Conditions: Metastatic Gastric Cancer Metastatic Breast Cancer Metastatic Colorectal Cancer Metastatic Lung Cancer
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 25
Healthy volunteers: no

Brief summary:
The purpose of this clinical study is to assess the safety and tolerability and efficacy of active immunotherapy with dose escalation and cohort expansion of OBI-833 in advanced/metastatic gastric, lung, colorectal, or breast cancer subjects.

Detailed description:

Arms:
arm 1: Each subject will be given a total of 10 doses of OBI-833/OBI-821 subcutaneously at weeks 1,2,3,4,6,8,12,16,20,and 24 (Visits 1,2,3,4,5,6,7,8,9 and 10, respectively). Post treatment, subjects will be continually evaluated for safety and immune response every 4 weeks until the end of study, which is 12 weeks after the last dose, i.e., week 36. Subsequently, subjects will be followed for survival every 8 weeks up to 12 months after the end of study. arm 2: Each subject will be given OBI-833/OBI-821 at Weeks 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, and every 8 weeks thereafter (Visits 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and every 8 weeks thereafter) until disease progression. For the subjects discontinued treatment because of disease progression, subjects will be continually evaluated for safety and immune response every 8 weeks until the end of the study, which is 24 weeks after the last dose.

Interventions: intervention 1: OBI-833/OBI-821
Intervention descriptions: intervention 1: None

Protocol document:
Prot_000.pdf: 
&OLQLFDO3URWRFRO2%,

2%,3KDUPD,QF

&RQILGHQWLDO
CLINICAL PROTOCOL
An Open-Label Study to Assess the Safety,
Tolerability, and Efficacy of Active Immunotherapy 
with Dose Escalation and Cohort Expansion of OBI-
833 (Globo H-CRM197) in Advanced/Metastatic
Gastric, Lung, Colorectal, or Breast Cancer
Subjects
Product Name:
OBI-833/OBI-821
Protocol Number:
OBI-833-001
Protocol Version:
Version 10.3 – 30/Jul/2020 (US and Taiwan)
US IND Number: 
16138
Sponsor:
OBI Pharma, Inc.
5RRP:)<XDQ4X6WUHHW
1DQNDQJ6RIWZDUH3DUN

7DLSHL7DLZDQ

52&

&RUQHUVWRQH&RXUW:HVW6XLWH

6DQ'LHJR&$

86$

$GGLWLRQDO6WXG\&RQWDFW,QIRUPDWLRQZLOOEHSURYLGHGLQDVHSDUDWHGRFXPHQW

7+(,1)250$7,21&217$,1(',17+,635272&2/,6&21),'(17,$/$1',6,17(1'(')257+(86(2)&/,1,&$/
,19(67,*$7256,7,67+(3523(57<2)2%,3+$50$,1&25,7668%6,',$5,(6$1'6+28/'127%(&23,('%<
25',675,%87('723(56216127,192/9(',17+(&/,1,&$/,19(67,*$7,212)2%,2%,81/(6668&+
3(56216$5(%281'%<$&21),'(17,$/,7<$*5((0(17:,7+2%,3+$50$,1&




&OLQLFDO3URWRFRO2%,

2%,3KDUPD,QF
9HUVLRQ±-XO
&RQILGHQWLDO
3DJHRI

TABLE OF CONTENTS
6<1236,6 
/,672)$%%5(9,$7,216$1''(),1,7,212)7(506 
 
*2$/6$1'2%-(&7,9(6 
 
3ULPDU\2EMHFWLYH 
 
6HFRQGDU\2EMHFWLYH 
 
([SORUDWRU\2EMHFWLYH 
 
%$&.*5281'$1'5$7,21$/()25'(9(/230(17 
 
&DQFHU,PPXQRWKHUDS\ 
 
*ORER+([SUHVVLRQLQ6ROLG7XPRUV 
 
2%,*ORER+&50,PPXQRORJLFDO3URILOH 
 
1RQFOLQLFDO3KDUPDFRORJ\ 
 
7R[LFRORJ\ 
 
5DWLRQDOHIRU7ULDO'HVLJQ 
 
5DWLRQDOHIRU6WDUWLQJ'RVH 
 
(/,*,%,/,7<&5,7(5,$ 
 
,QFOXVLRQ&ULWHULD 
 
([FOXVLRQ&ULWHULD 
 
75($70(173/$1 
 
6XEMHFW(QUROOPHQWDQG'RVH(VFDODWLRQ3URFHGXUH 
 
2%,2%,$GPLQLVWUDWLRQ6FKHGXOHDQG3URFHGXUH 
 
678'<352&('85(6 
 
6FUHHQLQJ3KDVH±3ULRUWR)LUVW'RVLQJRIWKH,QYHVWLJDWLRQDO'UXJ
6FUHHQLQJ9LVLW 
 
7UHDWPHQW3HULRG:HHN±9LVLW 
 
7UHDWPHQW3HULRG:HHNWR:HHN9LVLWWR9LVLW 
 
7UHDWPHQW3HULRG:HHNWR:HHN9LVLWWR9LVLWRU'LVHDVH
3URJUHVVLRQ 
 
3RVW7UHDWPHQW3HULRGWR(QGRI6WXG\:HHNWR:HHN9LVLWWR
9LVLWIRU'RVH(VFDODWLRQ3KDVHDIWHUGLVHDVHSURJUHVVLRQIRU&RKRUW
([SDQVLRQ3KDVH 
 
)ROORZ8S3HULRG8SWR0RQWKV)ROORZLQJ(QGRI6WXG\LH:HHNV
WR 
 
(DUO\7HUPLQDWLRQ 
 
2WKHU6WXG\3URFHGXUHV 
 
0$1$*(0(172)72;,&,7<$1'75($70(17',6&217,18$7,21
 
 
*HQHUDO0DQDJHPHQW 
 
0DQDJHPHQWRI'UXJ,QGXFHG7R[LFLWLHV 


&OLQLFDO3URWRFRO2%,

2%,3KDUPD,QF
9HUVLRQ±-XO
&RQILGHQWLDO
3DJHRI

 
'HILQLWLRQDQG0DQDJHPHQWRI'RVH/LPLWLQJ7R[LFLW\ 
 
*XLGHOLQHVIRU,QGLYLGXDO6XEMHFW6WXG\7UHDWPHQW2%,2%,
'LVFRQWLQXDWLRQ 
 
75($70(1763(50,77('$1'352+,%,7(''85,1*678'< 
 
3HUPLWWHG7UHDWPHQWVGXULQJ6WXG\ 
 
3URKLELWHG7UHDWPHQWVGXULQJ6WXG\ 
 
,19(67,*$7,21$/'58*,1)250$7,21 
 
2%,*ORER+&50 
 
2%, 
 
&OLQLFDO7ULDO0DWHULDO&706XSSO\3DFNDJLQJ/DEHOLQJDQG6WRUDJH 
 
678'<(1'32,17 
 
3ULPDU\(QGSRLQWV 
 
6HFRQGDU\(QGSRLQWV 
 
6DIHW\$VVHVVPHQW 
 
6DIHW\9DULDEOHV 
 5(63216(&5,7(5,$ 
 
'HILQLWLRQVIRU0HDVXUDELOLW\RI7XPRU/HVLRQV 
 
5HFRUGLQJ7XPRU/HVLRQV 
 
5HVSRQVH(YDOXDWLRQ 
 &5,7(5,$)255(029$/)52035272&2/7+(5$3<$1'2))
678'<&5,7(5,$ 
 
&ULWHULDIRU5HPRYDOIURP3URWRFRO7KHUDS\ 
 
2II6WXG\&ULWHULD 
 67$7,67,&$/&216,'(5$7,216 
 
+\SRWKHVHV 
 
7DUJHW6DPSOH6L]H 
 
6DIHW\DQG7R[LFLW\ 
 
6WDWLVWLFDO0HWKRGV 
 
6DIHW\$QDO\VLV 
 
,PPXQH5HVSRQVH$QDO\VLV 
 
([SORUDWRU\$QDO\VLVRI2WKHU%LRPDUNHUV 
 $'9(56((9(176$1'6(5,286$'9(56((9(176 
 
$GYHUVH(YHQWV 
 
$QWLFLSDWHG$GYHUVH(YHQWV 
 
$VVHVVPHQWRI5HODWLRQVKLSWR7UHDWPHQW 
 
6HULRXV$GYHUVH(YHQWV 
 
5HSRUWLQJRI6HULRXV$GYHUVH(YHQWV 
 
3UHJQDQF\ 
 
'DWDDQG6DIHW\0RQLWRULQJ%RDUG 


&OLQLFDO3URWRFRO2%,

2%,3KDUPD,QF
9HUVLRQ±-XO
&RQILGHQWLDO
3DJHRI

 678'<$'0,1,675$7,21$1'021,725,1* 
 
,QVWLWXWLRQDO5HYLHZ%RDUG$SSURYDO 
 
,QIRUPHG&RQVHQW)RUPV 
 
6WXG\&RQGXFWDQG0RQLWRULQJ 
 
&DVH5HSRUW)RUPV 
 
6RXUFH'RFXPHQWV 
 
5HWHQWLRQRI'RFXPHQWV 
 
4XDOLW\&RQWURODQG4XDOLW\$VVXUDQFH 
 
'UXJ$FFRXQWDELOLW\ 
 
6WXG\&RPSOHWLRQ'LVFRQWLQXDWLRQ7HUPLQDWLRQ 
 8VHRI,QIRUPDWLRQDQG3XEOLFDWLRQ 
 5()(5(1&(6 
 $33(1',&(6 
$SSHQGL[,2%,DQG2%,0L[LQJ,QVWUXFWLRQ)2568%&87$1(286
$'0,1,675$7,21 
$SSHQGL[,,3URKLELWHG&RQFRPLWDQW0HGLFDWLRQ
$SSHQGL[,,,(&2*3HUIRUPDQFH6WDWXVDQG5(&,67*XLGHOLQH

LIST OF TABLES
7DEOH 
7LPHDQG(YHQW6FKHGXOHIRU'RVH(VFDODWLRQ3KDVH 
7DEOH 
7LPHDQG(YHQW6FKHGXOHIRU&RKRUW([SDQVLRQ3KDVH 
7DEOH 
2YHUDOO5HVSRQVH7DEOH 
 
 



&OLQLFDO3URWRFRO2%,

2%,3KDUPD,QF
9HUVLRQ±-XO
&RQILGHQWLDO
3DJHRI

SYNOPSIS
Name of Company:
2%,3KDUPD,QF
Name of Compound:

2%,*ORER+&50DQG2%,$GMXYDQW
>2%,2%,@
Study Title:
$Q2SHQ/DEHO6WXG\WR$VVHVVWKH6DIHW\7ROHUDELOLW\DQG(IILFDF\RI
$FWLYH,PPXQRWKHUDS\ZLWK'RVH(VFDODWLRQDQG&RKRUW([SDQVLRQRI2%,
*ORER+&50LQ$GYDQFHG0HWDVWDWLF*DVWULF/XQJ&RORUHFWDO
RU%UHDVW&DQFHU6XEMHFWV
Phase of 
Development:
86DQG7DLZDQ±DUPRIPXOWLQDWLRQDO3KDVH,GRVHHVFDODWLRQDQGFRKRUW
H[SDQVLRQVWXG\
Objectives:
x
7RHYDOXDWHWKHVDIHW\DQGWROHUDELOLW\RI2%,2%,LQVXEMHFWV
ZLWKDGYDQFHGPHWDVWDWLFJDVWULFOXQJFRORUHFWDORUEUHDVWFDQFHU
x
7RDVVHVVKXPRUDOLPPXQHUHVSRQVHVDQWL*ORER+,J*DQG,J0
SURGXFWLRQIROORZLQJVXEFXWDQHRXVDGPLQLVWUDWLRQRI2%,2%,
x
7XPRUUHVSRQVHSHU5(&,67FULWHULD
Endpoints:
3ULPDU\
6DIHW\DQG7ROHUDELOLW\
6HFRQGDU\
,PPXQHUHVSRQVHDQWL*ORER+,J*DQG,J0SURGXFWLRQ 

7XPRUUHVSRQVHSHU5(&,67FULWHULD
Design:
2SHQODEHOQRQUDQGRPL]HGGRVHHVFDODWLRQDQGFRKRUWH[SDQVLRQWULDO
Dose Groups and
Treatments:
7KLVVWXG\FRQVLVWVRIGRVHHVFDODWLRQSKDVHDQGFRKRUWH[SDQVLRQSKDVH$
VWDQGDUGWULDOGHVLJQZLOOEHXVHGIRU2%,2%,GRVHHVFDODWLRQ
SKDVH7KHGRVLQJRI2%,ZLOOEHGLYLGHGLQWRFRKRUWV
x
&RKRUW2%,HTXLYDOHQWWRȝJ*ORER+ȝJ2%,
x
&RKRUW2%,HTXLYDOHQWWRȝJ*ORER+ȝJ2%,
x
&RKRUW2%,HTXLYDOHQWWRȝJ*ORER+ȝJ2%,
8SRQDOORIWKHGRVHHVFDODWLRQSKDVHVXEMHFWVFRPSOHWLQJLQMHFWLRQVRI
2%,2%,2%,6FLHQWLILF&RPPLWWHHMXVWLILHGVDIHW\HIILFDF\DQG
LPPXQHUHVSRQVHGDWDRIDOOWKHGRVHHVFDODWLRQSKDVHVXEMHFWVDQG
UHFRPPHQGPJRI2%,DVWKHGRVHOHYHOIRUFRKRUWH[SDQVLRQSKDVHLQ
OXQJFDQFHU1RQ6PDOO&HOO/XQJ&DQFHU16&/&8SWR16&/&
VXEMHFWVZLOOEHHQUROOHGLQWKHFRKRUWH[SDQVLRQSKDVH
Route of 
Administration
x
6XEFXWDQHRXVVF


&OLQLFDO3URWRFRO2%,

2%,3KDUPD,QF
9HUVLRQ±-XO
&RQILGHQWLDO
3DJHRI

Dosing Frequency 
and Study Duration:
>'RVH(VFDODWLRQ3KDVH@
(DFKVXEMHFWLQGRVHHVFDODWLRQSKDVHZLOOEHJLYHQDWRWDORIGRVHVRI
2%,2%,VXEFXWDQHRXVO\DW:HHNVDQG
9LVLWVDQGUHVSHFWLYHO\
3RVWWUHDWPHQWVXEMHFWVZLOOEHFRQWLQXDOO\HYDOXDWHGIRUVDIHW\DQGLPPXQH
UHVSRQVHHYHU\ZHHNVXQWLOWKHHQGRIWKHVWXG\ZKLFKLVZHHNVDIWHU
WKHODVWGRVHLH:HHN6XEVHTXHQWO\VXEMHFWVZLOOEHIROORZHGIRU
VXUYLYDOHYHU\ZHHNVXSWRPRQWKVDIWHUWKHHQGRIWKHVWXG\

>&RKRUW([SDQVLRQ3KDVH@
,Q FRKRUW H[SDQVLRQ SKDVH VXEMHFWV ZLOO EH JLYHQ 2%,2%, DW
:HHNVDQGHYHU\ZHHNVWKHUHDIWHU9LVLWV
         DQG HYHU\  ZHHNV WKHUHDIWHU XQWLO GLVHDVH
SURJUHVVLRQRUġXSWR\HDUDIWHUWKHODVWVXEMHFWUHFHLYHVWKHILUVWGRVHRI
VWXG\WUHDWPHQW)RUWKHVXEMHFWVGLVFRQWLQXHGWUHDWPHQWEHFDXVHRIGLVHDVH
SURJUHVVLRQVXEMHFWVZLOOEHFRQWLQXDOO\HYDOXDWHGIRUVDIHW\DQGLPPXQH
UHVSRQVHHYHU\ZHHNVXQWLOWKHHQGRIWKHVWXG\ZKLFKLVZHHNVDIWHU
WKHODVWGRVH
6XEMHFWVPD\FRQWLQXHWREHWUHDWHGDWGLVFUHWLRQRIWKHLQYHVWLJDWRUDIWHU
GLVHDVHSURJUHVVLRQ7KHIROORZLQJFOLQLFDOVLWXDWLRQVVKRXOGEHFRQIRUPHG
IRU FRQWLQXRXV LQMHFWLRQ DIWHU GLVHDVH SURJUHVVLRQ )'$ *XLGDQFH IRU
,QGXVWU\
²6XEMHFWVFRQWLQXHWRPHHWDOORWKHUVWXG\SURWRFROHOLJLELOLW\FULWHULD
²$OOGUXJUHODWHGWR[LFLWLHVUHVROYHGWRWKHEDVHOLQHOHYHO
²1RGHWHULRUDWLRQRIVXEMHFWSHUIRUPDQFHVWDWXV
²'RHVQRWGHOD\LPPLQHQWLQWHUYHQWLRQWRSUHYHQWVHULRXVFRPSOLFDWLRQV
RIGLVHDVHSURJUHVVLRQHJ&16PHWDVWDVHV
)RU WKH VXEMHFWV ZKR DUH HOLJLEOH DQG ZLOOLQJ WR FRQWLQXH LQMHFWLRQ DIWHU
GLVHDVHSURJUHVVLRQVXEMHFWVZLOOEHWUHDWHGZLWK2%,2%,HYHU\
ZHHNVIRUDGGLWLRQDOLQMHFWLRQVZKLFKLVDWRWDORIZHHNVDIWHUGLVHDVH
SURJUHVVLRQWRHYDOXDWHFOLQLFDODQGLPPXQHUHVSRQVHV
6XEVHTXHQWO\VXEMHFWVZLOOEHIROORZHGXSIRUVXUYLYDODIWHU(QGRI6WXG\
Dose Limiting 
Toxicity (DLT)
$QHYHQWLQWKHGRVHHVFDODWLRQSKDVHVXEMHFWVZLOOEHFRQVLGHUHGDGRVH
OLPLWLQJ WR[LFLW\ '/7 LI LW RFFXUV ZLWKLQ WKH ILUVW  ZHHNV DIWHU WKH
DGPLQLVWUDWLRQRI2%,2%,DQGPHHWVWKHIROORZLQJFULWHULD

$Q\*UDGHRU*UDGHWR[LFLWLHVFRQVLGHUHGDWOHDVWSRVVLEO\UHODWHG
WRWKHLQYHVWLJDWLRQDOGUXJ
Selection Criteria:
Inclusion Criteria:

6XEMHFWV\HDUVRIDJH
 [Dose Escalation Phase]
+LVWRORJLFDOO\RUF\WRORJLFDOO\FRQILUPHGGLDJQRVLVRIJDVWULFOXQJ
FRORUHFWDORUEUHDVWFDQFHURQILOH
[Cohort Expansion Phase]
+LVWRORJLFDOO\RUF\WRORJLFDOO\FRQILUPHGGLDJQRVLVRI*ORER+SRVLWLYH
16&/&

[Dose Escalation Phase]
6XEMHFWVZLWKUHFXUUHQWRUPHWDVWDWLFLQFXUDEOHGLVHDVHWKDWIDLOHGWR


&OLQLFDO3URWRFRO2%,

2%,3KDUPD,QF
9HUVLRQ±-XO
&RQILGHQWLDO
3DJHRI

UHVSRQGWRDWOHDVWRQHOLQHRIDQWLFDQFHUVWDQGDUGWKHUDS\DQGIRUZKLFK
VWDQGDUGWUHDWPHQWLVQRORQJHUHIIHFWLYHRUWROHUDEOH
[Cohort Expansion Phase] 
6XEMHFWVZLWKPHWDVWDWLF16&/&ZKRKDYHDFKLHYHGVWDEOHGLVHDVH6'
RUSDUWLDOUHVSRQVH35VWDWXVDIWHUDWOHDVWUHJLPHQRIDQWLFDQFHU
WKHUDS\LHFKHPRWKHUDS\RUWDUJHWHGWKHUDS\RU3'3'/
DQWDJRQLVWVHLWKHUDORQHRULQFRPELQDWLRQDQGWKHUHDUHQRVWDQGDUG
WUHDWPHQWVDYDLODEOHH[FHSWSHUPLWWHG7DUJHWRU3'3'/WKHUDSLHVDV
OLVWHGLQVHFWLRQLHDGGRQZLWKRQJRLQJILUVWOLQH7DUJHWHGWKHUDS\
RU3'3'/WKHUDS\

0HDVXUDEOHGLVHDVHLHSUHVHQWZLWKDWOHDVWRQHPHDVXUDEOHOHVLRQSHU
5(&,67YHUVLRQ>(LVHQKDXHU@

[Dose Escalation Phase]
1R NQRZQ FHQWUDO QHUYRXV V\VWHP &16 PHWDVWDVHV RU QHXURORJLFDO
V\PSWRPVSRVVLEO\UHODWHGWRDFWLYH&16PHWDVWDVLVLQ'RVH(VFDODWLRQ
3KDVH
[Cohort Expansion Phase]
6XEMHFWV ZLWK DV\PSWRPDWLF &16 PHWDVWDVHV IRU DW OHDVW IRXU ZHHNV
EHIRUHVWXG\GUXJWUHDWPHQW

3HUIRUPDQFHVWDWXV(&2*d

2UJDQ)XQFWLRQ5HTXLUHPHQWV±6XEMHFWVPXVWKDYHDGHTXDWHRUJDQ
IXQFWLRQVDVGHILQHGEHORZ

$67$/7;8/1XSSHUOLPLWRIQRUPDO

$67$/7d;8/1>ZLWKXQGHUO\LQJOLYHUPHWDVWDVLV@

7RWDOELOLUXELQd;8/1

6HUXPFUHDWLQLQHd;8/1

$1&t/

3ODWHOHWV!/

6XEMHFWV RI FKLOGEHDULQJ SRWHQWLDO PXVW DJUHH WR XVH DFFHSWDEOH
FRQWUDFHSWLYHPHWKRGVGXULQJWUHDWPHQWDQGXQWLOWKHHQGRIWKHVWXG\
6XEMHFW QRW RI FKLOGEHDULQJ SRWHQWLDO LH SHUPDQHQWO\ VWHULOL]HG
SRVWPHQRSDXVDOFDQEHLQFOXGHGLQVWXG\3RVWPHQRSDXVDOLVGHILQHG
DVPRQWKVZLWKQRPHQVHVZLWKRXWDQDOWHUQDWLYHPHGLFDOFDXVH

$ELOLW\WR XQGHUVWDQGDQGWKH ZLOOLQJQHVVWR VLJQ DZULWWHQLQIRUPHG
FRQVHQWGRFXPHQWDFFRUGLQJWRLQVWLWXWLRQDOJXLGHOLQHV
Selection Criteria:

Exclusion Criteria

3DWLHQWV ZKR KDYH QRW UHFHLYHGVWDQGDUG FKHPRWKHUDS\ KRUPRQDO RU
WDUJHWHGWKHUDS\IRUWKHLUXQGHUO\LQJDGYDQFHGPHWDVWDWLFFDQFHU

6XEMHFWVZKRDUHSUHJQDQWRUEUHDVWIHHGLQJDWHQWU\

6XEMHFWVZLWKVSOHQHFWRP\

6XEMHFWV ZLWK NQRZQ RU FOLQLFDOO\ PDQLIHVW V\PSWRPDWLF &16
PHWDVWDVHVLQDose Escalation Phase

6XEMHFWVZLWK+,9LQIHFWLRQDFWLYHKHSDWLWLV%LQIHFWLRQRUDFWLYH
KHSDWLWLV&LQIHFWLRQ

6XEMHFWV ZLWK DQ\ DXWRLPPXQH RU RWKHU GLVRUGHUV UHTXLULQJ LYRUDO
VWHURLGVRULPPXQRVXSSUHVVLYHRULPPXQRPRGXODWRU\WKHUDSLHV

HJ7\SHMXYHQLOHRQVHWGLDEHWHVPHOOLWXVDQWLERG\SRVLWLYHIRU
UKHXPDWRLG DUWKULWLV *UDYH¶V GLVHDVH +DVKLPRWR¶V WK\URLGLWLV
OXSXVVFOHURGHUPDV\VWHPLFYDVFXOLWLVKHPRO\WLFDQHPLDLPPXQH


&OLQLFDO3URWRFRO2%,

2%,3KDUPD,QF
9HUVLRQ±-XO
&RQILGHQWLDO
3DJHRI

PHGLDWHGWKURPERF\WRSHQLD&URKQ¶VGLVHDVH8OFHUDWLYHFROLWLVRU
SVRULDVLVHWF

6XEMHFWVZLWKDQ\NQRZQXQFRQWUROOHGLQWHUFXUUHQWLOOQHVVLQFOXGLQJ
RQJRLQJ RU DFWLYH LQIHFWLRQV V\PSWRPDWLF FRQJHVWLYH KHDUW IDLOXUH
1<+$!XQVWDEOHDQJLQDSHFWRULVFDUGLDFDUUK\WKPLDRUSV\FKLDWULF
LOOQHVVVRFLDO VLWXDWLRQV WKDW ZRXOG OLPLW FRPSOLDQFH ZLWK VWXG\
UHTXLUHPHQWV

[Dose Escalation Phase] 
6XEMHFWV ZLWK DQ\ RI WKH IROORZLQJ 0(',&$7,216 ZLWKLQ  ZHHNV
SULRUWR,3WUHDWPHQWH[FHSWSHUPLWWHGWKHUDSLHVDVOLVWHGLQVHFWLRQ

&KHPRWKHUDSHXWLF$JHQW

,PPXQRWKHUDS\>P$EV,QWHUIHURQV&\WRNLQHVH[FHSW*&6)@

,PPXQRVXSSUHVVDQWVHJF\FORVSRULQUDSDP\FLQWDFUROLPXV
ULWX[LPDEDOHPWX]XPDEQDWDOL]XPDEHWF

,9RUDOVWHURLGVH[FHSWVLQJOHSURSK\ODFWLFXVHLQ&705,VFDQRU
RWKHURQHWLPHXVHLQDSSURYHGLQGLFDWLRQV7KHLQWHUYDOEHWZHHQ
,9RUDOVWHURLGVDGPLQLVWUDWLRQDQGILUVWGRVHRI2%,2%,
PXVWEHPRUHWKDQSKDUPDFRORJLFDOGXUDWLRQRUKDOIOLYHVRI
DGPLQLVWHUHGVWHURLGVZKLFKHYHULVORQJHU8VHVRILQKDOHGDQG
WRSLFDOVWHURLGVDUHDOORZHG

$QRWKHULQYHVWLJDWLRQDOGUXJ

[Cohort Expansion Phase]
6XEMHFWV ZLWK DQ\ RI WKH IROORZLQJ 0(',&$7,216 ZLWKLQ  ZHHNV
SULRUWR,3WUHDWPHQWH[FHSWSHUPLWWHGWKHUDSLHVDVOLVWHGLQVHFWLRQ

&KHPRWKHUDSHXWLF$JHQW

,PPXQRWKHUDS\ >,QWHUIHURQV &\WRNLQHV@ H[FHSW 3'3'/
DQWDJRQLVWV

,PPXQRVXSSUHVVDQWV HJ F\FORVSRULQ UDSDP\FLQ WDFUROLPXV
ULWX[LPDEDOHPWX]XPDEQDWDOL]XPDEF\FORSKRVSKDPLGHHWF

,9RUDOVWHURLGVH[FHSWVLQJOHSURSK\ODFWLFXVHLQ&705,VFDQRU
RWKHURQHWLPHXVHLQDSSURYHGLQGLFDWLRQV7KHLQWHUYDOEHWZHHQ
,9RUDOVWHURLGVDGPLQLVWUDWLRQDQGILUVWGRVHRI2%,2%,
PXVW EH PRUH WKDQ SKDUPDFRORJLFDO GXUDWLRQ RU  KDOIOLYHV RI
DGPLQLVWHUHG VWHURLGV ZKLFKHYHU LV ORQJHU 8VHV RI LQKDOHG DQG
WRSLFDOH[FHSWRQLQMHFWLRQVLWHVWHURLGVDUHDOORZHG

$QRWKHULQYHVWLJDWLRQDOGUXJ

6XEMHFWV ZLWK SOHXUDO HIIXVLRQV DQGRU DVFLWHV GXH WR PDOLJQDQF\
UHTXLULQJSDUDFHQWHVLVHYHU\ZHHNVRUPRUHIUHTXHQWO\
 6XEMHFWV ZLWK DQ\ NQRZQ VHYHUH DOOHUJLHV HJ DQDSK\OD[LV WR DQ\
DFWLYHRULQDFWLYHLQJUHGLHQWVLQWKHVWXG\GUXJV
Study Evaluation
and Assessment:
[Dose Escalation Phase]
x
7XPRUVWDWXVFRQILUPDWLRQ)XOOERG\&7VFDQVFKHVWDEGRPHQDQG
SHOYLVZLOOEHSHUIRUPHGDWVFUHHQLQJDQGWKHQHYHU\ZHHNVWLOOWKH
HQGRIWKHVWXG\
x
6DIHW\DQGWR[LFLW\DGYHUVHHYHQWVZLOOEHHYDOXDWHGDWHDFKYLVLWLH
:HHNVDQG(QGRI6WXG\
x
+HPDWRORJ\VHUXPFKHPLVWU\DQGXULQHDQDO\VLVZLOOEHFRQGXFWHGDW
HDFKYLVLWLH:HHNVDQG


&OLQLFDO3URWRFRO2%,

2%,3KDUPD,QF
9HUVLRQ±-XO
&RQILGHQWLDO
3DJHRI

x
,PPXQRORJ\WHVWIRUDQWL*ORER+,J*DQG,J0ZLOOEHFRQGXFWHGDW
:HHNVDQG
x
7XPRUVSHFLILF DQWLJHQ WHVWLQJ &($ IRU DOO HQUROOHG VXEMHFWV WR EH
SHUIRUPHGSULRUWRWUHDWPHQWDQGHYHU\ZHHNVXQWLOWKHHQGRIWKH
VWXG\

[Cohort Expansion Phase]
x
7XPRUVWDWXVFRQILUPDWLRQ)XOOERG\&7VFDQVFKHVWDEGRPHQDQG
SHOYLVZLOOEHSHUIRUPHGDWVFUHHQLQJ:HHNVDQGWKHQHYHU\
ZHHNVXQWLOGLVHDVHSURJUHVVLRQRUXSWR\HDUDIWHUWKHODVWVXEMHFW
UHFHLYHVWKHILUVWGRVHRIVWXG\WUHDWPHQW)RUWKHFRQWLQXRXVLQMHFWLRQ
VXEMHFWV DIWHU GLVHDVH SURJUHVVLRQ VXEMHFWV ZLOO SHUIRUP WXPRU
DVVHVVPHQWHYHU\ZHHNVXQWLOHQGRIVWXG\
x
6DIHW\DQGWR[LFLW\DGYHUVHHYHQWVZLOOEHHYDOXDWHGDWHDFKYLVLWWLOO
WKHHQGRIWKHVWXG\
x
+HPDWRORJ\VHUXPFKHPLVWU\DQGXULQHDQDO\VLVZLOOEHFRQGXFWHGDW
HDFKYLVLWWLOOWKHHQGRIWKHVWXG\
x
,PPXQRORJ\WHVWIRUDQWL*ORER+,J*DQG,J0ZLOOEHFRQGXFWHGDW
:HHNVDQGHYHU\YLVLWWKHUHDIWHUWLOOWKHHQG
RIWKHVWXG\
x
7XPRUVSHFLILFDQWLJHQWHVWLQJ&($DQG&<)5$IRUDOOHQUROOHG
VXEMHFWVLQVHOHFWHGVLWHVWREHSHUIRUPHGDWVFUHHQLQJ:HHNV
HYHU\ĹZHHNVWKHUHDIWHUXQWLOGLVHDVHSURJUHVVLRQDQGHQGRIVWXG\YLVLW
Exploratory Analysis [Dose Escalation Phase]
([SORUDWRU\WHVWVIRUWKHIROORZLQJELRPDUNHUVZLOOEHFRQGXFWHGDW:HHNV
DQG
x
,+&IRU*ORER+66($66($DQG3'/:HHNIURP
SDUDIILQDWHGPDWHULDORIRULJLQDOVXUJHU\VSHFLPHQV
x
0RQLWRULQJRILPPXQHUHVSRQVHRIDQWL*ORER+DQWL66($DQGDQWL
66($DQWLERG\SURGXFWLRQ
x
&7&:HHNDQGRQO\
x
$'&&DQG&'&
x
7FHOODQG%FHOOUHVSRQVHV:HHNVDQG

[Cohort Expansion Phase]
([SORUDWRU\ WHVWV IRU WKH IROORZLQJ ELRPDUNHUV ZLOO EH FRQGXFWHG DW
6FUHHQLQJ:HHNVDQGHYHU\ZHHNVWKHUHDIWHU
XQWLOHQGRIVWXG\
x
,+&IRU*ORER+66($66($DQG3'/6FUHHQLQJIURPIUHVK
SUHSDUHGSUHIHUUHGRUSDUDIILQDWHGPDWHULDORIRULJLQDOVXUJHU\
VSHFLPHQV
x
0RQLWRU LPPXQH UHVSRQVH RI DQWL*ORER + DQWL66($ DQG DQWL
66($DQWLERG\SURGXFWLRQ
x
&7&:HHNDQG(QGRI6WXG\(DUO\7HUPLQDWLRQ


&OLQLFDO3URWRFRO2%,

2%,3KDUPD,QF
9HUVLRQ±-XO
&RQILGHQWLDO
3DJHRI

x
$'&&DQG&'&
x
7FHOODQG%FHOOUHVSRQVHVDW:HHNVRUDIWHUXQWLO373FRQWLQXH
YLVLWVDIWHUHLWKHUDQWL*ORER+DQWL66($RUDQWL66($,J*
UHDFKHVPJPOLQWKHVHUXP
x
%7FHOOLPPXQRJHQRPLFDQDO\VLV6FUHHQLQJ:HHNVDQG
HYHU\ZHHNVWLOOZHHNVDIWHUVWGLVHDVHSURJUHVVLRQ
x
([YLYR,PPXQRJHQLFLW\$QDO\VLV6FUHHQLQJYLVLW
x
&REDV(*)50XWDWLRQ7HVWVZLOOEHFRQGXFWHGDW:HHNVDQG
SRVWWUHDWPHQWSHULRGDQG(QGRI6WXG\IRUDOOVXEMHFWVZLWKNQRZQ
(*)5PXWDWLRQVLQVHOHFWHG7DLZDQVLWHV&REDV(*)50XWDWLRQ7HVWV
ZLOODOVREHFRQGXFWHGDW(DUO\7HUPLQDWLRQYLVLWIRUWKHHDUO\
WHUPLQDWLRQVXEMHFWVRWKHUWKDQ3'
Study Management: [Dose Escalation Phase]
x
$IWHUFRPSOHWLQJLQMHFWLRQVRI2%,2%,LHDW9LVLW:HHN
LQWKHILUVWRUVXEMHFWVDWWKHORZHUGRVHFRKRUWLQGRVHHVFDODWLRQ
SKDVH LI WKHUH DUH QR VXEMHFWV RI WKH ILUVW  RU WKHUH DUH OHVV WKDQ 
VXEMHFWVRIWKHILUVWZKRGHYHORS'/7HQUROOPHQWFDQEHVWDUWHGLQWKH
QH[WKLJKHUGRVHFRKRUW
x
$Q\VXEMHFWZKRGHYHORSVDQ\'/7ZLOOEHGLVFRQWLQXHGIURPVWXG\
WUHDWPHQW
x
$OOVXEMHFWVZKRKDYHD*UDGHRUFOLQLFDORUODERUDWRU\DEQRUPDOLW\
DW WKH WLPH RI ZLWKGUDZDO IURP WKH VWXG\ PXVW EH IROORZHG XQWLO
UHVROXWLRQWR*UDGHRUOHVVXQOHVVLWLVXQOLNHO\WRLPSURYHEHFDXVHRI
XQGHUO\LQJGLVHDVH
x
,IWKHUHLVPRUHWKDQVXEMHFWRIWKHILUVWZKRGHYHORS'/7LQGRVH
HVFDODWLRQ SKDVH WKHQ GRVH HVFDODWLRQ ZLOO EH VXVSHQGHG XQWLO D IXOO
UHYLHZE\WKH'DWDDQG6DIHW\0RQLWRULQJ%RDUG5HFRPPHQGDWLRQIRU
GRVHUHGXFWLRQZLOOUHVXOWIURPWKHGLVFXVVLRQRIHPHUJLQJVDIHW\GDWD
E\WKH'60%,IGRVHUHGXFWLRQLVUHTXLUHGIRUWKHVXEMHFWVLQ&RKRUW
PJFRKRUWWKHVWXG\ZLOOEHVXVSHQGHGWHPSRUDOO\DQGFDQRQO\EH
UHVXPHGWR IXUWKHUHQUROO &RKRUW VXEMHFW ZLWKRXWGRVH UHGXFWLRQ LI
MXVWLILHGE\UHFRPPHQGDWLRQRIWKH'60%XSRQDQDO\VLVRIHPHUJLQJ
VDIHW\GDWD$'DWDDQG6DIHW\0RQLWRULQJ%RDUGZLOOEHHVWDEOLVKHGWR
DVVLVWWKH6SRQVRULQPRQLWRULQJVXEMHFWVDIHW\ULVNEHQHILWDQGGHFLVLRQ
IRUGRVHHVFDODWLRQGRVHUHGXFWLRQDQGWHUPLQDWLRQRIWKHVWXG\
x
3DWLHQWVZKRSUHPDWXUHO\ZLWKGUDZIURPGRVHHVFDODWLRQSKDVHZLOOEH
UHSODFHG7RPHHWWKHUHSODFHPHQWDVXEMHFWVKRXOGIXOILOOWKHIROORZLQJ
FULWHULD
1RWUHFHLYHVDWRWDORI2%,2%,LQMHFWLRQVGXULQJWKHGRVH
HVFDODWLRQSKDVHDQG5HDVRQRIQRWFRPSOHWLQJLQMHFWLRQVLVRWKHU
WKDQGHYHORSPHQWRIUHODWHGDGYHUVHHYHQWRUD'/7HJQRQFRPSOLDQFH
RUZLWKGUHZRIFRQVHQW
x
2%, 6FLHQWLILF &RPPLWWHH MXVWLILHG VDIHW\ HIILFDF\ DQG LPPXQH
UHVSRQVHGDWDRIDOOWKHGRVHHVFDODWLRQSKDVHVXEMHFWVDQGUHFRPPHQG
PJRI2%,DVWKHGRVHOHYHOIRUFRKRUWH[SDQVLRQSKDVHLQOXQJ
FDQFHU16&/&


&OLQLFDO3URWRFRO2%,

2%,3KDUPD,QF
9HUVLRQ±-XO
&RQILGHQWLDO
3DJHRI

[Cohort Expansion Phase]
x
3DWLHQWVZLOOEHWUHDWHGXQWLOGLVHDVHSURJUHVVLRQLQWROHUDEOHWR[LFLW\
ZLWKGUDZDORIFRQVHQWRUXSWR\HDUDIWHUWKHODVWVXEMHFWUHFHLYHVWKH
ILUVWGRVHRIVWXG\WUHDWPHQW3DWLHQWVZLOOWKHQHQWHUWKHSRVWWUHDWPHQW
SHULRGDQGIROORZXSSKDVH
x
6XEMHFWVPD\FRQWLQXHIRUWUHDWPHQWDWGLVFUHWLRQRIWKHLQYHVWLJDWRUDIWHU
GLVHDVH SURJUHVVLRQ 7KH IROORZLQJ FOLQLFDO VLWXDWLRQV VKRXOG EH
FRQIRUPHGIRUFRQWLQXRXVLQMHFWLRQDIWHUGLVHDVHSURJUHVVLRQ
²6XEMHFWVFRQWLQXHWRPHHWDOORWKHUVWXG\SURWRFROHOLJLELOLW\FULWHULD
²$OOGUXJUHODWHGWR[LFLWLHVUHVROYHGWRWKHEDVHOLQHOHYHO
²1RGHWHULRUDWLRQRIVXEMHFWSHUIRUPDQFHVWDWXV
² 'RHV QRW GHOD\ LPPLQHQW LQWHUYHQWLRQ WR SUHYHQW VHULRXV
FRPSOLFDWLRQVRIGLVHDVHSURJUHVVLRQHJ&16PHWDVWDVHV
)RUWKHVXEMHFWVGLVFRQWLQXHGWUHDWPHQWEHFDXVHRIGLVHDVHSURJUHVVLRQ
VXEMHFWVZLOOEHFRQWLQXDOO\HYDOXDWHGIRUVDIHW\DQGLPPXQHUHVSRQVH
HYHU\ZHHNVXQWLOHQGRIWKHVWXG\ZKLFKLVZHHNVDIWHUWKHODVW
GRVH)RUWKHVXEMHFWVZKRDUHHOLJLEOHDQGZLOOLQJFRQWLQXRXVLQMHFWLRQ
DIWHUGLVHDVHSURJUHVVLRQVXEMHFWVZLOOEHWUHDWHGZLWK2%,2%,
HYHU\ZHHNVIRUDGGLWLRQDOLQMHFWLRQVZKLFKLVDWRWDORI
ZHHNV DIWHU GLVHDVH SURJUHVVLRQ WR HYDOXDWH FOLQLFDO DQG LPPXQH
UHVSRQVHV6XEVHTXHQWO\VXEMHFWVZLOOEHIROORZHGXSIRUVXUYLYDOHYHU\
ZHHNVXSWRZHHNVDIWHU(QGRI6WXG\


