A Phase 2 Study Evaluating the Efficacy and Safety of Selinexor (KPT-330) in Patients With Recurrent Gliomas
Phase: PHASE2
Conditions: Glioblastoma, Glioma
Sponsor: Karyopharm Therapeutics Inc


&RQILGHQWLDO
3DJHRI
9HUVLRQ
.&3.,1*

$3+$6(678'<(9$/8$7,1*7+(()),&$&<$1'6$)(7<2)
6(/,1(;25.37,13$7,(176:,7+5(&855(17*/,20$6

6WXG\1DPH
.,1*.37LQ*OLRPDV


6SRQVRU
.DU\RSKDUP7KHUDSHXWLFV,QF


&RRUGLQDWLQJ,QYHVWLJDWRU
0'3K'
IRU'HQPDUN

&RRUGLQDWLQJ,QYHVWLJDWRU
0'
IRU86

(XGUD&71XPEHU


3URWRFROLGHQWLILFDWLRQQXPEHU
.&3

3URWRFROYHUVLRQ
9HUVLRQ6HS

$PHQGPHQW±9HUVLRQ1RY

$PHQGPHQW±9HUVLRQ-XO

$PHQGPHQW±9HUVLRQ0DU

$PHQGPHQW±9HUVLRQ-XO\

$PHQGPHQW±9HUVLRQ1RYHPEHU


&21),'(17,$/,1)250$7,21
7KLV GRFXPHQW LV WKH VROH SURSHUW\ RI .DU\RSKDUP 7KHUDSHXWLFV ,QF .DU\RSKDUP  7KLV
GRFXPHQWDQGDQ\DQGDOOLQIRUPDWLRQFRQWDLQHGKHUHLQKDVWREHFRQVLGHUHGDQGWUHDWHGDVVWULFWO\
FRQILGHQWLDO7KLVGRFXPHQWVKDOOEHXVHGRQO\IRUWKHSXUSRVHRIWKHGLVFORVXUHKHUHLQSURYLGHG
1RGLVFORVXUHRUSXEOLFDWLRQVKDOOEHPDGHZLWKRXWWKHSULRUZULWWHQFRQVHQWRI.DU\RSKDUP
PPD
PPD

6HOLQH[RU.37
.DU\RSKDUP7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO.&3
1RYHPEHU
&RQILGHQWLDO
3DJHRI
9HUVLRQ
&RQWDFW$GGUHVVHV
6SRQVRU
.DU\RSKDUP7KHUDSHXWLFV,QF
:HOOV$YHQXH
1HZWRQ0$

&RRUGLQDWLQJ,QYHVWLJDWRU
IRU'HQPDUN

0'3K'





3KRQH

)D[

(PDLO


&RRUGLQDWLQJ,QYHVWLJDWRU
IRU86
0'



3KRQH

)D[

(PDLO

'UXJ6XSSO\
.DU\RSKDUP7KHUDSHXWLFV,QF

3URWRFRO&RPPLWWHH
9HULVWDW

0'

0'3K'

0'3K'

3K'.DU\RSKDUP7KHUDSHXWLFV
0'

PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

PPD
PPD
PPD
PPD
PPD
PPD
PPD

Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
Confidential 
Page 4 of 137 
Version 6.0 
Investigator’s Agreement 
 
I have read the attached protocol entitled 
“A PHASE 2 STUDY EVALUATING THE EFFICACY AND SAFETY OF SELINEXOR 
(KPT-330) IN PATIENTS WITH RECURRENT GLIOMAS”  
and agree to abide by all provisions set forth therein. 
I agree to comply with the International Conference on Harmonisation Tripartite Guideline on 
Good Clinical Practice, all applicable national regulations as well as the requirements of the 
appropriate Institutional Review Board/Independent Ethics Committee and any other institutional 
requirements. 
I agree to ensure that the confidential information contained in this document will not be used for 
any purpose other than the evaluation or conduct of the clinical investigation without the prior 
written consent of the study Sponsor. 
 
 
 
 
 
 
Signature  
  
Date (dd Month yyyy) 
Investigator  
  
  
Investigator’s Institution 
  
  
 

6HOLQH[RU.37
.DU\RSKDUP7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO.&3
1RYHPEHU
&RQILGHQWLDO
3DJHRI
9HUVLRQ
6<1236,6
3URWRFROLGHQWLILHUQR
.&3
3URWRFROYHUVLRQ'DWH
9HUVLRQ1RYHPEHU
6WXG\QDPH
.,1*.37LQ*OLRPDV
7LWOH

$ 3+$6(  678'< (9$/8$7,1* 7+( ()),&$&< $1' 6$)(7< 2)
6(/,1(;25.37,13$7,(176:,7+5(&855(17*/,20$6
(XGUD&7QR

&RRUGLQDWLQJ,QYHVWLJDWRUIRU
'HQPDUN
0'3K'
&RRUGLQDWLQJ,QYHVWLJDWRUIRU
86
0'
6SRQVRU
.DU\RSKDUP7KHUDSHXWLFV,QF
:HOOV$YHQXH
1HZWRQ0$
6WXG\GHVLJQ
x
2SHQODEHOPXOWLFHQWHU3KDVHVWXG\
x
3DWLHQWVZLOOEHHQUROOHGLQWRHLWKHU

0HGLFDO$UP$UP
%$UP&DQG$UP'IRUSDWLHQWVZKRDUHQRWHOLJLEOHIRUVXUJHU\


3DWLHQWVLQWKH
0HGLFDO$UP$UPV%&DQG'ZLOOEHWUHDWHGZLWKVHOLQH[RUDORQH3DWLHQWV
ZLOOEHWUHDWHGXQWLOSURJUHVVLRQRIGLVHDVHRUWKHGHYHORSPHQWRIXQDFFHSWDEOH
WR[LFLWLHV3DWLHQWVZLOODOVREHIROORZHGIRUVXUYLYDOVWDWXV
6WDUWGDWH
-DQXDU\
'XUDWLRQRIVWXG\
(QUROOPHQWLVDQWLFLSDWHGWRWDNHDSSUR[LPDWHO\PRQWKV
7KHWUHDWPHQWSHULRGIRUDQLQGLYLGXDOSDWLHQWLVH[SHFWHGWREHXSWRPRQWKVEXW
WKHUHLVQRPD[LPXPGXUDWLRQIRUWUHDWPHQW7UHDWPHQWLQDOODUPVRIWKHVWXG\ZLOO
FRQWLQXHXQWLOGLVHDVHSURJUHVVLRQRUGHYHORSPHQWRIXQDFFHSWDEOHWR[LFLWLHV
(QGRIVWXG\ZLOOEHZKHQWKHODVWSDWLHQWLQWKHVWXG\KDVGLHGKDVEHHQRIIVWXG\
WUHDWPHQWIRUPRQWKVKDVEHHQORVWWRIROORZXSRUKDVZLWKGUHZFRQVHQW
ZKLFKHYHURFFXUVILUVW
7RWDOQXPEHURIVLWHV
$SSUR[LPDWHO\
6WXG\SRSXODWLRQV
3ULPDU\3DWLHQW3RSXODWLRQ$UPV
%&DQG'
3DWLHQWVZLWK:+2*UDGHJOLRPDVJOLREODVWRPD>*%0@DQGVXEYDULDQWVDW
ILUVW GLDJQRVLV ZLWK UHFXUUHQW GLVHDVH ZKR KDYH IDLOHG SULRU WUHDWPHQW ZLWK
UDGLDWLRQWKHUDS\DQGWHPR]RORPLGHDQGZKRPHHWWKHLQFOXVLRQDQGQRQHRIWKH
H[FOXVLRQFULWHULDDUHHOLJLEOHIRUHQUROOPHQW
2EMHFWLYHV

3ULPDU\REMHFWLYH$UPV%
&DQG'
x
7R GHWHUPLQH WKH HIILFDF\ RI VHOLQH[RU LQ DGXOWV ZLWK UHFXUUHQW *%0 DV
GHWHUPLQHGE\WKHPRQWKSURJUHVVLRQIUHHVXUYLYDOP3)6UDWH
6HFRQGDU\REMHFWLYHV$UPV
%&DQG'

x
7R GHWHUPLQH WKH HIILFDF\ RI VHOLQH[RU LQ DGXOWV ZLWK UHFXUUHQW *%0 DV
GHWHUPLQHG E\ UHVSRQVH UDWH DFFRUGLQJ WR WKH 5HVSRQVH $VVHVVPHQW LQ
1HXUR2QFRORJ\5$12FULWHULD
x
7R GHWHUPLQH WKH HIILFDF\ RI VHOLQH[RU LQ DGXOWV ZLWK UHFXUUHQW *%0 DV
HVWLPDWHGE\PHGLDQRYHUDOOVXUYLYDO26
x
7R GHWHUPLQH WKH HIILFDF\ RI VHOLQH[RU LQ DGXOWV ZLWK UHFXUUHQW *%0 DV
GHWHUPLQHGE\PHGLDQSURJUHVVLRQIUHHVXUYLYDO3)6
x
7RHYDOXDWHVDIHW\DQGWROHUDELOLW\RIVHOLQH[RU
PPD
PPD
CCI
CCI
C
CI

6HOLQH[RU.37
.DU\RSKDUP7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO.&3
1RYHPEHU
&RQILGHQWLDO
3DJHRI
9HUVLRQ
([SORUDWRU\REMHFWLYHV
3ODQQHGVDPSOHVL]H

$SSUR[LPDWHO\  SDWLHQWV DUH SODQQHG WR EH HQUROOHG


$OWKRXJK DSSUR[LPDWHO\  SDWLHQWV ZHUH SODQQHG WR EH HQUROOHG LQ $UP%
PHGLFDO DUP  PJP WZLFH ZHHNO\ HQUROOPHQW ZDV VWRSSHG WR H[SORUH
DOWHUQDWLYHGRVLQJLQ3URWRFRO9HUVLRQVWRSRWHQWLDOO\LPSURYHWROHUDELOLW\
7KHVWXG\LVFRQWLQXLQJZLWKWZRUDQGRPL]HGDUPV$UPV&DQG'ERWKXVLQJ
6LPRQ¶V WZRVWDJH GHVLJQ ZLWK IODW GRVLQJ WKDW ZHUH DGGHG LQ 3URWRFRO
9HUVLRQ $SSUR[LPDWHO\  SDWLHQWV ZLOO EH LQFOXGHG LQ HDFK RI WKH
UDQGRPL]HGIODWGRVLQJPHGLFDODUPV$UP&PJWZLFHZHHNO\DQG$UP'
PJZHHNO\
,QFOXVLRQFULWHULD
 3DWKRORJLFDOO\ FRQILUPHG GLDJQRVLV RI *%0 LQFOXGLQJ DOO KLVWRORJLF
YDULDQWVDWILUVWGLDJQRVLVZLWKUDGLRJUDSKLFHYLGHQFHRIUHFXUUHQWGLVHDVH
DIWHUWUHDWPHQWZLWKUDGLRWKHUDS\DQGWHPR]RORPLGH
 $JH\HDUV
 .DUQRIVN\3HUIRUPDQFH6WDWXV.36
 3DWLHQWVHQUROOLQJLQWKH0HGLFDO$UP$UPV%&RU'PXVWEHRQD
VWDEOHRUGHFUHDVLQJGRVHRIFRUWLFRVWHURLGVRUQRQHIRUDWOHDVWGD\V
SULRUWRWKHEDVHOLQH&705,
 3DWLHQWV PXVW KDYH UHFHLYHG SULRU WUHDWPHQW ZLWK UDGLDWLRQ WKHUDS\ DQG
WHPR]RORPLGHDOO$UPV
 0HDVXUDEOH GLVHDVH DFFRUGLQJ WR 5$12 JXLGHOLQHV ZLWKLQ  GD\V RI
VWDUWLQJ WUHDWPHQW 0HDVXUDEOH GLVHDVH
 LV QRW
UHTXLUHG
 :ULWWHQ LQIRUPHG FRQVHQW REWDLQHG SULRU WR DQ\ VFUHHQLQJ SURFHGXUHV
3DWLHQWVPXVWEHZLOOLQJDQGDEOHWRFRPSO\ZLWKWKHSURWRFRODQGDZDUHRI
WKHLQYHVWLJDWLRQDOQDWXUHRIWKLVVWXG\
 3DWLHQWVPXVWKDYHDGHTXDWHERQHPDUURZIXQFWLRQDQGRUJDQIXQFWLRQZLWKLQ
ZHHNVRIVWXG\WUHDWPHQWDVGHILQHGE\WKHIROORZLQJODERUDWRU\FULWHULD
R
+HPDWRSRLHWLF IXQFWLRQ WRWDO ZKLWH EORRG FHOO :%& FRXQW
PPñDEVROXWHQHXWURSKLOFRXQW$1&PPñSODWHOHW
FRXQWPPñKHPRJORELQJG/
R
+HSDWLF IXQFWLRQ ELOLUXELQ   WLPHV WKH XSSHU OLPLW RI QRUPDO
8/1 $/7   WLPHV 8/1 $67   WLPHV 8/1 XQOHVV
ELOLUXELQ HOHYDWLRQ LV UHODWHG WR *LOEHUW¶V 6\QGURPH IRU ZKLFK
ELOLUXELQPXVWEHWLPHV8/1
R
5HQDO IXQFWLRQ HVWLPDWHG FUHDWLQLQH FOHDUDQFH RI   P/PLQ
FDOFXODWHG XVLQJ WKH IRUPXOD RI &RFNURIW DQG *DXOW RU RWKHU
VWDQGDUGPHWKRGVDWWKHWUHDWLQJLQVWLWXWLRQ
 $OO IHPDOH SDWLHQWV RI FKLOGEHDULQJ SRWHQWLDO PXVW DJUHH WR XVH UHOLDEOH
PHWKRGVRIELUWKFRQWUROGXULQJVWXG\WUHDWPHQWDQGIRUPRQWKVDIWHUWKH
ODVW GRVH RI VWXG\ GUXJ DQG KDYH D QHJDWLYH VHUXP SUHJQDQF\ WHVW DW
VFUHHQLQJ5HOLDEOHPHWKRGVRIFRQWUDFHSWLRQLQFOXGHLQWUDXWHULQHGHYLFHV
KRUPRQDOFRQWUDFHSWLYHV>FRQWUDFHSWLYHSLOOVLPSODQWVWUDQVGHUPDOSDWFKHV
KRUPRQDOYDJLQDOGHYLFHVRULQMHFWLRQVZLWKSURORQJHGUHOHDVH@DEVWLQHQFH
RUVWHULOL]DWLRQRIWKHSDUWQHU
 )HUWLOHPDOHVPXVWEHZLOOLQJWRHPSOR\UHOLDEOHPHWKRGVRIFRQWUDFHSWLRQ
GXULQJVWXG\WUHDWPHQWDQGIRUPRQWKVDIWHUWKHODVWGRVHRIVWXG\GUXJ
CCI
CCI
CCI

6HOLQH[RU.37
.DU\RSKDUP7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO.&3
1RYHPEHU
&RQILGHQWLDO
3DJHRI
9HUVLRQ
 $UFKLYHGSDUDIILQHPEHGGHGWLVVXHDSSUR[LPDWHO\XQVWDLQHGVOLGHVLI
OHVVFRQWDFW6SRQVRURUDWXPRUEORFNPXVWEHDYDLODEOHIRUFRUUHODWLYH
VWXGLHV




 3DWLHQWVHQUROOLQJLQWKHPHGLFDODUP$UPV%&RU'PXVWKDYHDQLQWHUYDO
RIDWOHDVWZHHNVIURPFRPSOHWLRQRIUDGLDWLRQWKHUDS\DQGVWXG\XQOHVV
WKHUHLVKLVWRORJLFSURRIRIDFWLYHWXPRUIURPLQWHUYHQLQJUHVHFWLRQ
([FOXVLRQFULWHULD
 3DWLHQWVPXVWQRWKDYHVLJQLILFDQWPHGLFDOLOOQHVVWKDWLQWKH,QYHVWLJDWRU¶V
RSLQLRQFDQQRWEHDGHTXDWHO\FRQWUROOHGZLWKDSSURSULDWHWKHUDS\RUZRXOG
FRPSURPLVHWKHSDWLHQW¶VDELOLW\WRWROHUDWHWKLVWKHUDS\
 GD\VIURPSULRUWHPR]RORPLGHZHHNVIURPQLWURVRXUHDZHHNV
IURPRWKHUFKHPRWKHUDS\RULQYHVWLJDWLRQDODJHQWVSULRUWRVWDUWRIWUHDWPHQW
ZLWKLQVWXG\
 8QVWDEOHFDUGLRYDVFXODUIXQFWLRQ
 .QRZQDFWLYHKHSDWLWLV$%RU&LQIHFWLRQRUNQRZQWREHSRVLWLYHIRU+&9
51$RU+%V$J+%9VXUIDFHDQWLJHQKHSDWLWLVWHVWLQJLVQRWUHTXLUHG
 .QRZQ+,9LQIHFWLRQ+,9WHVWLQJLVQRWUHTXLUHG
 0DUNHGO\GHFUHDVHGYLVXDODFXLW\LIDWWULEXWHGWRRWKHUFDXVHVWKDQ*%0
 $FWLYHLQIHFWLRQUHTXLULQJSDUHQWHUDOV\VWHPLFDQWLELRWLFV
 3DWLHQWVZLWKFRDJXODWLRQSUREOHPVDQGPHGLFDOO\VLJQLILFDQWEOHHGLQJLQWKH
PRQWKSULRUWRVWDUWRIWUHDWPHQWHJSHSWLFXOFHUHSLVWD[LVVSRQWDQHRXV
EOHHGLQJ3ULRUKLVWRU\RI'97RU3(LVQRWH[FOXVLRQDU\
 3DWLHQWVZKRDUHSUHJQDQWRUEUHDVWIHHGLQJ
 2WKHUFDQFHUH[FHSWQRQPHODQRPDVNLQFDQFHURUFDUFLQRPDLQVLWXRIWKH
FHUYL[XQOHVVLQFRPSOHWHUHPLVVLRQDQGRIIDOOWKHUDS\IRUWKDWGLVHDVHIRU
DPLQLPXPRI\HDUV
 3DWLHQWVPXVWQRWKDYHVLJQLILFDQWO\GLVHDVHGRUREVWUXFWHGJDVWURLQWHVWLQDO
WUDFW PDODEVRUSWLRQ XQFRQWUROOHG YRPLWLQJ RU GLDUUKHD RU LQDELOLW\ WR
VZDOORZRUDOPHGLFDWLRQV
 'HK\GUDWLRQ RI 1DWLRQDO &DQFHU ,QVWLWXWH 1&, &RPPRQ 7HUPLQRORJ\
&ULWHULDIRU$GYHUVH(YHQWV&7&$(JUDGH
 3DWLHQWVPXVWQRWKDYHVHULRXVSV\FKLDWULFRUPHGLFDOFRQGLWLRQVWKDWFRXOG
LQWHUIHUHZLWKWUHDWPHQW
 +LVWRU\RIRUJDQDOORJUDIW
 &RQFXUUHQWWKHUDS\ZLWKDSSURYHGRULQYHVWLJDWLRQDODQWLFDQFHUWKHUDSHXWLFV
 3ULRUWUHDWPHQWZLWKEHYDFL]XPDERURWKHUGLUHFW9(*)9(*)5LQKLELWRUV
)RU DQ\ TXHVWLRQ RI WKH GHILQLWLRQ RI D GLUHFW 9(*)9(*)5 LQKLELWRU
FRQVXOW6SRQVRU
 $UPV&DQG'RQO\ERG\VXUIDFHDUHDPWRDYRLGDGRVHH[FHHGLQJ
WKHPD[LPXPDOORZDEOHGRVHRIPJP
 0DMRUVXUJHU\ZHHNVSULRUWRWKHVWDUWRIVWXG\WUHDWPHQW
7UHDWPHQWSODQ

6HOLQH[RUWDNHQRUDOO\ZLOOEHJLYHQRQFHZHHNO\GRVHVRUWZLFHZHHNO\
GRVHVGXULQJ:HHNVRIHDFKZHHNF\FOH3DWLHQWVZKRDUHFXUUHQWO\EHLQJ
WUHDWHGWZLFHZHHNO\IRU:HHNVXQGHUDSUHYLRXVYHUVLRQRIWKHSURWRFROPD\
DW WKH GLVFUHWLRQ RI WKH LQYHVWLJDWRU KDYH WKH IUHTXHQF\ RI VHOLQH[RU GRVLQJ
LQFUHDVHGWRWZLFHZHHNO\IRU:HHNV2QHF\FOHLVGHILQHGDVGD\VRU
ZHHNV6HOLQH[RUVKRXOGEHWDNHQZLWKDOLJKWPHDODQGP/R]RIZDWHU


CCI
CCI
CCI

6HOLQH[RU.37
.DU\RSKDUP7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO.&3
1RYHPEHU
&RQILGHQWLDO
3DJHRI
9HUVLRQ
$UPV%&DQG'0HGLFDO$UPP,77DQG33SRSXODWLRQV
$UP % $SSUR[LPDWHO\  SDWLHQWV ZKR ZHUH QRW HOLJLEOH IRU VXUJHU\ ZHUH
SODQQHGWREHWUHDWHGZLWKVHOLQH[RUPJPWZLFHZHHNO\(QUROOPHQWLQ
$UP%ZDVVWRSSHGWRH[SORUHDOWHUQDWLYHGRVLQJLQ3URWRFRO9HUVLRQVWR
SRWHQWLDOO\LPSURYHWROHUDELOLW\$OWKRXJKHQUROOPHQWLQ$UP%KDVEHHQVWRSSHG
WKHVWXG\LVFRQWLQXLQJZLWKWZRUDQGRPL]HGDUPV$UPV&DQG'ZLWKIODW
GRVLQJWKDWZHUHDGGHGLQ3URWRFRO9HUVLRQ3DWLHQWVSUHYLRXVO\HQUROOHGLQ
$UP%ZLWKPJPGRVLQJZKRDUHDWDGRVHRIPJPRUJUHDWHUZLOOEH
FRQYHUWHGWRPJWZLFHZHHNO\IODWGRVLQJKRZHYHULIWKHSDWLHQWLVFXUUHQWO\
DWDORZHUGRVHWKH,QYHVWLJDWRUVKRXOGFRQWDFWWKHPHGLFDOPRQLWRUWRGHWHUPLQH
WKHVWDUWLQJGRVHIRUIODWGRVLQJ
*%0 SDWLHQWV HQUROOHGXQGHU 3URWRFRO 9HUVLRQV LH DIWHUFHVVDWLRQRI
$UP% HQUROOPHQW ZLOO EH UDQGRPO\ DOORFDWHG LQ D  UDWLR WR RQH RI WKH
IROORZLQJWUHDWPHQWDUPV
$UP & $SSUR[LPDWHO\  SDWLHQWV ZKR DUH QRW HOLJLEOH IRU VXUJHU\ ZLOO EH
WUHDWHG ZLWK VHOLQH[RU  PJ WZLFH ZHHNO\ HJ 0RQGD\ DQG :HGQHVGD\
7XHVGD\DQG7KXUVGD\:HGQHVGD\DQG)ULGD\7KXUVGD\DQG6DWXUGD\GXULQJ
:HHNVRIHDFKZHHNF\FOH,QWKHILUVWVWDJHSDWLHQWVZLOOEHDFFUXHG,I
WKHUHLVDWPRVWRQHP3)6UHVSRQVHLQWKHILUVWSDWLHQWVQRIXUWKHUHQUROOPHQW
ZLOOEHDOORZHGLQ$UP&
CCI

6HOLQH[RU.37
.DU\RSKDUP7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO.&3
1RYHPEHU
&RQILGHQWLDO
3DJHRI
9HUVLRQ
$UP ' $SSUR[LPDWHO\  SDWLHQWV ZKR DUH QRW HOLJLEOH IRU VXUJHU\ ZLOO EH
WUHDWHGZLWKVHOLQH[RUPJRQFHZHHNO\,QWKHILUVWVWDJHSDWLHQWVZLOOEH
DFFUXHG,IWKHUHLVDWPRVWRQHP3)6UHVSRQVHLQWKHILUVWSDWLHQWVQRIXUWKHU
HQUROOPHQWZLOOEHDOORZHGLQ$UP'
7UHDWPHQW LQ DOO DUPV RI WKH VWXG\ ZLOO FRQWLQXH XQWLO GLVHDVH SURJUHVVLRQ RU
GHYHORSPHQWRIXQDFFHSWDEOHWR[LFLWLHV
3ULPDU\DQDO\VLVSDUDPHWHU
PRQWKVSURJUHVVLRQIUHHVXUYLYDOP3)6UDWHSURJUHVVLRQRIGLVHDVHGHILQHG
DFFRUGLQJWRWKH5$12FULWHULD1RWHWKDWDZLQGRZRIGD\VZLOOEHDOORZHG
DURXQG WKH PRQWK YLVLW DQG ZLOO EH DSSOLHG WR WKH FDOFXODWLRQ RI WKH SRLQW
HVWLPDWHRIP3)6
6HFRQGDU\DQDO\VLV
SDUDPHWHUV
x
5HVSRQVHUDWHDFFRUGLQJWRWKH5$12FULWHULD
x
0HGLDQRYHUDOOVXUYLYDO26
x
0HGLDQSURJUHVVLRQIUHHVXUYLYDO3)6
x
6DIHW\
([SORUDWRU\DQDO\VLV
SDUDPHWHUVVXSSRUWLYHVWXGLHV
RQEORRGDQGWXPRUVDPSOHV

6WXG\SURFHGXUHV
'LVHDVHVWDWXVZLOOEHPHDVXUHGE\FRQWUDVWHQKDQFHG05,RU&7LQFOXGLQJ
SUHFRQWUDVW77)/$,5DQGSRVWFRQWUDVW7DQG7ZHLJKWHG)/$,5DQG
DVVHVVHGXVLQJWKH5$12FULWHULDDWVFUHHQLQJ

  ZHHNV DIWHU &\FOH  'D\  DQG DSSUR[LPDWHO\ HYHU\  ZHHNV
WKHUHDIWHU
6DIHW\DVVHVVPHQW
6DIHW\ZLOOEHPRQLWRUHGE\DVVHVVLQJYLWDOVLJQVDQGZHLJKWSHUIRUPDQFHVWDWXV
QHXURORJLFDO H[DPLQDWLRQV RSKWKDOPLF H[DPLQDWLRQV SK\VLFDO H[DPLQDWLRQV
(&*VDQGFRQFRPLWDQWPHGLFDWLRQXVH
$OO DGYHUVH HYHQWV RFFXUULQJ GXULQJ WKH FRXUVH RI WKH WULDO DQG WR WKH H[WHQW
SRVVLEOHIRUXSWRGD\VDIWHUWKHODVWGRVHRIVWXG\PHGLFDWLRQZLOOEHFDSWXUHG
GRFXPHQWHGDQGUHSRUWHG7R[LFLW\LVJUDGHGDFFRUGLQJWRWKHFXUUHQWYHUVLRQRI
1&,&7&$(YHUVLRQ
6DIHW\EORRGVDPSOHVLQFOXGLQJEORRGFRXQWFOLQLFDOFKHPLVWU\LQFOXGLQJOLYHU
IXQFWLRQWHVWV76+DQGFRDJXODWLRQZLOOEHFROOHFWHG
6WDWLVWLFDOFRQVLGHUDWLRQV
7KLVVWXG\ZLOODVVHVVHIILFDF\RIVHOLQH[RULQSDWLHQWVZLWKJOLRPDV(IILFDF\ZLOO
EHGHILQHGDVWKHSURSRUWLRQRISDWLHQWVLQ$UPV%&DQG'ZLWKQRSURJUHVVLRQ
DQGZKRDUHVWLOODOLYHPRQWKVDIWHUVWDUWRIVWXG\GUXJWUHDWPHQWP3)67KH
5$12FULWHULDZLOOEHXVHG
%DVHGRQKLVWRORJLFDOLQIRUPDWLRQFRQWDLQHGLQWKHOLWHUDWXUHWKHWULDOZRXOGEH
FRQVLGHUHGDVXFFHVVLIWKHUHLVHYLGHQFHWRVXJJHVWDP3)6UDWHDVKLJKDV
CCI
CCI

6HOLQH[RU.37
.DU\RSKDUP7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO.&3
1RYHPEHU
&RQILGHQWLDO
3DJHRI
9HUVLRQ
(QUROOPHQW LQ $UP % ZDV VWRSSHG WR H[SORUH DOWHUQDWLYH GRVLQJ LQ 3URWRFRO
9HUVLRQVWRSRWHQWLDOO\LPSURYHWROHUDELOLW\$QDVVHVVPHQWRIWKHHIILFDF\
GDWDSULRUWRWKHIRUPDO3)6DQDO\VLVIRUWKHILUVWSDWLHQWVLQ$UP%UHYHDOHG
FOLQLFDOO\PHDQLQJIXOHIILFDF\LQWKLVFKDOOHQJLQJSDWLHQWSRSXODWLRQ7KHVWXG\LV
FRQWLQXLQJZLWKWZRUDQGRPL]HGDUPV$UPV&DQG'ERWKXVLQJ6LPRQ¶VWZR
VWDJHGHVLJQZLWKIODWGRVLQJWKDWZHUHDGGHGLQ3URWRFRO9HUVLRQ,IWKHUHLV
QRP3)6UHVSRQVHLQWKHILUVWSDWLHQWVDFFUXHGLQ$UPV&RU'QRIXUWKHU
HQUROOPHQWZLOOEHDOORZHGLQWKDWDUP

5DQGRPL]DWLRQSURFHGXUH
)RUWKH0HGLFDO$UPSDWLHQWVZKRDUHHQUROOHGXQGHU3URWRFRO9HUVLRQRU
DERYHDQGPHHWWKHHQUROOPHQWFULWHULDZLOOEHDOORFDWHGE\PHDQVRIDFRPSXWHU
JHQHUDWHGUDQGRPL]DWLRQOLVWLQDUDWLRWR$UPV&DQG'3DWLHQWVHQUROOHG
SULRUWR3URWRFRO9HUVLRQDQGVXUJLFDOSDWLHQWVZLOOQRWEHUDQGRPL]HG
6DPSOHVL]HFDOFXODWLRQ



,1)250$7,2172%(3529,'('5(*$5',1*6$(6

,QWKHFDVHRIDVHULRXVDGYHUVHHYHQW6$(WKHFRPSOHWHG6$(IRUPPXVWEHVHQWWR
3KDUPDFRYLJLODQFH'HSDUWPHQW
.DU\RSKDUP7KHUDSHXWLFV,QF
(PDLOSKDUPDFRYLJLODQFH#NDU\RSKDUPFRP
)D[86
*HUPDQ\

CCI
CCI

6HOLQH[RU.37

.DU\RSKDUP7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO.&3

1RYHPEHU
&RQILGHQWLDO
3DJHRI
9HUVLRQ
7DEOH6FKHGXOHRI$VVHVVPHQWV'XULQJWKH6WXG\

6FUHHQLQJ
&\FOH
&\FOH
&\FOH
(QGRI
7UHDWPHQW
)ROORZ
XS
6XUYLYDO
)ROORZ
XS
9LVLWZLQGRZ>GD\V@
3ULRUWRVWDUWRIVWXG\
GUXJ
'D\RI
HDFKZHHN

'D\RI
HDFKF\FOH
'D\RI
HDFKF\FOH
GD\VSRVW
ODVWGRVH
GD\V
GD\V
GD\V
GD\V
GD\V
GD\V
GD\V
GD\V
,QIRUPHGFRQVHQW

;







,QFOXVLRQDQGH[FOXVLRQ
FULWHULD

;






'HPRJUDSKLFV
;







0HGLFDOKLVWRU\

;







5DQGRPL]DWLRQ

;






3UHJQDQF\WHVWLI
DSSOLFDEOH


;



;


%RG\KHLJKWDQGZHLJKW


;
;
;
;
;


%6$

;
;
;
;



9LWDOVLJQV


;
;
;
;
;


3K\VLFDOH[DPLQDWLRQDQG
.DUQRIVN\36


;
;
;
;
;


6WDQGDUGFOLQLFDO
QHXURORJLFDOH[DPLQDWLRQ

;

;
;
;
;


2SKWKDOPLFH[DP

;







2[\JHQVDWXUDWLRQ


;






OHDG(&*

;




;


8ULQDO\VLV


;






+HPDWRORJ\&%&

;

;
;
;
;


76+

;



;


&RPSOHWHVHUXPFKHPLVWU\

;

;


;


/LPLWHGVHUXPFKHPLVWU\




;
;



&RDJXODWLRQWHVWV


;






$VVHVVPHQWRIGLVHDVHVWDWXV
LQFOXGLQJ&705,

;


;
;

;

&KHVWUDGLRJUDSK
;







6HOLQH[RUGRVLQJ



;
;
;



&\WRUHGXFWLYHVXUJHU\









CCI

6HOLQH[RU.37

.DU\RSKDUP7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO.&3

1RYHPEHU
&RQILGHQWLDO
3DJHRI
9HUVLRQ

%HIRUHWKHILUVWVWXG\VSHFLILFPHDVXUHVDUHSHUIRUPHG5HVXOWVIURPWHVWVVFDQVSHUIRUPHGEHIRUHZULWWHQLQIRUPHGFRQVHQWLVREWDLQHGPD\EHXVHGDVVSHFLILHGLQWKLVWDEOH

0HGLFDOKLVWRU\LQFOXGHVEDVHOLQHV\PSWRPVDVZHOODVDGHWDLOHGKLVWRU\RISULRUFDQFHUWKHUDSLHVLQFOXGLQJVWDUWDQGVWRSGDWHVGLVHDVHSURJUHVVLRQGXULQJRUDIWHUWKHUDS\DVZHOODV
GLVFRQWLQXDWLRQVGXHWRLQWROHUDELOLW\RUDQ\RWKHUVHULRXVLOOQHVV

2QO\$UPV&DQG'ZLOOEHUDQGRPL]HG5DQGRPL]DWLRQPXVWRFFXUGD\VEHIRUHWKHVWDUWRIGRVLQJRQ&\FOH'D\

$SSOLFDEOHIRUZRPHQRIFKLOGEHDULQJSRWHQWLDO6HUXPE+&*WHVWZLWKLQGD\VEHIRUHWKHILUVWGRVHRIVWXG\GUXJ7REHUHSHDWHGE\XULQHWHVWLIGDWHRIILUVWUHVXOWH[FHHGVWKHGD\ZLQGRZ
8ULQHSUHJQDQF\WHVWLQJLVWREHSHUIRUPHGDVFOLQLFDOO\LQGLFDWHGGXULQJWKHVWXG\$Q\SRVLWLYHXULQHSUHJQDQF\WHVWPXVWEHFRQILUPHGZLWKDVHUXPE+&*WHVW

%RG\KHLJKWZLOOEHPHDVXUHGDWVFUHHQLQJRQO\

9LWDOVLJQVEORRGSUHVVXUHSXOVHDQGWHPSHUDWXUH

)XOOSK\VLFDOH[DPLQDWLRQIRUEDVHOLQHDQGHQGRIWUHDWPHQW(27YLVLW3K\VLFDOH[DPLQDWLRQVGXULQJWKHVWXG\VKRXOGEHV\PSWRPGLUHFWHG

$FRPSOHWHQHXURORJLFDOH[DPLVWREHFRPSOHWHGDWVFUHHQLQJEDVHOLQHH[DPDQGWKH(27YLVLW1HXURORJLFDOH[DPLQDWLRQVGXULQJWKHVWXG\VKRXOGEHV\PSWRPGLUHFWHG$Q\QHXURORJLFDOGHILFLWV
QRWHGGXULQJWKHEDVHOLQHH[DPPXVWEHIROORZHGDWVXEVHTXHQWYLVLWV$Q\QHZQHXURORJLFDOFRPSODLQWVUHSRUWHGE\WKHSDWLHQWDQGDQ\GHILFLWVREVHUYHGE\WKHLQYHVWLJDWRUVKRXOGEHDVVHVVHGDQG
IROORZHGDWVXEVHTXHQWYLVLWV

$IXOORSKWKDOPLFH[DPZLOOEHFRQGXFWHGE\DQRSWRPHWULVWRURSKWKDOPRORJLVWDWVFUHHQLQJ$GGLWLRQDORSKWKDOPLFDVVHVVPHQWVZLOOEHFRPSOHWHGGXULQJWKHVWXG\DVFOLQLFDOO\LQGLFDWHG

7KHIXOORSKWKDOPLFDVVHVVPHQWVLQFOXGHVSULRUWRGLODWLRQ
EHVWFRUUHFWHGYLVXDODFXLW\DQGVOLWODPSH[DPLQDWLRQLQFOXGLQJWRQRPHWU\IROORZLQJGLODWLRQIXQGRVFRS\DQGVOLWODPSH[DPWRGRFXPHQWOHQVFODULW\,IDFDWDUDFWLVVHHQGXULQJWKHH[DPIRUQHZO\
HQUROOLQJSDWLHQWVRUHQUROOHGSDWLHQWVIRUZKRPQRFDWDUDFWVKDYHEHHQGHWHFWHGWRGDWHWKHFDWDUDFWZLOOEHJUDGHGXVLQJD*UDGHVFDOH6HFWLRQ$SSHQGL[+RZHYHUSDWLHQWVHQUROOHG
XQGHUDSULRUYHUVLRQRIWKHSURWRFROZKRKDGGHWHFWDEOHFDWDUDFWVJUDGHGDFFRUGLQJWRWKH/HQV2SDFLWLHV&ODVVLILFDWLRQ6\VWHP/2&6,,,ZLOOFRQWLQXHWRKDYHWKHLUFDWDUDFWVJUDGHGDFFRUGLQJWR
/2&6,,,DQGZLOOQRWVZLWFKWRWKH*UDGHVFDOH
 3XOVHR[LPHWU\LVSHUIRUPHGIRUSDWLHQWVDWUHVWEUHDWKLQJURRPDLUDWVFUHHQLQJWKHQRQO\LIFOLQLFDOO\LQGLFDWHG
 (&*VWREHSHUIRUPHGSUHGRVHLQDVXSLQHSRVLWLRQ(&*VPD\EHSHUIRUPHGDVFOLQLFDOO\LQGLFDWHGGXULQJWKHWUHDWPHQWSKDVH
 8ULQDO\VLVZLOOLQFOXGHXULQHELOLUXELQJOXFRVHKHPRJORELQNHWRQHVS+SURWHLQVFUHHQLQJDQGWKHQLIFOLQLFDOO\LQGLFDWHG
 +HPDWRORJ\KHPRJORELQKHPDWRFULWUHGEORRGFHOOFRXQWZKLWHEORRGFHOO:%&FRXQW:%&GLIIHUHQWLDOO\PSKRF\WHVPRQRF\WHVQHXWURSKLOVHRVLQRSKLOVEDVRSKLOVSODWHOHWV:%&
GLIIHUHQWLDOPD\EHDXWRPDWHGRUPDQXDODVSHULQVWLWXWLRQDOVWDQGDUGV5HWLFXORF\WHVPD\EHGRQHRQO\ZKHQFOLQLFDOO\LQGLFDWHG'XULQJWKHWUHDWPHQWSKDVHODEVFDQEHGRQHGD\VSULRUWRYLVLW
 &RPSOHWHVHUXPFKHPLVWU\IRUEDVHOLQH&\FOHVDQGDQG(27YLVLWLQFOXGHVVRGLXPSRWDVVLXPFKORULGHELFDUERQDWH%81FUHDWLQLQHJOXFRVHFDOFLXPSKRVSKDWHPDJQHVLXP$/7$67
DONDOLQHSKRVSKDWDVHWRWDOELOLUXELQ/'+WRWDOSURWHLQDOEXPLQDP\ODVHOLSDVHFUHDWLQHNLQDVHDQGXUDWH'XULQJWKHWUHDWPHQWSKDVHODEVFDQEHGRQHGD\VSULRUWRYLVLW


 &RDJXODWLRQWHVWLQFOXGHSURWKURPELQWLPH37LQWHUQDWLRQDOQRUPDOL]DWLRQUDWLR,15DQGDFWLYDWHGSDUWLDOWKURPERSODVWLQWLPHD377VFUHHQLQJRQO\DQGLIFOLQLFDOO\LQGLFDWHG
 'LVHDVHVWDWXVZLOOEHPHDVXUHGE\FRQWUDVWHQKDQFHG05,RU&7IRUSDWLHQWVXQDEOHRUXQZLOOLQJWRXQGHUJR05,DWEDVHOLQH$&705,VFDQSHUIRUPHGDVSDUWRIFOLQLFDOHYDOXDWLRQRIGLVHDVH
VWDWXVDVSDUWRIVWDQGDUGRIFDUHFDQEHXVHGDVEDVHOLQH&705,VFDQSURYLGHGVWXG\WUHDWPHQWZLOOVWDUWZLWKLQGD\VIRUDOOSDWLHQWVLQ$UPV%&DQG'




