
=><6C6@G;D
C3=3:;9DI
J
k**LPR1,
STTn$
UlUW\#\#YZ
+$
\S"\#[o$
So$ x)P&1R&Q,
x$_$,
/0
)1$,
c6889@3A56<D
67
cibe
G9<9
E6@>C68EF5DCD
3<4
F9E3A5A5D
c
=F86<5=
5<79=A56<I
_&/M
kP0,
ST\#S$
w{W"YZ
+$
!Tn[!$
\#$% &'()
*%)
+,
'-%)
.//01234205/
6748775
194040:21
;
<9=>?01947@3//012347A
3542B75@C
>0<9=0D>?2/=/
35A
/7DE=
4E=0D
571D0/2/
F3140D@3<>?3
35A
2547DF7D05@B3==3
<7G7</
25 >342754/
824?
1?D0521
?7>34242/
H
G2DE/
25F714205I
J(K-'LL
M+N)
O$PP%
QRSPPTU
V%
P$WPX!%
\#P% YZ,[\]+-)
^%)
+,
'-%)
_21D0620=7
35A
.54213517D
`==E50/EDG72<<3517I
a+--)
O$P"%
bQcSOTU
V%
OW"XO!W%
\#O% deN,Z(
f%
geKKh)
i%j%k%XM%)
lZm
n
o+pq'p)
g'[Zm
r
o-+Z(+p)
les'((+
tZ\p'['(,Z)
k+-ZNN'
u'-q+p)
l,+Vv'(Z+
a'p+h)
uZ--Z'L
g\e]-'N
tZ]])
l+,v
k%
l,+Z(w+p])
jZx,\pZ'
d(m+pN\() y'mZ(+
dwZXz'\em+v)
r--Z\,
^+[Z)
{p'mK\pm
z%
u\\m)
|ZL
t%
fp+,+()
.
>2<04
/4EA9
0F 4D7=7<2=E=36
}
3
=0501<053<
354260A9
3B325/4
~;.@C
}
25
10=62534205
824?
724?7D 4D35/
134?747D
3D47D23<
1?7=07=60<234205
;.~
0D
D3A20FD7E7519
36<34205
.
25 >342754/
824?
?7>34017<<E<3D
13D1250=3
~~I
z
a-Z(
i(x\O$P%
%
\#\#% geKKh)
d%f%)
+,
'-%)
;D7=7<2=E=36
25
10=62534205
824?
36<34205
25
>342754/
824?  
3AG3517A
?7>34017<<E<3D
13D1250=3I
z\ep('\K
&+V',\-\]h)
O$PW%
QQS\#TU
V%
XP%
\#% {p'vL+p)
z%M%)
+,
'-%)
3F749
35A
3142G249
0F
3542@@
354260A9
25
>342754/
824?  
3AG3517A
13517DI
y
r(]z
k+m)
O$PO%
QQSO"TU
V%
OX"%
\#% |\V'-Z'()
l%^%)
+,
'-%)
3F749
3142G249
35A
2==E57
10DD7<347/
0F
3542@@
354260A9
25 13517DI
y
r(]z
k+m)
O$PO%
QQSO"TU
V%
O\#X%
\#"% o\p'(]h)
t%)
+,
'-%)
>0543570E/
4E=0D@/>712F21
?E=0D3<
35A
17<<E<3D
2==E57
D7/>05/7/
40
@@
25
?7>34017<<E<3D
13D1250=3I
a-Z(
a'(x+p
M+N)
O$$%
bRSP\#TU
V%
\#\#OXP%
\#W% rZN+(v'e+p)
r%d%)
+,
'-%)
78
D7/>05/7
7G3<E34205
1D247D23
25
/0<2A
4E=0ED/
7G2/7A
~`;
BE2A7<257
G7D/205
II
rep\V+'(
z\ep('\K
a'(x+p)
O$$%
cSOTU
V%
OO!XOW%
\#!% MeN,Z()
f%z%l%)
+,
'-%)
7
78
BE2A7<257/
40
7G3<E347
4?7
D7/>05/7
40
4D734=754
25
/0<2A
4E=0D/
0G3D235
13517DI
z\ep('\K
,v+
y',Z\('a'(x+p
J(N,Z,e,+)
O$$%
QS"TU
V%
!WX !!%
\#% {ew-+h)
f%z%)
+,
'-%)
<2B262<249
35A
D7/>05/7
BE2A7<257/
F0D
>?3/7
``
1<25213<
4D23</
25 35AD0B75@25A7>75A754
>D0/4347
13517D
710==75A34205/
FD0=
4?7
>D0/4347@/>712F21 3542B75
80D25B
BD0E>I
z\ep('\K
a-Z(Zx'i(x\-\]h)
P%
bSPPTU
V%
\#"PX\#"W%
$% lxv+p)
&%J%)
+,
'-%)
7/2B5
35A
75A
>0254/
0F
1<25213<
4D23</
F0D
>342754/
824?
>D0BD7//2G7
>D0/4347
13517D
35A
13/4D347
<7G7</
0F
47/40/47D057
710==75A34205/
0F
4?7
>D0/4347 13517D
1<25213<
4D23</
80D25B
BD0E>I
z\ep('\K
a-Z(Zx'i(x\-\]h)
O$$!%
QSWTU
V%
PP!X PP%
P% j+p]\,+)
J%)
+,
'-%)
7
78
BE2A7<257/
40
7G3<E347
4?7
D7/>05/7
40
4D734=754
25
/0<2A
4E=0D/
0G3D235
13517DI
z\ep('\K
,v+
y',Z\('a'(x+p
J(N,Z,e,+)
O$$$%
SP!TU
V%
P\#X P\#%
O% geKKh)
d%f%)
+,
'-%)
.
>?3/7
``
/4EA9
0F
;~
25
>342754/
824?
?7>34017<<E<3D
13D1250=3 8?0
?3G7
>D0BD7//7A
05
/0D3F7526I
(Z,+m
rep\V+'(
f'N,p\+(,+p\z)
O$P%
STU
V%
\#X "P%
\#% -'v'(('()
l%j%)
+,
'-%)
`A7542F2134205
0F
3142G7
1?7=04?7D3>9
D7B2=75/
25
3AG3517A
62<23D9
4D314
13D1250=3
3
D7G278
0F
1?7=04?7D3>9
4D23</
25
4?7
>3/4
480
A713A7/I
&+V', i(x\-)
O$P%
SPTU
V%
\#X$%
#$ %&&'()*+', #$-#.//01234
.
5&'67869%(+'
,:%:;,
+6*:'6*%  
| IJK20                               | L0MNJ3/O3P1M                                                                                                                                                                                                                                       |
|-------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| RPJSKT KNO3U3OVW XYTTV KNO3U0Z K[T0 |                                                                                                                                                                                                                                                    |
| Q                                   | OP NKJJV P1 KTT /J0\23M0KM0 /0J]PJSK1N0 ^3O_PYO J0MOJ3NO3P1W aVS/OPSMZ [YO KS[YTKOPJVW b0MOJ3NO02 31 /_VM3NKTTV MOJ01YPYM KNO3U3OVZ [YO KS[YTKOPJV K12 K[T0 OP NKJJV PYO ^PJc P] K T3d_O PJ M0201OKJV 1KOYJ0 e0WdWZ T3d_O _PYM0^PJcZ P]]3N0 ^PJcfW |
| `                                   | h1 [02 ijQk P] O_0 O3S0W .S[YTKOPJV K12 NK/K[T0 P] KTT M0T]\NKJ0Z [YO Y1K[T0 OP NKJJV PYO K1V ^PJc KNO3U3O30MW l/ K12 K[PYO SPJ0 O_K1 jQk P] ^Kc31d _PYJMW                                                                                         |
| g                                   | h1 [02 njQk P] O_0 O3S0W oK/K[T0 P] P1TV T3S3O02 M0T]\NKJ0Z NP1]3102 OP [02 PJ N_K3J SPJ0 O_K1 jQk P] ^Kc31d _PYJMW                                                                                                                                |
| m                                   | `QQk [02J32201W oPS/T0O0TV 23MK[T02W oK11PO NKJJV P1 K1V M0T]\NKJ0W qPOKTTV NP1]3102 OP [02 PJ N_K3JW                                                                                                                                              |
| p j                                 | L0K2W                                                                                                                                                                                                                                              |
%&%'
'+8<

&=>?@>Abcd=
,Ebefg
,Dbh=  
\#$-r
%&&'()*s
t
5
+u*v)5&;<u
+v%,,*7*+%:*8(
,w,:'9  
| Points assigned   |                 |                 |           |
|-------------------|-----------------|-----------------|-----------|
| Parameter         | 1               | 2               | 3         |
| Ascites           | Absent          | Slight          | Moderate  |
| Bilirubin         | <2 mg/dL        | 2-3 mg/dL       | > mg/dL   |
| (34.2             | (34.2 to 51.3   | (>51.3          |           |
| micromol/liter)   | micromol/liter) | micromol/liter) |           |
| Albumin           | >.3.5 g/dL (35  | 2.8-3.5 g/dL    | <2.8 g/dL |
| g/liter)          | (28 to 35       | ( <28 g/liter)  |           |
| g/liter)          |                 |                 |           |
| Prothrombin time  |                 |                 |           |
| Seconds over      | <4              | 4-6             | >6>       |
| control           |                 |                 |           |
| INR               | <1.7            | 1.7-2.3         | >2.3      |
| Ence phalopathy   | None            | Grade 1-2       | Grade 3-4 |  
Modified Child-Pugh classification of the severity of liver disease according to the degree of ascites, the plasma concentrations of bilirubin and albumin, the prothrombin time, and the degree of encephalopathy. A total score of 56 is considered grade A (well-compensated disease); 7-9 is grade B (significant functional compromise); and 10-15 is grade C (decompensated disease). These grades correlate with one- and two-year patient survival: grade A - 100 and 85 percent; grade B - 80 and 60 percent; and grade C - 45 and 35 percent.  
#$%&
'(()*+,./
01+,2,)+
,003*)45)6'7)+
5)8(1*8)
.5,7)5,'
9,55.:
;<=>
?@A
BCD>>=E=BDF=G?
=>
HD>@I
G?
F<@
J@B@?F
C@DJ?=?K
EJGL
BC=?=BDC
>FMI=@>
A=F<
BD?B@J =LLM?GF<@JDN=@>
F<DF
@O@?
=E
>GL@
?@A
C@>=G?>
DNN@DJ
DF
F<@
H@K=??=?K
GE
D
FJ@DFL@?F
GJ
=E
F<@ FGFDC
FMLGJ
HMJI@?
IG@>
?GF
=?BJ@D>@
>MH>FD?F=DCCPQ
FMLGJ
J@KJ@>>=G?>
GJ
>FDH=C=RDF=G?>
L=K<F
>F=CC GBBMJ
CDF@JS
;<@
=JTU
A@J@
BJ@DF@I
M>=?K
H=VI=L@?>=G?DC
L@D>MJ@L@?F>
WD>
NJ@O=GM>CP
A=I@CP M>@I
=?
F<@
XGJCI
Y@DCF<
ZJKD?=RDF=G?
BJ=F@J=D[S
\GJ
F<=>
FJ=DCQ
F<@
BG?B@NF>
GE
F<@
=JTU
DJ@ BGLH=?@I
A=F<
T]U^_;
`S`
FG
BGL@
MN
A=F<
F<@
LGI=E=@I
=JTUS \GJ
LGI=E=@I
=JTUQ
G?CP
FDJK@F
D?I
L@D>MJDHC@
C@>=G?>
DJ@
FDa@?
=?FG
DBBGM?FS
^?
BG?FJD>F
FG
F<@ T]U^_;
`S`
BJ=F@J=DQ
F<@
LGI=E=@I
=JTU
BJ=F@J=D
WD[
J@bM=J@
BG?E=JLDF=G?
GE
HGF<
NJGKJ@>>=G?
D?I J@>NG?>@
HP
=LDK=?K
DF
c
A@@a>
DEF@J
=?=F=DC
=LDK=?K
D?I
WH[
IG
?GF
?@B@>>DJ=CP
>BGJ@
F<@ DNN@DJD?B@
GE
?@A
C@>=G?>
D>
NJGKJ@>>=O@
I=>@D>@
=E
F<@
>ML
GE
C@>=G?
I=DL@F@J>
GE
FDJK@F
C@>=G?> WL=?=LML
GE
`d
LL
N@J
C@>=G?Q
LDe=LML
GE
f
FDJK@F
C@>=G?>Q
LDe=LML
GE
g
N@J
GJKD?[
D?I L@D>MJDHC@
?@A
C@>=G?>
IG@>
?GF
=?BJ@D>@
HP
h
gdiS ;<@
>DL@
L@F<GI
GE
D>>@>>L@?F
D?I
F<@
>DL@
F@B<?=bM@
><GMCI
H@
M>@I
FG
B<DJDBF@J=R@
@DB< =I@?F=E=@I
D?I
J@NGJF@I
FDJK@F
C@>=G?W>[
DF
HD>@C=?@Q
IMJ=?K
F<@
FJ=DCQ
D?I
DF
F<@
@?I
GE
FJ=DC
O=>=FS jCC
L@D>MJ@L@?F>
><GMCI
H@
J@BGJI@I
=?
L@FJ=B
?GFDF=G?S
;<@
LGI=E=@I
=JTU
HD>@I
G?
T]U^_; `S`
DJ@
I=>NCDP@I
H@CGAS  
| Measurable Response                                                           | Non-Measurable Response                                                                                  | Overall Response   |       |
|-------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------|--------------------|-------|
| Using Modified irRC                                                           |                                                                                                          |                    |       |
| Index and New, Measurable                                                     | Non-Index Lesions                                                                                        | New, Non-          |       |
| Lesions (Tumor Burden)¹                                                       | Measurable Lesions                                                                                       |                    |       |
| Decrease 100%                                                                 | Absent                                                                                                   | Absent             | irCR² |
| irPR²                                                                         |                                                                                                          |                    |       |
| Decrease 100%                                                                 | Stable                                                                                                   | Any                |       |
| Unequivocal progression                                                       | irPR 2                                                                                                   |                    |       |
| Decrease 100%                                                                 | Any                                                                                                      |                    |       |
| Decrease ≥ 30%                                                                | Absent / Stable                                                                                          | Any                | irPR² |
| irPR²                                                                         |                                                                                                          |                    |       |
| Decrease ≥ 30%                                                                | Unequivocal progression                                                                                  | Any                |       |
| Decrease < 30% to increase <                                                  | Absent / Stable                                                                                          | Any                | irSD  |
| 20%                                                                           |                                                                                                          |                    |       |
| Decrease < 30% to increase <                                                  | Unequivocal progression                                                                                  | Any                | irSD  |
| 20%                                                                           | irPD                                                                                                     |                    |       |
| Increase ≥ 20%                                                                | Any                                                                                                      | Any                |       |
| Decreases assessed relative to baseline                                       |                                                                                                          |                    |       |
| 2                                                                             | Assuming that the response (irCR and irPR) and progression (irPD) are confirmed by a second, consecutive |                    |       |
| assessment at least 4 weeks apart (normally it should be done 6 weeks apart). |                                                                                                          |                    |       |  
Overall Responses Derived from Changes in Index, Non-Index, and New Lesions  
#$%&
'(()*+,+
.
/)+,//0*)
1'/(2)
(3)('3'4,5*
(356)+03)1
789:;<
77=
=:>8 "?@9AB
;ACD;:;
EFG:;8
FH
>GFFI
DJKF
LFGI
KFM
77=
K:>8
NOP?