&OLQLFDO3URWRFRO2%,

2%,3KDUPD,QF
9HUVLRQ±-XO
&RQILGHQWLDO
3DJHRI


LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
$'&&

DQWLERG\GHSHQGHQWFHOOPHGLDWHGF\WRWR[LFLW\
$(

DGYHUVHHYHQW
$/&

DEVROXWHO\PSKRF\WHFRXQW 

$/.$QDSODVWLF/\PSKRPD.LQDVH
$/76*37
VHUXPJOXWDPLFS\UXYLFWUDQVDPLQDVH
$1&$

DQWLQHXWURSKLOF\WRSODVPLFDQWLERG\
$676*27
VHUXPJOXWDPLFR[DORDFHWLFWUDQVDPLQDVH
%81

EORRGXUHDQLWURJHQ
&'&

FRPSOHPHQWGHSHQGHQWF\WRWR[LFLW\
&$

FDQFHUDQWLJHQ
&($

FDUFLQRHPEU\RQLFDQWLJHQ
&16

FHQWUDOQHUYRXVV\VWHP
&5

FRPSOHWHUHVSRQVH
&5)

FDVHUHSRUWIRUP
&50
DFWLYHDQGQRQWR[LFIRUPRIGLSKWKHULDWR[LQ'7FDOOHGFURVVUHDFWLQJ
PDWHULDO&50
&7

FRPSXWHUL]HGWRPRJUDSK\
&7&

FLUFXODWLQJWXPRUFHOO
&7&$(

FRPPRQWHUPLQRORJ\FULWHULDIRUDGYHUVHHYHQWV
&<)5$F\WRNHUDWLQIUDJPHQW
'/7

GRVHOLPLWLQJWR[LFLW\
(&*

HOHFWURFDUGLRJUDP
(&2*

(DVWHUQ&RRSHUDWLYH2QFRORJ\*URXS
()

HMHFWLRQIUDFWLRQ
(*)5(SLGHUPDO*URZWK)DFWRU5HFHSWRU
(65

HU\WKURF\WHVHGLPHQWDWLRQUDWH
)$&6

IOXRUHVFHQFHDFWLYDWHGFHOOVRUWLQJ
)'$

)RRGDQG'UXJ$GPLQLVWUDWLRQ
*E
*ORER+SUHFXUVRU*EDOVRFDOOHGVWDJHVSHFLILFHPEU\RQLFDQWLJHQ
66($
*&6)

JUDQXORF\WHFRORQ\VWLPXODWLQJIDFWRU
*0&6)

JUDQXORF\WHPDFURSKDJHFRORQ\VWLPXODWLQJIDFWRU
+%9

KHSDWLWLV%YLUXV
+&&

KHSDWRFHOOXODUFDUFLQRPD
+&9

KHSDWLWLV%YLUXV
+,9

KXPDQLPPXQRGHILFLHQF\YLUXV
,&)

LQIRUPHGFRQVHQWIRUP
,&+*&3

,QWHUQDWLRQDO&RQIHUHQFHRI+DUPRQL]DWLRQ*RRG&OLQLFDO3UDFWLFH 

,+&,PPXQRKLVWRFKHPLVWU\
,5%

,QVWLWXWLRQDO5HYLHZ%URDG
./+

NH\KROHOLPSHWKHPRF\DQLQ
/'+

ODFWDWHGHK\GURJHQDVH
/9()

OHIWYHQWULFXODUHMHFWLRQIUDFWLRQ
P$%V

PRQRFORQDODQWLERGLHV
05,

PDJQHWLFUHVRQDQFHLPDJLQJ
06.&&

0HPRULDO6ORDQ.HWWHULQJ&DQFHU&HQWHU
08*$

PXOWLSOHJDWHGDFTXLVLWLRQVFDQ


&OLQLFDO3URWRFRO2%,

2%,3KDUPD,QF
9HUVLRQ±-XO
&RQILGHQWLDO
3DJHRI

1&,

1DWLRQDO&DQFHU,QVWLWXWH
1.FHOO

QDWXUDONLOOHUFHOO
1.7FHOO

QDWXUDONLOOHU7FHOO
12$(/

QRREVHUYHGDGYHUVHHIIHFWOHYHO
16&/&QRQVPDOOFHOOOXQJFDQFHU
26

RYHUDOOVXUYLYDO
3%6

SKRVSKDWHEXIIHUVDOLQH
3'

SURJUHVVLYHGLVHDVH
3'SURJUDPPHGGHDWK
3'/

SURJUDPPHGGHDWKOLJDQG
3(7

SRVLWURQHPLVVLRQWRPRJUDSK\
35

SDUWLDOUHVSRQVH
5%&

UHGEORRGFHOOFRXQWV
5(&,67

UHVSRQVHHYDOXDWLRQFULWHULDLQVROLGWXPRUV
5)

UKHXPDWRLGIDFWRU
6$(V

VHULRXVDGYHUVHHYHQWV
6&

VXEFXWDQHRXV
6'

VWDEOHGLVHDVH
623

VWDQGDUGRSHUDWLQJSURFHGXUH
66($

VWDJHVSHFLILFHPEU\RQLFDQWLJHQ
66($

*ORER+SUHFXUVRU*EDOVRFDOOHGVWDJHVSHFLILFHPEU\RQLFDQWLJHQ
66($

VLDO\O*EDOVRFDOOHGVWDJHVSHFLILFHPEU\RQLFDQWLJHQ
7.,7\URVLQH.LQDVH,QKLELWRU
8/1

XSSHUOLPLWRIQRUPDO
:%&

ZKLWHEORRGFHOOFRXQWV
:+2

:RUOG+HDOWK2UJDQL]DWLRQ


&OLQLFDO3URWRFRO2%,

2%,3KDUPD,QF
9HUVLRQ±-XO
&RQILGHQWLDO
3DJHRI
1
GOALS AND OBJECTIVES
1.1
Primary Objective
x 7R HYDOXDWH WKH VDIHW\ DQG WROHUDELOLW\ RI 2%,2%, LQ VXEMHFWV ZLWK
DGYDQFHGPHWDVWDWLFJDVWULFOXQJFRORUHFWDORUEUHDVWFDQFHU

1.2
Secondary Objective
x 7RDVVHVVKXPRUDOLPPXQHUHVSRQVHVDQWL*ORER+,J*DQG,J0SURGXFWLRQIROORZLQJ
VXEFXWDQHRXVDGPLQLVWUDWLRQRI2%,2%,
x 7XPRUUHVSRQVHSHU5(&,67FULWHULD

1.3
Exploratory Objective
x 7RDVVHVVRWKHULPPXQHUHVSRQVHVDVPHDVXUHGE\H[SORUDWRU\DQDO\VLVRIDQWL*ORER+
DQWL66($DQGDQWL66($DQWLERGLHV&7&$'&&DQG&'&
x 7RDVVHVV*ORER+66($66($DQG3'/H[SUHVVLRQLQWXPRUWLVVXHVDPSOHV
x 7RDVVHVV&HOOXODULPPXQHUHVSRQVHV7FHOODQG%FHOOUHVSRQVHV

2
BACKGROUND AND RATIONALE FOR DEVELOPMENT
2.1
Cancer Immunotherapy
5HFHQWDGYDQFHVLQWKHDVSHFWVRIFHOOXODULPPXQRORJ\DQGWXPRU±KRVWLPPXQHLQWHUDFWLRQV
KDYHOHGWRWKHGHYHORSPHQWRIHIIHFWLYHLPPXQHEDVHGWKHUDSLHVFDSDEOHRIUHGXFLQJWXPRU
VL]HLQSDWLHQWVZLWKPHWDVWDWLFFDQFHU&XUUHQWO\WKHUHDUHWKUHHPDLQDSSURDFKHVWRFDQFHU
LPPXQRWKHUDS\DQRQVSHFLILFVWLPXODWLRQRILPPXQHUHDFWLRQVE\VWLPXODWLQJHIIHFWRUFHOOV
DQGRU LQKLELWLQJ UHJXODWRU\ FHOOV DQ DFWLYH LPPXQL]DWLRQ WR HQKDQFH VSHFLILF DQWLWXPRU
UHDFWLRQV NQRZQ DV FDQFHU YDFFLQHV DQG D SDVVLYH WUDQVIHU RI DQWLWXPRU DQWLERGLHV RU
DFWLYDWHG LPPXQH FHOOV ZLWK DQWLWXPRU DFWLYLW\ DOVR NQRZQ DV DGRSWLYH LPPXQRWKHUDS\
'H9LWDHWDO
&DQFHULPPXQRWKHUDS\LVEDVHGRQWKHWKHRU\WKDWWXPRUVSHFLILFDQWLJHQVFDQEHUHFRJQL]HG
ZKHQSURFHVVHGE\DQGSUHVHQWHGWRDSURSHUO\WUDLQHGLPPXQHV\VWHP7KHPDOLJQDQWFHOOV
DUHFRPPRQO\FKDUDFWHUL]HGE\WKHDSSHDUDQFHRIODUJHDQGXQXVXDOSURWHLQDQGFDUERK\GUDWH
PRWLIV RQ WKHLU FHOO VXUIDFHV ZKLFK GLVWLQJXLVK WKHP IURP WKHLU QRUPDO FHOO FRXQWHUSDUWV
5DELQRYLFK HW DO  7KH LGHQWLILFDWLRQ RI WXPRUDVVRFLDWHG DQWLJHQV UHFRJQL]HG E\
FHOOXODURUKXPRUDOHIIHFWRUVRIWKHLPPXQHV\VWHPKDVRSHQHGQHZSHUVSHFWLYHVIRUFDQFHU
WKHUDS\ ,Q WKH SDVW WZR GHFDGHV VHYHUDO PRQRFORQDO DQWLERGLHV KDYH SURYLGHG VXIILFLHQW
HIILFDF\DQGVDIHW\GDWDWRJDLQUHJXODWRU\DSSURYDOIRUSDVVLYHLPPXQRWKHUDS\RIFDQFHU
7KHVHLQFOXGHHGUHFRORPDE0DE$ULWX[LPDEDQWL&'WUDVWX]XPDE+HUFHSWLQ
JHPWX]DPDE]RJDPLFLQ0\ORWDUJDQGDOHPWX]XPDE&$03$7+DQWL&'


&OLQLFDO3URWRFRO2%,

2%,3KDUPD,QF
9HUVLRQ±-XO
&RQILGHQWLDO
3DJHRI
5HFHQWO\FKDFKLPHULFPRQRFORQDODQWLERG\DJDLQVW*'KDVEHHQVKRZQWRLPSURYH
VXUYLYDORIKLJKULVNQHXUREODVWRPDSDWLHQWVLQD3KDVH,,,WULDOPDNLQJWKLVWKHILUVWHIIHFWLYH
DQWLFDQFHUDQWLERG\WDUJHWLQJFDUERK\GUDWHDQWLJHQV<XHWDO,QDGGLWLRQWRSDVVLYH
LPPXQRWKHUDS\ZLWKWKHVHPRQRFORQDODQWLERGLHVDFWLYHLPPXQRWKHUDS\RIKXPDQFDQFHULV
D UDSLGO\ JURZLQJ H[SHULPHQWDO DUHD WDUJHWLQJ SHSWLGLF DV ZHOO DV FDUERK\GUDWH WXPRU
DVVRFLDWHG DQWLJHQV 7KH ELRWHFKQRORJ\ DQG SKDUPDFHXWLFDO LQGXVWULHV KDYH RQO\ UHFHQWO\
VXFFHVVIXOO\GHYHORSHGFDQFHUYDFFLQHV,Q*DUGDVLOZDVDSSURYHGLQWKH86DQGLWLV
WKH ILUVW FDQFHU SUHYHQWLYH YDFFLQH DJDLQVW WKH KXPDQ SDSLOORPDYLUXV WKDW FDXVHV FHUYLFDO
FDQFHUDQGJHQLWDOZDUWV,Q-XO\1RUWKZHVW%LRWKHUDSHXWLFVUHFHLYHGDSSURYDORILWV
SHUVRQDOL]HGWKHUDSHXWLFYDFFLQHIRUEUDLQFDQFHU'&9D[%UDLQLQ6ZLW]HUODQG,Q$SULO
WKH5XVVLDQ0LQLVWU\RI3XEOLF+HDOWKLVVXHGDUHJLVWUDWLRQFHUWLILFDWHIRUWKHXVHRI
2QFRSKDJHYLWHVSHQ LQ WKHWUHDWPHQW RINLGQH\FDQFHUSDWLHQWV DW LQWHUPHGLDWHULVNIRU
GLVHDVH UHFXUUHQFH http://www.antigenics.com/news/2008/0408.phtml 7KHVH VXFFHVVIXO
FDVHVDUHHQFRXUDJLQJLQUHDIILUPLQJWKHGHYHORSPHQWRI*ORER+DVDQLPPXQRWKHUDSHXWLF
WDUJHWIRUVROLGWXPRUVVXFKDVEUHDVWJDVWULFOXQJFRORUHFWDORYDULDQSDQFUHDWLFDQGSRVVLEO\
RWKHUFDQFHUW\SHV
,QDGMXYDQWLPPXQL]DWLRQWULDOVWKHSULPDU\WDUJHWLVWKH³PLQLPDOUHVLGXDOGLVHDVH´ZKLFK
FRQVLVWVRIDVPDOOQXPEHURIWXPRUFHOOVRUHDUO\PLFURPHWDVWDVHVWKDWPD\SHUVLVWIRUORQJ
SHULRGVDIWHUDSSDUHQWUHVHFWLRQRIDOOUHVLGXDOWXPRUV=KDQJHWDO=KDQJHWDOD
=KDQJHWDOE=KDQJHWDO$FWLYHLPPXQRWKHUDS\ZLWKWKHUDSHXWLFYDFFLQHVLVD
JRRGVWUDWHJ\WRWDUJHWPLQLPDOUHVLGXDOGLVHDVHDQGSUHYHQWUHODSVHE\LQGXFLQJDQWLERGLHVRI
VXIILFLHQWWLWHUDJDLQVWWXPRUDQWLJHQVWRHOLPLQDWHUHVLGXDOWXPRUFHOOVIURPWKHSHULWRQHDO
FDYLW\EORRGDQGO\PSKDWLFV\VWHPVDQGWRLQKLELWPLFURPHWDVWDVHV+RZHYHUWKHLPPXQH
UHVSRQVHWRFDQFHUDQWLJHQVLVVXSSUHVVHGLQFDQFHUSDWLHQWV6RWRPD\RUHWDO 3DZHOHF
HWDO.KRQJDQG5HVWLIR,QWKHSDVWIHZ\HDUVPHWKRGVKDYHEHHQGHYHORSHGWR
V\QWKHVL]H DQWLJHQV WKDW PLPLF QDWXUDO FDQFHU DQWLJHQV 0XVVHOOL HW DO  ZKLFK DUH
FRQMXJDWHG WR D SRWHQW LPPXQRJHQ DV D FDUULHU DQG FRDGPLQLVWHUHG ZLWK DQ LPPXQR
VWLPXODWRU\PROHFXOHDVDQDGMXYDQWWKDWFDQUHOLDEO\SURYRNHDQLPPXQHUHVSRQVH
0DQ\RIWKHPRUHWXPRUUHVWULFWHGPRQRFORQDODQWLERGLHVGHULYHGE\LPPXQL]DWLRQRIPLFH
ZLWKKXPDQWXPRUFHOOVKDYHEHHQGLUHFWHGDJDLQVWFDUERK\GUDWHDQWLJHQVH[SUHVVHGDWWKHFHOO
VXUIDFH0HQDUGHWDO=KDQJHWDOD&HOOVXUIDFHFDUERK\GUDWHVDUHFKDUDFWHULVWLF
RI GLIIHUHQW VWDJHV RI QRUPDO GHYHORSPHQW DQG GLIIHUHQWLDWLRQ GLVWLQFW FDUERK\GUDWHV DUH
H[SUHVVHGLQWLVVXHDQGFHOOVSHFLILFPDQQHUVGXULQJWKRVHSURFHVVHV6HYHUDOFDUERK\GUDWH
DQWLJHQV/LYLQJVWRQD/LYLQJVWRQHW DO /LYLQJVWRQDQG5DJXSDWKLKDYH
SURYHQ WR EH SURPLVLQJ WDUJHWV IRU LPPXQRWKHUDS\ ,PPXQL]DWLRQ DJDLQVW FDUERK\GUDWH
DQWLJHQVFRQMXJDWHGWRLPPXQRVWLPXODWRU\PROHFXOHVUHVXOWVLQKXPRUDODQWLERG\UHVSRQVH
SULPDULO\ DQ ,J0 DQWLERG\ UHVSRQVH 7KHVH DQWLERGLHV DUH NQRZQ WR LQGXFH FRPSOHPHQW
GHSHQGHQWF\WRWR[LFLW\&'&LQIODPPDWLRQDQGSKDJRF\WRVLVRIWXPRUFHOOVE\WKHUHWLFXOR
HQGRWKHOLDOV\VWHPRSVRQL]DWLRQ
,QDGGLWLRQWR&'&,J*DQWLERGLHVRIVXEFODVVHV,J*DQG,J*LQKXPDQVFDQDOVRLQGXFH
DQWLERG\GHSHQGHQWFHOOPHGLDWHGF\WRWR[LFLW\$'&&7KH\DUHLGHDOO\VXLWHGIRUHUDGLFDWLRQ
RIUHVLGXDOWXPRUFHOOVDQGV\VWHPLFRULQWUDSHULWRQHDOPLFURPHWDVWDVHVZKLFKKDYHEHHQZHOO
GRFXPHQWHGLQDYDULHW\RIPRXVHH[SHULPHQWV&DUERK\GUDWHDQWLJHQVKDYHEHHQFKRVHQDV
WDUJHWVIRUDFWLYHLPPXQRWKHUDS\LQFOXGH*ORER+5DJXSDWKLHWDO; 6ORYLQHWDO


&OLQLFDO3URWRFRO2%,

2%,3KDUPD,QF
9HUVLRQ±-XO
&RQILGHQWLDO
3DJHRI
$OOHQHWDO*LOHZVNLHWDO*0:KLWHHWDO; /LYLQJVWRQHWDOD
/LYLQJVWRQ HW DO E; /LYLQJVWRQ E +HOOLQJ HW DO  &KDSPDQ HW DO D
&KDSPDQHWDOE*'/LYLQJVWRQ*'+HOOLQJHWDO 0F&DIIHU\HWDO
 5DJXSDWKLHWDOV7Q0DF/HDQHWDO; /RQJHQHFNHUHWDO/RQJHQHFNHU
HWDO6DQGPDLHUHWDODQG7Q$OOHQHWDO
6LDO\O7QV7QLVDGLVDFFKDULGHWXPRUDVVRFLDWHGDQWLJHQH[SUHVVHGRQWKH08&PXFLQRQ
DQXPEHURIKXPDQFDQFHUFHOOVDQGLVDVVRFLDWHGZLWKPRUHDJJUHVVLYHGLVHDVH7KHUDWRSH
YDFFLQH%LRPLUD,QF(GPRQWRQ$OEHUWD&DQDGDDQG0HUFN.*D$RI'DUPVWDGW*HUPDQ\
LVDFDQFHUYDFFLQHZKLFKFRQVLVWVRIDV\QWKHWLF67QDQWLJHQFRQMXJDWHGWR./+.H\KROH
OLPSHWKHPRF\DQLQFRPELQHGZLWKDQLPPXQRVWLPXODQWDGMXYDQW'HWR[70GHULYHGIURP
EDFWHULD$3KDVH,,,WULDORI7KHUDWRSHYDFFLQHV7Q./+YV./+LQZRPHQZLWK
PHWDVWDWLFEUHDVWFDQFHUVKRZHGWKDW7KHUDWRSHYDFFLQHZDVZHOOWROHUDWHGZLWKPLQLPDO
WR[LFLW\ 7KH PRVW FRPPRQ DGYHUVH HIIHFWV ZHUH LQGXUDWLRQ DQG HU\WKHPD DW WKH VLWH RI
LQMHFWLRQ:KLOHWKHUHVXOWVRIWKLVWULDOGLGQRWPHHWWKHSULPDU\HQGSRLQWVRIWLPHWRGLVHDVH
SURJUHVVLRQDQGRYHUDOOVXUYLYDO DVXEVHTXHQW post-hoc DQDO\VLVVKRZHGWKDWZRPHQZKR
UHFHLYHGFRQFXUUHQWHQGRFULQHDQG7KHUDWRSHYDFFLQHWUHDWPHQWKDGDVLJQLILFDQWRYHUDOO
VXUYLYDOEHQHILWYHUVXVWKRVHZKRUHFHLYHGHQGRFULQHWKHUDS\DORQH,EUDKLPHWDO
2.2
Globo H Expression in Solid Tumors
&DQFHUFHOOV FRQWDLQXQLTXHWXPRUDVVRFLDWHGFDUERK\GUDWHDQWLJHQV7$&$VWKDWDUHQRW
FRPPRQWRPRVWRIWKHKRVWFHOOVXUIDFHV7KHH[SUHVVLRQOHYHORIFHOOVXUIDFHFDUERK\GUDWH
DQWLJHQVLVRIWHQVLJQLILFDQWO\LQFUHDVHGRQFDUFLQRJHQLFWUDQVIRUPDWLRQ=KDQJHWDOD
=KDQJ HW DO E 7KXV 7$&$V RIIHU WKH SRWHQWLDO IRU D WDUJHWHG LPPXQRWKHUDSHXWLF
DSSURDFKWRWKHWUHDWPHQWRIFHUWDLQIRUPVRIFDQFHU$PRQJ7$&$JUHDWLQWHUHVWKDVEHHQ
IRFXVHGRQWKHLPPXQRJHQLFSRWHQWLDORI*ORER+WKHWHUPLQDOKH[DVDFFKDULGHSRUWLRQRIWKH
JO\FROLSLG*ORER+LVKLJKO\H[SUHVVHGLQHSLWKHOLDOFDQFHUVVXFKDVEUHDVWFDQFHURYDULDQ
FDQFHUHQGRPHWULDOFDQFHUJDVWULFFDQFHUFRORQFDQFHUSDQFUHDWLFFDQFHUOXQJFDQFHUDQG
SURVWDWHFDQFHU=KDQJHWDOELWLVH[SUHVVHGRQWKHFDQFHUFHOOVXUIDFHDVDJO\FROLSLG
DQGSRVVLEO\DVDJO\FRSURWHLQ0LRWWLHWDO
*ORER+LVDOVRH[SUHVVHGDWORZHUOHYHOVRQVRPHQRUPDOOXPLQDOVXUIDFHV=KDQJHWDO
+RZHYHUWKHDQWLJHQLVSUHGRPLQDQWO\ORFDOL]HGWRWKHDSLFDOFHOOVDWVHFUHWRU\ERUGHUV²VLWHV
WKDWDSSHDUWREHLQDFFHVVLEOHWRLPPXQHVXUYHLOODQFH,Q3KDVH,WULDOVGLVFXVVHGEHORZ*ORER
+ DQWLJHQ H[SUHVVHG DW WKH VHFUHWRU\ ERUGHUV RI QRUPDO HSLWKHOLDO WLVVXHV LQGXFHG QHLWKHU
WROHUDQFHQRUDXWRLPPXQLW\RQFHDQWLERGLHVZHUHHOLFLWHGVXJJHVWLQJWKDWWKHDQWLJHQVDUH
VHTXHVWHUHGIURPWKHLPPXQHV\VWHP
5HFHQWZRUNKDVVKRZQWKDW*ORER+DQGWKH*ORERVHULHV6WDJH6SHFLILF(PEU\RQLF$QWLJHQ
66($DQG6WDJH6SHFLILF(PEU\RQLF$QWLJHQ66($DUHH[SUHVVHGRQHSLWKHOLDO
FDQFHUFHOOVDQGFRUUHVSRQGLQJFDQFHURXVVWHPFHOOV&KDQJHWDOE /RXHWDO
66($*ELVDSHQWDVDFFKDULGHSUHFXUVRURI*ORER+DQGLVDOVRNQRZQDVVWDJHVSHFLILF
HPEU\RQLFDQWLJHQ66($8QWLOUHFHQWO\66($DQG66($KDYHEHHQNQRZQDVPDUNHUV
IRUKXPDQHPEU\RQLFVWHPFHOOVWKDWFDQEHREVHUYHGRQO\LQVWHPFHOOVGXULQJWKHHPEU\RQLF
GHYHORSPHQWVWDJH&KDQJHWDOE/RXHWDO)LQGLQJRI*ORER+66($DQG
66($RQWKHFDQFHUVWHPFHOOVVXJJHVWVWKDWLQSULQFLSOHWKH*ORER+SURWHLQFRQMXJDWHG


&OLQLFDO3URWRFRO2%,

2%,3KDUPD,QF
9HUVLRQ±-XO
&RQILGHQWLDO
3DJHRI
LPPXQRWKHUDS\QRWRQO\WDUJHWVWKHFDQFHUFHOOVEXWDOVRWKHFDQFHUVWHPFHOOVIRUHUDGLFDWLRQ
7KHVDPHVWXG\DOVRUHYHDOHG*ORER+H[SUHVVLRQLQEUHDVWFDQFHUVSHFLPHQV
DQG66($H[SUHVVLRQLQYDULRXVWXPRUV&KDQJHWHOD
,WLVQRWHZRUWK\WKDWVLPLODUWR*ORER+66($DQG66($H[SUHVVLRQLQQRUPDOWLVVXHV
ZDVSUHGRPLQDQWO\DWWKHVHFUHWRU\ERUGHUVRIHSLWKHOLXP&KDQJHWDOEZKHUHDFFHVVWR
WKHLPPXQHV\VWHPLVUHVWULFWHG,PPXQL]DWLRQRIPLFHZLWK*ORER+./+DQG*ORER+
&50LQGXFHGDQWLERGLHVUHDFWLYHZLWK*ORER+66($DQG66($VXJJHVWLQJWKDWD
*ORER+EDVHGYDFFLQHZLOOWDUJHWWXPRUFHOOVH[SUHVVLQJ*ORER+66($DQG66($
+XDQJHWDO
5HFHQWGDWDKDYHVKRZQWKDW*ORER+66($DQG66($VRFDOOHG*ORER6HULHV7$&$V
DUHKLJKO\H[SUHVVHGRQKXPDQFDQFHUVSHFLPHQVIURPYDULRXVVROLGWXPRUW\SHV7KHVHGDWD
VKRZ*ORER+H[SUHVVLRQLQEUHDVWFDQFHUVSHFLPHQV66($H[SUHVVLRQLQ
  WXPRUV DQG 66($ H[SUHVVLRQ LQ   'U $ <X 7DLZDQ
XQSXEOLVKHGGDWD7KLVUHVHDUFKDOVRVKRZHG*ORER+H[SUHVVLRQLQ66($
H[SUHVVLRQ LQ   DQG 66($ H[SUHVVLRQ LQ   JDVWULF FDQFHU
VSHFLPHQV,QDGGLWLRQWKHGDWDDOVRUHYHDOHGKLJK*ORERVHULHVH[SUHVVLRQLQOXQJFDQFHU
VDPSOHVZLWK*ORER+H[SUHVVLRQLQ66($H[SUHVVLRQLQDQG
66($H[SUHVVLRQLQRIWKHVDPSOHVDQDO\]HG'DWDVXEPLWWHGIRUSXEOLFDWLRQ
E\'U$<XDW&KDQJ*XQJ0HPRULDO+RVSLWDO7DLZDQ
*ORERVHULHV7$&$VDUHDOVRKLJKO\H[SUHVVHGLQFRORQFDQFHU$UHFHQWSXEOLFDWLRQVKRZHG
WKDW*ORER+LVH[SUHVVHGLQGLIIHUHQWFRORQFDQFHUFHOOOLQHV66($LVH[SUHVVHG
RQFRORQFDQFHUFHOOOLQHVDQG66($LVH[SUHVVHGRQFRORQFDQFHUFHOOOLQHV
/RXHWDO
,QWKLVSKDVHFOLQLFDOWULDOWKHSURSRVHGSODQLVWRHQUROOVXEMHFWVZLWKDGYDQFHGPHWDVWDWLF
LQFXUDEOHJDVWULFEUHDVWFRORUHFWDORUOXQJFDQFHUDQGVXEVHTXHQWO\HYDOXDWHWKHH[SUHVVLRQ
OHYHOVLQWKH*ORERVHULHV7$&$V
2.3
OBI-833 (Globo H-CRM197) Immunological Profile
5HFHQWVWXGLHVKDYHUHYHDOHGWKDWWKHH[SUHVVLRQRIVRPHJO\FDQVVXFKDV*ORER+DQG66($
DQG66($ZDVREVHUYHGRQEUHDVWFDQFHUFHOOVDQGEUHDVWFDQFHUVWHPFHOOV%&6&V
&KDQJHWDOE+XDQJHWDO/RXHWDO$OOWKHVHILQGLQJVVXSSRUWDUDWLRQDOH
IRUWKHGHYHORSPHQWRIFDUERK\GUDWHEDVHGYDFFLQHVEDVHGRQWKHVHFDQFHUVSHFLILFJO\FDQV
1RWDEO\WKHUHFHQWVWXG\LQGLFDWHG*ORER+&50YDFFLQHHOLFLWHGPRUH,J*DQWLERGLHV
ZKLFKDUHPRUHVHOHFWLYHIRU*ORER+DQGWKH*ORERVHULHVHSLWRSHVLQFOXGLQJ66($DQG
66($DOORIZKLFKZHUHVSHFLILFDOO\RYHUH[SUHVVHGRQEUHDVWFDQFHUFHOOVDQGEUHDVWFDQFHU
VWHPFHOOVZLWK66($DWWKHKLJKHVWOHYHO!&KDQJHWDOE
*ORER+KDVEHHQHYDOXDWHGDVWKHWDUJHWRIDFWLYHLPPXQRWKHUDS\LQDIHZFOLQLFDOWULDOV
LQFOXGLQJWKHRQJRLQJ3KDVH,,863KDVH,,,7DLZDQFOLQLFDOWULDORI2%,2%,
3URWRFRO1R237XQGHUWKH86%%,1'VSRQVRUHGE\2%,3KDUPD,QF
7KH UDWLRQDOH IRU GHVLJQLQJ *ORER+ FRQMXJDWHG WR &50 D GLSKWKHULD WR[LQ PXWDQW
YDFFLQHLVEDVHGRQWKHWKHRU\WKDWWXPRUVSHFLILFFDUERK\GUDWHDQWLJHQVFDQEHUHFRJQL]HG


&OLQLFDO3URWRFRO2%,

2%,3KDUPD,QF
9HUVLRQ±-XO
&RQILGHQWLDO
3DJHRI
ZKHQSURFHVVHGDQGSUHVHQWHGWRDSURSHUO\WUDLQHGLPPXQHV\VWHP,PPXQL]DWLRQDJDLQVW
WKHVH FDUERK\GUDWH DQWLJHQV UHVXOWV LQ D KXPRUDO DQWLERG\ UHVSRQVH 7KHVH DQWLERGLHV DUH
NQRZQWRLQGXFHFRPSOHPHQWPHGLDWHGF\WRWR[LFLW\&'&LQIODPPDWLRQDQGSKDJRF\WRVLV
RI WXPRU FHOOV E\ WKH UHWLFXORHQGRWKHOLDO V\VWHP RSVRQL]DWLRQ ,Q DGGLWLRQ WR &'& ,J*
DQWLERGLHVRIVXEFODVVHV,J*DQG,J*LQKXPDQVFDQDOVRLQGXFHDQWLERG\GHSHQGHQWFHOO
PHGLDWHG F\WRWR[LFLW\ $'&& 7KH\ DUH LGHDOO\ VXLWHG IRU HUDGLFDWLRQ RI WXPRU FHOOV DQG
V\VWHPLFPHWDVWDVHVZKLFKUHQGHUVSURPLVHVIRU2%,WREHXVHGDVDSRWHQWLDOFDQFHU
YDFFLQH
2.4
Nonclinical Pharmacology
2%,LVDJO\FRSURWHLQFRQMXJDWHFRPSULVHGRIDFDUERK\GUDWHWXPRUDQWLJHQ*ORER+
FRYDOHQWO\ OLQNHG WR DQ LQDFWLYH DQG QRQWR[LF IRUP RI GLSKWKHULD WR[LQ '7 FDOOHG FURVV
UHDFWLQJPDWHULDO  &50 DV D FDUULHUSURWHLQ ,W LV LQWHQGHGWR HYRNHDQLPPXQH
UHVSRQVH DJDLQVW FDQFHU FHOOV E\ FRDGPLQLVWHULQJ D QDWXUDO FDQFHU DQWLJHQ *ORER +
FRQMXJDWHGWRDSRWHQWLPPXQRVWLPXODWRU\DGMXYDQW&50
2%,LVDVDSRQLQEDVHGDGMXYDQWGHULYHGIURPWKHEDUNRIWKHQuillaja saponaria 46
0ROLQD WUHH  2%, LV VWUXFWXUDOO\ VLPLODU WR 46 EDVHG RQ WKH FRPSDULVRQ RI
SK\VLFRFKHPLFDOGDWD%RWK2%,DQG46H[LVWDVPL[WXUHVRILVRPHUV2%,VHUYHV
DVDQLPPXQRORJLFDODGMXYDQWWKDWFRXOGSRWHQWLDWHWKHKXPRUDODQWLERG\UHVSRQVHWR2%,
,QRUGHUWRFKDUDFWHUL]HWKHLPPXQRJHQLFSRWHQWLDORIWKHDQWLJHQDGMXYDQWFRPELQDWLRQ2%,
2%,ZDVWHVWHGLQWKUHHSKDUPDFRORJ\VWXGLHVLQFOXGLQJDQLPPXQRJHQLFLW\VWXG\
DQ//WXPRUEHDULQJPLFHPRGHOVWXG\DQGDFRPELQDWLRQWKHUDS\VWXG\ZLWKJHPFLWDELQH
7KHSKDUPDFRORJ\ VWXGLHVVKRZHGWKDW DFWLYHLPPXQRWKHUDS\ZLWK2%,2%, FDQ
HIIHFWLYHO\VWLPXODWHDQWL*ORER+,J0DQG,J*UHVSRQVHVLQDQin vivoPXULQHPRGHO0RXVH
YDFFLQDWHGZLWK2%,2%,FDQVLJQLILFDQWO\LQKLELWWXPRUJURZWKUDWHLQDQin vivo
VXEFXWDQHRXV*ORER+SRVLWLYHWXPRULPSODQWPRGHO,WZDVDOVRREVHUYHGWKDWWKHWUHDWPHQW
RIVWDQGDUGFKHPRWKHUDSHXWLFDJHQWJHPFLWDELQHIROORZHGE\YDFFLQDWHGZLWK2%,2%,
GLGQRWDIIHFWWKHSURGXFWLRQRIDQWL*ORER+,J0DQG,J*DQWLERGLHVLQGXFHGE\2%,
2%,
2YHUDOOWKHVHQRQFOLQLFDOSKDUPDFRORJ\VWXGLHVSURYLGHGVRXQGUDWLRQDOHWRVXSSRUWFOLQLFDO
LQYHVWLJDWLRQRI2%,2%,
'HWDLOHG LQIRUPDWLRQ RQ WKH QRQFOLQLFDO SKDUPDFRORJ\ VWXGLHV RI 2%,2%, LV
SURYLGHGLQWKH,QYHVWLJDWRU¶V%URFKXUH
2.5
Toxicology
7KHVDIHW\RI2%,2%,YDFFLQHZDVLQLWLDOO\HYDOXDWHGLQDQRQ*/3ZHHNUHSHDW
GRVHUDWWR[LFRORJ\VWXG\LQZKLFK2%,2%,DWGRVHVHTXLYDOHQWWRJRUJ
RI*ORER+ZHUHDGPLQLVWHUHGRQFHZHHNO\YLDVXEFXWDQHRXVLQMHFWLRQWR6SUDJXH'DZOH\
UDWVIRUZHHNV2%,2%,ZDVZHOOWROHUDWHGZLWKRXWREVHUYDWLRQRIDGYHUVHHIIHFWV