 %RWKSRVWHURDQWHULRUDQGODWHUDOILOPVVKRXOGEHREWDLQHGIRUEDVHOLQH1RWHWKLVWHVWGRHVQRWQHHGWREHUHSHDWHGLIUHVXOWVDUHDYDLODEOHIURPDWHVWSHUIRUPHGGD\VSULRUWRVWDUWRIWKHUDS\7KLV
WHVWVHUYHVDVDEDVHOLQHLQWKHHYHQWWKDWSDWLHQWVGHYHORSDQ\DGYHUVHHYHQWVGXULQJWKHVWXG\


$GYHUVHHYHQWV


;
;
;
;


&RQFRPLWDQWPHGLFDWLRQ
;
;
;
;
;
;


,QIRUPDWLRQRQVXUYLYDO
VWDWXVDQGDQWLFDQFHUWKHUDS\
DIWHUHQGRIVHOLQH[RU
WUHDWPHQW







;
CCI
CCI
CCI
CCI
CCI
CCI
CCI

6HOLQH[RU.37

.DU\RSKDUP7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO.&3

1RYHPEHU
&RQILGHQWLDO
3DJHRI
9HUVLRQ

$UPV%DQG&2UDOVHOLQH[RUPJZLOOEHJLYHQWZLFHZHHNO\HJ0RQGD\DQG:HGQHVGD\7XHVGD\DQG7KXUVGD\:HGQHVGD\DQG)ULGD\7KXUVGD\
DQG6DWXUGD\GXULQJ:HHNVRIHDFKZHHNF\FOH3DWLHQWVZKRDUHFXUUHQWO\EHLQJWUHDWHGWZLFHZHHNO\IRU:HHNVXQGHUDSUHYLRXVYHUVLRQRIWKHSURWRFROPD\DWWKHGLVFUHWLRQRIWKH
LQYHVWLJDWRUKDYHWKHIUHTXHQF\RIVHOLQH[RUGRVLQJLQFUHDVHGWRWZLFHZHHNO\IRU:HHNV$UP'2UDOVHOLQH[RUPJZLOOEHJLYHQRQFHZHHNO\'RVLQJZLOOEHVHOHFWHGEDVHGRQWKHILUVW
VWDJHUHVXOWVIRU$UPV&DQG'








 3DWLHQWVZKRGLVFRQWLQXHWKHUDS\IRUDQ\UHDVRQRWKHUWKDQZLWKGUDZDORIFRQVHQWZLOOEHHQFRXUDJHGWRKDYHDQ(27YLVLW7KH(27YLVLWVKRXOGWDNHSODFHGD\VGD\VDIWHUWKHLUODVWGRVHLI
SRVVLEOH
 %HIRUHGLVHDVHSURJUHVVLRQSDWLHQWVZKRGLVFRQWLQXHIRUUHDVRQVRWKHUWKDQSURJUHVVLRQRIGLVHDVHDQGZLWKGUDZDORIFRQVHQWIRUSDUWLFLSDWLRQLQWKHWULDOVKRXOGEHHQFRXUDJHGWRYLVLWWKHFOLQLFIRU
FOLQLFDOHYDOXDWLRQRIWKHLUGLVHDVHHYHU\ZHHNVDQGDVVHVVPHQWE\&705,HYHU\ZHHNVGD\VXQWLOSURJUHVVLRQRIGLVHDVHLVGHWHUPLQHG
 $IWHUGLVHDVHSURJUHVVLRQDOOSDWLHQWVZLOOEHHYDOXDWHGIRUVXUYLYDODQGIXUWKHUDQWLFDQFHUWKHUDS\HYHU\PRQWKVGD\VXQWLOWKH(QGRI6WXG\6HFWLRQ3DWLHQWV
ZKRKDYHQRWH[SLUHGRUSURJUHVVHGE\WKHGDWDDQDO\VLVFXWRIIGDWHIRUWKHP3)6UDWHZLOOEHFHQVRUHGDWWKHGDWHRIWKHLUODVWGLVHDVHDVVHVVPHQW3DWLHQWVZKRKDYHQRW
H[SLUHGE\WKHGDWDDQDO\VLVFXWRIIGDWHIRU26ZLOOEHFHQVRUHGDWWKHLUODVWGDWHNQRZQWREHDOLYH

CCI
CCI
CCI
CCI

Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 14 of 137 
Version 6.0 
GLOSSARY OF ABBREVIATIONS 
ADR 
Adverse Drug Reaction 
AE 
Adverse event 
ALT (SGPT) 
Alanine aminotransferase 
AML 
Acute myeloid leukemia 
ANC 
Absolute neutrophil count 
aPTT 
Activated partial thromboplastin time 
AST (SGOT) 
Aspartate aminotransferase 
BCNU 
Carmustine 
BSA 
Body surface area 
BUN 
Blood urea nitrogen 
CBC 
Complete blood count 
CCNU 
Lomustine 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CLL 
Chronic lymphocytic leukemia 
CR 
Complete response 
CT 
Computed tomography 
CTCAE 
Common terminology criteria for adverse events 
CYP450 
Cytochrome P450 
DLBCL 
Diffuse large B-cell lymphoma 
DLT 
Dose-limiting toxicity 
DVT 
Deep vein thrombosis 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EGFR 
Epidermal growth factor receptor 
EORTC 
European Organisation for Research and Treatment of Cancer 
EOT 
End of treatment 
FDA 
Food and Drug Administration 
FGFR 
Fibroblast growth factor receptor 
FLAIR 
Fluid-Attenuated Inversion Recovery 
GBM 
Glioblastoma  
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte colony-stimulating factor 
GM-CSF 
Granulocyte-macrophage colony-stimulating factor 
GSH 
Glutathione 
HBsAg 
hepatitis B virus surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HDPE 
High-density polyethylene 
HIV 
human immunodeficiency virus 
hr 
Hour 
HGG 
High-grade glioma 
IB 
Investigator’s Brochure 
IC50 
Inhibitory concentration, 50% (half maximal inhibitory concentration) 
ICH 
International Conference on Harmonisation 
IDH 
isocitrate dehydrogenase 
IEC 
Independent ethics committee 
IFN 
Interferon 
IMP 
Investigational medicinal product 
IRB 
Institutional review board 
K 
Karnofsky Performance Status 
LDH 
Lactate dehydrogenase 
LOCS III 
Lens Opacities Classification System III 

6HOLQH[RU.37
.DU\RSKDUP7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO.&3
1RYHPEHU

&RQILGHQWLDO
3DJHRI
9HUVLRQ
Pð
6TXDUHPHWHUERG\VXUIDFHDUHD
0HG'5$
0HGLFDO'LFWLRQDU\IRU5HJXODWRU\$FWLYLWLHV
PJ
0LOOLJUDP
P,77
0RGLILHGLQWHQWWRWUHDW
P/
0LOOLOLWHU
00
0XOWLSOHP\HORPD
05,
0DJQHWLFUHVRQDQFHLPDJLQJ
P51$
0HVVHQJHUULERQXFOHLFDFLG
07'
0D[LPXPWROHUDWHGGRVH
1$&
1DFHW\OF\VWHLQH
1&&1
1DWLRQDO&RPSUHKHQVLYH&DQFHU1HWZRUN
1&,
1DWLRQDO&DQFHU,QVWLWXWH
1&,&&7*
1DWLRQDO&DQFHU,QVWLWXWHRI&DQDGD±&OLQLFDO7ULDOV*URXS
1.
1HXURNLQLQ
26
2YHUDOOVXUYLYDO
3&5
3RO\PHUDVHFKDLQUHDFWLRQ
3&9
3URFDUED]LQHDQGYLQFULVWLQH
3'
3URJUHVVLYHGLVHDVH
3'*)5
3ODWHOHWGHULYHGJURZWKIDFWRUUHFHSWRU


3(
3XOPRQDU\HPEROLVP
3)6
3URJUHVVLRQIUHHVXUYLYDO


33
3HUSURWRFROSRSXODWLRQ
35
3DUWLDOUHVSRQVH
37&/
3HULSKHUDO7FHOOO\PSKRPD
T573&5
4XDQWLWDWLYHUHYHUVHWUDQVFULSWLRQSRO\PHUDVHFKDLQUHDFWLRQ
5$12
5HVSRQVH$VVHVVPHQWLQ1HXUR2QFRORJ\
5%&
5HGEORRGFHOO
5(%
5HVHDUFKHWKLFVERDUG
51$
5LERQXFOHLFDFLG
53'
5HFRPPHQGHG3KDVHGRVH
6$'5
6HULRXVDGYHUVHGUXJUHDFWLRQ
6$(
6HULRXVDGYHUVHHYHQW
6$0
6DGHQRV\OPHWKLRQLQH
6'
6WDEOHGLVHDVH
6,$'+
6\QGURPHRILQDSSURSULDWHDQWLGLXUHWLFKRUPRQHVHFUHWLRQ
6,1(
6HOHFWLYH,QKLELWRURI1XFOHDU([SRUW
62&
6\VWHP2UJDQ&ODVV
686$5
6XVSHFWHGXQH[SHFWHGVHULRXVDGYHUVHUHDFWLRQ
7.,
7\URVLQHNLQDVHLQKLELWRU
7PD[
7LPHWRPD[LPXPVHUXPFRQFHQWUDWLRQ
76+
7K\URLGVWLPXODWLQJKRUPRQH
763
7XPRUVXSSUHVVRUSURWHLQ
781(/
7HUPLQDOGHR[\ULERQXFOHRWLG\OWUDQVIHUDVHG873QLFNHQGODEHOLQJ
8/1
8SSHUOLPLWRIQRUPDO
9G
9ROXPHRIGLVWULEXWLRQ
9(*)
9DVFXODUHQGRWKHOLDOJURZWKIDFWRU
9(*)5
9DVFXODUHQGRWKHOLDOJURZWKIDFWRUUHFHSWRU
:%&
:KLWHEORRGFHOO
:+2
:RUOG+HDOWK2UJDQL]DWLRQ
;32
([SRUWLQ
C
CI
CCI

6HOLQH[RU.37
.DU\RSKDUP7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO.&3
1RYHPEHU

&RQILGHQWLDO
3DJHRI
9HUVLRQ
7$%/(2)&217(176
6\QRSVLV 
*ORVVDU\2I$EEUHYLDWLRQV 
7DEOHRI&RQWHQWV 
 
%DFNJURXQGDQG5DWLRQDOH 
 
%DFNJURXQG 
 
*OLREODVWRPD 
 
6HOLQH[RU 
 
;32DQG6HOLQH[RULQ+LJK*UDGH*OLRPDV+** 
 
6WXG\5DWLRQDOH 
 
2EMHFWLYHVRIWKH6WXG\ 
 
3ULPDU\2EMHFWLYHV 
 
6HFRQGDU\2EMHFWLYHV 
 
([SORUDWRU\2EMHFWLYHV 
 
,QYHVWLJDWLRQDO3ODQ 
 
2YHUYLHZRI6WXG\'HVLJQDQG'RVLQJ5HJLPHQ 
 
 
 
'HILQLWLRQVRI7UHDWPHQW&\FOHV 
 
7UHDWPHQW'XUDWLRQ 
 
(QGRI7UHDWPHQW9LVLW 
 
)ROORZ8S3KDVH 
 
5HJLVWUDWLRQ5DQGRPL]DWLRQRI3DWLHQWV 
 
,QYHVWLJDWLRQDO6LWHV 
 
6HOHFWLRQRIWKH6WXG\3RSXODWLRQ 
 
7DUJHW3DWLHQW3RSXODWLRQV 
 
,QFOXVLRQ&ULWHULD 
 
([FOXVLRQ&ULWHULD 
 
6FKHGXOHRI$VVHVVPHQWDQG3URFHGXUHV 
 
6WXG\$VVHVVPHQWV 
 
7XPRU$VVHVVPHQW 
 
([SORUDWRU\$VVHVVPHQWV 
 
6DIHW\DQG7ROHUDELOLW\$VVHVVPHQWV 
 
6WXG\3URFHGXUHV 
 
6FUHHQLQJ3URFHGXUHV 
 
7UHDWPHQW3KDVH 
 
(QGRI7UHDWPHQW 
 
)ROORZXS%HIRUH3URJUHVVLRQRI'LVHDVH 
 
6XUYLYDO)ROORZXS 
CCI

Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 17 of 137 
Version 6.0 
5.2.6 
End of Study ...................................................................................................... 46 
5.3 
Planned Treatment of the Patients after End of Treatment Phase ............................... 46 
5.4 
Removal of Patients from Treatment .......................................................................... 46 
5.5 
Study Discontinuation ................................................................................................. 46 
6 
Investigational Product .......................................................................................................... 47 
6.1 
Investigational medicinal product ............................................................................... 47 
6.2 
Preparation and Administration of Selinexor .............................................................. 47 
6.2.1 
Preparation and Administration of Selinexor .................................................... 47 
6.3 
Dose Modifications for Selinexor ............................................................................... 49 
6.3.1 
Selinexor Dose Reduction for Decreased Glomerular Filtration Rate .............. 55 
6.3.2 
Selinexor Dose Reduction in the Setting of Infection ....................................... 55 
6.3.3 
Dose Adjustments with Changes in BSA .......................................................... 56 
6.3.4 
Missed or Vomited Doses ................................................................................. 56 
6.4 
Concomitant Medication and Treatment ..................................................................... 56 
6.4.1 
Permitted Concomitant Medication .................................................................. 56 
6.4.2 
Restrictions and Prohibited Medications .......................................................... 57 
6.5 
Supportive Care Guidelines ........................................................................................ 58 
6.5.1 
Required 5-HT3 Antagonists ............................................................................ 58 
6.5.2 
Supportive Care Recommendations for Selinexor-Related Adverse Events .... 58 
6.5.3 
Liver Function Test Abnormalities ................................................................... 58 
7 
Assessment of Safety............................................................................................................. 59 
7.1 
Adverse Events and Laboratory Abnormalities Reporting ......................................... 59 
7.1.1 
Adverse Event ................................................................................................... 59 
7.1.2 
Adverse Drug Reaction ..................................................................................... 59 
7.1.3 
Serious Adverse Event ...................................................................................... 60 
7.1.4 
NOT to be reported as SAEs ............................................................................. 60 
7.1.5 
SUSAR/Unexpected Serious ADR ................................................................... 61 
7.2 
Reporting of SAEs ...................................................................................................... 61 
7.3 
Reporting of SUSARs/Expedited Reporting of Unexpected Serious ADRs .............. 62 
7.4 
Recording of Adverse Events ...................................................................................... 63 
7.5 
Laboratory Test Abnormalities ................................................................................... 63 
7.6 
Pregnancy .................................................................................................................... 64 
7.7 
Adverse Drug Reactions with Concomitant Medication ............................................. 64 
7.8 
Safety Surveillance ...................................................................................................... 64 
8 
Statistical Methods ................................................................................................................ 65 
8.1 
Trial Design and Hypotheses ...................................................................................... 65 
8.2 
Sample Size Calculation .............................................................................................. 65 
8.2.1 
Arm B (50 mg/m2 twice weekly) ...................................................................... 65 

Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 18 of 137 
Version 6.0 
8.2.2 
Flat Dosing Arms (Arm C and Arm D) ............................................................ 66 
8.3 
Evaluation Categories for Patients .............................................................................. 66 
8.3.1 
Modified Intent-to-Treat Population ................................................................. 66 
8.3.2 
Per Protocol Population ..................................................................................... 66 
8.3.3 
Surgical Patient Population ............................................................................... 67 
8.3.4 
Safety Population .............................................................................................. 67 
8.4 
Methods of Statistical Analysis ................................................................................... 67 
8.4.1 
General Statistical Considerations .................................................................... 67 
8.4.2 
Demographics and Baseline Characteristics ..................................................... 67 
8.4.3 
Efficacy Evaluation ........................................................................................... 68 
8.4.4 
Safety Evaluation .............................................................................................. 70 
8.5 
Interim and Final Analysis .......................................................................................... 71 
9 
Data Quality Assurance ......................................................................................................... 72 
10 Ethical Aspects ...................................................................................................................... 73 
10.1 
Good Clinical Practice ................................................................................................ 73 
10.2 
Patient Information and Informed Consent ................................................................. 73 
10.3 
Independent Ethics Committees and Regulatory Authorities ..................................... 73 
10.3.1 
Approval by Regulatory Authorities and Independent Ethics Committees ...... 73 
10.3.2 
Notification of the Study ................................................................................... 74 
10.3.3 
Obligation to Report and Document ................................................................. 74 
11 Conditions for Modifying the Protocol ................................................................................. 75 
12 Study Documentation, CRFs and Record-Keeping ............................................................... 76 
12.1 
Investigator’s Files/Retention of Documents .............................................................. 76 
12.2 
Source Documents and Background Data ................................................................... 76 
12.3 
Audits and Inspections ................................................................................................ 76 
12.4 
Case Report Forms ...................................................................................................... 77 
13 Monitoring of Study .............................................................................................................. 78 
14 Confidentiality of Trial Documents and Patient Records ..................................................... 79 
15 Study Report and Publication Policy..................................................................................... 80 
16 Appendices ............................................................................................................................ 81 
16.1 
Appendix 1 – Definitions According to ICH Guidelines for Clinical Safety Data 
Management, Definitions and Standards for Expedited Reporting, Topic E2 ............ 82 
16.2 
Appendix 2 – Karnofsky Performance Status ............................................................. 84 
16.3 
Appendix 3 – Cockroft-Gault Formula ....................................................................... 85 
16.4 
Appendix 4 – NCI-CTCAE version 4.03 .................................................................... 86 
16.5 
Appendix 5 Ophthalmic Examination ......................................................................... 87 
16.6 
Appendix 6 NCCN Clinical Practice Guidelines in Oncology: Antiemesis ............... 88 
16.7 
Appendix 7 NCCN Clinical Practice Guidelines in Oncology: Anorexia/Cachexia .. 90 

Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 19 of 137 
Version 6.0 
16.8 
Appendix 8  Glutathione (GSH)-, S-adenosylmethionine (SAM)-, or N-acetylcysteine 
(NAC)-containing Products (Representative List) ...................................................... 91 
16.9 
Appendix 9  Summary of Changes and Rationales for Changes to Protocol KCP-330-
004 ............................................................................................................................... 92 
16.9.1 
Summary and Rationale for Changes to Version 5.0 Protocol KCP-330-004 
Karyopharm Therapeutics Inc ........................................................................... 92 
16.9.2 
Summary and Rationale for Changes to Version 4.0 Protocol KCP-330-004 
Karyopharm Therapeutics Inc. .......................................................................... 95 
16.9.3 
Summary and Rationale for Changes to Version 3.0 Protocol KCP-330-004 
Karyopharm Therapeutics Inc. ........................................................................ 100 
16.9.4 
Summary and Rationale for Changes to Version 2.0 Protocol KCP-330-004 
Karyopharm Therapeutics Inc. ........................................................................ 109 
16.9.5 
Summary and Rationale for Changes to Version 1.0 Protocol KCP-330-004 
Karyopharm Therapeutics Inc. ........................................................................ 115 
17 References ........................................................................................................................... 136 
 
List of Figures 
 
Figure 1: Rate of Tumor Growth (A) and Survival (B) of Mice over Time with XPO1 Inhibitors 
KPT-276 and KPT-330 (Selinexor) ...................................................................................... 26 
Figure 2: Overview of study design ............................................................................................. 32 
 
List of Tables 
 
Table 1: Schedule of Assessments During the Study ................................................................. 11 
Table 2: KPT-330 Concentration in Human Tumor Tissue and Plasma ..................................... 24 
Table 3: Pre-Surgery Dosing Table ............................................................................................. 31 
Table 4: Summary of the Proposed RANO Response Criteria ................................................... 39 
Table 5: Prespecified Dose/Schedule Modifications for Adverse Events Related to Study Drug 50 
Table 6: Supportive Care and Dose Adjustment Guidelines ....................................................... 50 
Table 7: Classification of Adverse Events by Causality .............................................................. 59 
 
 

Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 20 of 137 
Version 6.0 
1 BACKGROUND AND RATIONALE 
1.1 
Background 
1.1.1 Glioblastoma 
High-grade gliomas (HGG) are defined as World Health Organization (WHO) Grade 3 and 4 
tumors of glial origin. Grade 4 tumors are called glioblastoma (GBM). With approximately 70%, 
GBM is the most common type of malignant primary brain tumors. More than 14,000 cases are 
newly diagnosed in adults in the United States each year.1 
The prognosis of GBM is very poor. An extensive infiltration of the surrounding brain tissue limits 
the accessibility in surgical resection. Aggravating the blood-brain barrier is an obstacle for many 
chemotherapeutic agents. Only small and lipophilic molecules, e.g. nitrosoureas, are able to reach 
their target. Furthermore, GBM is frequently refractory to cytotoxic agents. Median overall 
survival (OS) from first diagnosis is about 13-18 months. 
First-line therapy 
For a long time, standard therapy comprised surgical resection followed by radiotherapy. In a 
randomized Phase 3 trial by the EORTC (European Organisation for Research and Treatment of 
Cancer) and the NCIC-CTG (National Cancer Institute of Canada – Clinical Trials Group), a 
significant benefit of concomitant radiotherapy and temozolomide plus six cycles of adjuvant 
chemotherapy over radiotherapy alone could be demonstrated for the first time. With the addition 
of the oral alkylating agent temozolomide, a median survival of 14.6 versus 12.1 months with 
radiotherapy alone was achieved. Patients had a two-year survival rate of 25.6% with radiotherapy 
plus temozolomide versus 10.4% with radiotherapy alone.2-4 
Recurrent disease 
Irrespective of the first-line therapy, patients with HGG have a high risk for relapse within 6 to 11 
months after the primary treatment.5 There is still no established standard treatment for recurrent 
HGG. Nitrosourea-based regimens are commonly used, e.g. carmustine (BCNU) or lomustine 
(CCNU) alone or combined with procarbazine and vincristine (PCV). 6-months progression-free 
survival (6mPFS) rates of approximately 20% were seen.6-9 
One other option is the treatment with temozolomide in a continuous dose-intense (50 mg/m²/d) 
regimen that could overcome resistance to standard therapy. In the RESCUE study, patients with 
GBM achieved a 6mPFS rate of 23.9% and the median overall survival (OS) was 9.3 months. 
Another Phase 2 study with 37 patients revealed a 6mPFS rate of 19% and a median OS of 
7 months. However, the benefit of continuous temozolomide was only true for GBM patients who 
had not experienced progression while on extended adjuvant treatment, i.e. beyond six cycles. Also, 
the success of this treatment strategy seems to be dependent on previous treatment with 
bevacizumab. One advantage of the regimen is its tolerability with a lower hematologic toxicity 
and nausea/vomiting compared to other chemotherapies such as nitrosoureas or other 
temozolomide schedules.6, 10, 11 
GBM was found to be one of the most vascularized human tumors with a high expression of 
vascular endothelial growth factor (VEGF). VEGF expression is associated with a poor prognosis. 

Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 21 of 137 
Version 6.0 
Promising results were obtained with targeted therapies such as the monoclonal antibody 
bevacizumab that binds to VEGF inhibiting its activity, for which 6mPFS is 25% to 46%. 
Bevacizumab also showed a positive impact on quality of life.12-18 
As high activity of signal transduction pathways such as PI3K, AKT and mTOR (mammalian target 
of rapamycin) is associated with a poor prognosis, many inhibitors targeting various objectives in 
these pathways have reached Phase 1and 2 clinical trials. For example, the effect of the mTOR 
inhibitor added to bevacizumab after failure of a bevacizumab-containing second-line treatment 
was investigated, but did not show sufficient activity.19, 20 
Many other targets have recently been or are currently under investigation: Although amplification 
of epidermal growth factor receptor (EGFR) can be detected in approximately 40% of GBM, 
EGFR-inhibiting drugs such as erlotinib did not show sufficient activity in monotherapy.21 The 
EGFR antibody nimotuzumab is currently under investigation due to its lack of toxicity, although 
first data have proven only modest efficacy.22 
Similarly, nintedanib, a small, oral, triple angiokinase inhibitor targeting vascular endothelial 
growth factor receptor (VEGFR) 1-3, FGFR 1-3, and PDGFR-α/β, failed to show clinically relevant 
antitumor activity. In a Phase 2 study with 25 patients in second- or third-line therapy, best response 
was stable disease (SD) achieved by 12% of patients; one patient previously treated with 
bevacizumab had SD for more than 17 months. All other patients progressed within the first four 
28-day cycles. Median progression-free survival (PFS) was 1 month and median OS was 
6 months.23 
Vandetanib is a multitargeted tyrosine kinase inhibitor (TKI) of VEGF-2, EGFR, and the 
rearranged-during-transfection oncogene. In a Phase 2 trial with 64 patients with recurrent GBM 
and recurrent anaplastic glioma (AG), the 6mPFS was 6.5% in the GBM arm and 7.0% in the AG 
arm. Median OS was 6.3 months in the GBM arm and 7.6 months in the AG arm. Only 12.5% of 
GBM patients had radiographic response. Seizures were an unexpected toxicity of this therapy.24 
Another attempt was to investigate the activity of the TKIs imatinib combined with hydroxyurea. 
In a Phase 2 study with 231 patients, the combination therapy was, in fact, well tolerated, but its 
clinical antitumor activity was low with a 6mPFS of 10.6% and a median OS of 26 weeks.25 
With the lipophilic oral camptothecin analogue gimatecan, a similar 6mPFS rate of 12% was 
achieved in a Phase 2 study with 29 patients with recurrent GBM.26 Slightly better successes were 
achieved with the microtubule-destabilizing agent verubulin (MPC-6827) in combination with 
carboplatin, with a 6mPFS rate of 21% and a median PFS of 8 weeks. This combination was 
administered to 19 patients in one Phase 1 study.27 
Another approach currently under investigation is treatment with the antiangiogenic agent 
pazopanib in combination with the ErbB inhibitor lapatinib. Although the regimen has already 
shown limited antitumor activity in Phase 1/2 studies, pharmacokinetic (PK) data has revealed 
subtherapeutic doses of lapatinib, so this combination is still a candidate for further trials.28 
In summary, recurrent GBM still has poor outcome and treatment remains a challenge, as these 
data consistently show. Consequently, new treatment options for patients with recurrent GBM are 
desperately needed. 

Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 22 of 137 
Version 6.0 
1.1.2 Selinexor 
Selinexor is a Selective Inhibitor of Nuclear Export (SINE) compound that binds and inactivates 
Exportin 1 (XPO1), forcing the nuclear retention of key tumor suppressor proteins (TSPs). 
Transient retention of TSPs in the nucleus at high levels via XPO1 blockade activates their cell 
cycle checkpoint and genome surveying actions. This leads to the death of nearly all types of 
malignant cells, whereas normal cells undergo transient cell cycle arrest and recovery when the 
export block is released. The reactivation of multiple tumor suppressor pathways and inhibition of 
translation of key pro-survival proteins through inhibition of a non-redundant, single protein 
represents a novel approach to the treatment of neoplastic diseases including those with multiple 
genomic alterations and resistance mechanisms. More information about the mechanism of action, 
pharmacology, pre-clinical, and clinical studies with selinexor is available in the Selinexor/KPT-
330 Investigator’s Brochure (IB). 
Selinexor is being evaluated in multiple Phase 1 and 2 studies in patients with heavily pretreated 
relapsed and/or refractory hematological and solid tumor malignancies. More than 1,100 patients 
have received selinexor to date (as of 01 October 2015). Evidence of anti-cancer activity has been 
observed in a substantial number of patients and selinexor has been sufficiently well-tolerated to 
allow many of these patients to remain on therapy for prolonged periods, including several patients 
who have remained on treatment for over 12 months, with the longest treatment duration thus far 
of > 24 months. 
The main side effects of selinexor seen in heavily pretreated Phase 1 patients to date have been 
fatigue, nausea, anorexia, vomiting, and thrombocytopenia. These adverse events (AEs) are 
mainly Grades 1 and 2, and may be mitigated or eliminated with standard supportive care. Their 
prevalence and intensity typically decline after 4-8 weeks of treatment. Selinexor treatment is not 
associated with significant major organ toxicity. 
 
1.1.2.1 Preclinical Data 
A brief summary of preclinical data is provided below. More detailed information is available in 
the Selinexor/KPT-330 IB. 
In vitro experiments with continuous (72 hr) exposure to selinexor demonstrated potent pro 
apoptotic activity across a broad panel of tumor-derived cell lines and patient samples in culture, 
with the majority of 50% inhibitory concentration (IC50) values for cytotoxicity < 800 nM and 
most hematologic tumor lines having IC50 values of 20 – 400 nM for selinexor. In contrast, normal 
cells typically underwent (or remained in) cell cycle arrest but were resistant to apoptosis-
induction; cytotoxicity IC50 values were typically > 1 µM (based on results seen with MRC-5 
cells). Maximum selinexor serum levels of 1-2 µM are typically achieved in cancer patients 
following selinexor oral doses of 40-100 mg (~25-60 mg/m2). 
Selinexor, as well as other SINE compounds, have been administered in non-clinical efficacy 
studies to mice and dogs and in toxicology studies to rats and monkeys, with every-other-day oral 
dosing regimens (2-3 doses per week). Dosing regimens were designed based on pharmacodynamic 
observations that the biological effects of oral selinexor have durations > 48 hours. Efficacy was 
seen with these intermittent dosing regimens at doses of selinexor 5-20 mg/kg (15-60 mg/m2) in 
mouse models of myeloma, mantle cell lymphoma (MCL), T-cell acute lymphocytic leukemia 
(T-ALL) xenografts, and solid tumor models. Selinexor treatment resulted in significant survival 

6HOLQH[RU.37
.DU\RSKDUP7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO.&3
1RYHPEHU

&RQILGHQWLDO
3DJHRI
9HUVLRQ
DGYDQWDJHVLQPRGHOVRI001+/&//$0/DQG$//DVZHOODVVROLGWXPRUPRGHOVLQFOXGLQJ
SURVWDWHEUHDVWPHODQRPDFRORQFDQFHURYDULDQFDQFHUQHXUREODVWRPDDQGVHYHUDOVDUFRPDV,Q
DGGLWLRQ PDUNHG V\QHUJ\ ZDV REVHUYHG ZKHQ VHOLQH[RU ZDV FRPELQHG ZLWK D YDULHW\ RI
FKHPRWKHUDSLHV DQG WDUJHWHG WKHUDSLHV LQFOXGLQJ SODWLQXPV WD[DQHV WRSRLVRPHUDVH , DQG ,,
LQKLELWRUVGH[DPHWKDVRQHF\WDUDELQHSURWHDVRPHLQKLELWRUVYDULRXVW\URVLQHNLQDVHLQKLELWRUV
7.,V3'LQKLELWRUVDQG%&/LQKLELWRUV
6HOLQH[RUKDGOLWWOHHIIHFWRQQRUPDOQRQPDOLJQDQWO\PSKRF\WHVRURWKHUQRQWUDQVIRUPHGFHOOV
ZKLFKFRUUHODWHGZLWKWKHORZLQFLGHQFHLQDQLPDOVRIWKHW\SLFDOVLGHHIIHFWVVHHQZLWKPRVWDQWL
FDQFHU WKHUDSLHV VXFK DV VLJQLILFDQW P\HORVXSSUHVVLRQ DORSHFLD PXFRVLWLV DQG RWKHU
JDVWURLQWHVWLQDO *, G\VIXQFWLRQ 6HOLQH[RU GRHV LQGXFH D UHGXFWLRQLQ SODWHOHW FRXQWV ZLWKRXW
DIIHFWLQJSODWHOHWIXQFWLRQDQGZLWKPLQLPDOHIIHFWVRQQXPEHUVRIPHJDNDU\RF\WHV7KHHIIHFWV
RIVHOLQH[RURQSODWHOHWJHQHUDWLRQDUHSULPDULO\UHODWHGWRDVORZLQJRIPDWXUDWLRQRIVWHPFHOOVWR
PHJDNDU\RF\WHV
7KHPDMRUVLGH HIIHFWVDFURVV DOODQLPDO PRGHOV VWXGLHG ZHUH UHGXFHGDSSHWLWHZLWKDQRUH[LD
LQGXFHGZHLJKWORVVWKDWZDVSDUWLDOO\FRQVLVWHQWZLWKVDWLHW\LQGXFWLRQ6LPLODUHIIHFWVDUHREVHUYHG
LQKXPDQVZKHUHKLJKFDORULFIRRGVDQGDSSHWLWHVWLPXODQWVLQFOXGLQJJOXFRFRUWLFRLGVDUHNQRZQ
WRLPSURYHDSSHWLWHDQGPLWLJDWHZHLJKWORVV
&OLQLFDO'DWD
 3KDUPDFRNLQHWLFV
2UDO VHOLQH[RU SKDUPDFRNLQHWLFV 3. DUH SUHGLFWDEOH DSSUR[LPDWHO\ GRVHSURSRUWLRQDO DQG
H[KLELWPRGHUDWHWRPRGHUDWHO\KLJKLQWHUSDWLHQWYDULDELOLW\DFURVVDZLGHGRVHUDQJHRIGRVHVLQ
PDOH DQG IHPDOH SDWLHQWV ZLWK DGYDQFHG KHPDWRORJLFDO PDOLJQDQFLHV RU VROLG WXPRUV 7RWDO
H[SRVXUH $8&LQI ZDV VLJQLILFDQWO\ JUHDWHU IROORZLQJ VHOLQH[RU DGPLQLVWUDWLRQ ZLWK IRRG VR
SDWLHQWVWDNLQJVHOLQH[RUVKRXOGEHLQVWUXFWHGWRWDNHVHOLQH[RUZLWKIRRGLQRUGHUWRRSWLPL]H
VHOLQH[RUDEVRUSWLRQ
7KHHOLPLQDWLRQWHUPLQDOKDOIOLIHWRIVHOLQH[RULVDSSUR[LPDWHO\KRXUV7KHGXUDWLRQRI
SKDUPDFRG\QDPLFHIIHFWEDVHGRQ;32P51$LQFUHDVHGXHWR;32LQKLELWLRQLV!KRXUV
0D[LPDO VHUXP FRQFHQWUDWLRQV &PD[ RI  0 KDYH EHHQ DFKLHYHG DW GRVHV RI  PJ
PJPZKLFKDUHEHORZWKHPD[LPXPWROHUDWHGGRVH07'RIPJPJP
$QDQDO\VLVRIH[LVWLQJ3.GDWDIURP3KDVHVWXGLHV.&3DQG.&3VXSSRUWV
WKHXVHRIIL[HGUDWKHUWKDQERG\VXUIDFHDUHD%6$EDVHGGRVLQJ$VDUHVXOWVHOLQH[RUGRVH
VFKHGXOHVZLOOKHQFHIRUWKEHEDVHGRQIODWGRVHV,QDVHSDUDWHVWXG\LQSDWLHQWVZLWKDGYDQFHG
VDUFRPDV .&3 QR GHWHFWDEOH GLIIHUHQFH LQ VHOLQH[RU H[SRVXUH ZDV REVHUYHG LQ WKH
SUHVHQFHRIDKLJKIDWRUORZIDWPHDO






CCI

6HOLQH[RU.37
.DU\RSKDUP7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO.&3
1RYHPEHU

&RQILGHQWLDO
3DJHRI
9HUVLRQ
7DEOH.37&RQFHQWUDWLRQLQ+XPDQ7XPRU7LVVXHDQG3ODVPD

%/4 EHORZOLPLWRITXDQWLWDWLRQQJP/
 'DWDQRWDYDLODEOH
 6DIHW\
2YHUDOO$(VLQSDWLHQWVUHFHLYLQJVLQJOHDJHQWVHOLQH[RUKDYHEHHQJHQHUDOO\ORZJUDGHFRQVLVWHQW
ZLWKHYHQWVREVHUYHGLQSDWLHQWVZLWKRWKHUKHPDWRORJLFDOPDOLJQDQFLHVDQGUHVSRQVLYHWRVWDQGDUG
VXSSRUWLYHFDUH
)HZHU$(VKDYHEHHQUHSRUWHGLQSDWLHQWVUHFHLYLQJVHOLQH[RUSOXVGH[DPHWKDVRQHSDUWLFXODUO\
OHYHOVRIQDXVHDFRQVLVWHQWZLWKGH[DPHWKDVRQH¶VUHGXFWLRQLQVHOLQH[RU¶VPDLQVLGHHIIHFWVRI
QDXVHDDQRUH[LDDQGIDWLJXH
3RWHQWLDO5LVNV
3UHOLPLQDU\FOLQLFDOVDIHW\UHVXOWVIRU!SDWLHQWVKDYHEHHQHYDOXDWHGDVRI0D\DQG
WKHHQWLUHVDIHW\SURILOHLVQRWIXOO\NQRZQDWWKLVWLPH,QWKHFXUUHQWVWXG\PHDVXUHVZLOOEHWDNHQ
WRHQVXUHWKHVDIHW\RISDWLHQWVLQFOXGLQJWKHXVHRIVWULQJHQWLQFOXVLRQDQGH[FOXVLRQFULWHULDDQG
FORVHPRQLWRULQJ
,IWR[LFLWLHVDUHHQFRXQWHUHGDGMXVWPHQWVZLOOEHPDGHWRVWXG\WUHDWPHQWDVGHWDLOHGEHORZ$OO
$(VDQGVHULRXVDGYHUVHHYHQWV6$(VZLOOEHUHFRUGHGGXULQJWKHWULDODQGIRUXSWRGD\VDIWHU
WKHODVWGRVHRIVWXG\WUHDWPHQWRUXQWLOWKHLQLWLDWLRQRIDQRWKHUDQWLFDQFHUWKHUDS\ZKLFKHYHU
RFFXUVILUVW
,QRQJRLQJFOLQLFDOWULDOVDVRI0D\WKHPRVWFRPPRQ$(VVXVSHFWHGWREHUHODWHGWR
VHOLQH[RULQFLGHQFHVLQSDUHQWKHVHVKDYHEHHQORZJUDGHQDXVHDIDWLJXHDQRUH[LD
YRPLWLQJDQGPLOGPRGHUDWHWKURPERF\WRSHQLD0RVWRIWKHVHVLGHHIIHFWV
FDQEHPDQDJHGHIIHFWLYHO\ZLWKGRVHPRGLILFDWLRQDQGRUVXSSRUWLYHFDUHLQLWLDWHGSULRUWRILUVW
GRVLQJ ,Q D SUHYLRXV VWXG\ RQH SDWLHQW KHDYLO\ SUHWUHDWHG IRU UHFXUUHQW SDQFUHDWLF FDQFHU
GHYHORSHG DFXWH FHUHEHOODU V\QGURPH IROORZLQJ  GRVHV RI VHOLQH[RU DW  PJP %6$ WZLFH
ZHHNO\7KHSDWLHQWH[SHULHQFHGDEQRUPDOVSHHFKORVVRIFRRUGLQDWLRQDQGZDVXQDEOHWRZDON
6LQFHWKHGDWHRIWKHLQLWLDOUHSRUWHGHYHQWWKLVSDWLHQWLVUHFRYHULQJZLWKERWKVSHHFKDQGPRELOLW\
UHFRYHUHGWRQHDUEDVHOLQHRYHUaZHHNV1RRWKHUSDWLHQWVKDYHUHSRUWHGVLPLODUV\PSWRPVWR
GDWH
3OHDVHUHIHUWRWKH6HOLQH[RU.37,%IRUWKHPRVWFXUUHQWVDIHW\LQIRUPDWLRQ
5HSURGXFWLYH5LVNV
0DFURVFRSLFDQGPLFURVFRSLFFKDQJHVLQUHSURGXFWLYHRUJDQVZHUHQRWHGGXULQJUDWDQGPRQNH\
WR[LFRORJ\VWXGLHVPRVWUHVROYHGRUSDUWLDOO\UHVROYHGGXULQJWKHUHFRYHU\SHULRG7KHORQJWHUP
PPD

Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 25 of 137 
Version 6.0 
effects of these changes on reproductive potential are unknown. Secondary developmental effects 
due to reduced maternal body weights were also noted during a study on rat embryo/fetal 
development. Please see the Selinexor/KPT-330 IB for additional information. As it is unknown if 
selinexor produces any reproductive toxicity in humans, all patients must agree to use effective 
contraception (see Section 6.4.1.1) during the study and for 3 months after the end of treatment. 
1.1.2.2.3 Efficacy 
Clinical Evidence of Anti-Cancer Activity 
Hematologic Malignancies: In the dose escalation phase of study KCP-330-001, tumor load 
reductions and disease stabilization have been noted across many tumor types, consistent with the 
broad anti-tumor mechanism and results observed in preclinical studies. Responses have been 
documented in patients with MM, mantle cell lymphoma and DLBCL, CLL, Richter’s Syndrome, 
and AML. Durability for 6-12 months has been observed. The safety and tolerability of selinexor 
in patients with relapsed peripheral T-cell lymphomas (PTCL and CTCL) are being evaluated in a 
separate arm. Optimal twice-weekly dosing (e.g., dosing on Days 1, 2 vs. 1, 3 vs. 1, 4) is being 
explored in additional arms. 
Solid Tumor Malignancies: In the dose escalation phase of study KCP-330-002, disease 
stabilization or responses for > 4 months has been observed in patients with colon cancer, cervical 
adeno- and squamous cancers, and endometrial stromal sarcoma. Tumor shrinkage has also been 
observed in patients with melanoma, head and neck cancers, Ewing sarcoma, and others. Dose 
expansion in patients with prostate, ovarian, squamous (head and neck, lung, and cervical), colon, 
and high-grade malignant gliomas is ongoing. Optimal twice-weekly dosing as described above is 
being explored in additional arms. 
1.1.3 XPO1 and Selinexor in High-Grade Gliomas (HGG) 
XPO1 is overexpressed in HGG, and the degree of over-expression correlates with tumor grade 
and survival. One substrate of XPO1 is p27, which functions as a tumor suppressor through cell 
cycle control29 and requires phosphorylation at its Ser10 site in order to interact with XPO1.30 In 
vitro studies have shown that in glioma, the expression of Ser10-phosphorylated p27 correlates 
directly with XPO1 expression; both are overexpressed in higher-grade lesions. The expression of 
total p27 correlates indirectly with XPO1 expression, and increase in total p27 protein levels is 
associated with lower-grade tumors. In contrast, low p27 levels are associated with a poor 
prognosis. These findings strengthen the rationale for studying the use of XPO1 inhibition in HGG 
and offer a point of entry into investigation of a disease-specific mechanism of action. 
The XPO1 inhibitors KPT-276 and KPT-330 (selinexor) were evaluated in a murine orthotopic 
patient-derived xenograft (PDX) model of GBM.35 Adult primary human glioma cells infected with 
a luciferase-expressing virus to allow serial imaging were injected into three groups of 10 mice 
each. When the bioluminescence level of the tumors reached 1,000 times its starting value, 
treatment of two of the groups with KPT-276 and KPT-330 (selinexor) began, with the third group 
acting as a control. 
As shown in Figure 1, over time the inhibitors had a significant effect on the rate of tumor growth 
(A) and survival (B). The main side effect in the mice was weight loss, but this could be overcome 
with dosing adjustments. 

Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 26 of 137 
Version 6.0 
Figure 1: Rate of Tumor Growth (A) and Survival (B) of Mice over Time with XPO1 
Inhibitors KPT-276 and KPT-330 (Selinexor) 
 
Investigation of a mechanism of efficacy for XPO1 inhibition in HGG has shown an increase in 
apoptosis, but not cell cycle arrest, in vitro and in vivo. Preliminary results indicate that this effect 
may be mediated through sequestration of mRNA for Mcl1, an anti-apoptotic member of the Bcl2 
family, in the nucleus through inhibition of XPO1. This leads to failure of translation of Mcl1 and 
restoration of apoptosis; these inquiries are ongoing. Luxol Fast Blue/Cresyl Violet staining of 
sectioned mice brains of treated animals revealed no significant abnormalities in myelin health, 
and the treated mice had no significant neurologic side effects. 
1.2 
Study Rationale 
Patients with GBM have a high risk for recurrence shortly after first-line therapy. The overall 
survival times of patients with recurrent GBM are poor, approximately 10 months at the highest 
despite various new treatment approaches within recent years. Consequently, new treatment 
options are desperately needed. 
The cytotoxicity of selinexor against glioma (LN-229, U87MG, T-98G) cell lines was evaluated in 
MTT assays. IC50 values for selinexor ranged from 40 to 80 nM. Following this, seven patient-
derived HGG lines (four adult, three pediatric) were treated with selinexor in culture conditions 
where dose-responsive growth inhibition in all seven HGG lines (IC50 range 6-354 nM) was 
observed.35 Given these results, the ability of selinexor to inhibit in vivo growth of various glioma 
tumors was tested. In a xenograft model of glioma, U87MG cells were inoculated into severe 
combined immunodeficiency disease mice and selinexor was orally administered at 15 mg/kg three 
times weekly. Mean tumor weight and volume were significantly reduced with selinexor treatment 
(p<0.001). Selinexor has shown significant activity in multiple in-vitro glioma models. In a patient-
derived orthotopic model of HGG, BT145-wt-mCLP cells were injected intracranially into nude 
mice and tumor growth was measured by bioluminescence imaging and MRI at discrete time 
points.35 Selinexor at 20 and 25 mg/kg was administered via oral gavage three times a week 
(Monday, Wednesday, and Friday). All vehicle-treated mice were sacrificed by treatment day 79 
due to tumor progression and neurological symptoms. A significant prolongation in survival was 
observed in selinexor treatment groups (p < 0.0001). Tumor growth was markedly suppressed, 
based on bioluminescence imaging, and verified by MRI imaging. In addition, the number of 
TUNEL+ cells was significantly higher with selinexor treated tumors. These studies demonstrate 

6HOLQH[RU.37
.DU\RSKDUP7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO.&3
1RYHPEHU

&RQILGHQWLDO
3DJHRI
9HUVLRQ
SRWHQWLQYLWURDQGLQYLYRHIILFDF\RIVHOLQH[RUDJDLQVWDYDULHW\RIJOLRPDWXPRUPRGHOVDVDVLQJOH
DJHQW7KHVHGDWDIXUWKHUVXSSRUWWKHGHYHORSPHQWRIVHOLQH[RUIRUWKHWKHUDS\RIJOLRPD
$PD[LPXPWROHUDWHGGRVH07'RIPJPWZLFHZHHNO\'D\VDQGZDVGHWHUPLQHGLQ
WKHRQJRLQJGRVHHVFDODWLRQ3KDVHVWXG\.&32=0LQSDWLHQWVZLWKDGYDQFHG
VROLGWXPRUV7KH07'ZDVEDVHGRQWZRGRVHOLPLWLQJWR[LFLWLHV'/7VLQSDWLHQWVWUHDWHGDW
PJPWZLFHZHHNO\µSUREDEO\UHODWHG¶DV\PSWRPDWLF*UDGHK\SRQDWUHPLDDQGµSRVVLEO\
UHODWHG¶ DFXWH FHUHEHOODU V\QGURPH ZLWK DWD[LD DQG G\VDUWKULD 1R SDWLHQWV LQ DQ\ VWXG\ PD\
UHFHLYHGRVHVDERYHPJPRQFHRUWZLFHZHHNO\$VDVHOLQH[RUGRVHRIPJPWZLFHZHHNO\
ZDV WROHUDWHG DQG FOHDUHG '/7 HYDOXDWLRQ LQ .&3 WKH VDPH GRVH DQG VFKHGXOH ZDV
LQLWLDOO\FKRVHQIRUWKHFXUUHQWVWXG\+RZHYHUDQDO\VLVRISURORQJHGGRVLQJUHVXOWVLQ.&3
GHPRQVWUDWHGWKDWDGRVHRIPJPaPJWZLFHZHHNO\KDGDFFHSWDEOHHIILFDF\DQG
LPSURYHGORQJWHUPWROHUDELOLW\7KHUHIRUHWKHUHYLVHGUHFRPPHQGHG3KDVHGRVH53'RI
.37DVVLQJOHDJHQWIRUXVHLQWKLVVWXG\LVPJWZLFHZHHNO\DQGPJRQFHZHHNO\a
WRaPJPUHVSHFWLYHO\
(QUROOPHQWLQ$UP%ZDVVWRSSHGWRH[SORUHDOWHUQDWLYHGRVLQJLQ3URWRFRO9HUVLRQVWR
SRWHQWLDOO\LPSURYHWROHUDELOLW\$QDVVHVVPHQWRIWKHHIILFDF\GDWDSULRUWRWKHIRUPDO3)6DQDO\VLV
IRUWKHILUVWSDWLHQWVLQ$UP%UHYHDOHGFOLQLFDOO\PHDQLQJIXOHIILFDF\LQWKLVFKDOOHQJLQJSDWLHQW
SRSXODWLRQ 7ZR SDWLHQWV LQ $UP % KDYH KDG SDUWLDO UHVSRQVH 35V ZLWK 3)6 ! GD\V


DVHGRQWKHGDWDWRGDWHWKHVWXG\WHDP
KDVFRQFOXGHGWKDWSDWLHQWHQUROOPHQWVKRXOGFRQWLQXHQRWZLWKVWDQGLQJWKHUHVXOWVRIIRUPDO3)6
DQDO\VLVEXWDWDUHGXFHGVWDUWLQJGRVH$OWKRXJKHQUROOPHQWLQ$UP%KDVEHHQVWRSSHGWKHVWXG\
LVFRQWLQXLQJZLWKWZRUDQGRPL]HGDUPV$UPV&DQG'ERWKXVLQJ6LPRQ¶VWZRVWDJHGHVLJQ
ZLWKIODWGRVLQJWKDWZHUHDGGHGLQ3URWRFRO9HUVLRQ%DVHGRQWKHSURORQJHGGRVLQJUHVXOWVLQ
.&3SDWLHQWVLQ$UP&ZLOOUHFHLYHPJVHOLQH[RUWZLFHZHHNO\ZKLOHSDWLHQWVLQ$UP
'ZLOOUHFHLYHPJRQFHZHHNO\3DWLHQWVFRQWLQXLQJLQ$UPV
%ZKRDUHDWDGRVHRI
PJPRUJUHDWHUZLOOEHFRQYHUWHGWRPJWZLFHZHHNO\IODWGRVLQJKRZHYHULIWKHSDWLHQW
LVFXUUHQWO\DWDORZHUGRVHWKH,QYHVWLJDWRUVKRXOGFRQWDFWWKHPHGLFDOPRQLWRUWRGHWHUPLQHWKH
VWDUWLQJGRVHIRUIODWGRVLQJ
3DWLHQWVZLOOEHWUHDWHGXQWLOSURJUHVVLRQRIGLVHDVHRUXQDFFHSWDEOHWR[LFLWLHVRFFXU6DIHW\GDWD
REWDLQHGLQ3KDVHVWXGLHVWRGDWHKDYHVKRZQWKDWSDWLHQWVEHLQJRQVWXG\IRUDWLPHSHULRGRI
VHYHUDO PRQWKV GR QRW KDYH DQ LQFUHDVHG ULVN IRU GHYHORSLQJ DGYHUVH HIIHFWV 1R FXPXODWLYH
WR[LFLWLHVKDYHEHHQREVHUYHGVRIDUDQGDGYHUVHHIIHFWVKDYHJHQHUDOO\EHHQPDQDJHDEOHZLWK
VXSSRUWLYHPHDVXUHV7KXVZHFRQVLGHUWKDWVDIHW\RIWKHSDWLHQWVZLOOQRWEHDIIHFWHGHYHQZKHQ
VWXG\PHGLFDWLRQZLOOEHDGPLQLVWHUHGIRUDORQJHUWLPHSHULRG
,WLVEHOLHYHGWKDWVHOLQH[RUPD\EHRIEHQHILWLQSDWLHQWVZKRUHTXLUHF\WRUHGXFWLYHVXUJHU\IRU
UHFXUUHQWGLVHDVHDVSDUWRIWKHLUURXWLQHFDUH:KLOHGHWHUPLQDWLRQRI3)6LQSDWLHQWVZLWKQR
LPDJLQJHYLGHQFHRIWXPRUSRVWVXUJHU\LVSUREOHPDWLFVHOLQH[RUPD\EHQHILWWKHVHSDWLHQWVE\
WUHDWLQJWKHVPDOODPRXQWRIUHVLGXDOFDQFHUQRWGHWHFWDEOHE\LPDJLQJ






CCI
C
CI
CCI

Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 28 of 137 
Version 6.0 
 
 
  

6HOLQH[RU.37
.DU\RSKDUP7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO.&3
1RYHPEHU

&RQILGHQWLDO
3DJHRI
9HUVLRQ
 2%-(&7,9(62)7+(678'<

3ULPDU\2EMHFWLYHV
7KHDLPRIWKHVWXG\LVWRGHWHUPLQHWKHHIILFDF\RIVHOLQH[RULQDGXOWVZLWKUHFXUUHQW*%0DV
GHWHUPLQHGE\WKHPRQWKVSURJUHVVLRQIUHHVXUYLYDOP3)6UDWH$UPV%&DQG'

6HFRQGDU\2EMHFWLYHV
6HFRQGDU\REMHFWLYHVRIWKHVWXG\$UPV%&DQG'DUH
x 7RGHWHUPLQHWKHHIILFDF\RIVHOLQH[RULQDGXOWVZLWKUHFXUUHQW*%0DVGHWHUPLQHGE\
UHVSRQVHUDWHDFFRUGLQJWRWKH5HVSRQVH$VVHVVPHQWLQ1HXUR2QFRORJ\5$12FULWHULD
VHH7DEOH
x 7RGHWHUPLQHWKHHIILFDF\RIVHOLQH[RULQDGXOWVZLWKUHFXUUHQW*%0DVGHWHUPLQHGE\
PHGLDQRYHUDOOVXUYLYDO26
x 7RGHWHUPLQHWKHHIILFDF\RIVHOLQH[RULQDGXOWVZLWKUHFXUUHQW*%0DVGHWHUPLQHGE\
PHGLDQSURJUHVVLRQIUHHVXUYLYDO3)6
x 7RHYDOXDWHVDIHW\DQGWROHUDELOLW\RIVHOLQH[RU

([SORUDWRU\2EMHFWLYHV
CCI

6HOLQH[RU.37
.DU\RSKDUP7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO.&3
1RYHPEHU

&RQILGHQWLDO
3DJHRI
9HUVLRQ
 ,19(67,*$7,21$/3/$1

2YHUYLHZRI6WXG\'HVLJQDQG'RVLQJ5HJLPHQ
7KLVLVDQRSHQODEHOPXOWLFHQWHU3KDVHVWXG\WRHYDOXDWHWKHHIILFDF\DQGVDIHW\RIRUDOVHOLQH[RU
LQSDWLHQWVZLWKUHFXUUHQWJOLRPDV
,QLWLDOO\ WKH VWXG\ LQFOXGHG  DUPV

PHGLFDODUP$UP%IRUSDWLHQWV
ZKRDUHQRWHOLJLEOHIRUVXUJHU\7KHVWDUWLQJGRVHIRU$UPV
%ZDVPJPWZLFHZHHNO\
ZLWKRQHF\FOHGHILQHGDVGD\VRUGRVHV
(QUROOPHQWLQ$UP%ZDVVWRSSHGWRH[SORUHDOWHUQDWLYHGRVLQJLQ3URWRFRO9HUVLRQVWR
SRWHQWLDOO\LPSURYHWROHUDELOLW\7ZRDUPV$UPV&DQG'ZHUHDGGHGWRWKH0HGLFDO$UPLQ
3URWRFRO9HUVLRQ3DWLHQWVLQWKHSULPDU\SRSXODWLRQHQUROOHGXQGHU3URWRFRO9HUVLRQRU
DERYHZLOOEHUDQGRPL]HGWR$UP&DQG$UP'DSSUR[LPDWHO\SDWLHQWVSHUDUPWRH[SORUH
DOWHUQDWLYHGRVLQJWRSRWHQWLDOO\LPSURYHWROHUDELOLW\6HH6HFWLRQIRUUDWLRQDOH$VFKHPDWLFRI
WKHVWXG\GHVLJQLVSURYLGHGLQ)LJXUH
$IWHU VFUHHQLQJ DQG UHJLVWUDWLRQUDQGRPL]DWLRQ LQ WKH VWXG\ SDWLHQWV HQUROOLQJ

UDQGRPL]HG WR $UP & ZLOO UHFHLYH  PJ VHOLQH[RU RUDOO\ WZLFH ZHHNO\ HJ 0RQGD\ DQG
:HGQHVGD\ 7XHVGD\ DQG 7KXUVGD\ :HGQHVGD\ DQG )ULGD\ 7KXUVGD\ DQG 6DWXUGD\ GXULQJ
:HHNV  RI HDFK ZHHN F\FOH 3DWLHQWV ZKR DUH FXUUHQWO\ EHLQJ WUHDWHG WZLFH ZHHNO\ IRU
:HHNVXQGHUDSUHYLRXVYHUVLRQRIWKHSURWRFROPD\DWWKHGLVFUHWLRQRIWKHLQYHVWLJDWRUKDYH
WKHIUHTXHQF\RIVHOLQH[RUGRVLQJLQFUHDVHGWRWZLFHZHHNO\IRU:HHNV3DWLHQWVUDQGRPL]HG
WR$UP'ZLOOUHFHLYHPJVHOLQH[RURUDOO\ZHHNO\2QHF\FOHLVGD\VZHHNVDQGVKRXOG
LQFOXGHHLWKHUZHHNO\RUWZLFHZHHNO\GRVHV3DWLHQWVFRQWLQXLQJLQ$UPV
%ZKRDUH
DWDGRVHRIPJPRUJUHDWHUZLOOEHFRQYHUWHGWRPJWZLFHZHHNO\IODWGRVLQJKRZHYHULI
WKHSDWLHQWLVFXUUHQWO\DWDORZHUGRVHWKH,QYHVWLJDWRUVKRXOGFRQWDFWWKHPHGLFDOPRQLWRUWR
GHWHUPLQHWKHVWDUWLQJGRVHIRUIODWGRVLQJ7KHGRVHPD\EHUHGXFHGGXHWR$(VUHODWHGWRVWXG\
GUXJWRDPLQLPXPGRVHRIPJRQFHZHHNO\VHH7DEOH




3DWLHQWVZLOOEHWUHDWHGXQWLOSURJUHVVLRQRIGLVHDVHRUWKHGHYHORSPHQWRIXQDFFHSWDEOHWR[LFLWLHV
$OOSDWLHQWVZLOOWKHQXQGHUJRWKH(QGRI7UHDWPHQW(27YLVLW
(QUROOPHQWLQ$UPV&DQG'LVEDVHGRQ6LPRQ¶VWZRVWDJHGHVLJQ)RUPDOVWDWLVWLFDODQDO\VHV
IRUHIILFDF\ZLOOSHUWDLQRQO\WRWKHPHGLFDODUPVLQWKHSULPDU\SRSXODWLRQ$UPV%&DQG'



CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

6HOLQH[RU.37
.DU\RSKDUP7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO.&3
1RYHPEHU
&RQILGHQWLDO
3DJHRI
9HUVLRQ
CCI

6HOLQH[RU.37
.DU\RSKDUP7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO.&3
1RYHPEHU
&RQILGHQWLDO
3DJHRI
9HUVLRQ
)LJXUH2YHUYLHZRIVWXG\GHVLJQ
3ULPDU\
3DWLHQW
3RSXODWLRQ
*%0
3DWLHQWVZKR
DUHQRWHOLJLEOH
IRUVXUJHU\
&RQWLQXLQJLQ
$UP%
5DQGRPL]DWLRQ
WR$UP&RU'
$UP '
$UP&
7UHDWPHQWZLWK
PJVHOLQH[RUWZLFH
ZHHNO\XQWLO3'
7UHDWPHQWZLWKPJ
VHOLQH[RURQFHZHHNO\
XQWLO3'
$EEUHYLDWLRQV$* DQDSODVWLFJOLRPD*%0 JOLREODVWRPD3' SURJUHVVLYHGLVHDVH
,IWKHGRVHIRUDSDWLHQWFRQWLQXLQJLQ$UP
%LVPJPWKH,QYHVWLJDWRUVKRXOGFRQWDFWWKHPHGLFDOPRQLWRUWRGHWHUPLQHWKHVWDUWLQJGRVHIRUIODWGRVLQJ
5HIHUWR7DEOHIRUGRVHPRGLILFDWLRQV
CCI
CCI

6HOLQH[RU.37
.DU\RSKDUP7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO.&3
1RYHPEHU

&RQILGHQWLDO
3DJHRI
9HUVLRQ
 'HILQLWLRQVRI7UHDWPHQW&\FOHV
7ZLFHZHHNO\'RVH6FKHGXOHV
x 6HOLQH[RUZLOOEHWDNHQRUDOO\WZLFHZHHNO\GXULQJ:HHNVRIHDFKZHHNF\FOH
x ,QFOXGHVSDWLHQWVLQ$UPV
&ZKRHQUROOHGXQGHU3URWRFRO9HUVLRQRUDERYHDQG
$UPV
%FRQWLQXLQJSDWLHQWVZKRVWDUWHGRQPJPGRVLQJ
x





2QFHZHHNO\'RVH6FKHGXOHV
x $UP'6HOLQH[RUZLOOEHWDNHQRUDOO\RQFHZHHNO\GXULQJ:HHNVRIHDFKZHHNF\FOH
$OO'RVH6FKHGXOHV
x $OOF\FOHVDUHGD\VZHHNVORQJ
x 6WXG\GUXJDGPLQLVWUDWLRQPD\EHGHOD\HGIRUWR[LFLW\DFFRUGLQJWRSURWRFRO6HFWLRQ
 7UHDWPHQW'XUDWLRQ
3DWLHQWVPD\FRQWLQXHWRUHFHLYHWUHDWPHQWZLWKVHOLQH[RUXQWLOHLWKHUSURJUHVVLRQRIGLVHDVHLV
GHWHUPLQHG DFFRUGLQJ WR WKH 5$12 FULWHULD XQDFFHSWDEOH WR[LFLWLHV RFFXU ZKLFK SUHFOXGHV
IXUWKHUWUHDWPHQWZLWKVHOLQH[RUSDWLHQW¶VFRQVHQWLVZLWKGUDZQRULIWKH,QYHVWLJDWRUIHHOVLWLVLQ
WKHSDWLHQW¶VEHVWLQWHUHVW7KHWUHDWPHQWSHULRGIRUDQLQGLYLGXDOSDWLHQWLVH[SHFWHGWREHXSWR
PRQWKVEXWWKHUHLVQRPD[LPXPGXUDWLRQIRUWUHDWPHQW&OLQLFDOO\VWDEOHSDWLHQWVZLWK&705,
VFDQVKRZLQJERUGHUOLQHSURJUHVVLRQDUHDOORZHGWRFRQWLQXHRQVWXG\DWWKHGLVFUHWLRQRIWKH
,QYHVWLJDWRUSURYLGHGWKDWUHHYDOXDWLRQLVSHUIRUPHGZLWKLQZHHNV,ISURJUHVVLRQLVFRQILUPHG
WKHGDWHRIWKHILUVW&705,VFDQVKRXOGEHFRQVLGHUHGWLPHRISURJUHVVLRQ'HWDLOVRIWKHVWXG\
VFKHGXOHDUHLOOXVWUDWHGLQWKHVWXG\IORZFKDUW7DEOH
 (QGRI7UHDWPHQW9LVLW
3DWLHQWV ZKR GLVFRQWLQXH WUHDWPHQW ZLOO EH HQFRXUDJHG WR XQGHUJR DQ (27 YLVLW XQOHVV WKH\
ZLWKGUDZFRQVHQWWRSDUWLFLSDWHLQWKHWULDO
 )ROORZ8S3KDVH
%HIRUH SURJUHVVLRQ RI GLVHDVH SDWLHQWV ZKR GLVFRQWLQXH IRU UHDVRQV RWKHU WKDQ SURJUHVVLRQ RI
GLVHDVHDQGZLWKGUDZDORIFRQVHQWIRUSDUWLFLSDWLRQLQWKHWULDOVKRXOGEHHQFRXUDJHGWRYLVLWWKH
FOLQLFIRUFOLQLFDOHYDOXDWLRQRIWKHLUGLVHDVHHYHU\ZHHNVGD\VDQGDVVHVVPHQWE\&705,
VFDQHYHU\ZHHNVGD\VXQWLOSURJUHVVLRQRIGLVHDVHLVGHWHUPLQHG
$IWHUGLVHDVHSURJUHVVLRQDOOSDWLHQWVZLOOEHHYDOXDWHGIRUVXUYLYDODQGIXUWKHUWKHUDS\HYHU\
PRQWKVGD\V3DWLHQWVZKRKDYHQRWH[SLUHGRUSURJUHVVHGE\WKHGDWDDQDO\VLVFXWRIIGDWH
IRUWKHP3)6UDWHZLOOEHFHQVRUHGDWWKHGDWHRIWKHLUODVWGLVHDVHDVVHVVPHQW3DWLHQWVZKRKDYH
CCI
CCI
CCI

6HOLQH[RU.37
.DU\RSKDUP7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO.&3
1RYHPEHU

&RQILGHQWLDO
3DJHRI
9HUVLRQ
QRWH[SLUHGE\WKHGDWDDQDO\VLVFXWRIIGDWHIRU26ZLOOEHFHQVRUHGDWWKHLUODVWGDWHNQRZQWREH
DOLYH

5HJLVWUDWLRQ5DQGRPL]DWLRQRI3DWLHQWV
3DWLHQWV ZKR PHHW WKH HQUROOPHQW FULWHULD ZLOO EH UHJLVWHUHG LQ WKH VWXG\ LQ WKH

 0HGLFDO $UP $UPV & DQG ' GHSHQGHQW RQ WKH UHTXLUHPHQW IRU VXUJHU\
(QUROOPHQWLVDQWLFLSDWHGWRWDNHDSSUR[LPDWHO\PRQWKV(QUROOPHQWLQ$UP%ZDVVWRSSHGWR
H[SORUHDOWHUQDWLYHGRVLQJLQ3URWRFRO9HUVLRQV
)RUWKH0HGLFDO$UPSDWLHQWVLQWKHSULPDU\SRSXODWLRQZKRHQUROOHGXQGHU3URWRFRO9HUVLRQ
RUDERYHZLOOEHUDQGRPL]HGYLDWKH('&V\VWHPLQDUDWLRWR$UPV&DQG'
3DWLHQWHOLJLELOLW\ZLOOEHUHYLHZHGE\WKH0HGLFDO0RQLWRUIRUHDFKSDWLHQWSDUWLFLSDWLQJLQWKH
VWXG\DIWHUWKHSDWLHQWFRPSOHWHVDOOVFUHHQLQJSURFHGXUHVDQGEHIRUHWKHSDWLHQWUHFHLYHVVWXG\
WUHDWPHQW7KHUHZLOOEHQRH[FHSWLRQV$Q\TXHVWLRQVVKRXOGEHDGGUHVVHGWRWKH6SRQVRUSULRUWR
UHJLVWUDWLRQUDQGRPL]DWLRQ7KHHOLJLELOLW\FKHFNIRUP3DWLHQW5HJLVWUDWLRQ)RUPZLOOEHVHQWIURP
WKHVLWHWR.DU\RSKDUP7KHUDSHXWLFVE\HPDLOIRUHYDOXDWLRQ8SRQFRQILUPDWLRQRIHOLJLELOLW\
.DU\RSKDUP 7KHUDSHXWLFV ZLOO DVVLJQDSDWLHQWQXPEHUDQGUHWXUQWKHVLJQHG HOLJLELOLW\ FKHFN
IRUP3DWLHQW5HJLVWUDWLRQ)RUPYLDHPDLOWRWKHVLWH7KH3DWLHQW5HJLVWUDWLRQ)RUPZLOOFRQILUP
WKHWUHDWPHQWDUPLQZKLFKWKHSDWLHQWZLOOSDUWLFLSDWH
7KH ILUVW SODQQHG GRVH RI VWXG\ GUXJ ZLOO EH DGPLQLVWHUHG

QRPRUHWKDQGD\VIROORZLQJUDQGRPL]DWLRQ$UPV&DQG'

,QYHVWLJDWLRQDO6LWHV
$SSUR[LPDWHO\VLWHVZLOOSDUWLFLSDWHLQWKHVWXG\5HFUXLWPHQWZLOOEHFRPSHWLWLYHDWHDFKVLWH
XQWLOWKHSODQQHGWRWDOQXPEHURIDSSUR[LPDWHO\SDWLHQWVLVUHDFKHG$OLVWRIDOOSDUWLFLSDWLQJ
LQYHVWLJDWLRQDO VLWHV LQFOXGLQJ LQIRUPDWLRQ UHJDUGLQJ QDPHV RI WKH 3ULQFLSDO ,QYHVWLJDWRUV DQG
FRQWDFWGHWDLOVDGGUHVVSKRQHID[HPDLOZLOOEHKDQGOHGVHSDUDWHO\
CCI
CCI

6HOLQH[RU.37
.DU\RSKDUP7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO.&3
1RYHPEHU

&RQILGHQWLDO
3DJHRI
9HUVLRQ
 6(/(&7,212)7+(678'<3238/$7,21

7DUJHW3DWLHQW3RSXODWLRQV
3ULPDU\3DWLHQW3RSXODWLRQ
3DWLHQWVZLWKSDWKRORJLFDOO\FRQILUPHG*%0LQFOXGLQJDOOKLVWRORJLFYDULDQWVZLWKUDGLRJUDSKLF
HYLGHQFHRIUHFXUUHQWGLVHDVHDIWHUIDLOXUHRIUDGLDWLRQWKHUDS\DQGWHPR]RORPLGHZLOOEHHOLJLEOH
IRUHQUROOPHQWLQ$UPV
&DQG'RIWKHVWXG\(QUROOPHQWLQ$UP%ZDVVWRSSHGWRH[SORUH
DOWHUQDWLYHGRVLQJLQ3URWRFRO9HUVLRQV






,QFOXVLRQ&ULWHULD
7REHHOLJLEOHIRUWKLVWULDOSDWLHQWVPXVWIXOILOOWKHIROORZLQJFULWHULD
 3DWKRORJLFDOO\FRQILUPHGGLDJQRVLVRI*%0LQFOXGLQJDOOKLVWRORJLFYDULDQWVDWILUVW
GLDJQRVLVZLWKUDGLRJUDSKLFHYLGHQFHRIUHFXUUHQWGLVHDVHDIWHUWUHDWPHQWZLWK
UDGLRWKHUDS\DQGWHPR]RORPLGH
 $JH\HDUV
 .DUQRIVN\3HUIRUPDQFH6WDWXV.36
 3DWLHQWVHQUROOLQJLQWKH0HGLFDO$UP$UPV%&RU'PXVWEHRQDVWDEOHRUGHFUHDVLQJ
GRVHRIFRUWLFRVWHURLGVRUQRQHIRUDWOHDVWGD\VSULRUWRWKHEDVHOLQH&705,
 3DWLHQWVPXVWKDYHUHFHLYHGSULRUWUHDWPHQWZLWKUDGLDWLRQWKHUDS\DQGWHPR]RORPLGHDOO
$UPV
 0HDVXUDEOHGLVHDVHDFFRUGLQJWR5$12JXLGHOLQHVZLWKLQGD\VRIVWDUWLQJ
WUHDWPHQW0HDVXUDEOHGLVHDVH
LVQRWUHTXLUHG
 :ULWWHQLQIRUPHGFRQVHQWREWDLQHGSULRUWRDQ\VFUHHQLQJSURFHGXUHV3DWLHQWVPXVWEH
ZLOOLQJDQGDEOHWRFRPSO\ZLWKWKHSURWRFRODQGDZDUHRIWKHLQYHVWLJDWLRQDOQDWXUHRI
WKLVVWXG\
 3DWLHQWVPXVWKDYHDGHTXDWHERQHPDUURZIXQFWLRQDQGRUJDQIXQFWLRQZLWKLQZHHNVRI
VWXG\WUHDWPHQWDVGHILQHGE\WKHIROORZLQJODERUDWRU\FULWHULD
R +HPDWRSRLHWLFIXQFWLRQWRWDOZKLWHEORRGFHOO:%&FRXQWPPñ
DEVROXWHQHXWURSKLOFRXQW$1&PPñSODWHOHWFRXQWPPñ
KHPRJORELQJG/
R +HSDWLFIXQFWLRQELOLUXELQWLPHVWKHXSSHUOLPLWRIQRUPDO8/1
$/7WLPHV8/1$67WLPHV8/1XQOHVVELOLUXELQHOHYDWLRQLV
UHODWHGWR*LOEHUW¶V6\QGURPHIRUZKLFKELOLUXELQPXVWEHWLPHV8/1
R 5HQDOIXQFWLRQHVWLPDWHGFUHDWLQLQHFOHDUDQFHRIP/PLQFDOFXODWHGXVLQJ
WKHIRUPXODRI&RFNURIWDQG*DXOW6HFWLRQ$SSHQGL[RURWKHUVWDQGDUG
PHWKRGVDWWKHWUHDWLQJLQVWLWXWLRQ
 $OOIHPDOHSDWLHQWVRIFKLOGEHDULQJSRWHQWLDOPXVWDJUHHWRXVHUHOLDEOHPHWKRGVRIELUWK
FRQWUROGXULQJVWXG\WUHDWPHQWDQGIRUPRQWKVDIWHUWKHODVWGRVHRIVWXG\GUXJDQGKDYH
CCI
CCI
CCI

6HOLQH[RU.37
.DU\RSKDUP7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO.&3
1RYHPEHU

&RQILGHQWLDO
3DJHRI
9HUVLRQ
DQHJDWLYHVHUXPSUHJQDQF\WHVWDWVFUHHQLQJ5HOLDEOHPHWKRGVRIFRQWUDFHSWLRQLQFOXGH
LQWUDXWHULQHGHYLFHVKRUPRQDOFRQWUDFHSWLYHV>FRQWUDFHSWLYHSLOOVLPSODQWVWUDQVGHUPDO
SDWFKHVKRUPRQDOYDJLQDOGHYLFHVRULQMHFWLRQVZLWKSURORQJHGUHOHDVH@DEVWLQHQFHRU
VWHULOL]DWLRQRIWKHSDUWQHU
)HUWLOHPDOHVPXVWEHZLOOLQJWRHPSOR\UHOLDEOHPHWKRGVRIFRQWUDFHSWLRQGXULQJVWXG\
WUHDWPHQWDQGIRUPRQWKVDIWHUWKHODVWGRVHRIVWXG\GUXJ
$UFKLYHGSDUDIILQHPEHGGHGWLVVXHDSSUR[LPDWHO\XQVWDLQHGVOLGHVLIOHVVFRQWDFW
6SRQVRURUDWXPRUEORFNPXVWEHDYDLODEOHIRUFRUUHODWLYHVWXGLHV



3DWLHQWVHQUROOLQJLQWKH0HGLFDO$UP$UPV%&RU'PXVWEHRQDVWDEOHRU
GHFUHDVLQJGRVHRIFRUWLFRVWHURLGVRUQRQHIRUDWOHDVWGD\VSULRUWRWKHEDVHOLQH
&705,

([FOXVLRQ&ULWHULD
3DWLHQWVZLWKDQ\RIWKHIROORZLQJZLOOQRWEHHOLJLEOHIRUWKHVWXG\
 3DWLHQWVPXVWQRWKDYHVLJQLILFDQWPHGLFDOLOOQHVVWKDWLQWKH,QYHVWLJDWRU¶VRSLQLRQFDQQRW
EHDGHTXDWHO\FRQWUROOHGZLWKDSSURSULDWHWKHUDS\RUZRXOGFRPSURPLVHWKHSDWLHQW¶V
DELOLW\WRWROHUDWHWKLVWKHUDS\
 GD\VIURPSULRUWHPR]RORPLGHZHHNVIURPQLWURVRXUHDZHHNVIURPRWKHU
FKHPRWKHUDS\RULQYHVWLJDWLRQDODJHQWVSULRUWRVWDUWRIWUHDWPHQWZLWKLQVWXG\
 8QVWDEOHFDUGLRYDVFXODUIXQFWLRQ
 .QRZQDFWLYHKHSDWLWLV$%RU&LQIHFWLRQRUNQRZQWREHSRVLWLYHIRU+&951$RU
+%V$J+%9VXUIDFHDQWLJHQKHSDWLWLVWHVWLQJLVQRWUHTXLUHG
 .QRZQ+,9LQIHFWLRQ+,9WHVWLQJLVQRWUHTXLUHG
 0DUNHGO\GHFUHDVHGYLVXDODFXLW\LIDWWULEXWHGWRRWKHUFDXVHVWKDQ*%0
 $FWLYHLQIHFWLRQUHTXLULQJSDUHQWHUDOV\VWHPLFDQWLELRWLFV
 3DWLHQWVZLWKFRDJXODWLRQSUREOHPVDQGPHGLFDOO\VLJQLILFDQWEOHHGLQJLQWKHPRQWKSULRU
WRVWDUWRIWUHDWPHQWHJSHSWLFXOFHUHSLVWD[LVVSRQWDQHRXVEOHHGLQJ3ULRUKLVWRU\RI
'97RU3(LVQRWH[FOXVLRQDU\
 3DWLHQWVZKRDUHSUHJQDQWRUEUHDVWIHHGLQJ
2WKHUFDQFHUH[FHSWQRQPHODQRPDVNLQFDQFHURUFDUFLQRPDLQVLWXRIWKHFHUYL[
XQOHVVLQFRPSOHWHUHPLVVLRQDQGRIIDOOWKHUDS\IRUWKDWGLVHDVHIRUDPLQLPXPRI
\HDUV
3DWLHQWVPXVWQRWKDYHVLJQLILFDQWO\GLVHDVHGRUREVWUXFWHGJDVWURLQWHVWLQDOWUDFW
PDODEVRUSWLRQXQFRQWUROOHGYRPLWLQJRUGLDUUKHDRULQDELOLW\WRVZDOORZRUDO
PHGLFDWLRQV
'HK\GUDWLRQRI1DWLRQDO&DQFHU,QVWLWXWH1&,&RPPRQ7HUPLQRORJ\&ULWHULDIRU
$GYHUVH(YHQWV&7&$(JUDGH
3DWLHQWVPXVWQRWKDYHVHULRXVSV\FKLDWULFRUPHGLFDOFRQGLWLRQVWKDWFRXOGLQWHUIHUHZLWK
WUHDWPHQW
+LVWRU\RIRUJDQDOORJUDIW
&RQFXUUHQWWKHUDS\ZLWKDSSURYHGRULQYHVWLJDWLRQDODQWLFDQFHUWKHUDSHXWLFV
CCI

Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 37 of 137 
Version 6.0 
16.  Prior treatment with bevacizumab or other direct VEGF/ VEGFR inhibitors. For any 
question of the definition of a direct VEGF/VEGFR inhibitor, consult Sponsor.  
17. Arms C and D only: BSA <1.2 m2, to avoid a dose exceeding the maximum allowable 
dose of 70 mg/m2. 
18. Major surgery < 4 weeks prior to the start of study treatment 

6HOLQH[RU.37
.DU\RSKDUP7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO.&3
1RYHPEHU

&RQILGHQWLDO
3DJHRI
9HUVLRQ
 6&+('8/(2)$66(660(17$1'352&('85(6
3OHDVHUHIHUWRWKH6FKHGXOHRI$VVHVVPHQWVDWWKHHQGRIWKHV\QRSVLVIRUDQRYHUYLHZ7DEOH
'DWDZLOOEHFROOHFWHGYLDWKHFRPSOHWLRQRIDQHOHFWURQLF&DVH5HSRUW)RUPH&5)IRUHDFK
HQUROOHGSDWLHQW7KH,QYHVWLJDWRUVKRXOGFRQILUPHOLJLELOLW\RIWKHSDWLHQWDFFRUGLQJWRWKHLQFOXVLRQ
DQGH[FOXVLRQFULWHULDRIWKHVWXG\:ULWWHQ,QIRUPHG&RQVHQWPXVWEHREWDLQHGEHIRUHDQ\VWXG\
VSHFLILFDVVHVVPHQWLVSHUIRUPHG$VWXG\VSHFLILFDVVHVVPHQWLVGHILQHGDVDSURFHGXUHWKDWLVQRW
SDUWRIWKHURXWLQH DVVHVVPHQWV SHUIRUPHGIRUGLDJQRVWLFSXUSRVHVRUVWDQGDUGFDUH6FUHHQLQJ
DVVHVVPHQWVVKRXOGRFFXUZLWKLQGD\VRIWKHILUVWDGPLQLVWUDWLRQRIVWXG\GUXJ
3DWLHQWVZKRGRQRWPHHWWKHHOLJLELOLW\FULWHULDZLOOQRWEHHQUROOHGLQWKHVWXG\3DWLHQWVVKRXOG
UHFHLYHWKHLUILUVWGRVHRIVWXG\WUHDWPHQWDVVRRQDVSRVVLEOHDIWHUUHJLVWUDWLRQUDQGRPL]DWLRQEXW
QRWODWHUWKDQ
GD\VDIWHUUDQGRPL]DWLRQ$UPV&DQG'