Q8RF9I
KD;8
FH
RFGG8RKDFJ? S?T8JKGU
DJE89K
V
KD;8O? W?XGGFB
KY8
>GFFI
KF
RGFK
HF9
WZ
;DJ:K8O
AK
9FF;
K8;M89AK:98? [?\8JK9DH:L8
BDKYDJ
S
YF:9O
FH
RFGG8RKDFJ
AK
""ZZ
<"WZZ
L
HF9
"V
;DJ:K8O? V?=9AJOH89
O89:;
DJKF
GA>8G8I
R9UFEDAGO? ]?^;;8IDAK8GU
H988_8
KY8
R9UFEDAGO
:M9DLYK
AK
<SZ`\
F9
RFGI89? a?7KF98
AK
<SZ`\
F9
RFGI89
:JKDG
OYDM;8JK
FJ
I9U
DR8?
%&%'
bgaoa<

Cs
D@=X
=:>8  
"?
@9AB
;ACD;:;
EFG:;8
FH
>GFFI
DJKF
GAE8JI89
KFM
cS
d@=X
K:>8NOP?
Q8RF9I
KD;8
FH
RFGG8RKDFJ
S?T8JKGU
DJE89K
e
KF
"Z
KD;8O? W?\8JK9DH:L8
BDKYDJ
S
YF:9O
FH
RFGG8RKDFJ
AK
""ZZ
<"WZZ
L
HF9
"Z
;DJ:K8O? [?=9AJOH89
MGAO;A
DJKF
GA>8G8I
R9UFEDAGO? V?^;;8IDAK8GU
H988_8
KY8
R9UFEDAGO
:M9DLYK
AK
<SZ`\
F9
RFGI89? ]?7KF98
AK
<SZ`\
F9
RFGI89
:JKDG
OYDM;8JK
FJ
I9U
DR8? =:>8
fA>8G
OYF:GI
DJRG:I8g "?
bAKD8JK
^I8JKDHD89 S?
7A;MG8
^@
N789:;
"h
\URG8
"h
@AU
"8KR?P W?
7A;MG8
KUM8
NMGAO;Ah
O89:;P [?
7A;MG8
EFG:;8 V?
\FGG8RKDFJ
KD;8 ]?
iA9RFI8
NDH
KYDO
OUOK8;
DO
AEADGA>G8P  
#$%&'(()*+,)
.
+'/'
0122)0/,1*
)2)3)*/4
5)67,5)+
89
3'*7:'0/75)5
;<=>?@>
>=>AB@
CDEE
F>
?>GH?<><
I@DAJ
K
?>GHJADL><
M><DGKE
B>?M
H?
<DKJAH@D@
BNKB
KGGI?KB>EO ?>PE>GB@
BN>
>=>ABQ
;<=>?@>
>=>AB@
CDEE
F>
K@@>@@><
FO
BN>
DA=>@BDJKBH?
PH?
@>=>?DBOR
?>EKBDHA@NDS
BH BN>
DA=>@BDJKBDHAKE
S?H<IGBR
SH@@DFE>
>BDHEHJD>@R
KA<
CN>BN>?
BN>
>=>AB
M>>B@
G?DB>?DK
HP
KA
T;U KA<
BN>?>PH?>
?>VID?>@
DMM><DKB>
AHBDPDGKBDHA
BH
;@B?KW>A>GKXY><ZMMIA>
[KBD>AB
TKP>BOQ /\]
^_``_abcd
efgbfh`]i
ab``
h]
j_``]jk]l
^_g
]fj\
')m n ;U
opqp;U
=>?@DHA
rQst n qN>
<KB>
KA<
BDM>
CN>A
BN>
;U
@BK?B><
KA<
@BHSS><  
n pNKAJ>@
DA
upZ
pqp;U
J?K<>
KA<
BN>
MKvDMIM
pqp
J?K<>
KBBKDA>< n wN>BN>?
BN>
;U
D@
@>?DHI@
H?
AHB n ZA=>@BDJKBH?
GKI@KEDBO
?KBDAJ
KJKDA@B
<I?=KEIMKF
H?
B?>M>EDMIMKF
oO>@
H?
AHt n ;GBDHA
BKx>A
CDBN
?>JK?<
BH
<I?=KEIMKF
y
B?>M>EDMIMKFX
GHMFDAKBDHA
KJ>AB n zIBGHM>
,c
fllbkb_c{
k\]
^_``_abcd
efgbfh`]i
ab``
h]
j_``]jk]l
^_g
4')i
fi
f||`bjfh`]m n }KB>
;U
M>B
G?DB>?DK
PH?
@>?DHI@
;U n }KB>
ZA=>@BDJKBH?
F>GKM>
KCK?>
HP
@>?DHI@
;U  
n ;U
D@
@>?DHI@
<I>
BH
S?HBHGHE
BN>?KSOQ n }KB>
HP
NH@SDBKEDLKBDHA n }KB>
HP
<D@GNK?J> n [?HFKFE>
GKI@>
HP
<>KBN n }KB>
HP
<>KBN n ;IBHS@O
S>?PH?M>< n }>@G?DSBDHA
HP
;U n pKI@KEDBO
K@@>@@M>AB
DA
?>EKBDHA
BH
TBI<O
S?HG><I?>o@t
U=>AB@R
CNDGN
K?>
IA>VID=HGKEEO
<I>
BH
<D@>K@>
S?HJ?>@@DHAR
@NHIE<
AHB
F>
?>SH?B><
K@
KA
;U <I?DAJ
BN>
@BI<OQ 4k~l
g]j_glbcd
|]gb_l
fcl
^_``_a.~|
^_g
fle]gi]
]e]cki
fcl
i]gb_~i
fle]gi]
]e]cki ;<=>?@>
>=>AB@
KA<
@>?DHI@
K<=>?@>
>=>AB@
CDEE
F>
?>GH?<><
P?HM
BDM>
HP
@DJAKBI?>
HP
DAPH?M>< GHA@>ABR
BN?HIJNHIB
BN>
B?>KBM>AB
S>?DH<
KA<
DAGEI<DAJ
BN>
PHEEHCIS
S>?DH<
o!s
<KO@
KPB>?
BN> EK@B
<H@>
HP
<I?=KEIMKF
y
B?>M>EDMIMKFtQ }I?DAJ
BN>
GHI?@>
HP
BN>
@BI<O
KEE
;U@
KA<
T;U@
@NHIE<
F>
S?HKGBD=>EO
PHEEHC><
IS
PH?
>KGN @IF>GBQ
U=>?O
>PPH?B
@NHIE<
F>
MK<>
BH
HFBKDA
K
?>@HEIBDHA
PH?
KEE
>=>AB@R
>=>A
DP
BN>
>=>AB@ GHABDAI>
KPB>?
<D@GHABDAIKBDHAX@BI<O
GHMSE>BDHAQ \#$
%
&'()*+,
-.&+/0,.0'*&
$1/2
,1*%,2*0,
$/1
1*%&/0&
/,3*1
,3%0
-.&*%&*
41/51*&&./06
%0,3*1*$/1* +/0,.0'*&
,/
3%7*
,'2/1
%&&*&&2*0,&6
-1'5
/1
41/+*-'1*81*9%,*:;<&
2'&,
(*
+%4,'1*'0,.9
,3* 4%,.*0,
.&
+/0&.-*1*,/
3%7*
+/0$.12*=>
%0?.99
3%7*
0/
$'1,3*1
,'2/1
%&&*&&2*0,&@ A3*
.07*&,.5%,/1
.&
1*&4/0&.(9*
$/1
$/99/?.05
%99
:;<&
'0,.9
1*&/9',./06
'0,.9
,3*
&'()*+,
1*,'10&
,/ (%&*9.0*
&,%,'&6
/1
'0,.9
,3*
+/0-.,./0
3%&
&,%(.9.B*?.,3
,3*
*C4*+,%,./0
,3%,
.,
?.99
1*2%.0 +31/0.+6
*7*0
.$
,3.&
*C,*0-&
(*D/0&,'-D
4%1,.+.4%,./0@
\#$%$&' ()*+,
-.*/0+)1
2/*+-3&4/)
&)*
4/,+345
2&)&1(2()4
16+*(7) 0
84219
-/:
+226)(; 2(*+&4(*<
+)-60+/);:(7&4(*<
&)*
/);+226)(=2(*+&4(*
: &34+/)0
8*6:>&762&? 2/)/4@(:&'5
/:+)3/2?+)&4/)
A+4@
/4@(:
' /*63409
\#B/34/?(:
CD  
| XF CE=LIGBBLDAL F\@B@D@?LBLDF GHCBB>DLQBLAC@FL  TL=E TDFE ]CBRSE^ HGNME F\L?>CALNDE P= DFA CDF\E@ONL` w XF CEPG CONL F\@LTDFE MC\@DCHN@BB@FG=J  CBB>DL BLAC@FL  BLI\@DCEB IG>NA I>= CD L@=NJ  G=?@DE_ GBL HF\LB DGF  LA EPLICH@NJ CDF\LE ?>CALNDEZ w x\LF\= EPICH BB>DLQBLAC@FL TDFE ]@DAKG= N@OG=F CJ DAI@FG=E H E>I\ LTDFE^ @=LDGFA CDF\LE ?>CALNDE G=DF_P@CLDE \G>NA OL F\G=>?\NJ LT@N>FLA G=>NLGF@DJ NFL=D@CTL FCGN?J ]LZ?_ ACEL@  P=G?LECGD_ I BCF@D BLACI@FGDE_ @ACHLIFCGDE^ FG@PECONL BB>DLQ BLAC@FL TDFZ XF\L@OEDI GH@INL= NFL=D@CTL FCGN?J_ @NE>I\LTDFE E\G>NA OLB@D@?LA ECHF\LJM=CBB>DL =N@FAZ kD=@N =LIGBBLDA@FCGDE HNMZ w qJBPFGB@CI @DAFGPCI@N F\L=@PJ E\G>NA OLIGDECAL=  HG=NMQ?=@AL ]k=@AL t G=n_>DNLE GF\L=MCE PICHA^ TDFEZ  w yG= PLECFLD ]zlFG"A@JE^ NGMQ?=@AL ]k=@AL n^G=ELT= ]k@AL {|} LTDFE_ P=GBPFNJ E@= PLADCEGL tFGnB?K~?A@J sG=X€Le>CT@NLDFZ w qGBL LTDFE MC\ ? N~L\GA H=BGOCAFJ @DAKG= BGF@NCJ LZ? _ BJGI@=ACFE_ G=F\L= ECBCN@= LTDFE TDCHF\LJ@=DGFI>=LDFNJ GFLA CD F\L ?>CALNDE \G>NA P=G?LE @PCANJ FG\C? AGELX€IG=FC EL=CAE ]BLF\JNP=LADCEGNDL @FnGpB?K~?A@J^ LTDCHF\LTDF CEk=@AL n_@DACH INCD @N E>PCIGD E\? @DAKG= F\L  @EOLDINC @N GDHC=B@FGDZ WGDECAL=_ @EDLIE@=J_ ACEI> CD? MF\ LE>AJ P\ECI@D_  AP=GBPFNJ P>=EL PIC@NEF IGDE>NF@CGDZ w XH EJBPFGBE =LI> GM ELD A>=CD? IG=FC EL=CA F@PL=CD? ]n'A@JEGH F@PL=^_ CDI=L@E F\ IG=FC EL=CA  EL]P=ADCEGL AEƒZ?_ >PFGn p B?K~?A@J sG=X€Le>CT@NLDF"^ >DFCN E@OCNr@FGD =CBPGTLBLDF GH EJBPFGBE_ \LD=E>BL IG=FC EL=CA F@PL=CD? @F ENGML= @FL]zn'A@JEGH<=>? @ABCDCEF=@CGD BGACHI@FGDE HF>AJ =>?KEFAJ =L?CBLD MCNOLB@A FG B@D@?L PGFDC@N BB>DLQ=N@FA RSEO@LA GDELT=CFJ GHF=L@BLDQLBL=?DF FGUCIFLE ?=@AL P=VWX Y RS T"Z[ XD @ACFGD  \LI=CFL@ HG=PLB@D F ACEIGDFC>@GD HEF>AJ =>?KEFAJ =L?CB D O@ELA GDWY ?=@ALKET=CFJ ]@ONL  GM^_ PL=B@D FNJ ACEIGDFC>L EF>AJ =>?KEFAJ =L?CBLD HG=F\LHGNMCD? IGACFGDE` a XD@OCNFJ G=LA>I G=FC EL=CA F@AEL HbcdB?GHP=LADCEGL P= A@J ]G=Le>CT@NLDF^ f,.g% hif$j+ GHF\LE@= GH\LCBB>DLQBLAC@FL @ATL=E TDF ]CBRS^ a k=@AL l=I> DI GH@P=LTCG>ENJ LUP=CDIA F=@BLDQ=LN@FA CBRS HGNMCD? =LE>BPFCGD HAECD? #&'-$ h VG AELBGACHI@FGD #&'-$ i mGNA EF>J =>?KEFAJ =L?CBLD AGEL>DFCN k=@AL n=EGN>FCD FGk=@AL bco XH FGUCIFJ MG=ELD_ F\LD=@ Ek=AL lG=k@AL pZ qF>AJ =>?KEFAJ =L?CBLD I@ OL=E>BLA GDILTDF E@OCNrLE FG k=@AL bc@HFL= IGBPNLFCGD HEFL=GCA F@PL=Z s@FCLDE MC\LDAGI=CDP@F\CLE M\GB@J=Le>C PGND?LA G= IGDFC>LA EF=GCA LPN@IBLDF I@ OL=F@A MCF\E>AJ A=>?KEFAJ =L?CBLD G F\LHGNMCD? IGACFGDE` tZ Y\L TDF E@OCNrLE @DACEIGDF=NLAZ nZ Y\L P@FCLD EIND @NJ EF@ONL EPL=XDTLEFC?@G=  FL@CD? P\JECI@DuE INCD @N v>A?LBLDFZ lZ <GEL HP=LADCEGL @= FbcdB?KA@J G=Le>CT@NLDFZ                    |
|--------------------|
| 9*:,6.; 4'%'/$1$%. |  
#$
%&'()
&*+,
-. /00/*
./123+4
-(2+'5,
-. #$
/00/*
.'(02*/674
-(2+'5
8/(#%&'()
$&*+),
20#$
2009*':0'%25+' &'()
&*+,
;<2*+(5&'*/9),
=-;=5+2/*6
-*3'(
;*)+29',
>?@40/9+AB  
CDEFG
H I'J*%27
/ +A'2*%& 956
+/123+4K
)9%4
(97L)+%4
('720'* 054
M'J(05* +64
%2)3/*+29'%B
>6'5)
(8
+/792%'6*)
M6/NB CDEFG
O >'(05* +64
%2)3/*+29'
)+%4
(97L)+%4
('720'*B=/+'P
Q/(5)40J+/0523
5046)'
/(62J5)'
6& )
/8RSTUV=K
A/6%)+94%(97L)+%4
('720'*K
5%283/0J6'+
N/(W9J)A/N
* '&2%*3
/8J5*3('+2)K)+9%4
(97L)+%4
('720'*
054M'3/*+29'%
/(')90'%B=/+'P
X9%4
(97L)+%4
('720'*
)A/96%
M'J(05* +64
%2)3/*+29'%
2*Y(5%'
Z'&*+)
N2A 7 6W'A/%
8(0/M2%+4
5*%L/(
0/+5624
['B7K
04/35(%2+)K
/(/+A'(
)20265(
'&*+)
&*28+A'45(*/+39('*+64
/+'%
2*+A'792%'6*)BX20265(4K
3/*)2%'(
NA+ (
)+9%4
(97L)+%4
('720'*
)A/96%
M'J(05* +64%2)3/*+29'%
2*Y(5%'
S &*+)
N2A 7 6W'A/%
8(0/M2%+4
5*%L/(
0/+5624[
'B7K
04/35(%2+)K
/(+A'(
)20265(
'&*+)
&*28+A'45(*/+39('*+64
/+'%
2*+A'
792%'6*)
[NA'*+ 4%/*+(5J2%64
0J(/&'
+Y(5%'
\]9J/*+('50'*N2+A
)4+'023
)+'(/2%)
5* 8/6N2*7
896+5J'(=/+'P
.A(
5 )/0''13J+2/*)
+J'(05* +
%2)3/*+295/*
8)+9%4
(978/(Y(5%'
^ &*+)
_2B'K
A4J'(+A4/2%)0K
A4J/+ (2%)0K
.4J']%25M'+)
0'62+9)`B  
+5J'(`B a b/('
J/+*
2009*/)9J(')2&
93A5).=Q2*AM+/()
_'B7K
2*86105M,56)/
('8
+/A'2*%& 956
)'3+2/*)
8+A'20#$)
8/()J'328
+4J'/82009*/)9J(')2&`
)A/96%
M'3/*)2%'(
8/('&*+)
/(')J/*%27
+/)4+'023
)+'(/2%)B
>(/7')2/*
+9)'/80/('J/+*
2009*/)9J(')2& )A/96%
J(/3'%
0/('5J2%64
*'& +)
N2A 7 6W'A/%
8(0/M2%+45*%L/(
0/+5624
['B7K
04/35(%2+)K
/(+A'(
)20265(
'&*+)
&*28+A'45(*/+
39('*+64
/+'%
2*+A'792%'6*)
[NA'*+ )
&*+)
5('*/+(')J/*%27+/
)4+'023
)+'(/2%)B a c2+A
6/*7:+'(0
) /2%
5* /+A'(
2009*/)9J(')2&
9)K3/*)2%'(
* %8/(defghijklmn
opiqfjn
J*'90/*25
_>rK
8/(0'64
W*/N
5)defghijklmnjspne
J*'90/*25`
J(/A46512)K
75+(/2*')2*56
J(/+'32/*K
5%7693/)' 0/*2+/(*7B a I2)3/*+295/*
8)+9%4
(97L)+%4
('720'*
)/+05*%5+'
8/(Y(5%'
ZLY(5%'
^2*865005+/(4
'53+2/*)
5+(2M9'%
/635
+90/(
')J/*'_'B7K
2*865005+/(4
'53+2/*
5+)2'
/80'+5) 23
%)'5
*%640JA
*/%')`B-/*+295/*
8)+9%4
(97L)+%4
('720'* +A) +95/*
)A96%
M' 5)%9J/*
5M'*82+:()W
5*64)2
8/(+A5J 2'*B  