&OLQLFDO3URWRFRO2%,

2%,3KDUPD,QF
9HUVLRQ±-XO
&RQILGHQWLDO
3DJHRI
$Q DGGLWLRQDO WR[LFRORJ\ VWXG\ RI 2%,2%, D */3 ZHHN UHSHDWGRVH UDW
WR[LFRORJ\ VWXG\ ZLWK DQ LQWHULP DQDO\VLV DW  ZHHNV ZDV FRQGXFWHG WR HYDOXDWH 
VXEFXWDQHRXVLQMHFWLRQVLQFDQFHUSDWLHQWVLQWKHSODQQHG3KDVH,FOLQLFDOWULDO7KHSRWHQWLDO
WR[LFLW\ RI WKH WHVW DUWLFOH 2%, DQG DGMXYDQW 2%, ZDV DVVHVVHG IRU VHSDUDWH
DGPLQLVWUDWLRQ RU DV D FRIRUPXODWLRQ YLD VXEFXWDQHRXV LQMHFWLRQ RQFH ZHHNO\ WR 6SUDJXH
'DZOH\UDWVIRUZHHNV'RVLQJ3KDVH,QDGGLWLRQUHYHUVLELOLW\SHUVLVWHQFHRUGHOD\HG
RFFXUUHQFHRIDQ\HIIHFWVZHUHDVVHVVHGLQDZHHNUHFRYHU\SHULRGDIWHUWKH'RVLQJ3KDVH
7KHGRVHVRI2%,2%,LQWKHWR[LFRORJ\VWXG\HTXLYDOHQWWRJDQGJ*ORER
+DQGJRI2%,ZHUHVHOHFWHGEDVHGRQWKHSODQQHGFOLQLFDOGRVHUDQJHRI3KDVH,
VWXG\  7KH RQO\ REVHUYDWLRQ FDXVHG E\ 2%, DGPLQLVWUDWLRQ LQ FRPELQDWLRQ ZLWK WKH
DGMXYDQW2%,RQFHZHHNO\IRUZHHNVLQUDWVZDVPLQLPDOHQKDQFHPHQWRIWKHORFDO
LUULWDWLRQ WKDW WKH DGMXYDQW SURGXFHG DW WKH LQMHFWLRQ VLWHV  ,QMHFWLRQ VLWH LUULWDWLRQV ZHUH
UHVROYHG FOLQLFDOO\ ZLWKLQ D ZHHN DQG UHVROYHG PLFURVFRSLFDOO\ ZLWKLQ WKUHH ZHHNV SRVW
DGPLQLVWUDWLRQ
7KHWR[LFRORJ\VWXGLHVGHPRQVWUDWHGWKHVDIHW\DQGLPPXQRJHQLFLW\RIWKHYDFFLQHDGMXYDQW
FRPELQDWLRQRI2%,2%,DQGVKRZHGWKDWWKHYDFFLQHZDVZHOOWROHUDWHGDWGRVHV
DERYHWKDWRIWKHSURSRVHGFOLQLFDOGRVHVRQDSHUNJERG\ZHLJKWEDVLV$OOILQGLQJVQRWHGLQ
WKHZHHNQRQ*/3DQGLQWKHZHHNLQWHULPDQDO\VLVRIWKHZHHN*/3UHSHDWHGGRVH
WR[LFRORJ\ VWXGLHV LQ UDWV ZHUH QRW FRQVLGHUHG DGYHUVH DQG ZHUH OLNHO\ GXH WR
LQIODPPDWRU\LPPXQRVWLPXODWRU\UHVSRQVHVWRWKHDGMXYDQW2%,
'HWDLOHG LQIRUPDWLRQ RQ WKH WR[LFRORJ\ VWXGLHV RI 2%,2%, DUH SURYLGHG LQ WKH
,QYHVWLJDWRU¶V%URFKXUH
2.6
Rationale for Trial Design 
7KH SULPDU\ SXUSRVH RI WKH FOLQLFDO WULDO LV WR LQYHVWLJDWH VDIHW\ DQG WROHUDELOLW\ RI 2%,
2%,LQVXEMHFWVZLWKDGYDQFHGPHWDVWDWLFLQFXUDEOHJDVWULFOXQJFRORUHFWDORUEUHDVW
FDQFHU0HDQZKLOHWKHKXPRUDOLPPXQHUHVSRQVHVLHDQWL*ORER+,J*DQG,J0SURGXFWLRQ
IROORZLQJDGPLQLVWUDWLRQRI2%,2%,ZLOOEHDVVHVVHGDVWKHVHFRQGDU\REMHFWLYHRI
WKLVVWXG\([SORUDWRU\DQDO\VLVRIRWKHULPPXQHUHVSRQVHVVXFKDV*ORER+66($66($
 3'/ H[SUHVVLRQ LQ WXPRU WLVVXH VDPSOHV DQWL*ORER + DQWL66($ DQWL66($
DQWLERGLHV&7&$'&&&'&ZLOOEHFRQGXFWHGDVDSSURSULDWH
8SRQWKHFRPSOHWLRQRILQMHFWLRQVRI2%,2%,LQVXEMHFWVLQWKHGRVHHVFDODWLRQ
SKDVH2%,6FLHQWLILF&RPPLWWHHMXVWLILHGVDIHW\HIILFDF\DQGLPPXQHUHVSRQVHGDWDRIDOOWKH
GRVHHVFDODWLRQSKDVHVXEMHFWVDQGUHFRPPHQGPJGRVHRI2%,DQGOXQJFDQFHU1RQ
6PDOO &HOO /XQJ &DQFHU IRU FRKRUW H[SDQVLRQ 8S WR  OXQJ FDQFHUV VXEMHFWV DUH WR EH
HQUROOHGLQWKHFRKRUWH[SDQVLRQSKDVH
2%,2%,VKRZHGDGHOD\HGDQWLERG\UHVSRQVHLQDSUHYLRXVGRVHHVFDODWLRQSKDVHVWXG\,Q
WKLVVLWXDWLRQFOLQLFDOSURJUHVVLRQPD\RFFXUEHIRUHWKHWUHDWPHQWKDVKDGVXIILFLHQWWLPHWREH
HIIHFWLYH7KXVFRQWLQXRXVLQMHFWLRQDIWHUGLVHDVHSURJUHVVLRQZLOOEHWKHSRWHQWLDODSSURDFK
WRDGGUHVVWKLVLVVXH7KHUHIRUHFOLQLFDOSURJUHVVLRQWKDWLVDV\PSWRPDWLFDQGRULVQRWOLNHO\
WRUHVXOWLQOLIHWKUHDWHQLQJFRPSOLFDWLRQVZLWKIXUWKHUSURJUHVVLRQHJQHZRQVHW&HQWUDO
1HUYRXV6\VWHP&16PHWDVWDVHVPD\DOORZWKHFRQWLQXRXVDGPLQLVWUDWLRQRI2%,2%,


&OLQLFDO3URWRFRO2%,

2%,3KDUPD,QF
9HUVLRQ±-XO
&RQILGHQWLDO
3DJHRI
DWWKHGLVFUHWLRQRILQYHVWLJDWRUDQGVXEMHFWVVKRXOGEHIXOO\LQIRUPHGIRUWKHVXEVHTXHQW
WUHDWPHQW )'$ *XLGDQFH IRU ,QGXVWU\ &OLQLFDO &RQVLGHUDWLRQVIRU 7KHUDSHXWLF &DQFHU 9DFFLQHV

2.7
Rationale for Starting Dose
7KHLQLWLDOSODQQHGVWDUWLQJGRVHLQWKLV)LUVWLQ+XPDQFOLQLFDOWULDOLVJRI2%,LQ
*ORER+HTXLYDOHQWLQFRPELQDWLRQZLWKWKHDGMXYDQWJRI2%,%DVHGRQWKH
UHSRUWHG12$(/IROORZLQJZHHNO\6&LQMHFWLRQVRIJRI2%,SOXVJRI
2%,WKHKLJKHVWGRVHHYDOXDWHGLQWKHZHHNWR[LFRORJ\VWXG\LQUDWVWKLVGRVHRI2%,
2%,  J J ZDV FKRVHQ DV WKH KLJKHVW DQWLFLSDWHG KXPDQ GRVH LQ WKH
SURSRVHG 3KDVH , FOLQLFDO VWXG\  7KLV SURSRVHG GRVLQJ SODQ LV FRQVLVWHQW ZLWK WKH )'$
*XLGDQFH IRU GHYHORSPHQWDO WR[LFLW\ VWXGLHV IRU SUHYHQWLYH DQG WKHUDSHXWLF YDFFLQHV IRU
LQIHFWLRXVGLVHDVHLQGLFDWLRQVDQGWKHSURSRVHG:+2*XLGHOLQHVRQ WKHQRQFOLQLFDO
HYDOXDWLRQRIYDFFLQHDGMXYDQWVDQGDGMXYDQWHGYDFFLQHV
3
ELIGIBILITY CRITERIA
3.1
Inclusion Criteria
 6XEMHFWV\HDUVRIDJH
 [Dose Escalation Phase]
+LVWRORJLFDOO\RUF\WRORJLFDOO\FRQILUPHGGLDJQRVLVRIJDVWULFOXQJFRORUHFWDORUEUHDVW
FDQFHURQILOH
[Cohort Expansion Phase]
+LVWRORJLFDOO\RUF\WRORJLFDOO\FRQILUPHGGLDJQRVLVRI*ORER+SRVLWLYH16&/&
 [Dose Escalation Phase] 
6XEMHFWVZLWKUHFXUUHQWRUPHWDVWDWLFLQFXUDEOHGLVHDVHWKDWIDLOHGWRUHVSRQGWRDWOHDVW
RQHOLQHRIVWDQGDUGDQWLFDQFHUWKHUDS\DQGIRUZKLFKVWDQGDUGWUHDWPHQWLVQRORQJHU
HIIHFWLYHRUWROHUDEOH
[Cohort Expansion Phase] 
6XEMHFWVZLWKPHWDVWDWLF16&/&ZKRKDYHDFKLHYHGVWDEOHGLVHDVH6'RUSDUWLDO
UHVSRQVH35VWDWXVDIWHUDWOHDVWUHJLPHQRIDQWLFDQFHUWKHUDS\LHFKHPRWKHUDS\RU
WDUJHWHGWKHUDS\RU3'3'/DQWDJRQLVWVHLWKHUDORQHRULQFRPELQDWLRQDQGWKHUH
DUHQRVWDQGDUGWUHDWPHQWVDYDLODEOHH[FHSWSHUPLWWHG7DUJHWRU3'3'/WKHUDSLHVDV
OLVWHGLQVHFWLRQLHDGGRQZLWKILUVWOLQHRQJRLQJ7DUJHWHGWKHUDS\RU3'3'/
WKHUDS\
 0HDVXUDEOH GLVHDVH LH SUHVHQW ZLWK DW OHDVW RQH PHDVXUDEOH OHVLRQ SHU 5(&,67
YHUVLRQ>(LVHQKDXHU@
 [Dose Escalation Phase]
1RNQRZQFHQWUDOQHUYRXVV\VWHP&16PHWDVWDVHVRUQHXURORJLFDOV\PSWRPV
SRVVLEO\UHODWHGWRDFWLYH&16PHWDVWDVLVLQ'RVH(VFDODWLRQ3KDVH
[Cohort Expansion Phase]
6XEMHFWVZLWKDV\PSWRPDWLF&16PHWDVWDVHVIRUDWOHDVWIRXUZHHNVEHIRUHVWXG\GUXJ
WUHDWPHQW


&OLQLFDO3URWRFRO2%,

2%,3KDUPD,QF
9HUVLRQ±-XO
&RQILGHQWLDO
3DJHRI
 3HUIRUPDQFHVWDWXV(&2*d
 2UJDQ)XQFWLRQ5HTXLUHPHQWV±6XEMHFWVPXVWKDYHDGHTXDWHRUJDQIXQFWLRQVDVGHILQHG
EHORZ

$67$/7;8/1XSSHUOLPLWRIQRUPDO

$67$/7d;8/1>ZLWKXQGHUO\LQJOLYHUPHWDVWDVLV@

7RWDOELOLUXELQd;8/1

6HUXPFUHDWLQLQHd;8/1

$1&t/

3ODWHOHWV!/
 6XEMHFWVRIFKLOGEHDULQJSRWHQWLDOPXVWDJUHHWRXVHDFFHSWDEOHFRQWUDFHSWLYHPHWKRGV
GXULQJWUHDWPHQWDQGXQWLOWKHHQGRIWKHVWXG\6XEMHFWQRWRIFKLOGEHDULQJSRWHQWLDO
LHSHUPDQHQWO\VWHULOL]HGSRVWPHQRSDXVDOFDQEHLQFOXGHGLQVWXG\3RVWPHQRSDXVDO
LVGHILQHGDVPRQWKVZLWKQRPHQVHVZLWKRXWDQDOWHUQDWLYHPHGLFDOFDXVH
 $ELOLW\WRXQGHUVWDQGDQGWKHZLOOLQJQHVVWRVLJQDZULWWHQLQIRUPHGFRQVHQWGRFXPHQW
DFFRUGLQJWRLQVWLWXWLRQDOJXLGHOLQHV

3.2
Exclusion Criteria
 3DWLHQWVZKRKDYHQRWUHFHLYHGVWDQGDUGFKHPRWKHUDS\KRUPRQDORUWDUJHWHGWKHUDS\
IRUWKHLUXQGHUO\LQJFDQFHU
 6XEMHFWVDUHSUHJQDQWRUEUHDVWIHHGLQJDWHQWU\
 6XEMHFWVZLWKVSOHQHFWRP\
 6XEMHFWVZLWKNQRZQRUFOLQLFDOO\PDQLIHVWV\PSWRPDWLF&16PHWDVWDVHVLQDose
Escalation Phase
 6XEMHFWVZLWK+,9LQIHFWLRQDFWLYHKHSDWLWLV%LQIHFWLRQRUDFWLYHKHSDWLWLV&LQIHFWLRQ
 6XEMHFWV ZLWK DQ\ DXWRLPPXQH RU RWKHU GLVRUGHUV UHTXLULQJ ,9RUDO VWHURLGV RU
LPPXQRVXSSUHVVLYHRULPPXQRPRGXODWRU\WKHUDSLHV

HJ 7\SH  MXYHQLOH RQVHW GLDEHWHV PHOOLWXV DQWLERG\ SRVLWLYH IRU UKHXPDWRLG
DUWKULWLV *UDYH¶V GLVHDVH +DVKLPRWR¶V WK\URLGLWLV OXSXV VFOHURGHUPD V\VWHPLF
YDVFXOLWLVKHPRO\WLFDQHPLDLPPXQHPHGLDWHGWKURPERF\WRSHQLD&URKQ¶VGLVHDVH
8OFHUDWLYHFROLWLVRUSVRULDVLVHWF
 6XEMHFWVZLWKDQ\NQRZQXQFRQWUROOHGLQWHUFXUUHQWLOOQHVVLQFOXGLQJRQJRLQJRUDFWLYH
LQIHFWLRQVV\PSWRPDWLFFRQJHVWLYHKHDUWIDLOXUH1<+$!XQVWDEOHDQJLQDSHFWRULV
FDUGLDFDUUK\WKPLDRUSV\FKLDWULFLOOQHVVVRFLDOVLWXDWLRQVWKDWZRXOGOLPLWFRPSOLDQFH
ZLWKVWXG\UHTXLUHPHQWV
 [Dose Escalation Phase] 
6XEMHFWV ZLWK DQ\ RI WKH IROORZLQJ 0(',&$7,216 ZLWKLQ  ZHHNV SULRU WR ,3
WUHDWPHQWH[FHSWSHUPLWWHGWKHUDSLHVDVOLVWHGLQVHFWLRQ

&KHPRWKHUDSHXWLF$JHQWV

,PPXQRWKHUDS\>P$EV,QWHUIHURQV&\WRNLQHVH[FHSW*&6)@


&OLQLFDO3URWRFRO2%,

2%,3KDUPD,QF
9HUVLRQ±-XO
&RQILGHQWLDO
3DJHRI

,PPXQRVXSSUHVVDQWV HJ F\FORVSRULQ UDSDP\FLQ WDFUROLPXV ULWX[LPDE
DOHPWX]XPDEQDWDOL]XPDEHWF

,9RUDOVWHURLGVH[FHSWVLQJOHSURSK\ODFWLFXVHLQ&705,VFDQRURWKHURQHWLPHXVH
LQDSSURYHGLQGLFDWLRQV7KHLQWHUYDOEHWZHHQ,9RUDOVWHURLGVDGPLQLVWUDWLRQDQG
ILUVWGRVHRI2%,2%,PXVWEHPRUHWKDQSKDUPDFRORJLFDOGXUDWLRQRU
KDOIOLYHV RI DGPLQLVWHUHG VWHURLGV ZKLFKHYHU LV WKH ORQJHU 8VHV RI LQKDOHG DQG
WRSLFDOVWHURLGVDUHDOORZHG

$QRWKHULQYHVWLJDWLRQDOGUXJ

[Cohort Expansion Phase]
6XEMHFWV ZLWK DQ\ RI WKH IROORZLQJ 0(',&$7,216 ZLWKLQ  ZHHNV SULRU WR ,3
WUHDWPHQWH[FHSWSHUPLWWHGWKHUDSLHVDVOLVWHGLQVHFWLRQ

&KHPRWKHUDSHXWLF$JHQWV

,PPXQRWKHUDS\>,QWHUIHURQV&\WRNLQHV@H[FHSW3'3'/DQWDJRQLVWV

,PPXQRVXSSUHVVDQWV HJ F\FORVSRULQ UDSDP\FLQ WDFUROLPXV ULWX[LPDE
DOHPWX]XPDEQDWDOL]XPDEF\FORSKRVSKDPLGHHWF

,9RUDOVWHURLGVH[FHSWVLQJOHSURSK\ODFWLFXVHLQ&705,VFDQRURWKHURQHWLPHXVH
LQDSSURYHGLQGLFDWLRQV7KHLQWHUYDOEHWZHHQ,9RUDOVWHURLGVDGPLQLVWUDWLRQDQG
ILUVWGRVHRI2%,2%,PXVWEHPRUHWKDQSKDUPDFRORJLFDOGXUDWLRQRU
KDOIOLYHVRIDGPLQLVWHUHGVWHURLGVZKLFKHYHULVORQJHU8VHVRILQKDOHGDQGWRSLFDO
VWHURLGVH[FHSWRQLQMHFWLRQVLWHVDUHDOORZHG

$QRWKHULQYHVWLJDWLRQDOGUXJ
 6XEMHFWVZLWKSOHXUDOHIIXVLRQVDQGRUDVFLWHVGXHWRPDOLJQDQF\UHTXLULQJSDUDFHQWHVLV
HYHU\ZHHNVRUPRUHIUHTXHQWO\
 6XEMHFWVZLWKDQ\NQRZQVHYHUHDOOHUJLHVHJDQDSK\OD[LVWRDQ\DFWLYHRULQDFWLYH
LQJUHGLHQWVLQWKHVWXG\GUXJV

4
TREATMENT PLAN
4.1
Subject Enrollment and Dose Escalation Procedure
7KLVLVD3KDVH,RSHQODEHOQRQUDQGRPL]HGVWXG\ZLWKWZRSKDVHVGRVHHVFDODWLRQSKDVH
DQGFRKRUWH[SDQVLRQSKDVH%RWKSKDVHVHYDOXDWHVDIHW\DQGWROHUDELOLW\RI2%,
$VWDQGDUGWULDOGHVLJQZLOOEHXVHGIRU2%,2%,GRVHHVFDODWLRQSKDVH7KH
GRVLQJRI2%,ZLOOEHGLYLGHGLQWRFRKRUWV
z
&RKRUW2%,HTXLYDOHQWWRȝJ*ORER+ȝJ2%,
z
&RKRUW2%,HTXLYDOHQWWRȝJ*ORER+ȝJ2%,
z
&RKRUW2%,HTXLYDOHQWWRȝJ*ORER+ȝJ2%,

,QWKHGRVHHVFDODWLRQSKDVHWKHILUVWWKUHHVXEMHFWVRIPJGRVHFRKRUW&RKRUWVKRXOGEH
HQUROOHGVHTXHQWLDOO\ZLWKDWOHDVWDKRXULQWHUYDO,IWKHUHLVQR'/7REVHUYHGLQDQ\RI


&OLQLFDO3URWRFRO2%,

2%,3KDUPD,QF
9HUVLRQ±-XO
&RQILGHQWLDO
3DJHRI
WKHVHVXEMHFWVWKHWULDOZLOOSURFHHGWRHQUROOVXEMHFWVLQWRWKHPJGRVHFRKRUW&RKRUW,I
RQHRXWRIWKHILUVWWKUHH&RKRUWVXEMHFWVGHYHORSVD'/7DQDGGLWLRQDOWKUHHVXEMHFWVZLOO
EHIXUWKHUHQUROOHG,IOHVVWKDQRIWKHVXEMHFWVLHRQO\RIWKHVXEMHFWVGHYHORS'/7
GRVHHVFDODWLRQWRPJZLOOEHSURFHHGHG,IPRUHWKDQRIVXEMHFWVGHYHORS'/7WKHVWXG\
ZLOOEH VXVSHQGHGWHPSRUDOO\DQGFDQRQO\ EH UHVXPHGWR IXUWKHUHQUROO &RKRUWVXEMHFW
ZLWKRXWGRVHUHGXFWLRQMXVWLILHGE\UHFRPPHQGDWLRQRIWKH'60%XSRQDQDO\VLVRIHPHUJLQJ
VDIHW\GDWD
)RUPJGRVHFRKRUW&RKRUWILUVWO\WKUHHSDWLHQWVZLOOEHHQUROOHG,IWKHUHLVQR'/7
REVHUYHGLQDQ\RIWKHVHVXEMHFWVWKHWULDOZLOOSURFHHGWRHQUROOVXEMHFWVLQWRWKHPJGRVH
FRKRUW&RKRUW,IRQHRXWRIWKHILUVWWKUHH&RKRUWVXEMHFWVGHYHORSVD'/7DQDGGLWLRQDO
WKUHHVXEMHFWVZLOOEHIXUWKHUHQUROOHG,IOHVVWKDQRIWKHVXEMHFWVLHRQO\RIWKH
VXEMHFWVGHYHORS'/7GRVHHVFDODWLRQWRPJZLOOEHSURFHHGHG,IPRUHWKDQRIVXEMHFWV
VXIIHUIURP'/7'DWDDQG6DIHW\0RQLWRULQJ%RDUGZLOOUHYLHZWKHVDIHW\GDWDWRUHFRPPHQG
LI WKH VWXG\ VKRXOG EH VXVSHQGHG RU GHHVFDODWH WR SUHYLRXV ȝJ FRKRUW WR FRPSOHWH D
PD[LPXPRIVXEMHFWV
)RUμJGRVHFRKRUW&RKRUWILUVWO\WKUHHVXEMHFWVZLOOEHHQUROOHGLQWKLVFRKRUWV,IRQH
RXWRIWKHILUVWWKUHH&RKRUWVXEMHFWVGHYHORSVD'/7DQDGGLWLRQDOWKUHHVXEMHFWVZLOOEH
IXUWKHUHQUROOHG,IQRQHRIWKHILUVWWKUHHRUOHVVWKDQRIWKHVXEMHFWVH[SHULHQFH'/7DWWKH
μJGRVHOHYHOWKHQWKLVGRVHZLOOEHPD[LPXPGRVHIRUHVFDODWLRQSKDVH,IPRUHWKDQ
RIVXEMHFWVH[SHULHQFH'/7DWWKLVGRVHOHYHOVWXG\ZLOOEHVXVSHQGHGWHPSHUDWHO\DQG
'60%ZLOOUHYLHZVDIHW\GDWDWRUHFRPPHQGLIWKHVWXG\VKRXOGEHGHHVFDODWHWRμJWR
FRPSOHWHDPD[LPXPRIVXEMHFWV
8SRQWKHFRPSOHWLRQRILQMHFWLRQVRI2%,2%,LQVXEMHFWVLQWKHGRVHHVFDODWLRQ
SKDVH2%,6FLHQWLILF&RPPLWWHHMXVWLILHGVDIHW\HIILFDF\DQGLPPXQHUHVSRQVHGDWDRIDOOWKH
GRVHHVFDODWLRQSKDVHVXEMHFWVDQGUHFRPPHQGPJGRVHRI2%,IRUFRKRUWH[SDQVLRQ
2%,6FLHQWLILF&RPPLWWHHDOVRH[DPLQHGWKHGDWDRIDOOWKHGRVHHVFDODWLRQSKDVHVXEMHFWVDQG
SUHFOLQLFDOHIILFDF\GDWDWRHYDOXDWHWKHW\SHRIFDQFHUVWREHQHILWIURP 2%,2%,
WUHDWPHQW  2%, 6FLHQWLILF &RPPLWWHH GHWHUPLQHG WKDW OXQJ FDQFHU 1RQ6PDOO &HOO /XQJ
&DQFHUVXEMHFWVZLWK6'RU35WXPRUVWDWXV DUHWREHHQUROOHGIRUSUHOLPLQDU\DQWLWXPRU
DFWLYLW\HYDOXDWLRQ8SWRVXEMHFWVDUHWREHHQUROOHGLQWKHFRKRUWH[SDQVLRQSKDVH
7KHWRWDOQXPEHURIVXEMHFWVWREHHQUROOHGLQWKHVWXG\LVWKXVIOH[LEOHDPD[LPXPQXPEHU
RIVXEMHFWVFDQEHHQUROOHGLQWKHGRVHHVFDODWLRQSKDVHDQGDPD[LPXPQXPEHURI
VXEMHFWVFDQEHHQUROOHGLQWKHFRKRUWH[SDQVLRQSKDVH$PD[LPXPRIWRWDOVXEMHFWVFDQEH
HQUROOHGLQWKLV3KDVH,VWXG\
'RVHPRGLILFDWLRQPD\EHFRQVLGHUHGDVMXVWLILHGE\HPHUJLQJVDIHW\GDWD6XEMHFWWXPRU
ELRSV\WLVVXHVDPSOHVZLOOEHFROOHFWHGDW:HHNXVLQJIUHVKSUHSDUHGRUSDUDIILQDWHGPDWHULDO
IURPRULJLQDOVXUJHU\VSHFLPHQVWRWHVWIRUH[SUHVVLRQOHYHORI*ORER+66($66($DQG
3'/IRUGDWDDQDO\VLVSXUSRVH,+&GDWDLVQRWIRUHOLJLELOLW\FULWHULDIRU'RVH(VFDODWLRQ
3KDVHEXWRQO\*ORER+16&/&VXEMHFWVZLOOEHHQUROOHGLQ&RKRUW([SDQVLRQ3KDVH
6XEMHFWVZKRDUHHOLJLEOHIRUSDUWLFLSDWLRQLQWKLVVWXG\ZLOOEHHQUROOHGLQWRWKHGRVHFRKRUW
WKDWLVRSHQDWWKHWLPHWKHVXEMHFWLVUHJLVWHUHGIRUHQUROOPHQWLQ'RVH(VFDODWLRQ3KDVH


&OLQLFDO3URWRFRO2%,

2%,3KDUPD,QF
9HUVLRQ±-XO
&RQILGHQWLDO
3DJHRI
)RUHDFKVXEMHFWLQGRVHHVFDODWLRQSKDVHPD[LPXPRIGRVHVRI2%,HTXLYDOHQWWR
RUJRI*ORER+2%,ȝJZLOOEHDGPLQLVWHUHGVXEFXWDQHRXVO\DW:HHNV
DQG9LVLWVDQGUHVSHFWLYHO\3DWLHQWV
ZKR SUHPDWXUHO\ ZLWKGUDZ IURP GRVH HVFDODWLRQ SKDVH ZLOO EH UHSODFHG 7R PHHW WKH
UHSODFHPHQWDVXEMHFWVKRXOGIXOILOOWKHIROORZLQJFULWHULD1RWUHFHLYHVDWRWDORI2%,
2%,LQMHFWLRQVGXULQJWKHGRVHHVFDODWLRQSKDVHDQG5HDVRQRIQRWFRPSOHWLQJ
LQMHFWLRQVLVRWKHUWKDQGHYHORSPHQWRIUHODWHGDGYHUVHHYHQWRUD'/7HJQRQFRPSOLDQFH
RUZLWKGUHZRIFRQVHQW
)RU&RKRUW([SDQVLRQ3KDVHSDWLHQWVZLOOEHWUHDWHGVXEFXWDQHRXVO\DW:HHNV
DQGHYHU\ZHHNVXQWLOGLVHDVHSURJUHVVLRQLQWROHUDEOHWR[LFLW\ZLWKGUDZDORI
FRQVHQWRUXSWR\HDUDIWHUWKHODVWVXEMHFWUHFHLYHVWKHILUVWGRVHRIVWXG\WUHDWPHQW6XEMHFWV
PD\ FRQWLQXH WUHDWPHQW DIWHU GLVHDVH SURJUHVVLRQ DW GLVFUHWLRQ RI WKH LQYHVWLJDWRU 7KH
IROORZLQJ FOLQLFDO VLWXDWLRQV VKRXOG EH FRQIRUPHG IRU FRQWLQXHG LQMHFWLRQ DIWHU GLVHDVH
SURJUHVVLRQ)'$*XLGDQFHIRU,QGXVWU\
²6XEMHFWVFRQWLQXHWRPHHWDOORWKHUVWXG\SURWRFROHOLJLELOLW\FULWHULD
²$OOGUXJUHODWHGWR[LFLWLHVUHVROYHGWRWKHEDVHOLQHOHYHO
²1RGHWHULRUDWLRQRIVXEMHFWSHUIRUPDQFHVWDWXV
² 'RHV QRW GHOD\ LPPLQHQW LQWHUYHQWLRQ WR SUHYHQW VHULRXV FRPSOLFDWLRQV RI GLVHDVH
SURJUHVVLRQHJ&16PHWDVWDVHV
)RU WKH VXEMHFWV GLVFRQWLQXHG WUHDWPHQW EHFDXVH RI GLVHDVH SURJUHVVLRQ VXEMHFWV ZLOO EH
FRQWLQXDOO\HYDOXDWHGIRUVDIHW\DQGLPPXQHUHVSRQVHHYHU\ZHHNVXQWLOWKHHQGRIWKHVWXG\
ZKLFKLVZHHNVDIWHUWKHODVWGRVH)RUWKHVXEMHFWVZKRDUHHOLJLEOHDQGZLOOLQJWRFRQWLQXH
LQMHFWLRQDIWHUGLVHDVHSURJUHVVLRQVXEMHFWVZLOOEHWUHDWHGZLWK2%,2%,HYHU\
ZHHNVIRUDGGLWLRQDOLQMHFWLRQVZKLFKLVDWRWDORIZHHNVDIWHUGLVHDVHSURJUHVVLRQWR
HYDOXDWH FOLQLFDO DQG LPPXQH UHVSRQVHV 6XEVHTXHQWO\ VXEMHFWV ZLOO EH IROORZHG XS IRU
VXUYLYDOHYHU\ZHHNVXSWRZHHNVDIWHU(QGRI6WXG\
:HHNLVGHILQHGDVWKHYLVLWZLWKWKHILUVWVFDGPLQLVWUDWLRQRILQYHVWLJDWLRQDOGUXJ%ORRG
VDPSOHVZLOOEHFROOHFWHGIRUURXWLQHEORRGWHVWSDUWRIVDIHW\DVVHVVPHQWDQGHYDOXDWLRQRI
LPPXQHUHVSRQVHVDWYDULRXVZHHNVDVLQGLFDWHGLQWKH7LPHDQG(YHQWV6FKHGXOH7DEOHDQG
)ROORZLQJWKHODVWGRVHRIVWXG\GUXJVXEMHFWVZLOOEHHYDOXDWHGIRUVDIHW\DQGLPPXQH
UHVSRQVHHYHU\ZHHNVIRUGRVHHVFDODWLRQSKDVHRUZHHNVIRUFRKRUWH[SDQVLRQSKDVHXQWLO
WKH HQG RI WKH VWXG\ ³(QG RI 6WXG\´ ZKLFK LV  RU  ZHHNV DIWHU WKH ODVW GRVH
DGPLQLVWUDWLRQ)RUVXEMHFWVHOLJLEOHIRUFRQWLQXHGLQMHFWLRQDIWHUGLVHDVHSURJUHVVLRQVKRXOG
EHIXOO\LQIRUPHGWKHIRUHVHHDEOHULVNVRUGLVFRPIRUWVDQGRWKHUDOWHUQDWLYHWUHDWPHQWRSWLRQV
4.2
OBI-833/OBI-821 Administration Schedule and Procedure
)RUHDFKGRVHDGPLQLVWUDWLRQDYLDORI2%,GUXJSURGXFWDQGDYLDORI2%,GUXJ
SURGXFWZLOOEHXVHG7KHGRVLQJVROXWLRQZLOOEHSUHSDUHGE\PL[LQJWKHWZRFRPSRQHQWV
SULRUWRLQMHFWLRQ7KHPL[LQJLQVWUXFWLRQIRUHDFKGRVHOHYHORI2%,2%,LVVKRZQ
LQ$SSHQGL[,


&OLQLFDO3URWRFRO2%,

2%,3KDUPD,QF
9HUVLRQ±-XO
&RQILGHQWLDO
3DJHRI
x
)RUGRVHHVFDODWLRQSKDVHHQUROOHGVXEMHFWVZLOOEHWUHDWHGIRUDPD[LPXPRIGRVHVRI
2%,2%,VFDW:HHNVDQG9LVLWWR9LVLW)RU
&RKRUW([SDQVLRQ3KDVHVXEMHFWVZLOOEHWUHDWHGXQWLOGLVHDVHSURJUHVVLRQ
x
$GRVHRIJ2%,J2%,J2%,J2%,RUJ
2%,J2%,PL[WXUHZLOOEHLQMHFWHGVXEFXWDQHRXVO\DFFRUGLQJWRUHVSHFWLYH
FRKRUWVDQGLQHVFDODWLRQSKDVHDQGμJ2%,μJ2%,LQFRKRUW
H[SDQVLRQSKDVH
x
$GPLQLVWUDWLRQ RI 2%,2%, FRPELQDWLRQ VKRXOG EH FRPSOHWHG ZLWKLQ  KRXUV
DIWHUPL[LQJ
x
6XEFXWDQHRXVLQMHFWLRQVFRYHUWKHDUPOHIWRUULJKWLVSUHIHUDEOH
x
,ID[LOODU\O\PSKQRGHVZHUHUHPRYHGDYRLGLQMHFWLRQVRQWKHVDPHDUP
x
,ID[LOODU\O\PSKQRGHVRQERWKVLGHVOHIWDQGULJKWZHUHUHPRYHGLQMHFWLRQVFDQEHPDGH
RQWKHWKLJKOHIWRUULJKW
x
,IORFDOUHDFWLRQRFFXUVURWDWHRUDOWHUQDWHWKHLQMHFWLRQVLWHDURXQGWKHDUPVDQGWKLJKVWR
PLQLPL]HLQMHFWLRQVLWHLUULWDWLRQ

5
STUDY PROCEDURES 
5.1
Screening Phase – Prior to First Dosing of the Investigational Drug
(Screening Visit)
$VLJQHG,QIRUPHG&RQVHQW)RUPZLOOEHSURSHUO\REWDLQHGIROORZLQJDIXOOH[SODQDWLRQRIWKH
VWXG\SURWRFRODQGSULRUWRFRQGXFWLQJDQ\VWXG\UHODWHGSURFHGXUHV
)RU'RVH(VFDODWLRQ3KDVHWKHVFUHHQLQJEDVHOLQHHYDOXDWLRQVDUHWREHFRQGXFWHGZLWKLQ
GD\VSULRUWRILUVWGRVLQJRIWKHLQYHVWLJDWLRQDOGUXJ$OOHQWU\HOLJLELOLW\DVVHVVPHQWPXVWEH
SHUIRUPHGSULRUWRILUVWGRVLQJRIWKHLQYHVWLJDWLRQDOGUXJ
x
5HFRUGGHPRJUDSKLFV
x
2EWDLQVLJQLILFDQWPHGLFDOKLVWRU\RWKHUXQGHUO\LQJGLVHDVHFRQGLWLRQDQGKLVWRU\DORQJ
WKHSUHYLRXVPRQWKV
x
&RQILUPHOLJLELOLW\FULWHULDPHHWLQJDOOLQFOXVLRQFULWHULDQRWKDYLQJDQ\H[FOXVLRQFULWHULD
x
3HUIRUPSK\VLFDOH[DPLQDWLRQLQFOXGLQJYLWDOVLJQVEORRGSUHVVXUHUHVSLUDWRU\UDWHSXOVH
DQGERG\WHPSHUDWXUHKHLJKWZHLJKWDQG(&2*SHUIRUPDQFHVWDWXV
x
&RQGXFWXULQHSUHJQDQF\WHVW,QFDVHRISRVLWLYHUHVXOWVWKHVXEMHFWZLOOQRWEHHOLJLEOHIRU
WKHVWXG\
x
&RQGXFWURXWLQHXULQDO\VLVS+SURWHLQJOXFRVHVSHFLILFJUDYLW\NHWRQHELOLUXELQDQG
XURELOLQRJHQ$QDO\VLVRIXULQDU\VHGLPHQWV5%&:%&HSLWKHOLDOFDVWVK\DOLQHFDVWV
DQGEDFWHULDOLVRSWLRQDO
x
&RQGXFW KHPDWRORJ\ WHVW  LQFOXGHV KHPRJORELQ KHPDWRFULW :%& 5%& SODWHOHW
GLIIHUHQWLDOV5)DQG(65


&OLQLFDO3URWRFRO2%,

2%,3KDUPD,QF
9HUVLRQ±-XO
&RQILGHQWLDO
3DJHRI
x
&RQGXFW VHUXP FKHPLVWU\ DQDO\VLV  LQFOXGHV VRGLXP SRWDVVLXP FKORULGH FDOFLXP
PDJQHVLXP%81FUHDWLQLQH$/7$67DONDOLQHSKRVSKDWDVHWRWDO SURWHLQ DOEXPLQ
WRWDOELOLUXELQ/'+DP\ODVHOLSDVHFKROHVWHUROWULJO\FHULGHVFRUWLVRO77IUHH7
DQG76+
x
&RQGXFW +%9 HJ +%V$J +%H$J DQG LI FOLQLFDOO\ LQGLFDWHG +%F$E DQGRU +%9
'1$ +&9 HJ DQWL+&9 WHVWLQJ &RQGXFW +,9 WHVWLQJ LI QR KLVWRULFDO GDWD DUH
DYDLODEOH 2SWLRQDO WHVWV HJ YLUDO ORDG FDQEHRUGHUHGEDVHGRQODE WHVW UHVXOWV DQG
,QYHVWLJDWRU¶V FOLQLFDO MXGJPHQW IRU VXVSHFWHG DFWLYH LQIHFWLRQ RQ IROORZXS YLVLWV
$QWLYLUDO DJHQWV DUH DOORZHG IRU WKH WUHDWPHQW DQG PDQDJHPHQW RI YLUDO LQIHFWLRQV
+RZHYHU LQWHUIHURQ WKHUDS\ LV QRW DOORZHG DQG LI LQGLFDWHG WKH VXEMHFW QHHGV WR EH
H[FOXGHGIURPWKHVWXG\
x
3HUIRUP/HDG(&*
x
3HUIRUP7XPRU$VVHVVPHQW

)XOOERG\&7VFDQVFKHVWDEGRPHQDQGSHOYLVZLOOEHSHUIRUPHGDWVFUHHQLQJDQG
XVHGDVWKHEDVHOLQHVFDQ,IIXOOERG\&7VFDQKDVEHHQSHUIRUPHGZLWKLQZHHNV
EHIRUHWKHVFUHHQLQJH[DPWKHGDWHFRQVHQWIRUPVLJQE\SDWLHQWWKHQWKLVSUHYLRXVO\
SHUIRUPHGVFDQFDQEHXVHGDVWKHEDVHOLQHVFDQ

7RLGHQWLI\DQGUHFRUGOHVLRQVWREHHYDOXDWHGIRUUHVSRQVHEDVHGRQ5(&,67
FULWHULD

,PDJLQJZLOOEHDVVHVVHGE\WKHVWXG\VLWHUDGLRORJLVWRUGHOHJDWHGLQYHVWLJDWRUV

)RUFRKRUWH[SDQVLRQSKDVHDQLQWHUYDORIDWOHDVWZHHNVLVUHTXLUHGIRU6WDEOH
'LVHDVH6'VWDWXVDQLQWHUYDORIDWOHDVWZHHNVLVUHTXLUHGIRU3DUWLDO5HVSRQVH
35VWDWXV
x
5HFRUGXVHRIFRQFRPLWDQWPHGLFDWLRQV
x
3HUIRUP UHWHVWLQJ RI ODE DVVHVVPHQWV D UHWHVW PD\ EH DOORZHG DIWHU  ZHHN RU E\
,QYHVWLJDWRUV¶MXGJPHQWIURPWKHLQLWLDOODEWHVWWRUHFRQILUPWKHVXEMHFW¶VRUJDQIXQFWLRQ
RU FRQGLWLRQ +RZHYHU WKH DVVHVVPHQW QHHGV WR EH FRQGXFWHG ZLWKLQ WKH VSHFLILHG
VFUHHQLQJSHULRGSULRUWRILUVWGRVLQJRIWKHLQYHVWLJDWLRQDOGUXJ
x
3HUIRUPSUHWUHDWPHQWWXPRUVSHFLILFDQWLJHQWHVWLQJ&($IRUDOOHQUROOHGVXEMHFWV

)RU&RKRUW([SDQVLRQ3KDVHWKHVFUHHQLQJEDVHOLQHHYDOXDWLRQVDUHWREHFRQGXFWHGZLWKLQ
GD\VSULRUWRILUVWGRVLQJRIWKHLQYHVWLJDWLRQDOGUXJ$OOHQWU\HOLJLELOLW\DVVHVVPHQWPXVWEH
SHUIRUPHGSULRUWRILUVWGRVLQJRIWKHLQYHVWLJDWLRQDOGUXJ
x
2EWDLQWXPRUELRSV\WLVVXHVDPSOHVRISULPDU\VLWHDQGGLVWDQWPHWDVWDVHVLISRVVLEOH
ZKLFK ZLOO EH WHVWHG IRU *ORER + 66($ 66($ DQG 3'/ H[SUHVVLRQ E\
LPPXQRKLVWRFKHPLVWU\ VSHFLILHG LQ 6HFWLRQ  ³2WKHU 6WXG\ 3URFHGXUHV´ $OWKRXJK
IUHVKVSHFLPHQVDUHSUHIHUUHGPRVWVXEMHFWVVKRXOGKDYHKLVWRULFDOWXPRUWLVVXHVSHFLPHQV
DYDLODEOHZKLFKFDQEHVXEPLWWHGWRWKHFHQWUDOODEIRUWHVWLQJ,IWXPRUWLVVXHVDPSOHVDUH
QRWDYDLODEOHIUHVKWXPRUWLVVXHVDPSOHVVKRXOGEHDFTXLUHG)RU&RKRUW([SDQVLRQ3KDVH
IUHVKDUFKLYHGWXPRUELRSVLHVWRWHVW*ORER+H[SUHVVLRQDUHHVVHQWLDO
x
5HFRUGGHPRJUDSKLFV