6WXG\$VVHVVPHQWV
 7XPRU$VVHVVPHQW
7KH GLVHDVH VWDWXV ZLOO EH PHDVXUHG E\ FRQWUDVWHQKDQFHG 05, RU &7 IRU SDWLHQWV XQDEOH RU
XQZLOOLQJWRXQGHUJR05,VFDQVLQFOXGLQJSUHFRQWUDVW77)/$,5DQGSRVWFRQWUDVW7DQG
7ZHLJKWHG)/$,5DQGDVVHVVHGXVLQJWKH5$12FULWHULD7DEOH








5DGLRJUDSKLFUHVSRQVHZLOOEHGHWHUPLQHGE\FRPSDULVRQWRWKHWXPRUPHDVXUHPHQWREWDLQHGDW
EDVHOLQH$UPV%&DQG'
IRUSDWLHQWV7XPRUSURJUHVVLRQPD\DOVR
EHGHWHUPLQHGE\FRPSDULVRQZLWKEDVHOLQHWXPRUPHDVXUHPHQW







6HH7DEOHIRUWKHGHILQLWLRQRIUHVSRQVH
CCI
CCI
CCI
CCI

6HOLQH[RU.37
.DU\RSKDUP7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO.&3
1RYHPEHU

&RQILGHQWLDO
3DJHRI
9HUVLRQ
7DEOH6XPPDU\RIWKH3URSRVHG5$125HVSRQVH&ULWHULD
&ULWHULRQ
&5
35
6'
3'
7JDGROLQLXPHQKDQFLQJ
GLVHDVH
1RQH
Ļ
ĻEXW
Ĺ
Ĺ
7)/$,5

6WDEOHRUĻ
6WDEOHRUĻ
6WDEOHRUĻ
Ĺ
1HZOHVLRQV

1RQH
1RQH
1RQH
3UHVHQW
&RUWLFRVWHURLGV

1RQH
6WDEOHRUĻ
6WDEOHRUĻ
1$
&OLQLFDOVWDWXV
6WDEOHRUĹ
6WDEOHRUĹ
6WDEOHRUĹ
Ļ
5HTXLUHPHQWIRUUHVSRQVH
$OO
$OO
$OO
$Q\
1RWHV
$EEUHYLDWLRQV&5 FRPSOHWHUHVSRQVH35 SDUWLDOUHVSRQVH6' VWDEOHGLVHDVH3' SURJUHVVLYHGLVHDVH
ĻGHFUHDVH
ĹLQFUHDVH
3URJUHVVLRQRFFXUVZKHQWKLVFULWHULRQLVSUHVHQW
,QFUHDVHLQFRUWLFRVWHURLGVDORQHZLOOQRWEHWDNHQLQWRDFFRXQWLQGHWHUPLQLQJSURJUHVVLRQLQWKHDEVHQFHRISHUVLVWHQWFOLQLFDO
GHWHULRUDWLRQ
7KHEDVHOLQH&705,VFDQPXVWEHUHFRUGHGDQGPHDVXUHGZLWKLQGD\VSULRUWRWUHDWPHQWVWDUW
$&705,VFDQSHUIRUPHGDVSDUWRIVWDQGDUGRIFDUHFDQEHXVHGDVWKHEDVHOLQH&705,VFDQ
SURYLGHG VWXG\ WUHDWPHQW ZLOO VWDUW ZLWKLQ WKH GD\ ZLQGRZ







 ([SORUDWRU\$VVHVVPHQWV
CCI
CCI

6HOLQH[RU.37
.DU\RSKDUP7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO.&3
1RYHPEHU

&RQILGHQWLDO
3DJHRI
9HUVLRQ
 6DIHW\DQG7ROHUDELOLW\$VVHVVPHQWV
6DIHW\ZLOOEHPRQLWRUHGE\DVVHVVLQJODERUDWRU\SDUDPHWHUVSK\VLFDOH[DPLQDWLRQVYLWDOVLJQV
DQG ZHLJKW SHUIRUPDQFH VWDWXV QHXURORJLFDO H[DPLQDWLRQV DQG FRQFRPLWDQW PHGLFDWLRQ XVH
,QIRUPDWLRQUHJDUGLQJ$(VZLOOEHFROOHFWHGDQGHDFK$(ZLOOEHJUDGHGDFFRUGLQJWRWKH1&,
&7&$( FXUUHQW HGLWLRQ YHUVLRQ  6HFWLRQ  $SSHQGL[  EHJLQQLQJ DW GD\ RI ILUVW
DGPLQLVWUDWLRQ RI VWXG\ GUXJ WKURXJKRXW WKH WUHDWPHQW SHULRG DQG WR WKH H[WHQW SRVVLEOH XQWLO
GD\VDIWHUODVWGRVHRIVWXG\GUXJ
/DERUDWRU\$VVHVVPHQWV
7KHVWDQGDUGFOLQLFDOODERUDWRU\DQDO\VLVLVWREHSHUIRUPHGE\WKHVWXG\VLWH¶VORFDOODERUDWRULHV
DFFRUGLQJWRWKH6FKHGXOHRI$VVHVVPHQWV0RUHIUHTXHQWH[DPLQDWLRQVPD\EHSHUIRUPHGDWWKH
,QYHVWLJDWRU¶VGLVFUHWLRQLIPHGLFDOO\LQGLFDWHGUHVXOWVVKRXOGEHUHFRUGHGRQWKHH&5)V
$WDQ\WLPHGXULQJWKHVWXG\DEQRUPDOODERUDWRU\SDUDPHWHUVWKDWDUHFOLQLFDOO\UHOHYDQWHJ
LQWHUUXSWLRQ RU GHOD\ RI VWXG\ WUHDWPHQW OHDG WR FOLQLFDO V\PSWRPV RU UHTXLUH WKHUDSHXWLF
CCI

Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 41 of 137 
Version 6.0 
intervention) must be recorded in the eCRF. When abnormal laboratory values or test results 
constitute an AE, they must be recorded on the eCRF Adverse Events page. 
Every effort must be made to follow the schedule outlined in the Schedule of Assessments. Safety 
laboratory assessments on the day of a study visit must be completed prior to study drug 
administration. 
5.2 
Study Procedures 
5.2.1 Screening Procedures  
All patients will be screened and screening procedures must be performed within 14 days prior to 
the start of study treatment unless otherwise indicated in the table below. These include the 
following:  
Procedure 
Notes 
Signed written informed consent 
Obtained prior to any study specific assessments are 
performed 
Confirmation of eligibility (Days -7 
to -1) 
Please refer to Section 4. 
Demographics and medical history 
• Age, gender, ethnic background 
• Details on tumor diagnosis 
• Details on prior cancer therapy, including start and 
stop dates, disease progression during or after 
therapy, as well as discontinuation due to toxicities 
• Previous and concurrent relevant diseases 
• Current symptoms and/or residual toxicities from 
prior therapies 
Pregnancy test (if applicable) 
(Days -7 to -1) 
A serum pregnancy test will be performed in pre-
menopausal women and women who are post-
menopausal for < 2 years.  
Physical examination and vital signs 
(Days - 7 to -1) 
• Body height and weight 
• BSA (to ensure no patient exceeds the maximum 
allowable dose of 70 mg/m2) 
• Blood pressure, pulse, temperature 
• Physical examination 
Karnofsky performance status 
(Days - 7 to -1) 
Please refer to Section 16.2; Appendix 2 
Standard clinical neurological 
examination  
A complete neurological exam will be performed 
(baseline exam).  
Ophthalmic exam 
A full ophthalmic exam will be conducted by an 
optometrist or ophthalmologist at screening. Additional 
ophthalmic assessments will be completed during the 

6HOLQH[RU.37
.DU\RSKDUP7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO.&3
1RYHPEHU

&RQILGHQWLDO
3DJHRI
9HUVLRQ
VWXG\LIFOLQLFDOO\LQGLFDWHG


3ULRUWRGLODWLRQEHVWFRUUHFWHGYLVXDO
DFXLW\DQGVOLWODPSH[DPLQDWLRQLQFOXGLQJWRQRPHWU\
IROORZLQJGLODWLRQIXQGRVFRS\DQGVOLWODPSH[DPWR
GRFXPHQWOHQVFODULW\,IDFDWDUDFWLVVHHQGXULQJWKH
H[DPIRUQHZO\HQUROOLQJSDWLHQWVRUHQUROOHGSDWLHQWV
IRUZKRPQRFDWDUDFWVKDYHEHHQGHWHFWHGWRGDWHWKH
FDWDUDFWZLOOEHJUDGHGXVLQJD*UDGHVFDOH
6HFWLRQ$SSHQGL[+RZHYHUSDWLHQWVHQUROOHG
XQGHUDSULRUYHUVLRQRIWKHSURWRFROZKRKDGGHWHFWDEOH
FDWDUDFWVJUDGHGDFFRUGLQJWRWKH/HQV2SDFLWLHV
&ODVVLILFDWLRQ6\VWHP/2&6,,,ZLOOFRQWLQXHWRKDYH
WKHLUFDWDUDFWVJUDGHGDFFRUGLQJWR/2&6,,,DQGZLOOQRW
VZLWFKWRWKH*UDGHVFDOH
2[\JHQVDWXUDWLRQ'D\VWR
3XOVHR[LPHWU\LVSHUIRUPHGIRUSDWLHQWVDWUHVWEUHDWKLQJ
URRPDLU
&DUGLDFHYDOXDWLRQ
OHDGHOHFWURFDUGLRJUDP(&*
8ULQDO\VLV'D\VWR
8ULQHELOLUXELQJOXFRVHKHPRJORELQNHWRQHVS+
SURWHLQ
+HPDWRORJ\&%&
+HPRJORELQKHPDWRFULW5%&FRXQW:%&FRXQW:%&
GLIIHUHQWLDOO\PSKRF\WHVPRQRF\WHVQHXWURSKLOV
HRVLQRSKLOVEDVRSKLOVSODWHOHWV:%&GLIIHUHQWLDOPD\
EHDXWRPDWHGRUPDQXDODVSHULQVWLWXWLRQDOVWDQGDUGV
5HWLFXORF\WHVPD\EHGRQHRQO\ZKHQFOLQLFDOO\
LQGLFDWHG
&RPSOHWHFOLQLFDOFKHPLVWU\
6RGLXPSRWDVVLXPFKORULGHELFDUERQDWH%81
FUHDWLQLQHJOXFRVHFDOFLXPSKRVSKDWHPDJQHVLXP
$/7$67DONDOLQHSKRVSKDWDVHWRWDOELOLUXELQWRWDO
SURWHLQDOEXPLQDP\ODVHOLSDVHFUHDWLQLQHNLQDVH
XUDWH/'+
&RDJXODWLRQ'D\VWR
3URWKURPELQWLPH37LQWHUQDWLRQDOQRUPDOL]DWLRQUDWLR
,15DQGDFWLYDWHGSDUWLDOWKURPERSODVWLQWLPHD377
76+'D\VWR
7K\URLGVWLPXODWLQJKRUPRQH76+
$VVHVVPHQWRIGLVHDVHVWDWXV
7KHGLVHDVHVWDWXVZLOOEHPHDVXUHGE\&705,VFDQ
LQFOXGLQJSUHFRQWUDVW77)/$,5DQGSRVWFRQWUDVW
7DQG7ZHLJKWHG)/$,51RWHWKH&705,VFDQ
GRHVQRWQHHGWREHUHSHDWHGLIUHVXOWVDUHDYDLODEOHIURP
DVFDQSHUIRUPHGGD\VSULRUWRVWDUWRIWKHUDS\
&KHVWUDGLRJUDSK
%RWKSRVWHURDQWHULRUDQGODWHUDOILOPVVKRXOGEHREWDLQHG
IRUEDVHOLQH1RWHWKLVWHVWGRHVQRWQHHGWREHUHSHDWHG
LIUHVXOWVDUHDYDLODEOHIURPDWHVWSHUIRUPHGGD\V
CCI

6HOLQH[RU.37
.DU\RSKDUP7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO.&3
1RYHPEHU

&RQILGHQWLDO
3DJHRI
9HUVLRQ
SULRUWRVWDUWRIWKHUDS\7KLVWHVWVHUYHVDVDEDVHOLQHLQ
WKHHYHQWWKDWSDWLHQWVGHYHORSDQ\$(VGXULQJWKHVWXG\


5DQGRPL]DWLRQ'D\WRSULRUWR
ILUVWGRVHRIVWXG\GUXJRQ'D\
3OHDVHUHIHUWR6HFWLRQ
&RQFRPLWDQWPHGLFDWLRQ
&RQFRPLWDQWPHGLFDWLRQFXUUHQWO\XVHG
6XSSRUWLYHFDUH
,QLWLDWHGSULRUWRILUVWVHOLQH[RUGRVHVHH6HFWLRQ
 7UHDWPHQW3KDVH
'XULQJWKHWUHDWPHQWSKDVHWKHIROORZLQJDVVHVVPHQWVDUHWREHSHUIRUPHGDVOLVWHGLQWKHVFKHGXOH
RIDVVHVVPHQWV&\FOHVDQGZHHNO\'D\>GD\V@&\FOHV'D\VDQG>GD\V@
&\FOHV'D\>GD\V@

3URFHGXUH
1RWHV
3K\VLFDOH[DPLQDWLRQDQGYLWDOVLJQV x %RG\ZHLJKW
x %6$WRHQVXUHQRSDWLHQWH[FHHGVWKHPD[LPXP
DOORZDEOHGRVHRIPJP
x %ORRGSUHVVXUHSXOVHWHPSHUDWXUH
x 3K\VLFDOH[DPLQDWLRQV\PSWRPGLUHFWHG
.DUQRIVN\SHUIRUPDQFHVWDWXV
3OHDVHUHIHUWR6HFWLRQ$SSHQGL[
6WDQGDUGFOLQLFDOQHXURORJLFDO
H[DPLQDWLRQ
$V\PSWRPGLUHFWHGQHXURORJLFDOH[DPZLOOEH
SHUIRUPHG$Q\QHXURORJLFDOGHILFLWVQRWHGGXULQJWKH
EDVHOLQHH[DPPXVWEHIROORZHG$Q\QHZQHXURORJLFDO
FRPSODLQWVUHSRUWHGE\WKHSDWLHQWDQGDQ\GHILFLWV
REVHUYHGE\WKHLQYHVWLJDWRUVKRXOGEHDVVHVVHGDQG
IROORZHG
&DUGLDFHYDOXDWLRQ
OHDG(&*DVFOLQLFDOO\LQGLFDWHGGXULQJWKH
WUHDWPHQWSKDVH
+HPDWRORJ\
+HPRJORELQKHPDWRFULW5%&FRXQW:%&FRXQW:%&
GLIIHUHQWLDOO\PSKRF\WHVPRQRF\WHVQHXWURSKLOV
HRVLQRSKLOVEDVRSKLOVSODWHOHWV:%&GLIIHUHQWLDOPD\
EHDXWRPDWHGRUPDQXDODVSHULQVWLWXWLRQDOVWDQGDUGV
5HWLFXORF\WHVPD\EHGRQHRQO\ZKHQFOLQLFDOO\
LQGLFDWHG/DEVFDQEHGRQHGD\VSULRUWRYLVLW
CCI
CCI
CCI

6HOLQH[RU.37
.DU\RSKDUP7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO.&3
1RYHPEHU

&RQILGHQWLDO
3DJHRI
9HUVLRQ
6HOLQH[RUGRVLQJ
3OHDVHUHIHUWR6HFWLRQ


$(VDQGFRQFRPLWDQWPHGLFDWLRQ
$VVHVVHGRQDQRQJRLQJEDVLV
6XSSRUWLYHFDUH
6XSSRUWLYHPHDVXUHVIRURSWLPDOPHGLFDOFDUHZLOOEH
SURYLGHGGXULQJWKH7UHDWPHQW3KDVHVHH6HFWLRQ
 (QGRI7UHDWPHQW
3DWLHQWV ZKR GLVFRQWLQXH WKHUDS\ IRU DQ\ UHDVRQ RWKHU WKDQ ZLWKGUDZDO RI FRQVHQW ZLOO EH
HQFRXUDJHGWRKDYHDQ(27YLVLW7KH(27YLVLWVKRXOGWDNHSODFHGD\VGD\VDIWHUWKHLU
ODVWGRVHLISRVVLEOH$WWKH(27YLVLWWKHSDWLHQWVZLOOXQGHUJRWKHIROORZLQJVDIHW\DVVHVVPHQWV
CCI
CCI
CCI
CCI

Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 45 of 137 
Version 6.0 
Procedure 
Notes 
Pregnancy test (if applicable) 
A serum pregnancy test will be performed in pre-
menopausal women and women who are post-
menopausal for < 2 years to exclude that a pregnancy 
occurred under treatment 
Physical examination and vital signs • Body weight 
• Blood pressure, pulse, temperature 
• Physical examination 
Karnofsky performance status  
Please refer to Section 16.2; Appendix 2 
Standard clinical neurological 
examination  
A complete neurological exam will be performed 
Cardiac evaluation  
12-lead ECG 
Hematology  
Hemoglobin, hematocrit, RBC count, WBC count, WBC 
differential, lymphocytes, monocytes, neutrophils, 
eosinophils, basophils, platelets. WBC differential may 
be automated or manual as per institutional standards. 
Reticulocytes may be done only when clinically 
indicated.  
Complete clinical chemistry  
Sodium, potassium, chloride, bicarbonate, BUN, 
creatinine, glucose, calcium, phosphate, magnesium, 
ALT, AST, alkaline phosphatase, total bilirubin, total 
protein, albumin, amylase, lipase, creatinine kinase, 
urate, LDH.  
TSH 
TSH.  
AEs and concomitant medication 
Assessed on an ongoing basis until 30 days after the last 
dose of study medication (EOT visit). 
5.2.4 Follow-up Before Progression of Disease 
Patients who discontinue for reasons other than progression of disease (and withdrawal of consent 
for participation in the trial) should be encouraged to visit the clinic for clinical evaluation of their 
disease every 4 weeks (±7 days) and assessment by CT/MRI every 8 weeks (±7 days) until 
progression of disease is determined.  
Patients lost to follow up should be recorded as such on the eCRF. For patients who are lost to 
follow-up, the Investigator should show "due diligence" by documenting in the source documents 
steps taken to contact the patient, e.g., dates of telephone calls, registered letters, etc. 
5.2.5 Survival Follow-up 
After disease progression all patients will be evaluated for survival and further anticancer therapy 
every 3 months (±14 days). Patients who have not expired or progressed by the data analysis cutoff 
date for the 6mPFS rate will be censored at the date of their last disease assessment. Patients who 

Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 46 of 137 
Version 6.0 
have not expired by the data analysis cutoff date for OS will be censored at their last date known 
to be alive. 
5.2.6 End of Study 
End of study will be when the last patient in the study has died, has been off study treatment for 
12 months, has been lost to follow-up, or has withdrawn consent, whichever occurs first 
5.3 
Planned Treatment of the Patients after End of Treatment Phase 
After completion of the EOT visit, patients will generally be treated at the discretion of the 
Investigator according to standard medical routine. 
5.4 
Removal of Patients from Treatment 
Patients will be free to discontinue treatment or withdraw from the study at any time, for any reason, 
or they may be withdrawn/removed if necessary in order to protect their health (see reasons for 
withdrawal below). It is understood by all concerned that an excessive rate of withdrawals can 
render the study uninterpretable; therefore, unnecessary withdrawal of patients should be avoided. 
Patients will be removed from further treatment for the following reasons: 
• Disease progression 
• Adverse Event (unacceptable toxicity) 
• Non-compliance 
• Patient no longer consents to participate in the study 
• Intercurrent illness that interferes with study assessments 
• Incidence or severity of AEs in this study indicates a potential health hazard to the patient 
• Investigator discretion for any reason 
• Pregnancy 
• Termination of the study by the Sponsor 
If a patient has fails to attend scheduled assessments or withdraws consent to participate in the 
study, every effort will be made to determine the reasons and circumstances as completely and 
accurately as possible. 
When a patient discontinues study treatment, the EOT visit should be performed, if possible. The 
eCRF section entitled “End of Treatment” must be completed in all cases. If the reason for removal 
of a patient from the study is an AE or an abnormal laboratory test result, the principal specific 
event or test will be recorded on the eCRF. 
5.5 
Study Discontinuation 
The whole study may be discontinued at the discretion of the Sponsor in the event of any of the 
following: 
•  Medical or ethical reasons affecting the continued performance of the study 
•  Difficulties in the recruitment of patients 
  

Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 47 of 137 
Version 6.0 
6 INVESTIGATIONAL PRODUCT 
6.1 
Investigational medicinal product 
An investigational medicinal product (IMP) is a pharmaceutical form of an active substance or 
placebo being tested or used as a reference in a clinical trial, including products already with a 
marketing authorisation but used or assembled (formulated or packaged) in a way different from 
the authorised form, or when used for an unauthorised indication, or when used to gain further 
information about the authorised form. 
The IMP in this study is selinexor (KPT-330). 
The Investigator or other appropriate individual, who is designated by the local Principal 
Investigator, should maintain records of the inventory at the site, the use for each patient and 
delivery, storage and destruction. Investigators should maintain records that adequately document 
that patients were provided the doses specified in the protocol and reconcile all investigational 
product(s) received from the Sponsor. 
6.2 
Preparation and Administration of Selinexor 
6.2.1 Preparation and Administration of Selinexor 
The Investigator or responsible site personnel must instruct the patient or caregiver to take the study 
drug as per protocol. Study drug will be dispensed to the patient by authorized site personnel only. 
All dosages prescribed to the patient and all dose changes during the study must be recorded on the 
eCRF. 
Tablets, including instructions for administration, are dispensed by study personnel on an 
outpatient basis. Patients will be provided with an adequate supply of study drug for self-
administration at home until at least their next scheduled study visit. 
6.2.1.1  Drug Name, Formulation and Storage 
INN:  
selinexor 
Company´s Drug ID: KPT-330 
Chemical name: 
(Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N'-(pyrazin-
2-yl)acrylohydrazide 
Classification: 
Cell biological modifier: Apoptosis inducing agent 
Mechanism of action: Selinexor is a Selective Inhibitor of Nuclear Export (SINE) that 
specifically blocks nuclear export by binding irreversibly to XPO1 protein.  
Molecular formula: C17H11F6N7O 
Molecular weight: 
443.31 

6HOLQH[RU.37
.DU\RSKDUP7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO.&3
1RYHPEHU
&RQILGHQWLDO
3DJHRI
9HUVLRQ
7DEOHWV
6HOLQH[RU .37 IRU RUDO DGPLQLVWUDWLRQ ZLOO EH VXSSOLHG DV HLWKHU  DQG  PJ WDEOHWV
VXSSOLHGLQERWWOHVRUPJWDEOHWVVXSSOLHGLQEOLVWHUSDFNV7KHLQLWLDOGUXJSURGXFWIRUWKH
VWXG\ZLOOEHWKHDQGPJWDEOHWVZLWKWUDQVLWLRQWRWKHPJWDEOHWVDVWKHVHVXSSOLHVEHFRPH
DYDLODEOH
/DEHOOLQJ
(DFKERWWOHEOLVWHUSDFNRIVHOLQH[RUWDEOHWVZLOOEHODEHOOHGLQDFFRUGDQFHZLWKFXUUHQW,&+*&3
)'$DQGVSHFLILFQDWLRQDOUHTXLUHPHQWV
6WRUDJH
DQGPJ7DEOHWVLQ%RWWOHV
x 7DEOHWVRIVHOLQH[RUGUXJSURGXFWZLOOEHVWRUHGDWDPELHQWWHPSHUDWXUHLQZKLWHKLJK
GHQVLW\SRO\HWK\OHQH+'3(ERWWOHVLQDORFNHGDQGVHFXUHGDUHDZLWKUHVWULFWHGDFFHVV
x

x 6WRUDJHRIWDEOHWVVHOLQH[RUWDEOHWVFDQEHVWRUHGDWURRPWHPSHUDWXUHRUUHIULJHUDWHGIURP
Û&GRQRWIUHH]H5RRPWHPSHUDWXUHVWRUDJHLVUHFRPPHQGHG
PJ7DEOHWVLQ%OLVWHU3DFNV
x



x $OO VHOLQH[RU WDEOHWV PXVW EH NHSW LQ DQ DSSURSULDWH OLPLWHG DFFHVV VHFXUH SODFH XQWLO
GLVSHQVHG GHVWUR\HG RU UHWXUQHG WR .DU\RSKDUP 7KHUDSHXWLFV ,QF RU GHVLJQHH IRU
GHVWUXFWLRQ
x 6HOLQH[RUWDEOHWVFDQEHVWRUHGDWURRPWHPSHUDWXUHRUUHIULJHUDWHGDWRUEHORZÛ)RU
Û&GRQRWIUHH]H5RRPWHPSHUDWXUHVWRUDJHLVUHFRPPHQGHG7KHVWXG\VLWHZLOOEH
UHTXLUHGWRPDLQWDLQDORJRIWKHWHPSHUDWXUHZKHUHWKHVWXG\PHGLFDWLRQLVVWRUHG
5RXWHRI$GPLQLVWUDWLRQ
6HOLQH[RULVWREHWDNHQRUDOO\ZLWKLQDSSUR[LPDWHO\PLQXWHVRIDOLJKWPHDOWRJHWKHUZLWK
P/R]RIZDWHU:KHQWDNHQRQGD\RIVXUJHU\WKHSDWLHQWVKRXOGWDNHVHOLQH[RUZKLOH
IDVWLQJXVLQJR]RIZDWHU
3DWLHQWVFRQWLQXLQJLQ$UPV
%ZKRDUHDWDGRVHRIPJPRUJUHDWHUZLOOEHFRQYHUWHGWR
PJWZLFHZHHNO\IODWGRVLQJKRZHYHULIWKHSDWLHQWLVFXUUHQWO\DWDORZHUGRVHWKH,QYHVWLJDWRU
VKRXOGFRQWDFWWKHPHGLFDOPRQLWRUWRGHWHUPLQHWKHVWDUWLQJGRVHIRUIODWGRVLQJ
)RU$UPV
%DQG&VHOLQH[RUZLOOEHJLYHQDWDQRUDOIL[HGGRVHRIPJWZLFH
ZHHNO\>HJ0RQGD\DQG:HGQHVGD\7XHVGD\DQG7KXUVGD\:HGQHVGD\DQG)ULGD\7KXUVGD\
CCI
CCI
CCI
CCI
CCI

6HOLQH[RU.37
.DU\RSKDUP7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO.&3
1RYHPEHU

&RQILGHQWLDO
3DJHRI
9HUVLRQ
DQG6DWXUGD\@GXULQJ:HHNVRIHDFKZHHNF\FOHGRVHVVKRXOGQRWEHDGPLQLVWHUHGOHVVWKDQ
KUVDSDUW

)RU$UP'VHOLQH[RUZLOOEHJLYHQDWDQRUDOIL[HGGRVHRUPJRQFHZHHNO\HJ0RQGD\RI
HDFKZHHN
&RPSOLDQFH
7KH,QYHVWLJDWRUVKRXOGHQVXUHWKDWWKHLQYHVWLJDWLRQDOSURGXFWLVXVHGRQO\LQDFFRUGDQFHZLWKWKH
SURWRFRO $OO GRVHV JLYHQ DUH WR EH GRFXPHQWHG LQ WKH H&5) LQFOXGLQJ H[DFW GRVH DQG GDWH
DGPLQLVWHUHG7KH3ULQFLSDO,QYHVWLJDWRURUWKHGHVLJQHHZLOODFFRXQWIRUWKHQXPEHURIWDEOHWV
GLVSHQVHGDJDLQVWWKRVHVWRUHGDWWKHVLWH$Q\GHYLDWLRQVDQGPLVVHGGRVHVZLOOEHUHFRUGHGLQWKH
H&5) DQG GUXJ DFFRXQWDELOLW\ ORJV IRU YHULILFDWLRQ ZLWK WKH UHDVRQV IRU PLVVHG GRVHV 7KH
,QYHVWLJDWRUGHVLJQHHZLOOWU\WRHQVXUHFRPSOHWHFRPSOLDQFHZLWKWKHGRVLQJVFKHGXOHE\SURYLGLQJ
WLPHO\LQVWUXFWLRQVWRWKHSDWLHQWV,WZLOOEHUHTXHVWHGIURPSDWLHQWVWRGRFXPHQWLQWDNHRIVHOLQH[RU
LQDSDWLHQWGLDU\
7KHLQYHVWLJDWLRQDOSURGXFWVKRXOGEHVWRUHGDVVSHFLILHGE\WKH6SRQVRUDQGLQDFFRUGDQFHZLWK
DSSOLFDEOHUHJXODWRU\UHTXLUHPHQWV

'RVH0RGLILFDWLRQVIRU6HOLQH[RU
7R[LFLW\ZLOOEHJUDGHGDFFRUGLQJWR1&,&7&$(YHUVLRQ6HFWLRQ$SSHQGL[WKH
WKHUDS\PRGLILFDWLRQVGHVFULEHGEHORZDUHDSSOLHGDFFRUGLQJWRWKLVVHYHULW\JUDGLQJ
,IPRUHWKDQRQHGLIIHUHQWW\SHRIWR[LFLW\RFFXUVFRQFXUUHQWO\WKHPRVWVHYHUHJUDGHZLOOGHWHUPLQH
WKHPRGLILFDWLRQ
5HHVFDODWLRQRIWKHVWXG\GUXJLVRQO\DOORZHGDVRXWOLQHGLQWKHVHFWLRQVWKDWDSSO\IRUWKHVSHFLILF
WR[LFLW\,IWR[LFLW\UHTXLUHVDWUHDWPHQWGHOD\RIPRUHWKDQGD\VWKHSDWLHQWZLOOEHWDNHQRII
VWXG\WUHDWPHQW
(DFK GRVH PRGLILFDWLRQ RU WUHDWPHQW GHOD\ KDV WR EH GRFXPHQWHG LQ WKH H&5) LQFOXGLQJ WKH
UHVSHFWLYHUHDVRQ
%DVHGRQSUHOLPLQDU\REVHUYDWLRQVIURPWKHRQJRLQJ3KDVHVWXGLHVLQSDWLHQWVZLWKDGYDQFHG
KHPDWRORJLFDODQGVROLGWXPRUVVHOLQH[RU.37VKRZVDUHDVRQDEO\ZLGHWKHUDSHXWLFUDQJH
ZLWKDFWLYLW\IURPaPJPWRPJPDSSUR[LPDWHO\PJWRPJRUDOO\7KHUHIRUHLQ
RUGHUWRRSWLPL]HVSHFLILFDQWLWXPRUDFWLYLW\DQGWROHUDELOLW\GRVHUHGXFWLRQVDQGRUVFKHGXOH
PRGLILFDWLRQVZLOOEHDOORZHGDVGHVFULEHGLQ7DEOHDQG7DEOH3DWLHQWVVKRXOGDOVREHWUHDWHG
DJJUHVVLYHO\ZLWKVXSSRUWLYHFDUHWRUHGXFHWR[LFLWLHV
CCI

6HOLQH[RU.37
.DU\RSKDUP7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO.&3
1RYHPEHU

&RQILGHQWLDO
3DJHRI
9HUVLRQ
7DEOH3UHVSHFLILHG'RVH6FKHGXOH0RGLILFDWLRQVIRU$GYHUVH(YHQWV5HODWHGWR6WXG\
'UXJ
'RVH/HYHO
6WDUWLQJ'RVHRI6HOLQH[RU
$UPV
&
$UP'
'RVHOHYHO
PJWZLFHSHUZHHN
PJRQFHSHUZHHN
'RVHOHYHO
PJWZLFHSHUZHHN
PJRQFHSHUZHHN
'RVHOHYHO
PJRQFHSHUZHHN
PJRQFHSHUZHHN
'RVHOHYHO
PJRQFHSHUZHHN
PJRQFHSHUZHHN
'RVHOHYHO
'LVFRQWLQXHGRVLQJ
'LVFRQWLQXHGRVLQJ
3DWLHQWVZLOOFRQWLQXHWRUHFHLYHVHOLQH[RUXQWLOWKH\QHHGWREHKDYHWKHLUGRVHUHGXFHGEHORZ
PJRQFHSHUZHHNDWZKLFKWLPHVWXG\WUHDWPHQWZLOOEHGLVFRQWLQXHG
,ISDWLHQWVZKRZHUHEHLQJWUHDWHGWZLFHZHHNO\IRU:HHNVXQGHUDSUHYLRXVYHUVLRQRIWKH
SURWRFRODUHFRQWLQXLQJZLWKWKH:HHNVVFKHGXOHWKHGRVHPRGLILFDWLRQVLQ7DEOHVKRXOGEH
PDGHEDVHGRQWKH:HHNVVFKHGXOH
7DEOH6XSSRUWLYH&DUHDQG'RVH$GMXVWPHQW*XLGHOLQHV
7R[LFLW\DQG
,QWHQVLW\
6XSSRUWLYHWUHDWPHQW
6HOLQH[RU'RVH0RGLILFDWLRQ
)DWLJXHFRPPRQ
*UDGH
x 5XOHRXWRWKHUFDXVHVRIIDWLJXH
x (QVXUHDGHTXDWHFDORULFLQWDNHDQGDVVHVV
YROXPHVWDWXV
x &RQVLGHUDGGLWLRQRIPJ
GH[DPHWKDVRQHRUHTXLYDOHQWZLWKHDFK
GRVHRIVHOLQH[RUWKHGD\DIWHU
VHOLQH[RU
0DLQWDLQGRVH
*UDGH
,ILQWROHUDEOH
*UDGHIROORZ
JXLGHOLQHVIRU*UDGH
EHORZ
x 5XOHRXWRWKHUFDXVHVRIIDWLJXH
x (QVXUHDGHTXDWHFDORULFLQWDNHDQGDVVHVV
YROXPHVWDWXV
x &RQVLGHUDGGLWLRQRIPJ
GH[DPHWKDVRQHRUHTXLYDOHQWZLWKHDFK
GRVHRIVHOLQH[RUWKHGD\DIWHU
VHOLQH[RU
x )RUDGGLWLRQDOVXSSRUWVHH1&&1
JXLGHOLQHVD
x 0DLQWDLQGRVH
x &RQVXOWPHGLFDOPRQLWRUIRUDGGLWLRQDO
RSWLRQVVXFKDVWHPSRUDU\GRVH
UHGXFWLRQRUVKRUWGRVHLQWHUUXSWLRQV
HJVNLSGRVHV2ULJLQDOGRVHPD\
EHUHVXPHGZKHQSDWLHQW¶VFRQGLWLRQ
LPSURYHV
*UDGH
6HHJXLGHOLQHVIRU*UDGHIDWLJXH
x ,QWHUUXSWVHOLQH[RUGRVLQJXQWLOUHVROYHG
WR*UDGHIRUILUVWRFFXUUHQFHRI
*UDGHLIDGHTXDWHVXSSRUWLYHFDUH
UHVXOWHGLQIDWLJXHLPSURYLQJWR*UDGH
ZLWKLQGD\VUHVWDUWVHOLQH[RUDW
FXUUHQWGRVH
x 2WKHUZLVHUHVWDUWVHOLQH[RUDWRQHGRVH
OHYHOEHORZ7DEOH
CCI

Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 51 of 137 
Version 6.0 
Toxicity and 
Intensity 
Supportive treatment 
Selinexor Dose Modification 
Anorexia or Weight loss 
Grade 1 
• Rule out other causes of anorexia. 
• Assess dietary options (e.g., try a variety 
of other foods).  
• Add high-calorie supplements (e.g., 
Ensure®).  
• Consider addition of ≤ 4 mg 
dexamethasone or equivalent with each 
dose of selinexor +/- the day after 
selinexor. 
Maintain dose. 
Grade 2 
• Rule out other causes of anorexia. 
• Assess dietary options (e.g., try a variety 
of other foods).  
• Add high-calorie supplements (e.g., 
Ensure®).  
• Consider addition of ≤ 4 mg 
dexamethasone or equivalent with each 
dose of selinexor +/- the day after 
selinexor.  
• Consider megesterol acetate 80-400 mg 
daily (divided doses). 
• Consider anabolic steroids such as 
oxandrolone, or dronabinol (Marinol®) or 
other cannabinoid, mainly for patients 
who can’t tolerate steroids or at high risk 
to progress. 
• For additional supportive care see NCCN 
guidelinesb (Section 16.7; Appendix 7). 
Selinexor may be skipped intermittently 
(e.g., skip 1-2 doses) while supportive 
medications are instituted, usually for 
< 1 week.  
Grade 3  
See guidelines for Grade 2 anorexia. 
Interrupt dosing with selinexor. Restart 
selinexor at 1 dose level reduction (Table 
5) once anorexia resolves to Grade ≤ 2 and 
patient is clinically stable.  
Grade 4 (anorexia 
only) 
See guidelines for Grade 2 anorexia. 
• Stop dosing of selinexor.  
• Restart selinexor at 1 dose level 
reduction (Table 5) only if anorexia 
resolves to Grade ≤ 2, patient is 
clinically stable, and other contributing 
factors have been addressed.  

Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 52 of 137 
Version 6.0 
Toxicity and 
Intensity 
Supportive treatment 
Selinexor Dose Modification 
Nausea/- acute  (common) 
Grade 1 
• Ensure adequate caloric intake and assess 
volume status. 
• Consider alternate 5-HT3 antagonists 
and/or D2 antagonists as needed. 
Consider addition of NK1 antagonists. 
• Consider addition of ≤ 4 mg 
dexamethasone or equivalent with each 
dose of selinexor +/- the day after 
selinexor.  
 
Maintain dose. 
Grade 2 
(If intolerable 
Grade 2, follow 
guidelines for Grade 
3 below) 
• See guidelines for Grade 1 nausea 
• For additional options see NCCN 
guidelines for antiemesisc (Section 16.6; 
Appendix 6). 
Selinexor may be skipped intermittently 
(e.g., skip 1-2 doses) while supportive 
medications are instituted, usually for 
< 1 week. 
Grade 3 
• See guidelines for Grade 1 nausea 
• For additional options see NCCN 
guidelines for antiemesisc (Section 16.6; 
Appendix 6). 
• Interrupt selinexor dosing until resolved 
to Grade ≤ 2, For first occurrence of 
Grade 3, if adequate supportive care 
resulted in nausea improving to Grade 
≤ 1 within 3 days, restart selinexor at 
current dose. 
• Otherwise, restart selinexor at one dose 
level below (Table 5). 
• If nausea stabilizes for at least 4 weeks 
at Grade ≤ 1, then the original dose of 
selinexor may be resumed. 
Hyponatremia (common) 
Grade 1 (sodium 
levels <normal to 
130 nM) 
  
• Be certain sodium level is corrected for 
hyperglycemia (serum glucose 
> 150mmol/L). 
• Rule out other causes of low sodium 
(e.g., cardiac, hepatic, adrenal, renal and 
thyroid diseases, SIADH, Fanconi 
Syndrome, hyperglycemia, diuretic use). 
• Consider salt supplementation one to two 
times per day. 
Maintain dose. 
 
Grade 3 (sodium 
levels 126-129 nM) 
without symptoms  
• Be certain sodium level is corrected for 
hyperglycemia (serum glucose 
> 150mmol/L). 
• Consider immediate IV rehydration with 
appropriate saline solution. 
• Rule out other causes of low sodium 
(e.g., cardiac, hepatic, adrenal, renal and 
thyroid diseases, SIADH, Fanconi 
Syndrome, hyperglycemia, diuretic use). 
• Initiate salt supplementation two to three 
times per day. 
• Consider administration of appropriate 
saline solution and remeasure serum 
sodium levels. If (corrected) sodium is 
Grade ≤ 1, then patient may receive 
standard dosing. 
• If immediate sodium correction is not 
successful, skip one dose of selinexor, 
implement recommendations, and 
reassess sodium within 48 hours. 
Resume selinexor dosing at the same 
dose level when sodium is Grade ≤1 
(≥130 nM). 

Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 53 of 137 
Version 6.0 
Toxicity and 
Intensity 
Supportive treatment 
Selinexor Dose Modification 
Grade 3 (120-
125 nM) or Grade 4 
or any Grade 3 with 
symptoms 
• Correct sodium as per institutional 
guidelines 
• Initiate salt supplementation two to three 
times per day. 
• Delay selinexor until resolved to 
Grade ≤ 1 (≥ 130 nM) then reduce 
selinexor dose by 1 level (Table 5). 
Sodium should be reassessed after one 
dose of selinexor is skipped (i.e., within 
48 hours) and corrective measures 
implemented. 
• For Grade 3 hyponatremia, if serum 
sodium stabilizes to Grade ≤ 1 for at 
least 4 weeks, then original dose of 
selinexor may be resumed. 
Diarrhea (common) 
Grade 1+2 
  
• Diet recommendation as per guidelines 
(Benson, 2004)d. 
• Institute standard anti-diarrheal therapy. 
• After the first occurrence of diarrhea, 
loperamide 2 mg should be considered 
prophylactically approximately 1-2 hrs 
before the administration of selinexor and 
repeated every 4 hrs for the first 12 hrs. 
For Grade 2 only, reduce selinexor one 
dose level (Table 5) until resolved to Grade 
≤ 1, then re-start at the current dose level. 
 