| H37 :70/% o<70/'3F70$;'&  0,F%4 3,G9CI J KLMNOLP RMWbfLTSX UL _ ZQNMuOLvWRXTULPbfNM Rf TXYQOLYT h QZfTS LkNYSOPX ^STONMV RWSkPONLMch RWfaLPOX _ ljZQ RMW O`SM RTbfNM RfX NMWbROSWd J mLMTNWSP eZfYLMRPX MW[USbONLZT ]NSR  bLMTZfOd H37 :70/% z<*'G/ 13*3/%701 ,ƒ49*$13*4CI J KLMNOLP TXYQOLYT WRNfX MWbLTNWSP `LTQNORf"OLMd J ePLYQOfX TRP TX SYNb TOSPLNWT ^SdVh QPSWMNTLS …OLuYVtlVWRX e† LP[‡SrZNgRfSMOcd J ˆSNYRV RTbfNM RfX NMWbROSWh bLMTNWSP m`TO mn_NO`bLMOPRT RMW PSQRO NMjv_SlTd:70/% z ^TXYQOLYRNbp YSWNbRf NMOSPgMONL WbROSWp fNYNOMV TOPZYSMORf {]\c sLfW TOZX PZVtTOWX PSVNYSM WLTSZMONf |PRWS uPTLfZONM  |PRWS }~ € [U OLkNbOX _LPTSMh O`SMPR T |PRWS LP|RWS vd € [U OLkNbOX YQPLgST OL|PRWS }~' O`SM  WbNTLM OPSNMORS TZWX WPZVtTOWX PSVNYSM _NfaS RTW                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     |                                                                                                                                                                                                                                    |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
|                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     |                                                                                                                                                                                                                                    |
| H37 5,9:70/%I J KLMNOLP QRONSMT ULPTNVM RWTXYQOLYT UQMSZYLMNOT LP[\] ^MS_ LTSO LP_ TSMNV T`LPOMST LUaPSRO` LPbZV`cd eRONSMT T`LZfW aSgRfZOSW _NO`YRVM RWQZfYLMRPX UZMbONL STh NMbfZWNMV LO`SP WNRVMLTONb QPLSWZPT RWSbPNaSW  fL_d J iZTQSbOW QMZYLMNOT `LZfW aS N bLMUPYSW _NO`PRWNLVPRQ`Nb NYRVM RWLO`SP NMUSbONLZT RMW NTSR jPfROW ONLfVST SkbfZWSh RM YRRVSW TSbPNaSW  fL_ J [MNORf _LPljZQ YRXNMbfZWS bfNM Rf Sg ZONLMh YLNOLPMV LU LkXVSMRONL gR T QZfS LkNYSOPX ^STONMV RWSkPONLMch fRaLPOX _LPljZQh RMW`NVj PSTLfZONM mnTbRMd J mLMTNWSP eZfYLMRPX MW[USbONLZT ]NSR  mLMTZfO |                                                                                                                                                                                                                                    |
| ?3E'&19 .0,0F%*%,1                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | :70/% o ^RTXYQOLYRNbh fNM Rf LP WNRVMLTONb LaTSPgRONLMT  fXp NMOSPgMONL  O NMWbROSWc qL WTSYLWNUbROLMT PSrZNWd sL_SgPh bLMTNWSP `LfWNMV TOZWX PZVtTOWX PSVNYSM WLTSRbfNM RfX QPL NROS MW WZPNMV WRMLTONb _LPljZQ ULPO`SP SONLfVSTd |
| 5,9 :70/% :%,%70G :+'/0,&%w,%+*3,'14x),1%74'0G y+,F D'4%0  <)yDC                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |                                                                                                                                                                                                                                    |  
!"  
#$%&'(
)**+,%-.%/'01%
2 0&1'3,45/6%74
86,14 #%67'19
:70/%
3(1;%86%,1
<=>) ? 586%74'3,
@ABCD34%
.3/'(&013,4  
reviated Title: Immune Checkpoint Inhibition
sion Date: 04/28/21  
| still no improvement with a to inflixing in                 | s and consider prophylactic antibiotics, antifungals, or anti-PJ   |
the discretion of the treating provider ). Caution rule of the treating provider ). Caution rule of the s                                                               |                                          |                    |
|-------------------------------------------------------------|--------------------------------------------------------------------|---------------------------------------------------------------|------------------------------------------|--------------------|
| insidered and prompt treatment with IV methylprednisolone 2 | Grade 3 or 4 (severe or new symptoms, new/worsening hypot          | romptly initiate empiric IV methylprednisolone 1 to 4 mg/kg/d | cssary, discussing with study physician. |                    |
| onsider, as necessary, discussing with study physicial      |                                                                    |                                                               |                                          |                    |
| sing the content of the content of the content.             | portive care (e.g., oxygen).                                       |                                                               |                                          |                    |
| pitalize the patient                                        |                                                                    |                                                               |                                          |                    |
| /kg/day started                                             | ted infections) 1                                                  | threatening):                                                 |                                          |                    |
| rmanently discontinue study drug/study                      |                                                                    |                                                               |                                          |                    |
| igment and after completion                                 | 98                                                                 |                                                               |                                          |                    |
| roid taper                                                  | gimen                                                              | lf-care ADL; oxyge                                            | eatening respira                         | vention indication |
| promise, urge                                               | g., tracheostor                                                    |                                                               |                                          |                    |
| rade 3: sever                                               | Frade 4: life                                                      |                                                               |                                          |                    |
| rade 3 or 4                                                 | tubation])                                                         |                                                               |                                          |                    |
| (ndicated)                                                  |                                                                    |                                                               |                                          |                    |  
| QRIEFGHIJKLS + T4#"/43 $ 2:'1/4'2 0('(:).3%(/8 4 "(30.U#/34-%"/2 A()84'"#(% 1"#7 -3('1"#67 43-0(#6.2 "#)4V.% 0()"/2 9-0(2 "#-3.(28 $3W9#-: 45.3)(2.%"# 43)% 8 "#2/4%D 3.%(/8 4 )4V.% 13$4(/"# A29-0 (2.1"7 1.3"/4#.(% 2"6#7 (8"%.92D* X Y0.# 2:'1/4'2 3.5(%9/"4# 8-(/. 13$4(/"# 291.-/87 / -4#29% (2936.4# &13"#-8 "#()84'"#(% 2936.: "''.8"(/.%: V"/049 (#:8.%(:*  X ?Z[T\BZ ]^_ `abC,B]acZ b]c`_ [cd e,[\B_ d[\`Z ,eaB]Zb aB\^ ?Z[e, \]a,B + ?(/".#2 049%8 )./043960%: .5(%9/.8 439%.4/(#: %/.3#("5. ./"4%6: A.*67 8"2.(  1346.2"4#7 /0.3 '.8"-(/4#27 3"#$.-/"4#2D7 "#-%98"#6 /.2"#6 $43-%2/3"89' $-%. /4&"#7 ./-* + b/.34"82 049%8 ).-4#2"8.3  "#/0.()2#- 4$-%.(3 %/.3#("5. ./"4%6:7 .5#$43%V>63(8. 5#/27 "#438. /413.5#/ 14.#"(% 1346.2"4# /0"6.3 (8. 5#/7 "-%98"#6 1.3$4(/"#*  + c2. (#%6.2"- (3.$9%:f /0.:-(#'(2g:'1/4'2 $1.34(/"# (#8 1.3"/4# 2* HIJKL s A`"(30.t 2/4% $3.W9#-: 4$uv45.3 )(2.%"# 138(:D AC4%"/2t (:'1/4'("-f -%"# (% 438"(6#42/"- 4)2.35(/"4#2  %:f B4 82.'48"$-(/4#2* QRI HIJKL sS + T4#"/43 -%2.: $43V 2.#"6 2:'1/4'2* + C4#2"8.3 2:'1/4'("- 3.('.#7 "-%98"#6 0:83(/"4#7 .%-/34%:. 3.1%(-'.#/7 8"./(3: -0(#6.2 A*67 \'.3"-(# `"./ - \24-"(/4# -4%"/2 8./D7 %41.3('"8. (# 4/0.3 29143/"5. -(3'.(293.*  + a$ 2:'1/4'2 1.32"/ -4#2"8.3 -0 g"#6 %(-/4$.3"#f $142"/5. 3( 2   EFG HIJKL HLFLIJM HNOKJFPLhOJIiLjkRMOlm nJIoL OFlmOF pLIqRJlOFjrlLmOF pLIqRJlOF   |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
!  
"#$%&'()* + ,#-.