&OLQLFDO3URWRFRO2%,

2%,3KDUPD,QF
9HUVLRQ±-XO
&RQILGHQWLDO
3DJHRI
x
2EWDLQVLJQLILFDQWPHGLFDOKLVWRU\RWKHUXQGHUO\LQJGLVHDVHFRQGLWLRQDQGKLVWRU\DORQJ
WKHSUHYLRXVPRQWKV
x
&RQILUPHOLJLELOLW\FULWHULDPHHWLQJDOOLQFOXVLRQFULWHULDQRWKDYLQJDQ\H[FOXVLRQFULWHULD
x
3HUIRUPSK\VLFDOH[DPLQDWLRQLQFOXGLQJYLWDOVLJQVEORRGSUHVVXUHUHVSLUDWRU\UDWHSXOVH
DQGERG\WHPSHUDWXUHKHLJKWZHLJKWDQG(&2*SHUIRUPDQFHVWDWXV
x
&RQGXFWXULQHSUHJQDQF\WHVW,QFDVHRISRVLWLYHUHVXOWVWKHVXEMHFWZLOOQRWEHHOLJLEOHIRU
WKHVWXG\
x
&RQGXFWURXWLQHXULQDO\VLVS+SURWHLQJOXFRVHVSHFLILFJUDYLW\NHWRQHELOLUXELQDQG
XURELOLQRJHQ$QDO\VLVRIXULQDU\VHGLPHQWV5%&:%&HSLWKHOLDOFDVWVK\DOLQHFDVWV
DQGEDFWHULDOLVRSWLRQDO
x
&RQGXFW KHPDWRORJ\ WHVW  LQFOXGHV KHPRJORELQ KHPDWRFULW :%& 5%& SODWHOHW
GLIIHUHQWLDOV5)DQG(65
x
&RQGXFW VHUXP FKHPLVWU\ DQDO\VLV  LQFOXGHV VRGLXP SRWDVVLXP FKORULGH FDOFLXP
PDJQHVLXP%81FUHDWLQLQH$/7$67DONDOLQHSKRVSKDWDVHWRWDO SURWHLQ DOEXPLQ
WRWDOELOLUXELQ/'+DP\ODVHOLSDVHFKROHVWHUROWULJO\FHULGHVFRUWLVRO77IUHH7
DQG76+
x
&RQGXFW +%9 HJ +%V$J +%H$J DQG LI FOLQLFDOO\ LQGLFDWHG +%F$E DQGRU +%9
'1$ +&9 HJ DQWL+&9 WHVWLQJ &RQGXFW +,9 WHVWLQJ LI QR KLVWRULFDO GDWD DUH
DYDLODEOH 2SWLRQDOWHVWVHJYLUDO ORDGFDQEHRUGHUHGEDVHGRQODE WHVW UHVXOWV DQG
,QYHVWLJDWRU¶V FOLQLFDO MXGJPHQW IRU VXVSHFWHG DFWLYH LQIHFWLRQ RQ IROORZXS YLVLWV
$QWLYLUDO DJHQWV DUH DOORZHG IRU WKH WUHDWPHQW DQG PDQDJHPHQW RI YLUDO LQIHFWLRQV
+RZHYHU LQWHUIHURQ WKHUDS\ LV QRW DOORZHG DQG LI LQGLFDWHG WKH VXEMHFW QHHGV WR EH
H[FOXGHGIURPWKHVWXG\
x
3HUIRUP/HDG(&*
x
3HUIRUP7XPRU$VVHVVPHQW

)XOOERG\&7VFDQVFKHVWDEGRPHQDQGSHOYLVZLOOEHSHUIRUPHGDWVFUHHQLQJDQG
XVHGDVWKHEDVHOLQHVFDQ,IIXOOERG\&7VFDQKDVEHHQSHUIRUPHGZLWKLQZHHNVRI
WKH VFUHHQLQJ H[DP WKH GDWH FRQVHQW IRUP VLJQ E\ SDWLHQW WKHQ WKLV SUHYLRXVO\
SHUIRUPHGVFDQFDQEHXVHGDVWKHEDVHOLQHVFDQ

7RLGHQWLI\DQGUHFRUGOHVLRQVWREHHYDOXDWHGIRUUHVSRQVHEDVHGRQ5(&,67
FULWHULD

,PDJLQJZLOOEHDVVHVVHGE\WKHVWXG\VLWHUDGLRORJLVWRUGHOHJDWHGLQYHVWLJDWRUV

)RUFRKRUWH[SDQVLRQSKDVHDQLQWHUYDORIDWOHDVWZHHNVLVUHTXLUHGIRU6WDEOH
'LVHDVH6'VWDWXVDQLQWHUYDORIDWOHDVWZHHNVLVUHTXLUHGIRU3DUWLDO5HVSRQVH
35VWDWXV
x
5HFRUGXVHRIFRQFRPLWDQWPHGLFDWLRQV
x
3HUIRUP UHWHVWLQJ RI ODE DVVHVVPHQWV D UHWHVW PD\ EH DOORZHG DIWHU  ZHHN RU E\
,QYHVWLJDWRUV¶MXGJPHQWIURPWKHLQLWLDOODEWHVWWRUHFRQILUPWKHVXEMHFW¶VRUJDQIXQFWLRQ
RU FRQGLWLRQ +RZHYHU WKH DVVHVVPHQW QHHGV WR EH FRQGXFWHG ZLWKLQ WKH VSHFLILHG
VFUHHQLQJSHULRGSULRUWRILUVWGRVLQJRIWKHLQYHVWLJDWLRQDOGUXJ
x
3HUIRUP SUHWUHDWPHQW WXPRUVSHFLILF DQWLJHQ WHVWLQJ &($ DQG &<)5$ IRU DOO
HQUROOHGVXEMHFWVLQVHOHFWHGVLWHV


&OLQLFDO3URWRFRO2%,

2%,3KDUPD,QF
9HUVLRQ±-XO
&RQILGHQWLDO
3DJHRI
x
&ROOHFWEORRGVDPSOHVIRUH[SORUDWRU\DQDO\VLVRIWKH%7FHOOLPPXQRJHQRPLFDQG([
YLYRLPPXQRJHQLFLW\DQDO\VLVLQVHOHFWHG7DLZDQVLWHV

5.2
Treatment Period: Week 1 – Visit 1
(OLJLEOHVXEMHFWZLOOEHWUHDWHGZLWKWKHILUVWGRVHRIWKHLQYHVWLJDWLRQDOGUXJDFFRUGLQJWRWKH
DVVLJQHG FRKRUWGRVDJH WKDW LV FXUUHQWO\ HQUROOLQJ DW WKH WLPH WKH VXEMHFW LV HOLJLEOH IRU
HQUROOPHQW6HFWLRQ
)RU&RKRUWLQGRVHHVFDODWLRQSKDVH2%,HTXLYDOHQWWRJ*ORER+2%,J
ZLOOEHDGPLQLVWHUHGVXEFXWDQHRXVO\VF6XEMHFWVHQUROOHGLQ&RKRUWZLOOEHDGPLQLVWHUHG
2%,HTXLYDOHQWWRJ*ORER+2%,ȝJVXEFXWDQHRXVO\VFZKLOHVXEMHFWV
LQ&RKRUWZLOOEHDGPLQLVWHUHG2%,HTXLYDOHQWWRJ*ORER+2%,J
VXEFXWDQHRXVO\VF)RUFRKRUWH[SDQVLRQ2%,HTXLYDOHQWWRJ*ORER+2%,
ȝJZLOOEHDGPLQLVWHUHG
7KHIROORZLQJHYDOXDWLRQVDUHWREHFRQGXFWHGGXULQJ:HHNYLVLWVDVVSHFLILHGEHORZ
x
3HUIRUPSK\VLFDOH[DPLQDWLRQLQFOXGLQJYLWDOVLJQVEORRGSUHVVXUHUHVSLUDWRU\UDWHSXOVH
DQGERG\WHPSHUDWXUHDQGZHLJKWSULRUWRDGPLQLVWUDWLRQRILQYHVWLJDWLRQDOGUXJ
x
&RQGXFWURXWLQHXULQDO\VLVS+SURWHLQJOXFRVHVSHFLILFJUDYLW\NHWRQHELOLUXELQDQG
XURELOLQRJHQSULRUWRDGPLQLVWUDWLRQRILQYHVWLJDWLRQDOGUXJ$QDO\VLVRIXULQDU\VHGLPHQWV
5%&:%&HSLWKHOLDOFDVWVK\DOLQHFDVWVDQGEDFWHULDOLVRSWLRQDO
x
&RQGXFW KHPDWRORJ\ WHVW  LQFOXGHV KHPRJORELQ KHPDWRFULW :%& 5%& SODWHOHW
GLIIHUHQWLDOV5)DQG(65SULRUWRDGPLQLVWUDWLRQRILQYHVWLJDWLRQDOGUXJ
x
&RQGXFW VHUXP FKHPLVWU\ DQDO\VLV  LQFOXGHV VRGLXP SRWDVVLXP FKORULGH FDOFLXP
PDJQHVLXP%81FUHDWLQLQH$/7$67DONDOLQHSKRVSKDWDVHWRWDO SURWHLQ DOEXPLQ
WRWDOELOLUXELQ/'+DP\ODVHOLSDVHFKROHVWHUROWULJO\FHULGHVFRUWLVRO77IUHH7
DQG76+SULRUWRDGPLQLVWUDWLRQRILQYHVWLJDWLRQDOGUXJ
x
&ROOHFWEORRGVDPSOHVIRUWKHPHDVXUHPHQWRIDQWL*ORER+,J*DQG,J0WLWHUVSULRUWR
DGPLQLVWUDWLRQRILQYHVWLJDWLRQDOGUXJ
x
)RU'RVH(VFDODWLRQ3KDVHRQO\2EWDLQWXPRUELRSV\WLVVXHVDPSOHVRISULPDU\VLWHDQG
GLVWDQWPHWDVWDVHVLISRVVLEOHZKLFKZLOOEHWHVWHGIRU*ORER+66($66($DQG3'
/ H[SUHVVLRQ E\ LPPXQRKLVWRFKHPLVWU\ VSHFLILHG LQ 6HFWLRQ  ³2WKHU 6WXG\
3URFHGXUHV´$OWKRXJKIUHVKVSHFLPHQVDUHSUHIHUUHGPRVWVXEMHFWVVKRXOGKDYHKLVWRULFDO
WXPRUWLVVXHVSHFLPHQVDYDLODEOHZKLFKFDQEHVXEPLWWHGWRWKHFHQWUDOODEIRUWHVWLQJ,I
WXPRUWLVVXHVDPSOHVDUHQRWDYDLODEOHIUHVKWXPRUWLVVXHVDPSOHVVKRXOGEHDFTXLUHGSULRU
WRDGPLQLVWUDWLRQRILQYHVWLJDWLRQDOGUXJ+RZHYHULQFDVHVZKHUHWXPRUELRSVLHVPD\QRW
EHSRVVLEOHVXEMHFWVDUHQRWUHTXLUHGWRVXEPLWWLVVXHVDPSOHV
x
&ROOHFW EORRG VDPSOHV IRU H[SORUDWRU\ DQDO\VLV RI WKH IROORZLQJ ELRPDUNHUV SULRU WR
DGPLQLVWUDWLRQRILQYHVWLJDWLRQDOGUXJ
x
0RQLWRULQJRILPPXQHUHVSRQVHRIDQWL*ORER+DQWL66($DQGDQWL66($
DQWLERG\SURGXFWLRQ
x
&7&RQO\LQVHOHFWHG7DLZDQVLWHV


&OLQLFDO3URWRFRO2%,

2%,3KDUPD,QF
9HUVLRQ±-XO
&RQILGHQWLDO
3DJHRI
x
$'&&DQG&'&
x
$GPLQLVWHULQYHVWLJDWLRQDOGUXJVXEFXWDQHRXVO\
x
5HFRUGXVHRIFRQFRPLWDQWPHGLFDWLRQV
x
0RQLWRUDQGUHFRUGDGYHUVHHYHQWVDVVHVVHGE\1&,&7&$(YSRVWDGPLQLVWUDWLRQRI
LQYHVWLJDWLRQDOGUXJ
x
&ROOHFWEORRGVDPSOHIRUWKHVXEMHFWVZLWKNQRZQ(*)5PXWDWLRQVWREHDQDO\]HGLQWKH
&REDV(*)50XWDWLRQ7HVWVLQFRKRUWH[SDQVLRQSKDVH

5.3
Treatment Period Week 2 to Week 4 (Visit 2 to Visit 4)
,QYHVWLJDWLRQDOGUXJZLOOEHDGPLQLVWHUHGVXEFXWDQHRXVO\DW:HHNVDQG9LVLWVDQG
UHVSHFWLYHO\
7KHIROORZLQJHYDOXDWLRQVDUHWREHFRQGXFWHGGXULQJ:HHNVWR9LVLW9LVLWDV
VSHFLILHGEHORZ
x
3HUIRUPSK\VLFDOH[DPLQDWLRQLQFOXGLQJYLWDOVLJQVEORRGSUHVVXUHUHVSLUDWRU\UDWHSXOVH
DQG ERG\ WHPSHUDWXUH DQG ZHLJKW  :HHNV   DQG  9LVLWV   DQG  SULRU WR
DGPLQLVWUDWLRQRILQYHVWLJDWLRQDOGUXJ
x
&RQGXFWURXWLQHXULQDO\VLVS+SURWHLQJOXFRVHVSHFLILFJUDYLW\NHWRQHELOLUXELQDQG
XURELOLQRJHQSULRUWRDGPLQLVWUDWLRQRILQYHVWLJDWLRQDOGUXJ$QDO\VLVRIXULQDU\VHGLPHQWV
5%&:%&HSLWKHOLDOFDVWVK\DOLQHFDVWVDQGEDFWHULDOLVRSWLRQDO:HHNVDQG
9LVLWVDQGSULRUWRDGPLQLVWUDWLRQRILQYHVWLJDWLRQDOGUXJ
x
&RQGXFW KHPDWRORJ\ WHVW  LQFOXGHV KHPRJORELQ KHPDWRFULW :%& 5%& SODWHOHW
GLIIHUHQWLDOV5)DQG(65:HHNVDQG9LVLWVDQGSULRUWRDGPLQLVWUDWLRQRI
LQYHVWLJDWLRQDOGUXJ
x
&RQGXFW VHUXP FKHPLVWU\ DQDO\VLV  LQFOXGHV VRGLXP SRWDVVLXP FKORULGH FDOFLXP
PDJQHVLXP%81FUHDWLQLQH$/7$67DONDOLQHSKRVSKDWDVHWRWDO SURWHLQ DOEXPLQ
WRWDOELOLUXELQ/'+DP\ODVHOLSDVHFKROHVWHUROWULJO\FHULGHVFRUWLVRO77IUHH7
DQG76+:HHNVDQG9LVLWVDQGSULRUWRDGPLQLVWUDWLRQRILQYHVWLJDWLRQDO
GUXJ
x
&ROOHFWEORRGVDPSOHVIRUWKHPHDVXUHPHQWRIDQWL*ORER+,J*DQG,J0:HHNVDQG
9LVLWVDQGSULRUWRDGPLQLVWUDWLRQRILQYHVWLJDWLRQDOGUXJ
x
&ROOHFWEORRGVDPSOHVIRUH[SORUDWRU\DQDO\VLVRIWKHIROORZLQJELRPDUNHUV±:HHNVDQG
9LVLWVDQGSULRUWRDGPLQLVWUDWLRQRILQYHVWLJDWLRQDOGUXJ
x
0RQLWRULQJRILPPXQHUHVSRQVHRIDQWL*ORER+DQWL66($DQGDQWL66($
DQWLERG\SURGXFWLRQ
x
$'&&DQG&'&
x
3HUIRUP /HDG (&* ± :HHN  9LVLW  RQO\ IRU 'RVH (VFDODWLRQ 3KDVH SULRU WR
DGPLQLVWUDWLRQRILQYHVWLJDWLRQDOGUXJ
x
$GPLQLVWHULQYHVWLJDWLRQDOGUXJVXEFXWDQHRXVO\±:HHNVDQG9LVLWVDQG
x
5HFRUGXVHRIFRQFRPLWDQWPHGLFDWLRQV±:HHNVDQG9LVLWVDQG


&OLQLFDO3URWRFRO2%,

2%,3KDUPD,QF
9HUVLRQ±-XO
&RQILGHQWLDO
3DJHRI
x
0RQLWRUDQGUHFRUGDGYHUVHHYHQWVDVVHVVHGE\1&,&7&$(Y±:HHNVDQG
9LVLWVDQG

5.4
Treatment Period: Week 6 to Week 24 (Visit 5 to Visit 10) or Disease 
Progression
[Dose Escalation Phase]
,QYHVWLJDWLRQDOGUXJZLOOEHDGPLQLVWHUHGVXEFXWDQHRXVO\DW:HHNVDQG
9LVLWWR9LVLWUHVSHFWLYHO\
7KHIROORZLQJHYDOXDWLRQVDUHWREHFRQGXFWHGDWWKHVHZHHNVRUYLVLWV
x
3HUIRUPSK\VLFDOH[DPLQDWLRQLQFOXGLQJYLWDOVLJQVEORRGSUHVVXUHUHVSLUDWRU\UDWHSXOVH
DQGERG\WHPSHUDWXUHDQGZHLJKW±:HHNVDQG9LVLW±9LVLW
DVVHVVPHQWVWREHSHUIRUPHGSULRUWRDGPLQLVWUDWLRQRILQYHVWLJDWLRQDOGUXJ
x
&RQGXFWURXWLQHXULQDO\VLVS+SURWHLQJOXFRVHVSHFLILFJUDYLW\NHWRQHELOLUXELQDQG
XURELOLQRJHQ$QDO\VLVRIXULQDU\VHGLPHQWV5%&:%&HSLWKHOLDOFDVWVK\DOLQHFDVWV
DQGEDFWHULDOLVRSWLRQDO±:HHNVDQG9LVLW9LVLWDVVHVVPHQWV
WREHSHUIRUPHGSULRUWRDGPLQLVWUDWLRQRILQYHVWLJDWLRQDOGUXJ
x
&RQGXFW KHPDWRORJ\ WHVW  LQFOXGHV KHPRJORELQ KHPDWRFULW :%& 5%& SODWHOHW
GLIIHUHQWLDOV5)DQG(65±:HHNVDQG9LVLW9LVLWDVVHVVPHQWV
WREHSHUIRUPHGSULRUWRDGPLQLVWUDWLRQRILQYHVWLJDWLRQDOGUXJ
x
&RQGXFW VHUXP FKHPLVWU\ DQDO\VLV  LQFOXGHV VRGLXP SRWDVVLXP FKORULGH FDOFLXP
PDJQHVLXP%81FUHDWLQLQH$/7$67DONDOLQHSKRVSKDWDVHWRWDO SURWHLQ DOEXPLQ
WRWDOELOLUXELQ/'+DP\ODVHOLSDVHFKROHVWHUROWULJO\FHULGHVFRUWLVRO77IUHH7
DQG76+±:HHNDQG9LVLW±9LVLWDVVHVVPHQWVWREHSHUIRUPHG
SULRUWRDGPLQLVWUDWLRQRILQYHVWLJDWLRQDOGUXJ&ROOHFWEORRGVDPSOHVIRUPHDVXUHPHQWRI
DQWL*ORER+,J*DQG,J0WLWHU±:HHNVDQG9LVLW9LVLWVDPSOHV
WREHFROOHFWHGSULRUWRDGPLQLVWUDWLRQRILQYHVWLJDWLRQDOGUXJ
x
&ROOHFWEORRGVDPSOHVIRUH[SORUDWRU\DQDO\VLVIRUWKHIROORZLQJELRPDUNHUV±:HHNV
DQG9LVLW9LVLWSULRUWRDGPLQLVWUDWLRQRILQYHVWLJDWLRQDOGUXJ
x
0RQLWRULQJRILPPXQHUHVSRQVHRIDQWL*ORER+DQWL66($DQGDQWL66($
DQWLERG\SURGXFWLRQ
x
$'&&DQG&'&
x
&ROOHFWEORRGVDPSOHVIRUH[SORUDWRU\DQDO\VLVIRUWKHIROORZLQJELRPDUNHUV±:HHN
9LVLWSULRUWRDGPLQLVWUDWLRQRILQYHVWLJDWLRQDOGUXJ
x
&7&RQO\LQVHOHFWHG7DLZDQVLWHV
x
&ROOHFWEORRGVDPSOHIRUH[SORUDWRU\FHOOXODULPPXQHUHVSRQVH±:HHNVDQG
9LVLW9LVLWSULRUWRDGPLQLVWUDWLRQRILQYHVWLJDWLRQDOGUXJ
x
7FHOODQG%FHOOLPPXQHUHVSRQVHLQVHOHFWHG7DLZDQVLWHV


&OLQLFDO3URWRFRO2%,

2%,3KDUPD,QF
9HUVLRQ±-XO
&RQILGHQWLDO
3DJHRI
x
3HUIRUPWXPRUDVVHVVPHQWDFFRUGLQJWRWKH5(&,67FULWHULDLQFOXGLQJ&7VFDQDV
UHTXLUHG HYHU\  ZHHNV ± :HHNV  DQG  9LVLWV  DQG  UHVSHFWLYHO\ SULRU WR
DGPLQLVWUDWLRQRILQYHVWLJDWLRQDOGUXJ
x
3HUIRUPWXPRUVSHFLILFDQWLJHQWHVWLQJ&($IRUDOOHQUROOHGVXEMHFWVHYHU\ZHHNV±
:HHNVDQG9LVLWVDQGUHVSHFWLYHO\
x
3HUIRUP/HDG(&*DW:HHNVDQG9LVLWVDQGUHVSHFWLYHO\RQO\DVVHVVPHQWV
WREHSHUIRUPHGSULRUWRDGPLQLVWUDWLRQRILQYHVWLJDWLRQDOGUXJ
x
$GPLQLVWHULQYHVWLJDWLRQDOGUXJVXEFXWDQHRXVO\±:HHNVDQG9LVLW
9LVLW
x
5HFRUGXVHRIFRQFRPLWDQWPHGLFDWLRQV±HYHU\9LVLW9LVLW9LVLW
x
0RQLWRUDQGUHFRUGDGYHUVHHYHQWVDVVHVVHGE\1&,&7&$(Y ±HYHU\9LVLW9LVLW
9LVLW

[Cohort Expansion Phase]
,QYHVWLJDWLRQDOGUXJZLOOEHDGPLQLVWHUHGVXEFXWDQHRXVO\DW:HHNVDQG
HYHU\ZHHNVWKHUHDIWHUXQWLOGLVHDVHSURJUHVVLRQ

x
3HUIRUPSK\VLFDOH[DPLQDWLRQLQFOXGLQJYLWDOVLJQVEORRGSUHVVXUHUHVSLUDWRU\UDWHSXOVH
DQGERG\WHPSHUDWXUHDQGZHLJKW±:HHNVDQGHYHU\ZHHNVXQWLO
GLVHDVHSURJUHVVLRQDVVHVVPHQWVWREHSHUIRUPHGSULRUWRDGPLQLVWUDWLRQRILQYHVWLJDWLRQDO
GUXJ
x
&RQGXFWURXWLQHXULQDO\VLVS+SURWHLQJOXFRVHVSHFLILFJUDYLW\NHWRQHELOLUXELQDQG
XURELOLQRJHQ$QDO\VLVRIXULQDU\VHGLPHQWV5%&:%&HSLWKHOLDOFDVWVK\DOLQHFDVWV
DQGEDFWHULDOLVRSWLRQDO±:HHNVDQGHYHU\ZHHNVXQWLOGLVHDVH
SURJUHVVLRQDVVHVVPHQWVWREHSHUIRUPHGSULRUWRDGPLQLVWUDWLRQRILQYHVWLJDWLRQDOGUXJ
x
&RQGXFW KHPDWRORJ\ WHVW  LQFOXGHV KHPRJORELQ KHPDWRFULW :%& 5%& SODWHOHW
GLIIHUHQWLDOV5)DQG(65±:HHNVDQGHYHU\ZHHNVXQWLOGLVHDVH
SURJUHVVLRQDVVHVVPHQWVWREHSHUIRUPHGSULRUWRDGPLQLVWUDWLRQRILQYHVWLJDWLRQDOGUXJ
x
&RQGXFW VHUXP FKHPLVWU\ DQDO\VLV  LQFOXGHV VRGLXP SRWDVVLXP FKORULGH FDOFLXP
PDJQHVLXP%81FUHDWLQLQH$/7$67DONDOLQHSKRVSKDWDVHWRWDO SURWHLQ DOEXPLQ
WRWDOELOLUXELQ/'+DP\ODVHOLSDVHFKROHVWHUROWULJO\FHULGHVFRUWLVRO77IUHH7
DQG 76+ ± :HHN       DQG HYHU\  ZHHNV XQWLO GLVHDVH SURJUHVVLRQ
DVVHVVPHQWVWREHSHUIRUPHGSULRUWRDGPLQLVWUDWLRQRILQYHVWLJDWLRQDOGUXJ&ROOHFWEORRG
VDPSOHVIRUPHDVXUHPHQWRIDQWL*ORER+,J*DQG,J0WLWHU±:HHNV
DQGHYHU\ZHHNVXQWLOGLVHDVHSURJUHVVLRQVDPSOHVWREHFROOHFWHGSULRUWRDGPLQLVWUDWLRQ
RILQYHVWLJDWLRQDOGUXJ
x
&ROOHFWEORRGVDPSOHVIRUH[SORUDWRU\DQDO\VLVIRUWKHIROORZLQJELRPDUNHUV±:HHNV
    DQG HYHU\  ZHHNV XQWLO GLVHDVH SURJUHVVLRQ SULRU WR DGPLQLVWUDWLRQ RI
LQYHVWLJDWLRQDOGUXJ
x
0RQLWRULQJRILPPXQHUHVSRQVHRIDQWL*ORER+DQWL66($DQGDQWL66($
DQWLERG\SURGXFWLRQ
x
$'&&DQG&'&


&OLQLFDO3URWRFRO2%,

2%,3KDUPD,QF
9HUVLRQ±-XO
&RQILGHQWLDO
3DJHRI
x
&ROOHFW EORRG VDPSOHV IRU H[SORUDWRU\ DQDO\VLV IRU WKH IROORZLQJ ELRPDUNHUV²'RVH
(VFDODWLRQ3KDVH:HHN9LVLWRU&RKRUW([SDQVLRQ3KDVH:HHNYLVLWV
SULRUWRDGPLQLVWUDWLRQRILQYHVWLJDWLRQDOGUXJ
x
&7&RQO\LQVHOHFWHG7DLZDQVLWHV
x
&ROOHFWEORRGVDPSOHIRUH[SORUDWRU\FHOOXODULPPXQHUHVSRQVHRQO\LIHLWKHUDQWL*ORER
+DQWL66($RUDQWL66($VHUXPFRQFHQWUDWLRQUHDFKHVPJPO±FRQWLQXHYLVLWV
SULRUWRDGPLQLVWUDWLRQRILQYHVWLJDWLRQDOGUXJ:HHN9LVLWVRUDIWHU
x
7FHOODQG%FHOOLPPXQHUHVSRQVHLQVHOHFWHG7DLZDQVLWHV
x
&ROOHFWEORRGVDPSOHVIRUH[SORUDWRU\DQDO\VLVIRUWKHIROORZLQJELRPDUNHUV²:HHN
DQGHYHU\ZHHNVXQWLOZHHNVDIWHUWKHVWGLVHDVHSURJUHVVLRQ9LVLWV
DQGHYHU\ZHHNVXQWLOZHHNVDIWHUWKHVWGLVHDVHSURJUHVVLRQSULRUWRDGPLQLVWUDWLRQ
RILQYHVWLJDWLRQDOGUXJ
x
%7FHOOLPPXQRJHQRPLFDQDO\VLVLQVHOHFWHG7DLZDQVLWHV
x
3HUIRUPWXPRUDVVHVVPHQWDFFRUGLQJWRWKH5(&,67FULWHULDLQFOXGLQJ&7VFDQDV
UHTXLUHGHYHU\ZHHNV²:HHNVDQGHYHU\ZHHNVXQWLOGLVHDVHSURJUHVVLRQSULRU
WRDGPLQLVWUDWLRQRILQYHVWLJDWLRQDOGUXJ
x
3HUIRUPWXPRUVSHFLILFDQWLJHQWHVWLQJ&($DQG&<)5$IRUDOOHQUROOHGVXEMHFWVLQ
VHOHFWHGVLWHVHYHU\ZHHNV²:HHNVDQGHYHU\ZHHNVXQWLOGLVHDVHSURJUHVVLRQ
x
3HUIRUP/HDG(&*DW:HHNVDQGZHHNVDIWHUILQDOLQMHFWLRQRUGLVHDVHSURJUHVVLRQ
DVVHVVPHQWVWREHSHUIRUPHGSULRUWRDGPLQLVWUDWLRQRILQYHVWLJDWLRQDOGUXJ
x
$GPLQLVWHULQYHVWLJDWLRQDOGUXJVXEFXWDQHRXVO\²:HHNVDQGHYHU\
ZHHNVXQWLOGLVHDVHSURJUHVVLRQ
x
5HFRUGXVHRIFRQFRPLWDQWPHGLFDWLRQV²HYHU\YLVLWXQWLOGLVHDVHSURJUHVVLRQ
x
0RQLWRUDQGUHFRUGDGYHUVHHYHQWVDVVHVVHGE\1&,&7&$(Y²HYHU\YLVLWXQWLOGLVHDVH
SURJUHVVLRQ
x
&ROOHFWEORRGVDPSOHDWZHHNVDQGIRUWKHVXEMHFWVZLWKNQRZQ(*)5PXWDWLRQVWR
EHDQDO\]HGLQWKH&REDV(*)50XWDWLRQ7HVWV

5.5
Post Treatment Period to End of Study: Week 28 to Week 36 (Visit 11 to 
Visit 13) for Dose Escalation Phase; after disease progression for Cohort 
Expansion Phase
7KHIROORZLQJHYDOXDWLRQVDUHWREHFRQGXFWHGHYHU\ZHHNVIRU'RVH(VFDODWLRQ3KDVHRU
HYHU\ZHHNVIRU&RKRUW([SDQVLRQ3KDVHXQWLOWKHHQGRIWKHVWXG\³(QGRI6WXG\´ZKLFK
LVZHHNV'RVH(VFDODWLRQ3KDVHRUZHHNV&RKRUW([SDQVLRQ3KDVHDIWHUWKHODVW
VXEFXWDQHRXVGRVHRIWKHLQYHVWLJDWLRQDOGUXJ
x
3HUIRUPSK\VLFDOH[DPLQDWLRQLQFOXGLQJYLWDOVLJQVEORRGSUHVVXUHUHVSLUDWRU\UDWHSXOVH
DQGERG\WHPSHUDWXUHDQGZHLJKW
x
&RQGXFWURXWLQHXULQDO\VLVS+SURWHLQJOXFRVHVSHFLILFJUDYLW\NHWRQHELOLUXELQDQG
XURELOLQRJHQ$QDO\VLVRIXULQDU\VHGLPHQWV5%&:%&HSLWKHOLDOFDVWVK\DOLQHFDVWV
DQGEDFWHULDOLVRSWLRQDO


&OLQLFDO3URWRFRO2%,

2%,3KDUPD,QF
9HUVLRQ±-XO
&RQILGHQWLDO
3DJHRI
x
&RQGXFW KHPDWRORJ\ WHVW  LQFOXGHV KHPRJORELQ KHPDWRFULW :%& 5%& SODWHOHW
GLIIHUHQWLDOV5)DQG(65
x
&RQGXFW VHUXP FKHPLVWU\ DQDO\VLV  LQFOXGHV VRGLXP SRWDVVLXP FKORULGH FDOFLXP
PDJQHVLXP%81FUHDWLQLQH$/7$67DONDOLQHSKRVSKDWDVHWRWDO SURWHLQ DOEXPLQ
WRWDOELOLUXELQ/'+DP\ODVHOLSDVHFKROHVWHUROWULJO\FHULGHVFRUWLVRO77IUHH7
DQG76+
x
&ROOHFWEORRGVDPSOHVIRUPHDVXUHPHQWRIDQWL*ORER+,J*DQG,J0WLWHU
x
&ROOHFWEORRGVDPSOHVIRUH[SORUDWRU\DQDO\VLVIRUWKHIROORZLQJELRPDUNHUV
x
0RQLWRULQJRILPPXQHUHVSRQVHRIDQWL*ORER+DQWL66($DQGDQWL66($
DQWLERG\SURGXFWLRQ
x
$'&&DQG&'&
x
&ROOHFW EORRG VDPSOHV IRU H[SORUDWRU\ DQDO\VLV IRU WKH IROORZLQJ ELRPDUNHUV ± 'RVH
(VFDODWLRQ3KDVH:HHN9LVLWRU&RKRUW([SDQVLRQ3KDVH(QGRIVWXG\
x
&7&RQO\LQVHOHFWHG7DLZDQVLWHV
x
&ROOHFWEORRGVDPSOHIRUH[SORUDWRU\FHOOXODULPPXQHUHVSRQVHRQO\LIHLWKHUDQWL*ORER
+DQWL66($RUDQWL66($VHUXPFRQFHQWUDWLRQUHDFKHVPJPO±FRQWLQXHYLVLWV
SULRUWRDGPLQLVWUDWLRQRILQYHVWLJDWLRQDOGUXJ:HHNDIWHUWKHODVWLQMHFWLRQ373
x
7FHOODQG%FHOOLPPXQHUHVSRQVHLQVHOHFWHG7DLZDQVLWHV
x
&ROOHFWEORRGVDPSOHVIRUH[SORUDWRU\DQDO\VLVIRUWKHIROORZLQJELRPDUNHUV²&RKRUW
([SDQVLRQ3KDVHZHHNVDIWHUVWGLVHDVHSURJUHVVLRQ
x
%7FHOOLPPXQRJHQRPLFDQDO\VLVRQO\LQVHOHFWHG7DLZDQVLWHV
x
3HUIRUPWXPRUDVVHVVPHQWDFFRUGLQJWRWKH5(&,67FULWHULDDWZHHNV9LVLWIRU
'RVH(VFDODWLRQ3KDVHRUDWHYHU\YLVLWIRUWKHFRQWLQXRXVLQMHFWLRQVXEMHFWVDIWHUGLVHDVH
SURJUHVVLRQLQ&RKRUW([SDQVLRQ3KDVH,IWKHGDWDRI&7DVVHVVPHQWDUHDYDLODEOHZLWKLQ
ZHHNVSULRUWRWKHVFKHGXOHGYLVLWWKHDVVHVVPHQWRI&7PD\QRWEHSHUIRUPHGEDVHGRQ
WKHLQYHVWLJDWRU¶VGLVFUHWLRQ
x
3HUIRUPWXPRUVSHFLILFDQWLJHQWHVWLQJ&($IRUDOOHQUROOHGVXEMHFWVDWZHHNV9LVLW
IRU'RVH(VFDODWLRQ3KDVHRU(QGRI6WXG\YLVLWIRU&RKRUW([SDQVLRQ3KDVHLQVHOHFWHG
VLWHV&($DQG&<)5$
x
3HUIRUPOHDG(&*DWWKHYLVLWVGHVFULEHGLQ7DEOHDQG
x
5HFRUGXVHVRIFRQFRPLWDQWPHGLFDWLRQVHYHU\YLVLW
x
0RQLWRUDQGUHFRUGDGYHUVHHYHQWVDVVHVVHGE\1&,&7&$(YHYHU\YLVLW
x
$GPLQLVWHULQYHVWLJDWLRQDOGUXJVXEFXWDQHRXVO\HYHU\YLVLWIRUWKHFRQWLQXRXVLQMHFWLRQ
VXEMHFWVDIWHUGLVHDVHSURJUHVVLRQLQ&RKRUW([SDQVLRQ3KDVH
x
&ROOHFWEORRGVDPSOHDWSRVWWUHDWPHQWSHULRGDQG(QGRI6WXG\IRUWKHVXEMHFWVZLWK
NQRZQ(*)5PXWDWLRQVWREHDQDO\]HGLQWKH&REDV(*)50XWDWLRQ7HVWVLQFRKRUW
H[SDQVLRQSKDVH




&OLQLFDO3URWRFRO2%,

2%,3KDUPD,QF
9HUVLRQ±-XO
&RQILGHQWLDO
3DJHRI
5.6
Follow-Up Period (Up to 12 Months Following End of Study, i.e., Weeks
44 to 84)
8QOHVVWKHVXEMHFWPHHWVWKHRIIVWXG\FULWHULD6HFWLRQDOOVXUYLYLQJVXEMHFWVZLOOEH
IROORZHGXSIRUVXUYLYDOVWDWXVE\SKRQHFRQWDFWRUVXEMHFWV¶FOLQLFYLVLWHYHU\ZHHNVIRU
'RVH(VFDODWLRQ3KDVHRUZHHNVIRU&RKRUW([SDQVLRQ3KDVHIRUXSWRZHHNVRUZHHNV
UHVSHFWLYHO\IROORZLQJWKH(QGRI6WXG\(DUO\7HUPLQDWLRQYLVLW
5.7
Early Termination 
6XEMHFWVZKRSUHPDWXUHO\WHUPLQDWHGVWXG\WUHDWPHQWRUHYDOXDWLRQIRUDQ\UHDVRQVRWKHUWKDQ
GLVHDVHSURJUHVVLRQH[FHSWFRQWLQXRXVLQSRVWWUHDWPHQWSHULRGZLOORQO\QHHGWRFRPSOHWH
(DUO\7HUPLQDWLRQ9LVLWIRUWKHIROORZLQJHYDOXDWLRQVEHIRUHGLVFRQWLQXDWLRQIURPWKHVWXG\RU
FRQWLQXLQJ RQWR WKH IROORZXS SKDVH 'LVHDVH SURJUHVVLYH VXEMHFWV ZKR DUH QRW ZLOOLQJ WR
FRQWLQXHLQWRWKHSRVWWUHDWPHQWSHULRGZLOOWKHSHUIRUP(R6YLVLW,IODEGDWDLVDYDLODEOHZLWKLQ
ZHHNSULRUWR(R6(R7ODEWHVWVFDQEHZDLYHG6XUYLYLQJVXEMHFWVZLOOWKHQHQWHU)ROORZ
XSSHULRGWRIROORZXSVXUYLYDOVWDWXVE\SKRQHFRQWDFWRUVXEMHFWV¶FOLQLFYLVLWZHHNVIRU
&RKRUW([SDQVLRQ3KDVHIRUXSWRZHHNV
x
3HUIRUPSK\VLFDOH[DPLQDWLRQDQGPHDVXUHYLWDOVLJQVEORRGSUHVVXUHUHVSLUDWRU\UDWH
SXOVHDQGERG\WHPSHUDWXUH:HLJKW
x
&RQGXFWURXWLQHXULQDO\VLVS+SURWHLQJOXFRVHVSHFLILFJUDYLW\NHWRQHELOLUXELQDQG
XURELOLQRJHQ$QDO\VLVRIXULQDU\VHGLPHQWV5%&:%&HSLWKHOLDOFDVWVK\DOLQHFDVWV
DQGEDFWHULDOLVRSWLRQDO
x
&RQGXFWKHPDWRORJ\WHVWLQFOXGHVKHPRJORELQKHPDWRFULW:%&5%&SODWHOHW
GLIIHUHQWLDOV5)DQG(65
x
&RQGXFWVHUXPFKHPLVWU\DQDO\VLVLQFOXGHVVRGLXPSRWDVVLXPFKORULGHFDOFLXP
PDJQHVLXP%81FUHDWLQLQH$/7$67DONDOLQHSKRVSKDWDVHWRWDOSURWHLQDOEXPLQ
WRWDOELOLUXELQ/'+DP\ODVHOLSDVHFKROHVWHUROWULJO\FHULGHVFRUWLVRO77IUHH7
DQG76+
x
&ROOHFWEORRGVDPSOHVIRUPHDVXUHPHQWRIDQWL*ORER+,J*DQG,J0WLWHU
x
&ROOHFWEORRGVDPSOHVIRUH[SORUDWRU\DQDO\VLVIRUWKHIROORZLQJELRPDUNHUV
x
0RQLWRULQJRILPPXQHUHVSRQVHRIDQWL*ORER+DQWL66($DQGDQWL66($
DQWLERG\SURGXFWLRQ
x
&7&RQO\LQVHOHFWHG7DLZDQVLWHV
x
$'&&DQG&'&
x
3HUIRUP/HDG(&*
x
3HUIRUP7XPRUDVVHVVPHQWDFFRUGLQJWR5(&,67FULWHULDLQFOXGLQJ&7VFDQDV
UHTXLUHG,IWKHGDWDRI&7DVVHVVPHQWDUHDYDLODEOHZLWKLQZHHNVSULRUWRWKH(7YLVLW
WKHDVVHVVPHQWRI&7PD\QRWEHSHUIRUPHGEDVHGRQWKHLQYHVWLJDWRU¶VGLVFUHWLRQ
x
3HUIRUPWXPRUVSHFLILFDQWLJHQWHVWLQJ&($DQG&<)5$IRUDOOHQUROOHGVXEMHFWVLQ
VHOHFWHGVLWHV
x
5HFRUGDGYHUVHHYHQWVDVVHVVHGE\1&,&7&$(Y