Grade 3  
• Institute intravenous fluids  
• Diet recommendation as per guidelines 
(Benson, 2004)d.  
• Institute standard anti-diarrheal therapy. 
• Once the symptoms resolve to Grade ≤ 1, 
loperamide 2 mg should be considered 
prophylactically approximately 1-2 hrs 
before the administration of selinexor and 
repeated every 4 hrs for the first 12 hrs. 
• Delay selinexor dosing until resolved to 
Grade ≤ 1, then reduce selinexor dose by 
one dose level (Table 5). 
• If diarrhea stabilizes for at least 4 weeks 
at Grade ≤ 1, then original dose of 
selinexor may be resumed. 
Grade 4 
• Rule out other causes of diarrhea, 
including infectious agents.  
• In case of opportunistic infection, 
withdraw all steroids (with tapering if 
medically appropriate) until culture is 
negative.  
• Follow institutional guidelines for Grade 
4 diarrhea. 
Delay selinexor dosing until resolved to 
Grade ≤ 1, then reduce selinexor dose by 
one dose level (Table 5). 
Thrombocytopenia 
Grade 1  
In cases of marked reduction in platelet 
numbers from baseline, consider 
implementing platelet growth factors (e.g. 
eltrombopag or romiplostim ± oprelvekin 
[IL 11]).). 
Maintain dose. 
Grade 2  
• Strongly consider implementing platelet 
growth factors (e.g. eltrombopag or 
romiplostim ± oprelvekin [IL 11]). 
• Monitor platelet counts weekly. 
If Grade 2 thrombocytopenia persists 
> 14 days, delay selinexor dosing until 
platelet count returns to Grade ≤, then re-
start at the current dose level. 

Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 54 of 137 
Version 6.0 
Toxicity and 
Intensity 
Supportive treatment 
Selinexor Dose Modification 
Grade 3 
Thrombocytopenia 
without bleeding 
 
• Initiate platelet growth factors (e.g. 
eltrombopag or romiplostim ± oprelvekin 
[IL 11]).). 
• Monitor platelet counts at least weekly. 
• Consider holding anti-platelet agents. 
• Delay selinexor dosing until the 
patient’s platelet count returns to Grade 
≤ 2.  
• For Grade 2, restart selinexor at same 
dose level taken once weekly only until 
platelet counts resolve to Grade ≤ 1, 
then resume twice-weekly dosing at 
current dose. 
• Second occurrence: delay selinexor 
dosing until platelet counts return to 
Grade ≤ 2. For Grade 2, restart selinexor 
at same dose level taken once weekly 
only until platelet counts resolve to 
Grade ≤ , then resume twice-weekly 
dosing at one dose level below (Table 
5). 
• If platelet counts stabilize at Grade ≤ 1 
for at least 4 weeks, then original dose 
of selinexor may be resumed. 
Grade 4 
Thrombocytopenia 
without bleeding 
 
• Follow guidelines for Grade 3 
thrombocytopenia without bleeding. 
• Transfuse as per institutional guidelines. 
• Delay selinexor dosing until platelet 
counts return to Grade ≤ 2. For Grade 2, 
restart selinexor at same dose level 
taken once weekly only until platelet 
counts resolve to Grade ≤ 1, then resume 
twice-weekly dosing at one dose level 
(Table 5). 
• If platelet counts stabilize at Grade ≤1 
for at least 4 weeks, then original dose 
of selinexor may be resumed. 
≥ Grade 3 
Thrombocytopenia 
associated with 
bleeding 
• Transfuse as per institutional guidelines. 
• Follow guidelines for Grade 3 
thrombocytopenia without bleeding. 
Delay selinexor dosing until platelet counts 
return to Grade ≤ 1, and then resume 
selinexor dosing at one dose level below 
(Table 5).  
Neutropenia 
Grade 3 neutropenia 
without fever 
Implement growth factors per institutional 
guidelines. 
Delay dosing with selinexor until the 
patient’s ANC returns to Grade ≤ 2. 
Resume dosing with selinexor at current 
dose. 
Grade 4 neutropenia 
without fever 
Implement growth factors per institutional 
guidelines. 
• Delay dosing with selinexor until the 
patient’s ANC returns to Grade ≤ 2. 
Resume dosing with selinexor at current 
dose. 
• Second occurrence: delay dosing with 
selinexor until the patient’s ANC returns 
to Grade ≤ 2 then reduce selinexor dose 
by one dose level (Table 5).  

Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 55 of 137 
Version 6.0 
Toxicity and 
Intensity 
Supportive treatment 
Selinexor Dose Modification 
Grade 3 or 4 
neutropenia with 
fever (febrile 
neutropenia) 
• Implement growth factors per 
institutional guidelines. 
• Implement broad anti-microbial coverage 
per institutional guidelines. 
• Please note that selinexor has not been 
associated to date with any opportunistic 
infections 
Delay dosing with selinexor until the 
patient’s ANC returns to Grade ≤1, fever 
has resolved and patient is stable, then 
reduce selinexor dose by one dose level 
(Table 5). 
Anemia 
Grade 1 or 2 
Initiate standard supportive care and follow 
institutional guidelines. 
 
Maintain dose. 
Grade 3 
Delay dosing with selinexor until resolved 
to Grade ≤ 2, then resume dosing with 
selinexor at current dose. 
Grade 3 
(symptomatic) or 
Grade 4 
Delay dosing with selinexor until resolved 
to Grade ≤ 2, then reduce selinexor dose by 
one dose level. 
Other clinically significant selinexor-related AEs* 
 
Grade 1 or 2 
Initiate standard supportive care and follow 
institutional guidelines. 
Maintain dose. 
Grade 3 
Delay dose until resolved to Grade ≤ 1, 
then reduce by one dose (Table 5). 
Grade 4 
Delay dose until resolved to Grade ≤ 1, 
then reduce by two dose levels (Table 5). 
All dose modifications should be based on the worst preceding toxicity. 
*Isolated values of Grade ≥ 3 alkaline phosphatase values will NOT require dose interruption. Determination of liver vs. bone etiology should 
be made, and evaluation of gamma-glutamyl transferase (GGT), 5'-nucleotidase (5’NT), or other liver enzymes should be performed. 
Note: for combinations of Grade 1 or 2 adverse events (e.g., nausea, fatigue, anorexia) that significantly impair the patient’s quality of life, 1-2 
doses of selinexor may be skipped and aggressive supportive care implemented. Selinexor may then be restarted at the original dose. 
aNational Comprehensive Cancer Network®. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Fatigue. Available at 
http://www.nccn.org/professionals/physician_gls/pdf/fatigue.pdf31  
bNational Comprehensive Cancer Network®. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Palliative Care, version 
1.2014. Fort Washington, NY. April 2014. Available at: 
http://www.lls.org/content/nationalcontent/resourcecenter/freeeducationmaterials/generalcancer/pdf/facts.pdf32 
cNational Comprehensive Cancer Network®. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Antiemesis, version 
2.2014. Fort Washington, NY. April 2014. Available at: http://www.nccn.org/professionals/physician_gls/PDF/antiemesis.pdf. 33 
dBenson AB, Ajani JA, Catalano RB, et al. Recommended guidelines for the treatment of cancer treatment-induced diarrhea. J Clin Onc 2004; 
22:2918. 34 
If the patient tolerates a reduced dose for at least four weeks, patients may be dose escalated to the 
dose they received prior to the reduction after authorization from medical monitor and Principal 
Investigator. 
6.3.1 Selinexor Dose Reduction for Decreased Glomerular Filtration Rate 
Selinexor is not significantly eliminated by the kidney; therefore, no dose alteration of selinexor is 
required with renal dysfunction. If dialysis is implemented during selinexor treatment, then 
selinexor should always be given after dialysis. 
6.3.2 Selinexor Dose Reduction in the Setting of Infection 
Patients with active uncontrolled infections should have selinexor treatment withheld until the 
infection has resolved or the patient is clinically stable. Dexamethasone should be adjusted per 
institutional guidelines, and adrenal suppression considered. After the infection has stabilized 
clinically or resolved, selinexor treatment may continue at the original dose. Missed doses will not 

Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 56 of 137 
Version 6.0 
be replaced. Patients may continue on antibiotics for prolonged periods while re-initiating their 
selinexor regimen at the discretion of the Investigator. Prophylactic antibiotics are permitted 
concurrently with selinexor treatment, but are not required. 
6.3.3 Dose Adjustments with Changes in BSA 
Patient BSA will be assessed to ensure that the 60 mg or 80 mg dose does not result in a dose 
>70 mg/m2. If a patient’s dose will exceed this limit, the Investigator should contact the medical 
monitor prior to administration to discuss appropriate dosing. 
6.3.4 Missed or Vomited Doses 
A maximum of two doses may be given per week; doses should not be administered less than 36 hrs 
apart. Every effort should be made to avoid missed doses. 
• Missed doses: Doses held due to AE will not be considered missed.  
• Vomited doses: If a dose is vomited within 1 hr of ingestion, it will be replaced. If vomiting 
occurs more than 1 hr after dosing, it will still be considered a complete dose. 
6.4 
Concomitant Medication and Treatment 
Concomitant medication is defined as any prescription or over-the-counter preparation, including 
vitamins and supplements. Patients may continue their baseline medication(s). All concomitant 
medication(s) must be reported in the eCRF. Any diagnostic, therapeutic or surgical procedure 
performed during the study period should be recorded, including the dates, description of the 
procedure(s) and any clinical findings.  
6.4.1 Permitted Concomitant Medication 
Patients will receive concomitant medications to manage cancer symptoms, AEs, intercurrent 
illnesses, and supportive care agents, such as, pain medications, anti-emetics, short courses of low 
dose oral steroids, and anti-diarrheal agents are allowed that are medically necessary as standard 
care. Medications to treat concomitant diseases like diabetes, hypertension, etc. are allowed. 
6.4.1.1 Prevention of Pregnancy 
Patients should not become pregnant or father a child while on this study because the drugs in this 
study can affect an unborn baby. Women should not breastfeed a baby while on this study. It is 
important patients understand the need to use birth control while on this study. Female patients of 
child-bearing potential must have a negative serum pregnancy test at screening and agree to use 
reliable methods of contraception for three months after their last dose of medication. Such 
methods include intrauterine devices, hormonal contraceptives [contraceptive pills, implants, 
transdermal patches, hormonal vaginal devices or injections with prolonged release], abstinence or 
sterilization of the partner. Male patients must use a reliable method of contraception (abstinence 
or contraception with one of the above-described methods for your partner) if sexually active with 
a female of child-bearing potential. Total (true) abstinence (when this is in line with the preferred 
and usual lifestyle of the patient), is an acceptable method of contraception. Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, post- ovulation methods) and withdrawal are not 

Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 57 of 137 
Version 6.0 
acceptable methods of contraception. For both male and female patients, effective methods of 
contraception must be used throughout the study and for three months following the last dose. 
6.4.1.2 Use of Blood Products 
During the administration of selinexor, patients may receive RBC or platelet transfusions, if 
clinically indicated, per institutional guidelines. Patients who require repeated transfusion support 
should be discussed with the Primary Investigator, Sponsor, and medical monitor. 
Appropriate anti-coagulation is allowed during the study (e.g.: low molecular weight heparin, 
direct factor Xa inhibitors, etc.). 
Patients may receive supportive care with erythropoietin, darbepoetin, G-CSF or GM-CSF, 
pegylated growth factors, and platelet stimulatory factors, in accordance with clinical practice or 
institutional guidelines or as recommended in Table 6 prior to entry and throughout the study. 
6.4.2 Restrictions and Prohibited Medications 
Concurrent therapies: Concurrent therapy with glucocorticoids as specified herein is allowed. 
Concurrent therapy with any other approved or investigative anticancer therapeutic is not allowed. 
Other investigational agents should not be used during the study. Use of any immunosuppressive 
agents during the study must be confirmed by the medical monitor. 
Alcohol: Ethanol should be avoided on selinexor dosing days as it may compete for glutathione 
(GSH)-mediated metabolism. 
Diet: There are no dietary restrictions on this study. Patients should maintain adequate caloric 
and fluid intake. 
Medications: There are no longer any restrictions on the use of acetaminophen (paracetamol) or 
acetaminophen/paracetamol)-containing products in combination with selinexor, EXCEPT on days 
on selinexor dosing, when acetaminophen (paracetamol) must not exceed a total daily dose of 
1 gram. Although acetaminophen (paracetamol) use in combination with selinexor was restricted 
in previous selinexor studies based on theoretical interactions with GSH, ongoing clinical safety 
evaluations on the use of these drugs together have not shown any significant clinical or laboratory 
abnormalities with doses of acetaminophen (paracetamol) of up to 1 gram and selinexor up to 
55 mg/m2 (approximately 80-100 mg). 
Patients should not take GSH-, S-adenosylmethionine (SAM)-, or N-acetylcysteine (NAC)-
containing products during their participation in this study as these products may enhance the 
metabolism of selinexor. See Section 16.8; Appendix 8 for a list of representative products. Patients 
must report all prescription and non-prescription medicines to their physicians during this study. 
Concurrent warfarin or other Coumadin-derived anticoagulants are prohibited. 

Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 58 of 137 
Version 6.0 
6.5 
Supportive Care Guidelines 
6.5.1 Required 5-HT3 Antagonists 
In order to minimize nausea, unless contraindicated, all patients must receive 5-HT3 antagonists 
(ondansetron 8 mg or equivalent), starting before the first dose of selinexor and continued 2-3 times 
daily thereafter, as needed. Alternative treatment may be provided if the patient does not tolerate 
5-HT3 antagonists. 
6.5.2 Supportive Care Recommendations for Selinexor-Related Adverse Events 
Supportive measures for optimal medical care shall be provided during participation in this study. 
Based on clinical observations in over 730 adult patients treated with selinexor as of 31 May 2015, 
the main side effects have been primarily related to anorexia with poor caloric and fluid intake, 
fatigue and nausea. Thrombocytopenia also occurs, although it is rarely associated with bleeding.  
In addition to required 5-HT3 prophylaxis, supportive care including additional anti-nausea/anti-
emetic therapy, acid suppression (proton-pump inhibitors [PPI] and/or H2-blockers) and other 
treatments may be administered as follows: 
• Glucocorticoids: ≤4 mg dexamethasone [or equivalent] on the day of, and the day after, 
each selinexor dose, with a maximum of 16 mg/week) may also be used as needed to 
improve appetite, reduce nausea or vomiting, and minimize fatigue. 
• Appetite stimulants: megesterol acetate at a dose of 80-400 mg daily.  
• Centrally acting agents: per National Comprehensive Cancer Network® [NCCN] Clinical 
Practice Guidelines® see, respectively, Section 16.6; Appendix 6 and Section 16.7; 
Appendix 7. 
• Neurokinin-1 receptor antagonist (NK1R antagonist): Aprepitant or equivalent should be 
considered and will be covered for selected patients who have severe nausea and vomiting 
Supportive care guidelines for managing AEs are provided in Table 6. 
6.5.2.1 Infection 
Appropriate broad-spectrum intravenous antibiotics and antifungal agents should be started 
immediately in patients who develop fever or other signs of systemic infection. Selinexor should 
be suspended in any patient with Grade 4 infection or clinical sepsis (in the absence of documented 
infection) until the condition is stabilized. Selinexor can then be re-started at the same dose. See 
also Table 6. 
6.5.3 Liver Function Test Abnormalities 
Since selinexor is metabolized by GSH conjugation, hepatic GSH depletion might occur. 
Therefore, in patients who develop liver function test abnormalities, supportive measures such as 
SAM 400 mg orally 1-4 times per day or other drugs that can replace GSH should be considered. 

Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 59 of 137 
Version 6.0 
7 ASSESSMENT OF SAFETY 
The Selinexor/KPT-330 IB will be used as reference document for selinexor and will be provided 
to the Investigators. 
7.1 
Adverse Events and Laboratory Abnormalities Reporting 
7.1.1 Adverse Event 
An adverse event (AE) is defined in the International Conference on Harmonisation (ICH) 
Guideline for Good Clinical Practice (GCP) as “any untoward medical occurrence in a patient or 
clinical investigation patient administered a pharmaceutical product and that does not necessarily 
have a causal relationship with this treatment” (ICH E6:1.2). 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding, for example), symptom or disease temporally associated with the use of a medicinal 
product, whether or not it is considered related to the medicinal product. 
The Investigator will make a judgment regarding whether or not the AE was related to study drug, 
as outlined below in Table 7. 
Table 7: Classification of Adverse Events by Causality 
Not related 
The lack of a temporal relationship of the event to study treatment makes a causal 
relationship not reasonably possible, or other drugs, therapeutic interventions or 
underlying conditions provide a sufficient explanation. 
Possibly related The temporal relationship of the event to study treatment makes a causal relationship 
reasonably possible, and the event is more likely explained by exposure to the study 
treatment than by any other drugs, therapeutic interventions or underlying conditions. 
Related 
The temporal relationship of the event to study treatment makes a definitive 
relationship, and the event is more likely explained by exposure to the study treatment 
than by any other drugs, therapeutic interventions or underlying conditions. 
 
For the purpose of safety analyses, all AEs that are classified as possible or probable will be 
considered treatment-related events. 
7.1.2 Adverse Drug Reaction 
All untoward and unintended responses to a medicinal product related to any dose administered. 
The phrase “responses to a medicinal product” means that a causal relationship between the 
medicinal product and the AE is at least a reasonable possibility, i.e. the relationship cannot be 
ruled out. 
A serious adverse drug reaction (SADR) is an adverse drug reaction (ADR) that meets the 
definition of serious (provided below). 

Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 60 of 137 
Version 6.0 
7.1.3 Serious Adverse Event 
A serious adverse event (SAE) is defined as an AE that 
• Is fatal 
• Is life threatening (places the patient at immediate risk of death) 
• Requires in-patient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect 
• Other important medical events 
A hospitalization meeting the regulatory definition for “serious” is any inpatient hospital admission 
that includes a minimum of an overnight stay in a healthcare facility. Any AE that does not meet 
one of the definitions of serious (e.g., visit to an emergency room, outpatient surgery, or requires 
urgent investigation) may be considered by the Investigator to meet the “other significant medical 
hazard” criterion for classification as an SAE. Examples include allergic bronchospasm, 
convulsions, and blood dyscrasias. 
Important medical events are defined as those occurrences that may not be immediately life 
threatening or result in death, hospitalization, or disability, but may jeopardize the patient or require 
medical or surgical intervention to prevent one of the other outcomes listed above. Medical 
judgment should be exercised in deciding whether such an AE should be considered serious. 
In addition, all cases of cerebellar toxicities of Grade 3 or higher must be captured as an SAE and 
reported to the regulatory authorities, IRBs, ECs, and Investigators in an expedited Safety Report 
within 7 days of awareness of the event. 
7.1.4 NOT to be reported as SAEs 
For this study, the following conditions or planned events are not classified as SAEs: 
• Progression, deterioration or other events secondary to the malignancy under study 
(including new metastatic lesions) or death due to progression. 
• Hospitalization for the performance of protocol-required procedures or administration of 
study treatment. However, hospitalization or a prolonged hospitalization for a 
complication of therapy administration will be reported as an SAE. 
• Hospitalization or procedures planned prior to study start. A pre-planned procedure must 
be documented in the source documents. However, hospitalization or prolonged 
hospitalization for a complication remains to be reported as an SAE. 
• An elective hospitalization for a pre-existing condition unrelated to the studied indication. 
• Hospital admission that is not associated with an AE (e.g. social hospitalization for 
purpose of respite care). 
• Routine treatment or monitoring of the studied indication not associated with any 
deterioration in condition. 

Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 61 of 137 
Version 6.0 
• The administration of blood or platelet transfusion as routine treatment of studied 
indication. However, hospitalization or prolonged hospitalization for a complication of 
such transfusions remains to be reported as an SAE. 
• Emergency outpatient treatment or observation that does not result in admission, unless 
fulfilling other seriousness criteria above. 
7.1.5 SUSAR/Unexpected Serious ADR 
A SUSAR/Unexpected Serious ADR is defined as a suspected unexpected serious adverse reaction. 
An unexpected AE is any adverse drug event, the specificity or severity of which is not consistent 
with the current Selinexor/KPT-330 IB. Also, reports that provide significant information on the 
specificity or severity of a known, already documented AE constitute unexpected AEs. An event 
more specific or more severe than described in the IB would be considered “unexpected”. All 
suspected adverse reactions related to selinexor which occur in the trial and that are both 
unexpected and serious (SUSARs/Unexpected Serious ADR) are subject to expedited reporting. 
7.2 
Reporting of SAEs 
Any clinical AE or abnormal laboratory test value that is serious occurring during the course of the 
study from the date of signing the informed consent, irrespective of the treatment received by the 
patient, must be reported to the Sponsor within 24 hrs (expedited notification). For each patient, all 
SAEs must be reported up to 30 days after the last dose of investigational product. SAEs occurring 
more than 30 days after a patient is discontinued from the study treatment may be reported at the 
discretion of the Investigator. 
The completed SAE form must be sent to: 
Pharmacovigilance Department 
Karyopharm Therapeutics Inc. 
Email: pharmacovigilance@karyopharm.com 
Fax: +1-617-334-7617 (US) 
+49-89-9218-5650 (Germany) 
 
The Sponsor will medically review all SAEs. 
The following detailed information must be recorded for each SAE in the SAE report form: 
• A description of the AE  
• The severity grade as assessed by the Investigator according to the definitions in 
NCI-CTCAE Version 4.03 (Section 16.4, Appendix 4) 
• The date of becoming serious and the date of becoming known (if different) 
• The reason for seriousness 
• The outcome of the SAE at the time of the report 
• Information on administration of the study drug and any action taken 
• Information on any treatment procedures necessary for the SAE, concomitant 
medications, relevant lab tests and relevant medical history 

Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 62 of 137 
Version 6.0 
If in any one patient the same SAE occurs on several occasions, then the SAE in question must be 
documented and assessed anew each time. 
The Investigator is required to submit SAE Follow-up reports until the SAE has resolved or 
stabilized and all queries have been answered. 
7.3 
Reporting of SUSARs/Expedited Reporting of Unexpected Serious ADRs 
Sites within the EU: 
Karyopharm Therapeutics will ensure the notification of the appropriate ethics committees, 
competent authorities, and participating Investigators of all SUSARs events occurring at the sites 
in accordance with local legal requirements, statutes, and the European Clinical Trial Directive as 
follows: 
• Reporting of the SUSAR to the Competent Authorities and Ethics Committees within 
15 days (or within 7 days for fatal and life-threatening events). 
• Sending the event to all participating Investigators for information. 
 
In addition, all events that require a new assessment of the risk-benefit ratio will be reported to the 
Ethics Committee and the Competent Authority of each concerned Member State within 15 days. 
This includes: 
• Single reports of expected serious adverse reactions with unexpected outcome.  
• An increase in the rate of occurrence of expected serious adverse reactions which is 
judged to be clinically relevant. 
• Post-study SUSARs that occur after the patient has completed a clinical trial. 
• New events related to the conduct of the trial or the development of the investigational 
medicinal products and likely to affect the safety of the patients. 
Sites in the United States: 
Karyopharm Therapeutics will ensure Expedited reporting of unexpected Serious ADR to FDA in 
accordance with local legal requirements, statutes and ICH topic E2A  (Section 16.1, Appendix 1) 
as follows: 
• Reporting of the unexpected Serious ADR to FDA within 15 days (or within 7 days for 
fatal and life-threatening events) 
• Sending the event to all participating Investigators for information (with confirmation of 
receipt). 
Investigators must notify their Institutional Research Board (IRB) or Research Ethics Boards 
(REBs) in accordance with local regulations and file the report with their Investigator Site File. 
The Sponsor is responsible to ensure that the latest Selinexor/KPT-330 IB is used as the source 
document for determining the expectedness of an SAE.  

Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 63 of 137 
Version 6.0 
7.4 
Recording of Adverse Events 
The Investigator is responsible for ensuring that all AEs observed by the Investigator or reported 
by patients are properly and no later than 7 days after patients visit recorded in the patient’s medical 
records and the eCRF.  
The following AE attributes must be assigned by the Investigator:  
• Severity grade according to the NCI-CTCAE criteria Version 4.03 (Section 16.4, 
Appendix 4) 
• Start date and stop date (or date of last assessment) 
• Outcome 
• Causality to study drug and chemotherapy (to be assessed as either related or unrelated) 
• Any action taken with study medication 
• Any treatment administered to the patient or procedure performed due to the adverse 
event  
AEs will be followed until they resolve to baseline or are considered stable. It will be left to the 
Investigator’s clinical judgment to determine whether an AE is related and of sufficient severity to 
require the patient’s removal from treatment or from the study. A patient may also voluntarily 
withdraw from treatment due to what he or she perceives as an intolerable AE. If either of these 
situations arises, the patient should be strongly encouraged to undergo an end-of-study assessment 
and be under medical supervision until symptoms cease or the condition becomes stable. 
Pre-existing diseases, when worsening during study therapy, have to be considered as AEs. They 
can lead to SAEs, if the meet the criteria described in Section 7.1.3. 
Intensity of AEs will be graded using the NCI-CTCAE, version 4.03 (Section 16.4, Appendix 4). 
If an AE occurs which is not described in the CTCAE version 4.03, the four-point scale below will 
be used. 
Mild: 
Discomfort noticed but no disruption of normal daily 
activity 
Moderate: 
Discomfort sufficient to reduce or affect daily activity 
Severe: 
Inability to work or perform normal daily activity 
Life-threatening: Represents an immediate threat to life 
7.5 
Laboratory Test Abnormalities 
Laboratory test results will be recorded on the laboratory results pages of the eCRF. In the event 
of unexplained abnormal laboratory test values, the tests should be repeated immediately (within 
24 hrs) and followed up until they have returned to the normal range and/or an adequate explanation 
of the abnormality is found.  
Laboratory test value abnormalities as such should not be reported on the AE page of the eCRF as 
AEs unless they are treatment-emergent and they satisfy one or more of the following conditions 
for clinical significance: 
1. Accompanied by clinical symptoms. 

Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 64 of 137 
Version 6.0 
2. Leading to a change in study medication (e.g. dose modification, interruption or perma-
nent discontinuation). 
3. Requiring a change in concomitant therapy (e.g. addition of, interruption of, discontinua-
tion of, or any other change in a concomitant medication, therapy or treatment). 
Please note: Any laboratory result abnormality fulfilling the criteria for an SAE should be reported 
as such, in addition to being recorded as an AE in the eCRF. 
7.6 
Pregnancy 
Pregnancy per se is not considered an AE. A medical occurrence observed in the mother or 
fetus/newborn would be an AE. 
Female patients must be instructed to immediately inform the Investigator if they become pregnant 
during the study. If a patient becomes pregnant, study treatment must immediately be stopped and 
the patient must be withdrawn from the study. Pregnancies occurring up to 3 months after the 
completion of the last treatment cycle must also be reported to the Investigator.  The Investigator 
should counsel the patient and discuss the risks of continuing the pregnancy and the possible effects 
on the fetus. The patient should be monitored until the conclusion of the pregnancy.  
Pregnancy occurring in the partner of a male patient participating in the study should also be 
reported to the Investigator.   The partner should be counselled and followed as described above.  
 
The investigator must report all pregnancies within 24 hours of knowledge to the Karyopharm 
Pharmacovigilance Department.  
7.7 
Adverse Drug Reactions with Concomitant Medication 
The Investigators must be aware that for all concomitant medications the regulations of post-
marketing reporting for suspected ADRs apply, i.e. reporting to the marketing authorization holder 
or the local regulatory bodies. 
7.8 
Safety Surveillance 
Regular safety teleconferences between the site Investigators and the Sponsor will be conducted. 
Any safety issues will be discussed and minutes recorded and distributed to all attendees.  

6HOLQH[RU.37
.DU\RSKDUP7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO.&3
1RYHPEHU

&RQILGHQWLDO
3DJHRI
9HUVLRQ
 67$7,67,&$/0(7+2'6

7ULDO'HVLJQDQG+\SRWKHVHV
7KLVWULDOKDVEHHQGHVLJQHGDVDQRSHQODEHOPXOWLSOHDUPPXOWLFHQWHU3KDVHVWXG\


3DWLHQWVLQ0HGLFDO$UPV%DQG&ZLOOEHWUHDWHGZLWK
VHOLQH[RUDORQHWZLFHZHHNO\3DWLHQWVLQ0HGLFDO$UP'ZLOOEHWUHDWHGZLWKVHOLQH[RURQFH
ZHHNO\
7KHSULPDU\WULDOREMHFWLYHLVWRGHWHUPLQHWKHHIILFDF\RIVHOLQH[RULQDGXOWVZLWKUHFXUUHQW*%0
DVGHWHUPLQHGE\WKHP3)6%DVHGRQKLVWRORJLFDOLQIRUPDWLRQFRQWDLQHGLQWKHOLWHUDWXUHWKHWULDO
ZRXOGEHFRQVLGHUHGDVXFFHVVLIWKHUHLVHYLGHQFHWRVXJJHVWDP3)6UDWHDVKLJKDV6LPRQ¶V
WZRVWDJHGHVLJQZLOOEHXVHGWRDGGUHVVWKHSULPDU\REMHFWLYHZLWKWKHIROORZLQJK\SRWKHVLVWR
EHWHVWHGIRUWKHSULPDU\HIILFDF\HQGSRLQWRIP3)6

+WUXH3)6UDWHDWPRQWKVYHUVXV+WUXH3)6UDWHDWPRQWKV
3)6LVGHILQHGDVWKHWLPHIURPVWDUWRIWUHDWPHQWXQWLOWKHILUVWGRFXPHQWHGSURJUHVVLRQXVLQJWKH
5$12FULWHULDRUGHDWKIURPDQ\FDXVH
6HFRQGDU\REMHFWLYHVLQFOXGHWKHIROORZLQJ
x 7RGHWHUPLQHWKHHIILFDF\RIVHOLQH[RULQDGXOWVZLWKUHFXUUHQW*%0DVGHWHUPLQHGE\
UHVSRQVHUDWHDFFRUGLQJWRWKH5$12FULWHULD
x 7RGHWHUPLQHWKHHIILFDF\RIVHOLQH[RULQDGXOWVZLWKUHFXUUHQW*%0DVGHWHUPLQHGE\
PHGLDQRYHUDOOVXUYLYDO26
x 7RGHWHUPLQHWKHHIILFDF\RIVHOLQH[RULQDGXOWVZLWKUHFXUUHQW*%0DVGHWHUPLQHGE\
PHGLDQSURJUHVVLRQIUHHVXUYLYDO3)6
x 7RHYDOXDWHVDIHW\DQGWROHUDELOLW\RIVHOLQH[RU
,WLVEHOLHYHGWKDWVHOLQH[RUPD\EHRIEHQHILWLQSDWLHQWVZKRUHTXLUHF\WRUHGXFWLYHVXUJHU\IRU
UHFXUUHQWGLVHDVHDVSDUWRIWKHLUURXWLQHFDUH










6DPSOH6L]H&DOFXODWLRQ
 $UP%PJPWZLFHZHHNO\
CCI
CCI
CCI

6HOLQH[RU.37
.DU\RSKDUP7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO.&3
1RYHPEHU
&RQILGHQWLDO
3DJHRI
9HUVLRQ
 )ODW'RVLQJ$UPV$UP&DQG$UP'

(YDOXDWLRQ&DWHJRULHVIRU3DWLHQWV
 0RGLILHG,QWHQWWR7UHDW3RSXODWLRQ
7KHWUHDWHGSRSXODWLRQPRGLILHGLQWHQWWRWUHDWSRSXODWLRQ>P,77@ZLOOFRQVLVWRIDOOSDWLHQWVLQ
$UPV%&DQG'ZKRUHFHLYHDWOHDVWRQHGRVHRIVWXG\PHGLFDWLRQDQGKDYHDWOHDVWRQHSRVW
EDVHOLQHHIILFDF\IROORZXSDVVHVVPHQWXQOHVVWKHSDWLHQWGLVFRQWLQXHGWUHDWPHQWSULRUWRWKHILUVW
SRVWEDVHOLQHDVVHVVPHQWGXHWRGHDWKWR[LFLW\RUGLVHDVHSURJUHVVLRQ7KLVSRSXODWLRQZLOOEH
XVHGIRUSULPDU\DQDO\VHVRIHIILFDF\DGGLWLRQDOVHQVLWLYLW\DQDO\VHVZLOOEHSHUIRUPHGRQWKLV
SRSXODWLRQDVGHVFULEHGLQ6HFWLRQ


 3HU3URWRFRO3RSXODWLRQ
7KHSHUSURWRFROSRSXODWLRQ33ZLOOFRQVLVWRIDOO$UPV%&DQG'SDWLHQWVZKRKDYHEHHQ
DGPLQLVWHUHGDWOHDVWPRQWKVRIVWXG\GUXJWUHDWPHQWZKRDUHFRPSOLDQWZLWKVWXG\DVVHVVPHQWV
DQG KDYH UHFHLYHG DW OHDVW  RIWKHLU SUHVFULEHG VWXG\PHGLFDWLRQDQGZKRKDYHQRPDMRU
SURWRFROYLRODWLRQVWKDWZRXOGFRPSURPLVHWKHDVVHVVPHQWRIHIILFDF\0DMRUYLRODWLRQVZLOOEH
GHWHUPLQHGLQGHSHQGHQWO\RINQRZOHGJHRIUHVSRQVHWRWKHUDS\7KLVSRSXODWLRQZLOOEHXVHGIRU
VXSSRUWLYHLQIHUHQFHVFRQFHUQLQJHIILFDF\KRZHYHULIWKHUHDUHPDMRUGLIIHUHQFHVEHWZHHQWKH
CCI
CCI
CCI

6HOLQH[RU.37
.DU\RSKDUP7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO.&3
1RYHPEHU

&RQILGHQWLDO
3DJHRI
9HUVLRQ
UHVXOWV LQ WKLV SRSXODWLRQ DQG WKRVH REWDLQHG LQ WKH P,77 SRSXODWLRQ WKLV ZLOO EH WDNHQ LQWR
FRQVLGHUDWLRQLQWKHGHFLVLRQWRFRQWLQXHWRODWHUSKDVHVWXGLHVRULQWKHGHVLJQRIIXUWKHUVWXGLHV





 6DIHW\3RSXODWLRQ
7KH VDIHW\ SRSXODWLRQ ZLOO FRQVLVW RI DOO SDWLHQWV ZKR KDYH UHFHLYHG DQ\ DPRXQW RI VWXG\
PHGLFDWLRQ7KHVDIHW\SRSXODWLRQZLOOLQFOXGHERWKWKHQRQVXUJLFDODQGVXUJLFDOSDWLHQWJURXSV
DQDO\VHVRIVDIHW\ZLOOEHSURGXFHGIRUERWKWKHSRRORIVXUJLFDODQGQRQVXUJLFDOSDWLHQWVDVZHOO
DVHDFKJURXSVHSDUDWHO\

0HWKRGVRI6WDWLVWLFDO$QDO\VLV
 *HQHUDO6WDWLVWLFDO&RQVLGHUDWLRQV
7DEXODWLRQV ZLOO EH SURGXFHG IRU DSSURSULDWH GHPRJUDSKLF EDVHOLQH HIILFDF\ DQG VDIHW\
SDUDPHWHUV )RU FDWHJRULFDO YDULDEOHV VXPPDU\ WDEXODWLRQV RI WKH QXPEHU DQG SHUFHQWDJH RI
SDWLHQWVZLWKLQHDFKFDWHJRU\ZLWKDFDWHJRU\IRUPLVVLQJGDWDRIWKHSDUDPHWHUZLOOEHSUHVHQWHG
DV ZHOO DV WZRVLGHG  FRQILGHQFH LQWHUYDOV &, XQOHVV RWKHUZLVH VWDWHG )RU FRQWLQXRXV
YDULDEOHVWKHQXPEHURISDWLHQWVPHDQPHGLDQVWDQGDUGGHYLDWLRQ6'PLQLPXPDQGPD[LPXP
YDOXHVZLOOEHSUHVHQWHG7LPHWRHYHQWGDWDZLOOEHVXPPDUL]HGXVLQJ.DSODQ0HLHUPHWKRGRORJ\
XVLQJ WK WK PHGLDQ DQG WK SHUFHQWLOHV ZLWK DVVRFLDWHG VLGHG  &,V DV ZHOO DV
SHUFHQWDJHRIFHQVRUHGREVHUYDWLRQV
1RLPSXWDWLRQRIPLVVLQJHIILFDF\GDWDLVSODQQHG)RUWLPHWRHYHQWDQDO\VHVSDWLHQWVZKRKDYH
QRHIILFDF\HYDOXDWLRQVIRU GLVHDVHUHFXUUHQFHZLOOEHFRQVLGHUHG FHQVRUHGDWWLPH )RU26
SDWLHQWVZLOOEHFHQVRUHGRQWKHGDWHWKH\ZHUHODVWNQRZQWREHDOLYHUHJDUGOHVVRIGLVHDVHVWDWXV
)RU$(VPLVVLQJGDWHVZLOOQRWEHLPSXWHGKRZHYHULISDUWLDOGDWHVDUHDYDLODEOHWKH\ZLOOEH
XVHGWRDVVHVVLIWKH$(RFFXUUHGGXULQJWKHWUHDWPHQWSHULRG0LVVLQJVHYHULWLHVRI$(VZLOOQRW
EHLPSXWHGDQGZLOOEHFRQVLGHUHGPLVVLQJLQDQ\WDEXODWLRQVRI$(VHYHULW\,IDQ$(LVPLVVLQJ
DUHVSRQVHWRWKHTXHVWLRQUHJDUGLQJUHODWLRQVKLSWRWUHDWPHQWWKHHYHQWZLOOEHFRQVLGHUHGWREH
UHODWHG
)RUPDOVWDWLVWLFDODQDO\VHVIRUHIILFDF\DVGHVFULEHGLQWKHIROORZLQJVHFWLRQVDQGFRQVLVWHQWZLWK
6LPRQ¶VWZRVWDJHGHVLJQZLOOSHUWDLQRQO\WRWKHSULPDU\SDWLHQWSRSXODWLRQVP,77DQG33
WKDW LQFOXGH QRQVXUJLFDO *%0 SDWLHQWV 'HVFULSWLYH VWDWLVWLFV RQO\ ZLOO EH SUHVHQWHG IRU WKH
VXUJLFDOJURXS
 'HPRJUDSKLFVDQG%DVHOLQH&KDUDFWHULVWLFV
7KHGHPRJUDSKLFFKDUDFWHULVWLFVWREHVXPPDUL]HGZLOOLQFOXGHJHQGHUUDFHHWKQLFLW\+LVSDQLF
RULJLQDQGDJHDWWLPHRIFRQVHQW)RUJHQGHUUDFHDQG+LVSDQLFRULJLQWKHVXPPDU\VWDWLVWLFV
ZLOOEHWKHQXPEHUDQGSHUFHQWDJHRISDWLHQWVZLWKLQHDFKFDWHJRU\7KHFDWHJRULHVIRUUDFHZLOOEH
CCI
CCI

6HOLQH[RU.37
.DU\RSKDUP7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO.&3
1RYHPEHU