/0 1(/".#
2'1345"#67
3(89%:
/(1.3
2/4"82
5.3;<=8(:2
#8-42"8.3
140:%(-/"
(#/")4-27
(#/"$96(%27
#8"1(3/"-9%(37
#/">?@
/3.('.#
A3.$
/4-93.#/
BC
69"8.%#2
$43/3.('.#
4$-(#.3>%(/ ( 8
"#$.-/"4#2D*  
|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`abXcY #%D #9I)'%,$ )'81&)%02&1 I'5),%#$ ,*'&5 %)#$51T9,0 1,& 5)' 6&$',1 68#*,$+& 05)' 8D#$6 51T9,03 Z M)$D#*&'7 ,D$&+D,'F7 *#D+8 #$6 2%BD8*F IBD#+,$ 5) '&D)18%#$  .',*& QR#$U%)G*,FD3 Z \$+& %B I,%#&$ D9I')(#$67 ',*81F %,I&' D%)#*D  '(&def *,FD $*+)D#*&' I)BF1,+%# ,$%#0)+D7 ,$%#586,1D7 $* %#gNh %'&,9&$ @'&5 %)+8'&$% iM  68#*&1$D 5)'%&,9&$ )5+,$&'g '&1,% , * #$5&+%#)$D-3 :;<=> jX;k @.',*& UA#,'B&C D%)1 5'&E8$+F )5dl )(&' 0,D&1#$ I'*,FJ :;<=> j g m)'I,%#&$D '&,* 2#%BNAg!)'NALg ! #$B0%)'D7 B)1*D%8F '86PD%*F '&6#9&$ 8%#1 '&D)18%#$  .',*& QRn D%8*F '86PD%*F '&6#9&$ +, 0&'D89&* WX; :;<=> jX;kY Z N')9I%1F #$%,& 9I#'+ 4]9&%BF1I'&*$#D)1$& !%)/96P[6*,F )' &E8#(,1&$%3 Z o)$#%)' D 1 5'&E8$+F ,*()189& ,$*9,#$%,  BF*',%#)$3O)1* D%8F '86PD%*F '&6#9&$ 8%#1 '&D)18%#$  .',*& QR S 45 %)T#+%F 2)'D&$7 %B&$', D .',*& U)'.,*& G3 S 45 %)T#+%F 9I')(&D %).',*& QRV %B&$ D%8*F '86PD%*F '&6#9&$ +, 0& '&D89&* ,5%&' +)9I1&%#)$ 5D%&')#* %,I&'3 :;<=> ? @A#,'B&C D%)1 5'&E8$+F )5G%)H (&' 0,D&1#$ I'*,FJ 1#9#%$6 D%'89&$%,1 KAL- @M)1#%DC ,0*)9#$,1 I,#$J 98+8D )'01 * #$ D%)1- @N&'5),%#$C (,D & #$%&'($%#)  % #$*+,%&*-   |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
.',*&
/01)23
45$&6,%#(&
,$* )#5&+%#)$7
+ %#8&
.',*&
! 9,$,6&9&$%
3  
| -+&*. ,8%A#*&$8' +)&*.8$4 &-A*.E D*.%-' &#F 4$),8'&$:* )&4F .:(G)&4F .*($%*' +8.3-4* =$+&8H$,&F 48*)'& $%A.8?* &3.-4* IJK$&6' !54-F)E C D*.%-' &#F 4$),8'&$:* )&4F .:(+8. !; 3.-4* =,8#$&) 'A-&$*') .*-4 K$&6 >L1/C5 $'6@&8.)  M;/'F(.-4* #.(* $'&*)$' A.+8-&$'GN&*)$'-# A*.+8-&$' $' -FA&$*' .*-4 K$&6N>E OPQRS T D*.%-' &#F 4$),8'&$:* )&:4F .:(G)&4F .*($%*'E  U V.(*'& 3N,8'):#& -'4$%-(' -4G8. ,#'),AF -)A.8 $-&*E U N+ )&$# '8$%A.8?*%*'& K$6' M4-F)B   |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| ,8'&$:* )&.8$4) -'4 A.8%A&#F -4 +:.&6* $%%:'8):A.*)-'& (*'&) <*E(B $'+#H%-@ -& W %(GX( NYB%-F@*.A-&4  M '4ZK*X) -+&*. $'&-# 48)*-& &6* 4$),.*&$8' +&6*.-$'( A.8?$4*.;E [Q\]^_`7 a'):.* 3N,8'):#& &8 .:#*8&@K*# A.+8-&$' -4.*+ &8$'+#H%-@ #-* +8. (*'.-# (:$4-',* @+8. :)$'( +#H%-@E N+A*.8-&$' ) ):A*,&4B ,8'):#& -):.(*8' HA.$',4 $'-@48%$'-# ):.(*F $%%*4$-&*#F K$&68: -'F4*#-F E U b',* &6 A-&$*' )%A.8?$'(B .-4:#F &-A*. )&8$4) ?*.cde 4-F) '4,8)$4*. A86F#-,&$ -'&$@8,)B -'&$+:(-#)B '4 &$CDf &.*-%*' <.*+ &8,:.*'& g>  (:$4*#') +8.&*-%*' 8+,-'*.C .*#-& - 4 $'+*,&$8');E h`i OPQRS OS`SPQj O\^RQ`kS!" #$%$&'( )*#+,-.*/012 3.-4* 50$-.6*7 #$+* &6.*-'$( ,8')*9:',); <3.-4* =>8#$&)7 *?. -@48%$'-# A$'B +*?.2 $#*:)2 A*.$&8'*-# )$('2 3.-4* 5>8#$&)7 #+*C &6.*-'$( ,8')*9:',)B :.(*'& $'&*.?'&$8 4,-&*4; <3.-4* =D.+8-&$'7 $'?-) * '&.?'&$8 $'4,-&*42 3.-4* 5D.+8-&$'7 #$+*C&6.-'$( ,8')*9:',)2 :.(*'& $'&*.?'&$8 4,-&*4;  l_P h`iOPQRS U m8'$&8. -'4*?-#:&* #$?. +:',&$8 *)7 /nLB 1 D-'4LoE U a?-#:&* +8.-#&*.'-$?* &$8#(*) <E(B ?$.-# 6*A-&$)B 4 *-  A.8(*)$8'B , %$&-' %*4$,-&8');E pSqQ]^r sSjtQ]R ulvrw N'+#$H%-@ )68:#4 '8&@* :)*4 +8.%-'-(*%*'& 8+ $%%:'*C.#-&4 6A-&$)E OPQRS x s/nL 8./1LyV1g -'4 Iz{|}~€ $+ @-)*#$' 8.%-#B !EWC =E"@-)*#$' +@-)*#$' ' g8 4)*%84$+,-&8')E ' N+ $&K8.)*'B &6*'.- )3.4* ME U >8'&$:* 1ƒL%8'$&8.'( A*. 8&,#E "u…h†  r‡QRS P ^ˆˆSR^Q]Sji ‰ _Š ]‡^r Sk]^_`  ‹^`R Œ\^RQ`kS ‹_P ˆQ`QŒSˆS`] _‹ pSqQ]^r sSjtQ]R ulv†wŽ ^`p[[ qQ]^S`r                                                                                                                                                                                                                                                                                                                                                                                                                                                               |  
| abG FGHIJ Kc d e?XW*$( &,=(?fW&T V]?_<&X '=2g.>L?AX@ ?^(U !T'#,$U>E W&T<* ?^$T<'&> =T]?>$ (<)h('^<&X '(?>'*^,A d i= &'(?>*WT<&  4jklmn !<& T'#,$U>@ V'&><,?(@ $>&?V>$(U@ ,<>VW <&X [T]>W,U h]><V$&A d i= ?^&T <>h?(<T?& L0#T'O,$U>E '([ >?&@ h(')hT*U >$( h(?,&<>'? !T'#)X-_X,$U So'(ip?fW<^$*?&TA d i= >T<* &'<)h('^?)?&T [<]& OT'C,$U>?h<T !'#)X-_X,$U =' h(?,&<>'? So'(ip?fW<^$*?&T@ V'&><,?( $ <T'&$* ['(_Wh$&, >T$( h')hT (?$)?& [<]ip)?T]U*h(?,&<>'*&? #T' ` )X-_X,$UA d i= >T<* &'<)h('^?)?&T [<]& OT'C U,$>?h<T #'`)X-_X,$U '= ip)?T]U*h(?,&<>'*&?@ h(')hT*U >$( <))W&'>Wh(?><^  L<A?@  )UV'h]?&*$T? )'= $ T<*EA q<>VW  [<T]>W,U h]><V$& = )UV'h]?&*$T? )'=T<* >&'T$^<*%?A rstuvwxHy z{b|uI }~yJ |zJI€ d o&V? T] h$T<?& >)h('^<&X@ ($,W*U T$h?( >T'<,> ^?('ƒ ,$U> &,V'><,?( h']U*$VT< & $T<%'V>@ $&T<=WX$*>@ &, T<BS" T(?$)?& L(?= T'VW(?&T 3…  XW<,?*&> ='(T?$)?& '=V$&?(B (?*$T $ , <&=?VT<'&>EA abG FGHIJ †bG‰c d S(')hT*U <&T$? )h<(V ip)?T]U*h(?,&<>'*&? $T!' # )X-_X,$U '(?fW<^$*?&TA d i= >T<* &'<)h('^?)?&T [<]& #T'O,$U>?h<T !'#)X-_X,$U  )?T]U*h(?,&<>'*&? ip'(?fW<^$*?&T@ h(')hT*U >$( ?$)?& [<] <))W&'>Wh(?><^ T]($hU L<A?@ )UV'h]?&*$T? )'=T<* "ACŠ!X ?^(U !#]'W(> T]?&$h?( <&V'>W*T$<'& [T] ?h$T'*XU V&>W*TEA q<>VW  [<T]>W,U h]><V$& =)UV'h]?& > *$T? <&'T$^<*%?A rstuvwxHy z{b|uI }~yJ|zI€ d e?fW>T Yh$T'*XU V&>W*T@ $&,h?(=') $%,')<&$* [ & '(_Wh $, <)$X& $>h(' <$T?A d o&V? T] h$T<?& >)h('^<&X@ ($,W*U T$h?( >T'<,> ^?('ƒ ,$U> &,V'><,?( h']U*$VT< $&T<%'V>@ $&T<=WX$*>@ &, T<BS"   |
|---|
| $%&'()$*+ $&,-'( ./ 0123 $&,456789:; <= %$>?*<& '()$*@ 0!A"BCD%$>?*<& = %$>?*<& $%'()$*E FGHIJ K LMN. '( M2. 0OA"D123 $&, 476P89:; <=%$>?*<& &'()$*@ 0OBCD%$>?*<& <= %$>?*<& $%'()$*+ $&,-'( ./ 0!ACD123 $&, 4Q6P89:; <=%$>?*<& &'()$*@ 0!ACB OA"D%$>?*<& =%$>?*<& $%&'()$*E R S?()$& T*U ,<>V'&T<W? >T,U ,(WX->T,U (?X<)?& ='($&UV>? )??T<&X YUZ>*$[V(<T?$ LMN. $&,-'( M2.0OD123\%<*(W%& 0# D 123[<T]'W <& $* =&, X> '= V]'*?>T$< LA?@ *^$T, *_ <&? S"`E $&,<T]?$%>&V '=$&U $*T?(&$<^? V$W>?A g'( ?*^$T<'&>  T($>)< >? 4ƒ89:;‡ '( ?*^$T<'&>  ./4789:;ˆ R Y'*, >TWU (WX->T,U (?X<)?& ,'>? W&T<* (?>'*WT<&  jklmn45 R e?>W)? TW,U  > (WX-T,U (?X<)?& = ?*^$T<'&> ,[&X($,? T'jklmn45 [<T]& !`,$U>&, =T?( V')h*?T<'& '= >T?('<, T$h?(A R S?()$& T*U ,<>V'&T<W? >T,U ,(WX->T,U (?X<)?& =T]?*^$T<'&> ,' &T,[&X($,? T'jklmn45 [<T]& !`,$U>A FGHIJ † LMN.'( M2. 0CA"D123 $&, 4'P89:; <=%$>?*<& &'()$*@ 0CB#"D %$>?*<& =%$>?*<& $%&'()$*+ $&,-'( ./ 0OA"D123 $&, 45P689:; <=%$>?*<& &'()$*@ 0OA"B! D   |  
I-'%.'*
6-'+
I,OK-'*I
?[
PK)B'(*&
+,-I'%.'*
,+O%*'-\-'(%IB
)*+'OI),*&/E  
!"#  
$%&'()*
+$%&'()*%$*,-.%(/ 01234
56789
,-7:9;<"=>:?
)+$%&'()**,-.%(@
;<"=$%&'()*
+$%&'()*
%$,-.%(A%*BC,-9D
;!"=>:?
)+$%&'()*
,-.%(@;!"E=$%&'()*
+$%&'()*
%$,-.%(/  
F G,'(H%I),*& I-%&.) &';J=>:?
,-'(H%I),*& $(-K$*;L=>:?@
M'-.%* I(N
B)&O,*I)K'&IKBN
-KPC&IBN
-'P).'*E F Q'-.%* I(N
B)&O,*I)K'
&IBNB-KPC&IBN
-'P).'*
+,-%*NO&' .''I)*P
RNS&(%TO-)I'%
6789%*BC,7:9;#=>:?
U$)(-K$*;<=>:?
T)IV,K
)* %(
+*B P&
,+OV,('&I%)
WE'@
(H%IB
(X )*'Q"YZ
%*B)IV'%$&*O
,+%*N%(I'-*%)H'
O%K&'/E  
fo1
klmnc4d2_`ola
t4u1`v43y z {,*)I,%*B'H%(KI'
()H+K*OI),
'&|
789@ : Q%*B9DE z }H%(K +I'
,-%(I'-*%)H'
I),(P'&
6EP@
H)-%(
V'M%I)&@
B '% M-,P'&),*@
O .)I%*
.'B)O%I,*&@
T,-&'*)P
,+()H'O)V,&)W'EP@
M,-I%(
H')*IV-,.$&)Z/E z G,RD~U
M%I)'*&|
'H%(KI'
K%*I) H'
RD~H)-%(
,B@K%*I) H'
RD&7P@
,-RD'7P z G,R[~U
M%I)'*&|
'H%(KI'
K%*I) H'
R[~H)-%(
,B z [  ,*&)B'-O,*&K(I)*P
V'M%I,(P)&ICi*+'OI),K&
)'%
MO)%(&I-'P%B)*P
OV%*P'C).M('.'*I%),*
C,+
%*I)H .' -%( B)O%I,*&
+-%*NM%I)'*
T)V%*'(H%IB
RD~H)-%(
,B;<"
i>C.( z [,*&)B'O,*&K(I)*P
V'M%I,(P)&ICi*+'OI),K&
)'%
MO)%(&I-'P%B)*P
OV%*P'C).M('.'*I%),*
C,+
%*I)H-%(
R[~.'B)O%I,*&
+  
]4^2_`ab4cd2_3
efgahi*+()j.%$
&V,K(B
*,I$'K&'B
+,-.%*%P'.'*I
,+)..K*'\-(%IB
VM%I)&Eklm
nc4d2_`ola
pkqgr
egr
o1gs2at4au1`v43
scow 04l412c
0x`32lu4  
g]q
a234
1`a
x32lu4
po1 2l244l_
op]4^2_`a
b4cd2_3efgah
`l]^2_`4la  
| ; Ž0qE+*) .-F)0E.? /@0(.q ,Fl<m1s0jqr 0')3 !?,'-*31t E.?(+ 0'*?(,.1 F?@01 *)(ip),'(.q ,)01,+'-j ; Ž0/,ii0.- /,1E+? @0p*?,+q(1?' /,.1(-0) *2-,i(.*+ E?)*1,E.-r (./+E-(.q ",p+0) *10 i0.? ,F+('0) p FE1(,.j ; %,.1(-0)r *1.0/1*)3r -(1/E (.q >?@1E-3 p@1(/*.j ; kF 0'.? (1p0)(?0. s"•?,'-*31t ,)> 10.r *-('01?(q*,) 1Ep0/? ,Œ(/?3 ,20(iiE.0–i0-(*?0 BDr)0/,ii0.- ?,1*) p)0-.(1,0 !?,•iqnq-*3 —˜,)k&0E('*+0.?j ; kF 1?(+ .,(ip),'0i0.? >(@. •?,'-*310p(? !,•iqnq-*3 ,F p)0-.(1,0 —˜,)k&0E('*+0.?r /,.1(-0) * (?,.*+ >,)Ep *.- ?)0*i0. >(@k&i0 - ?@3+p)0.(1,+.0 •?,#iqnq-*3j ; kF 1?(+ .,(ip),'0i0.? >(@. •?,'-*310p(? !,•iqnq-*3 ,F k&i0?@3+p)0-.(1,+.0r /,.1(-0) * (?,.*+ 2-,i(.*+ >,)Ep s(./+E-(.q +'0) 2(,p13t *.-(i*q. sj0r +('0) E+?*1,E.-tr *.- /,.1(-0) 1?*(.q iiE.,1Ep)01('  s(j0r i3/,p@0.+*?0 i,F?(+ "j™ š!q0')3 !•@,E)1 ?@0.*p0) (./,1E+?*(,. >?@ 0p*?,+q3 /,.1E+?tj "(1/E  >(?@1E-3 p@1(/*. Fi3/,p@0.+*?0 i,F?(+ 1 .,? *'(+20j GWxJf›cKe HbIwJN VœQeMwHN}   |
|---|
| GHIJKLMN OPQIROSQ TUSV KWNXYZ[\]^_` abML R WIcKJ IR MJdKLN  eHMJfW  g h, -10i,-(F/*?,.1j g kF Blmno  0+'*?(,.1 )0p 1.? 1(q.F/*.? >,)10.(q 2*10- ,. (.'01?(q*,) 10 i0.?r @0.)* 1 -01/)(20- F,)0+'*?(,.1  ?@0),> 20+,>j g <,) *+?)*.1i( 10 +'*?(,.1r 0 (.1?)E/(,.1 *?2, i F 1@*-0 ) (F ?)*.1i( 10 )( .,?(1+*?0- 2E? s*? .3?(i0t,/E)1 (.0?(.q ,F 0(?@) fWuRMKHfWv eJRweW IRHfvW Ix yGSzJfdMR NuIc{MWHKLfIW GHIJKLMN OPQIROSQ T|}~USV KWN X€Z[\]^_` fxWIRcKJ KL eHMJfW GHIJKLMN OPQIROSQ T}~eKHMJfW KN X'ƒZY\]^_` fx MJdKLN TUSV KL eKHMJfW g $,+- 1?E3 )Eqn1?-3 )0q(i0. -,10 E.?(+)01,E?(.  Bom,)Blm "…†‡ˆ‰Š‹† g kF ?,Œ(/?3 >,)10.r ?@0.)* 1 -01/)(20- F,)0+'*?(,.1  ?@0),>1 20+,>j g kF ?,Œ(/?3 ip),'01 ?,Bom,)Blm "…†‡ˆ‰Š‹ )01Ei0 ?E-3 )Eqn1?-3 )0q(i0. *F?0) /,ip+0?(,. F1?0),(- ?*p0)   |  
GHIJKLMN
OPQIROSQ g $,+1?E3
)Eqn1?-3
)0q(i0.
-,10 ; 0qE+*)
.-F)0E.?
/@0(.q
,Fl<m1s0jqr
0')3
!-*31t
E.?(+  
!"#  
$%&
'()*+
,-(./)0*123456789: ; <,)
$%&=
>(?@$A/B =C
D'*+E?0
F,)2?@$A&*.-$%&*1*2,'0  
o0
(.1?)E/(,.1
*?2,?i
F
1@*-0
)(F
?)*.1i( 10
)(.,?