&OLQLFDO3URWRFRO2%,

2%,3KDUPD,QF
9HUVLRQ±-XO
&RQILGHQWLDO
3DJHRI
x
5HFRUGXVHRIFRQFRPLWDQWPHGLFDWLRQV
x
6XEMHFWVZKRGLVFRQWLQXHGWKHVWXG\WUHDWPHQWRUHYDOXDWLRQEHIRUH(QGRI6WXG\IRU
UHDVRQVRWKHUWKDQGLVHDVHSURJUHVVLRQZLOOEHIROORZHGXSIRUGLVHDVHVWDWXVE\FOLQLF
YLVLWXQWLO'LVHDVH3URJUHVVLRQ6DPHHYDOXDWLRQVZLOOEHFRQGXFWHGDVWKRVHGHILQHGLQ
WKH3RVW7UHDWPHQW3HULRG
x
(*)5ZLOOEHDQDO\]HGIRUWKHHDUO\WHUPLQDWLRQVXEMHFWVRWKHUWKDQ3'

5.8
Other Study Procedures
7XPRUWLVVXHVDPSOHVDQGKLVWRORJ\SDWKRORJ\UHSRUWLISRVVLEOHZLOOEHFROOHFWHGDW:HHN
SULRUWRDGPLQLVWUDWLRQRIWKHLQYHVWLJDWLRQDOGUXJDQGEHVXEPLWWHGWRDFHQWUDOODERUDWRU\WR
WHVWWKHH[SUHVVLRQOHYHOVRI*ORER+66($66($DQG3'/E\LPPXQRKLVWRFKHPLVWU\
DVZHOODVRWKHUWXPRUPDUNHUVWKDWPD\EHH[SUHVVHGLQWKHOXQJJDVWULFFRORUHFWDORUEUHDVW
WXPRUV1RWHWKDWVXEMHFWWXPRUELRSV\WLVVXHVDPSOHVZLOOEHFROOHFWHGWRWHVWWKHH[SUHVVLRQ
OHYHOVRI*ORER+66($66($DQGRU3'/ZLOOEHFRQGXFWHGDW:HHNIRUGDWD
DQDO\VLVSXUSRVHDQGQRWIRUHOLJLELOLW\FULWHULDLQ'RVH(VFDODWLRQ3KDVH7XPRUELRSV\WLVVXH
VDPSOHVDUHPDQGDWRU\IRU&RKRUW([SDQVLRQVXEMHFWVWRWHVW*ORER+DQGRWKHUWXPRUPDUNHUV
VXFKDV66($66($DQGRU3'/DUHIRUGDWDDQDO\VLVSXUSRVHV*ORER+H[SUHVVLRQ
OHYHOVZLOOEHFROOHFWHGDQGWHVWHGDWVFUHHQLQJYLVLWIRUHOLJLELOLW\
%ORRGVDPSOHVZLOOEHFROOHFWHGDWYDULRXVYLVLWVVKRZQLQ7DEOHDQGDQGVWRUHGZLWKWKH
LQWHQWLRQRISHUIRUPLQJVFLHQWLILFUHVHDUFKRULPPXQRORJLFDODQDO\VLVRQKXPRUDODQGFHOOXODU
PHGLDWHGLPPXQHUHVSRQVHVDQGLPPXQRJHQLFLW\RIWKHYDFFLQHXVLQJLQKRXVHJO\FDQFKLS
DQG4XDQWLWDWLYH(/,6$WRGHWHFWLPPXQHUHVSRQVHDQGPRQLWRUWXPRUUHVSRQVHE\ELRPDUNHUV
7KHVHWHVWVZLOOLQFOXGHPHDVXUHPHQWRIDQWL*ORER+,J*DQG,J0SURGXFWLRQ%ORRGVDPSOHV
ZLOODOVREHFROOHFWHGIRUH[SORUDWRU\DQDO\VLVRIYDULRXVELRPDUNHUVDVIROORZV
x
0RQLWRULQJRILPPXQHUHVSRQVHRIDQWL*ORER+DQWL66($DQGDQWL66($
DQWLERG\SURGXFWLRQ
x
&7&RQO\LQVHOHFWHG7DLZDQVLWHV
x
$'&&DQG&'&
x
7FHOODQG%FHOOLPPXQHUHVSRQVHLQVHOHFWHG7DLZDQVLWHV
x
%7FHOOLPPXQRJHQRPLFDQDO\VLVLQVHOHFWHG7DLZDQVLWHV
x
([YLYRLPPXQRJHQLFLW\DQDO\VLVLQVHOHFWHG7DLZDQVLWHV
x
&REDV(*)50XWDWLRQ7HVWVLQVHOHFWHG7DLZDQVLWHV

7LVVXHDQGEORRGVDPSOHVZLOOEHDQDO\]HGXVLQJTXDOLILHGDVVD\VE\FRQWUDFWHGODERUDWRULHV
XQGHUWKHVXSHUYLVLRQRI2%,3KDUPD,QF
,QRUGHUWRHYDOXDWHWKHWUHDWPHQWUHVSRQVHDQGWKHWKHUDSHXWLFPHFKDQLVPRILPPXQRWKHUDSLHV
WRVSHFLILFWXPRUELRORJ\EORRGDQGWXPRUVDPSOHVQHHGWREHVWRUHGIRUSUHVHQWDQGUHOHYDQW
IXWXUHVWXGLHVLQRUGHUWRIXUWKHUH[SORUHWKHDQWLWXPRULPPXQHPHFKDQLVPDJDLQVWVSHFLILF
WXPRUELRORJ\


&OLQLFDO3URWRFRO2%,

2%,3KDUPD,QF
9HUVLRQ±-XO
&RQILGHQWLDO
3DJHRI
)XWXUHVWXGLHVZLOOEHFDUULHGRXWGXULQJDQGDIWHUWKHHQGRIWKHFOLQLFDOWULDO7KLVPD\EHGXH
WRDQ\WUHQGVRUUHVXOWVWKDWFRXOGSRWHQWLDOO\UDLVHIXUWKHUTXHVWLRQVDQGK\SRWKHVHVOHDGLQJWR
FUXFLDOILQGLQJVDQGEUHDNWKURXJKVLQFDQFHUWUHDWPHQW
7KHUHTXLUHGVWXG\SURFHGXUHVDUHVXPPDUL]HGLQWKH7LPHDQG(YHQWV6FKHGXOH7DEOH
EHORZ


&OLQLFDO3URWRFRO2%,

2%,3KDUPD,QF

9HUVLRQ±-XO&RQILGHQWLDO
3DJHRI

Table 1
Time and Event Schedule for Dose Escalation Phase
Phases
9LVLW,'
Screening
Treatment Period
Post Treatment Period
Follow-
Up
Early
Termi-
nation*
End of 
Study
6FUHHQLQJ
9LVLW
9
9
9
9
9
9
9
9
9
9
9
9
9


Corresponding Week
1
2
3
4
6
8
12
16
20
24
28
32
36
44-84

9LVLWZLQGRZ'D\






1$
,QIRUPHG&RQVHQW
;




'HPRJUDSKLFV	0HGLFDO
+LVWRU\
;




,QFOXVLRQ([FOXVLRQ
&ULWHULD
;




3K\VLFDO([DPLQDWLRQ	
9LWDO6LJQV
;
;
;
;
;
;

;
(&*
;



;


;

;

;

;

;
8ULQH3UHJQDQF\7HVW
;




+,9+%9DQG+&9
7HVW
;




6XUYLYDO



;

          Treatments
5HJLVWUDWLRQ	&RKRUW
$VVLJQPHQW

;



$GPLQLVWHU,QYHVWLJDWLRQDO
'UXJ

;
;
;
;
;
;
;
;
;
;





Laboratory Assessments
8ULQH$QDO\VLV
+HPDWRORJ\
6HUXP&KHPLVWU\
;
;
;
;
;
;

;


&OLQLFDO3URWRFRO2%,

2%,3KDUPD,QF

9HUVLRQ±-XO&RQILGHQWLDO
3DJHRI

Table 1.
Time and Event Schedule for Dose Escalation Phase (Continued)
Phases
9LVLW,'
Screening
Treatment Period
Post Treatment Period
Follow-
Up
Early
Termi-
nation*
End of 
Study
6FUHHQLQJ
9LVLW
9
9
9
9
9
9
9
9
9
9
9
9
9


Corresponding Week
1
2
3
4
6
8
12
16
20
24
28
32
36
44-84

9LVLWZLQGRZ'D\






1$
Laboratory Assessment (cont’d)
7XPRUVDPSOHIRU,+&

;



%ORRGVDPSOHVIRUDQWL
*ORER+,J*DQG,J0

;

;
;
;
;
;
;
;
;
;
;
;

;
%ORRGIRUH[SORUDWRU\
DQDO\VLVRIELRPDUNHUV

;

;
;
;
;
;
;
;
;
;
;
;

;
Other Assessments
$GYHUVH(YHQWV

;
;
;
;
;

;
&RQFRPLWDQW
0HGLFDWLRQV
;
;
;
;
;
;

;
7XPRU$VVHVVPHQW
;






;


;


;

;
7XPRU6SHFLILF$QWLJHQ
;






;


;


;

;
&HOOXODULPPXQH
UHVSRQVHV







;
;
;
;






(DUO\WHUPLQDWLRQLVGHILQHGDVWKHWLPHSRLQWDWZKLFKWKHVXEMHFWZLWKGUDZVIURPWKHVWXG\EHIRUHFRPSOHWLQJDOOUHTXLUHGWUHDWPHQWVDQGHYDOXDWLRQVLH:HHN7KHVHDVVHVVPHQWVVKRXOGEH
REWDLQHGZKHQWKHVXEMHFWSHUPDQHQWO\GLVFRQWLQXHVWKHVWXG\WUHDWPHQWRUFRQWLQXLQJRQWRWKHIROORZXSSKDVHKRZHYHULPDJLQJHJ&7VFDQVGRHVQRWQHHGWREHDFTXLUHGDJDLQLIODVWLPDJLQJ
ZDVGRQHZLWKLQZHHNV
6XEMHFWVZKRGLVFRQWLQXHGWKHVWXG\WUHDWPHQWRUHYDOXDWLRQEHIRUH(QGRI6WXG\IRUUHDVRQVRWKHUWKDQGLVHDVHSURJUHVVLRQZLOOEHIROORZHGXSIRUGLVHDVHVWDWXVE\FOLQLFYLVLWXQWLO'LVHDVH
3URJUHVVLRQ6DPHHYDOXDWLRQVZLOOEHFRQGXFWHGDVWKRVHGHILQHGLQWKH3RVW7UHDWPHQW3HULRG

,IVFUHHQLQJDVVHVVPHQWLVSHUIRUPHGZLWKLQGD\VSULRUWR9LVLWDWWKHVDPHODERUDWRU\XULQHDQDO\VLVKHPDWRORJ\DQGVHUXPFKHPLVWU\DUHQRWUHTXLUHGDW9LVLW


,QFOXGHV(&2*SHUIRUPDQFHVFRUHZHLJKWDQGKHLJKWDWVFUHHQLQJ,QFOXGHVZHLJKWDWWUHDWPHQWSHULRGSRVWWUHDWPHQWSHULRGDQGHDUO\WHUPLQDWLRQYLVLW9LWDOVLJQVLQFOXGHEORRGSUHVVXUH
UHVSLUDWRU\UDWHSXOVHDQGERG\WHPSHUDWXUH

$Q(&*ZLOOEHSHUIRUPHGDWWKHWLPHRIVFUHHQLQJDW:HHNVDQG9LVLWVDQGDQG(QGRI6WXG\UHVSHFWLYHO\RUDWWKHHDUO\WHUPLQDWLRQYLVLWLIVXEMHFWLV
GLVFRQWLQXHGSULRUWR:HHN(QGRI6WXG\)RUDQ\VXEMHFWZKRH[SHULHQFHGDVLJQLILFDQWFDUGLRYDVFXODUUHODWHGPHGLFDOHYHQWHJWDFK\FDUGLDXQVFKHGXOHGWHVWVZLOOEHFRQGXFWHGSHU
,QYHVWLJDWRU¶VMXGJPHQW

8ULQHSUHJQDQF\WHVWLVWREHSHUIRUPHGRQO\RQVXEMHFWVRIFKLOGEHDULQJSRWHQWLDO)ROORZXSSUHJQDQF\WHVWLQJGXULQJWKHVWXG\SHULRGZLOOEHSHUIRUPHGDWWKH,QYHVWLJDWRU¶VGLVFUHWLRQ


&OLQLFDO3URWRFRO2%,

2%,3KDUPD,QF

9HUVLRQ±-XO&RQILGHQWLDO
3DJHRI


&RQGXFW+%9HJ+%V$J+%H$JDQGLIFOLQLFDOO\LQGLFDWHG+%F$EDQGRU+%9'1$+&9HJDQWL+&9WHVWLQJ&RQGXFW+,9WHVWLQJLIQRKLVWRULFDOGDWDDUHDYDLODEOH2SWLRQDO
WHVWVHJYLUDOORDGFDQEHRUGHUHGIRUVXVSHFWHGDFWLYHLQIHFWLRQDWIROORZXSYLVLWVEDVHGRQWKH,QYHVWLJDWRU¶VFOLQLFDOMXGJPHQW

9LWDOVLJQVEORRGSUHVVXUHUHVSLUDWRU\UDWHSXOVHDQGWHPSHUDWXUHDQGLQVSHFWLRQRILQMHFWLRQVLWHVZLOOEHPRQLWRUHGDWPLQXWHVDWPLQXWHVDQGWKHQDWKRXUPLQXWHVDIWHU
LQMHFWLRQ)RUHYHU\&RKRUWVWKHILUVWWKUHHVXEMHFWVVKRXOGEHKRVSLWDOL]HGIROORZLQJILUVWGRVHRIWKHLQYHVWLJDWLRQDOGUXJLQMHFWLRQYLWDOVLJQVDQGLQVSHFWLRQRILQMHFWLRQVLWHVZLOOEH
PRQLWRUHGDIWHULQMHFWLRQRILQYHVWLJDWLRQDOGUXJIRUIROORZLQJWLPHSRLQWDWPLQXWHVDWPLQXWHVDWKRXUPLQXWHVDWKRXUPLQXWHVDWKRXUPLQXWHVEHIRUH
EHGDQGEHIRUHGLVFKDUJH

&RQGXFWURXWLQHXULQDO\VLVS+SURWHLQJOXFRVHVSHFLILFJUDYLW\NHWRQHELOLUXELQDQGXURELOLQRJHQ$QDO\VLVRIXULQDU\VHGLPHQWV5%&:%&HSLWKHOLDOFDVWVK\DOLQHFDVWVDQGEDFWHULDO
LVRSWLRQDO

+HPDWRORJ\LQFOXGHVKHPRJORELQKHPDWRFULW:%&5%&SODWHOHWGLIIHUHQWLDOV5)DQG(65

6HUXPFKHPLVWU\LQFOXGHVVRGLXPSRWDVVLXPFKORULGHFDOFLXPPDJQHVLXP%81FUHDWLQLQH$/7$67DONDOLQHSKRVSKDWDVHWRWDOSURWHLQDOEXPLQWRWDOELOLUXELQ/'+DP\ODVHOLSDVH
FKROHVWHUROWULJO\FHULGHVFRUWLVRO77IUHH7DQG76+

7XPRUELRSV\WLVVXHVDPSOHVRISULPDU\VLWHDQGGLVWDQWPHWDVWDVHVLISRVVLEOHZLOOEHFROOHFWHGIRU*ORER+66($66($DQG3'/H[SUHVVLRQE\LPPXQRKLVWRFKHPLVWU\VSHFLILHGLQ
6HFWLRQ³2WKHU6WXG\3URFHGXUHV´$OWKRXJKIUHVKVSHFLPHQVDUHSUHIHUUHGPRVWVXEMHFWVVKRXOGKDYHKLVWRULFDOWXPRUWLVVXHVSHFLPHQVDYDLODEOHZKLFKFDQEHVXEPLWWHGWRWKHFHQWUDO
ODEIRUWHVWLQJ,IWXPRUWLVVXHVDPSOHVDUHQRWDYDLODEOHIUHVKWXPRUWLVVXHVDPSOHVVKRXOGEHDFTXLUHG+RZHYHULQFDVHVZKHUHWXPRUELRSVLHVPD\QRWEHSRVVLEOHVXEMHFWVDUHQRWUHTXLUHG
WRVXEPLWWLVVXHVDPSOHV

6DPSOHVZLOOEHFROOHFWHGIRUDQDO\VLVRI$QWL*ORER+,J*DQG,J0WLWHUVE\DFRQYHQWLRQDOPHWKRG

6DPSOHVZLOOEHFROOHFWHGIRUH[SORUDWRU\DQDO\VLVRIWKHIROORZLQJELRPDUNHUVDQGLPPXQRORJLFDOUHVSRQVHV$QWL66($DQGDQWL66($DQWLERG\WLWHUVE\LQKRXVHGHYHORSPHQWNLW$QWL
*ORER+DQWL66($DQGDQWL66($DQWLERGLHVE\JO\FDQDUUD\DQG4XDQWLWDWLYH(/,6$DVZHOODV$'&&DQG&'&6DPSOHVZLOORQO\EHFROOHFWHGDWYLVLWVZHHNVDQG
HDUO\WHUPLQDWLRQIRUH[SORUDWRU\DQDO\VLVRI&7&LQVHOHFWHG7DLZDQVLWHV

$GYHUVHHYHQWVZLOOEHDVVHVVHGE\1&,&7&$(Y)RUWKHVXEMHFWZKRZLWKGUDZVWUHDWPHQWGXULQJWKHWUHDWPHQWSHULRGDGYHUVHHYHQWVVKRXOGEHUHFRUGHGWKURXJKGD\VDIWHUWKHODVW
DGPLQLVWUDWLRQRILQYHVWLJDWLRQDOGUXJ2%,2%,

&RQFRPLWDQWGUXJVVKRXOGEHUHFRUGHGLQFOXGLQJDQ\PHGLFDWLRQWDNHQZLWKLQGD\VSULRUWRVWGRVLQJRIWKHLQYHVWLJDWLRQDOGUXJ)RUWKHVXEMHFWZKRZLWKGUDZVWKHVWXG\GXULQJWKH
WUHDWPHQWSHULRGFRQFRPLWDQWGUXJVKRXOGEHUHFRUGHGXQWLOGD\VDIWHUWKHODVWDGPLQLVWUDWLRQRILQYHVWLJDWLRQDOGUXJ

7XPRUDVVHVVPHQWZLOOEHDFFRUGLQJWRWKH5(&,67FULWHULDLQFOXGLQJ&7VFDQDVUHTXLUHG&7VFDQZLOOEHSHUIRUPHGDWGHVLJQDWHGWLPHVGXULQJWUHDWPHQW7KHZLQGRZSHULRGIRU&7
VFDQVLV±GD\VIURPWKHSODQQHGYLVLWSHUSURWRFROVFKHGXOH,IWKHGDWDRI&7DVVHVVPHQWDUHDYDLODEOHZLWKLQZHHNVSULRUWRWKHVFKHGXOHGYLVLWWKHDVVHVVPHQWRI&7PD\QRWEH
SHUIRUPHGEDVHGRQWKHLQYHVWLJDWRU¶VGLVFUHWLRQ8QVFKHGXOHGWXPRUDVVHVVPHQWVFDQDOVREHSHUIRUPHGDWWKH,QYHVWLJDWRU¶VGLVFUHWLRQ0HWKRGRORJ\XVHGWRDVVHVVWXPRUVGXULQJWKHVWXG\
SHULRGVKRXOGEHFRQVLVWHQWZLWKWKHPHWKRGRORJ\XVHGDWEDVHOLQHVFUHHQLQJ)RUVXEMHFWVZKHUH&7VFDQVDUHFRQWUDLQGLFDWHG05,VFDQEHSHUIRUPHGLQVWHDG

7XPRUVSHFLILFDQWLJHQWHVWLQJ&($IRUDOOHQUROOHGVXEMHFWVWREHSHUIRUPHGSULRUWRWUHDWPHQWDQGHYHU\ZHHNVXQWLOWKHHQGRIWKHVWXG\

:KROHEORRGVDPSOHZLOOEHFROOHFWHGWRWHVWLQGXFHG%DQG7FHOOUHVSRQVHVLQVHOHFWHG7DLZDQVLWHV






&OLQLFDO3URWRFRO2%,

2%,3KDUPD,QF

9HUVLRQ±-XO&RQILGHQWLDO
3DJHRI

Table 2
Time and Event Schedule for Cohort Expansion Phase
Phases
9LVLW,'
Screening
Treatment Period
Post Treatment Period
Follow-
Up
Early 
Termination
End of 
Study
6FUHHQLQJ
9LVLW
9
9
9
9
9
9
9
9
9
9 9a)LQDO
,QMHFWLRQ
373
373



Corresponding 
Week
1
2
3
4
6
8
12
16
20
24
q8 weeks
ZNV
DIWHUILQDO
LQMHFWLRQ
RUZNV
IRU
FRQWLQXRXV
LQMHFWLRQ
ZNV
DIWHUILQDO
LQMHFWLRQ
RUZNV
IRU
FRQWLQXRXV
LQMHFWLRQ
ZNV
DIWHUILQDO
LQMHFWLRQ
RUZNV
IRU
FRQWLQXRXV
LQMHFWLRQ
24 wks 
after End 
of Study
9LVLWZLQGRZ'D\








,QIRUPHG&RQVHQW
;




7XPRUVDPSOHIRU
,+&
;




'HPRJUDSKLFV	
0HGLFDO+LVWRU\
;




,QFOXVLRQ([FOXVLRQ
&ULWHULD
;




3K\VLFDO
([DPLQDWLRQ	9LWDO
6LJQV
;
;
;
;
;
;
;

;
(&*
;






;




;

;

;
8ULQH3UHJQDQF\7HVW
;




+,9+%9DQG+&9
7HVW
;




6XUYLYDO



;

          Treatments
$GPLQLVWHU
,QYHVWLJDWLRQDO'UXJ

;
;
;
;
;
;
;
;
;
;
;
;
;
;


Laboratory Assessments
8ULQH$QDO\VLV
+HPDWRORJ\
6HUXP&KHPLVWU\
;
;
;
;
;
;
;

;


&OLQLFDO3URWRFRO2%,

2%,3KDUPD,QF

9HUVLRQ±-XO&RQILGHQWLDO
3DJHRI

Table 2.
Time and Event Schedule for Cohort Expansion Phase (Continued)
Phases
9LVLW,'
Screening
Treatment Period
Post Treatment Period
Follow-
Up
Early 
Termination
End of 
Study
6FUHHQLQJ
9LVLW
9
9
9
9
9
9
9
9
9
9 9a)LQDO
,QMHFWLRQ
373
373



Corresponding Week
1
2
3
4
6
8
12
16
20
24
q8 weeks
ZNVDIWHU
ILQDO
LQMHFWLRQRU
ZNVIRU
FRQWLQXRXV
LQMHFWLRQ
ZNV
DIWHUILQDO
LQMHFWLRQ
RUZNV
IRU
FRQWLQXRXV
LQMHFWLRQ
ZNV
DIWHUILQDO
LQMHFWLRQ
RUZNV
IRU
FRQWLQXRXV
LQMHFWLRQ
24 wks 
after 
End of 
Study
9LVLWZLQGRZ'D\








Laboratory Assessment (cont’d)
%ORRGVDPSOHVIRU
DQWL*ORER+,J*DQG
,J0

;

;
;
;
;
;
;
;
;
;
;
;
;

;
%ORRGIRUH[SORUDWRU\
DQDO\VLVRI
ELRPDUNHUV

;

;
;
;
;
;
;
;
;
;
;
;
;

;
Other Assessments
$GYHUVH(YHQWV

;
;
;
;
;

;
&RQFRPLWDQW
0HGLFDWLRQV
;
;
;
;
;
;

;
7XPRU$VVHVVPHQW
;






;


;
;
;
;
;

;
7XPRU6SHFLILF
$QWLJHQ
;






;


;
;


;

;
&HOOXODULPPXQH
UHVSRQVHV






FRQWLQXHYLVLWVDIWHUHLWKHUDQWL*ORER+66($66($
,J*VHUXPFRQFHQWUDWLRQUHDFKHVPJPO




,PPXQRJHQRPLF
;




;

;

;

;
;




([YLYR
,PPXQRJHQLFLW\
;
















&REDV(*)5
0XWDWLRQ7HVWV

;





;



;
;

;

;
)RUWKHHDUO\WHUPLQDWLRQVXEMHFWVRWKHUWKDQ3'
,IVFUHHQLQJDVVHVVPHQWLVSHUIRUPHGZLWKLQGD\VSULRUWR9LVLWDWWKHVDPHODERUDWRU\XULQHDQDO\VLVKHPDWRORJ\DQGVHUXPFKHPLVWU\DUHQRWUHTXLUHGDW9LVLW
2QO\VWDUWVDIWHU:HHNVDQGHYHU\ZHHNVWKHUHDIWHUWLOOZHHNVDIWHUVWGLVHDVHSURJUHVVLRQ


&OLQLFDO3URWRFRO2%,

2%,3KDUPD,QF

9HUVLRQ±-XO&RQILGHQWLDO
3DJHRI



7XPRUELRSV\WLVVXHVDPSOHVRISULPDU\VLWHDQGGLVWDQWPHWDVWDVHVLISRVVLEOHZLOOEHFROOHFWHGIRU*ORER+66($66($DQG3'/H[SUHVVLRQE\LPPXQRKLVWRFKHPLVWU\VSHFLILHGLQ
6HFWLRQ³2WKHU6WXG\3URFHGXUHV´DW6FUHHQLQJYLVLW$OWKRXJKIUHVKVSHFLPHQVDUHSUHIHUUHGPRVWVXEMHFWVVKRXOGKDYHKLVWRULFDOWXPRUWLVVXHVSHFLPHQVDYDLODEOHZKLFKFDQEH
VXEPLWWHGWRWKHFHQWUDOODEIRUWHVWLQJ,IWXPRUWLVVXHVDPSOHVDUHQRWDYDLODEOHIUHVKWXPRUWLVVXHVDPSOHVVKRXOGEHDFTXLUHG2QO\*ORER+SRVLWLYHVXEMHFWVDUHHOLJLEOH

,QFOXGHV(&2*SHUIRUPDQFHVFRUHZHLJKWDQGKHLJKWDWVFUHHQLQJ,QFOXGHVZHLJKWDWWUHDWPHQWSHULRGSRVWWUHDWPHQWSHULRGDQGHDUO\WHUPLQDWLRQYLVLW9LWDOVLJQVLQFOXGHEORRGSUHVVXUH
UHVSLUDWRU\UDWHSXOVHDQGERG\WHPSHUDWXUH

$Q(&*ZLOOEHSHUIRUPHGDWWKHWLPHRIVFUHHQLQJDW:HHNVDQGZHHNVDIWHUILQDOLQMHFWLRQDVZHOODV(R6YLVLW)RUDQ\VXEMHFWZKRH[SHULHQFHGDVLJQLILFDQWFDUGLRYDVFXODUUHODWHG
PHGLFDOHYHQWHJWDFK\FDUGLDXQVFKHGXOHGWHVWVZLOOEHFRQGXFWHGSHU,QYHVWLJDWRU¶VMXGJPHQW

8ULQHSUHJQDQF\WHVWLVWREHSHUIRUPHGRQO\RQVXEMHFWVRIFKLOGEHDULQJSRWHQWLDO)ROORZXSSUHJQDQF\WHVWLQJGXULQJWKHVWXG\SHULRGZLOOEHSHUIRUPHGDWWKH,QYHVWLJDWRU¶VGLVFUHWLRQ

&RQGXFW+%9HJ+%V$J+%H$JDQGLIFOLQLFDOO\LQGLFDWHG+%F$EDQGRU+%9'1$+&9HJDQWL+&9WHVWLQJ&RQGXFW+,9WHVWLQJLIQRKLVWRULFDOGDWDDUHDYDLODEOH2SWLRQDO
WHVWVHJYLUDOORDGFDQEHRUGHUHGIRUVXVSHFWHGDFWLYHLQIHFWLRQDWIROORZXSYLVLWVEDVHGRQWKH,QYHVWLJDWRU¶VFOLQLFDOMXGJPHQW

9LWDOVLJQVEORRGSUHVVXUHUHVSLUDWRU\UDWHSXOVHDQGWHPSHUDWXUHDQGLQVSHFWLRQRILQMHFWLRQVLWHVZLOOEHPRQLWRUHGDWPLQXWHVDWPLQXWHVDQGWKHQDWKRXUPLQXWHVDIWHU
LQMHFWLRQ

&RQGXFWURXWLQHXULQDO\VLVS+SURWHLQJOXFRVHVSHFLILFJUDYLW\NHWRQHELOLUXELQDQGXURELOLQRJHQ$QDO\VLVRIXULQDU\VHGLPHQWV5%&:%&HSLWKHOLDOFDVWVK\DOLQHFDVWVDQGEDFWHULDO
LVRSWLRQDO

+HPDWRORJ\LQFOXGHVKHPRJORELQKHPDWRFULW:%&5%&SODWHOHWGLIIHUHQWLDOV5)DQG(65

6HUXPFKHPLVWU\LQFOXGHVVRGLXPSRWDVVLXPFKORULGHFDOFLXPPDJQHVLXP%81FUHDWLQLQH$/7$67DONDOLQHSKRVSKDWDVHWRWDOSURWHLQDOEXPLQWRWDOELOLUXELQ/'+DP\ODVHOLSDVH
FKROHVWHUROWULJO\FHULGHVFRUWLVRO77IUHH7DQG76+

6DPSOHVZLOOEHFROOHFWHGIRUDQDO\VLVRI$QWL*ORER+,J*DQG,J0WLWHUVE\DFRQYHQWLRQDOPHWKRG

6DPSOHVZLOOEHFROOHFWHGIRUH[SORUDWRU\DQDO\VLVRIWKHIROORZLQJELRPDUNHUVDQGLPPXQRORJLFDOUHVSRQVHV$QWL66($DQGDQWL66($DQWLERG\WLWHUVE\LQKRXVHGHYHORSPHQWNLW$QWL
*ORER+DQWL66($DQGDQWL66($DQWLERGLHVE\JO\FDQDUUD\DQG4XDQWLWDWLYH(/,6$DVZHOODV$'&&DQG&'&6DPSOHVZLOORQO\EHFROOHFWHGDWYLVLWVDQG(QGRI
6WXG\(DUO\7HUPLQDWLRQZHHNVDQG(QGRI6WXG\(DUO\7HUPLQDWLRQIRUH[SORUDWRU\DQDO\VLVRI&7&LQVHOHFWHG7DLZDQVLWHV

$GYHUVHHYHQWVZLOOEHDVVHVVHGE\1&,&7&$(Y)RUWKHVXEMHFWZKRZLWKGUDZVWUHDWPHQWGXULQJWKHWUHDWPHQWSHULRGDGYHUVHHYHQWVVKRXOGEHUHFRUGHGWKURXJKGD\VDIWHUWKHODVW
DGPLQLVWUDWLRQRILQYHVWLJDWLRQDOGUXJ

&RQFRPLWDQWGUXJVVKRXOGEHUHFRUGHGLQFOXGLQJDQ\PHGLFDWLRQWDNHQZLWKLQGD\VSULRUWRVWGRVLQJRIWKHLQYHVWLJDWLRQDOGUXJ)RUWKHVXEMHFWZKRZLWKGUDZVWKHVWXG\GXULQJWKH
WUHDWPHQWSHULRGFRQFRPLWDQWGUXJVKRXOGEHUHFRUGHGXQWLOGD\VDIWHUWKHODVWDGPLQLVWUDWLRQRILQYHVWLJDWLRQDOGUXJ

7XPRUDVVHVVPHQWZLOOEHDFFRUGLQJWRWKH5(&,67FULWHULDLQFOXGLQJ&7VFDQDVUHTXLUHG&7VFDQZLOOEHSHUIRUPHGDWGHVLJQDWHGWLPHVGXULQJWUHDWPHQW7KHZLQGRZSHULRGIRU&7
VFDQVLV±GD\VIURPWKHSODQQHGYLVLWSHUSURWRFROVFKHGXOH,IWKHGDWDRI&7DVVHVVPHQWDUHDYDLODEOHZLWKLQZHHNVSULRUWRWKHVFKHGXOHGYLVLWWKHDVVHVVPHQWRI&7PD\QRWEH
SHUIRUPHGEDVHGRQWKHLQYHVWLJDWRU¶VGLVFUHWLRQ8QVFKHGXOHGWXPRUDVVHVVPHQWVFDQDOVREHSHUIRUPHGDWWKH,QYHVWLJDWRU¶VGLVFUHWLRQ0HWKRGRORJ\XVHGWRDVVHVVWXPRUVGXULQJWKHVWXG\
SHULRGVKRXOGEHFRQVLVWHQWZLWKWKHPHWKRGRORJ\XVHGDWEDVHOLQHVFUHHQLQJ)RUVXEMHFWVZKHUH&7VFDQVDUHFRQWUDLQGLFDWHG05,VFDQEHSHUIRUPHGLQVWHDG%UDLQ&705,FDQEHHYDOXDWHG
SHU,QYHVWLJDWRU¶VMXGJHPHQW

7XPRUVSHFLILFDQWLJHQWHVWLQJ&($DQG&<)5$IRUDOOHQUROOHGVXEMHFWVLQVHOHFWHGVLWHVWREHSHUIRUPHGSULRUWRWUHDWPHQWDW:HHNVDQGHYHU\ZHHNVXQWLOGLVHDVHSURJUHVVLRQ
DQGHQGRIVWXG\YLVLW

:KROHEORRGVDPSOHZLOOEHFROOHFWHGWRWHVWLQGXFHG%DQG7FHOOUHVSRQVHVLQVHOHFWHG7DLZDQVLWHV

:KROHEORRGVDPSOHZLOOEHFROOHFWHGWRWHVW%DQG7FHOO,PPXQRJHQRPLF$QDO\VLVLQVHOHFWHG7DLZDQVLWHV

2QO\IRUWKHVXEMHFWVZKRDUHHOLJLEOHWRFRQWLQXRXVLQMHFWLRQDIWHUGLVHDVHSURJUHVVLRQ

:KROHEORRGVDPSOHZLOOEHFROOHFWHGWRWHVW([YLYR,PPXQRJHQLFLW\$QDO\VLVLQVHOHFWHG7DLZDQVLWHV

&REDV(*)50XWDWLRQ7HVWVZLOOEHFRQGXFWHGDW:HHNVSRVWWUHDWPHQWSHULRGDQG(QGRI6WXG\IRUDOOVXEMHFWVZLWKNQRZQ(*)5PXWDWLRQVLQVHOHFWHG7DLZDQVLWHV

,IWXPRUDVVHVVPHQWZDVSHUIRUPHGZLWKLQGD\VSULRUWRHDUO\WHUPLQDWLRQYLVLWWXPRUDVVHVVPHQWLVQRWUHTXLUHG7KHGDWDRIWXPRUDVVHVVPHQWZLWKLQGD\VSULRUWRHDUO\WHUPLQDWLRQYLVLW
LVDFFHSWDEOHIRU(DUO\7HUPLQDWLRQYLVLW



&OLQLFDO3URWRFRO2%,

2%,3KDUPD,QF

9HUVLRQ±-XO&RQILGHQWLDO
3DJHRI
6
MANAGEMENT OF TOXICITY AND TREATMENT 
DISCONTINUATION
6.1
General Management
9LWDOVLJQVEORRGSUHVVXUHUHVSLUDWRU\UDWHSXOVHDQGWHPSHUDWXUHDQGLQVSHFWLRQRILQMHFWLRQ
VLWHVZLOOEHPRQLWRUHGDWPLQXWHVDWPLQXWHVDQGWKHQDWKRXUPLQXWHVDIWHU
HDFKLQMHFWLRQRILQYHVWLJDWLRQDOGUXJ
)RUFRKRUWLQGRVHHVFDODWLRQSKDVHWKHILUVWWKUHHVXEMHFWVVKRXOGEHKRVSLWDOL]HGIROORZLQJILUVW
GRVHRIWKHLQYHVWLJDWLRQDO GUXJLQMHFWLRQYLWDO VLJQV DQGLQVSHFWLRQRI LQMHFWLRQVLWHVZLOOEH
PRQLWRUHGDIWHULQMHFWLRQRILQYHVWLJDWLRQDOGUXJIRUIROORZLQJWLPHSRLQWDWPLQXWHVDW
PLQXWHVDWKRXUPLQXWHVDWKRXUPLQXWHVDWKRXUPLQXWHVEHIRUHEHGDQG
EHIRUHGLVFKDUJH
6.2
Management of Drug-Induced Toxicities
5LVNVWRWKHSDWLHQWVZLOOEHPLWLJDWHGZLWKFDUHIXOFOLQLFDOPRQLWRULQJDQGHYDOXDWLRQRIODERUDWRU\
VDIHW\SDUDPHWHUV
7KHPRVWOLNHO\DGYHUVHHIIHFWVDQWLFLSDWHGLQWKLVVWXG\DUHORFDOVNLQUHDFWLRQDWWKHLQMHFWLRQVLWH
IHYHUFKLOOVDQGVZHDWVDVDGLUHFWHIIHFWRIDFWLYHLPPXQRWKHUDS\7KHVHDGYHUVHHIIHFWVVHOGRP
UHTXLUHWKHUDS\EXWDQWLSUXULWLFVPD\EHXVHGRQO\LIV\PSWRPDWLF,IQHFHVVDU\16$,'VPD\EH
XVHGWRFRQWUROIHYHUDQGSDLQEXWVWHURLGVDUHSURKLELWHG3UHPHGLFDWLRQZLWKDQWLSUXULWLFVRU
VWHURLGVLVSURKLELWHG7KHVWXG\WUHDWPHQWZLOOFRQWLQXHGHVSLWHWKHVHV\PSWRPV
6OLJKWWRPRGHUDWHGHUPDOHGHPDDQGHU\WKHPDZHUHREVHUYHGLQDQLPDOVWXGLHVDOWKRXJKWKHVH
ZHUHQRWFRQVLGHUHGDGYHUVHHIIHFWV,QYHVWLJDWRUVVKRXOGWUHDWWKHVHFRQGLWLRQVSHUWKHLUQRUPDO
SUDFWLFH6XEMHFWVZLOOEHLQVWUXFWHGWRQRWLI\WKH,QYHVWLJDWRULIWKH\H[SHULHQFHGUDLQDJHRIIOXLG
LQMHFWLRQVLWHUHDFWLRQZLWKEUHDNLQVNLQDQGEOXHEODFNGLVFRORUDWLRQDQGVZHOOLQJ
/HVVFRPPRQEXWPRUHVHYHUHDOOHUJLFUHDFWLRQVLQFOXGHVHYHUHEURQFKRVSDVPDQGDQDSK\OD[LV
,QWKHSUHVHQFHRIWKHVHFRQGLWLRQVWUHDWPHQWVKRXOGEHLPPHGLDWHO\GLVFRQWLQXHGDQGWKHVXEMHFW
WUHDWHG ZLWK HSLQHSKULQH VWHURLGV R[\JHQ YROXPH VXSSRUW RU RWKHU EURQFKRGLODWRUV DQG
VXSSRUWLYH FDUH DV QHHGHG 7KH VWXG\ WUHDWPHQW ZLOO EH GLVFRQWLQXHG DQG WKH VXEMHFW ZLOO EH
FRQWLQXRXVO\PRQLWRUHGDQGPD\EHZLWKGUDZQIURPWKHVWXG\
$XWRLPPXQHGLVRUGHUPD\RFFXUVLQFHORZOHYHO RI*ORER+LV H[SUHVVHGE\HSLWKHOLDO FHOOV
+RZHYHUWKHOLNHOLKRRGRIDXWRLPPXQHGLVRUGHULVUDUHVLQFH*ORER+H[SUHVVLRQLVFRQILQHGWR
WKHDSLFDOHSLWKHOLDOFHOOVDWOXPHQERUGHUVDVLWHZKLFKDSSHDUVQRWWREHDFFHVVLEOHWRWKHLPPXQH
V\VWHP,PPXQHFRPSOH[GLVHDVHDVPDQLIHVWHGE\VNLQMRLQWUHQDORURWKHUFKDQJHVFRXOGRFFXU
EXWWKHVHVKRXOGEHUDUHLQWKHDEVHQFHRISULRUH[SRVXUHWR*ORER+
7UHDWPHQWZLOOEHGLVFRQWLQXHGLIWKHUHLVHYLGHQFHRIIUHTXHQWWR[LFLWLHVDVVRFLDWHGZLWKVHYHUH
HSLWKHOLDO FHOO LQMXU\ ,I DQ\ 6$(¶V UHTXLUH WKH XVH RI LPPXQRVXSSUHVVLYH WKHUDSLHV HJ
F\FORVSRULQUDSDP\FLQWDFUROLPXVULWX[LPDEDOHP]XWXPDEQDWDOL]XPDELYRUDOVWHURLGHWFRU
LPPXQRPRGXODWRU\ WKHUDSLHV HJ SODVPDSKHUHVLV LQWUDYHQRXV LPPXQRJOREXOLQV WKHQ WKH
VXEMHFWVKRXOGEHWHUPLQDWHGIURPWKHWUHDWPHQWDQGFRQWLQXHWREHIROORZHGXSXQWLOGLVHDVH
SURJUHVVLRQHDUO\WHUPLQDWLRQRUHQGRIVWXG\