&RQILGHQWLDO
3DJHRI
9HUVLRQ
WKRVHUHFRUGHGLQWKHGDWDEDVH)RUDJHDWWLPHRIFRQVHQWWKHPHDQPHGLDQPLQLPXPPD[LPXP
DQGVWDQGDUGGHYLDWLRQZLOOEHSURYLGHGIRUHDFKJURXSDQGWKHWRWDOVDPSOH
%DVHOLQHFKDUDFWHULVWLFVLQFOXGH3HUIRUPDQFH6WDWXVGXUDWLRQIURPLQLWLDOGLDJQRVLVUHVSRQVHWR
SUHYLRXVWKHUDS\<1'HPRJUDSKLFVDQGEDVHOLQHFKDUDFWHULVWLFVZLOOEHVXPPDUL]HGVHSDUDWHO\
IRUSDWLHQWVLQHDFKWUHDWPHQWDUP
 (IILFDF\(YDOXDWLRQ
3ULPDU\$QDO\VLV5DWHRIP3)6
7KHDQDO\VLVRIP3)6ZLOOEHSHUIRUPHGE\FDOFXODWLQJWKHSRLQWHVWLPDWHRIWKHSHUFHQWDJHRI
QRQVXUJLFDO*%0SDWLHQWVZKRKDYHQHLWKHUSURJUHVVHGQRUGLHGDWPRQWKVIROORZLQJWKHVWDUW
RIWKHUDS\ZKHUHSURJUHVVLRQZLOOEHGHWHUPLQHGE\WKH5$12FULWHULD,QRUGHUWRDFFRPPRGDWH
SRWHQWLDOFKDQJHV LQ LQGLYLGXDO SDWLHQW YLVLW VFKHGXOHV D ZLQGRZ RI GD\V ZLOO EH DOORZHG
DURXQGWKHPRQWKYLVLWIRUWKHSULPDU\DQDO\VLVRIUDWHRIPRQWK3)67KLVZLQGRZZLOOEH
DSSOLHGWRWKHFDOFXODWLRQRIWKHSRLQWHVWLPDWHRIP3)6DFWXDOWLPHVRIHYHQWVSURJUHVVLRQRU
GHDWKZLOOEHXVHGIRUWKH.DSODQ0HLHUVWDWLVWLFDOVXPPDU\RI3)67KHSULPDU\DQDO\VLVZLOOEH
SHUIRUPHGZKHQDOOSDWLHQWVKDYHGLHGFRPSOHWHGPRQWKVRIVWXG\WUHDWPHQWKDYHZLWKGUDZQ
RUKDYHEHHQORVWWRIROORZXS
7REHFRQVLVWHQWZLWK6LPRQ¶VGHVLJQDORZHURQHVLGHG&,ZLOOEHSUHVHQWHGRQUDWHRI
P3)6DGGLWLRQDOO\IRUGHVFULSWLYHSXUSRVHVDWZRVLGHG&,ZLOODOVREHFDOFXODWHG7KH
P3)6UHVXOWVZLOOEHSUHVHQWHGIRUWKHILUVWVWDJHRIWKHVWXG\VHSDUDWHO\IRU$UPV%&DQG'
DQGIRUERWKVWDJHVFRPELQHGVHSDUDWHO\IRU$UPV&DQG'FRQVLVWHQWZLWK6LPRQ¶VGHVLJQ

6HFRQGDU\$QDO\VHV
5HVSRQVHWRWKHUDS\5HVSRQVHZLOOEHGHWHUPLQHGDVREMHFWLYHUHVSRQVHUDWH255GHILQHG
DVHLWKHUFRPSOHWHUHVSRQVH&5RUSDUWLDOUHVSRQVH35XVLQJWKH5$12FULWHULDFDOFXODWHGDV
DSURSRUWLRQDQGLQFOXGLQJDWZRVLGHG&,,QDGGLWLRQWRDVVLVWLQHYDOXDWLQJWKHHYLGHQFHRI
HIILFDF\DQGWREHFRQVLVWHQWZLWKWKHDSSURDFKXVHGIRUUDWHRIP3)6DORZHURQHVLGHG&,
RQUHVSRQVHUDWHZLOOEHFDOFXODWHG%DVHGRQSULRUVWXGLHVSUHOLPLQDU\HYLGHQFHRIHIILFDF\ZRXOG
EHSURYLGHGLIWKLVORZHUOLPLWZHUHWRH[FHHG
0HGLDQ2YHUDOO6XUYLYDO26ZLOOEHFDOFXODWHGIURPWKHGDWHRIVWDUWRIVWXG\WKHUDS\WRWKH
GDWHRIGHDWK3DWLHQWVZKRDUHVWLOODOLYHSULRUWRWKHGDWDFXWRIIIRUILQDOHIILFDF\DQDO\VLVRUZKR
GURSRXWSULRUWRVWXG\HQGZLOOEHFHQVRUHGDWWKHGD\WKH\ZHUHODVWNQRZQWREHDOLYH7KHDQDO\VLV
RI26ZLOOEHEDVHGRQWKH.DSODQ0HLHUPHWKRGIRUHVWLPDWLRQRIVXPPDU\VWDWLVWLFVDQGLQFOXGH
WKHWKWKPHGLDQDQGWKSHUFHQWLOHVDQGDVVRFLDWHG&,V$ORZHURQHVLGHG&,RQ
PHGLDQ26ZLOODOVREHFDOFXODWHG7KHVHFRQGDU\DQDO\VLVIRU26ZLOOEHSHUIRUPHGZKHQDOO
SDWLHQWVKDYHGLHGKDYHEHHQRIIVWXG\WUHDWPHQWIRUPRQWKVKDYHEHHQORVWWRIROORZXSRU
KDYHZLWKGUDZQ
0HGLDQ3URJUHVVLRQIUHH6XUYLYDO3)6ZLOOEHFDOFXODWHGIURPWKHGDWHRIVWDUWRIVWXG\WKHUDS\
WRWKHGDWHRISURJUHVVLRQEDVHGRQ5$12FULWHULDRUGDWHRIGHDWKVKRXOGSURJUHVVLRQQRWKDYH
CCI

6HOLQH[RU.37
.DU\RSKDUP7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO.&3
1RYHPEHU

&RQILGHQWLDO
3DJHRI
9HUVLRQ
RFFXUUHG7KHDQDO\VLVRIPHGLDQ3)6ZLOOEHVLPLODUWRWKDWRI26XVLQJWKH.DSODQ0HLHUPHWKRG
DVQRWHGDERYHDFWXDOHYHQWWLPHVZLOOEHXVHGLQWKLVDQDO\VLV
6HQVLWLYLW\$QDO\VHV
$VHQVLWLYLW\DQDO\VLVRIWKHSULPDU\HQGSRLQWRIP3)6ZLOOEHSHUIRUPHGWRDVVHVVWKHSRWHQWLDO
LQIOXHQFHRIFDXVDOLW\RIGHDWKVRQVWXG\ZKHUHGHDWKVGXHWRFDXVHVWKDWDUHFOHDUO\XQUHODWHGWR
WKHGLVHDVHRUVWXG\GUXJZRXOGEHH[FOXGHGIURPWKHGHILQLWLRQRI3)66HQVLWLYLW\DQDO\VHVZLOO
EHSHUIRUPHGRQWKHGDWDREWDLQHGIURPERWKVWDJHVRI6LPRQ¶VWZRVWDJHGHVLJQDQGZLOOFRQVLVW
RIRQHVLGHGORZHU&,VRQWKHUDWHRIP3)6
([SORUDWRU\$QDO\VHV
CCI

6HOLQH[RU.37
.DU\RSKDUP7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO.&3
1RYHPEHU
&RQILGHQWLDO
3DJHRI
9HUVLRQ
 6DIHW\(YDOXDWLRQ
6DIHW\DQDO\VHVZLOOEHFRQGXFWHGXVLQJWKH6DIHW\3RSXODWLRQ&DWHJRULHVIRUVXPPDUL]DWLRQZLOO
FRQVLVWRIHDFKLQGLYLGXDODUPDVZHOODVDFDWHJRU\IRU*%0QRQVXUJLFDOFRQVLVWLQJRI$UPV%
&DQG'DQGDQRYHUDOOWRWDO
7KHFRPSDULVRQRIVDIHW\DQGWROHUDELOLW\RIVHOLQH[RULQ$UPV%&DQG'ZLOOEHDVVHVVHGXVLQJ
DGHVFULSWLYHUHYLHZRIWKHHQGSRLQWVGHVFULEHGLQWKLVVHFWLRQLQDGGLWLRQWRWKHIROORZLQJ
x 'LIIHUHQFHLQLQFLGHQFHRIFRPPRQ$(VRFFXUULQJLQRIWKHVDIHW\SRSXODWLRQXVLQJ
)LVKHU¶VH[DFWWHVW6LPLODUO\WKHGLIIHUHQFHLQWKHJUDGLQJRIFRPPRQ$(VZLOOEHDVVHVVHG
XVLQJ)LVKHU¶H[DFWWHVWDVDSSURSULDWHHJWKHGLVWULEXWLRQRIWKHJUDGHVLVQRWVSDUVH
GLIIHUHQWJUDGHVPD\EHFROODSVHGIRUWKHIHDVLELOLW\RISHUIRUPLQJ)LVKHU¶VWHVW
x ,QFLGHQFHRIGRVHUHGXFWLRQDQGLQFLGHQFHRIGRVHLQWHUUXSWLRQZLOOEHDVVHVVHGE\)LVKHU¶V
H[DFWVHSDUDWHO\ZKHQWKHUHDUHPDQ\YDOXHVLQWKHQXPEHURIGRVHUHGXFWLRQRUQXPEHU
RIGRVHUHGXFWLRQ,IGRVHUHGXFWLRQDQGGRVHLQWHUUXSWLRQDUHFRPPRQLQDOODUPVWKH
QXPEHU RI GRVH UHGXFWLRQV DQG QXPEHU RI GRVH LQWHUUXSWLRQV ZLOO EH FRPSDUHG DPRQJ
WUHDWPHQWDUPVXVLQJ.UXVNDO:DOOLVWHVW
$GYHUVH(YHQWV
$(V ZLOO EH FRGHG XVLQJ WKH 0HG'5$ GLFWLRQDU\ DQG GLVSOD\HG LQ WDEOHV DQG OLVWLQJV XVLQJ
6\VWHP2UJDQ&ODVV62&DQG3UHIHUUHG7HUP
$QDO\VHVRI$(VZLOOEHSHUIRUPHGIRUWKRVHHYHQWVWKDWDUHFRQVLGHUHGWUHDWPHQWHPHUJHQWZKHUH
WUHDWPHQWHPHUJHQWLVGHILQHGDVDQ\$(ZLWKRQVHWRUZRUVHQLQJRIDSUHH[LVWLQJFRQGLWLRQRQRU
DIWHUWKHILUVWDGPLQLVWUDWLRQRIVWXG\PHGLFDWLRQWKURXJKGD\VIROORZLQJODVWGRVHRUDQ\HYHQW
FRQVLGHUHGGUXJUHODWHGE\WKH,QYHVWLJDWRUWKURXJKWKHHQGRIWKHVWXG\$(VZLWKSDUWLDOGDWHV
ZLOOEHDVVHVVHGXVLQJWKHDYDLODEOHGDWHLQIRUPDWLRQWRGHWHUPLQHLIWUHDWPHQWHPHUJHQW$(VZLWK
FRPSOHWHO\PLVVLQJGDWHVZLOOEHDVVXPHGWREHWUHDWPHQWHPHUJHQW
$(V ZLOO EH VXPPDUL]HG E\ SDWLHQW LQFLGHQFH UDWHV WKHUHIRUH LQ DQ\ WDEXODWLRQ D SDWLHQW
FRQWULEXWHVRQO\RQFHWRWKHFRXQWIRUDJLYHQ$(SUHIHUUHGWHUP
7KH QXPEHU DQG SHUFHQWDJH RI SDWLHQWV ZLWK DQ\ WUHDWPHQWHPHUJHQW $( ZLOO EH VXPPDUL]HG
RYHUDOODQGIRUHDFKDUP7KHQXPEHUDQGSHUFHQWDJHRISDWLHQWVZLWKWUHDWPHQWHPHUJHQW$(V
DVVHVVHGE\WKH,QYHVWLJDWRUDVDWOHDVWSRVVLEO\UHODWHGWRWUHDWPHQWZLOODOVREHWDEXODWHG7KH
QXPEHUDQGSHUFHQWDJHRISDWLHQWVZLWKDQ\JUDGHWUHDWPHQWHPHUJHQW$(ZLOOEHWDEXODWHGLQ
WKHVDPHPDQQHU,QWKHHYHQWDSDWLHQWH[SHULHQFHVUHSHDWHGHSLVRGHVRIWKHVDPH$(WKHQWKH
HYHQWZLWKWKHKLJKHVWVHYHULW\DQGRUVWURQJHVWFDXVDOUHODWLRQVKLSWRVWXG\WUHDWPHQWZLOOEHXVHG
IRUSXUSRVHVRIWDEXODWLRQV
CCI

Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 71 of 137 
Version 6.0 
• Serious AEs will also be tabulated.  
• No formal hypothesis-testing analysis of AE incidence rates will be performed.  
• All AEs (treatment emergent and post-treatment) will be listed in patient data listings.  
• By-patient listings will be provided for the following: patient deaths; serious AEs; and 
AEs leading to withdrawal.  
8.4.4.2 Laboratory Data 
The actual value and change from baseline to each on study evaluation will be summarized for 
each clinical laboratory parameter, including hematology and clinical chemistry. In the event of 
repeat values, the last non-missing value per study day/time will be used.  
Severity of select clinical lab measures will be determined using CTCAE v.4.03 criteria (e.g. those 
measures that have a corresponding CTCAE grade classification). Labs with CTCAE grades 
greater than or equal to 3 will be presented in a data listing. Shift tables that present changes from 
baseline to worst on-study values  
8.4.4.3 Vital Signs and Physical Examinations 
The actual value and change from baseline to each on study evaluation will be summarized for vital 
signs. By-patient listings of vital sign measurements will be presented in data listings.  
Physical examination results at screening will be summarized; all other abnormal physical 
examination data were to be recorded on the AE eCRF. All examination findings will be presented 
in a data listing.  
8.4.4.4 Concomitant Medications 
The use of concomitant medications will be included in by-patient data listings. 
8.5 
Interim and Final Analysis 
In accordance with Simon’s two-stage optimal design36, there will be a preliminary assessment of 
efficacy for Arms B, C, and D after the first 12 non-surgical patients enrolled in each arm have 
6-month data available to assess PFS. Note that this initial analysis may take place sooner than 
when the 12th patient has available data, should there be 2 or more PFS responders after fewer than 
12 patients. Should the trial be terminated at the first stage for Arms B, C, and D, all efficacy and 
safety analyses as noted above will be performed. Patient enrollment into the trial will continue 
while the first stage analysis is being conducted. 
The final analysis of the primary endpoint will take place after there are 30 patients evaluable for 
analysis of 6mPFS separately in Arm C and Arm D, as enrollment in Arm B was stopped to explore 
alternative dosing in Protocol Versions ≥ 4.0 (see details in Section 8.2). Additional data 
summarization may take place after all available survival data are collected, or after Sponsor 
decision, as appropriate.  

Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 72 of 137 
Version 6.0 
9 DATA QUALITY ASSURANCE 
Accurate and reliable data collection will be assured by verification and cross–check of the eCRFs 
against the Investigator’s records by the study monitor (source document verification), and the 
maintenance of a drug–dispensing log by the Investigator. Data for this study will be recorded via 
eCRF. It will be transcribed by the site from the source documents onto the eCRF. Data are 
reviewed and checked for omissions, apparent errors, and values requiring further clarifications 
using computerized and manual procedures. Data queries requiring clarification are communicated 
to the site for resolution. Only authorized personnel will make corrections to the clinical database 
and an audit trail will document all corrections. 
 

Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 73 of 137 
Version 6.0 
10 ETHICAL ASPECTS 
10.1 Good Clinical Practice 
The Investigator will ensure that the study is performed in accordance with the international 
standards of GCP and according to all local laws and regulations concerning clinical studies. 
10.2 Patient Information and Informed Consent 
It is the responsibility of the Investigator to obtain written informed consent from each patient, or 
their legally authorized representative, participating in this study, after an adequate explanation of 
the aims, importance, anticipated benefits, potential hazards and consequences of the study 
according to applicable local laws. Written informed consent must be obtained before any study-
specific procedures are performed. It must be also explained to the patient that they are completely 
free to refuse to enter the study or to withdraw from it at any time, for any reason, without incurring 
any penalty or withholding of treatment on the part of the Investigator.  
With the declaration of consent, the patient agrees to the collection of data about his/her disease 
being recorded within the context of the clinical trial and that it may be transferred to the Sponsor 
in pseudonymized form. 
The patient also agrees to allow the monitor/auditor health authorities to verify the patient data 
collected against the patient’s original medical records for the purpose of source data verification.  
The informed consent form personally signed and dated by the patient, or their legally authorized 
representative, must be kept on file by the Investigator(s) and documented in the eCRF and the 
patient’s medical records. The Investigator must confirm with the Sponsor that he/she has obtained 
written informed consent. 
If new safety information results in significant changes to the risk/benefit assessment, the consent 
form should be reviewed and updated if necessary. All patients (including those already being 
treated) should be informed of the new information and must give their written informed consent 
to continue in the study. 
If family doctors are to be informed of their patients’ participation in the clinical study, this should 
be mentioned in the consent form. 
10.3 Independent Ethics Committees and Regulatory Authorities 
10.3.1 Approval by Regulatory Authorities and Independent Ethics Committees 
It is the responsibility of the Sponsor to obtain and maintain independent approval from the 
applicable regulatory authority and a positive opinion from the competent ethics committees to 
conduct the study in accordance with local legal requirements and statutes.  
Indemnity insurance will be arranged for the trial patients in accordance with the applicable local 
law.  

Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 74 of 137 
Version 6.0 
10.3.2 Notification of the Study 
The Sponsor is responsible for notifying the competent regional authority about the study and all 
Principal Investigators at the participating investigational sites, if applicable by local law. 
10.3.3 Obligation to Report and Document 
The Sponsor and the Investigator are responsible for complying with the requirements for reporting 
and documentation in accordance with local legal requirements and statutes. 

Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 75 of 137 
Version 6.0 
11 CONDITIONS FOR MODIFYING THE PROTOCOL 
Protocol modifications to ongoing studies must be made via amendment. The Sponsor is 
responsible for obtaining independent approval for substantial amendments from the applicable 
regulatory authority and a positive opinion from the competent ethics committees in accordance 
with local legal requirements, statutes and the European Clinical Trial Directive. Approval must 
be obtained before any changes can be implemented, except for changes necessary in order to 
eliminate an immediate hazard to trial patients or when the changes are non-substantial and involve 
only logistical or administrative aspects of the trial (e.g. change of telephone numbers). 

Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 76 of 137 
Version 6.0 
12 STUDY DOCUMENTATION, CRFS AND RECORD-KEEPING 
12.1 Investigator’s Files/Retention of Documents 
The Investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should be 
classified into two separate categories: Investigator’s study file and patient data. 
The Investigator’s study file will contain all essential documents such as the protocol/amendments, 
case report and query forms, patient information and informed consent form, ethics committee and 
regulatory authority approval, notification of the federal regulatory authority and competent 
regional authorities (if applicable), drug records, staff curriculum vitae and authorisation forms, 
and other appropriate documents/correspondence, etc. 
Patient data includes patient hospital/clinic records (e.g. medical reports, surgery reports 
appointment 
book, 
medical 
records, 
pathology 
and 
laboratory 
reports, 
ECG, 
electroencephalogram, X-ray, etc.), signed informed consent forms and patient screening and 
eligibility screening forms.  
The Investigator must keep these two categories of documents on file for as long as legally required 
by local and national regulations, or local IRB/ethics board policies whichever is longer, after 
completion or discontinuation of the study. The documents must be archived in a secure place and 
treated as confidential material.  
Should the Investigator wish to assign the study records to another party or move them to another 
location, the Sponsor must be notified in advance. 
If the Investigator cannot guarantee this archiving requirement at the investigational site for any or 
all of the documents, special arrangements must be made between the Investigator and the Sponsor 
to store these in sealed containers outside of the site so that they can be returned sealed to the 
Investigator in the event of a regulatory audit. Where source documents are required for the 
continued care of the patient, appropriate copies should be made for storing outside of the site. 
All documents must be archived in a secure place and treated as confidential material. 
12.2 Source Documents and Background Data 
The Investigator shall supply the Sponsor on request with any required background data from the 
study documentation or clinic records. This is particularly important when errors in data 
transcription are suspected. In the event of special problems and/or governmental queries or 
requests for audit inspections, it is also necessary to have access to the complete study records, 
provided that patient confidentiality is protected. According to the standards of the data protection 
law, all data obtained in the course of a clinical study must be treated with discretion in order to 
guarantee the rights of the patient’s privacy. 
12.3 Audits and Inspections 
This study may be audited by the Sponsor, any person authorised by the Sponsor, or the competent 
health authority in order to determine the authenticity of the recorded data and compliance with the 
study protocol.  

Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 77 of 137 
Version 6.0 
The Investigator must be aware that source documents for this trial should be made available to 
appropriately qualified personnel working on behalf of the Sponsor/monitor/auditor/health 
authority inspectors after appropriate notification for the purposes of source data verification and 
proper review of the study progress. The verification of the eCRF data must be done via direct 
inspection of the source documents. The Investigator agrees to comply with the Sponsor and 
regulatory authority requirements regarding the auditing of the study. 
All materials used in clinical studies are subjected to quality control. 
12.4 Case Report Forms 
This study will use Electronic Data Capture (EDC). The designated Investigator site staff will enter 
the data required by the protocol into the Electronic Case Report Forms (eCRF). The eCRFs have 
been built using fully validated secure web-enabled software that conforms to 21 CFR Part 11 
requirements. Investigator site staff will not be given access to the EDC system until they have 
been trained. Automatic validation programs check for data discrepancies in the eCRFs and allow 
modification or verification of the entered data by the Investigator site staff. 
The Investigator is responsible for assuring that the data entered into eCRF is complete, accurate, 
and that entry and updates are performed in a timely manner. 
 

Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 78 of 137 
Version 6.0 
13 MONITORING OF STUDY 
The monitor is responsible for familiarizing the Investigator(s) and the entire center staff involved 
in the study with all study procedures, including the administration of the study drug. 
The monitor will visit the clinical study center before the first patient has been enrolled (initiation 
visit). During the study, the monitor will visit the site regularly to check the completeness of patient 
records, the accuracy of entries on the eCRFs (source data verification), the adherence to the 
protocol to GCP, the progress of enrollment, and to ensure that study drug is being stored, 
dispensed, and accounted for according to specifications.  
Key study personnel must be available to assist the monitor during these visits. The Investigator 
(or his/her deputy) agrees to cooperate with the monitor to ensure that any problems detected in 
the course of these monitoring visits are resolved. 

Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 79 of 137 
Version 6.0 
14 CONFIDENTIALITY OF TRIAL DOCUMENTS AND PATIENT RECORDS 
The Investigator and the Sponsor (or designated person) must ensure that all data obtained in the 
course of a clinical study is treated with discretion in order to guarantee the rights of the patient’s 
privacy, according to the standards of the data protection law. eCRFs or other documents should 
be submitted to the Sponsor in pseudonymised form. The Investigator should keep a patient 
identification log showing codes and names. The Investigator should maintain documents not 
intended for submission to the Sponsor, e.g., patients’ written consent forms, in the strictest 
confidence. 

Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 80 of 137 
Version 6.0 
15 STUDY REPORT AND PUBLICATION POLICY  
This study will be entered into a clinical trial protocol registry and clinical results database. The 
Sponsor is responsible for the timely reporting of study data.  
Study data may be analyzed and submitted to regulatory authorities in one or more interim clinical 
study reports (CSR) when ≥ 75% of patients have potentially completed ≥ 2 cycles of treatment or 
discontinued from the study. Any additional data for patients continuing to receive study treatment 
past the data cutoff, as allowed by the protocol, will be reported in a final CSR once all patients 
have discontinued from the study. The final, integrated CSR will be completed approximately one 
year after the end of the study (whether completed or prematurely terminated). The report has to 
be approved by the responsible specialist chosen by the Sponsor, the statistician, and the 
coordinating Investigator by provision of their signatures.  
The results from this study will be submitted for publication and made available through an on-
line clinical results database. The main publication will be a full publication of all data from all 
sites. Any publication of the results, either in part or in whole (abstracts in journals, oral 
presentations, etc.) by Investigators or their representatives will require a pre-submission review 
by the Sponsor and the coordinating Investigators. The two coordinating Investigators will have 
the opportunity to be the first and the last authors and corresponding authors for the main 
publication, unless they choose otherwise. The remaining positions will be based on recruitment, 
good data quality, and scientific input to the study. The final author list will be a joint agreement 
between the coordinating Investigators and the Sponsor. For all other publications, the order of the 
authors will be determined according to recruitment, data quality, and significant scientific input 
to the study, after consulting the coordinating Investigators. 
 

Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 81 of 137 
Version 6.0 
16 APPENDICES 
Appendix 1:  
Definitions According to ICH Guidelines for Clinical Safety Data 
Management, Definitions and Standards for Expedited Reporting, 
Topic E2 
Appendix 2: 
Karnofsky Performance Status 
Appendix 3:  
Cockroft-Gault Formula 
Appendix 4 
National Cancer Institute Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.03 
Appendix 5: 
Ophthalmic Examination 
Appendix 6: 
NCCN Clinical Practice Guidelines in Oncology: Antiemesis 
Appendix 7: 
NCCN Clinical Practice Guidelines in Oncology: Anorexia/Cachexia 
Appendix 8: 
Glutathione (GSH)-, S-adenosylmethionine (SAM)-, or N-acetylcysteine 
(NAC)-containing Products (Representative List) 
Appendix 9: 
Summary of Changes and Rationale for Changes to Protocol KCP-330-004 

Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 82 of 137 
Version 6.0 
16.1 Appendix 1 – Definitions According to ICH Guidelines for Clinical Safety Data 
Management, Definitions and Standards for Expedited Reporting, Topic E2 
An adverse event is any untoward medical occurrence in a patient or clinical investigation patient 
who has been administered a pharmaceutical product, and which does not necessarily have to have 
a causal relationship with this treatment. 
Adverse reactions are defined as all untoward and unintended responses to an IMP related to any 
dose administered. 
An SAE or serious adverse reaction is any experience that suggests a significant hazard, 
contraindication, side effect or precaution. It is any adverse event that at any dose fulfills at least 
one of the following criteria: 
• is fatal (results in death) (NOTE: Death is an outcome, not an event) 
• is life-threatening (NOTE: The term “life-threatening” refers to an event in which the 
patient was at immediate risk of death at the time of the event; it does not refer to an 
event which could hypothetically have caused a death had it been more severe) 
• required in-patient hospitalisation or prolongation of existing hospitalisation 
• results in persistent or significant disability/incapacity 
• is a congenital anomaly/birth defect 
• is medically significant or requires intervention to prevent one or other of the outcomes 
listed above 
 
Medical and scientific judgement should be exercised in deciding whether expedited reporting to 
the Sponsor is appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalisation but may jeopardise the patient or 
may require intervention to prevent one of the outcomes listed in the definitions above. These 
situations should also usually be considered serious. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalisation, or development 
of drug dependency or drug abuse. 
An unexpected adverse event is one where the nature or severity is not consistent with the applicable 
product information. 
Causality is initially assessed by the Investigator. With respect to the obligation to report and 
document SAEs (i.e., to regulatory authorities, ethics committees, and other Investigators), 
causality can be one of two possibilities: 
 
• No (unrelated; equals not drug-related) 
• Yes (remotely, possibly, or probably drug-related) 
 
All adverse events not assessed as definitively “not drug-related” by the Investigator will be 
considered as ADRs. 

Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 83 of 137 
Version 6.0 
A suspected unexpected serious adverse reaction (SUSAR) is a serious adverse reaction whose 
nature or severity is not consistent with the applicable product information. 
It is important that the severity of an adverse event is not confused with the seriousness of the 
event. For example, vomiting which persists for many hours may be severe, but is not necessarily 
an SAE. On the other hand, stroke which results in only a limited degree of disability may be 
considered a mild stroke, but would be an SAE. 
An SAE occurring during the study or which comes to the attention of the Investigator during the 
protocol-defined follow-up period, must be reported, whether considered treatment-related or not. 
In addition, SAEs occurring after this time should be reported if considered related to test “drug”. 
Such preliminary reports will be followed by detailed descriptions later that will include copies of 
hospital case reports, autopsy reports and other documents. 
For SAEs, at a minimum the following must be assessed and recorded on the adverse events page 
of the eCRF: intensity (severity), relationship to test substance, action taken, and outcome to date. 
The obligation to document and report must be adhered to according to the national and inter-
national laws and regulations.  
For contact details and fax no. for SAE reporting, please refer to page 10. 

Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 84 of 137 
Version 6.0 
16.2 Appendix 2 – Karnofsky Performance Status  
 
100% 
Normal, no complaints, no signs of disease 
90% 
Capable of normal activity, few symptoms or signs of disease 
80% 
Normal activity with some difficulty, some symptoms or signs 
70% 
Caring for self, not capable of normal activity or work 
60% 
Requiring some help, can take care of most personal requirements 
50% 
Requires help often, requires frequent medical care 
40% 
Disabled, requires special care and help 
30% 
Severely disabled, hospital admission indicated but no risk of death 
20% 
Very ill, urgently requiring admission, requires supportive measures or 
treatment 
10% 
Moribund, rapidly progressive fatal disease processes 
0% 
Death 
 Source: Karnofsky DA, Burchenal JH. The Clinical Evaluation of Chemotherapeutic Agents in Cancer. In:  
                MacLeod CM (Ed), Evaluation of Chemotherapeutic Agents. Columbia Univ Press 1949:196 

Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 85 of 137 
Version 6.0 
16.3 Appendix 3 – Cockroft-Gault Formula 
 
Calculated CLCR (ml/min) =   
 
[(140 – patient’s age in years) x patient’s actual body weight in kilograms] * 
  
 
72 x patient’s serum creatinine (in mg/dL) 
 
*: x 0.85 for females 
 
 
Calculated CLCR (ml/min) =   
 
[(140 – patient’s age in years) x patient’s actual body weight in kilograms] x K* 
  
 
Patient’s serum creatinine (in µmol/L) 
 
K*: 1.23 for males, 1.05 for females 
 
 

Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 86 of 137 
Version 6.0 
16.4 Appendix 4 – NCI-CTCAE version 4.03 
 
Available at: http://evs.nci.nih.gov/ftp1/CTCAE/About.html 
 
 
 

Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 87 of 137 
Version 6.0 
16.5 Appendix 5 
Ophthalmic Examination 
 
An ophthalmic examination by an optometrist or ophthalmologist is required at Screening and if 
clinically indicated during the study (e.g., monitoring of pre-existing cataracts, visual 
disturbances). 
The examination is to include the following:  
Prior to dilation: 
• best corrected visual acuity  
• slit lamp examination 
• tonometry 
Following dilation:  
• fundoscopy 
• slit lamp examination to document lens clarity  
If a cataract/lens opacity is seen during the examination for newly enrolling patients or enrolled patients for 
whom no cataract/lens opacity have been detected to date, the cataract/lens opacity will be graded according 
to a Grade 1-4 system (modified from Optometric Clinical Practice Guideline: Care of the Adult Patient 
with Cataracts: available on the American Optometric Association website: www.aoa.org). However, 
patients enrolled under a prior version of the protocol who had detectable cataracts graded according to the 
LOCS III will continue to have their cataracts graded according to LOCS III and will not switch to the 
Grade 1-4 scale.  
Grading of Cataracts* 
Cataract Type 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Nuclear 
Yellowing and sclerosis of the 
lens nucleus 
Mild 
Moderate 
Pronounced 
Severe 
Cortical 
Measured as aggregate 
percentage of the intrapupillary 
space occupied by the opacity 
Obscures 10% 
of 
intrapupillary 
space 
Obscures 10% 
-50% of intra-
pupillary 
space 
Obscures 50% 
-90% of intra-
pupillary 
space 
Obscures 
>90% of 
intrapupillary 
space 
Posterior subcapsular 
Measured as the aggregate 
percentage of the posterior 
capsular area occupied by the 
opacity 
Obscures 10% 
of the area of 
the posterior 
capsule 
Obscures 30% 
of the area of 
the posterior 
capsule 
Obscures 50% 
of the area of 
the posterior 
capsule 
Obscures 
>50% of the 
area of the 
posterior 
capsule 
*Designation of cataract severity that falls between grade levels can be made by addition of a + sign (e.g., 
1+, 2+). Grading of cataracts is usually done when pupil is dilated. 
 
 

Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 88 of 137 
Version 6.0 
16.6 Appendix 6 
NCCN Clinical Practice Guidelines in Oncology: Antiemesis 
Reproduced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Antiemesis V.2.2014.33 © 2014 National Comprehensive Cancer 
Network, Inc. All rights reserved. The NCCN Guidelines® and illustrations herein may not be reproduced in any form for any purpose without the express written permission of the 
NCCN. To view the most recent and complete version of the NCCN Guidelines, go online to www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, 
NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 

Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 89 of 137 
Version 6.0 
 
 
Reproduced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Antiemesis V.2.2014.33 © 2014 National Comprehensive Cancer 
Network, Inc. All rights reserved. The NCCN Guidelines® and illustrations herein may not be reproduced in any form for any purpose without the express written permission of the 
NCCN. To view the most recent and complete version of the NCCN Guidelines, go online to www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, 
NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 

Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 90 of 137 
Version 6.0 
16.7 Appendix 7 
NCCN Clinical Practice Guidelines in Oncology: Anorexia/Cachexia 
 
 
Reproduced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Palliative Care V.1.201432 © 2014 National Comprehensive Cancer 
Network, Inc. All rights reserved. The NCCN Guidelines® and illustrations herein may not be reproduced in any form for any purpose without the express written permission of the 
NCCN. To view the most recent and complete version of the NCCN Guidelines, go online to www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, 
NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 

Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 91 of 137 
Version 6.0 
16.8 Appendix 8 
 Glutathione (GSH)-, S-adenosylmethionine (SAM)-, or N-
acetylcysteine (NAC)-containing Products (Representative List) 
Glutathione (GSH) 
N-acetylcysteine (NAC) 
S-adenosylmethionine (SAM) 
Product Name 
Ingredient 
Product Name 
Ingredient 
Product Name 
Ingredient 
Glutathione 
glutathione 
Antidote for 
acetaminophen 
(paracetamol) 
overdose 
acetylcysteine  
SAM-e 
Complete 
S-adenosyl-
methionine 
L-Glutathione 
L-glutathione 
Cerefolin NAC: 
medical food 
for age-related 
memory loss 
L-methylfolate 
vitamin B12 
N-acetyl 
cysteine 
SAMe 
S-adenosyl-L-
methionine 
Glutathione 
reduced 
glutathione 
NAC 
N-acetyl 
cysteine 
Double Strength 
SAMe 400 
S-adenosyl-
methionine 
Reduced 
glutathione with 
alpha lipoic acid 
Setria L-
glutathione 
N-A-C Sustain 
N-acetyl L-
cysteine 
 
 
Glutathione, 
Cysteine & C 
glutathione 
L-cysteine 
vitamin C 
Best NAC 
Detox 
Regulators 
N-acetyl 
cysteine 
 
 
(Mega-) 
Liposomal 
Glutathione 
glutathione 
 
 
 
 
Lypospheric 
GSH 
glutathione 
 
 
 
 
Ivory Caps Skin 
Enhancement 
Formula 
glutathione 
 
 
 
 
 

Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 92 of 137 
Version 6.0 
16.9 Appendix 9 
 Summary of Changes and Rationales for Changes to 
Protocol KCP-330-004 
16.9.1 Summary and Rationale for Changes to Version 5.0 Protocol KCP-330-004 
Karyopharm Therapeutics Inc 
 
A Phase 2 Study Evaluating the Efficacy and Safety of Selinexor (KPT-330) in 
Patients with Recurrent Gliomas 
Clinical Trial Protocol No 
Sponsor Protocol No. KCP-330-004 
Development Phase: 
Phase 2 
Investigational Product: 
Selinexor 
Indication: 
Glioblastoma 
Sponsor: 
Karyopharm Therapeutics Inc. 
Drug Discoverer: 
Karyopharm Therapeutics Inc. 
Sponsor Address: 
85 Wells Avenue 
Newton, MA  02459  
USA 
From: Version 5.0 dated 01 July 2015 
To: Version 6.0 dated 13 November 2015 
 
 
 

6HOLQH[RU.37
.DU\RSKDUP7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO.&3
1RYHPEHU

&RQILGHQWLDO
3DJHRI
9HUVLRQ
6XPPDU\DQG5DWLRQDOHIRU&KDQJHV
7KHFOLQLFDOVWXG\SURWRFRO.&3$3KDVH6WXG\(YDOXDWLQJWKH(IILFDF\DQG6DIHW\RI
6HOLQH[RU.37LQ3DWLHQWVZLWK5HFXUUHQW*OLRPDVKDVEHHQDPHQGHGE\WKH6SRQVRUIRU
WKHIROORZLQJUHDVRQV
x 7RHOLPLQDWH$UPV(DQG)ZKLFKZHUHLQWURGXFHGLQWKHODVWSURWRFRODPHQGPHQWEXWGLG
QRW\HWFRQWDLQHQUROOHGSDWLHQWVDVWKHVHDUPVDUHQRWJRLQJIRUZDUGGXHWREXGJHWDU\
OLPLWDWLRQV
x 7RDGGDQH[FOXVLRQFULWHULRQUHTXLULQJSDWLHQWVQRWWRKDYHXQGHUJRQHPDMRUVXUJHU\ZLWKLQ
IRXUZHHNVSULRUWR&\FOH'D\
7KHUHYLVHGSURWRFRO9HUVLRQGDWHG1RYHPEHUZLOOEHVXEPLWWHGE\WKH3ULQFLSDO
,QYHVWLJDWRUV WR DOO DSSOLFDEOH ,QVWLWXWLRQDO 5HYLHZ %RDUGV ,5%V ,QGHSHQGHQW (WKLFV
&RPPLWWHHV,(&VRU5HVHDUFK(WKLFV%RDUGV5(%VDQGE\.DU\RSKDUP7KHUDSHXWLFV,QFWR
DOODSSOLFDEOH5HJXODWRU\$XWKRULWLHV
'HVFULSWLRQVRIWKHNH\FKDQJHVWKDWKDYHEHHQPDGHWRSURWRFRO.&39HUVLRQIURP
WKHSUHYLRXV9HUVLRQLQFOXGLQJUDWLRQDOHVIRUWKHFKDQJHVDUHOLVWHGEHORZ
$GPLQLVWUDWLYH
x 8SGDWHGWKHYHUVLRQQXPEHUDQGGDWHRIWKHSURWRFROIURP9HUVLRQGDWHG-XO\
WR9HUVLRQGDWHG1RYHPEHU0RGLILHGVHFWLRQV*OREDO
x 5HPRYHG2]PRVLVDQG*62PE+DVFRQWDFWVIRUUHSRUWLQJRI6$(VDQGSUHJQDQFLHVE\
WKHVLWHV2]PRVLVZDVLQFRUUHFWO\DGGHGDVWKHFRQWDFWIRUUHSRUWVIRU1RUWK$PHULFDLQ
9HUVLRQ  RI WKH SURWRFRO 7KH 3KDUPDFRYLJLODQFH 'HSDUWPHQW DW .DU\RSKDUP
7KHUDSHXWLFV,QFZLOOQRZUHFHLYHUHSRUWVIRUERWKWKH(8DQG1RUWK$PHULFD0RGLILHG
VHFWLRQV,QIRUPDWLRQWREHSURYLGHGUHJDUGLQJ6$(VDQG6HFWLRQVDQG
x 5HPRYHG*62PE+DVDFRQWUDFWUHVHDUFKRUJDQL]DWLRQDQGUHSODFHGZLWK.DU\RSKDUP
7KHUDSHXWLFV ,QF 0RGLILHG VHFWLRQV 7LWOH 3DJH &RQWDFW $GGUHVVHV *ORVVDU\ RI
$EEUHYLDWLRQVDQG6HFWLRQVDQG
x


6WXG\'HVLJQ
x (OLPLQDWHG$UPV(DQG)ZKLFKKDGEHHQLQWURGXFHGLQWKHODVWSURWRFRODPHQGPHQWEXW
GLGQRW\HWFRQWDLQHQUROOHGSDWLHQWVEHFDXVHWKHVHDUPVDUHEHLQJUHPRYHGIURPWKHVWXG\
GXHWREXGJHWDU\OLPLWDWLRQV0RGLILHGVHFWLRQV*OREDO
x 5HYLVHGWKHHQGRIVWXG\GHILQLWLRQWRFODULI\WKDWWKHVWXG\ZLOOFRQWLQXHXQWLOWKHODVW
SDWLHQWLQWKHVWXG\KDVGLHGKDVEHHQRIIVWXG\WUHDWPHQWIRUPRQWKVKDVEHHQORVWWR
IROORZXSRUKDVZLWKGUDZQFRQVHQWZKLFKHYHURFFXUVILUVW0RGLILHGVHFWLRQV
6\QRSVLVDQG6HFWLRQ
CCI

Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 94 of 137 
Version 6.0 
Inclusion/Exclusion Criteria 
• Added an exclusion criterion requiring patients not to have undergone major surgery within 
four weeks prior to Cycle 1 Day 1. (Modified sections: Synopsis and Section 4.3) 
Background 
• Updated the number of patients (from 900 to > 1,100) exposed to selinexor in order to be 
consistent with the most recent version of the Investigatgor’s Brochure (as of 31 May 2015). 
(Modified section: Section 1.1.2.2). 
• Updated the number of patients (from 650 to 730) whose safety results have been analyzed 
to be consistent with the most recent version of the Investigatgor’s Brochure (as of 
31 May 2015). (Modified sections: Sections 1.1.2. and 6.5.2). 
• Updated the reported frequencies of the most common AEs to be consistent with the most 
recent version of the Investigatgor’s Brochure (as of 31 May 2015). (Modified section: 
Section 1.1.2.2). 
• Replaced “Figure 2: Overview of Study Design” to reflect the elimination of Arms E and 
F. (Modified section: Section 3.1.1)  
Classification of Adverse Events by Causality 
• Revised the definitions in the Classification of Adverse Events by Causality table for 
clarity. (Modified section: Table 7) 
Declaration of Helsinki 
• Deleted statement concerning the Declaration of Helsinki because it is not applicable to this 
study. However wording was retained that requires Investigators to comply with 
international standards for GCPs. (Modified section: Section 10.1) 
Study Reporting 
• Added text to explain that one or more interim CSRs may be submitted to regulatory 
authorities, in addition to the final CSR. (Modified section: Section 15) 
 

Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 95 of 137 
Version 6.0 
 
16.9.2 Summary and Rationale for Changes to Version 4.0 Protocol KCP-330-004 
Karyopharm Therapeutics Inc. 
 
A Phase 2 Study Evaluating the Efficacy and Safety of Selinexor (KPT-330) in 
Patients with Recurrent Gliomas 
Clinical Trial Protocol No 
Sponsor Protocol No. KCP-330-004 
Development Phase: 
Phase 2 
Investigational Product: 
Selinexor 
Indication: 
Glioblastoma 
Sponsor: 
Karyopharm Therapeutics Inc. 
Drug Discoverer: 
Karyopharm Therapeutics Inc. 
Sponsor Address: 
85 Wells Avenue 
Newton, MA  02459  
USA 
 
 
From: Version 4.0 dated 23 March 2015 
To: Version 5.0 dated 01 July 2015 
 
 

6HOLQH[RU.37
.DU\RSKDUP7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO.&3
1RYHPEHU

&RQILGHQWLDO
3DJHRI
9HUVLRQ
6XPPDU\DQG5DWLRQDOHIRU&KDQJHV
7KHFOLQLFDOVWXG\SURWRFRO.&3$3KDVH6WXG\(YDOXDWLQJWKH(IILFDF\DQG6DIHW\RI
6HOLQH[RU.37LQ3DWLHQWVZLWK5HFXUUHQW*OLRPDVKDVEHHQDPHQGHGE\WKH6SRQVRUWR
LQFRUSRUDWHFKDQJHVVXJJHVWHGE\WKH,QYHVWLJDWRUVDQGLQWHUQDOO\WRSURYLGHFODULW\WRHOLPLQDWH
LQFRQVLVWHQFLHVEHWZHHQVHFWLRQVDQGWRFRUUHFWSULRUHUURUV
7KH UHYLVHG SURWRFRO 9HUVLRQ  GDWHG  -XO\  ZLOO EH VXEPLWWHG E\ WKH 3ULQFLSDO
,QYHVWLJDWRUV WR DOO DSSOLFDEOH ,QVWLWXWLRQDO 5HYLHZ %RDUGV ,5%V ,QGHSHQGHQW (WKLFV
&RPPLWWHHV,(&VRU5HVHDUFK(WKLFV%RDUGV5(%VDQGE\.DU\RSKDUP7KHUDSHXWLFV,QFWR
DOODSSOLFDEOH5HJXODWRU\$XWKRULWLHV
'HVFULSWLRQVRIWKHNH\FKDQJHVWKDWKDYHEHHQPDGHWRSURWRFRO.&39HUVLRQIURP
WKHSUHYLRXV9HUVLRQLQFOXGLQJUDWLRQDOHIRUWKHFKDQJHVDUHOLVWHGEHORZ
$GPLQLVWUDWLYH
x 8SGDWHGWKHYHUVLRQQXPEHUDQGGDWHRISURWRFROIURP9HUVLRQGDWHG0DUFK
WR9HUVLRQGDWHG-XO\0RGLILHGVHFWLRQV*OREDO
x 8SGDWHGVWDUWGDWHWR-DQXDU\EHFDXVHVLWHVGLGQRWVWDUWWKHVWXG\XQWLO3URWRFRO
9HUVLRQZDVDSSURYHG0RGLILHGVHFWLRQ6\QRSVLV>6WDUWGDWH@
x 8SGDWHGWLPHIRUHQUROOPHQWWRDSSUR[LPDWHO\PRQWKV0RGLILHGVHFWLRQV6\QRSVLV
>'XUDWLRQRIWUHDWPHQW@DQG6HFWLRQ
x &KDQJHG³DQGRWKHUEUDLQFDQFHUV´WR³JOLRPDV´WRDYRLGFRQIXVLRQZLWKPHWDVWDVHV
0RGLILHGVHFWLRQV*OREDO
x &ODULILHGWKDWUDQGRPL]DWLRQZLOOEHSHUIRUPHGYLDWKH('&V\VWHP0RGLILHGVHFWLRQ
6HFWLRQ
%DFNJURXQG
x 8SGDWHG
VLGH
HIIHFWV
VHOLQH[RU
EDFNJURXQG
LQIRUPDWLRQ
SUHFOLQLFDO
GDWD
DQGQXPEHURISDWLHQWVWUHDWHGZLWKVHOLQH[RUEDVHGRQLQIRUPDWLRQLQ
WKH6HOLQH[RU.37,%Y$SULO0RGLILHGVHFWLRQV6HFWLRQV
DQG
6WXG\'HVLJQ
x



x


x 5HYLVHGWKHHQGRIVWXG\GHILQLWLRQWRFODULI\WKDWWKHVWXG\ZLOOFRQWLQXHDIWHUFROOHFWLRQRI
GDWDIRUWKHSULPDU\DQDO\VLVP3)60RGLILHGVHFWLRQV6\QRSVLV>'XUDWLRQRIVWXG\@
DQG6HFWLRQ
x 5HYLVHGWKHP,77SRSXODWLRQWRLQFOXGHSDWLHQWVZKRGLVFRQWLQXHGWUHDWPHQWSULRUWRWKH
ILUVWSRVWEDVHOLQHDVVHVVPHQWGXHWRGHDWKWR[LFLW\RUGLVHDVHSURJUHVVLRQ7KHFKDQJH
CCI
CCI
CCI

6HOLQH[RU.37
.DU\RSKDUP7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO.&3
1RYHPEHU

&RQILGHQWLDO
3DJHRI
9HUVLRQ
ZDVPDGHWRWDNHDPRUHFRQVHUYDWLYHDSSURDFKE\LQFOXGLQJSDWLHQWVZKRGRQRWKDYHDW
OHDVWRQHSRVWGRVLQJHIILFDF\HYDOXDWLRQGXHWRGHDWKWR[LFLW\RUGLVHDVHSURJUHVVLRQLQ
WKHSRSXODWLRQWKDWZLOOEHXVHGIRUSULPDU\DQDO\VHVRIHIILFDF\0RGLILHGVHFWLRQ
6HFWLRQ
x





x





x



x




7UHDWPHQWV
x &KDQJHG GRVLQJ IUHTXHQF\ RI VHOLQH[RU IURP WZLFH ZHHNO\ GXULQJ :HHNV  RI HDFK
ZHHNF\FOHWRWZLFHZHHNO\GXULQJ:HHNVRIHDFKF\FOHIRUDUPVZLWKWZLFHZHHNO\
GRVLQJ'XULQJGLVFXVVLRQVZLWK.DU\RSKDUPPHGLFDOPRQLWRUV,QYHVWLJDWRUVLQGLFDWHGWKDW
WKH\EHOLHYHGWKDWVRPHSDWLHQWVFRXOGEHQHILWIURPGRVLQJGXULQJ:HHNHVSHFLDOO\LI
WKH\ZHUHWROHUDWLQJWKHGUXJZHOODQGGLGQRWUHTXLUHDGRVLQJEUHDNWRPLWLJDWHVLGHHIIHFWV
7KHSURWRFRO6HFWLRQLQFOXGHVSURYLVLRQVIRUGRVHVWREHVNLSSHGLQWHUPLWWHQWO\WR
DGGUHVVVLGHHIIHFWVSURYLGLQJIOH[LELOLW\WRWKH,QYHVWLJDWRUVWRPRGLI\GRVLQJIUHTXHQF\
DVQHFHVVDU\3DWLHQWVZKRDUHFXUUHQWO\EHLQJWUHDWHGWZLFHZHHNO\IRU:HHNVXQGHUD
SUHYLRXV YHUVLRQ RI WKH SURWRFRO PD\ DW WKH GLVFUHWLRQ RI WKH LQYHVWLJDWRU KDYH WKH
IUHTXHQF\ RI VHOLQH[RU GRVLQJ LQFUHDVHG WR WZLFH ZHHNO\ IRU :HHNV  0RGLILHG
VHFWLRQV6\QRSVLV>3ODQQHGVDPSOHVL]H7UHDWPHQWSODQ@7DEOH)LJXUH6HFWLRQV
DQG
6WXG\$VVHVVPHQWV
x 3URYLGHGDGGLWLRQDOGHWDLOIRUWKHQHXURORJLFDOH[DPLQDWLRQVWRLPSURYHFRQVLVWHQF\DFURVV
VLWHVDQGSDWLHQWV$FRPSOHWHQHXURORJLFDOH[DPLQDWLRQLVWREHSHUIRUPHGDWVFUHHQLQJDQG
WKH(QGRI7UHDWPHQWYLVLW1HXURORJLFDOH[DPLQDWLRQVGXULQJWKHVWXG\VKRXOGEHV\PSWRP
GLUHFWHG$Q\QHXURORJLFDOGHILFLWVQRWHGGXULQJWKHEDVHOLQHH[DPPXVWEHIROORZHGDW
CCI
CCI
CCI
CCI

6HOLQH[RU.37
.DU\RSKDUP7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO.&3
1RYHPEHU

&RQILGHQWLDO
3DJHRI
9HUVLRQ
VXEVHTXHQWYLVLWV$Q\QHZQHXURORJLFDOFRPSODLQWVUHSRUWHGE\WKHSDWLHQWDQGDQ\GHILFLWV
REVHUYHG E\ WKH LQYHVWLJDWRU VKRXOG EH DVVHVVHG DQG IROORZHG DW VXEVHTXHQW YLVLWV
0RGLILHGVHFWLRQV7DEOHDQG6HFWLRQVDQG
x


x 0RGLILHGWKHGHVFULSWLRQRIWKH2SKWKDOPLF([DPLQDWLRQLQ$SSHQGL[WRLQFOXGHPRUH
LQIRUPDWLRQRQRSKWKDOPLFH[DPLQDWLRQLQFOXGLQJUHSODFHPHQWRIWKH/HQV2SDFLWLHV
&ODVVLILFDWLRQ6\VWHP,,,/2&6,,,FDWDUDFWJUDGLQJV\VWHPZLWKDJUDGLQJV\VWHP
IRUQHZO\HQUROOLQJSDWLHQWVDQGHQUROOHGSDWLHQWVIRUZKRPQRFDWDUDFWVKDYHEHHQ
GHWHFWHGWRGDWH0RGLILHGVHFWLRQV6\QRSVLV>6DIHW\DVVHVVPHQWV@7DEOHDQG
6HFWLRQVDQG
x $GGHGXULQHSUHJQDQF\WHVWLQJDVFOLQLFDOO\LQGLFDWHGGXULQJWKHVWXG\DVDVDIHW\PHDVXUH
WRSURYLGHDGGLWLRQDOPRQLWRULQJIRUSUHJQDQFLHV0RGLILHGVHFWLRQ7DEOH
,QFOXVLRQ([FOXVLRQ&ULWHULD
x 5HYLVHGLQFOXVLRQFULWHULRQDWRFODULI\WKDWWKHSDWLHQW¶VEUDLQWXPRUPXVWEHGLDJQRVHG
DV*%0DWILUVWGLDJQRVLV7KLVFKDQJHZDVPDGHWRDYRLGWKHLQFOXVLRQRISDWLHQWVZLWK
ORZHUJUDGHWXPRUVWKDWDWDUHKLVWRORJLFDOO\*%0DWWKHWLPHRIWKHSDWLHQW¶VVHFRQG
VXUJHU\0RGLILHGVHFWLRQV6\QRSVLV>6WXG\SRSXODWLRQV,QFOXVLRQFULWHULD@
6HFWLRQ
x



x



x





x 5HYLVHGLQFOXVLRQFULWHULRQWRLQFUHDVHWKHWKUHVKROGOHYHOVIRULQFOXVLRQIRUELOLUXELQ
[8/1$67[8/1DQG$/7[8/17KHFKDQJHVZHUHPDGHWR
EURDGHQWKHLQFOXVLRQUHTXLUHPHQWVIRUELOLUXELQ$67DQG$/7DQGDOLJQWKHPZLWK
RWKHU.DU\RSKDUPFOLQLFDOVWXGLHV
x

CCI
CCI
CCI
CCI
CCI

6HOLQH[RU.37
.DU\RSKDUP7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO.&3
1RYHPEHU

&RQILGHQWLDO
3DJHRI
9HUVLRQ

6WDWLVWLFDO$QDO\VLV
x




x $GGHGWLPLQJIRUSULPDU\DQDO\VLVP3)6DQGWKHVHFRQGDU\DQDO\VLVIRU26IRUFODULW\
DQGXSGDWHGWKHWLPLQJIRUP3)6FHQVRULQJIRUVXUYLYDODFFRUGLQJO\0RGLILHGVHFWLRQV
7DEOHDQG6HFWLRQVDQG
3URSK\ODFWLF6XSSRUWLYH&DUH
x 8SGDWHGWKHVXSSRUWLYHFDUHDQGGRVHDGMXVWPHQWJXLGHOLQHVIRUVHOLQH[RUUHODWHGWR[LFLWLHV
EDVHGRQUHFHQWVDIHW\GDWD0RGLILHGVHFWLRQ7DEOH
x $GGHGVXEVHFWLRQIRUGRVHUHGXFWLRQIRUGHFUHDVHG*)5DVDVDIHW\PHDVXUH0RGLILHG
VHFWLRQ1HZ6HFWLRQ
$GYHUVH(YHQWV
x 5HPRYHG$SSHQGL[³$GYHUVH(YHQW&DWHJRULHVIRU'HWHUPLQLQJ5HODWLRQVKLSWR7HVW
'UXJ´WRUHPRYHLQFRQVLVWHQFLHVLQDGYHUVHHYHQWUHSRUWLQJLQIRUPDWLRQ0RGLILHG
VHFWLRQV6HFWLRQDQG$SSHQGL[
x $GGHGWH[WWRFODULI\WKDWSUHJQDQF\SHUVHLVQRWFRQVLGHUHGDQ$(EXWWKDWDPHGLFDO
RFFXUUHQFHREVHUYHGLQWKHPRWKHURUIHWXVQHZERUQZRXOGEHDQ$(0RGLILHGVHFWLRQ
6HFWLRQ
CCI
CCI

Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 100 of 137 
Version 6.0 
16.9.3 Summary and Rationale for Changes to Version 3.0 Protocol KCP-330-004 
Karyopharm Therapeutics Inc. 
 
A Phase 2 Study Evaluating the Efficacy and Safety of Selinexor (KPT-330) in 
Patients with Recurrent Glioblastoma or Other Brain Cancers after Failure of 
Radiation Therapy and Temozolomide 
Clinical Trial Protocol No 
Sponsor Protocol No. KCP-330-004 
Development Phase: 
Phase 2 
Investigational Product: 
Selinexor 
Indication: 
Glioblastoma 
Sponsor: 
Karyopharm Therapeutics Inc. 
Drug Discoverer: 
Karyopharm Therapeutics Inc. 
Sponsor Address: 
85 Wells Avenue 
Newton, MA  02459  
USA 
 
 
From: Version 3.0 dated July 16, 2014 
To: Version 4.0 dated March 23, 2015 
 
 

6HOLQH[RU.37
.DU\RSKDUP7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO.&3
1RYHPEHU

&RQILGHQWLDO
3DJHRI
9HUVLRQ
6XPPDU\DQG5DWLRQDOHIRU&KDQJHV
7KHFOLQLFDOVWXG\SURWRFRO.&3$3KDVH6WXG\(YDOXDWLQJWKH(IILFDF\DQG6DIHW\RI
6HOLQH[RU.37LQ3DWLHQWVZLWK5HFXUUHQW*OLREODVWRPDRU2WKHU%UDLQ&DQFHUVDIWHU)DLOXUH
RI5DGLDWLRQ7KHUDS\DQG7HPR]RORPLGHKDVEHHQDPHQGHGE\WKH6SRQVRUWRLQFRUSRUDWHFKDQJHV
VXJJHVWHGE\WKH,QYHVWLJDWRUVDQGLQWHUQDOO\WRUHYLVHUHSRUWLQJIRUFHUHEHOODUWR[LFLWLHVRI*UDGH
RUKLJKHUDVUHTXHVWHGE\WKH)'$WRSURYLGHFODULW\WRHOLPLQDWHLQFRQVLVWHQFLHVEHWZHHQVHFWLRQV
DQGWRFRUUHFWSULRUHUURUV
7KH UHYLVHG SURWRFRO 9HUVLRQ  GDWHG 0DUFK   ZLOO EH VXEPLWWHG E\ WKH 3ULQFLSDO
,QYHVWLJDWRUV WR DOO DSSOLFDEOH ,QVWLWXWLRQDO 5HYLHZ %RDUGV ,5%V ,QGHSHQGHQW (WKLFV
&RPPLWWHHV,(&VRU5HVHDUFK(WKLFV%RDUGV5(%VDQGE\.DU\RSKDUP7KHUDSHXWLFV,QFWR
DOODSSOLFDEOH5HJXODWRU\$XWKRULWLHV
'HVFULSWLRQVRIWKHNH\FKDQJHVWKDWKDYHEHHQPDGHWRSURWRFRO.&39HUVLRQIURP
WKHSUHYLRXV9HUVLRQLQFOXGLQJUDWLRQDOHIRUWKHFKDQJHVDUHOLVWHGEHORZ
$GPLQLVWUDWLYH
x ,QWHUQDO FKDQJHV VXJJHVWHG E\ WKH 6SRQVRU WR SURYLGH FODULW\ DQG WR HOLPLQDWH
LQFRQVLVWHQFLHVEHWZHHQVHFWLRQVDQGWRFRUUHFWSULRUHUURUV0RGLILHGVHFWLRQV*OREDO
x 8SGDWHGWKHYHUVLRQQXPEHUDQGGDWHRISURWRFROIURP9HUVLRQGDWHG-XOWR
9HUVLRQGDWHG0DU0RGLILHGVHFWLRQV*OREDO
x 0LQRUFRUUHFWLRQVWRJUDPPDUWKURXJKRXW0RGLILHGVHFWLRQV*OREDO
x 8SGDWHG6SRQVRUDGGUHVVIURP0HUFHU5RDG1DWLFN0$WR:HOOV$YHQXH
1HZWRQ0$0RGLILHGVHFWLRQV*OREDO
x &RUUHFWHGWLWOHVRISURWRFRODSSURYHUV0RGLILHGVHFWLRQ$SSURYDORIWKH3URWRFRO
x 0RYHG 6XPPDU\ DQG 5DWLRQDOH IRU &KDQJHV IRU 9HUVLRQ  WR 9HUVLRQ  SUHYLRXV
6HFWLRQ  WR D QHZ DSSHQGL[ $SSHQGL[  6HFWLRQ QXPEHULQJ KDV FKDQJHG
DFFRUGLQJO\$OVRDGGHGWKH5DWLRQDOHIRU&KDQJHVIRU9HUVLRQWR9HUVLRQDVDQHZ
DSSHQGL[ 6HFWLRQ  IRU FRQVLVWHQF\ RI SUHVHQWDWLRQ DFURVVSURWRFROV0RGLILHG
VHFWLRQV6HFWLRQVDQGDQGJOREDOFKDQJHWRVHFWLRQQXPEHULQJ
x 8SGDWHGVWDUWGDWHWR-XO\0RGLILHGVHFWLRQ6\QRSVLV>6WDUWGDWH@
x $GGHG
 DW 2]PRVLV 5HVHDUFK ,QF DV WKH FRQWDFW SHUVRQ IRU 6$(V DQG
SUHJQDQFLHVDW1RUWK$PHULFDQVLWHVDQGSURYLGHGKHUSKRQHDQGID[QXPEHUV0RGLILHG
VHFWLRQV,QIRUPDWLRQWREHSURYLGHGUHJDUGLQJ6$(VSUHJQDQF\6HFWLRQVDQG
x 8SGDWHGQXPEHURIVLWHVSDUWLFLSDWLQJLQWKHWULDOWR³DSSUR[LPDWHO\´0RGLILHGVHFWLRQV
6\QRSVLV>7RWDOQXPEHURIVLWHV@DQG6HFWLRQ
x 0LQRUHGLWRULDOUHYLVLRQVIRU$SSHQGL[,&+*XLGDQFHRQ&OLQLFDO'DWD0DQDJHPHQWWR
UHPRYHRXWGDWHGZRUGLQJUHODWHGWRUHSRUWLQJRI6$(VWKDWRFFXUZLWKLQWKUHHZHHNVRI
VWRSSLQJWUHDWPHQWDQGWRDOLJQWKHLQIRUPDWLRQWREHLQFOXGHGIRU6$(VLQWKHH&5)ZLWK
WKHUHTXLUHPHQWVRIWKHSURWRFRO0RGLILHGVHFWLRQ6HFWLRQ
PPD

6HOLQH[RU.37
.DU\RSKDUP7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO.&3
1RYHPEHU

&RQILGHQWLDO
3DJHRI
9HUVLRQ
6\QRSVLV
x 5HPRYHGDOOUHIHUHQFHVWRWKHSURWRFROERG\ZLWKLQWKHV\QRSVLVDQGUHSODFHGZLWKUHOHYDQW
WH[WDVQHHGHGIRUFODULW\7KHV\QRSVLVLVFRQVLGHUHGDVWDQGDORQHGRFXPHQWDQGVKRXOG
QRWFRQWDLQUHIHUHQFHVWRVHFWLRQVLQWKHSURWRFROERG\0RGLILHGVHFWLRQ6\QRSVLV
x 5HSODFHGWH[WUHODWHGWRVWXG\WUHDWPHQWZLWKGXUDWLRQVIRUHQUROOPHQWWUHDWPHQWSHULRGV
DQGWKHVWXG\0RGLILHGVHFWLRQV6\QRSVLV>'XUDWLRQRIVWXG\6HFWLRQVDQG@
x $GGHG GHWDLOV UHODWHG WR PHDVXUHPHQW RI GLVHDVH VWDWXV IRU FODULW\ 0RGLILHG VHFWLRQ
6\QRSVLV>6WXG\SURFHGXUHV@
x $GGHGGHWDLOVUHODWHGWRVDIHW\DVVHVVPHQWVIRUFODULW\0RGLILHGVHFWLRQ6\QRSVLV>6DIHW\
DVVHVVPHQW@
%DFNJURXQGDQG5DWLRQDOH
x &RQGHQVHG DQG UHDUUDQJHG EDFNJURXQG VHFWLRQV WR DOLJQ ZLWK FXUUHQW LQIRUPDWLRQ RQ
VHOLQH[RUEDVHGRQUHFHQW3KDVHDQG3KDVHFOLQLFDOWULDOGDWD6HFWLRQ1XFOHDU
([SRUW IURP 9HUVLRQ  ZDV UHSODFHG ZLWK 6HFWLRQ  6HOLQH[RU 6HFWLRQ
6HOLQH[RU0HFKDQLVPRI$FWLRQDQG3UHFOLQLFDO6XPPDU\IURP9HUVLRQZDVUHSODFHG
ZLWK6HFWLRQ3UHFOLQLFDO'DWD6HFWLRQ6HOLQH[RU&OLQLFDO6XPPDU\IURP
9HUVLRQZDVUHSODFHGZLWK6HFWLRQ&OLQLFDO'DWDWKDWLQFOXGHVDVXEVHFWLRQRQ
UHSURGXFWLYHULVNV)LJXUHDQGWH[WUHODWHGWRSUHFOLQLFDOUHVSRQVHFXUYHVZHUHUHPRYHG
IURP6HFWLRQ;32DQG6HOLQH[RULQ+**IURP9HUVLRQ$OVRGHOHWHGRXWGDWHG
VWDWHPHQWVRQ&<3LQKLELWLRQVXEVWUDWHVLQ6HFWLRQ0RGLILHGVHFWLRQV6HFWLRQV
DQG
6HOLQH[RU'RVLQJ
x &KDQJHGWRIODWGRVLQJPJWZLFHZHHNO\GXULQJ:HHNVRIHDFKZHHNF\FOH$UPV
%&
DQGPJRQFHZHHNO\$UP'7KHUHYLVHGGRVHVDUHEDVHGRQWKH
DQDO\VLVRISURORQJHGGRVLQJUHVXOWVLQ.&3DGRVHRIPJPaPJWZLFH
ZHHNO\KDGDFFHSWDEOHHIILFDF\DQGLPSURYHGORQJWHUPWROHUDELOLW\DQGDGRVHRIPJP
aPJWZLFHZHHNO\ZDVWROHUDWHGDQGFOHDUHG'/7HYDOXDWLRQ


x


x $GGHGGHVFULSWLRQDQGVWRUDJHLQIRUPDWLRQIRUWKHQHZWDEOHWIRUPXODWLRQPJWDEOHWVLQ
EOLVWHUSDFNVWKDWWKHLQLWLDOGUXJSURGXFWIRUWKHVWXG\DQGPJWDEOHWVLQERWWOHV
ZLOOWUDQVLWLRQWRZKHQVXSSOLHVEHFRPHDYDLODEOH0RGLILHGVHFWLRQ6HFWLRQ
x 5HYLVHGSUHVSHFLILHGGRVHVFKHGXOHPRGLILFDWLRQVIRUDGYHUVHHYHQWVUHODWHGWRVWXG\GUXJ
0RGLILHGVHFWLRQV6HFWLRQ7DEOH
x 8SGDWHGWKHUDSHXWLFUDQJHIRUVHOLQH[RUIURP³PJPWRPJPRUDOO\WZLFHZHHNO\´
WR³PJPWRPJPDSSUR[LPDWHO\PJWRPJRUDOO\´EDVHGRQUHFHQW3KDVH
DQG3KDVHFOLQLFDOWULDOGDWD0RGLILHGVHFWLRQ6HFWLRQ
CC
I
CCI
CCI
CCI

6HOLQH[RU.37
.DU\RSKDUP7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO.&3
1RYHPEHU

&RQILGHQWLDO
3DJHRI
9HUVLRQ
x 5HYLVHGGRVHDGMXVWPHQWVZLWKFKDQJHVLQ%6$WRUHIOHFWIODWGRVLQJDQGUHPRYHGURXQGLQJ
GRVLQJJXLGHOLQHVEDVHGRQ%6$3DWLHQW%6$ZLOOEHVWLOOEHDVVHVVHGWRHQVXUHWKDWWKH
PJRUPJGRVHGRHVQRWUHVXOWLQDGRVH!PJP,IDSDWLHQW¶VGRVHZLOOH[FHHGWKLV
OLPLWWKH,QYHVWLJDWRUVKRXOGFRQWDFWWKHPHGLFDOPRQLWRUSULRUWRDGPLQLVWUDWLRQWRGLVFXVV
DSSURSULDWHGRVLQJ0RGLILHGVHFWLRQ6HFWLRQ'HOHWHGVHFWLRQ$SSHQGL[IURP
9HUVLRQ
x







x




x &ODULILHGZRUGLQJIRUPLVVHGGRVHV0RGLILHGVHFWLRQ6HFWLRQ
6WXG\'HVLJQ
x $VDSSUR[LPDWHO\KDOIRIWKHSDWLHQWVLQ$UP%KDGDOHYHOGRVHUHGXFWLRQHQUROOPHQWLQ
$UP%ZDVVWRSSHGWRH[SORUHDOWHUQDWLYHGRVLQJLQ3URWRFRO9HUVLRQWRSRWHQWLDOO\
LPSURYHWROHUDELOLW\$QDVVHVVPHQWRIWKHHIILFDF\GDWDSULRUWRWKHIRUPDO3)6DQDO\VLV
IRUWKHILUVWSDWLHQWVLQ$UP%UHYHDOHGFOLQLFDOO\PHDQLQJIXOHIILFDF\LQWKLVFKDOOHQJLQJ
SDWLHQWSRSXODWLRQ7ZRSDWLHQWVLQ$UP%KDYHKDG35VZLWK3)6!GD\V


%DVHGRQWKHGDWDWR
GDWHWKHVWXG\WHDPKDVFRQFOXGHGWKDWSDWLHQWHQUROOPHQWVKRXOGFRQWLQXHQRWZLWKVWDQGLQJ
WKHUHVXOWVRIIRUPDO3)6DQDO\VLVEXWDWDUHGXFHGVWDUWLQJGRVH$OWKRXJKHQUROOPHQWLQ
$UP%KDVEHHQVWRSSHGWKHVWXG\ZLOOFRQWLQXHZLWKWZRQHZDUPV$UPV&DQG'ERWK
XVLQJ6LPRQ¶VWZRVWDJHGHVLJQZLWKIODWGRVLQJ0RGLILHGVHFWLRQV6\QRSVLV>6WXG\
SRSXODWLRQ
 3ODQQHG VDPSOH VL]H 7UHDWPHQW SODQ 6WDWLVWLFDO
FRQVLGHUDWLRQV
@6HFWLRQVDQG
7DEOH)LJXUH
x $GGHG$UPV&DQG'WRFRPSDUHWKHHIILFDF\WROHUDELOLW\DQGVDIHW\RIVHOLQH[RUPJ
DGPLQLVWHUHGWZLFHZHHNO\GXULQJ:HHNVRIHDFKZHHNF\FOH$UP&ZLWKVHOLQH[RU
PJDGPLQLVWHUHGRQFHZHHNO\$UP'0RGLILHGVHFWLRQV6\QRSVLV>6WXG\GHVLJQ
 3ODQQHG VDPSOH VL]H ,QFOXVLRQ FULWHULD ([FOXVLRQ FULWHULD
7UHDWPHQWSODQ6WDWLVWLFDOFRQVLGHUDWLRQV5DQGRPL]DWLRQSURFHGXUHQHZVHFWLRQDQG
6HFWLRQV
DQG7DEOHVDQG)LJXUH
x $GGHGUDQGRPL]DWLRQIRUQHZ$UPV&DQG'0RGLILHGVHFWLRQV6\QRSVLV>6WXG\
GHVLJQ7UHDWPHQWSODQDQG5DQGRPL]DWLRQSURFHGXUHQHZVHFWLRQ@6HFWLRQV
DQG7DEOHVDQG)LJXUH
CCI
CCI
CCI
CCI
CCI
CCI
CCI

6HOLQH[RU.37
.DU\RSKDUP7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO.&3
1RYHPEHU

&RQILGHQWLDO
3DJHRI
9HUVLRQ
x








x 8SGDWHGWKHSODQQHGQXPEHURISDWLHQWVIURPWR0RGLILHGVHFWLRQV6\QRSVLV
>3ODQQHGVDPSOHVL]H@6HFWLRQ
x







6WXG\$VVHVVPHQWV
x &ODULILHG WLPLQJ DQG SXUSRVH RI HOHFWLYH 3(7 VFDQV 0RGLILHG VHFWLRQV 7DEOH 
6HFWLRQVDQG
x 5HGXFHGWKHIUHTXHQF\RI(&*VGXULQJWKHWUHDWPHQWSKDVHWR³DVFOLQLFDOO\LQGLFDWHG´
&DUGLDFDEQRUPDOLWLHVDUHQRWFRQVLGHUHGWREHDVDIHW\FRQFHUQ0RUHWKDQSDWLHQWV
KDYHUHFHLYHGVHOLQH[RUDVRI'HFHPEHUDQGQRVLJQLILFDQWFDUGLDFVLJQLILFDQW
DEQRUPDOLWLHVKDYHEHHQUHSRUWHG7KHIUHTXHQF\RI(&*VKDVEHHQUHGXFHGWRDOLJQZLWK
WKH VFKHGXOH XVHG LQ PRUH UHFHQW WULDOV DQG WR DYRLG XQQHFHVVDU\ WHVWLQJ 0RGLILHG
VHFWLRQV7DEOH6HFWLRQV
x





x &ODULILHG WKDW WKH PDUNHUV OLVWHG IRU LPPXQRKLVWRFKHPLVWU\ DQG 3&5 WHVWLQJ IRU IL[HG
ELRSV\VDPSOHVIURPSDWLHQWVLQWKH6XUJLFDO$UPDUHSRWHQWLDOPDUNHUVWKDWPD\EHWHVWHG
0RGLILHGVHFWLRQ6HFWLRQ
x 'HOHWHG IXQFWLRQDO SURWHRPLFV HYDOXDWLRQ E\ UHYHUVH SKDVH SURWHLQ DUUD\ EHFDXVH WKH
HYDOXDWLRQLVQRORQJHUSODQQHGIRUIL[HGELRSV\VDPSOHVIURPSDWLHQWVLQWKH6XUJLFDO$UP
0RGLILHGVHFWLRQ6HFWLRQ
x



CCI
CCI
CCI
CCI

6HOLQH[RU.37
.DU\RSKDUP7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO.&3
1RYHPEHU

&RQILGHQWLDO
3DJHRI
9HUVLRQ
x 'HOHWHG
EORRGGUDZVIRU$UP%EHFDXVHHQUROOPHQWLQ$UP%KDVEHHQVWRSSHGDQG
DGGLWLRQDO
GDWDDUHQRWQHHGHG


x




x 6SHFLILHGWKDWWKHRSKWKDOPRORJLFH[DPLVWREHSHUIRUPHGE\DQRSKWKDOPRORJLVWVSHFLILHG
(7'56DQG6QHOOHQ¶VDVPHWKRGVIRUGHWHUPLQLQJEHVWFRUUHFWHGYLVXDODFXLW\DQGDGGHG
WKH/2&6,,,DV$SSHQGL[0RGLILHGVHFWLRQV6HFWLRQVDQG7DEOH
x 5HYLVHG WKH WLPLQJ RI WKH ODE DVVHVVPHQWV WR LQFOXGH D ZLQGRZ RI  GD\V SULRU WR WKH
VFKHGXOHGYLVLW0RGLILHGVHFWLRQ7DEOH
x $GGHGWKDWDOOFDVHVRIFHUHEHOODUWR[LFLWLHVRI*UDGHRUKLJKHUPXVWEHFDSWXUHGDVDQ
6$(DQGUHSRUWHGWRWKHUHJXODWRU\DXWKRULWLHV,5%V(&VDQG,QYHVWLJDWRUVLQDQH[SHGLWHG
6DIHW\5HSRUWZLWKLQGD\VRIDZDUHQHVVRIWKHHYHQW7KH)'$UHTXLUHVWKHVHHYHQWVWR
EHUHSRUWHGZLWKLQGD\VRIWKHVLWHDQG6SRQVRUQRWLILFDWLRQRIWKHHYHQW0RGLILHG
VHFWLRQ6HFWLRQ
x $OLJQHG6FKHGXOHRI$VVHVVPHQWVZLWKVWXG\SURFHGXUHVDQGDGGHGZLQGRZVIRUHQGRI
WUHDWPHQW IROORZXS EHIRUH SURJUHVVLRQ RI GLVHDVH DQG VXUYLYDO IROORZXS 0RGLILHG
VHFWLRQV6HFWLRQVDQG7DEOH
,QFOXVLRQ([FOXVLRQ&ULWHULD
x










x 5HYLVHG LQFOXVLRQ FULWHULRQ  WR VSHFLI\ WKDW WKH &705, IRU PHDVXUDEOH GLVHDVH
DVVHVVPHQWPXVWWDNHSODFHZLWKLQGD\VRIVWDUWLQJWUHDWPHQWLQVWHDGRIZLWKLQGD\V
RIVWDUWLQJWUHDWPHQW)RUQRQVXUJLFDOSDWLHQWVWKH&705,VKRXOGEHQRPRUHWKDQZHHNV
ROG DW WUHDWPHQW VWDUW WR HQVXUH DQ DFFXUDWH EDVHOLQH 0RGLILHG VHFWLRQV 6\QRSVLV
>,QFOXVLRQFULWHULD@6HFWLRQVDQG7DEOH
x 5HYLVHGLQFOXVLRQFULWHULDDQGWRDOLJQZLWKXSGDWHGVWDQGDUGWH[WIRUSUHYHQWLRQRI
SUHJQDQF\ IRU FRQVLVWHQF\ DFURVV SURWRFROV 0RGLILHG VHFWLRQV 6\QRSVLV >,QFOXVLRQ
FULWHULD@6HFWLRQV
CCI
CCI
CCI
CCI
CCI

6HOLQH[RU.37
.DU\RSKDUP7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO.&3
1RYHPEHU

&RQILGHQWLDO
3DJHRI
9HUVLRQ
x




x


x



x


x $GGHG H[FOXVLRQ FULWHULRQ  WR H[FOXGH SDWLHQWV ZLWK %6$  P IURP EHLQJ
UDQGRPL]HGLQWR$UPV&DQG'WRSUHYHQWSDWLHQWVUDQGRPL]HGWR$UP'PJRQFH
ZHHNO\IURPH[FHHGLQJWKHPD[LPXPDOORZDEOHVHOLQH[RUGRVHRIPJP0RGLILHG
VHFWLRQV6\QRSVLV>([FOXVLRQFULWHULD@DQG6HFWLRQ
6WDWLVWLFDO$QDO\VLV
x $GGHGDZLQGRZRIGD\VDURXQGWKHPRQWKYLVLWIRUWKHSULPDU\DQDO\VLVRIUDWHRI
3)6WRDFFRXQWIRUSRWHQWLDOGLIIHUHQFHVEHWZHHQWKHZLQGRZIRUHYDOXDWLRQVDQGWKHDFWXDO
YLVLWVIRUWKHSDWLHQWVDQGSURYLGHIRUWKHLQFOXVLRQRIDOOFOLQLFDOO\PHDQLQJIXOSDWLHQWGDWD
LQWKHDQDO\VLV7KLVZLQGRZZLOOEHDSSOLHGWRWKHFDOFXODWLRQRIWKHSRLQWHVWLPDWHRI
P3)6$FWXDOWLPHVRIHYHQWVSURJUHVVLRQRUGHDWKZLOOEHXVHGIRUWKH.DSODQ0HLHU
VWDWLVWLFDOVXPPDU\RI3)60RGLILHGVHFWLRQV6\QRSVLV>3ULPDU\DQDO\VLVSDUDPHWHU@DQG
6HFWLRQ
x 5HYLVHG DQDO\VHV IRU DGGLWLRQ RI $UPV & ' ( DQG ) 0RGLILHG VHFWLRQV 6\QRSVLV
>3ODQQHGVDPSOHVL]H6WDWLVWLFDOFRQVLGHUDWLRQVDQG6DPSOHVL]HFDOFXODWLRQ@DQG6HFWLRQV
DQG
3URSK\ODFWLF6XSSRUWLYH&DUH
x 5HYLVHGWKHGRVHDGMXVWPHQWJXLGHOLQHVIRUVHOLQH[RUUHODWHGWR[LFLWLHVWRLQFOXGHVXSSRUWLYH
WUHDWPHQWEDVHGRQWKHHYHQWDQGWKHVHYHULW\RIWKHHYHQW7KHVHFKDQJHVZHUHPDGHWR
FRQVROLGDWH WKH UHFRPPHQGDWLRQV IRU $( PDQDJHPHQW LQ D VLQJOH WDEOH $GGHG GRVH
PRGLILFDWLRQJXLGHOLQHVIRUDQHPLDDVDVHSDUDWHURZ0RGLILHGVHFWLRQV6HFWLRQ
7DEOH
x 5HYLVHGWH[WDOORZLQJGRVHUHHVFDODWLRQWRDOLJQZLWK9HUVLRQ7KHWH[WZDVUHYLVHGLQ
9HUVLRQWRDOLJQZLWKWKHUHTXLUHPHQWIRUSURSK\ODFWLFWKHUDS\DGGHGLQ$PHQGPHQW
+RZHYHULQWKHFXUUHQWDPHQGPHQWSURSK\ODFWLFWKHUDS\KDVEHHQUHSODFHGZLWKVXSSRUWLYH
FDUHJXLGHOLQHV0RGLILHGVHFWLRQ6HFWLRQ
CCI
CCI
CCI
CCI

Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 107 of 137 
Version 6.0 
• Revised selinexor dose reduction in the setting of infection to recommend that 
dexamethasone should be adjusted per institutional guidelines and that adrenal suppression 
should be considered. (Modified section: Section 6.3.1) 
• Replaced prophylactic therapy (Section 6.2.1 in Version 3.0) with required and 
recommended supportive care guidelines (Section 6.5). Required supportive care includes 
administration of a 5-HT3 antagonist and recommended supportive care includes 
glucocorticoids, appetite stimulants, and centrally acting agents. These changes were made 
based on clinical experience in ongoing Phase 1 and Phase 2 clinical studies. 
Dexamethasone is no longer required supportive care but rather a supportive care option. 
Section 7.5 Supportive Care from Version 3.0 (now Section 6.5 Supportive Care 
Guidelines) was re-ordered for clarity, to reflect that much of the information in the text in 
Version 3.0 is now in Table 6. (Modified sections: Sections 1.1.2, 5.2.1, 5.2.2, 6.3, 6.3.1, 
and 6.5, Table 6) 
• Replaced “Liver enzyme increase” (Section 7.5.7 in Version 3.0) with “Liver Function Test 
Abnormalities” (Section 6.5.3) to update supportive measures to be taken in the event of 
GSH depletion. (New section: Section 6.5.3) 
• Replaced the use of olanzapine and mirtazapine (Sections 2.1.4, 6.2.1, 7.5.1, and 7.5.3 and 
Table 6 in Version 3.0) with references to the NCCN clinical practice guidelines in 
oncology for antiemesis and anorexia/cachexia based on feedback from the FDA. Added 
NCCN Guidelines for antiemesis as Appendix 7 and anorexia/cachexia as Appendix 8. 
(Modified sections: Section 6.5.2 and Table 6; New sections: Sections 16.7 and 16.8) 
• Clarified that the use of supportive care is in accordance with institutional guidelines or as 
recommended in the supportive care and dose adjustment guidelines (Table 6). (Modified 
section: Section 6.4.1.2) 
Concomitant Medications 
• Revised the text for prevention of pregnancy and related inclusion criteria with updated 
standard text for consistency across protocols (Modified sections: Synopsis [Inclusion 
criteria], Sections 4.2 and 6.4.1.1) 
• Deleted statement allowing warfarin. Concurrent warfarin or other Coumadin-derived 
anticoagulants are prohibited, as anticoagulants could increase the chance of bleeding in 
those patients with decreased platelets associated with selinexor. (Modified section: 
Section 6.4.2) 
• Concomitant medication guidelines were updated based on recent Phase 1 and Phase 2 
clinical trial results and Investigator input. (Modified section: Section 6.4.2) 
• Removed the acetaminophen (paracetamol) restriction as ongoing clinical safety 
evaluations on the use of selinexor in combination with acetaminophen (paracetamol) have 
not shown any significant clinical or laboratory abnormalities with doses of acetaminophen 
(paracetamol) up to 1 gram and selinexor up to 55 mg/m2 (approximately 80-100 mg). 
(Modified sections: Sections 6.4 and 6.4.2) 

Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 108 of 137 
Version 6.0 
• New guidance regarding GSH-, SAM-, or NAC-containing products was added, along with 
a new Appendix 9 listing representative products. These changes were based on FDA 
recommendations. (Modified sections: Sections 6.4.2 and 16.9) 
 

Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 109 of 137 
Version 6.0 
16.9.4 Summary and Rationale for Changes to Version 2.0 Protocol KCP-330-004 
Karyopharm Therapeutics Inc. 
 