(1+*?02E?s* .3?(i0t
,/E)1
(.0?(.q,F
0(?@)
fWuRMKHfWvefJRweW
IRHfvW
IxyGSzJfdMRNMuIc{MWHKLfIW  
| PNghLMRKQ fLjPQ hOMamORgMKd ROPQRNgbn t uRKQJNL jPmhLRNdMQL vJKNPQ MKgPQLMdhRO MQjPmhLRNdMQLwx RsLhMK hsbRaMKhN JLOhQRJKbr MlNJbMKd yRmNPO hQP aPKL RfNMgPO mPOfJQMRKx hblRQMbPO NMgPO sMRmQcn t uRKQMbPOr hQKPlQhOcr bMQlJ MKd iLjQJbc mjQMlhKn t zf MKgPQLMdhRO QJmPlL R{MlLc RsPMaaJKP|aPbMhLPr mORamLNc MKLhP amMOl z}aPLjcNmOPbKMQRNKP hL!Rkade~dbhc RO PJMghNPKLn t zf KRMamORgPaPKL iMjK €LR#bhcQPmML !Rkade~dbhc  aPLjcNmOPbKMQRNKP z}ROPJMghNPKLr RshMK NgPO sMRmQc vMfLjhQ KRL sPKbRPhNO bcw KbmORamLNc QhO PhaPK iMj MaaJKRQJmOPQMg LjOhmc vaclRmjPKNhLP aRfLMNwn yMQlJ  iMLj QLJbc mjQMlhK faclRmjPKNhLP MQKRLhgMNsPn B-9=8<,? @':ƒ=. +"E?Aƒ@.& t …KlP Lj mhLMPK QamROgMKdr OhbJNc LhmPO QLRMbQ gPO†‡ˆ bhcQ KblRQMbPO mRjcNhlLM hKLMsRlQr hKLMfJdhNQr Kb LM| ou  LOPhaPK vOPf LRlJOPKL ‰u  dJMbPNKQ fROLPhaPK Rf lhKPO|NhLb MKfPlLMRKQ JKLMN OPQRNJLMK  STUROSVU WXYZ[\]^ _ `PQJaP LJbc OJdeQLbc OPdMaPK f PNghLMRKQ biKdOhbP LRSTUROSVU WXYZ[\]^ iMLjK !kbhcQKb fLPO lRamNPLMRK fQLPORMb LhmPOn _ oPOahK LNc bMQlRKLMJP QLbc bOJdeQLbc OPdMaPK fLjPNghLMRKQ bR KLbiKdOhbP LRSTUROSVU WXYZ[\]^ iMLjK !kbhcQ _ oPOahK LNc bMQlRKLMJP QLbc bOJdeQLbc OPdMaP fK ROhKclQP aPPLMKd pcqQNhilOMLPhr KLjP hsQPKl RfhKc NLPOKhMgP lhJQPn D,<A @?:IA ŒAŽ> ‹:ƒ=. ;A:<<A-. :?>,8-  =IA; ?8:Ž@ A,;=' $%&'()*+ ,-. /01234567 89-:;<,= ,> ?@A=8- B@:=,>A. CDE:;C*E $FG&H()*+ ,-. /01234567 89 A=I,>. $)*+ ,> ?,@A=8- B@:=,>A. CDE:;C*E $G'()*+Š ‹'A> ; -:;<,= :;A=I,>. ?,@A=8- oPOahK LNc bMQlRKLMJP QLbc OJdeQLbc OPdMaPK   |
|---|  
:;
C-;,.A t uRKQJNL
iMjKPmORNdMQLn t RKMLRO
f QMdK
hbQcamLRaQ
jhahcsPONhLb
RljhKdPQ
MKOPKhN
fJKlLMR
vPndr
ORJLMKP
JOMKhNcQMr
PNghLb
QOJa
¡
hKb  
B9
>;,-@<8-@A
;8 -:>8@=,>A.
?>, ->8<A:;@
8- A>8:9A8>;
8-A,@8>:,=.8;A>
?8=;?234567
89-:;<,=
,>?,@A=8:;G(?,@A=89$)*+
,>?@A=8:;@8:9B*=8IA;
.:<A-@,>8:A&
9AI;
=I,>.
B+ ,-,A
.:@89:;A,=AI
:9>;,-@<8-@A
;8 ,8->;A.
9:;>A->8A@>
=I
:9>;,-@<8-@A
;8:;
,<=A
<,-,A.:@89:;@A:-.
=AI
:9>;,-@<8-@A
;8 &
CDE:;C*E$H&'()*+
,-./2134567
89-:;<,=
,>?@A=8:;CDE:;C*E$G&'(?,@A=8,./0234567
89A=I,>.
$)*+
,>?@A=8,@8->;A.
9:;>A 8;.
=AI
:9>;,-@<8-@A
;8 &
CDE:;C*E$%&'()*+
,-./01234567
89-:;<,=
,>?@A=8:;CDE:;C*E$FG&H()*+
,-./01234567
89A=I,>.
$)*+
,>?@A=8-:;
>A 8;.
,- 9:;>
=AI @
:9>;,-@<8-@A
;8
;<,-A
>=.8@:->8A
@>.
;@>.
;A8<A-+A;8>@
:;A-,=.@9->8:vPNghLb
QOJaC;,.A A-A;,=
8.,-A  
| lays and consider prophylactic antibiotics, antifungals, and anti-F   |                                                       |                               |                            |    |
|-----------------------------------------------------------------------|-------------------------------------------------------|-------------------------------|----------------------------|----|
| ecommendations in this row that the consider following the comment of the consider following
ecommendations in this row.                                                                       |                                                       |                               |                            |    |
| Grade 2, 3, or 4.                                                     |                                                       |                               |                            |    |
| ecrease in urine output, or proteinuria, recent IV contrast,          | .
iteroids should be considered in the absence of clear alternative
itiology (e.g., disease progression or infections).
in the should be thoroughly evaluated to rule out any                                                       | onitoring per study protocol. | eplacement, and diuretics. | ednisone at 1 to 2 mg/kg/day PO or worsens despite the state of a worsens despite the state of the state.
ednisone at 1 to 2 mg/kg/day PO or IV equivalent.
iditional workup .    |
| symptoms.                                                             | ncally monitor serum creatinine every 2 to 3 days and |                               |                            |    |
| onsult nephrologist and consider renal biopsy if clinical             |                                                       |                               |                            |    |
| or Grade 1:                                                           | Grade 2:                                              | ug/study regimen after complete
ug/study regimen after complete
steroid taper.                               | 106                        |    |
| old study drug/study regimen un                                       | toxicity worsens, then treat                          |                               |                            |    |
| ution to Grade <l or baseling                                         |                                                       |                               |                            |    |
| Ho dose modification                                                  | 3.0×baseline; > 1.5 to                                |                               |                            |    |
| erum creatinine >1.5                                                  |                                                       |                               |                            |    |
| ULN to 1.5×UI                                                         |                                                       |                               |                            |    |
| serum creatini                                                        | 3.0×ULN)                                              |                               |                            |    |
| Grade 2                                                               |                                                       |                               |                            |    |
| Grade 1                                                               |                                                       |                               |                            |    |
| (creatinine)                                                          |                                                       |                               |                            |    |  
obreviated Title: Immune Checkpoint Inhibition
ersion Date: 04/28/21  
| reatment (refer to current NCCN guidelines for treatment of canc
reatment (refer to current NCCN guidelines for treatment of canc
elated infections)."                                                                           | Any Grade:
Monitor for signs and symptoms of dermatitis (rash and pruritus)
Toxic                                                               |                                   |          |          |
|---------------------------------------------------------------------------|---------------------------------------------------------------|-----------------------------------|----------|----------|
| ad routine serum creatinine monitoring per study protocol.                | iphenhydramine or hydroxyzine) and topical therapy (e.g., ure |                                   |          |          |
| romptly start prednisone 1 to 2 mg/kg/day PO or IV equivalent, additional | iphenhydramine or hydroxyzine) and topical therapy (e.g.,     |                                   |          |          |
| pidermal Necrolysis (TEN), or other severe cutaneous adve                 | Permanently discontinue study drugs if SJS, TEN or SCAR .     |                                   |          |          |
| Carefully monitor serum creatinine on daily basis.                        | mollient, lotion, or institutional standard )                 |                                   |          |          |
| ction (SCAR) is suspected                                                 | obtain Dermatology consult                                    |                                   |          |          |
| lated infections). 3                                                      | Grade 3 or 4:                                                 | cated                             | Grade 1: | Grade 2: |
| ermanently discontinue study drug/study                                   | /study regimen until resolution                               | f toxicity worsens, then treat as |          |          |
| persistent (>1 week) Grade                                                | 107                                                           |                                   |          |          |
| nts, hold scheduled study                                                 | Grade <l or baseline                                          |                                   |          |          |
| Io dose modification                                                      |                                                               |                                   |          |          |
| General Guidanc                                                           |                                                               |                                   |          |          |
| egimen                                                                    | 3.0×baseline; >3.0                                            | refer to NCI CTCA                 |          |          |
| reatinine >6.0×UL                                                         | epending on type                                              |                                   |          |          |
| 5.0 for definition                                                        |                                                               |                                   |          |          |
| Grade                                                                     | Grade 4: serum                                                | everity/grade                     |          |          |
| Grade 3 or                                                                | Any Grade                                                     |                                   |          |          |
| 5.0×ULN)                                                                  |                                                               |                                   |          |          |
| eatinine                                                                  | skin rash)                                                    | Grade 1                           | Grade 2  |          |
| uding Pemphigoi                                                           |                                                               |                                   |          |          |
| sh or Dermatiti                                                           |                                                               |                                   |          |          |  
obreviated Title: Immune Checkpoint Inhibition
ersion Date: 04/28/21  
| XVQ PQRST UVQW\VQ]^_T`abQR c^deY C D/<7?;. f(%4&./;@3* C J%/45.;3 1<.&( 451%2 ,L4(.>3;5%('<17/;<( !./I4@AF@'&3 /% (M?16&;(<.* C D/<71'(% >/751.&;g./<* C h/<1./% (0.< /-%&7>ij?;( /-k1<(7l* C D/<71'(% 7F1<:/573 m%(-&:;3 4/%(.>&<!B&72;1< &;3 -(&71:;(* C K<2( .> 5&.1(< 745%/61<@= %&'?;3 .&5(% 7./1'7 6(%nop '&37 <'2/71'(% 5/>3;&2.1 &<.1:/27= &<.1-?@&;7= <' .1EJq .%(&4(< m%(- ./2?%(<. kD  @?1'(;<7 -/%.(&4(< /-2&<(%E %(;&. & ' 1<-(2.1/<7B* C D/<71'(%= &7<(27&%3= '172? 1<@ G.>7?'3 5>712&<*                                                                                                                                  |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
|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|
| XVQ wcuPQRSTY C D/<71'(% 2/<7?;.1<@ & ('/2%1<;@17. -/%(<'/2%1<( 6<.7* C D/<71'(%= &7<(27&%3= '172? 1<@ G.>7?'3 5>712&<* C h/<1./% 5&.1(<7 -/%71@< &'7345./47 -(<'/2%1<5&.>1(7* k/<E 75(21- 7345./47 1<2;?'( >&'2>(= -&.1@?(= :>&61/% 2>&<@(7= 2>&<@(' 4(<.&; 7 ?= 6(%.1@/= &:'/41<&; 51<= ? 7&; :/G(;                                                                                                                                                                                                                                                                                                                                   |
| $%&'( )* + ,- ./012.3 45%/6(7 ./$%&'( 89/% :&7(;1<= .><%7?4( '%?@A7.'3 %(@14(< &-.(% 2/45;(.1/< -7.(%/1' .&5(%* PQRST UVQW XVQ PQRST UY Z/;' 7.?3 %?@A7.'3 %(@14(< ?.1; %(7/;?.1<  $%&'( 89/%:&7(;1<* ,- ./012.3 45%/6(7 ./$%&'( 89/% :&7(;1<= .><%7?4( '%?@A7.'3 %(@14(< &-.(% 2/45;(.1/< -7.(%/1' .&5(%* ,- ./012.3 G/%7(<= .>(<%& 7$%'( [* XVQ PQRST W\VQ]^_T`abQR c^deY J(%4&< .;3 '172/<.1?( 7.'3 %?@A7.'3 %(@14(<* rcSVsQ^ctRabu m(*@= >35(%.>3/1'74= .>3%/1'.7= >35/. %1'74= v35(! '1&:(.7 4(;1.?7= >35/>371.= wcu PQRST m'(5<1@ / .>(35 /- (<'/2%1<5&.>3= %(- ./kD, v xy 6H*" -/%'(-1< @ .>( Dv  @%&'(A76%1.3B PTcTQR] Pz^SRcsT |  
| OPQRS T U, /)2>,/'56%(,3)9 VWP OPQRS TXYZ[\]RYZ^ _`WaS bY_`Qacde_WdQY[ fgh S\iQ_YWZjk : l,3'(,1 +%('23 7'$%+1, '%(2 3/,61'32 506(', 2)9 : m,1 )0+26(/ $.+,$)'(N$.+,'(0%1)>* 6,3)'/21 6,3)0-(%',3 ,5 %32/,61'3-<')( ,<0'/2 %) >23( ,52%1-.n>,13'< GoBD* 6,1(')-* BCD%3/512BFM%-),63)'/21 <,3%/(1+'3)* 2K $,1>,32)* %3/+1,-%6('3 -24 )* %72-%)6,.3(1,+'3 )(>0-%(',3 (2) =$,0< '(>%.3,(&20)5- '3/%<3,)'< 2%1-. )26,3/%1. %/123- ')05'623.?9 : H5 BCDp"9qrs U*,1BCDturvsU* ,163)'(23-. ,0(51%3<2 '3 u)0&2J 3( >2%)012>23()* '36-0/2 51 BF%()0&2J 3( 6.-2) %) 6-'3 %-. '3/6%(2/ 3 6,)'/21 6,3)0-(%',3 5%3 23/,61'3-<')(9                                                                                                                                                                                                |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
|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|  
!"#  
$%&'()*
+,-./'+)%*
+,-.01'%*
$.+,(23)',*
+$,( &'%*
4)0%5'2/60()
%3/72%83)9 : ;%('23)
$,0-/
&2($,10<$-.
24%-0(2/
,10-2,(%3. -(213%'422(',-<.
=29<
*/')2%
+1,<2)',3
6-0/'3<
&1%'3
>2(%) 2*
,1'3526(',3)?9 : @2+3/'<
, ($2)0+26(/
3,61'3 (+%$.*
>,3'(,1
%3/24%-0(2($.1,'/
5036(',
2)A
BCD*512BE%3/512BF%3/,($21
-4%3(23/,61'32
%/12-%(/
-%&)=29<*
&-,/
<-06,)2
%3/82(,3
-4 )*D<G!6?9 : H342)('<%,1)
$,0-/
%)80&I26()
7'$23/,61'3+%($'2)
7$,>%.12J0'
+,-3<2/
,163('02/
$,1>,3%12+%6>23(*
,63)0-(($2'1
+>%.
6%2+$.)'6%3)
,123/,61'3-<')(
%&,0(
51$2 >,3'(,13<
%/(12%>23
%521
6,>+-2(',3
5($2)0/.9 : H5
%+('23
K+1'36)
%3GL($%')$,0<(
,&2+,)'&-.
,5%0(,'>>032
%(012
=9<*
($.1,'/()*
+%3612(')*
$.+, )'(*
,1/'%&2()
'3 +/0)?*
($2'34)('<%,1
)$0-/
)23 %&-,/
)%>+-2
5,1%+1, '%(2
0,'>>032
%('&,/.
(2)'3<9  
$.+,'(0%1)>*
%3/%/123')05'623.M2K,61'32
43(
,5%>.-)2N'+%)2
'3612%)/%-),
'36-0/2
'3($))26(',3?  
WX$
#$%&'
(YZ[\]^&Z[_
`aXb'
cZ`abdef`Xe%Z\
'[&X\$Z[f%`adgh i j*18=<5
/1.*2+31<?385
*?=3./
J-<=53*1
D/1.*2+31/
D=253*-1.>
831.2-5/.