&OLQLFDO3URWRFRO2%,

2%,3KDUPD,QF

9HUVLRQ±-XO&RQILGHQWLDO
3DJHRI
6.3
Definition and Management of Dose Limiting Toxicity
x
$QHYHQWLQGRVHHVFDODWLRQSKDVHZLOOEHFRQVLGHUHGDGRVHOLPLWLQJWR[LFLW\'/7LILWRFFXUV
ZLWKLQWKHILUVWZHHNVDIWHUWKHDGPLQLVWUDWLRQRI2%,2%,DQGPHHWVWKHIROORZLQJ
FULWHULD

$Q\*UDGHRU*UDGHWR[LFLWLHVFRQVLGHUHGDWOHDVWSRVVLEO\UHODWHGWRWKH
LQYHVWLJDWLRQDOGUXJ

x
$Q\VXEMHFWZKRGHYHORSVD'/7ZLOOEHWHUPLQDWHGIURPVWXG\WUHDWPHQW
x
$OO VXEMHFWV ZKR KDYH D *UDGH  RU  FOLQLFDO RU ODERUDWRU\ DEQRUPDOLW\ DW WKH WLPH RI
ZLWKGUDZDOIURPWKHVWXG\PXVWEHIROORZHGXQWLOUHVROXWLRQWR*UDGHRUOHVVXQOHVVLWLV
XQOLNHO\WRLPSURYHEHFDXVHRIXQGHUO\LQJGLVHDVH
x
,IWKHUHLVDQ\VXEMHFWRIWKHILUVWRUWKHUHLVPRUHWKDQVXEMHFWRIWKHILUVWZKRGHYHORS
'/7WKHQWKHGRVHHVFDODWLRQZLOOEHVXVSHQGHGXQWLODIXOOUHYLHZE\WKH'DWDDQG6DIHW\
0RQLWRULQJ%RDUG'RVHPRGLILFDWLRQVXFKDVDGRVHUHGXFWLRQIRUWKHQH[WGRVHFRKRUW
PD\EHFRQVLGHUHGDVMXVWLILHGE\HPHUJLQJVDIHW\GDWD,IGRVHUHGXFWLRQLVUHTXLUHGIRUWKH
VXEMHFWVLQFRKRUWPJ&RKRUWVWXG\ZLOOEHVXVSHQGHGWHPSRUDOO\'DWDDQG6DIHW\
0RQLWRULQJ%RDUGZLOOUHYLHZWKHHPHUJLQJVDIHW\GDWDDQGLQVWUXFWLIWKHVWXG\FDQEHUHVXPHG
DQGFRQWLQXHWRHQUROO&RKRUWVXEMHFWZLWKRXWGRVHUHGXFWLRQ

6.4
Guidelines for Individual Subject Study Treatment (OBI-833/OBI-821)
Discontinuation
x
,QWKHHYHQWRIDt*UDGHLPPXQHDVVRFLDWHG$(RUHPHUJHQW6$(DVOLVWHGEHORZWKHVXEMHFW
LVUHTXLUHGWRGLVFRQWLQXHVWXG\GUXJWUHDWPHQW7KH'DWDDQG6DIHW\0RQLWRULQJ%RDUGZLOO
EHQRWLILHGRIWKHVHHYHQWVDQGVDIHW\UHSRUWLQJWRWKHYDULRXVKHDOWKDXWKRULWLHVZLOOIROORZ
HDFKFRXQWU\¶VUHVSHFWLYHKHDOWKDJHQF\JXLGHOLQHV

$XWRLPPXQHGLVHDVHVLQFOXGHGEXWQRWOLPLWHGWRVHYHUH*XLOODLQ%DUUp6\QGURPH*%6
RUFKURQLFLQIODPPDWRU\GHP\HOLQDWLQJSRO\QHXURSDWK\&,'3

(QFHSKDORSDWK\RUDQ\RWKHUVLJQLILFDQW&16LQYROYHPHQW

$QDSK\OD[LVRUUHVSLUDWRU\IDLOXUHUHTXLULQJLQWXEDWLRQDQGRUYHQWLODWRUVXSSRUW

,QGLFDWLRQIRUHPHUJHQF\LQWHUYHQWLRQDQGOLIHWKUHDWHQLQJFRQVHTXHQFHVVXFKDVPDOLJQDQW
K\SHUWHQVLRQVKRFNOHDGLQJWRYLWDORUJDQLPSDLUPHQWVHYHUHFDUGLDFDUUK\WKPLDVHWF

9DVFXOLWLVOHDGLQJWRVHYHUHLVFKHPLDDQGYDVFXODUQHXURSDWK\

1HSKULWLVOHDGLQJWRVHYHUHUHQDOLPSDLUPHQW

+HSDWLWLVOHDGLQJWRVHYHUHKHSDWLFG\VIXQFWLRQ

$GUHQDOLQVXIILFLHQF\±OLIHWKUHDWHQLQJDGUHQDOFULVLV

6HYHUHSDQFUHDWLWLV

7K\URLGLWLVOHDGLQJWRtJUDGHK\SHUWK\URLGLVPRUK\SRWK\URLGLVP

$XWRLPPXQHKHPRO\WLFDQHPLD

$QGDQ\RWKHUSRWHQWLDOOLIHWKUHDWHQLQJRUGLVDEOLQJDGYHUVHHYHQWVDWWULEXWDEOHWRWKH
VWXG\GUXJLQWKHRSLQLRQRIWKH,QYHVWLJDWRUDQGPHGLFDOPRQLWRU
x
,PPXQHUHODWHG$(VWKDWZRXOG127EHFRQVLGHUHGHPHUJHQWRUVHULRXVDQGPD\127UHTXLUH
VWXG\WUHDWPHQWGLVFRQWLQXDWLRQPD\LQFOXGH


&OLQLFDO3URWRFRO2%,

2%,3KDUPD,QF

9HUVLRQ±-XO&RQILGHQWLDO
3DJHRI

,QIODPPDWLRQWKDWFDQEHDWWULEXWDEOHWRDORFDODQWLWXPRUUHDFWLRQDWWXPRUVLWHVRULQ
GUDLQLQJO\PSKQRGHV7KLVLQFOXGHVLQIODPPDWRU\UHDFWLRQVDWVLWHVRIWXPRUUHVHFWLRQVRU
H[SRVHGWRUDGLDWLRQWKHUDS\
x
,IWR[LFLW\RFFXUVUHJDUGOHVVRILQYHVWLJDWLRQDOGUXJDGPLQLVWUDWLRQWKDWGRHVQRWPHHWVWXG\
WUHDWPHQWGLVFRQWLQXDWLRQFULWHULD

7KHLQYHVWLJDWLRQDOGUXJDGPLQLVWUDWLRQPD\EHGHOD\HGIRUXSWRFRQVHFXWLYHZHHNV

,QWKHHYHQWWKDWWKHDGPLQLVWUDWLRQRIWKHLQYHVWLJDWLRQDOGUXJLVGHOD\HGIRUPRUHWKDQ
FRQVHFXWLYH ZHHNV WKHQ WKH ,QYHVWLJDWRU VKRXOG FRQIHU ZLWK WKH 6SRQVRU¶V 0HGLFDO
0RQLWRUWRGLVFXVVWKHDSSURSULDWHQHVVRIFRQWLQXHGWUHDWPHQW
x
$OOVXEMHFWVLQERWKSKDVHVZKRGLVFRQWLQXHVWXG\WUHDWPHQWSUHPDWXUHO\VKRXOGXQGHUJRWKH
HDUO\WHUPLQDWLRQSURFHGXUHVDVGHVFULEHGLQ6HFWLRQ
x
$'DWDDQG6DIHW\0RQLWRULQJ%RDUGZLOOEHHVWDEOLVKHGWRDVVLVW6SRQVRULQPRQLWRULQJWKH
VXEMHFWVDIHW\ULVNEHQHILWGRVHHVFDODWLRQGRVHUHGXFWLRQDQGWHUPLQDWLRQRIWKHVWXG\

7
TREATMENTS PERMITTED AND PROHIBITED DURING STUDY
7.1
Permitted Treatments during Study
[Dose Escalation Phase]
 $QDOJHVLFV 1RQVWHURLGDO DQWLLQIODPPDWRU\ GUXJV 16$,' DQDOJHVLFV RWKHU WKDQ
16$,'OLNHDVSLULQDQGRSLDWHVPD\EHXVHGIRUSDLQFRQWURO
 *&6)DQG+HPDWRSRLHWLFJURZWKIDFWRUVZLOOEHDOORZHGin the dose escalation phase if 
deemed necessary by physicians
 $QWLKLVWDPLQH + DQG + DQG GHFRQJHVWDQW FHWLUL]LQH +&O IH[RIHQDGLQH +&O
OHYRFHWLUL]LQHDQGSVHXGRHSKHGULQH
 $QWLHPHWLFDQGDQWLSUXULWLFVWKHUDS\
 7KHUDS\ZLWKELVSKRVSKRQDWHVHJWRWUHDWERQHPHWDVWDVHVLVDWWKHGLVFUHWLRQRIWKH
LQYHVWLJDWRU

[Cohort Expansion Phase]
 $QDOJHVLFV1RQVWHURLGDODQWLLQIODPPDWRU\GUXJV16$,'DQDOJHVLFVRWKHUWKDQ
16$,'OLNHDVSLULQDQGRSLDWHVPD\EHXVHGIRUSDLQFRQWURO
 $QWLKLVWDPLQH+DQG+DQGGHFRQJHVWDQWGLSKHQK\GUDPLQHK\GUR[\]LQH
FLPHWLGLQHUDQLWLGLQHIDPRWLGLQHFHWLUL]LQH+&OIH[RIHQDGLQH+&OOHYRFHWLUL]LQHDQG
SVHXGRHSKHGULQH
 $QWLHPHWLFHJRQGDQVHWURQDQGDQWLSUXULWLFVHJGLSKHQK\GUDPLQHRUK\GUR[\]LQH
WKHUDS\
 7KHUDS\ZLWKELVSKRVSKRQDWHVHJWRWUHDWERQHPHWDVWDVHVLVDWWKHGLVFUHWLRQRIWKH
LQYHVWLJDWRU
(*)5$/.7.,VHJJHILWLQLEHUORWLQLEDIDWLQLEDQGFUL]RWLQLE(*)5P$E
1HFLWXPXPDEEHYDFL]XPDEDQG3'3'/LQKLELWRUVHJSHPEUROL]XPDEDQG
QLYROXPDE


&OLQLFDO3URWRFRO2%,

2%,3KDUPD,QF

9HUVLRQ±-XO&RQILGHQWLDO
3DJHRI
7.2
Prohibited Treatments during Study
7KHIROORZLQJWUHDWPHQWVDUHSURKLELWHGGXULQJWKH7UHDWPHQWDQG3RVWWUHDWPHQWSHULRGVRIWKH
VWXG\XQWLO(QGRI6WXG\$SSHQGL[,,
[Dose Escalation Phase]
 $QWLFDQFHUWUHDWPHQWQRRWKHUDQWLFDQFHUWKHUDS\LVDOORZHGGXULQJWKHVWXG\7KHOLVWRI
RWKHUFKHPRWKHUDS\DJHQWVFKHPRWKHUDSHXWLFDJHQWVDFWLYHRUSDVVLYHLPPXQRWKHUDS\
LQFOXGHVEXWLVQRWOLPLWHGWR
x
&KHPRWKHUDSHXWLFDJHQWVDQWLPHWDEROLWHVDON\ODWLQJDJHQWVYLQFDDONDORLG
HSLSRGRSK\OORWR[LQVWD[DQHVFDPSWRWKHFLQVDQWLWXPRUDQWLELRWLFVQLWURVRXUHDV
IRODWHDQDORJXHPHWDEROLFLQKLELWRUDQGPLVFHOODQHRXVF\WRWR[LFDJHQWV
x
6XUJHU\
x
5DGLRWKHUDS\
 %LRORJLF$JHQWV0RQRFORQDODQWLERGLHV,QWHUIHURQVDQG,QWHUOHXNLQV
 ,PPXQRWKHUDS\
F\FORVSRULQ
UDSDP\FLQ
WDFUROLPXV
ULWX[LPDE
DOHPWX]XPDE
QDWDOL]XPDEHWF
 6WHURLGVLYRUDOVWHURLGVH[FHSWVLQJOHSURSK\ODFWLFXVHLQ&705,VFDQRURWKHURQHWLPH
XVHLQDSSURYHGLQGLFDWLRQV7KHLQWHUYDOEHWZHHQLYRUDOVWHURLGVDGPLQLVWUDWLRQDQGILUVW
GRVHRI2%,2%,PXVWEHPRUHWKDQSKDUPDFRORJLFDOGXUDWLRQRUKDOIOLYHVRI
DGPLQLVWHUHGVWHURLGVZKLFKHYHULVWKHORQJHU
x
8VHVRILQKDOHGDQGWRSLFDOVWHURLGVDUHDOORZHG
 7\URVLQHNLQDVHLQKLELWRUV
 $OWHUQDWLYHDQGFRPSOHPHQWDU\PHGLFLQHPD\DIIHFWLPPXQHV\VWHP
 2WKHULQYHVWLJDWLRQDOGUXJV

[Cohort Expansion Phase]
 $QWLFDQFHUWUHDWPHQW7KHOLVWRIFKHPRWKHUDS\DJHQWVDFWLYHRUSDVVLYHLPPXQRWKHUDS\
$SSHQGL[,,LQFOXGHVEXWLVQRWOLPLWHGWR
x
&KHPRWKHUDSHXWLFDJHQWVDQWLPHWDEROLWHVDON\ODWLQJDJHQWVYLQFDDONDORLG
HSLSRGRSK\OORWR[LQVWD[DQHVFDPSWRWKHFLQVDQWLWXPRUDQWLELRWLFVQLWURVRXUHDV
IRODWHDQDORJXHPHWDEROLFLQKLELWRUDQGPLVFHOODQHRXVF\WRWR[LFDJHQWV
(*)5$/.7.,VDUHSHUPLWWHG
x
6XUJHU\
x
5DGLRWKHUDS\
 %LRORJLF $JHQWV ,QWHUIHURQV ,QWHUOHXNLQV 'HQRVXPDE 5$1./ LQKLELWRU *&6) DQG
+HPDWRSRLHWLFJURZWKIDFWRUV
 ,PPXQRWKHUDS\
F\FORVSRULQ
UDSDP\FLQ
WDFUROLPXV
ULWX[LPDE
DOHPWX]XPDE
QDWDOL]XPDEF\FORSKRVSKDPLGHHWFH[FHSW3'3'/DQWDJRQLVWV
 6WHURLGVLYRUDOVWHURLGVH[FHSWVLQJOHSURSK\ODFWLFXVHLQ&705,VFDQRURWKHURQHWLPH
XVHLQDSSURYHGLQGLFDWLRQV7KHLQWHUYDOEHWZHHQLYRUDOVWHURLGVDGPLQLVWUDWLRQDQGILUVW
GRVHRI2%,2%,PXVWEHPRUHWKDQSKDUPDFRORJLFDOGXUDWLRQRUKDOIOLYHVRI
DGPLQLVWHUHGVWHURLGVZKLFKHYHULVWKHORQJHU
x
7RSLFDOH[FHSWLQMHFWLRQVLWHVDQGLQKDOHGVWHURLGXVHLVDOORZHG


&OLQLFDO3URWRFRO2%,

2%,3KDUPD,QF

9HUVLRQ±-XO&RQILGHQWLDO
3DJHRI
 $OWHUQDWLYHDQGFRPSOHPHQWDU\PHGLFLQHPD\DIIHFWLPPXQHV\VWHP
 2WKHULQYHVWLJDWLRQDOGUXJV
6XEMHFWVZKRFRQWLQXRXVWUHDWPHQWDIWHUGLVHDVHSURJUHVVLRQDUHDOORZHGWRFRQFRPLWDQWXVHRI
DOODSSURYHGDQWLFDQFHUWKHUDSLHV

8
INVESTIGATIONAL DRUG INFORMATION
8.1
OBI-833 (Globo H-CRM197) 
Formulation: 
2%, LV VXSSOLHG DV D VWHULOH O\RSKLOL]HG SRZGHU GUXJ SURGXFW LQ VLQJOHXVH  P/ DPEHU
ERURVLOLFDWHJODVVVHUXPYLDOV(DFKYLDOFRQWDLQVJ*ORER+OLQNHGZLWK&50DORQJ
ZLWKSRWDVVLXPSKRVSKDWHEXIIHUHGVDOLQH6XFURVHDQGSRO\VRUEDWH.
7KH SK\VLFDO DSSHDUDQFH VSHFLILFDWLRQ IRU WKH GUXJ SURGXFW LV O\RSKLOL]HG FDNHSRZGHU 7KH
UHFRQVWLWXWHGVROXWLRQRI2%,GUXJSURGXFWLVDFOHDUOLTXLG
Supplier: 
2%,ZLOOEHVXSSOLHGE\2%,3KDUPD,QF
Source and Pharmacology:
2%, LV D JO\FRFRQMXJDWH FRPSULVHG RI D FDUERK\GUDWH WXPRU DQWLJHQ *ORER + ZKLFK LV
FRYDOHQWO\OLQNHGWRWKHFDUULHUSURWHLQDQLQDFWLYHDQGQRQWR[LFIRUPRIGLSKWKHULDWR[LQ'7
FDOOHGFURVVUHDFWLQJPDWHULDO&50
,PPXQL]DWLRQRIPLFHZLWK*ORER+&50'7LQGXFHGDQWLERGLHVUHDFWLYHZLWK*ORER+
66($DQG66($VXJJHVWLQJWKDWD*ORER+EDVHGYDFFLQHZLOOWDUJHWWXPRUFHOOVH[SUHVVLQJ
*ORER+66($DQG66($0RUHVSHFLILFDOO\DV*ORER+66($DQG66($DUHIRXQG
WREHH[SUHVVHGLQKXPDQWLVVXHVRIEUHDVWFDQFHUKHSDWRFHOOXODUFDQFHU+&&OXQJFDQFHURUDO
FDQFHUJDVWULFDQGSDQFUHDWLFFDQFHUVLWLVSRVWXODWHGWKDWWKHDQWL*ORER+66($DQG66($
 DQWLERGLHV JHQHUDWHG IURP LPPXQL]DWLRQ RI 2%,2%, FDQ WDUJHW WXPRU FHOOV LQ
DIRUHPHQWLRQHGFDQFHUW\SHV

8.2
OBI-821
Formulation: 
2%, LV O\RSKLOL]HG SRZGHUFDNH LQ LQGLYLGXDO  P/ DPEHU ERURVLOLFDWH JODVV VHUXP YLDO
FRQWDLQLQJJ2%,VRGLXPSKRVSKDWHEXIIHUHGVDOLQHDQG7UHKDORVH
Supplier: 
2%,ZLOOEHVXSSOLHGE\2%,3KDUPD,QF



&OLQLFDO3URWRFRO2%,

2%,3KDUPD,QF

9HUVLRQ±-XO&RQILGHQWLDO
3DJHRI
Source and Pharmacology:
2%,LVDVDSRQLQEDVHGDGMXYDQWGHULYHGIURPWKHEDUNRIWKHQuillaja saponaria 0ROLQDWUHH
2%,LVDSXULILHGVDSRQLQZKLFKLVVWUXFWXUDOO\VLPLODUWRGHVFULSWLRQVIRXQGLQWKHOLWHUDWXUH
IRUDQRWKHUDGMXYDQW462%,H[LVWVDVDPL[WXUHRILVRPHUV7KHSULPDU\FRPSRQHQWLV
GHVLJQDWHGDV2%,9$ZLWKWKHEDODQFHEHLQJDJURXSRIFORVHO\UHODWHGDQDORJV
2%,KDVEHHQVKRZQWRVWLPXODWHDYDULHW\RILPPXQRORJLFDODFWLYLWLHVLQFOXGLQJDQWLJHQ
VSHFLILFDQWLERG\WRFDUERK\GUDWHWXPRUDQWLJHQFRQMXJDWHGWRDFDUULHUSURWHLQ2%,DOVR
DXJPHQWVWKHLQGXFWLRQRIPDMRUKLVWRFRPSDWLELOLW\FRPSOH[0+&UHVWULFWHGFODVV,F\WRWR[LF7
O\PSKRF\WHVWRVXEXQLWDQWLJHQYDFFLQHVDVZHOODVDQWLJHQVSHFLILFFHOOXODUSUROLIHUDWLRQ

8.3
Clinical Trial Material (CTM) Supply, Packaging, Labeling and Storage 
$OO&70ZLOOEHVXSSOLHGE\2%,3KDUPDDQGPXVWUHPDLQXQGHUDGHTXDWHVHFXULW\VWRUDJH
FRQGLWLRQ'RQRWXVHDQ\&70DIWHUWKHH[SLUDWLRQGDWHZKLFKLVODEHOHGRQWKHLQYHVWLJDWLRQDO
GUXJFRQWDLQHU
Investigational Drug Supply
x
2%,HTXLYDOHQW WR ȝJ*ORER+ DQG 2%, ȝJ DUHSURYLGHGLQ VHSDUDWH
VLQJOHXVHYLDOV2%,LVPL[HGZLWK2%,DWWKHWLPHRIHDFKLQMHFWLRQZLWKLQKRXUV
DIWHU PL[LQJ )ROORZLQJ WKH LQMHFWLRQV WKH OHIWRYHU 2%,2%, PL[WXUHV DUH QRW
UHF\FODEOH
x
(DFKLQMHFWLRQGRVHFRQVLVWVRIDPL[WXUHRIJ2%,DQG2%,FRQWDLQLQJJ
JRUJRI*ORER+HTXLYDOHQWV2%,GUXJSURGXFWLVUHFRQVWLWXWHGLQZDWHUDQG
PL[HG ZLWK UHFRQVWLWXWHG 2%, LPPHGLDWHO\ 7KH IUHVKO\ FRPELQHG 2%,2%,
PL[WXUHLVDGPLQLVWHUHGE\VXEFXWDQHRXVLQMHFWLRQ6HH$SSHQGL[,IRUGHWDLOHGSURFHGXUHIRU
SUHSDUDWLRQDQGPL[LQJRI2%,DQG2%,IRULQMHFWLRQ
Packaging and Labeling 
x
3DFNDJLQJDQGWKHFRQWHQWVRIWKHODEHOZLOOEHLQDFFRUGDQFHZLWKDOODSSOLFDEOHUHJXODWRU\
UHTXLUHPHQWV

Investigational Drug Storage  
x
2%,DQG2%,DUHSURYLGHGLQVHSDUDWHVLQJOHXVHYLDOV2%,LVWREHPL[HGZLWK
2%,DWWLPHRILQMHFWLRQV7KHUHFRPPHQGHGVWRUDJHWHPSHUDWXUHIRUERWK2%,DQG
2%,GUXJSURGXFWYLDOVDUHEHWZHHQ±&



&OLQLFDO3URWRFRO2%,

2%,3KDUPD,QF

9HUVLRQ±-XO&RQILGHQWLDO
3DJHRI
9
STUDY ENDPOINT 
9.1
Primary Endpoints
7KHSULPDU\HQGSRLQWLVVDIHW\DQGWROHUDELOLW\RI2%,2%,DVVHVVHGE\DGYHUVHHYHQWV
FKDQJHVLQODERUDWRU\YDOXHVDQGFKDQJHVLQYLWDOVLJQVDQGSK\VLFDOH[DPUHVXOWV

9.2
Secondary Endpoints
x
,PPXQHUHVSRQVHDVDVVHVVHGE\DQWL*ORER+,J*DQG,J0SURGXFWLRQ
x
7XPRUUHVSRQVHSHU5(&,67FULWHULD

9.3
Safety Assessment  
x
7R[LFLW\DQGDGYHUVHHYHQWVZLOOEHDVVHVVHGE\1&,&7&$(YIROORZLQJVXEFXWDQHRXV
GRVHVRI2%,2%,LPPXQL]DWLRQ
x
6DIHW\DQGWR[LFLW\ZLOOEHDVVHVVHGDFFRUGLQJWRWKHGRVHRI2%,2%,WKHVXEMHFWV
UHFHLYHGDQGRQDOOVXEMHFWVZKRUHFHLYHGDWOHDVWRQHGRVHRI2%,2%,(YHU\HIIRUW
VKRXOGEHPDGHWRIROORZXSDOOVXEMHFWVDQGDOOVFKHGXOHGHYDOXDWLRQVVKRXOGEHSHUIRUPHG
XQWLOVWXG\FORVXUHRUWKHGHDWKRIWKHVXEMHFWVLUUHVSHFWLYHRIZLWKGUDZDOVIURPWKHWUHDWPHQWV
x
$Q\FOLQLFDOO\VLJQLILFDQWDEQRUPDOLWLHVSHUVLVWLQJDWWKHHQGRIWKHVWXG\HDUO\WHUPLQDWLRQZLOO
EHIROORZHGE\WKHLQYHVWLJDWRUXQWLOUHVROXWLRQRUXQWLODFOLQLFDOO\VWDEOHHQGSRLQWLVUHDFKHG

9.4
Safety Variables 
x
7R[LFLW\	DGYHUVHHYHQWVDVDVVHVVHGE\1&,&7&$(Y
x
6DIHW\ODERUDWRU\H[DPLQDWLRQ8ULQDO\VLVKHPDWRORJ\DQGVHUXPFKHPLVWU\
x
9LWDOVLJQVEORRGSUHVVXUHUHVSLUDWRU\UDWHSXOVHDQGWHPSHUDWXUH
x
/LYHUDQGUHQDOIXQFWLRQV
x
3K\VLFDOH[DP
x
(&*

10 RESPONSE CRITERIA
Criteria for Tumor Response by RECIST 1.1:
5(&,67ZLOOEHXVHGDVWKHJXLGHOLQHIRUWKHDQDO\VLVRIWKLVVWXG\,PDJHVZLOOEHWDNHQIURP
WKH FKHVW DEGRPHQ DQG SHOYLV DUHD $ %DVHOLQH6FUHHQLQJ WXPRU EXUGHQ ZLOO EH REWDLQHG E\
HYDOXDWLQJWKHHQWLUHRUJDQV\VWHPVLQFOXGHGLQWKHERG\V\VWHPVLPDJHG7KLVWXPRUEXUGHQZLOO
EHFDWHJRUL]HGDVHLWKHU0HDVXUDEOH7DUJHW/HVLRQVRU1RQ0HDVXUDEOH1RQ7DUJHW/HVLRQV
VHH6HFWLRQ7KHSXUSRVHRIHVWDEOLVKLQJWKLV%DVHOLQH6FUHHQLQJLVWRDOORZIRUVXEVHTXHQW
DVVHVVPHQWRIRQWUHDWPHQWUHVSRQVH


&OLQLFDO3URWRFRO2%,

2%,3KDUPD,QF

9HUVLRQ±-XO&RQILGHQWLDO
3DJHRI
10.1
Definitions for Measurability of Tumor Lesions
0HDVXUDEOH
7XPRUOHVLRQVPXVWEHDFFXUDWHO\PHDVXUHGLQDWOHDVWRQHGLPHQVLRQORQJHVWGLDPHWHULQWKH
SODQHRIPHDVXUHPHQWLVWREHUHFRUGHGZLWKDPLQLPXPVL]HRI
x
PPE\&7VFDQ&7VFDQVOLFHWKLFNQHVVUHFRPPHQGHGWREHLQEHWZHHQPPDQG
PP
x
PPFDOLSHUPHDVXUHPHQWE\FOLQLFDOH[DPOHVLRQVZKLFKFDQQRWEHDFFXUDWHO\PHDVXUHG
ZLWKFDOLSHUVVKRXOGEHUHFRUGHGDVQRQPHDVXUDEOH
x
PPE\FKHVW;UD\
x
0DOLJQDQWO\PSKQRGHV
7REHFRQVLGHUHGSDWKRORJLFDOO\HQODUJHGDQGPHDVXUDEOHDO\PSKQRGHPXVWEHtPPLQVKRUW
D[LVZKHQDVVHVVHGE\&7VFDQ&7VFDQVOLFHWKLFNQHVVUHFRPPHQGHGWREHLQEHWZHHQPP
DQGPP$WEDVHOLQHDQGGXULQJIROORZXSRQO\WKHVKRUWD[LVZLOOEHPHDVXUHGDQGIROORZHG
6HHDOVRQRWHVEHORZRQµ%DVHOLQHGRFXPHQWDWLRQRIWDUJHWDQGQRQWDUJHWOHVLRQV¶IRULQIRUPDWLRQ
RQO\PSKQRGHPHDVXUHPHQW7XPRUOHVLRQVVLWXDWHGLQDSUHYLRXVO\LUUDGLDWHGDUHDRULQDQDUHD
VXEMHFWHGWRRWKHUORFRUHJLRQDOWKHUDS\DUHXVXDOO\127FRQVLGHUHGPHDVXUDEOHXQOHVVWKHUHKDV
EHHQGHPRQVWUDWHGSURJUHVVLRQLQWKHOHVLRQ
1RQ0HDVXUDEOH
$OORWKHUOHVLRQVLQFOXGLQJVPDOOOHVLRQVORQJHVWGLDPHWHUPPRUSDWKRORJLFDOO\PSKQRGHV
ZLWKtWRPPVKRUWD[LVDVZHOODVWUXO\QRQPHDVXUDEOHOHVLRQV
/HVLRQVFRQVLGHUHGWUXO\QRQPHDVXUDEOHLQFOXGHOHSWRPHQLQJHDOGLVHDVHDVFLWHVSOHXUDORU
SHULFDUGLDOHIIXVLRQLQIODPPDWRU\EUHDVWGLVHDVHO\PSKDQJLWLFLQYROYHPHQWRIVNLQRUOXQJ
DEGRPLQDOPDVVHVDEGRPLQDORUJDQRPHJDO\LGHQWLILHGE\SK\VLFDOH[DPWKDWLVQRWPHDVXUDEOH
E\UHSURGXFLEOHLPDJLQJWHFKQLTXHV
10.2
Recording Tumor Lesions
:KHQPRUHWKDQPHDVXUDEOHOHVLRQLVSUHVHQWDWEDVHOLQHDOOOHVLRQVXSWRDPD[LPXPRI5 lesions 
totalDQGDPD[LPXPRI2 lesionsSHURUJDQUHSUHVHQWDWLYHRIDOOLQYROYHGRUJDQVVKRXOGEH
LGHQWLILHGDV target lesions DQGZLOOEHUHFRUGHGDQGPHDVXUHGDWEDVHOLQHWKLVPHDQVLQLQVWDQFHV
ZKHUHVXEMHFWVKDYHRQO\RURUJDQVLWHVLQYROYHGDPD[LPXPRIDQGOHVLRQVUHVSHFWLYHO\
ZLOOEHUHFRUGHG
$VXPRIWKHGLDPHWHUVORQJHVWIRUQRQQRGDOOHVLRQVVKRUWD[LVIRUQRGDOOHVLRQVIRUDOOWDUJHW
OHVLRQVZLOOEHFDOFXODWHGDQGUHSRUWHGDVWKHEDVHOLQHVXPGLDPHWHUV,IO\PSKQRGHVDUHWREH
LQFOXGHGLQWKHVXPWKHQDVQRWHGDERYHRQO\WKHVKRUWD[LVLVDGGHGLQWRWKHVXP7KHEDVHOLQH
VXPGLDPHWHUVZLOOEHXVHGDVUHIHUHQFHWRIXUWKHUFKDUDFWHUL]HDQ\REMHFWLYHWXPRUUHJUHVVLRQLQ
WKHPHDVXUDEOHGLPHQVLRQRIWKHGLVHDVH
$OORWKHUOHVLRQVRUVLWHVRIGLVHDVHLQFOXGLQJSDWKRORJLFDOO\PSKQRGHVVKRXOGEHLGHQWLILHGDV
non-target lesionsDQGVKRXOGDOVREHUHFRUGHGDWEDVHOLQH0HDVXUHPHQWVDUHQRWUHTXLUHGDQG
WKHVHOHVLRQVVKRXOGEHIROORZHGDVµSUHVHQW¶µDEVHQW¶RULQUDUHFDVHVµXQHTXLYRFDOSURJUHVVLRQ¶


&OLQLFDO3URWRFRO2%,

2%,3KDUPD,QF

9HUVLRQ±-XO&RQILGHQWLDO
3DJHRI
,QDGGLWLRQLWLVSRVVLEOHWRUHFRUGPXOWLSOHQRQWDUJHWOHVLRQVLQYROYLQJWKHVDPHRUJDQDVDVLQJOH
LWHP RQWKHFDVH UHFRUGIRUP HJ µPXOWLSOHHQODUJHGSHOYLFO\PSKQRGHV¶RUµPXOWLSOHOLYHU
PHWDVWDVHV¶
10.3
Response Evaluation
7DUJHW/HVLRQV
x
&RPSOHWH5HVSRQVH&5'LVDSSHDUDQFHRIDOOWDUJHWOHVLRQV$Q\SDWKRORJLFDOO\PSKQRGHV
ZKHWKHUWDUJHWRUQRQWDUJHWPXVWKDYHUHGXFWLRQLQVKRUWD[LVWRPP
x
3DUWLDO5HVSRQVH35$WOHDVWDGHFUHDVHLQWKHVXPRIGLDPHWHUVRIWDUJHWOHVLRQVWDNLQJ
DVUHIHUHQFHWKHEDVHOLQHVXPGLDPHWHUV
x
6WDEOH'LVHDVH6'1HLWKHUVXIILFLHQWVKULQNDJHWRTXDOLI\IRU35QRUVXIILFLHQWLQFUHDVHWR
TXDOLI\IRU3'WDNLQJDVUHIHUHQFHWKHVPDOOHVWVXPGLDPHWHUVZKLOHRQVWXG\0HDVXUHPHQWV
PXVWKDYHPHWWKH6'FULWHULDDWOHDVWRQFHDIWHUVWXG\HQWU\DWDPLQLPXPLQWHUYDORIZHHNV
x
3URJUHVVLYH'LVHDVH3'$WOHDVWDLQFUHDVHLQWKHVXPRIGLDPHWHUVRIWDUJHWOHVLRQV
WDNLQJDVUHIHUHQFHWKHVPDOOHVWVXPRQVWXG\WKLVLQFOXGHVWKHEDVHOLQHVXPLIWKDWLVWKH
VPDOOHVWRQVWXG\,QDGGLWLRQWRWKHUHODWLYHLQFUHDVHRIWKHVXPPXVWDOVRGHPRQVWUDWH
DQDEVROXWHLQFUHDVHRIDWOHDVWPP1RWHWKHDSSHDUDQFHRIRQHRUPRUHQHZOHVLRQVLVDOVR
FRQVLGHUHGSURJUHVVLRQ
x
$WHDFKWLPHSRLQWWKHSUHVHQFHRUDEVHQFHRIQHZOHVLRQVZLOOEHDVVHVVHG

1RQ7DUJHW/HVLRQV
x
&RPSOHWH5HVSRQVH&5'LVDSSHDUDQFHRIDOOQRQWDUJHWOHVLRQVDQGQRUPDOL]DWLRQRIWXPRU
PDUNHUOHYHO$OOO\PSKQRGHVPXVWEHQRQSDWKRORJLFDOLQVL]HPPVKRUWD[LV
x
6WDEOH'LVHDVH6'3HUVLVWHQFHRIRQHRUPRUHQRQWDUJHWOHVLRQVDQGRUPDLQWHQDQFHRI
WXPRUPDUNHUOHYHODERYHWKHQRUPDOOLPLWV
x
3URJUHVVLYH'LVHDVH3'8QHTXLYRFDOSURJUHVVLRQRIH[LVWLQJQRQWDUJHWOHVLRQV1RWHWKH
DSSHDUDQFHRIRQHRUPRUHQHZOHVLRQVLVDOVRFRQVLGHUHGSURJUHVVLRQ



&OLQLFDO3URWRFRO2%,

2%,3KDUPD,QF

9HUVLRQ±-XO&RQILGHQWLDO
3DJHRI
Table 3
Overall Response Table
Target Lesions
Non-Target Lesions
New Lesions1
Time Point Response
&5
&5
1R
&5
&5
6'
1R
35
&5
8(
1R
35
35
8(
1R
35
35
&5
1R
35
35
6'
1R
35
6'
8(
1R
6'
6'
&5
1R
6'
6'
6'
1R
6'
3'
$1<
<HV1R
3'
$1<
8QHTXLYRFDO3'3'
<HV1R
3'
$1<
$1<
<HV
3'
8(
1RQ3'
1R
8(
&5
1$
1R
&5
35
1$
1R
35
6'
1$
1R
6'
1$
6'
1R
6'
1$
&5
1R
&5
1$
8(
1R
8(
1$
1$
1R
8(

,GHQWLILFDWLRQRIQHZOHVLRQVDWDSRVWEDVHOLQHWLPHSRLQWZLOOUHVXOWLQWLPHSRLQWUHVSRQVHRI3',IDQLGHQWLILHGQHZ
OHVLRQVXEVHTXHQWO\EHFRPHV8(WKHWLPHSRLQWUHVSRQVHZLOOEHUHFRUGHGDV3'XQOHVVWKHQHZOHVLRQKDVSURYHQWRKDYH
UHVROYHG

,IDQRQWDUJHWOHVLRQLVFODVVLILHGDV8(DGHVLJQDWLRQRI35PD\EHDVVLJQHGEDVHGRQLQIRUPDWLRQIURPWKHWDUJHWOHVLRQV

1RWDUJHWOHVLRQVLGHQWLILHGDWEDVHOLQH

1RQRQWDUJHWOHVLRQVLGHQWLILHGDWEDVHOLQH

&5 FRPSOHWHUHVSRQVH35 SDUWLDOUHVSRQVH6' VWDEOHGLVHDVH3' SURJUHVVLYHGLVHDVH
8( XQDEOHWRHYDOXDWHDQG1$ QRWDSSOLFDEOH

11 CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND 
OFF STUDY CRITERIA
11.1
Criteria for Removal from Protocol Therapy
6XEMHFWVZLOOEHGLVFRQWLQXHGIURPWKHVWXG\WUHDWPHQWZLWKWKHLQYHVWLJDWLRQDOGUXJIRUDQ\RI
WKHIROORZLQJUHDVRQV
x
(YLGHQFHRIGLVHDVHSURJUHVVLRQEDVHGRQ5(&,67&ULWHULDVHH6HFWLRQLQGRVH
HVFDODWLRQSKDVH
x
1RQFRPSOLDQFH
x
6XEMHFWYROXQWDULO\ZLWKGUHZKLVKHUFRQVHQW
x
6XEMHFWGHYHORSVD'/7