;78=4/25.
1*2+314-567
1. 82<31 -<731.2-5/.>
2*183./+
435=-+7
82-1A i )*+
-<453/18
F36-;1*+9- 1 <
/1.*2+3/
F*+k=4>/E245
6*8/
F35638*<-5/.
674*5 +3.89
*+
:74/!Sl>-1. 8?=3./
;7-1/1.*2+31<?385>
2*183./+
86*5m/9
2*53 8/+3.8
N/A?>
!5*0
9?@k?.-7
9/567<4+/.138*<1/
+Cn/M=3J-</15O
-.4+*945315-*1
D5+/-9/1
F36+/<J-15
6*+9*1/
+4<-29/15
N/A?>67.+*2 5381/>
8E6*+9*1/8OA i C8*<-5/.
674*5 +3.89
9-7
;/5+-.
F356+/4<-29/15
6/+-47>F356*=
8 .7
+=?@85.7
+/?39/1
5/+=453*1>
-.F356*=2*+53 8/+3.8A i C8*<-5/.
:74/!.3-;/58
9/<35=8
NSlO
9-7;/5+-.
F356-4+* 3-5/
.3-;/52
6/+-47>
F356*=
8 .7
+=?@85.7
+/?39/1315/+=453*1>
-.F356*=
2+3 8/+3.8A
o1<76*.85=7.+=?@85.7
+/?39/1 8/531?
*D674/+?<72/93F6/1.3-?1*8532F*+k=4
38*35J/
D*+.3-;/52
k/5*-23.8A i o12/
4-53/18
* 5/+*3.8
-+/394+*J31?>
+-.=<7
5-4/+399=1*8=4+/83J
5+*3.8
N- 4+* 3-5/
1.F356?=3.-12/
*D/1.*2+31<?385O
*J/+pqr.-781.2*83./+
4*67<-253-153;*28>
-153D=?-<8>
1. 53mLs
5+/-9/1
N+/D
5*2=+/15tj
?=3./<18
D*+5/-9/1
*D2-1/+m<-5 - .
31D/253*18OA i )*+
4-53/18
F361*+9-<
/1.*2+31/
F*+k=4
N<-;*+57
-8/ 9/15*+
luC82-1O>
+/4-5
<;*+57
-8/ 9/15@luC
-82<31 -<731.2-5/.A  
!"  
#$%&'
( )*+
,-./
0 1.*2+314-567
* /+
-1674*5 +3.89
-1.
:74/!.3-;/58 9/<35=8>
6*<.85=7
+=?@85.7
+/?39/1.*8/
=153<
4-53/1
82<1 -<7
85-;</A B CD
5*E3257
F*+8/1>
56/1+8,+-./
G*+,-./
HAI5=.7
+=?@85.7
+/?39/1
2- ;/+8=9/.*12/
J15
8-;3<K/8
-1. D5/+
2*94</53*1*D
85/+*3.
5-4/+AL-53/18
F36/1.*2+314-563/8
F6*9-7+/M=3
4*<1?/.
*+2153=/.
85+*3.+/4<-29/15
N/A?>
-.+/1<
38=D32/17O2-1
;/+5-.
F3568=.7
+=?@85.7+/?39/1
* 56/D*<F31?
2*.35*18P!A :6/
J15
8-;3<K/8
-1.382*15+</.A0A : 1 6/
4-53/
82<1 -<7
85-;</
84/+31J/853?-*+ 5/-31?
467832-1Q82<31 -<
R=.?/9/15AGA S*8/
D4+/.138*/
-+TUV9?@.-7*+
/M=3J-</15A  
| U(# "#$%& '(#)V W X+3:?>7 03/+4,53>A5:7 +A?5/0 G.>?75+3 I03/+4,530 I?475+ .3/@ :53/4.70/ =9:?6047/ 3+4,536.789 3/ :4>53 .>9 53/4.70/@ 4+3:5/0, 657?.,9 :4.3E Y+:657.>H7+3 ,04+;;03/0E W *+, .>67503: K58.=3+,;.> 03/+4,530 K+,Z?6@0[467 8+:0 K578 5:+>.70/ 896+7 ,5/:; +, <960!Q\@.3/ :A?5/0 =9.3 03/+4,53>A5:7@ 6,+;67>9 537.0 ;65,4 ]^;0789>6,0/35:+>30 ! 7+ N;ABZA/.9 +,0L?5G.>037@ .:K0>.:,0>G.37 8+,;+30 ,06>.4;037 C0EA@ 89/,+4 75:30@ :[8+,;+30:DE W *+, ./03> 4,5:@ 0G, /89,.75+3@ 896+703:5+@ ,:84Z@ 5;;0/5.70>9 537.0 ]^4+,75 :0,5/: K78;530,.>+4,75 / .475G9E W ]:+>.70/ 896+7 ,5/:; ;.9 =07,./ K578,06>.4;037 80,.69@ K578+? : /9 ,?AB:7/9 ,0A5;03 70,?675+3@ ./K578+? 4+,75 :0,5/:E W ]:+>.70/ <960!/5.=07: ;0>57?: ;.9=07,./ K578.6,+ 5.70 /5.=074 80,.69@ K578+? : /9 ,?AB:7/9 ,0A5;03 70,?675+3@ ./ K578+? 4,5 :0,5/:E _3>98+/:7?9 ,?AB:7/9 ,0A5;03 :0753A +I8960,A>940;5. K803/5.A3+:754 K+,Z?6 5:+57G0 I+, /5.=074 Z07+.45/:E W _340 6.7503: + 70,+5/: .,05;6,+G53A@ ,./?>9 7.60, 5;;?3+:?6,0:5G 7,+5/: C. 6,+ 5.70 3/K578A?5/.340 +I 03/+4,53>A5:7D +G0,`ab/.9:3/4+:5/0, 6+89>.475 .375=+4:@ .375I?A.>:@ 3/ 75cJd 7,0.;03 C,0I 7+4?,037 eX  A?5/0>3: I+,70.;03 +I4.30,c>.7/ 53I0475+3:DE  Q+:0 \+/5I4.7+3: C-03,.> -?5/.340DM 3+0 Q+:0 \+/5I4.7+3: C-,./0 !DMe+/:0 ;+ I/54.7+3: Q+:0 \+/5I4.7+3: C-,./0 N@1+,2DM ]3 4+:?>7.5+3 K78,0>G.37 6 4,0754 :6045.>:7 4+3:5/0, 4+375? A :7?/9 /,?AB:7/9 ,0A5;03 I+ 4>53 .>B,/5+>A4 0G/34 +I6.34,075: h 5;6,+G0;037 5.;9>:0B56.:0E "#$%& '(#) *+, -./0 1+,203/+4,536.789 + 0, 78.3 96+7 ,5/:; .3/ <960!/5.=07:  ;0>57?:@ 8+>/:7?9 ,?AB:7/9 ,0A5;03 /+:0 ?375> 03/+4,536.789 :;67+;C:D .,0 4+37,>0/E F7?/9 ,?AB:7/9 ,0A5;03 4. =0,:?;0/ +340 G37 :.=5>H0: .3/ I70, 4+;6>075+3 +I :70,+5/ 7.60,E J.7503: K5803/+4,536.7850: K8+;.9 ,0L?5 6+>3A0/ +,4375?0/ :7,+5/ ,06>.4;037 C0EA@ ./,03> 5:?I54039D 4.3 =0,7./ K578:?/9 ,?AB:7/9 ,0A5;03 + 780I+>K53A 4+/57+3:M !E <80 G37 :.=5>H0: .3/5: 4+37,>0/E NE <80 6.7503 :4>3 .>9 :7.=>0 :60, 53G0:75A.+,  70.53A 689:54.3O: 4>53 .> P?/A0;037E 1E Q+:0 I6,0/35:+0 .,RST;AB/.9 +, 0L?5G.>037E ! f;9>.:0Bg56.:0 534,0.:/   |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
Q+:0
\+/5I4.7+3:
C-03,.>
-?5/.340DM3+0Q+:0
\+/5I4.7+3:
C-,./0
!DMe+/:0 ;+ I/54.7+3:Q+:0
\+/5I4.7+3:
C-,./0
N@1+,2DM]3
4+:?>7.5+3
K78,0>G.37
6 4,0754:6045.>:7
4+3:5/0,
4+375? A
:7?/9/,?AB:7/9
,0A5;03
I+4>53 .>B,/5+>A4
0G/34
+I6.34,075:h
5;6,+G0;037
5.;9>:0B56.:0E  
*+,
f39-,./0Wijk
;+/0:7
.9;67+;.54
0>G.75+3: 0,?;
.;9>:0
3/>56.:0@4+,75 :0,5/
7,0.;03
5:3+75/4.70/
:>+3A.:780,
. 3+ 780,:5A3
+,9;67+;:
I6.34,0754
3I>.;;.75+3EWlm
5:+>.70/
>G.75+3
I03H9;0:
K578+?
0G5/34
+I6.34,075:@4+375?0
;;?3+780,.69EWnop
I+,:5A3B9;67+;:
I6.34,075:Wqjrostpk
.6,+ 5.70
/5.A3+:754
0:53A
C0E@
.=/+;53.>
X<K5784+37,.:@
\uXJ
5I4>3 .>
:?654+3
I6.34,075:
.3/ +,./5+>A40G5/34
+ X<DWqjrostpk
+780,
4.?:0
+I0>G.7/
;9>:0B56.:0  
bbreviated Title: Immune Checkpoint Inhibition
Tersion Date: 04/28/21  
  
.cute Pancreatitis  
|
Promptly start systemic steroids prednisone 1 to 2 mg/kg/day PO or I equivalent                                                   |                     |                                         |              |
|---------------------------------------------------|---------------------|-----------------------------------------|--------------|
| Manage per amylase/lipase increased (asymptomatic |                     |                                         |              |
| fonsider gastroenterology referral                | for Grade 2,3 or 4: |                                         |              |
| For Any Grade                                     | For Grade 1:        | V hydration                             | IV hydration |
| ose Modification (Grade 2): Hold study
rules and resiment in resolution of the consider resolution
in consider resiment in order to the consider resilution of the consider                                                   |                     |                                         |              |
| Dose Modifications (General Guidance):            | nodifications (Grade 1): No dose
nodifications                     | Permanently discontinue study drug/stud |              |
| necialist                                         | regimen             |                                         |              |
| one                                               |                     |                                         |              |  
Y'&
HI,J&KL$Z [ \]^
Q RN_`S^_
Ba bPQ_?
cS^BRNS QbadP_O]NQPeS
\]^RNaC^RdS [ c;.061<
:/435
76D;34.65
/=436/.;1> 3.6=1;0D6
.0/3A>-6UA?
50<6;
9=/A6<0/1?
M62.0/1<?
86.;7/302
<>15=/86<?
/= 86502;./1<GU [ B/10./=
9;.061
M/=A61=;3
<>89./8<
-:6;52:6?
1;4<6?
D=.0A/?76:;D0/=
2:;1A6?
/=f6;g1<GU [ O/1<056=
;9 / 0;.6
50;A1/<.02
6<01A
-6U?
632.=/8>A=;8
1516=D
2/154.0/1
D6<.0A;/1<GU [ c6=M/8
<>89./8;20
=6;861
f0:N64=/3A>
21<43.
;<;9=/ 0;.6U  
#$%&'()*+(,2 -./
013456
7.1/763080.65
/308726129:;30.<
;15;4./1802
164=/9;.:>?6@234501A
B>;<.:610;C=;D0<
15C403;1EF;=6G  
HI,
J&KL$-56910A
/ .:6>9/M
164=/.@02.>?
=6M./
NOP Q RS
DTUVM/=
56M01 A
.:6OQA=;56W<D=0.>G J$I$&KX
J%*LKI+$  
| 67$ #$%&' L8 9 Z*4,/+-?O 2,4-1,2?=O +/,1N /4E T3J -,N+= GJ /,1245 9 [A32/4 )-N?*DE= 14,ND35 9 :-4,*?= 4-N?*G23J=F4-N?*G23J/1 G24.2=A-.242E-+ A=2G?* /23-  .-+/123*4, H-5EO 2AG-43/ *?+ND*I-3/4K5 9 V?*.G3D= ,2? ,= -./1 ,3-?*/+, G?-+4/,*- !3*W.EF\E+2= V[*?S] -^N/B2D-435 9 S0 4*/.G?*B-.-43 T/J4 W3*U+2=,-G/3 !*W.EF\E+2= G?-+4/,*- V[*?S]-^N/B2D-43O 1*4,/+-? 2 /3*42D T*?\NG 24+ G?*.G3D= ?-2 T/J2+/3*42D /..N4*,NG?-,/B 3J?2G= H-5EO S] > *3J-? /..N4*,NG?-,/B +G4/E * 3J-,G1/0 .<XK5                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
|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`8 9 Z*4,/+-?O 2,4-1,2?=O +/,1N /4E T3J,N+= GJ,/1245 9 [A32/4 )-N?*DE= 14,ND35 9 Z*4,/+-? J*,G/32Da3*45 9 V?*.G3D= /432- .G/?1 S].-3J=DG?-+4/,*D4- !3*W.EF\E+2= *? -^N/B2D-435 9 S0 4*/.G?*B-.-43 T/J4 W3*U+2=,-G/3 S]1*?3/ ,-?/+,O 1*4,/+-? 2 /3 D *42 T*?\NG 24+G?*.G3D= ?-2 T/J2+/3*42D /..N4*,NG?-,243 H-5EO S] > *?3J-? /..N4*,NG?-,/B +-G4/E * 3J-,G1/0 .<XK5 [41- ,32AD-O E?2+ND= 32G-? ,3*/+, B-?bcd 2+=,5 #$%&' _7$` 67$ #$%&' _7$`8 V-?.24 3D= +/,1*43/  N-,3+= ?NEF,3+= ?-E/.-45 |  
67$
njo#$%&'8 9 CJG?*.G3
+/2E4*,/
0/..N4-q.-+/23G?/J 2D
4-N?*.*3?,=4+?*.-,
/ .G*?324O
,/41?32/4
G3/-4,
.2=N4G?-+/132AD=  
!"  
e'$fgh %ij'k$7l7m$njo
#$%&' #'j'$%i
#kf&%jp'  
obreviated Title: Immune Checkpoint Inhibition
ersion Date: 04/28/21  
| impering in the supposition in the consider of the considered by t   |                                   |                                      |                                       |
|----------------------------------------------------------------------|-----------------------------------|--------------------------------------|---------------------------------------|
| sent o                                                               | .
Obtain a Neuropathy/neuropathic pain may be managed by appropriate
potential decompensation as described above.
Consider, as necessary, discussing with the study physician.                                   |                                      |                                       |
| Consider, as necessary, discussing with the study physician.         | ptain a Neurology consult         |                                      |                                       |
| Grade 1:                                                             | Grade 2:                          |                                      |                                       |
| lold study drug/study regimen dose until
esolution to Grade ≤ 1.                                                                      | mnntly discontinue study drug/stu | imen if it does not resolve to Grade | respiratory insufficiency or autonomy |
| vithin 30 days or if there are signs                                 |                                   |                                      |                                       |
| dose modification                                                    | GB: moderate sympto               | MO moderate; minim                   |                                       |
| vasthenia gravis                                                     | gnostic observation               | ocal or noninvasive                  |                                       |
| Guillain-Barre [G                                                    | mptomatic or m                    | ptoms; clinical                      | mting instrument                      |
| nly; intervention                                                    |                                   |                                      |                                       |
| l symptom                                                            | didicated)                        | Grade 2                              |                                       |
| Grade 1                                                              | (DL)                              |                                      |                                       |
| such as Guillai                                                      | y as thenia grav                  |                                      |                                       |
| yndromes                                                             | arre and                          |                                      |                                       |  
|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le` _`abc de`ftucv` e wxycz{|`a }x~ cv}{um L X)$3#*&'= ,3$&+3,':= *#3+4 #$0 Q%O34*: 2O3#+,$; L €&+)//&$* O)32#%,.k%)$; L j)   $#%)'3:/2%)/3 ,$*)9%,#$ &4').0: +$34.%; ?@ABCDEFGA HI JGBK L M%&')#*3 /,:9&34+& N4.: 3&*%)'&, /:3%O&$#, 0'(#3; 'O&: 3O)4.* %:2#+,.: 9&,*/#$#3%&'* #$,/)$#%)'&* 3%#$0 4*&' 342&'(#3)$ N,+)$34.%#$0 &4').0#3%; L S,%#&$3 4,9.& %) .&',% 3')#*3 /,:9&+,$*# %&3 N)'%&,/&$ Q#O 2.,3/,2O&'3# )'PT U; L PN /:,3%O&$#, 0'(#31.V& $4')%>#+%: 2'&3$%= +)$3#*&' 3%,#$0 5XOY #$O9%)' O&,2: #$,*#%)$  3&')#*3; M4+O%&',2:= #N34+& N4.= +,$ ,.3) &'( %)'&#$N)'+& %O *#,0$)3#; HZG[AF\]AI EKle` _`abc dm n).* 3%4: '40o3%*: '&0#/&$ *)3&4$%#. '&3).4%#$  U',*& pqr S&'/,$ %.: *#3+)$%#4& 3%*: '40o3%*: '&0#/&$ NU',*& g#/5Y *)&3$%'&3).( %) U',*& pqQ#%O$ gs*,:3)'#N%O&' , 3#0$ )N'&32#,%): #$34N#+&$: )' ,4%)$/#+ #$3%,9#.%:; le` _`abc fm _`abc de`f <U',*& gU^h3&(' 3:/2%)/3- .#/#%$0 3&.N +,'& 567- U',*& iU^h.#N&1 %O'&,$#0 +)3&W4$+3- 4'0&$% #&'($%#) #$*+,%&*- #$%49,#)$8 <U',*& gjUh3&(' ) /&*#+,.: 3#0$N+,$% 94 $)% #//&*#,%&.: #N&1 %O'&,$#0- O)32#%,.k%)$ ' #$%&'($%#) *+,%&*- .#/#%$0 ,&12') #,%& #$3%'4/&$%,. 5678 #$3%,9#.%:;   |
|---|  
!"  
| itial motion abnormalities when needed.
use oximetry (resting and exertion), and additional laboratory work
indicated Spiritude clinical evaluation, BNP, cardiac                                                                  | e.g., disease progression, other medications, or infections)                 |                                     |                    |
|------------------------------------------------------------------|------------------------------------------------------------------------------|-------------------------------------|--------------------|
| is important to consider here that the use of steroids as the prima
y plasmapheresis if not responsive to IV IG.                                                                  | omplete ardiac biopsy, including any other diagnostic procedures and when to |                                     |                    |
| rsening chest pain, arrhythmia, shortness of breath, peripheral  |                                                                              |                                     |                    |
| articularly in patients with baseline cardiopulmonary disease as | ensider, as necessary, discussing with the study physician                   | For Grade 1 (no definitive finding: |                    |
| Any Grade                                                        | Io dose modifications required unless                                        |                                     |                    |
| Permanently discontinue study drug/stud                          | 117                                                                          |                                     |                    |
| oven immune-mediated myocardit                                   |                                                                              |                                     |                    |
| Charter 1999.                                                    |                                                                              |                                     |                    |
| rgimen.                                                          |                                                                              |                                     |                    |
| rolongation of existing                                          | pitalization indicator                                                       | iting self care AD                  | reatening conseque |
| rade 4 MG: life                                                  | gnt intervention                                                             | Grade 1                             |                    |
| any Grade                                                        |                                                                              |                                     |                    |
| (adicated)                                                       | yocardit                                                                     |                                     |                    |  
obreviated Title: Immune Checkpoint Inhibition
ersion Date: 04/28/21 breviated Title: Immune Checkpoint Inhibition
Irsion Date: 04/28/21  
| t not the contrainding of plays depending the contrained with the contrained.
1 September 1 does a the first on the first event.
1 september 1 is in the contrained with the                                                      | s and consider prophylactic antibiotics, antifungals, or anti-P   |                                |                                |                    |
|------------------------------------------------------|-------------------------------------------------------------------|--------------------------------|--------------------------------|--------------------|
| NP, cardiac enzymes, ECG, ECHO, pulse oximetry (resting an
certion), and laboratory work-up as clinically indicated.                                                      | nd when to complete diagnostic procedures including a can         |                                |                                |                    |
| sisted to the control of the control of the control. | Monitor symptoms daily, hospitalize                               | uportive care (e.g., oxygen)   | ated infections)               |                    |
| r Grade 2-4                                          | opsy.                                                             |                                |                                |                    |
| ade 0, then the decision to reinitial                | / drug/study regimen will be bas                                  |                                |                                |                    |
| hold study drug/study regimen dose
during diagnostic work-up for other                                                      | tiologies. If study drug/study regime
eld, resume after complete resolutio                                                                   | gimen dose until resolution to | scontinue study drug/study reg |                    |
| nt and after completion                              | rade 3-4, permanently disconting                                  |                                |                                |                    |
| ol and the control of the control.                   | dy drug/study regime                                              |                                |                                |                    |
| Grade 0.                                             |                                                                   |                                |                                |                    |
| otoms*; clinical or                                  | 'reat myocarditis with                                            |                                |                                |                    |
| symptomatic or mild                                  | nstic observation                                                 | ly; intervention not           | irade 3: Severe w              | merapy or mechanic |
| th moderate activ                                    | tion indicated;                                                   | onsider "new or                |                                |                    |
| th minimal activ                                     | ervention indic                                                   |                                |                                |                    |
| set of symptom                                       | g., continuous                                                    | nyocarditis.                   |                                |                    |
| nild symptoms :                                      | exertion; inter                                                   | reatening cons                 | erring to paties               |                    |
| Frade 2, 3 or 4                                      | ences; urgen                                                      | symptoms" a                    |                                |                    |
| irade 4: Life                                        |                                                                   |                                |                                |                    |
| exertion)                                            |                                                                   |                                |                                |                    |
| dicated)                                             | Grade 2.                                                          |                                |                                |                    |  
:%4
12$34567; < =>?@A>B
CDA@E?F
G>BF@H?
DIFJKCA>KF
GCLJMKJ>F@ANOJC@PDLJQ
KRFPLE
SDT?FMCD@?
>PRBF
@?CB>U@KDL
KRFPLE@?PLRI@?H
RCEB
DKFQAV@HFQ
>RLIEBFQ
V@CFQ
?EPTD?IWPTQ
WRABDELJ
DGEPAF
VEUABK@@F
?PLRI@?H
VDIF G@HEBFX
DL>I@GPRLAJ
WBEDAV@?H
DIM>B
ARWLE
FSDL> @?H
PD > RB
D?ICB>HEF
DC@ILJN
Y?PBEDFI
H?BDL
GE@?HF
>GA@BEI?F
D?IGA@HRE KDJ
>PRBQ
D?IAVEB
PD?WE SZ>FEA
GDL@?HQ
I@GPRLAJ
HE@?H
RCGB>K
D
GLQ
?IAB>RWLE
P@KW?H
FAD@BQ
AD?I@H
RCGB>K
D
FEAIC>F@A?Q
DIM>B
EDPV@?H
RCN < YG
C>LJMKJ>F@A RCEPAIQ
D[ERB>LHJ
P?FRLAD@>?
FVRLI
WE>WAD@?EI
DBLJQ
S@AVCB>KCA
HR@ID?PE
> I@DH?>FA@P
CB>EIRBFN =J>PDBI@AF
KDJP>Z RB
S@AVC>LJMKJ>F@AX
BEG
A>HR@ID?PER?IEB
=J>PDBI@AFN
\]E?
WBDAV@?H
P>KCL@PDA>?FQ
BEG
A>HR@ID?PER?IEB
^?RK>?@AFMY_`N\@]E?
C>F@WLAJ
>GD?EU@FA?
aWRCBE]@>RFLJ
?T>S bDRA>@KKR?E
I@F>BEQ
P>?F@IEB
cVRKDA>LHJ
P?FRLAD@>?N < d>?F@IEBQ
DF?EPFDBJQ
I@FPR @?H
SAV EFRIJ
CVF@PD?N < Y?@ADL
S>BTZRC
FV>RLI
@?PLRIE
PL@? DL
E] RA@>?Q
PBEDA@?
T DFEQDLI> FEQ
_`eQ
fg[MPBEDA@? EQ
BJAV>PJAE
FI@KE?AD@>?
BDAE>BdZBEDPA@]E
CB>AE@?
L] Q
RB@?E
KJ>HLW@?Q
DI @A>?DL
W>BAJS>BTZRC
DF@?IPDAEIQ
@?PLRI@?H
D RKWEB
>GCF@WLEBVERKDA>LH@PDLM?A@W>IJ
AEF
a@NEQ
P>?F@IEB
SVA B
DBVERKDA>LH@FA
P>?FRLAD@>?
F?IPDAEI
? P>RLI
H@E
? IG>BBVERKDA>@I
GDPA>BQ
D?A@RPLEDB
?A@W>IJQ
D?A@ZFK>>AV
KRFPLEQD?A@FJ VEDF
hRPV
DF?A@Zi>!jQ
D?IM>B
F@H?DLZBEP>H?@A>
CDBA@PLED?A@W>IEFbN
d>?G@BKDA>J
EF@?H
KDJ@?PLRIE
LPAB>KJHBDCVJQ?EB]
P>?IRA@>?
FARI@EFQ
=cY>GAVEKRFPLEQ
D?IM>B
DKRFPLEW@>CFJN
d>?F@IEB
fD@RK  
!"  
#$%&'()*%+$,$%&'(-.*%+$),$%&'(/012$
34567 372745+
38'65297  
| GH@ ?@ABC MI $ J)10/)+ %3<4/)<% 2'0(3 12=)%02,+ 5)%40/'(\/)17 $ ]9/'01 F,.+)(63 =1%.(/; '120/', -'(./0)17 $ L)1%02,+; '%1,=%'+3; 20%=. 016 &/5 ,%.23 45%0='17 $ ^* =(01 '( ).+%, 0+'402(3 4+)6,%-0  :4'+/0=.('+3 0*2 =.(/3 9+,'/5016 '2V)+ /.9(, %&'() 016>; 4+)<4/(3 %'+ ^_ <,/53(4+,210%)(1, "/)K<6VN62'3 % /,<0= %/,+)02% '()16 &0/5 +,=0-16 4./ *+)< F,.+)(63 =1%.(/'1  $ ^* =(01 '( ).+%, 0`ab+'402(3 4+)6,%0-; %/'+ %3 ,<0= %/,+)02% :,76; 4+,210%), !/)"<6VN62'3 8])+^_,c.0-'(,1/>O 0*1) 0<4+)-,<,1/ &051 "/)[2'3%; =)1/0., '20/)1'( &)+N.4'12 %/'+ ,'<,1 &05^_<,/53(4+,210%)(1, "/)K<6VN62'3 $ ^* '/,+ %' )*^_<,/53(4+,210%)(1, '/")K<6VN62'3 /5,+ 0% 1) 0<4+)-,<,1/ &051 "/)[2'3%; =)1%02,+ %/' )* 0<<.1)%.4+,%0- /5+'43 %.=5'%dFe0159/)+% :,76; 01*(f<'9 '/ g<6VN6 ^_;<'39,+4'/2  " 12h&,N% '*/,+ 01/'( 2)%, '/ 5,20%=+,/0)1 */5,+'016 4+)-02,+ >7L'./0)1i ^/0%<4)+/'1 ) +.(, )/%,40 '12+,* /)01*(f<'9 (', *)+6,1+'( 6.02'1=, 9,*)+ .%016 *(f<'97 $ ]1=, /5 0 4'/,1 %<4+)-016; +'2.(3 /'4,+ %/)02% -,+   |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
|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|  
!"#  
$ %&'()
*+,-'(./0)1
*23%45'60
)+23%45)10'78'/0,1%
5).(2
9,/5)+.65(3
,-'(./,2
)+.(,)/'13 (/,+1'0-,,/0)(63
:,76;
20%,'
4+)6,%0)1;
/5,+
<,20='/)1%;
+01*,=/0)1%>7  
| WID CDEFG HIDJ`aGbD I cdeGfghDE idj GbigakX # l-+.4-0 *)=14-=* ,3-*/)Q 0/,-==/+' 2-*1.4(3m4-+B # n54(.+ ?/80-39) ,+*8346 (+',-=13/4 783/O(84.-+B # @-+*.'/06 (*+/,*(0)6 '.*,8 .+9 N42 /*8') 12*.,(+B # ;0-=143) *(0 op=/42)310/'+.*-3+/ "4-U=9ZP9'() * 4/=., *4/0-.'* (3-+9 N.420/,.O+9 184 70-= ?/80-39) ,+*834(+B # o7 (4/0 *( -7op=/42)310/'+.*-3+/ (4"-U=9ZP9'() 42/0 .* +- .=10-O/=/+4 N.2+ "4-L'()*6 ,-+*.'/0 *4( -7 .==8+-*810/*.O 420(1) *8,2(*q?r.+254-0* >/B96 .+73s=(5 (4 t=9ZP9 op6=()5/01(4'  " +'uN/P* (74/0 .+4(3 '-*/ (4 2/'.*,0/4.-+ 742/0(.+9 10-O.'/0 AB@(84.-+M o4.*=1-04(+ - 083/ -4*/1. (+'0/7 4-.+73s=(5 3(/ 7-09/+0(3 98.'(+,/ 5/7-0 8*.+9 73s=(5B # @-+*.'/0 N24 0 1(4./+ =()0/V8. op K613(*=(12/0*.B # n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q2-0892 /O(384.-+  083/-4(+) 34/0+(.O/ 4.-39) >/B9 '.*/(  10-9/*.-+6 , =.4(+ =/'.,(4-+* ('.7/,4.-+*A : @-+*834(.-+ N420/3O(+4 *1/,.(3*4 : q0/(4 ,-0'.+93)6 (*1/0.+*48-+(3 *4+'0 K0('/ ! : l-+.4-0 (*,3.+ (3) .+',(4/' K0('/ "6LU : q0/(4 ,-0'.+93) (*1/0.+*48 4 -+(3 *+'06 10- .(4/ ,3.+ (3 10,4./ 98.'/3+*6 (+'-42/0 *-,./4) 98.'/3+* >B96 ?@ 6 S-*/ l-'.7,(4-+* >R )K0('/AM w?-4/ . .* 1- .53/ 42(/O+4* N.2(+ .+73(==(4-0)  .==8+/ =/'.(4/  =/,2(+.*= ,-83' ,80 .+ /(03) -09(+*6 -=/ 742/= (0 +-4 /' *1/,.7(3) .+42/* 98.'/3+* S-*/ l-'.7,(4-+* >K0('/ !AM?-'*/ =-'.7,(4-+* S-*/ l-'.7,(4-+* >K0('/ "AMY-3'*48) '089Z*4 / ') 09.=/+ 84.3 0/*-384.+ [xyz{| !-05(*/3.+B o74-s.,4) N-0*/+6 42/+ 0( *K0'/ L-0K('/ UB}48') n42/0 o==8+/ l/'.(4/ v/(,4.-+*   |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
!"