&OLQLFDO3URWRFRO2%,

2%,3KDUPD,QF

9HUVLRQ±-XO&RQILGHQWLDO
3DJHRI
x
([WUDRUGLQDU\PHGLFDOFLUFXPVWDQFHV6XEMHFWZKRLQWKHRSLQLRQRIWKH,QYHVWLJDWRUVKRXOG
EHGLVFRQWLQXHGIRUWKHLUZHOOEHLQJRULIDWDQ\WLPHWKHWUHDWPHQWVSUHVFULEHGE\WKLVSURWRFRO
DUHGHWULPHQWDO WR WKHVXEMHFW¶VKHDOWKWKHVXEMHFW PD\EHZLWKGUDZQIURP WKHVWXG\ VHH
6HFWLRQ,QWKLVHYHQWUHDVRQVIRUZLWKGUDZDOVKRXOGEHFOHDUO\GRFXPHQWHG
x
,IVXEMHFWEHFRPHVSUHJQDQWRUUHTXLUHVEUHDVWIHHGLQJGXULQJWKH7UHDWPHQWSHULRG
x
6XEMHFWVZKRDUHRIISURWRFROWKHUDS\LQVWHDGRIGLVHDVHSURJUHVVLRQZLOOQHHGWRFRPSOHWH(QG
RI6WXG\9LVLW
x
$OOVXUYLYLQJVXEMHFWVZLOOEHIROORZHGXSIRUVXUYLYDOVWDWXVE\SKRQHFRQWDFWRUVXEMHFWV¶
FOLQLFYLVLWHYHU\ZHHNVIRUXSWRZHHNV

11.2
Off Study Criteria
x
'HDWK
x
/RVWWRIROORZXS$IWHU,QYHVWLJDWRUVRUVWXG\VWDIIKDYHDWWHPSWHGWRUHDFKWKHVXEMHFWDWOHDVW
WLPHVRYHUDZHHNSHULRGDQGIDLOHGWKHVXEMHFWPD\WKHQEHFRQVLGHUHGORVWWRIROORZXS
x
:LWKGUDZDORIFRQVHQW6XEMHFWGHFLGHVWRYROXQWDULO\ZLWKGUDZIURPWKHVWXG\ANDUHIXVHV
FROOHFWLRQRIIROORZXSLQIRUPDWLRQ

12 STATISTICAL CONSIDERATIONS 
12.1
Hypotheses
1RIRUPDOVWDWLVWLFDOK\SRWKHVHVZLOOEHWHVWHG
12.2
Target Sample Size
$PD[LPXPQXPEHURIVXEMHFWVFDQEHHQUROOHGLQWKHGRVHHVFDODWLRQSKDVHDQGDPD[LPXP
QXPEHURIVXEMHFWVFDQEHHQUROOHGLQWKHFRKRUWH[SDQVLRQSKDVH$PD[LPXPRIWRWDO
VXEMHFWVFDQEHHQUROOHGLQWKLV3KDVH,VWXG\7KHVDPSOHVL]HVIRUWKHVWXG\DUHQRWGULYHQE\
VWDWLVWLFDOFRQVLGHUDWLRQV7KHVWXG\LVFRQVLGHUHGDVSLORWDQGH[SORUDWRU\LQQDWXUHWRHYDOXDWH
WKHSRWHQWLDOGRVHUHVSRQVHUHODWLRQVKLSWRIDFLOLWDWHGRVHVHOHFWLRQIRUVXEVHTXHQWVWXGLHV
12.3
Safety and Toxicity
7R[LFLW\ JUDGHG E\ WKH 86 1&, &RPPRQ 7R[LFLW\ &ULWHULD 9HUVLRQ  LQ FRQMXQFWLRQ ZLWK
0HG'5$0HGLFDO'LFWLRQDU\IRU5HJXODWRU\$IIDLUVZLOOEHHPSOR\HGWRHYDOXDWHWKHVDIHW\
SURILOHRIWKHVWXG\WUHDWPHQWV6DIHW\YDULDEOHVWREHHYDOXDWHGDUHOLVWHGLQ6HFWLRQ

12.4
Statistical Methods

$QDO\WLFDO6HWV
x
7KH6DIHW\3RSXODWLRQLVWKHJURXSRIVXEMHFWVZKRUHFHLYHGDWOHDVWRQHGRVHRILQYHVWLJDWLRQDO
SURGXFWDQGKDGDWOHDVWRQHSRVWGRVHVDIHW\DVVHVVPHQW


&OLQLFDO3URWRFRO2%,

2%,3KDUPD,QF

9HUVLRQ±-XO&RQILGHQWLDO
3DJHRI
x
7KH,PPXQH5HVSRQVH3RSXODWLRQLVWKHJURXSRIVXEMHFWVZKRUHFHLYHGDWOHDVWRQHGRVHRI
LQYHVWLJDWLRQDOSURGXFWDQGKDGDQWL*ORER+,J*RU,J0SURGXFWLRQ
x
7KH7XPRU5HVSRQVH3RSXODWLRQZLOOLQFOXGHDOOHQUROOHGVXEMHFWV

3UHPDWXUH7HUPLQDWLRQDQG0LVVLQJ9DOXHV
$OODYDLODEOHGDWDZLOOEHGLVSOD\HGDQGXWLOL]HGLQGDWDDQDO\VLV6XEMHFWVSUHPDWXUHO\WHUPLQDWLQJ
WKHVWXG\WUHDWPHQWZLOOEHVXPPDUL]HG/LVWLQJVRIVXEMHFWVZLWKSUHPDWXUHWHUPLQDWLRQZLOOEH
SURYLGHGZLWKWKHGDWHVDQGUHDVRQVIRUWHUPLQDWLRQ0LVVLQJGDWDZLOOQRWEHUHSODFHGE\DQ\
HVWLPDWHGRULPSXWHGYDOXHV

%DVHOLQH
7KHEDVHOLQHVIRUFOLQLFDOILQGLQJVODERUDWRU\HYDOXDWLRQVYLWDOVLJQVSK\VLFDOH[DPLQDWLRQ(&*
DQGSHUIRUPDQFHVWDWXVDVGHWDLOHGLQ7DEOHDQG±7UHDWPHQWDQG3RVW7UHDWPHQW3HULRGVZLOO
EHHYDOXDWHGDWHQWU\

,QWHULP$QDO\VLV
1RLQWHULPDQDO\VLVZLOOEHSHUIRUPHG

12.5
Safety Analysis

$GYHUVH(YHQWV
$GYHUVHHYHQWVZLOOEHUHJDUGHGDV7UHDWPHQW(PHUJHQW7($(LIWKH\VWDUWHGRQRUDIWHUWKHGDWH
DQGWLPHRIDGPLQLVWUDWLRQRIWKHILUVWGRVHRIVWXG\GUXJRULIWKH\ZHUHSUHVHQWSULRUWRWKH
DGPLQLVWUDWLRQRIWKHILUVWGRVHRIVWXG\GUXJDQGLQFUHDVHGLQVHYHULW\GXULQJWKHVWXG\
$GYHUVH (YHQWV $(V ZLOO EH FRGHG XVLQJ WKH VWDQGDUG 0HGLFDO 'LFWLRQDU\ IRU 5HJXODWRU\
$FWLYLWLHV0HG'5$GLFWLRQDU\DQGJURXSHGE\V\VWHPRUJDQFODVVDQGSUHIHUUHGWHUPDQGHYHQWV
7($(VZLOOEHVXPPDUL]HGE\IUHTXHQF\DQGSURSRUWLRQRIWRWDOVXEMHFWVE\V\VWHPRUJDQFODVV
DQGSUHIHUUHGWHUPV6HSDUDWHVXPPDULHVZLOOEHJLYHQIRUDOOHYHQWVHYHQWVE\&7&JUDGHDQG
HYHQWVE\UHODWLRQVKLSWRVWXG\GUXJ$OO$(VZLOOEHSURYLGHGLQGDWDOLVWLQJV
6XEMHFWVZKRGLHGGXULQJWKHVWXG\ZLOOEHVXPPDUL]HGDQGOLVWHG6XEMHFWVZLWK6HULRXV$GYHUVH
(YHQWV 6$(V ZLOO EH VXPPDUL]HG DQG OLVWHG $(V OHDGLQJ WR GLVFRQWLQXDWLRQ RU OHDGLQJ WR
PRGLILFDWLRQRIGUXJGRVHZLOOEHVXPPDUL]HG

&OLQLFDO/DERUDWRU\3DUDPHWHUV
(DFK ODERUDWRU\ DQDO\VHV ZLOO EH VXPPDUL]HG XVLQJ GHVFULSWLYH VWDWLVWLFV PHDQ VWDQGDUG
GHYLDWLRQ PHGLDQ UDQJH PLQ PD[ &KDQJH IURP EDVHOLQH ZLOO DOVR EH VXPPDUL]HG 7KH
LQFLGHQFHRIPDUNHGO\DEQRUPDOODEYDOXHVZLOOEHSURYLGHG

2WKHU6DIHW\3DUDPHWHUV
2WKHU VDIHW\ SDUDPHWHUV VXFK DV YLWDO VLJQV (&*V FRQFRPLWDQW PHGLFDWLRQV DQG VWXG\ GUXJ
H[SRVXUHZLOOEHVXPPDUL]HGYLDVXPPDU\WDEOHVDQGGHVFULSWLYHVWDWLVWLFV


&OLQLFDO3URWRFRO2%,

2%,3KDUPD,QF

9HUVLRQ±-XO&RQILGHQWLDO
3DJHRI
12.6
Immune Response Analysis
7KHUHVXOWVRIDQWL*ORER+,J*DQG,J0WLWHUGHWHUPLQHGE\(/,6$DWHDFKDVVHVVPHQWWLPHSRLQW
SHUGRVHFRKRUWZLOOEHVXPPDUL]HGXVLQJGHVFULSWLYHVWDWLVWLFV&KDQJHIURPEDVHOLQH:HHN
ZLOODOVREHVXPPDUL]HG7KHPD[LPDOUHVSRQVHWLPHWRPD[LPDOUHVSRQVHDQGWKHDUHDXQGHUWKH
UHVSRQVHFXUYH IRUHDFK,J*W\SHPD\EHGHWHUPLQHGWR DLG WKHHYDOXDWLRQ RISRWHQWLDO GRVH
UHVSRQVHUHODWLRQVKLS
7KHLPPXQHUHVSRQVHPD\DOVREHDQDO\]HGDQGVXPPDUL]HGEDVHGRQWKHVROLGWXPRUFDQFHUW\SH
DVDSSURSULDWHRUEDVHGRQWKH,+&UHVXOWVRI*ORER+66($66($DQG3'/DQWLJHQDW
EDVHOLQH:HHNRUVFUHHQLQJ
12.7
Exploratory Analysis of Other Biomarkers
7KHUHVXOWVRIH[SORUDWRU\DQDO\VLVRIRWKHUELRPDUNHUV$QWL66($DQWL66($DQWLERGLHV
&7&$'&&&'&DWHDFKDVVHVVPHQWWLPHSRLQWSHUGRVHFRKRUWZLOOEHVXPPDUL]HGXVLQJ
GHVFULSWLYHVWDWLVWLFV&KDQJHIURPEDVHOLQH:HHNZLOODOVREHVXPPDUL]HG&HOOXODULPPXQH
UHVSRQVHV%FHOOVDQG7FHOOVZLOOEHDQDO\]HGIRUFRQWLQXRXVYLVLWVDIWHUHLWKHUVHUXPDQWL
*ORER + DQWL66($ RU DQWL66($ ,J* UHDFKHV  JPO DIWHU :HHN   %7 FHOO
LPPXQRJHQRPLFDQDO\VLVZLOOEHFRQGXFWHGDW6FUHHQLQJ:HHNVDQGHYHU\ZHHNV
XQWLOZHHNVDIWHUVWGLVHDVHSURJUHVVLRQ([YLYRLPPXQRJHQLFLW\$QDO\VLVZLOOEHFRQGXFWHGDW
VFUHHQLQJ YLVLW $QWL*ORER + DQWL66($ DQG DQWL66($ DQWLERG\ ZLOO EH HYDOXDWHG E\
4XDQWLWDWLYH(/,6$DQGJO\FDQDUUD\&REDV(*)50XWDWLRQ7HVWVZLOOEHFRQGXFWHGDW:HHNV
DQGSRVWWUHDWPHQWSHULRGIRUDOOVXEMHFWVZLWKNQRZQ(*)5PXWDWLRQVLQVHOHFWHG7DLZDQ
VLWHV
13 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS
7LPHO\DFFXUDWHDQGFRPSOHWHUHSRUWLQJDQGDQDO\VLVRIVDIHW\LQIRUPDWLRQIURPFOLQLFDOWULDOVDUH
FUXFLDOIRUWKHSURWHFWLRQRIVXEMHFWV,QYHVWLJDWRUVDQGWKH6SRQVRUDQGLVPDQGDWHGE\UHJXODWRU\
DJHQFLHV ZRUOGZLGH 7KH VSRQVRU KDV HVWDEOLVKHG VWDQGDUG RSHUDWLQJ SURFHGXUHV 623V LQ
FRQIRUPLW\ ZLWK UHJXODWRU\ UHTXLUHPHQWV ZRUOGZLGH WR HQVXUH DSSURSULDWH UHSRUWLQJ RI VDIHW\
LQIRUPDWLRQDOOFOLQLFDOWULDOVVSRQVRUHGE\2%,3KDUPD,QFRULWVDIILOLDWHVZLOOEHFRQGXFWHGLQ
DFFRUGDQFHZLWKWKRVHSURFHGXUHV
7KHLQYHVWLJDWRUDQGRUGHOHJDWHGVLWHVWDIILVUHVSRQVLEOHIRUGHWHFWLQJGRFXPHQWLQJDQGUHSRUWLQJ
HYHQWVWKDWPHHWWKHGHILQLWLRQRIDQ$GYHUVH(YHQW$(RU6HULRXV$GYHUVH(YHQW6$('XULQJ
WKHVWXG\ZKHQWKHUHLVDFRKRUWVDIHW\HYDOXDWLRQWKHLQYHVWLJDWRURUVLWHVWDIIZLOOEHUHVSRQVLEOH
IRUGHWHFWLQJGRFXPHQWLQJDQGUHSRUWLQJDOO$(VDQG6$(V$(VDQG6$(VZLOOEHFROOHFWHGIURP
WKHVWDUWRIGRVLQJRI2%,2%,DQGXQWLOWKH(QGRI6WXG\
13.1
Adverse Events
%DVHGRQ,&+JXLGHOLQHVDQDGYHUVHHYHQW$(LVGHILQHGDVDQ\XQWRZDUGPHGLFDORFFXUUHQFH
LQDFOLQLFDOVWXG\VXEMHFWDGPLQLVWHUHGDPHGLFLQDOSURGXFW$Q$(GRHVQRWQHFHVVDULO\KDYHD
FDXVDOUHODWLRQVKLSZLWKWKHWUHDWPHQW$Q$(FDQWKHUHIRUHEHDQ\XQIDYRUDEOHDQGXQLQWHQGHG
VLJQLQFOXGLQJDQDEQRUPDOILQGLQJV\PSWRPRUGLVHDVHWHPSRUDOO\DVVRFLDWHGZLWKWKHXVHRID
PHGLFLQDO SURGXFW ZKHWKHU RU QRW UHODWHG WR WKH LQYHVWLJDWLRQDO GUXJ   7KLV LQFOXGHV DQ\


&OLQLFDO3URWRFRO2%,

2%,3KDUPD,QF

9HUVLRQ±-XO&RQILGHQWLDO
3DJHRI
RFFXUUHQFHWKDWLVQHZLQRQVHWRUDJJUDYDWHGLQVHYHULW\RUIUHTXHQF\IURPWKHEDVHOLQHFRQGLWLRQ
RUDEQRUPDOUHVXOWVRIGLDJQRVWLFSURFHGXUHVLQFOXGLQJODERUDWRU\WHVWDEQRUPDOLWLHV
Treatment-Related AEs

$WUHDWPHQWUHODWHG$(LVDQHYHQWWKDWLVFRQVLGHUHGDVVRFLDWHGZLWKWKHXVHRIDVWXG\WUHDWPHQW
2%,2%,LIWKHDWWULEXWLRQLVSRVVLEO\SUREDEO\RUGHILQLWHO\UHODWHGE\WKHGHILQLWLRQV
OLVWHGLQ6HFWLRQ
$GYHUVHHYHQWV$(VDQGWR[LFLWLHVZLOOEHDVVHVVHGWKURXJKRXWWKHVWXG\DQGJUDGHGDFFRUGLQJ
WR861&,&RPPRQ7R[LFLW\&ULWHULD9HUVLRQGHYHORSHGE\WKH&DQFHU7KHUDS\(YDOXDWLRQ
3URJUDPDWWKH1DWLRQDO&DQFHU,QVWLWXWH7KHFULWHULDIRUXQDFFHSWDEOHWR[LFLWLHVVKRXOGLQFOXGH
DQ\t*UDGHWR[LFLW\ZLWKWKHH[FHSWLRQRIORFDOVNLQUHDFWLRQVIHYHUFKLOOLQJVZHDWVXUWLFDULD
DQGRU SUXULWLV VLQFH WKHVH DUH FRPPRQ VLGH HIIHFWV RI DQWLERG\DGMXYDQW DGPLQLVWUDWLRQ DUH
UHYHUVLEOHDQGFRQWUROOHGE\VXSSRUWLYHPDQDJHPHQW7KHRUHWLFDOO\LPPXQHFRPSOH[GLVHDVHDV
PDQLIHVWHGE\VNLQMRLQWUHQDORURWKHUPDQLIHVWDWLRQVFRXOGRFFXUEXWWKHVHVKRXOGEHUDUHLQ
WKHDEVHQFHRISULRUH[SRVXUHWRPRXVHSURWHLQ7KHVHZLOOEHDQLQGLFDWLRQWRVWRSWKHUDS\LQWKH
DIIHFWHGVXEMHFWVEXWDFFUXDORIQHZVXEMHFWVPD\FRQWLQXH
,QJHQHUDO*UDGH0LOGDQG*UDGH0RGHUDWHDGYHUVHHYHQWVDUHFRQVLGHUHGDFFHSWDEOH
*UDGH$(VDUH6HYHUHEXWUHYHUVLEOHRUPHGLFDOO\PDQDJHDEOHFRQGLWLRQVLQYROYLQJPDMRURUJDQ
DQGRUJDQIXQFWLRQ*UDGH$(VDUH/LIHWKUHDWHQLQJFRQVHTXHQFHVXUJHQWLQWHUYHQWLRQLQGLFDWHG
$Q\DGYHUVHHYHQWPXVWEHUHFRUGHGLQWKHVXEMHFWPHGLFDOUHFRUGVDQGRQWKHH&5)V7KHRQVHW
DQG HQG GDWHV VHYHULW\ GXUDWLRQ HIIHFW RQ LQYHVWLJDWLRQDO GUXJ DGPLQLVWUDWLRQ HJ
GLVFRQWLQXDWLRQUHODWLRQVKLSWRLQYHVWLJDWLRQDOGUXJDQGDGPLQLVWUDWLRQRIDQ\RWKHUGUXJVIRU
WUHDWPHQWRI$(VZLOOEHUHFRUGHGIRUHDFKDGYHUVHHYHQW
6XEMHFWVZLOOEHTXHVWLRQHGDQGRUH[DPLQHGE\WKH,QYHVWLJDWRURUKLVKHUGHVLJQHHIRUHYLGHQFH
RIDGYHUVHHYHQWV7KHTXHVWLRQLQJRIVXEMHFWVZLWKUHJDUGWRWKHSRVVLEOHRFFXUUHQFHRIDGYHUVH
HYHQWVZLOOEHJHQHUDOL]HGDV³+RZKDYH\RXEHHQIHHOLQJVLQFH\RXUODVWYLVLW"´7KHSUHVHQFHRU
DEVHQFHRIVSHFLILFDGYHUVHHYHQWVVKRXOGQRWEHVROLFLWHGIURPVXEMHFWV
13.2
Anticipated Adverse Events
3UHYLRXVUHSRUWVDQGFOLQLFDOVWXGLHVRQ*ORER+GLGQRWSUHVHQWZLWKDQ\GUXJUHODWHGVHULRXV
DGYHUVHHIIHFWV$GYHUVHHIIHFWVZHUHJHQHUDOO\PLOGWRPRGHUDWHZLWKWKHPRVWFRPPRQDGYHUVH
HIIHFWVEHHQPLOGIOXOLNHV\PSWRPVDQGWUDQVLHQWORFDOVNLQUHDFWLRQVDWWKHVXEFXWDQHRXVLQMHFWLRQ
VLWH +RZHYHU SRVVLELOLWLHV RI DQ DOOHUJLF RU DXWRLPPXQH UHDFWLRQ PD\ RFFXU DV ZLWK DOO
LPPXQRWKHUDS\DQGYDFFLQHV:KHQVHULRXVWR[LFLWLHVGXHWRLPPXQRWKHUDS\WUHDWPHQWGRRFFXU
SOHDVHIROORZWKHJXLGHOLQHVIRUWUHDWPHQWGLVFRQWLQXDWLRQLQ6HFWLRQ
13.3
Assessment of Relationship to Treatment  
7KH,QYHVWLJDWRUPXVWDVVHVVWKHUHODWLRQVKLSRIDQ\DGYHUVHHYHQWWRWKHXVHRILQYHVWLJDWLRQDO
GUXJEDVHGRQDYDLODEOHLQIRUPDWLRQXVLQJWKHIROORZLQJJXLGHOLQHV
x
1RWUHODWHG


&OLQLFDO3URWRFRO2%,

2%,3KDUPD,QF

9HUVLRQ±-XO&RQILGHQWLDO
3DJHRI
:LWKQRWHPSRUDOUHODWLRQVKLSZLWKDGPLQLVWUDWLRQRIWKHLQYHVWLJDWLRQDOGUXJ0D\KDYHQHJDWLYH
GHFKDOOHQJH DQG UHFKDOOHQJH LQIRUPDWLRQ 7\SLFDOO\ H[SODLQHG E\ H[WUDQHRXV IDFWRUV HJ
FRQFRPLWDQWGLVHDVHHQYLURQPHQWDOIDFWRUVRURWKHUPHGLFDWLRQVRUFKHPLFDOV
x
8QOLNHO\UHODWHG
:LWKDWHPSRUDOUHODWLRQVKLSWRDGPLQLVWUDWLRQRIWKHLQYHVWLJDWLRQDOGUXJWKDWPDNHVDFDXVDO
UHODWLRQVKLSLPSUREDEOHDQGLQZKLFKRWKHUPHGLFDWLRQVFKHPLFDOVRUXQGHUO\LQJGLVHDVHSURYLGH
SODXVLEOHH[SODQDWLRQV
x
3RVVLEO\UHODWHG
:LWKDUHDVRQDEOHWLPHVHTXHQFHWRDGPLQLVWUDWLRQRIWKHLQYHVWLJDWLRQDOGUXJEXWZKLFKFRXOG
DOVR EH H[SODLQHG E\ FRQFXUUHQW GLVHDVH RU RWKHU PHGLFDWLRQV RU FKHPLFDOV ,QIRUPDWLRQ RQ
WUHDWPHQWZLWKGUDZDOPD\EHODFNLQJRUXQFOHDU
x
3UREDEO\UHODWHG
:LWKD UHDVRQDEOHWLPH VHTXHQFHWR DGPLQLVWUDWLRQRIWKH LQYHVWLJDWLRQDOGUXJXQOLNHO\ WREH
DWWULEXWHGWRFRQFXUUHQWGLVHDVHRURWKHUPHGLFDWLRQVRUFKHPLFDOVDQGZKLFKIROORZVDFOLQLFDOO\
UHDVRQDEOHUHVSRQVHRQZLWKGUDZDOGHFKDOOHQJH
x
'HILQLWHO\UHODWHG
2FFXUVLQDSODXVLEOHWLPHUHODWLRQVKLSWRDGPLQLVWUDWLRQRIWKHLQYHVWLJDWLRQDOGUXJDQGZKLFK
FRQFXUUHQWGLVHDVHRURWKHUPHGLFDWLRQVRUFKHPLFDOVFDQQRWH[SODLQ7KHUHVSRQVHWRZLWKGUDZDO
RIWKHWUHDWPHQWVKRXOGEHFOLQLFDOO\SODXVLEOH
13.4
Serious Adverse Events
%DVHGRQ,&+JXLGHOLQHVD6$(LVGHILQHGDVDQ\XQWRZDUGPHGLFDORFFXUUHQFHWKDWDWDQ\GRVH
x
5HVXOWVLQGHDWK
x
,VOLIHWKUHDWHQLQJ7KHVXEMHFWZDVDWULVNRIGHDWKDWWKHWLPHRIWKHHYHQW,WGRHVQRWUHIHU
WRDQHYHQWWKDWK\SRWKHWLFDOO\PLJKWKDYHFDXVHGGHDWKLILWZHUHPRUHVHYHUH
x
5HVXOWVLQSHUVLVWHQWRUVLJQLILFDQWGLVDELOLW\LQFDSDFLW\
x
5HTXLUHVLQSDWLHQWKRVSLWDOL]DWLRQRUUHVXOWVLQSURORQJDWLRQRI(5YLVLWKUV
x
5HVXOWVLQFRQJHQLWDODEQRUPDOO\ELUWKGHIHFW
x
$UHPHGLFDOO\VLJQLILFDQW
$Q\LPSRUWDQWPHGLFDOHYHQWVWKDWPD\QRWEHLPPHGLDWHO\OLIHWKUHDWHQLQJRUUHVXOWLQGHDWKRU
KRVSLWDOL]DWLRQKUVEXWPD\MHRSDUGL]HWKHVXEMHFWRUPD\UHTXLUHLQWHUYHQWLRQWRSUHYHQWRQH
RIWKHRXWFRPHVOLVWHGLQWKHGHILQLWLRQDERYH
$OO 6$(V WKDW KDYH QRW UHVROYHG E\ WKH HQG RI WKH VWXG\ RU WKDW KDYH QRW UHVROYHG XSRQ
GLVFRQWLQXDWLRQ RI WKH VXEMHFW
V SDUWLFLSDWLRQ LQ WKH VWXG\ PXVW EH IROORZHG XQWLO DQ\ RI WKH
IROORZLQJRFFXUV
x
7KHHYHQWUHVROYHV
x
7KHHYHQWVWDELOL]HV
x
7KHHYHQWUHWXUQVWREDVHOLQHLIDEDVHOLQHYDOXHVWDWXVLVDYDLODEOH


&OLQLFDO3URWRFRO2%,

2%,3KDUPD,QF

9HUVLRQ±-XO&RQILGHQWLDO
3DJHRI
x
7KHHYHQWFDQEHDWWULEXWHGWRDQRWKHUDJHQWVRWKHUWKDQWKHVWXG\WUHDWPHQWVRUWRIDFWRUV
XQUHODWHGWRVWXG\FRQGXFW
x
,WEHFRPHVXQOLNHO\WKDWDQ\DGGLWLRQDOLQIRUPDWLRQFDQEHREWDLQHGVXEMHFWRUKHDOWKFDUH
SUDFWLWLRQHUUHIXVDOWRSURYLGHDGGLWLRQDOLQIRUPDWLRQORVWWRIROORZXSDIWHUGHPRQVWUDWLRQRI
GXHGLOLJHQFHZLWKIROORZXSHIIRUWV
$Q\ HYHQW UHTXLULQJ KRVSLWDOL]DWLRQ RU UHVXOWV LQ SURORQJDWLRQ RI KRVSLWDOL]DWLRQ WKDW RFFXUV
GXULQJWKHFRXUVHRIDVXEMHFW
VSDUWLFLSDWLRQLQDFOLQLFDOVWXG\PXVWEHUHSRUWHGDVD6$(H[FHSW
KRVSLWDOL]DWLRQVIRUWKHIROORZLQJ
x
6RFLDOUHDVRQVLQWKHDEVHQFHRIDQ$(
x
6XUJHU\RUSURFHGXUHSODQQHGEHIRUHHQWU\LQWRWKHVWXG\PXVWEHGRFXPHQWHGLQWKH&5)
x
(OHFWLYHKRVSLWDOL]DWLRQIRUWUHDWPHQWRIGLVHDVHHJVXEMHFWVEHWUHDWHGZLWKWKHILUVWGRVH
RIWKHLQYHVWLJDWLRQDOGUXJ

'LVHDVHSURJUHVVLRQVKRXOGQRWEHUHFRUGHGDVDQ$(RU6$(WHUPLQVWHDGVLJQVDQGV\PSWRPV
RIFOLQLFDOVHTXHODHUHVXOWLQJIURPGLVHDVHSURJUHVVLRQODFNRIHIILFDF\ZLOOEHUHSRUWHGLIWKH\
IXOILOOWKH6$(GHILQLWLRQVHH6HFWLRQ

13.5
Reporting of Serious Adverse Events
2%,3KDUPD,QFRULWVGHVLJQHHPXVWEHQRWLILHGRIWKHRFFXUUHQFHRIDOOVHULRXVDGYHUVHHYHQWV
ZKHWKHURUQRWGHHPHGGUXJUHODWHGRUH[SHFWHGZLWKLQKRXUVRIDZDUHQHVVRIWKHHYHQWE\WKH
,QYHVWLJDWRU7KLVUHSRUWLQJWLPHIUDPHDOVRDSSOLHVWRVHULRXVDGYHUVHHYHQWVIROORZXSUHSRUWIRU
QHZLQIRUPDWLRQXSGDWH
6HULRXVDGYHUVHHYHQWV6$(VUHTXLUHLPPHGLDWHQRWLILFDWLRQWR2%,3KDUPD,QFRULWVGHVLJQHH
VWDUWLQJIURPWKHGDWHRIILUVWGRVLQJDQGXQWLOWKHODVWIROORZXSYLVLWLQWKHSRVWWUHDWPHQWSHULRG
)RU VXEMHFWV ZKR ZLWKGUDZ WUHDWPHQW GXULQJ WKH WUHDWPHQW SHULRG WKH VHULRXV DGYHUVH HYHQWV
VKRXOGEHUHSRUWHGWR2%,3KDUPD,QFWKURXJKGD\VDIWHUWKHODVWDGPLQLVWUDWLRQRIVWXG\
SURGXFW
+RZHYHULIDQ\VHULRXVDGYHUVHHYHQWVRFFXUUHGDIWHUWKHUHSRUWLQJSHULRGGHILQHGDERYHLWLV
UHTXLUHGWREHUHSRUWHGZLWKLQKRXUVRIDZDUHQHVVLIDFDXVDOUHODWLRQVKLSLVVXVSHFWHG
$VIRUKHDOWKDXWKRULW\DOOVHULRXVDGYHUVHHYHQWVUHSRUWZLOOEHVXEPLWWHGDQGIROORZHGSHUORFDO
UHJXODWLRQV
7KHVSRQVRU2%,3KDUPD,QFZLOODOVREHUHVSRQVLEOHIRUFRPSOLDQFHZLWKDSSOLFDEOHSRUWLRQV
RIWKH86$3XEOLF+HDOWK6HUYLFH$FWWKH)HGHUDO)RRG'UXJDQG&RVPHWLF$FWDQGWKH&RGH
RI)HGHUDO5HJXODWLRQV&)57KHVHUHVSRQVLELOLWLHVLQFOXGHUHSRUWLQJDQ\XQH[SHFWHGIDWDORU
OLIHWKUHDWHQLQJ DGYHUVH H[SHULHQFH DVVRFLDWHG ZLWK XVH RI WKH SURGXFW E\ ID[ QR ODWHU WKDQ 
FDOHQGDUGD\VDIWHULQLWLDOUHFHLSWRIWKHLQIRUPDWLRQ>&)5F@UHSRUWLQJDQ\
DGYHUVHH[SHULHQFHDVVRFLDWHGZLWKXVHRIWKHSURGXFWWKDWLVERWKVHULRXVDQGXQH[SHFWHGLQZULWLQJ
QRODWHUWKDQFDOHQGDUGD\VDIWHULQLWLDOUHFHLSWRIWKHLQIRUPDWLRQ>&)5F@DQG
VXEPLWWLQJDQQXDOSURJUHVVUHSRUWV&)5


&OLQLFDO3URWRFRO2%,

2%,3KDUPD,QF

9HUVLRQ±-XO&RQILGHQWLDO
3DJHRI
13.6
Pregnancy
,ILWLVVXEVHTXHQWO\GLVFRYHUHGWKDWDVXEMHFWLVSUHJQDQWGXULQJWKHVWXG\SHULRGVWXG\WUHDWPHQW
ZLOOEHSHUPDQHQWO\GLVFRQWLQXHGLQDQDSSURSULDWHPDQQHU
7KH,QYHVWLJDWRUPXVWQRWLI\2%,3KDUPD,QFRULWVGHVLJQHHRIWKLVHYHQWZLWKLQKRXUVRI
DZDUHQHVV
7KHSUHJQDQF\HYHQWVUHTXLUHLPPHGLDWHQRWLILFDWLRQWR2%,3KDUPD,QFRULWVGHVLJQHHVWDUWLQJ
IURPWKHGDWHRIILUVWGRVLQJXQWLOWKHODVWIROORZXSYLVLWLQWKHSRVWWUHDWPHQWSHULRG)RUWKH
VXEMHFWZKRZLWKGUDZVWKHVWXG\GXULQJWKHWUHDWPHQWSHULRGWKHSUHJQDQF\HYHQWVVKRXOGEH
UHSRUWHGWR2%,3KDUPD,QFXQWLOGD\VDIWHUWKHODVWDGPLQLVWUDWLRQRIVWXG\SURGXFW
,QDGGLWLRQWKH,QYHVWLJDWRUPXVWUHSRUWWR2%,3KDUPD,QFRULWVGHVLJQHHIROORZXSLQIRUPDWLRQ
UHJDUGLQJWKHFRXUVHRIWKHSUHJQDQF\LQFOXGLQJSHULQDWDODQGQHRQDWDORXWFRPH
13.7
Data and Safety Monitoring Board 
$'DWDDQG6DIHW\0RQLWRULQJ%RDUGZLOOEHHVWDEOLVKHGWRDVVLVWWKH6SRQVRULQPRQLWRULQJ
VXEMHFWVDIHW\ULVNEHQHILWDQGGHFLVLRQIRUGRVHHVFDODWLRQGRVHPRGLILFDWLRQDQGWHUPLQDWLRQ
RIWKHVWXG\

14 STUDY ADMINISTRATION AND MONITORING 
14.1
Institutional Review Board Approval
7KLVSURSRVHGVWXG\PXVWKDYHWKHDSSURYDORIDSURSHUO\FRQVWLWXWHG,QVWLWXWLRQDO5HYLHZ%RDUG
,5%,QYHVWLJDWRUZLOOREWDLQZULWWHQDQGGDWHGDSSURYDOIURPWKH,5%IRUWKHSURWRFROSURWRFRO
DPHQGPHQWLQIRUPHGFRQVHQWIRUPVUHFUXLWPHQWPDWHULDOVDQGDQ\RWKHUZULWWHQLQIRUPDWLRQWR
EHSURYLGHGWRWKHVXEMHFWV
14.2
Informed Consent Forms
(DFKVXEMHFWRUDOHJDOO\DXWKRUL]HGUHSUHVHQWDWLYHPXVWJLYHZULWWHQFRQVHQWDQGVLJQRWKHU
ORFDOO\UHTXLUHGGRFXPHQWVDFFRUGLQJWRORFDOUHTXLUHPHQWVDIWHUWKHQDWXUHRIWKHVWXG\KDVEHHQ
IXOO\ H[SODLQHG 7KH FRQVHQW IRUP PXVW EH VLJQHG SULRU WR SHUIRUPDQFH RI DQ\ VWXG\UHODWHG
DFWLYLW\7KHFRQVHQWIRUPWKDWLVXVHGPXVWEHDSSURYHGERWKE\WKHVSRQVRUDQGE\WKHUHYLHZLQJ
,(&,5% 7KH LQIRUPHG FRQVHQW VKRXOG EH LQ DFFRUGDQFH ZLWK WKH FXUUHQW UHYLVLRQ RI WKH
'HFODUDWLRQ RI +HOVLQNL FXUUHQW ,QWHUQDWLRQDO &RQIHUHQFH RQ +DUPRQL]DWLRQ ,&+ DQG *RRG
&OLQLFDO3UDFWLFH*&3JXLGHOLQHVDQG2%,3KDUPD,QFRULWVGHVLJQHH¶VSROLF\
7KH,QYHVWLJDWRURUSHUVRQREWDLQLQJFRQVHQWDFFRUGLQJWRWKHLQVWLWXWLRQDOSROLFLHVDQGSURFHGXUHV
PXVWH[SODLQWRSRWHQWLDOVXEMHFWVRUWKHLUOHJDO UHSUHVHQWDWLYHVWKHDLPVPHWKRGVUHDVRQDEO\
DQWLFLSDWHG EHQHILWV DQG SRWHQWLDO KD]DUGV RI WKH WULDO DQG DQ\ GLVFRPIRUW WKH VXEMHFWV PD\
H[SHULHQFH6XEMHFWVZLOOEHLQIRUPHGWKDWWKH\DUHIUHHQRWWRSDUWLFLSDWHLQWKHWULDODQGWKDWWKH\
PD\ZLWKGUDZFRQVHQWWRSDUWLFLSDWHDWDQ\WLPH7KH\ZLOOEHWROGZKLFKDOWHUQDWLYHWUHDWPHQWV
DUHDYDLODEOHLIWKH\UHIXVHWRWDNHSDUWDQGWKDWVXFKUHIXVDOZLOOQRWSUHMXGLFHIXWXUHWUHDWPHQW
)LQDOO\ WKH\ ZLOO EH WROG WKDW WKHLU UHFRUGV PD\ EH H[DPLQHG E\ FRPSHWHQW DXWKRULWLHV DQG
DXWKRUL]HGSHUVRQVEXWWKDWSHUVRQDOLQIRUPDWLRQZLOOEHWUHDWHGDVVWULFWO\FRQILGHQWLDODQGZLOO