%&
bgaoa<

'()*+',-*.'/0
1-2)3(,4.
(+4.5-,*6
(+4.789(3*6
-0(+4.:;<
40/(=/+
>0/7
4-,80/+4
?@
98.'/3+*
7-04/(=/+
-7,(+/0:3(4 ( '
.+7/,4.-+*AB  
#$%&'
()*+#,-./0
1.2"3!456#/#7-
899*/:
&;+2<.-/,
10.+2-/7
$ ,-=.)>
%-:(?+,@A
=>6-+;#:0
B.@,C
6DE=FD$
G-H:I
J*-)#/+:
D.*9:/,
"3KJ*-)#/+:
?.I8/)*@,I>L
D*78/)*+:
G-H:I
8/M*I>
NBI:9#2,-/7
&0-/+#0
(H *,-./E$&;(
$+:,>0;.-/:
@,I# O
$DG +,-H :@
.?)#-0>
H/7O
$( )H:I@
H/,O
$GB 02#-/:
<;.@ #,@: O
$GP 0#/-:
#9-/.,I#@?:I# O
$%P @<#I,:
9-/.,I#@?:I# O1QR
0.)
*I:#/-,I.7:/O
&P .9<*,:)
.9.7I#<;>O
&P $(
.99./
P:I9-/.07>
&I-,:#
?.I$)H:I@
(H/,@O
8GD /,:I@-#0
*/7)-@:# O
-9$(
-99*/:S9:)-#,:#)H:I@
H/,O
8J 99*/.70=*-/O
8T /,I#H:/.*@O
J8 #@,I.-/:@-/#0O
GFP -H:I
?*/+,-.
:@O
G R .C:I
0-9-,.?/I9#0O
6U86#7/:,-+
I:@./#+:
-9#7/O
R&8R#,-./0
&/+:I
8/@,-*:O
R&
#,-./0
&.9<I:; @/-H
&#/+:I
R,C.I2O
BV WXYZ[\]^_`a
bc\dY]a
</:*9./-#
e?.I9:0>
2/.C
#@WXYZ[\]^_`a
]fcaX
</:*9./-#gOB'
1>9.*,;O
Ph I-.),;>I/-:O
Pi ;>I.j-/:O
P1 .,#0
=-I*=/O
PRF *9.I
/:+.@?#+,.IO
P%k ;>I.-)S@,9*0#,-/7
;.I9./:O
QGR <:I
0-9-,.?/I9#0E  
)I*7l@,)>
I:7-9:/
+# =:I@*9:)
./+::H/,
@#=-0m:@
,.JI#):
no#?,:I+.9<0:,-./
?@,:I.-)
,#<:IE
&./@-):IC;:, I
@,*)>
I*7l@,)>
I:7-9:/
@;.*0)=:
<I9#/ ,0>
)-@+./,-*:)
-/JI#):
":H/,@
C-; 7 02:;.)
?I9.=-),>#/)l.I
9.,#0->
C;:/, >)./,I#<-)0>-9<I.H:
,JI#):
p!*<./,I:#9:/
C-;@>,:9-+
@,:I.-)@
#/ ?.0C-/7
?*0,#<:ID.@:
6.)-?+#,./
eJI#):
hgLk.0)@,*>)I*7l@,)>
I:7-9:/
D.@:6.)-?+#,./
eJI#):
igLD-@+./,-*:
@,)>
I*7l@,)>
I:7-9:/  
(%6'g  
|                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| R*5 >%675/1-S T ULJLVI WKOJXYNZJLM XYJPK Y[IPOXQKIYOZJ \OJ]IXYOVLZK^ T UZ YJOZK WLYOIJX \ZKXOVJ LPX_`WYZ`X \OJNXZJaKIMLYP KLQYOZJX bI^Vc \I]K LJPdZK X[LeOJV Q[OMXc \NX[OJV LPdZK OYQ[JVc LMYIKOZJX  [ILKY  I LJP fMZP WKIXN c P_XWJIL ZKQ[IXY POQZ`\KYc  XeOJKLX[Ig LJP LJW[_MhOX bI^Vc IJKLMOiIP NKYOQL c JVOZIP`Lc j[IiOJVc [_WZYIJXOZc ZK YLQ[_ KPOg^ R*5 75/1- k*5lS T sQIYL`OJZW[I LPdZK LJYO[XL`OJIX `L_fILP`O K JOXYI P WKOJXYNZJLM XYLJPK Y[IPOXQKIYOZJ \Y[IOJ]XYOVLZK^ T tZJXOPIK W `IPOQLYZJ WIKOJXYNZJLM XYJPK WOZ YXNfIr JY PZXI^ T qYIKZOPX [ZNMP JZYfINXP\ZK NYOJI WK`IPOQLYZJ \HKLPI uvOJ\NXZJ KILQYOZJX^ |
| =*E)206 D/%/F-G-%0 75/1- k*5l R*5 75/1- kS m[I OJ\NXZJ KLYIZ\XYNP_ KNVdXYP_ KIVO`IJ `L_fI PIQKLXP f_nop ZK YI`WZKLOM_ JYIKNWYIP NJYOM KIXZMNYOJ \Y[I]JY^ R*5 75/1- lS m[I OJ\NXZJ KLYIZ\XYNP_ KNVdXYP_ KIVO`IJ `L_fI PIQKLXP nop ZK YI`WZKLOM_ JYIKNWYIP NJYOM KIXZMNYOJ \Y[I]JY^ qNfXIr JY O\NXZJ `L_fIVO]J LYnop Z\ Y[I OJYLM J\NXZJ KLYI^ >%6 75/1- HIJKLM HNOPLJQI                                                                                                                                                                                                                                                    |  
75/1w*5x R*5
75/1w*5xSyIK`LJ YM_
POXQZJYONI
XYP_
KNVdXYP_
KIVO`IJ^R*5
75/1w*5xS T ULJLVI
X]K
OJ\NXZJaKIMLYP
KLQYOZJX
WIKOJXYNZJLM
XYJPKX
bI^Vc
zUIWOJ [KOJIc
\ZMjIP
f_z{POW[IJ_PKL`OJI
LP\`ZYOPJIc
LPz{VMNQZ KYO Pg^tm s|
Z``ZJ
mIK`OJZMV_
tKOYIL
\ZKsP]IKX
|]JYX}
zU
OJYKL`NXQNMLK}
z{OJYKL]IJZNX}
~tz LYOZJM
tJQIK
zJXYONI^  
!"#  
$%&'()*%+,-./01
,/20)*%(  
3-45)06
75/1*&08-94-%0
:;<$ = >94-5()*%
?@ABC*(D*1)&2/0*%(  
HIJKL
YNTe\QST[K`
RIVKT\]
erTNK
JXPQKN`
JrKRI\sQUb
NKJ S
OT][KTP L
|YU]KaUJ
bVKTJ
rTUIVKWXT\
JIwVTPK
"`e\KTN
PQSX
sQJr{XP]
}rNQSTU_~YZ
PaKVN
aUJ
d YZ
IOOIU
dKVOQUI\b]
VQJKT
RIVYPaKVN
ZaUJN
Hx TJQIU\
USKV
xUNJQXK_  
| dVKTJ SIVPQUb\]` TNeKVQUNJXIUT\ NJUPV_ dVKTJ SIVPQUb\]` TNeKVQUNJXIUT\ NJUPV_ dVKTJ SIVPQUb\]` TNeKV J QUN XIUT\ NJUPV_ dVKTJ SIVPQUb\]` TNeKVQUNJXIUT\ NJUPV_ dVKTJ SIVPQUb\]` TNeKVQUNJXIUT\ NJUPV_                                    |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| ?%F/318 -0&0G+)+&1                                                                                                                                                                                                                       |
| hI\P NJX] VXbiNJP] VKbQOKU XJQ\ VKNI\XJQU  jklmno !IV [TNK\QU_ qIV YZNJrTPIsUbVTPK JIjkmlno "sQJrU tPT]NIVKNI\a JI jklmno !IV[TNK\QU sJrU !#PT]N` VKXOK JXP] VXbiNJP] VKbQOKU TPOQUQNJVTQIU_ uJrKVsQN` PQNSIUJQXK NJP] VXbiNJP] VKbQOKU_ |
| HIJKL MINKOIPQRSTJIUN TVKUIJVKWXQP RIVYZNUIJPKOKP JI [K V\TJP INXP] VKTOKU ^Q_K` aUJN PXKJIXUPKV\]QUb PQNKT c IVR \T[IVJ] T[UIVOT\QJKN UIJPKOKP JI[K S\QU T\] NQbUR USTJ_                                                                |
| MQNSIUJQXK NJP] VXbiNJP] VKbQOKU ^HIJKL qIVwTPK #\T[N` PKSQNIU JPQNSIUJQXK NrIX\P [K TNP IUTSIOeTU]Qb S\QU T\ NQbUi]OeJION` rKxUaNJQbTIVyN S\QU T\ zXPbOKUJ` TP SIUNX\JTQIU sJr K{eIUNV_c                                                |
|                                                                                                                                                                                                                                          |
| hI\P NJX] VXbiNJP] VKbQOKU XJQ\ VKNI\XJQU  jklmno !IV [TNK\QU_                                                                                                                                                                           |
| HI PNKOIPQRSTJIUN_                                                                                                                                                                                                                       |  
!"#  
$%&'())*&+,-+./01+
2 031/%&4  
5+67/18
970.+
%:1;+<6&1=$>(
? @<
6+74/%&
ABCDE%4+
-%./:301%&4  
@&8
970.+  
970.+
f  
970.+
g  
970.+
p  
970.+
v  
$%&'() *+,-.
/012*34 +56
71(,28
172,429(:4;(<
;7+7=>*2()6
127;
)77:*,
(=
52788
;4:=-) *
=4;742=6)*8
?+@AB%C875  
)=DEFGHIJK
LMFNO ;FG,2(
?PQ$&C5-7;8
RSFTUMIV
HG J IJOLS
DLPFSJK
RSFTUMIV
JK5= WSJGFX(K
5= (* /SJGFXM
?YC /SJGF
ALSZM
?YC[\]^_`ab\c]defgh
d\]^_  
|    |
|----|
| [\kk\l wu op!q " ozrp!q €ld\kk\l "u orpvq " ozrp!q cbhly} ft]ˆfdhlj €ld\kk\l !v orpmq u ozrp!q 'jah !cfy"het kh}fe]t ! ozrp!q ! ozrp!q  " ozrp!q " ozrp!q  ! ozrp!q ! ozrp!q    |
| ihbj d\kk\l mnm o"!p#q !! orpnq slh]k\lfe d t  [\kk\l !!n oupvq "m orpwq xjta_\lfy €ld\kk\l !v orpmq n orp!q ' fldbhytc`ƒ' fldbhyt "c |d [\kk\l "n ovp!q mw o"puq …haye\"f}ybj cft\bht …hayef "t |d €ld\kk\l "# orpvq !" orpnq xfyb_\hy ihbj d\kk\l nw! ompuq !w orpmq "c\kfly} afl" ihbj d\kk\l uvu o!"p†q #u o!pvq €ld\kk\l "v orpwq !r opuq …ja\e_bfctk " ihbj d\kk\l ur# o!pq # orp"q …jahbe_j\fctk " [\kk\l !u† onpmq r '_jb\fce "t   {ybh {ybh {ybh…ja\_tfe`…ja\fe]ybtkŠ}\c dbhyefl h dbhytc‰lc\dbflh ct\bht xfy"het fl ac]t‡yteb\flhtfly} cft\bht [\}fe "t  ~x{htafbye\j| e_\bydf| ylc khcfytel} cft\bht    |  
[\kk\l !r#
oupq u
ozrp!qxjt]bfy  
ld\kk\l w
orpuq "
ozrp!q  
[\kk\l uw
o!puq r  
!"#  
{hly} c]bflyj
cft\bhtha_bfe t  
P kRXVbN
MWRoaUMt
VXRpb]U Mbt
R{XbN
OM{RP XSpVbo] o _VtTWTVNab
\wMbt^
hNVPRS{o
aXMpbaRX
SRMo
habOo`S{MtWMP
wSVW
MX
Vga
NbSMRXUM|NpVX SRo
UtaX Mt
Nb`oT
VbNaoR
VwbORpVtRooMbNR]  
| '()*+,-./0 12+34  5+,678 9:;<=> &?%5$ @A+BC2.D -, / ./41A ) 1:+A/0 @A+BC2.D /0&( EA/,+F 80 &( 8G HA/,+F 2 9I> HA/,+ J1AK 2 9I> L P MNO  QRST UVWWVX c"d \![]Z^ ! \e[]!^ fagOb NhRMbN iVWWVX Yj \!]#^ ! \e[]!^ kRSWMbaN lXUVWWVX "" \[]j^ " \e[]!^  ! \e[]!^ ! \e[]!^ iVWWVX "#v \Z]^ ![# \c]d^ uSMt UXoaMNNkRXbMt XoVSMtNVwbaN`R aXw P UbaVXN  iVWWVX d[ \!]j^ ! \e[]!^ yXwRUbaVXN MoawRNbMaVXN yXwt`RzM iVWWVX Yj \!]#^ " \e[]!^ qTMtgaM iVWWVX !jZ \d]v^ " \e[]!^ qTVNabN lXUVWWVX # \[]"^ ! \e[]!^  " \e[]!^ ! \e[]!^ QRST UVWWVX YZ[ \!#][^ !Z \[]#^ _S`ab PN   QRST UVWWVX Y!Y \c]Z^ ![ \]c^ iVWWVX "v! \]j^ v \[]c^ lpRS NpaMbVT MU P  aXwRUbaVXN  QRST UVWWVX Y[j \!c]d^ # \[]"^ _XR`WV P XaM xU iVWWVX Yv \!]#^ d \[]"^ fVb oRSWaXo || fVb oRSWaXo ||  c \e[]!^ [  iVWWVX #Y \"]!^ [ LMSR LMSRLMSRyWW`XR bOSVWPUTb U pRXaM  yX}`STx pVaNX gx Mo pSVURo`SMt UVWptaUMbVXN yXw`NaVX SRtMbo S P MUbaVX  uRoWM pSaO P Mt  fRS{V`N TbRW oaNVSRN qTMNbORXaM gS R {aN  q`NU`tVnRbM Xo UVXRba{ N`R oaNVSRN _VtTWTVNab o  _RWpOagVoP   qTVUMSoabN_TSRraM~tVo MX tTWpOMbaU NTbRW oaNVSRN mnaX MoN`PUbMXRV`N baN`R oaNVSRN sRXSMt oaNVSRN MXo MoWaXNbSMaVX NbR UVXoabVXN iMSoaU NVSRN   |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
!"#  
$%&  
$ %$&'()*
+(,-./0
+('1
23)(45$./463&'. ($*
/78. 47
3)-*8$3
'-)8*$
'+)9$&'7$*
4)3$
8(4$:
;8)9.'$<.)3
4=(*$
>"? 2@%
A4*<$(3
*-B$4/)8'.C
2DEA47.8$
418.')(43+$(4 C
2FEA43&()$
18.')(43+$(4 C
GHIJF
AG'-./87
+'(H.)$(48' 7
I(B4.83)'.3
+J$*8/47 F/8$. 3C
GE A '11'.
E'K8/)0
G(8)$4C
GE 2L
AG'11'.
E$(18.'7B0
G(8)$4
+'(2*<$(3
L<.)3C
@GIA*4)/-6'+C
HD@A8.)$(3847
-.B*83$4 C J$*@%2
AJ$*8/47
@8/)'.4(0
+'%$B-74)'(0
2/)8< $3C
MA)'47
.-1N$(
'+&4)8$.3C
OEA&($+ *
)(1CFIGA30)$1
'(B4.
/73