&OLQLFDO3URWRFRO2%,

2%,3KDUPD,QF

9HUVLRQ±-XO&RQILGHQWLDO
3DJHRI
QRW EHSXEOLFO\ DYDLODEOH6XEMHFWV PXVWEHJLYHQWKHRSSRUWXQLW\ WR DVNTXHVWLRQV$IWHUWKLV
H[SODQDWLRQDQGEHIRUHHQWU\LQWRWKHWULDOFRQVHQWVKRXOGEHDSSURSULDWHO\UHFRUGHGE\PHDQVRI
WKH VXEMHFW
V RU KLVKHU OHJDO UHSUHVHQWDWLYH
V GDWHG VLJQDWXUH ,I D VXEMHFW DQG KLVKHU OHJDO
UHSUHVHQWDWLYH DUH XQDEOH WR UHDG WKH FRQVHQWLQJ SURFHVV ZLOO EH FRQGXFWHG DFFRUGLQJ WR WKH
LQVWLWXWLRQSROLFLHVDQGSURFHGXUHV
7KHVXEMHFWVKRXOGUHFHLYHDVLJQHGDQGGDWHGFRS\RIWKHLQIRUPHGFRQVHQWIRUP$FRS\RIWKH
VLJQHGLQIRUPHGFRQVHQWIRUPLQFOXGLQJDPHQGHGFRQVHQWVPXVWEHJLYHQWRWKHVXEMHFWSULRUWR
WKHVWXG\SDUWLFLSDWLRQ7KH,QYHVWLJDWRUPXVWNHHSHDFKVXEMHFW¶VVLJQHGFRQVHQWIRUPVRQILOH
DQGUHDGLO\DYDLODEOHIRUUHYLHZE\WKHPRQLWRUDQGIRULQVSHFWLRQE\WKHUHJXODWRU\DJHQF\DWDQ\
WLPH
14.3
Study Conduct and Monitoring
$OODVSHFWRIWKHVWXG\ZLOOEHFRQGXFWHGXQGHU,&+DQG*RRG&OLQLFDO3UDFWLFHJXLGHOLQHV,WZLOO
EHPRQLWRUHGE\TXDOLILHGLQGLYLGXDOVGHVLJQDWHGE\WKHVSRQVRU0RQLWRULQJZLOOEHFRQGXFWHG
DFFRUGLQJ WR *RRG &OLQLFDO 3UDFWLFH DQG VWDQGDUG RSHUDWLQJ SURFHGXUHV IRU FRPSOLDQFH ZLWK
DSSOLFDEOH JRYHUQPHQW UHJXODWLRQV 7KH ,QYHVWLJDWRU ZLOO DJUHH WR WKH PRQLWRU¶V DFFHVV WR WKH
FOLQLFDOVXSSOLHVGLVSHQVLQJDQGVWRUDJHDUHDDQGWRWKHFOLQLFDOILOHVRIWKHVWXG\VXEMHFWVDQGLI
UHTXHVWHGDJUHHVWRDVVLVWWKHPRQLWRU
14.4
Case Report Forms
'DWDIURPWKLVVWXG\ZLOOEHHQWHUHGLQHOHFWURQLF&DVH5HSRUW)RUPVH&5)VXVLQJDYDOLGDWHG
(OHFWURQLF'DWD&DSWXUH('&V\VWHPZLOOEHHPSOR\HGE\WKH6SRQVRUYLDDGHVLJQDWHG&RQWUDFW
5HVHDUFK2UJDQL]DWLRQ&526LWHSHUVRQQHOZLOOUHFHLYHGHWDLOHGWUDLQLQJRQFRPSOHWLRQRIWKH
H&5)V$OOGDWDHQWHUHGZLOOEHUHYLHZHGHOHFWURQLFDOO\DWDFHQWUDOORFDWLRQDQGDQ\GLVFUHSDQFLHV
RU FODULILFDWLRQV ZLOO EH FRUUHFWHG GXULQJ URXWLQH RQVLWH FOLQLFDO PRQLWRULQJ  &RQFRPLWDQW
PHGLFDWLRQVHQWHUHGLQWRWKHGDWDEDVHZLOOEHFRGHGXVLQJWKH:+2'UXJ5HIHUHQFH/LVW$GYHUVH
HYHQWV ZLOO EH FRGHG XVLQJ WKH 0HGLFDO 'LFWLRQDU\ IRU 5HJXODWRU\ $FWLYLWLHV 0HG'5$
WHUPLQRORJ\
,WLVWKH,QYHVWLJDWRU¶VUHVSRQVLELOLW\WRHQVXUHFRPSOHWLRQRIDOODSSOLFDEOHH&5)VDQGWRUHYLHZ
DQGDSSURYHDOOH&5)VDFFRUGLQJWRLQVWUXFWLRQVE\WKH6SRQVRUGHVLJQDWHG&52
14.5
Source Documents
,QDGGLWLRQWRURXWLQHPRQLWRULQJWKHVWXG\PD\EHHYDOXDWHGE\DQDXGLWRUGHVLJQDWHGE\2%,
3KDUPD,QFRULWVGHVLJQHHRUE\JRYHUQPHQWLQVSHFWRUVZKRQHHGWREHDOORZHGDFFHVVWRWKH
RULJLQDOPHGLFDOUHFRUGVDQGDOOWKHVWXG\GRFXPHQWV
14.6
Retention of Documents
,W LV WKH UHVSRQVLELOLW\ RI WKH ,QYHVWLJDWRU DQG KLVKHU VWDII WR PDLQWDLQ D FRPSUHKHQVLYH DQG
FHQWUDOL]HG ILOLQJ V\VWHP IRU DOO GRFXPHQWDWLRQ UHOHYDQW WR WKH SURWRFRO 6XFK GRFXPHQWDWLRQ
LQFOXGHV
x
&DVHVUHSRUWIRUPVPXVWEHDFFXUDWHDQGXSWRGDWH


&OLQLFDO3URWRFRO2%,

2%,3KDUPD,QF

9HUVLRQ±-XO&RQILGHQWLDO
3DJHRI
x
6XEMHFWORJUHFRUGVWKDWOLVWDOOVXEMHFWVZKRKDYHEHHQVFUHHQHGIRUVWXG\HQWU\LQFOXGLQJ
UHDVRQVZK\DVXEMHFWLVLQHOLJLEOH
x
6XEMHFWGUXJLQYHQWRU\UHFRUGVLQFOXGLQJUHFRUGVIRUWKHWRWDOQXPEHURILQYHVWLJDWLRQDOGUXJ
YLDOVSUHSDUHGDQGGLVSHQVHGIRUVWXG\VXEMHFW
x
&OLQLFDOVXSSOLHVVKLSPHQWIRUPVPXVWEHVLJQHGDQGGDWHG
x
,QIRUPHGFRQVHQWIRUPV6LJQHGFRQVHQWIRUPVIURPHDFKVXEMHFWPXVWEHDYDLODEOHDQG
YHULILHGIRUSURSHUGRFXPHQWDWLRQDQGDSSURYDO
7KHSURWRFROSURWRFRODPHQGPHQWWKHUHJXODWRU\DXWKRULW\DSSURYDO,5%DSSURYDOVSRQVRUDQG
&52FRUUHVSRQGHQFHDQGDQ\RWKHUGRFXPHQWVSHUWDLQLQJWRWKHFRQGXFWRIWKHSURWRFROPXVWEH
NHSWRQILOHE\WKH,QYHVWLJDWRU
7KHVHGRFXPHQWVVKRXOGEHUHWDLQHGE\WKH,QYHVWLJDWRUDFFRUGLQJWR,&+*&3JXLGHOLQHDQG
ORFDOUHJXODWLRQV
14.7
Quality Control and Quality Assurance
7R HQVXUH DFFXUDWH FRPSOHWH DQG UHOLDEOH GDWD 2%, 3KDUPD ,QF RU LWV UHSUHVHQWDWLYHV ZLOO
FRQGXFWSHULRGLFPRQLWRULQJYLVLWVWRHQVXUHWKDWWKHSURWRFRODQG*&3VDUHEHLQJIROORZHG7KH
PRQLWRUVZLOOUHYLHZVRXUFHGRFXPHQWVDQGHQVXUHWKHGDWDUHFRUGHGLQH&5)DUHDFFXUDWH
7KHVLWHPD\EHVXEMHFWHGWRUHYLHZE\WKH,5%DQGRUWRTXDOLW\DVVXUDQFHDXGLWVSHUIRUPHGE\
2%,3KDUPD,QFRULWVUHSUHVHQWDWLYHV
14.8
Drug Accountability
,WLVWKHUHVSRQVLELOLW\RIWKHFOLQLFDO,QYHVWLJDWRUWRHQVXUHWKDWDOOVWXG\GUXJUHFHLYHGDWWKHVLWH
ZLOOEHLQYHQWRULHGDQGDFFRXQWHGIRUWKURXJKRXWWKHVWXG\DQGUHFRUGHGLQWKHGUXJDFFRXQWDELOLW\
IRUPVPDLQWDLQHGLQWKH7ULDO&HQWHU)LOH7KHGUXJDFFRXQWDELOLW\ZLOOEHYHULILHGE\WKHPRQLWRU
GXULQJRQVLWHPRQLWRULQJYLVLWV6WXG\GUXJZLOOEHVWRUHGLQDOLPLWHGDFFHVVDUHDDFFRUGLQJWR
WHPSHUDWXUHVSHFLILFDWLRQVGHWDLOHGLQWKLVSURWRFRO
7KH,QYHVWLJDWRUZLOOFRQILUPWKDWDOORULJLQDOFRQWDLQHUVDUHUHWDLQHGDQGVWRUHGDFFRUGLQJWRWKH
LQVWLWXWLRQDOSROLF\XQWLOWKHVHFRQWDLQHUVDUHLQYHQWRULHGE\WKHVSRQVRU2ULJLQDOFRQWDLQHUVZLOO
QRWEHUHWDLQHGDQGVWRUHGLIQRW DOORZDEOHDFFRUGLQJWRLQVWLWXWLRQDOSROLF\8QOHVVRWKHUZLVH
LQVWUXFWHGE\WKHVSRQVRUWKH,QYHVWLJDWRUDJUHHVDWWKHHQGRIWKHVWXG\WRUHWXUQDOOUHWDLQHG
FRQWDLQHUVRIVWXG\GUXJWRWKHVSRQVRUDVLQVWUXFWHGE\WKHVLWHPDQDJHU$SKDUPDFLVWRIWKH
PHGLFDOFHQWHURUWKHDXWKRUL]HGSHUVRQQHOGHVLJQDWHGE\WKH,QYHVWLJDWRUZLOOILOORXWWKHGUXJ
DFFRXQWDELOLW\UHFRUGV$OOHQWULHVPXVWEHOHJLEOHDQGFRPSOHWH
2%,3KDUPD,QFRULWVGHVLJQHHZLOOHQVXUHSURSHUGLVSRVLWLRQRIRULJLQDOFRQWDLQHUVHPSW\RUIXOO
ZLWKUHWXUQHGRUXQXVHGVWXG\GUXJ$SSURSULDWHGRFXPHQWDWLRQZLOOEHPDLQWDLQHG,I2%,3KDUPD
,QFDXWKRUL]HV GHVWUXFWLRQDW WKHWULDO VLWHWKH ,QYHVWLJDWRU PXVWHQVXUHWKDWWKHPDWHULDOV DUH
GHVWUR\HG LQ FRPSOLDQFH ZLWK DSSOLFDEOH UHJXODWLRQ SROLF\ DFFRUGLQJ WR WKH LQVWLWXWLRQ¶V
GHVWUXFWLRQSROLF\DQGDQ\LQVWUXFWLRQVSURYLGHGE\2%,3KDUPD,QF
14.9
Study Completion/Discontinuation/Termination
x
7KHIROORZLQJVLWXDWLRQVDUHUHJDUGHGDVVWXG\FRPSOHWLRQ


&OLQLFDO3URWRFRO2%,

2%,3KDUPD,QF

9HUVLRQ±-XO&RQILGHQWLDO
3DJHRI

6XFFHVVIXOFRPSOHWLRQRIWKHWULDODWWKHFHQWHU

7KHUHTXLUHGQXPEHURIVXEMHFWVIRUWKHWULDOKDVEHHQUHFUXLWHG
x
6WXG\WHUPLQDWLRQFDQRFFXUDWDQ\WLPHHLWKHUE\WKH6SRQVRURUE\WKH,QYHVWLJDWRUSURYLGHG
WKHUHLVUHDVRQDEOHFDXVHDQGVXIILFLHQWQRWLFHLVJLYHQLQDGYDQFHRIWKHLQWHQGHGWHUPLQDWLRQ
5HDVRQVIRUVXFKDFWLRQWDNHQE\WKH6SRQVRUPD\LQFOXGHEXWDUHQRWOLPLWHGWR

)DLOXUHRIWKH,QYHVWLJDWRUWRFRPSO\ZLWKWKHSURWRFROWKH6SRQVRU
VSURFHGXUHVRU*&3
JXLGHOLQHV

(WKLFDOFRQFHUQV

6DIHW\DQGRUWR[LFLW\FRQFHUQV

6XIILFLHQWGDWDVXJJHVWLQJODFNRIHIILFDF\

,QDGHTXDWHUHFUXLWPHQWRIVXEMHFWVE\WKH,QYHVWLJDWRU

14.10 Use of Information and Publication
3OHDVHUHIHUWRWKH&OLQLFDO6WXG\$JUHHPHQW


&OLQLFDO3URWRFRO2%,

2%,3KDUPD,QF

9HUVLRQ±-XO&RQILGHQWLDO
3DJHRI
15 REFERENCES
 $OOHQ -5 +DUULV &5 DQG 'DQLVKHIVN\ 6-  3XUVXLW RI RSWLPDO FDUERK\GUDWHEDVHG
DQWLFDQFHUYDFFLQHVSUHSDUDWLRQRIDPXOWLDQWLJHQLFXQLPROHFXODUJO\FRSHSWLGHFRQWDLQLQJWKH
7Q0%UDQG/HZLV\DQWLJHQV-$P&KHP6RF
 &KDQJ..XR::DQJ0D7KH(SLGHPLRORJ\RI%UHDVW&DQFHULQ7DLZDQ-
&KLQHVH2QFRO
 &KDQJ::/HH&+/HH3/LQ-+VX&:+XQJ-7/LQ--<X-&6KDR/<X-:RQJ
&+DQG<X$/E([SUHVVLRQRI*ORER+DQG66($LQEUHDVWFDQFHUVWHPFHOOVDQG
WKHLQYROYHPHQWRIIXFRV\OWUDQVIHUDVHVDQGLQ*ORER+V\QWKHVLV31$691R
±
 &KDSPDQ3%0RUULVVH\'03DQDJHDV.6+DPLOWRQ:%=KDQ&'HVWUR$1:LOOLDPV/
,VUDHO 5- /LYLQJVWRQ 32 D ,QGXFWLRQ RI DQWLERGLHV DJDLQVW *0 JDQJOLRVLGH E\
LPPXQL]LQJPHODQRPDSDWLHQWVXVLQJ*0./+46YDFFLQHDGRVHUHVSRQVHVWXG\&OLQ
&DQFHU5HV
 &KDSPDQ3%0RUULVH\'3DQDJHDV.6 :LOOLDPV //HZLV--,VUDHO 5- +DPLOWRQ:%
/LYLQJVWRQ32E9DFFLQDWLRQZLWKDELYDOHQW*0DQG*'JDQJOLRVLGHFRQMXJDWH
YDFFLQH DWULDO FRPSDULQJGRVHV RI *'NH\KROHOLPSHWKHPRF\DQLQ &OLQ&DQFHU5HV

 'HYLWD+HOOPDQDQG5RVHQEXUJ&DQFHU 3ULQFLSOHVDQG3UDFWLFHRI2QFRORJ\ WK
(GLWLRQ
 *LOHZVNL 75DJXSDWKL*%KXWD6:LOOLDPV /-0XVVHOOL &=KDQJ;)%RUQPDQQ:*
6SDVVRYD 0 %HQFVDWK .3 3DQDJHDV .6 &KLQ - +XGLV &$ 1RUWRQ / +RXJKWRQ $1
/LYLQJVWRQ32'DQLVKHIVN\6-,PPXQL]DWLRQRIPHWDVWDWLFEUHDVWFDQFHUSDWLHQWVZLWK
DIXOO\V\QWKHWLFJORER+FRQMXJDWHDSKDVH,WULDO3URF1DWO$FDG6FL86$
 +HOOLQJ)6KDQJ$&DOYHV0=KDQJ65HQ6<X5.2HWWJHQ+)/LYLQJVWRQ32
,QFUHDVHGLPPXQRJHQLFLW\RI*'FRQMXJDWHYDFFLQHVFRPSDULVRQRIYDULRXVFDUULHUSURWHLQV
DQGVHOHFWLRQRI*'./+IRUIXUWKHUWHVWLQJ&DQFHU5HV
 +HOOLQJ)=KDQJ66KDQJ$$GOXUL6&DOYHV0.RJDQW\5/RQJHQHFNHU%0<DR7-
2HWWJHQ+)/LYLQJVWRQ32*0./+FRQMXJDWHYDFFLQHLQFUHDVHGLPPXQRJHQLFLW\LQ
PHODQRPDSDWLHQWVDIWHUDGPLQLVWUDWLRQZLWKLPPXQRORJLFDODGMXYDQW46&DQFHU5HV

 +XDQJ</+XQJ-7&KHXQJ6./HH+<&KX.&/L67/LQ<&5HQ&7&KHQJ7-+VX
7/ <X $/ :X &< :RQJ &+   &DUERK\GUDWHEDVHG YDFFLQHV ZLWK D JO\FROLSLG
DGMXYDQWIRUEUHDVWFDQFHU3URF1DWO$FDG6FL
 ,EUDKLP1.0XUUD\-/=KRX'0LWWHQGRUI($6DPSOH'7DXWFKLQ00LOHV'
6XUYLYDODGYDQWDJHLQSDWLHQWVZLWKPHWDVWDWLFEUHDVWFDQFHUUHFHLYLQJHQGRFULQHWKHUDS\SOXV
VLDO\O7Q./+YDFFLQHSRVWKRFDQDO\VLVRIDODUJHUDQGRPL]HGWULDO-&DQFHU
 .KRQJ+7DQG5HVWLIR131DWXUDOVHOHFWLRQRIWXPRUYDULDQWVLQWKHJHQHUDWLRQRI
WXPRUHVFDSHSKHQRW\SHV1DW,PPXQRO
 /LYLQJVWRQ 32 D $XJPHQWLQJ WKH LPPXQRJHQLFLW\ RI FDUERK\GUDWH WXPRU DQWLJHQV
6HPLQDUVLQ&DQ%LRO
 /LYLQJVWRQ 32 E $SSURDFKHV WR DXJPHQWLQJ WKH LPPXQRJHQLFLW\ RI PHODQRPD
JDQJLRVLGHVIURPZKROHPHODQRPDFHOOVWRJDQJLRVLGH.+/FRQMXJDWHYDFFLQHV,PPXQRO
5HYLHZV


&OLQLFDO3URWRFRO2%,

2%,3KDUPD,QF

9HUVLRQ±-XO&RQILGHQWLDO
3DJHRI
 /LYLQJVWRQ32*DQJOLRVLGHYDFFLQHVZLWKHPSKDVLVRQ*06HPLQ2QFRO

 /LYLQJVWRQ32$GOXUL6+HOOLQJ)<DR7-.HQVLO&51HZPDQ0-DQG0DUFLDQL'D
3KDVH  WULDO RI LPPXQRORJLFDO DGMXYDQW 46 ZLWK D *0 JDQJOLRVLGHNH\KROH OLPSHW
KDHPRF\DQLQFRQMXJDWHYDFFLQHLQSDWLHQWVZLWKPDOLJQDQWPHODQRPD9DFFLQH
 /LYLQJVWRQ32:RQJ*<&$GOXUL67DR<3DGDYDQ03DUHQWH5+DQORQ&-RQHV&DOYHV
0+HOOLQJ)5LWWHU*2HWWJHQ+)2OG/-E,PSURYHGVXUYLYDOLQVWDJH,,,PHODQRPD
SDWLHQWVZLWK*0DQWLERGLHVDUDQGRPL]HGWULDORIDGMXYDQWYDFFLQDWLRQZLWK*0JDQJOLRVLGH
-&OLQ2QFRO
 /LYLQJVWRQ 32 =KDQJ 6 /OR\G .2  &DUERK\GUDWH YDFFLQHV WKDW LQGXFH DQWLERGLHV
DJDLQVWFDQFHU5DWLRQDOH&DQFHU,PPXQRO,PPXQRWKHU
 /LYLQJVWRQ32	5DJXSDWKL*&DUERK\GUDWHYDFFLQHVWKDWLQGXFHDQWLERGLHVDJDLQVW
FDQFHU3UHYLRXVH[SHULHQFHDQGIXWXUHSODQV&DQFHU,PPXQRO,PPXQRWKHU
 /RQJHQHFNHU%05HGGLVK0.RJDQW\5DQG0DF/HDQ*',PPXQHUHVSRQVHVRI
PLFH DQG KXPDQ EUHDVW FDQFHU SDWLHQWV IROORZLQJ LPPXQL]DWLRQ ZLWK V\QWKHWLF VLDO\O7Q
FRQMXJDWHGWR./+SOXVGHWR[DGMXYDQW$QQ1<$FDG6FL
 /RQJHQHFNHU%05HGGLVK0.RJDQW\5DQG0DF/HDQ*'6SHFLILFLW\RIWKH,J*
UHVSRQVHLQPLFHDQGKXPDQEUHDVWFDQFHUSDWLHQWVIROORZLQJLPPXQL]DWLRQDJDLQVWV\QWKHWLF
VLDO\O7QDQHSLWRSHZLWKSRVVLEOHIXQFWLRQDOVLJQLILFDQFHLQPHWDVWDVLV$GY([S0HG%LRO

 /RX<::DQJ3<<HK6&&KXDQJ3./L67:X&<.KRR.++VLDR0+VX7/:RQJ
&+6WDJHVSHFLILFHPEU\RQLFDQWLJHQDVDSRWHQWLDOWKHUDSHXWLFWDUJHWLQJOLREODVWRPD
PXOWLIRUPHDQGRWKHUFDQFHUV3URF1DWO$FDG6FL
 0DF/HDQ*'5HGGLVK0.RJDQW\55:RQJ7*DQGKL66PROHQVNL06DPXHO-1DEKROW]
-0/RQJHQHFNHU%0,PPXQL]DWLRQRIEUHDVWFDQFHUSDWLHQWVXVLQJDV\QWKHWLFVLDO\O
7QJO\FRFRQMXJDWHSOXV'HWR[DGMXYDQW&DQFHU,PPXQRO,PPXQRWKHU
 0F&DIIHU\ 0 <DR 7- :LOOLDPV / /LYLQJVWRQ 32 +RXJKWRQ $1 &KDSPDQ 3% 
(QKDQFHG LPPXQRJHQLFLW\ RI %(& DQWLLGLRW\SLF PRQRFORQDO DQWLERG\ WKDW PLPLFV *'
JDQJOLRVLGHZKHQFRPELQHGZLWKDGMXYDQW&OLQ&DQFHU5HV
 0HQDUG67DJOLDEXH(&DQHYDUL6)RVVDWL*&ROQDJKQL0,*HQHUDWLRQRIPRQRFORQDO
DQWLERGLHVUHDFWLQJZLWKQRUPDODQGFDQFHUFHOOVRIKXPDQEUHDVW&DQFHU5HV
 0LRWWL6/HRQL)&DQHYDUL66RQQLQR6&ROQDJKL0,,PPXQREORWWLQJGHWHFWLRQRI
FDUERK\GUDWHHSLWRSHVLQJO\FROLSLGVDQGJO\FRSURWHLQVRIWXPRURULJLQ,Q2HWWJHQ+)HG
*DQJOLRVLGHVDQG&DQFHU:HLQKHLP9&+9HUODJVJHVHOOVFKDIWSS
 0XVVHOOL & /LYLQJVWRQ 32 5DJXSDWKL *  .H\KROH OLPSHW KHPRF\DQLQ FRQMXJDWH
YDFFLQHVDJDLQVWFDQFHUWKH0HPRULDO6ORDQ.HWWHULQJH[SHULHQFH-&DQFHU5HV&OLQ2QFRO
6XSSO5
 3DZHOHF*=HXWKHQ-.LHVVOLQJ5(VFDSHIURPKRVWDQWLWXPRULPPXQLW\&ULW5HY
2QFRJ
 5DELQRYLFK150F,QQHV3.OHLQ'/+DOO%)9DFFLQHWHFKQRORJLHVYLHZWRIXWXUH
6FLHQFH
 5DJXSDWKL*0H\HUV0$GOXUL6+RZDUG/0XVVHOOL//LYLQJVWRQ32,QGXFWLRQRI
DQWLERGLHVDJDLQVW*'JDQJOLRVLGHLQPHODQRPDSDWLHQWVE\YDFFLQDWLRQZLWK*'ODFWRQH
./+FRQMXJDWHSOXVLPPXQRORJLFDODGMXYDQW46,QW-&DQFHU


&OLQLFDO3URWRFRO2%,

2%,3KDUPD,QF

9HUVLRQ±-XO&RQILGHQWLDO
3DJHRI
 5DJXSDWKL * 3DUN 7 . =KDQJ 6 .LP , - *UDEHU / $GOXUL 5 /OR\G . 2
'DQLVKHIVN\6-	/LYLQJVWRQ32,PPXQL]DWLRQRIPLFHZLWKDIXOO\V\QWKHWLF
JORER + DQWLJHQ UHVXOWV LQ DQWLERGLHV DJDLQVW KXPDQ FDQFHU FHOOV $ FRPELQHG FKHPLFDO
LPPXQRORJLFDODSSURDFKWRWKHIDVKLRQLQJRIDQDQWLFDQFHUYDFFLQH$QJHZ&KHP,QW(G
(QJO
 6DQGPDLHU%02SDULQ'9+ROPEHUJ/$5HGGLVK0$0DF/HDQ*'/RQJHQHFNHU%0
(YLGHQFHRIDFHOOXODULPPXQHUHVSRQVHDJDLQVWVLDO\O7QLQEUHDVWDQGRYDULDQFDQFHU
SDWLHQWVDIWHUKLJKGRVHFKHPRWKHUDS\VWHPFHOOUHVFXHDQGLPPXQL]DWLRQZLWK7KHUDWRSH
67Q./+FDQFHUYDFFLQH-,PPXQRWKHU
 6ORYLQ6)5DJXSDWKL*$GOXUL68QJHUV*7HUU\..LP66SDVVRYD0%RUQPDQQ:*
)D]]DUL0'DQWLV/2ONLHZLF]./OR\G .2/LYLQJVWRQ32'DQLVKHIVN\6-6FKHU+,
 &DUERK\GUDWH YDFFLQHV LQ FDQFHU LPPXQRJHQLFLW\ RI D IXOO\ V\QWKHWLF JORER +
KH[DVDFFKDULGHFRQMXJDWHLQPDQ3URF1DWO$FDG6FL86$
 6RWRPD\RU(0%RUUHOOR,/HYLWVN\+,7ROHUDQFHDQGFDQFHUDFULWLFDOLVVXHLQWXPRU
LPPXQRORJ\&ULW5HY2QFRJ
 :KLWH$&&ORXWLHU3&RXJKOLQ57$SXULILHGVDSRQLQDFWVDVDQDGMXYDQWIRUD7
LQGHSHQGHQWDQWLJHQ$GY([S0HG%LRO
 <X $/ *LOPDQ $/ 2]ND\QDN 0) /RQGRQ :% .UHLVVPDQ 6* &KHQ +; 6PLWK 0
$QGHUVRQ%9LOODEODQFD-*0DWWKD\..6KLPDGD+*UXSS6$6HHJHU55H\QROGV&3
%X[WRQ $ 5HLVIHOG 5$ *LOOLHV 6' &RKQ 6/ 0DULV -0 6RQGHO 30  $QWL*'
$QWLERG\ZLWK*0&6),/DQG,VRWUHWLQRLQIRU1HXUREODVWRPD1HZ(QJ-0HG

 =KDQJ6*UDHEHU/$+HOOLQJ)5DJXSDWKL*$GOXUL6/OR\G.2/LYLQJVWRQ32
$XJPHQWLQJWKHLPPXQRJHQLFLW\RIV\QWKHWLF08&SHSWLGHYDFFLQHLQPLQH&DQFHU5HV

 =KDQJ6&RUGRQ&DUGR&=KDQJ+65HXWHU9($GOXUL6+DPLOWRQ:%/OR\G
.2	/LYLQJVWRQ32D6HOHFWLRQRIWXPRUDQWLJHQVDVWDUJHWVIRULPPXQHDWWDFN
XVLQJLPPXQRKLVWRFKHPLVWU\,)RFXVRQJDQJOLRVLGHV,QW-&DQFHU
 =KDQJ6=KDQJ+6&RUGRQ&DUGR&5HLWHU966LQJKDO$./OR\G.2/LYLQJVWRQ32
E6HOHFWLRQRIWXPRUDQWLJHQVDVWDUJHWVIRULPPXQHDWWDFNXVLQJLPPXQRKLVWRFKHPLVWU\
,,%ORRGJURXSUHODWHGDQWLJHQV,QW-&DQFHU
 =KDQJ6=KDQJ+65HXWHU9(6ORYLQ6)6FKHU+,	/LYLQJVWRQ3
([SUHVVLRQRISRWHQWLDOWDUJHWDQWLJHQVIRULPPXQRWKHUDS\RQSULPDU\DQGPHWDVWDWLFSURVWDWH
FDQFHUV&OLQ&DQFHU5HV
 *XLGDQFH IRU ,QGXVWU\&OLQLFDO &RQVLGHUDWLRQV IRU 7KHUDSHXWLF &DQFHU 9DDFLQHV 86
'HSDUWPHQWRI+HDOWKDQG+XPDQ6HUYLFHV)'$&%(52FWREHU


&OLQLFDO3URWRFRO2%,

2%,3KDUPD,QF

9HUVLRQ±-XO&RQILGHQWLDO
3DJHRI
16 APPENDICES
APPENDIX I: OBI-833 AND OBI-821 MIXING INSTRUCTION FOR 
SUBCUTANEOUS ADMINISTRATION
 Storage Condition:  Both 2%,DQG2%,YLDOVDUHWREHVWRUHGDWR&
 Study Cohorts
x
&RKRUW2%,HTXLYDOHQWWRȝJ*ORER+ȝJ2%,
x
&RKRUW2%,HTXLYDOHQWWRȝJ*ORER+ȝJ2%,
x
&RKRUW2%,HTXLYDOHQWWRȝJ*ORER+ȝJ2%,

 Investigational Drugs:
Orange Vial (OBI-821)

&RQWHQWVȝJ2%,LQVRGLXPSKRVSKDWHEXIIHUHGVDOLQHDQG7UHKDORVH$WWLPHRI
WUHDWPHQWZLWKDV\ULQJHDGGP/RUP/RIZDWHUIRULQMHFWLRQWR2UDQJH9LDO2%,
WRREWDLQ2%,VROXWLRQ Fully dissolveWKHFRQWHQWVRIWKHYLDO2UDQJH9LDOE\
JHQWO\LQYHUWLQJWKHYLDOWLPHVDo not shake the vial vigorously.$FFRUGLQJWRGUXJ
PL[LQJ SURFHGXUHV IRU WKUHH FRKRUWV 2%, LV PL[HG ZLWK 2%, LPPHGLDWHO\ IRU
LQMHFWLRQDIWHUUHFRQVWLWXWHGZLWK:),

Dosing Cohort
Water for Injection
(mL) added to 
Orange vial
Cohort 12%,HTXLYDOHQWWRȝJ*ORER+ȝJ2%,

Cohort 22%,HTXLYDOHQWWRȝJ*ORER+ȝJ2%,

Cohort 32%,HTXLYDOHQWWRȝJ*ORER+ȝJ2%,

Green Vial (OBI-833)
&RQWHQWVȝJ*ORER+OLQNHGZLWK&50ZLWKSRWDVVLXPSKRVSKDWHEXIIHUHGVDOLQH
6XFURVHDQGSRO\VRUEDWH.
$WWLPHRIWUHDWPHQWZLWKDV\ULQJHDGGDFFRUGLQJWRWKHUHVSHFWLYHFRKRUWP/RUP/
RIZDWHUIRULQMHFWLRQWR*UHHQ9LDOWRREWDLQ2%,VROXWLRQ Fully dissolveWKHFRQWHQWVRI
WKHYLDO*UHHQ9LDOE\JHQWO\LQYHUWLQJWKHYLDOWLPHVDo not shake the vial vigorously
$FFRUGLQJ WR GUXJ PL[LQJ SURFHGXUHV IRU WKUHH FRKRUWV 2%, LV PL[HG ZLWK 2%,
LPPHGLDWHO\IRULQMHFWLRQDIWHUUHFRQVWLWXWHGZLWK:),

Dosing Cohort
Water for Injection
(mL) added to Green 
Vial
Cohort 12%,HTXLYDOHQWWRȝJ*ORER+ȝJ2%,

Cohort 22%,HTXLYDOHQWWRȝJ*ORER+ȝJ2%,

Cohort 32%,HTXLYDOHQWWRȝJ*ORER+ȝJ2%,



&OLQLFDO3URWRFRO2%,

2%,3KDUPD,QF

9HUVLRQ±-XO&RQILGHQWLDO
3DJHRI

$WWKHWLPHRIWUHDWPHQWZLWKGUDZWKHFRQWHQWVRI*UHHQYLDO2%,DQGWKHDSSURSULDWH
DPRXQWRIZDWHUIRULQMHFWLRQDFFRUGLQJWRWKHWDEOHEHORZDQGWUDQVIHULQWR2UDQJH9LDO2%,
0L[WKHFRQWHQWVRIWKH2UDQJH9LDO2%,E\JHQWO\LQYHUWLQJWKHYLDOWLPHV
Do not shake the vial vigorously. $W WKLV SRLQW 2UDQJH 9LDO 2%, FRQWDLQV WKH
7UHDWPHQW2%,SOXV2%,LVUHDG\IRULQMHFWLRQLQWRWKHVWXG\VXEMHFW:LWKGUDZWKH
DSSURSULDWHYROXPHIURP2UDQJH9LDO2%,FRQWDLQLQJWKH7UHDWPHQWIRULQMHFWLRQ

Dosing Cohort
Volume of Green 
Vial (mL) to be 
added to Orange 
Vial (OBI-821)
Total Volume 
Administered (mL) 
from Orange Vial  
(OBI-821)
Cohort 12%,HTXLYDOHQWWRȝJ
*ORER+ȝJ2%,


Cohort 22%,HTXLYDOHQWWRȝJ
*ORER+ȝJ2%,


Cohort 32%,HTXLYDOHQWWRȝJ
*ORER+ȝJ2%,


:), :DWHUIRU,QMHFWLRQ
,WLVKLJKO\UHFRPPHQGHGWKDWthe administration of the combined product should occur 
within 2 hours from reconstitutionWRPLQLPL]HSRWHQWLDOPLFURELDOJURZWK,IDGPLQLVWUDWLRQ
LVQRWSRVVLEOHZLWKLQKRXUVIURPUHFRQVWLWXWLRQWKHFRPELQHGSURGXFWVKRXOGEHGHVWUR\HG
DFFRUGLQJWRWKHLQVWLWXWLRQDOSKDUPDF\6WDQGDUG2SHUDWLQJ3URFHGXUHDQGGRFXPHQWHGLQWKH
GUXJDFFRXQWDELOLW\UHFRUGV


&OLQLFDO3URWRFRO2%,

2%,3KDUPD,QF

9HUVLRQ±-XO&RQILGHQWLDO
3DJHRI
 Illustration of Drug Mixing Procedures:



&OLQLFDO3URWRFRO2%,

2%,3KDUPD,QF

9HUVLRQ±-XO&RQILGHQWLDO
3DJHRI



&OLQLFDO3URWRFRO2%,

2%,3KDUPD,QF

9HUVLRQ±-XO&RQILGHQWLDO
3DJHRI



&OLQLFDO3URWRFRO2%,

2%,3KDUPD,QF

9HUVLRQ±-XO&RQILGHQWLDO
3DJHRI
APPENDIX II:
PROHIBITED CONCOMITANT MEDICATION
[Dose Escalation Phase]
Chemotherapeutic Agents:
$QWLPHWDEROLWHV
9LQFDDONDORLG
(SLSRGRSK\OORWR[LQV
7D[DQHV
&DPSWRWKHFLQV

0LVFHOODQHRXVF\WRWR[LFDJHQWV
$ON\ODWLQJDJHQWV
$QWLWXPRUDQWLELRWLFV
1LWURVRXUHDV
Biologic Agents: 
0RQRFORQDODQWLERGLHVWUDVWX]XPDEFHWX[LPDEHWF
,QWHUIHURQV
,QWHUOHXNLQV
Immunotherapy 
F\FORVSRULQUDSDP\FLQWDFUROLPXVULWX[LPDE3'3'/DQWDJRQLVWV
,9RUDOVWHURLGH[FHSWVLQJOHSURSK\ODFWLFXVH LQ&705,VFDQRURWKHURQHWLPHXVHLQ
DSSURYHGLQGLFDWLRQV,QKDOHGDQGWRSLFDOXVHRIVWHURLGVDUHDOORZHG
Hormone therapy
(VWURJHQUHFHSWRUDQWDJRQLVWVVHOHFWLYHHVWURJHQUHFHSWRULQKLELWRUVDQGDURPDWDVHLQKLELWRUV
Target therapy
7\URVLQHNLQDVHLQKLELWRUVDQGPRQRFORQDODQWLERGLHV
Other non-cancer vaccine therapy
:DVKRXWSHULRGIRUFRQFRPLWDQWYDFFLQHVLVWZRZHHNVSULRUWR,3WUHDWPHQW
Alternative and complementary medicine may affect immune system 

[Cohort Expansion Phase]
Chemotherapeutic Agents:
$QWLPHWDEROLWHV
9LQFDDONDORLG
(SLSRGRSK\OORWR[LQV
7D[DQHV
&DPSWRWKHFLQV

0LVFHOODQHRXVF\WRWR[LFDJHQWV
$ON\ODWLQJDJHQWV
$QWLWXPRUDQWLELRWLFV
1LWURVRXUHDV
Biologic Agents: 
0RQRFORQDODQWLERGLHVH[FHSWQHFLWXPXPDEDQGEHYDFL]XPDE


&OLQLFDO3URWRFRO2%,

2%,3KDUPD,QF

9HUVLRQ±-XO&RQILGHQWLDO
3DJHRI
,QWHUIHURQV
,QWHUOHXNLQV
Immunotherapy 
F\FORVSRULQUDSDP\FLQWDFUROLPXVULWX[LPDEH[FHSW3'3'/DQWDJRQLVWV
,9RUDOVWHURLGH[FHSWVLQJOHSURSK\ODFWLFXVH LQ&705,VFDQRURWKHURQHWLPHXVHLQ
DSSURYHGLQGLFDWLRQV,QKDOHGDQGWRSLFDOXVHRIVWHURLGVDUHDOORZHG
Other non-cancer vaccine therapy
:DVKRXWSHULRGIRUFRQFRPLWDQWYDFFLQHVLVWZRZHHNVSULRUWR,3WUHDWPHQW
Alternative and complementary medicine may affect immune system 
Subjects who continuous treatment after disease progression are allowed to 
concomitant use of all approved anti-cancer therapies












&OLQLFDO3URWRFRO2%,

2%,3KDUPD,QF

9HUVLRQ±-XO&RQILGHQWLDO
3DJHRI
APPENDIX III: ECOG PERFORMANCE STATUS AND RECIST 1.1 
GUIDELINE
 ECOG Performance

These scales and criteria are used by doctors and researchers to assess how a subject's disease is 
progressing, assess how the disease affects the daily living abilities of the subject, and determine 
appropriate treatment and prognosis. They are included here for health care professionals to access.

ECOG PERFORMANCE STATUS*
Grade
ECOG

)XOO\DFWLYHDEOHWRFDUU\RQDOOSUHGLVHDVHSHUIRUPDQFHZLWKRXWUHVWULFWLRQ

5HVWULFWHGLQSK\VLFDOO\VWUHQXRXVDFWLYLW\EXWDPEXODWRU\DQGDEOHWRFDUU\RXWZRUN
RIDOLJKWRUVHGHQWDU\QDWXUHHJOLJKWKRXVHZRUNRIILFHZRUN

$PEXODWRU\DQGFDSDEOHRIDOOVHOIFDUHEXWXQDEOHWRFDUU\RXWDQ\ZRUNDFWLYLWLHV
8SDQGDERXWPRUHWKDQRIZDNLQJKRXUV

&DSDEOHRIRQO\OLPLWHGVHOIFDUHFRQILQHGWREHGRUFKDLUPRUHWKDQRIZDNLQJ
KRXUV

&RPSOHWHO\GLVDEOHG&DQQRWFDUU\RQDQ\VHOIFDUH7RWDOO\FRQILQHGWREHGRUFKDLU

'HDG
$VSXEOLVKHGLQ$P-&OLQ2QFRO
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity And 
Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982.
7KH(&2*3HUIRUPDQFH6WDWXVLVLQWKHSXEOLFGRPDLQWKHUHIRUHDYDLODEOHIRUSXEOLFXVH7RGXSOLFDWHWKHVFDOH
SOHDVHFLWHWKHUHIHUHQFHDERYHDQGFUHGLWWKH(DVWHUQ&RRSHUDWLYH2QFRORJ\*URXS5REHUW&RPLV0'*URXS
&KDLU

 RECIST 1.1 Guideline
3OHDVHILQGWKHUHIHUHQFHSXEOLVKHGLQ(XU-&DQFHU
E.A. Eisenhauer, P. Therasse, J. Bogaerts et al., “New Response Evaluation Criteria in Solid Tumours: 
Revised RECIST Guideline (Version 1.1),” European Journal of Cancer, 45 (3) 228-247 (2009).
KWWSFWHSFDQFHUJRYSURWRFROGHYHORSPHQWGRFVUHFLVWBJXLGHOLQHSGI