A Phase II, Two-Tier Study Evaluating the Efficacy and Safety of Selinexor (KPT-
330) in Patients with Recurrent Glioblastoma after Failure of Radiation Therapy 
and Temozolomide 
Clinical Trial Protocol No 
Sponsor Protocol No. KCP-330-004 
Development Phase: 
Phase 2 
Investigational Product: 
Selinexor 
Indication: 
Glioblastoma 
Sponsor: 
Karyopharm Therapeutics Inc. 
Drug Discoverer: 
Karyopharm Therapeutics Inc. 
Sponsor Address: 
85 Wells Avenue 
Newton, MA  02459  
USA 
 
 
From: Version 2.0 dated November 15, 2013 
To: Version 3.0 dated July 16, 2014 

6HOLQH[RU.37
.DU\RSKDUP7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO.&3
1RYHPEHU

&RQILGHQWLDO
3DJHRI
9HUVLRQ
7KHFOLQLFDOVWXG\SURWRFRO.&3$3KDVH7ZR7LHU6WXG\(YDOXDWLQJWKH(IILFDF\DQG
6DIHW\RI6HOLQH[RU.37LQ3DWLHQWVZLWK5HFXUUHQW*OLREODVWRPDDIWHU)DLOXUHRI5DGLDWLRQ
7KHUDS\DQG7HPR]RORPLGHKDVEHHQDPHQGHGE\WKH6SRQVRUWRLQFRUSRUDWHFKDQJHVVXJJHVWHG
LQWHUQDOO\DQGWRSURYLGHFODULW\WRHOLPLQDWHLQFRQVLVWHQFLHVEHWZHHQVHFWLRQVDQGWRFRUUHFWSULRU
HUURUV
7KH UHYLVHG SURWRFRO 9HUVLRQ  GDWHG -XO\   ZLOO EH VXEPLWWHG E\ WKH 3ULQFLSDO
,QYHVWLJDWRUV WR DOO DSSOLFDEOH ,QVWLWXWLRQDO 5HYLHZ %RDUGV ,5%V ,QGHSHQGHQW (WKLFV
&RPPLWWHHV,(&VRU5HVHDUFK(WKLFV%RDUGV5(%VDQGE\.DU\RSKDUP7KHUDSHXWLFV,QFWR
DOODSSOLFDEOH5HJXODWRU\$XWKRULWLHV
$GHVFULSWLRQRIWKHNH\FKDQJHVWKDWKDYHEHHQPDGHWRSURWRFRO.&39HUVLRQIURP
WKHSUHYLRXV9HUVLRQLQFOXGLQJUDWLRQDOHIRUWKHFKDQJHVDUHOLVWHGEHORZ
$GPLQLVWUDWLYH
x ,QWHUQDO FKDQJHV VXJJHVWHG E\ WKH 6SRQVRU WR SURYLGH FODULW\ DQG WR HOLPLQDWH
LQFRQVLVWHQFLHVEHWZHHQVHFWLRQVDQGWRFRUUHFWSULRUHUURUV0RGLILHGVHFWLRQV*OREDO
x 8SGDWHGWKHYHUVLRQQXPEHUDQGGDWHRISURWRFROIURP9HUVLRQGDWHG1RYWR
9HUVLRQGDWHG-XO\0RGLILHGVHFWLRQV*OREDO
x 8SGDWHG6SRQVRUQDPH1DPHFKDQJHGIURP130WR.DU\RSKDUP0RGLILHGVHFWLRQ
*OREDO
x 0LQRUFRUUHFWLRQVWRJUDPPDUWKURXJKRXW0RGLILHGVHFWLRQV*OREDO
x 8SGDWHGWKHHOHFWURQLFPDLODGGUHVVWRZKLFKWKHSDWLHQWUHJLVWUDWLRQIRUPZLOOEHVHQWIURP
WR
0RGLILHGVHFWLRQ6HFWLRQ
,QFOXVLRQ([FOXVLRQ&ULWHULD
x 5HYLVHGLQFOXVLRQFULWHULRQWRVSHFLI\WKDWIRUELOLUXELQHOHYDWLRQUHODWHGWR*LOEHUW¶V
6\QGURPHELOLUXELQOHYHOVPXVWEHWLPHV8/1EDVHGRQLQSXWIURPVWXG\,QYHVWLJDWRUV
0RGLILHGVHFWLRQV6\QRSVLV>LQFOXVLRQFULWHULD@6HFWLRQ
x 5HYLVHG LQFOXVLRQ FULWHULRQ   WR UHIOHFW 0HDVXUDEOH GLVHDVH DFFRUGLQJ WR 5HVSRQVH
$VVHVVPHQWLQ1HXUR2QFRORJ\>5$12@JXLGHOLQHVZLWKLQGD\VRIVWDUWLQJWUHDWPHQW
LQVWHDGRIZLWKLQGD\VRIVWDUWLQJWUHDWPHQW0RGLILHGVHFWLRQV6\QRSVLV>LQFOXVLRQ
FULWHULD@6HFWLRQ
x 5HYLVHG LQFOXVLRQ FULWHULRQ  WR GHFUHDVH WKH QXPEHU RI UHTXLUHG VOLGHV RI DUFKLYHG
SDUDIILQHPEHGGHGWLVVXHWKDWPXVWEHDYDLODEOHIURPXQVWDLQHGVOLGHVWRXQVWDLQHG
VOLGHVEXWLIOHVVWKDQWKH6SRQVRUPXVWEHFRQWDFWHG7KLVLVEDVHGRQ,QYHVWLJDWRU
IHHGEDFNUHJDUGLQJOLPLWHGDYDLODELOLW\RIDUFKLYDOWLVVXH0RGLILHGVHFWLRQV6\QRSVLV
>LQFOXVLRQFULWHULD@6HFWLRQ
x 5HPRYHGLQFOXVLRQFULWHULRQWKHUHVHFWLRQRIHQKDQFLQJWXPRUWLVVXHDPRXQWPJ
DQG RI QRQHQKDQFLQJ WXPRU WLVVXH DPRXQW  PJ EDVHG RQ LQSXW IURP VWXG\
,QYHVWLJDWRUV WKDW VSHFLILFDWLRQ RI WXPRU TXDQWLW\ LV LUUHOHYDQW DV SDWLHQWV XQGHUJRLQJ
F\WRUHGXFWLYHVXUJHU\DUHH[SHFWHGWRKDYHVL]DEOHWXPRUVDQGWKHUHIRUHWKHDYDLODELOLW\RI
WLVVXHIRUDQDO\VLVZLOOQRWEHDQLVVXH0RGLILHGVHFWLRQV6\QRSVLV>LQFOXVLRQFULWHULD@
6HFWLRQ6HFWLRQ
PPD
PPD

6HOLQH[RU.37
.DU\RSKDUP7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO.&3
1RYHPEHU

&RQILGHQWLDO
3DJHRI
9HUVLRQ
x 5HYLVHGH[FOXVLRQFULWHULRQWRVSHFLI\WKDWWKHWLPHSHULRGIURPWKHWLPHRIWUHDWPHQW
ZLWKRWKHUFKHPRWKHUDS\RULQYHVWLJDWLRQDODJHQWVPXVWEHDWOHDVWZHHNVSULRUWRWKHVWDUW
RIWUHDWPHQWZLWKLQWKHVWXG\WKHRSWLRQRIWKHWLPHSHULRGRIKDOIOLYHVZDVUHPRYHGGXH
WR WKH ZLGH YDULDELOLW\ LQ KDOI OLYHV RI GLIIHUHQW FKHPRWKHUDSLHV 0RGLILHG VHFWLRQV
6\QRSVLV>LQFOXVLRQFULWHULD@6HFWLRQ
x 5HYLVHG H[FOXVLRQ FULWHULRQ  WR VSHFLI\ WKDW D SULRU KLVWRU\ RI '97 RU 3( LV QRW
H[FOXVLRQDU\3DWLHQWVRQWKHRQJRLQJ3KDVHVWXGLHVZLWKVHOLQH[RUKDYHGHYHORSHGFDQFHU
UHODWHG'97RU3(GXULQJWKHVWXG\DQGKDYHFRQWLQXHGWUHDWPHQWZLWKVHOLQH[RUZKLOH
UHFHLYLQJ DSSURSULDWH '97 WUHDWPHQW ZLWK QR DSSDUHQW RXWZDUG HIIHFWV 0RGLILHG
VHFWLRQV6\QRSVLV>LQFOXVLRQFULWHULD@6HFWLRQ
x 5HPRYHGWKHH[FOXVLRQFULWHULRQWKDWVSHFLILHGWKDWSDWLHQWVZLWKERG\ZHLJKWVLJQLILFDQWO\
EHORZLGHDOERG\ZHLJKWLQWKHRSLQLRQRIWKH,QYHVWLJDWRUDUHWREHH[FOXGHG%DVHGRQ
,QYHVWLJDWRULQSXWWKDWWKLVLVLUUHOHYDQWIRUSDWLHQWVZLWKDGYDQFHFDQFHUHVSHFLDOO\VLQFH
WKH SURWRFRO LQFOXGHV UHTXLUHG SURSK\OD[LV IRU DQRUH[LD 0RGLILHG VHFWLRQV 6\QRSVLV
>LQFOXVLRQFULWHULD@6HFWLRQ
6WXG\'HVLJQ
x





x








x 5HPRYHGWKHUHTXLUHGDFFUXDORISDWLHQWVSHUVLWHFXUUHQWO\WKHUHLVQRWDUHTXLUHPHQW
IRUWKHQXPEHURISDWLHQWVWREHHQUROOHGDWHDFKVLWH0RGLILHG6HFWLRQ6HFWLRQ
x 5HYLVHGWKHDPRXQWUHTXLUHGWREHWDNHQZLWKVHOLQH[RUIURPP/RXQFHVWRP/
RXQFHV0RGLILHGVHFWLRQV6\QRSVLV>WUHDWPHQWSODQ@6HFWLRQ
x




x
$GGHG :HGQHVGD\)ULGD\ DV DQ RSWLRQ IRU GRVLQJ GD\V 0RGLILHG VHFWLRQV 6\QRSVLV
>WUHDWPHQWSODQ@6HFWLRQ6HFWLRQ6HFWLRQ
x


CCI
CCI
CCI
CCI

6HOLQH[RU.37
.DU\RSKDUP7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO.&3
1RYHPEHU

&RQILGHQWLDO
3DJHRI
9HUVLRQ


x

x &RQFXUUHQW :DUIDULQ RU RWKHU &RXPDGLQGHULYHG DQWLFRDJXODQWV DUH SURKLELWHG DV
DQWLFRDJXODQWV FRXOG LQFUHDVH WKH FKDQFH RI EOHHGLQJ LQ WKRVH SDWLHQWV ZLWK GHFUHDVHG
SODWHOHWVDVVRFLDWHGZLWKVHOLQH[RU0RGLILHGVHFWLRQ6HFWLRQ
6WXG\$VVHVVPHQWV
x 5HYLVHGWKH%DVHOLQHDVVHVVPHQWRI'LVHDVH6WDWXVE\05,LPDJLQJRIWKHEUDLQWRWDNH
SODFHZLWKLQGD\VSULRUWRVWDUWRIWUHDWPHQWLQVWHDGRIGD\VSULRUWRVWDUWRIWUHDWPHQW
0RGLILHGVHFWLRQ6HFWLRQ6HFWLRQ6HFWLRQ
x 5HYLVHGWKHWLPHSRLQWVIRUWKHFROOHFWLRQRIR[\JHQVDWXUDWLRQDQGFRDJXODWLRQDVVHVVPHQWV
WREHFROOHFWHGDWVFUHHQLQJDQGDWIXWXUHYLVLWVLIFOLQLFDOO\LQGLFDWHG0RGLILHGVHFWLRQV
6FKHGXOHRI$VVHVVPHQWV6HFWLRQ
x 5HYLVHGWKHWLPHSRLQWVIRUWKHDVVHVVPHQWRIXULQDO\VLVWREHFROOHFWHGDWVFUHHQLQJDQGDW
IXWXUH YLVLWV LI FOLQLFDOO\ LQGLFDWHG 0RGLILHG VHFWLRQV 6FKHGXOH RI $VVHVVPHQWV
6HFWLRQ6HFWLRQ6HFWLRQ
x 7KHRSKWKDOPRORJLFDOH[DPLQDWLRQDVVHVVPHQWZDVUHYLVHGWRVSHFLI\WKDWLIDFDWDUDFWLV
VHHQGXULQJWKHH[DPLQDWLRQWKHFDWDUDFWZLOOEHJUDGHGDFFRUGLQJWRWKH/HQV2SDFLWLHV
&ODVVLILFDWLRQ6\VWHP/2&6,,,7KLVFKDQJHZDVPDGHWRPRUHDFFXUDWHO\DVVHVVWKH
VWDWXVRIDQ\FDWDUDFW0RGLILHGVHFWLRQV6FKHGXOHRI$VVHVVPHQWV6HFWLRQ
x 5HYLVHGWKHWLPLQJRIWKHKHPDWRORJ\DVVHVVPHQWWRLQFOXGHDZLQGRZRIGD\VSULRUWR
WKH VFKHGXOHG YLVLW 0RGLILHG VHFWLRQV 6FKHGXOH RI $VVHVVPHQWV 6HFWLRQ 
6HFWLRQ6HFWLRQ
x



x 5HYLVHGWKHVXJJHVWHGWLPLQJRI05,VFDQVIRUSDWLHQWVZKRGLVFRQWLQXHGIRUUHDVRQVRWKHU
WKDQSURJUHVVLRQRIGLVHDVHWRHYHU\ZHHNV0RGLILHGVHFWLRQ6HFWLRQ6HFWLRQ

x 5HYLVHGDVVHVVPHQWRIGLVHDVHVWDWXVE\05,WRDOVRDOORZIRUDVVHVVPHQWRIGLVHDVHVWDWXV
E\&70RGLILHGVHFWLRQV6FKHGXOHRI$VVHVVPHQWV6HFWLRQ6HFWLRQ6HFWLRQ

x
&ODULILHGWKDWZKROH51$LQOHXNRF\WHVZLOOEHLVRODWHGIURPEORRGVDPSOHVIRU;32
LQKLELWLRQWLPHSRLQWVIRUVDPSOHFROOHFWLRQZDVUHYLVHGWRDQGKRXUVSUHDQGSRVW
GRVLQJ0RGLILHGVHFWLRQV6FKHGXOHRI$VVHVVPHQWV6HFWLRQ
x



CCI
CCI
CCI
CCI

6HOLQH[RU.37
.DU\RSKDUP7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO.&3
1RYHPEHU

&RQILGHQWLDO
3DJHRI
9HUVLRQ
x 5HYLVHGWKHDPRXQWRIEORRGWKDWZLOOEHFROOHFWHGIRUEORRGGUDZV

0RGLILHGVHFWLRQV6FKHGXOHRI$VVHVVPHQWV6HFWLRQ
x 5HYLVHG WKH DPRXQW RI EORRG WKDW ZLOO EH FROOHFWHG IRU EORRG GUDZV

0RGLILHGVHFWLRQV6FKHGXOHRI$VVHVVPHQWV6HFWLRQ
6DIHW\DQG7ROHUDELOLW\
x 6XSSRUWLYHFDUHDQGSURSK\ODFWLFJXLGHOLQHVZHUHXSGDWHGEDVHGRQUHFHQW3KDVHFOLQLFDO
WULDOUHVXOWVDQG,QYHVWLJDWRULQSXW0RGLILHGVHFWLRQ6HFWLRQ
x $GGHG&ODVVLILFDWLRQRI$GYHUVH(YHQWVE\&DXVDOLW\7DEOHWRDGYHUVHHYHQWVHFWLRQIRU
FODULILFDWLRQRI$(VUHODWHGRUQRWUHODWHGWRVWXG\GUXJ0RGLILHGVHFWLRQ6HFWLRQ
x 5HPRYHGWKHUHTXLUHGFROOHFWLRQRIPHGLFDOWHUPVDFFRUGLQJWR1&,&7&9HUVLRQQRW
DVUHSRUWHGE\WKHSDWLHQWIRU6$(V0RGLILHGVHFWLRQ6HFWLRQ
x 8SGDWHG WKH VDIHW\ WHOHFRQIHUHQFHV IURP PRQWKO\ WR UHJXODU WHOHFRQIHUHQFHV 6HFWLRQ
PRGLILHG6HFWLRQ
x 5HPRYHGWKHUHTXLUHPHQWRIJUDGLQJWKHWR[LFLW\RI$(VHYHU\ZHHNVIRUWKHILUVWF\FOHV
DQGHYHU\ZHHNVWKHUHDIWHU0RGLILHGVHFWLRQ6\QRSVLV>VDIHW\DVVHVVPHQW@
x 8SGDWHGLQIRUPDWLRQUHODWHGWRWKH07'WRVSHFLI\WKDWHVFDODWLQJEH\RQGPJPWZLFH
ZHHNO\LVSURKLELWHGLQDQ\VWXG\'HWDLOVRIWKHVHXSGDWHVWR.37GRVLQJLQIRUPDWLRQ
ZHUHGRFXPHQWHGLQD0D\DGGHQGXPWRWKH,QYHVWLJDWRUV%URFKXUHDQGSURYLGHG
WRDOO,QYHVWLJDWRUV0RGLILHGVHFWLRQV6HFWLRQ
x


x 7KHGRVHDGMXVWPHQWJXLGHOLQHVKDYHEHHQXSGDWHGEDVHGRQUHFHQWUHVXOWVRIWKH3KDVH
FOLQLFDOWULDOV0RGLILHGVHFWLRQV6HFWLRQ
x 8SGDWHG WKH HOHFWURQLF PDLO DGGUHVV WR ZKLFK WKH 6$( IRUPV ZLOO EH VHQW IURP

WR

0RGLILHG
VHFWLRQ
6HFWLRQ
6HOLQH[RU'RVLQJ
x











CCI
CCI
PPD
PPD
CCI
CCI

Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 114 of 137 
Version 6.0 
Table A: Pre-Surgery Dosing Table 
Group 
No. Of 
patients 
1st 
dose 
2nd 
dose 
3rd dose 
Surgery 
1 
5 
Day 1 
Day 3 
2 hr prior to surgery 
(Day 8) 
Day 8 
2 
5 
Day 1 
Day 3 
12 hr prior to surgery 
(Day 7 or 8) 
Day 8 
3 
5 
Day 1 
Day 3 
24 hr prior to surgery 
(Day 8) 
Day 9 
4 
5 
Day 1 
Day 3 
48 hr prior to surgery 
(Day 8) 
Day 10 
• Updated the pre-specified dose/schedule modifications table for adverse events related to 
study drug from the dose of 50 mg/m2 twice weekly to once weekly (D1) in order to 
optimize specific anti-tumor activity and patient’s tolerability. (Modified sections: 7.3 
Table 3) 

Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 115 of 137 
Version 6.0 
16.9.5 Summary and Rationale for Changes to Version 1.0 Protocol KCP-330-004 
Karyopharm Therapeutics Inc. 
 
A Phase II, Two-Tier Study Evaluating the Efficacy and Safety of Selinexor 
(KPT-330) in Patients with Recurrent Glioblastoma after Failure of Radiation 
Therapy and Temozolomide 
Clinical Trial Protocol No 
Sponsor Protocol No. KCP-330-004 
Development Phase: 
Phase 2 
Investigational Product: 
Selinexor 
Indication: 
Glioblastoma 
Sponsor: 
Karyopharm Therapeutics Inc. 
Drug Discoverer: 
Karyopharm Therapeutics Inc. 
Sponsor Address: 
85 Wells Avenue 
Newton, MA  02459  
USA 
 
 
From: Version 1.0 dated September 17, 2013 
To: Version 2.0 dated November 15, 2013 

6HOLQH[RU.37
.DU\RSKDUP7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO.&3
1RYHPEHU

&RQILGHQWLDO
3DJHRI
9HUVLRQ
5$7,21$/()25$0(1'0(17
7KLVSURWRFROKDVEHHQDPHQGHGWRDGGUHVVFRPPHQWVUHFHLYHGDIWHUUHYLHZRIWKHLQLWLDOSURWRFRO
E\ WKH )'$ 7KH 'DQLVK +HDOWK DQG 0HGLFLQHV $JHQF\ DOVR UHTXHVWHG WR FODULI\ WKH KRXU
UHSRUWLQJ UHTXLUHPHQW IRU VHULRXV DGYHUVH HYHQWV ZKLFK LV DOVR LQFOXGHG LQ WKLV SURWRFRO
DPHQGPHQW7KLVILQDOSURWRFRO9HUVLRQVXSHUVHGHVGUDIW9HUVLRQVXEPLWWHGWRWKH'DQLVK
+HDOWK DQG 0HGLFLQHV $JHQF\ WR DGGUHVV WKHLU FRPPHQW ,Q DGGLWLRQ WKLV DPHQGPHQW DOVR
LQFRUSRUDWHG FKDQJHV VXJJHVWHG LQWHUQDOO\ E\ WKH 6SRQVRU WR SURYLGH FODULW\ WR HOLPLQDWH
LQFRQVLVWHQFLHVEHWZHHQVHFWLRQVDQGWRFRUUHFWSULRUHUURUV
7KHVHFKDQJHVLQFOXGH
x 'HVFULELQJWKHXVHRIQHZGRVLQJDQGWKHWDEOHWIRUPXODWLRQSODQQHGIRUXVHLQWKLVVWXG\
,GHQWLILHVWKHLQLWLDOVWDUWLQJGRVHIRUDOOSDWLHQWVDWPJP
x 5HPRYLQJWKHLQLWLDOSURWRFROSURYLVLRQWRDOORZGRVHHVFDODWLRQLQVRPHSDWLHQWVWR
PJPRUKLJKHUEDVHGRQ
,QYHVWLJDWRU
VRSLQLRQDQGWROHUDELOLW\

x 5HYLVLQJWKHGRVHPRGLILFDWLRQFULWHULDLQWKHSURWRFRO6HFWLRQZLWKVSHFLILFGRVH
OHYHOVDQGVFKHGXOHVLQSODFHRI
IOH[LEOHGRVHUHGXFWLRQVRUVFKHGXOHPRGLILFDWLRQV

x &ODULI\LQJWKHGRVHDGMXVWPHQWJXLGHOLQHVLQ7DEOHWRFOHDUO\VSHFLI\ZKHQWKHVWXG\
GUXJVKRXOGEHGLVFRQWLQXHGLQWKHHYHQWRIRFFXUUHQFHRUUHFXUUHQFHRIHDFKWR[LFLW\
HLWKHUDWLQLWLDORFFXUUHQFHRUIROORZLQJGRVHUHGXFWLRQ
x &ODULI\LQJWKHGRVHUHGXFWLRQRUGLVFRQWLQXDWLRQFULWHULDLQ7DEOHIRUHDFKWR[LFLW\JUDGH
x 5HPRYLQJWKHSURYLVLRQVRIUHHVFDODWLQJWKHSUHYLRXVO\WR[LFGRVHDIWHUGRVHUHGXFWLRQ
IRUDQ\WR[LFLW\
x 5HYLVLQJWKHGRVHPRGLILFDWLRQFULWHULDIRUWKURPERF\WRSHQLDWRKROGWKHGUXJIRU
*UDGHWKURPERF\WRSHQLDXQWLOUHVROYHGWR*UDGHDQGWKHQUHVXPHDWDORZHUGRVH
VSHFLI\ZKHQWRIXUWKHUGRVHUHGXFHDQGZKHQWRGLVFRQWLQXHIRUUHFXUUHQWWR[LFLW\DQG
IRUUHQDOWR[LFLW\EDVHGRQ1&,&7&$(9HUVLRQFULWHULDIRUVHUXPFUHDWLQLQH
OHYHOV
x ([SDQGLQJWKHLQFOXVLRQFULWHULDWRDOORZHQUROOPHQWRISDWLHQWVZLWKDVSDUWDWH
DPLQRWUDQVIHUDVH$67OHYHOVOHVVWKDQWZLFHWKHXSSHUOLPLWRIQRUPDO;8/1
x


x



x 3URYLGLQJGDWDRQWKHWLPLQJRIRFFXUUHQFHRIWKURPERF\WRSHQLDLQUHODWLRQWRVWXG\GUXJ
DGPLQLVWUDWLRQLQ3KDVH,VWXGLHV
x $GGLQJRSKWKDOPRORJ\H[DPLQDWLRQGXULQJWKHVWXG\DVFOLQLFDOO\LQGLFDWHGLQDGGLWLRQWR
WKHSURWRFROVSHFLILHGVFUHHQLQJRSKWKDOPRORJ\H[DPLQDWLRQEDVHGRQWKHDGYHUVHHYHQW
RIEOXUUHGYLVLRQREVHUYHGLQWKH3KDVH,VWXGLHV
CCI
CCI

Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 117 of 137 
Version 6.0 
• Clarifying that Investigators are to report SAEs within 24 hours to the Sponsor, or 
designee, upon notification. 
Specific changes, by section, are displayed in the table in Boldface. [Note for changes not easily 
shown in a table, such as changes in the Schedule of Study Events, the original and revised table 
may be proved in separate pages as attachments that are referenced in the appropriate sections of 
the table.] 
Minor changes to correct typographical and other errors are not shown. A redline version of this 
document is available upon request. 

6HOLQH[RU.37
.DU\RSKDUP7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO.&3
1RYHPEHU

&RQILGHQWLDO
3DJHRI
9HUVLRQ
/LVWRI&KDQJHVIURPWKHLQLWLDOSURWRFROLQFRUSRUDWHGLQWRWKLV$PHQGPHQW
6HFWLRQ
3UHYLRXV:RUGLQJ
1HZ:RUGLQJ
5HDVRQIRU&KDQJH
7LWOH3DJH
'DWD0DQDJHPHQW2]PRVLV,QF
6WDWLVWLFV
2]PRVLV,QF

1RQH
$GLIIHUHQWYHQGRUZDVFKRVHQ
3URWRFROYHUVLRQ'DWH
9HUVLRQ
9HUVLRQ1RY

6\QRSVLV
6WXG\'HVLJQ
x
2SHQODEHOQRQUDQGRPL]HGPXOWLFHQWUH
3KDVH,,VWXG\
x






x
2SHQODEHOQRQUDQGRPL]HG
PXOWLFHQWUH3KDVH,,VWXG\
x








7H[WDOVR
XSGDWHVWKHHQGRIWUHDWPHQWIRU
0HGLFDO$UP%SDWLHQWVWRQRW
OLPLWGLVFRQWLQXDWLRQWRGLVHDVH
SURJUHVVLRQDORQH7KLVZDV
FKDQJHGWREHFRQVLVWHQWZLWK
6HFWLRQWKDWSURYLGHVPXOWLSOH
UHDVRQVIRUSRVVLEOHGUXJGHOD\RU
GLVFRQWLQXDWLRQ
6\QRSVLV
'XUDWLRQRI6WXG\
:LWKDQH[SHFWHGDFFUXDOUDWHRISDWLHQWVSHU
PRQWKDQGDWRWDOQXPEHURISDWLHQWV
SODQQHGWKHDQWLFLSDWHGHQUROOPHQWSHULRGLV
PRQWKV
6HOLQH[RUWDNHQRUDOO\ZLOOEHJLYHQ
WZLFHZHHNO\IRUDWRWDORIGRVHVSHU
F\FOH2QHF\FOHLVGHILQHGDVGD\VRU
GRVHV)RU6XUJLFDO$UPSDWLHQWV¶
WUHDWPHQWF\FOHVDUHGHILQHGDV
EHJLQQLQJZLWKSRVWRSHUDWLYH
UHVXPSWLRQRIWKHUDS\3DWLHQWVPD\
FRQWLQXHWRUHFHLYHWUHDWPHQWZLWK
6HOLQH[RULQUHSHDWHGF\FOHVXQWLOWKH\
OHDYHWKHVWXG\DVGHVFULEHGLQ6HFWLRQ
6WXG\GUXJDGPLQLVWUDWLRQPD\EH
GHOD\HGIRUWR[LFLW\DFFRUGLQJWRSURWRFRO
6HFWLRQ
&ODULILFDWLRQRISDWLHQW¶V
H[SHULHQFHRIGXUDWLRQRQVWXG\
6\QRSVLV
6WXG\3RSXODWLRQ
3DWLHQWVZLWK:+2JUDGH,9JOLRPDV
JOLREODVWRPD*%0DQGVXEYDULDQWVZLWK
UHFXUUHQWGLVHDVHZKRKDYHIDLOHGSULRU
WUHDWPHQWZLWKUDGLDWLRQWKHUDS\DQG
WHPR]RORPLGH


3DWLHQWVZLWK:+2*UDGHJOLRPDV
JOLREODVWRPD*%0DQGVXEYDULDQWVZLWK
UHFXUUHQWGLVHDVHZKRKDYHIDLOHGSULRU
WUHDWPHQWZLWKUDGLDWLRQWKHUDS\DQG
WHPR]RORPLGHDQGZKRPHHWWKHLQFOXVLRQ
DQGQRQHRIWKHH[FOXVLRQFULWHULDDUH
HOLJLEOHIRUHQUROOPHQW
8SGDWHVWKH*UDGHGHVLJQDWLRQWR
FXUUHQWIRUPDWDQGFODULILHVWKDW
LQFOXVLRQDQGH[FOXVLRQFULWHULD
PXVWDOVREHPHWE\SDWLHQWVIRU
HQUROOPHQWLQERWKVWXG\$UPV
CCI
CCI
CCI

6HOLQH[RU.37
.DU\RSKDUP7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO.&3
1RYHPEHU

&RQILGHQWLDO
3DJHRI
9HUVLRQ
6HFWLRQ
3UHYLRXV:RUGLQJ
1HZ:RUGLQJ
5HDVRQIRU&KDQJH
6\QRSVLV
3ODQQHG6DPSOH6L]H
$WRWDORISDWLHQWVDUHSODQQHGWREH
HQUROOHG

WKHUHPDLQGHUZLOO
EHHQUROOHGLQ$UP%PHGLFDODUP



$SSUR[LPDWHO\SDWLHQWVDUHSODQQHGWR
EHHQUROOHG


DSSUR[LPDWHO\
ZLOOEHHQUROOHGLQ$UP%0HGLFDO
$UP7KHSULPDU\SDWLHQWSRSXODWLRQV
,77DQG33DUHFRPSULVHGRI$UP%
0HGLFDO$UPSDWLHQWVRQO\


6\QRSVLV
,QFOXVLRQ&ULWHULD
>1(:7(;7@
+HSDWLFIXQFWLRQELOLUXELQWLPHVWKH
XSSHUOLPLWRIQRUPDO8/1$/7
WLPHV8/1$67WLPHV8/1
$OORZVIRUHQUROOPHQWRISDWHQWV
ZLWK$67OHYHOVEHORZ;WKH
8/1
6\QRSVLV7UHDWPHQW
3ODQ
3DWLHQWVZLOOUHFHLYH6HOLQH[RUWZLFHZHHNO\
0RQGD\:HGQHVGD\RU7XHVGD\7KXUVGD\
RUDOO\DWDVWDUWLQJGRVHRIPJPð7KHGRVH
PD\EHWLWUDWHGDVWROHUDWHGZLWKDPD[LPXP
GRVHRIPJPðDQGWKHPLQLPXPGRVHRI
PJPðDFFRUGLQJWRGRVHPRGLILFDWLRQ
JXLGHOLQHVLQWKHSURWRFRO2QHF\FOHLVGD\V
RUGRVHV
3DWLHQWVZLOOUHFHLYH6HOLQH[RUWZLFH
ZHHNO\0RQGD\:HGQHVGD\RU
7XHVGD\7KXUVGD\RUDOO\DWDVWDUWLQJGRVH
RIPJPð2QHF\FOHLVGD\VRU
GRVHV
'RVLQJLQIRUPDWLRQKDVEHHQ
UHYLVHGWREHWWHUUHIOHFWWKHFXUUHQW
SURWRFRODPHQGPHQWDQGWKHXVHRI
GUXJWDEOHWVLQWKLVVWXG\
CCI
CCI
CCI
CCI
CCI
CCI
CCI

6HOLQH[RU.37
.DU\RSKDUP7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO.&3
1RYHPEHU

&RQILGHQWLDO
3DJHRI
9HUVLRQ
6HFWLRQ
3UHYLRXV:RUGLQJ
1HZ:RUGLQJ
5HDVRQIRU&KDQJH
$UP%0HGLFDOFRKRUW>QHZWH[W@
8SWRSDWLHQWVZKRGRQRWUHTXLUHVXUJHU\
ZLOOEHWUHDWHGZLWK6HOLQH[RUWZLFHZHHNO\

7UHDWPHQWLQERWKDUPVRIWKHVWXG\ZLOO
FRQWLQXHXQWLOGLVHDVHSURJUHVVLRQRUWKH
GHYHORSPHQWRIXQDFFHSWDEOHWR[LFLWLHV,IDUP
%LVIXOO\DFFUXHG


$UP%0HGLFDOFRKRUW,77DQG33
SRSXODWLRQV$SSUR[LPDWHO\SDWLHQWV
ZKRGRQRWUHTXLUHVXUJHU\ZLOOEHWUHDWHG
ZLWK6HOLQH[RUWZLFHZHHNO\

7UHDWPHQWLQERWKDUPVRIWKHVWXG\ZLOO
FRQWLQXHXQWLOGLVHDVHSURJUHVVLRQRUWKH
GHYHORSPHQWRIXQDFFHSWDEOHWR[LFLWLHV
6FKHGXOHRI6WXG\
(YHQWV1RWHV
)XOORSKWKDOPRORJLFH[DPUHTXLUHGDW
VFUHHQLQJDQGLIFOLQLFDOO\LQGLFDWHG7KHH[DP
FDQEHRPLWWHGLIWKHSDWLHQWFDQQRWFRRSHUDWH
GXHWRIDFWRUVUHODWHGWR*%03ULRUWRGLODWLRQ
EHVWFRUUHFWHGYLVXDODFXLW\YLVXDOILHOG
H[DPLQDWLRQYLDDXWRPDWHGSHULPHWU\
WRQRPHWU\FRORUYLVLRQWHVW'LODWHG
IXQGRVFRS\DQGVOLWODPSH[DP


)XOORSKWKDOPRORJLFH[DPUHTXLUHGDW
VFUHHQLQJDQGLIFOLQLFDOO\LQGLFDWHG7KH
H[DPFDQEHRPLWWHGLIWKHSDWLHQWFDQQRW
FRRSHUDWHGXHWRIDFWRUVUHODWHGWR*%0
3ULRUWRGLODWLRQEHVWFRUUHFWHGYLVXDO
DFXLW\YLVXDOILHOGH[DPLQDWLRQYLD
DXWRPDWHGSHULPHWU\WRQRPHWU\FRORU
YLVLRQWHVW'LODWHGIXQGRVFRS\DQGVOLW
ODPSH[DP7KLVH[DPPD\EHUHSHDWHG
DVFOLQLFDOLQGLFDWHGWKURXJKRXWWKH
VWXG\

>7KHIROORZLQJLV1HZ7H[W@

(&*VWREHSHUIRUPHGLQDVXSLQH
SRVLWLRQDVIROORZVDWVFUHHQLQJ&\FOH
'D\SUHGRVHDQGKUVSRVWGRVH
DQG&\FOH'D\SUHGRVHDQG
KUVSRVWGRVH)RU&\FOHVDQGEH\RQG
SUHGRVHRQVSHFLILHGGD\VDQGDWWKH
ILQDOYLVLW

(OHFWLYH3(7)(7ZLOOEHSHUIRUPHG
DWEDVHOLQHSUHWUHDWPHQWSRVW
&KDQJHVPDGHWRQRWHVWRHQVXUH
FRQVLVWHQF\ZLWKDVVHVVPHQW
FKDQJHVDQGVSHFLILFWLPLQJ
SURYLGHGLQWKLV$PHQGPHQW
CCI
CCI

6HOLQH[RU.37
.DU\RSKDUP7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO.&3
1RYHPEHU

&RQILGHQWLDO
3DJHRI
9HUVLRQ
6HFWLRQ
3UHYLRXV:RUGLQJ
1HZ:RUGLQJ
5HDVRQIRU&KDQJH
WUHDWPHQWSUHRSHUDWLYHDQGSRVW
RSHUDWLYH

6WXG\5DWLRQDOH
,QWKH3KDVH,VWXG\.&3LQFOXGLQJ
SDWLHQWVZLWKDGYDQFHGVROLGWXPRU
PDOLJQDQFLHVWKHGRVHRIPJPð
DGPLQLVWHUHGWZLFHZHHNO\ZDVFKRVHQIRUWKH
H[SDQVLRQSKDVHRIWKHVWXG\EDVHGRQWKH
RFFXUUHQFHRI'/7V(YLGHQFHIRUDQWLWXPRU
DFWLYLW\ZDVH[LVWHQWDWWKLVGRVH
>1HZ7H[W@
,QWKHRQJRLQJGRVHHVFDODWLRQ3KDVH
VWXG\.&32=0LQ
SDWLHQWVZLWKDGYDQFHGVROLGWXPRUVD
6HOLQH[RUGRVHRIPJPWZLFHZHHNO\
ZDVWROHUDWHGDQGFOHDUHG'/7
HYDOXDWLRQ
([SORUDWRU\
2EMHFWLYHV
>1HZ7H[W@
CCI
CCI
CCI
CCI
CCI

6HOLQH[RU.37
.DU\RSKDUP7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO.&3
1RYHPEHU

&RQILGHQWLDO
3DJHRI
9HUVLRQ
6HFWLRQ
3UHYLRXV:RUGLQJ
1HZ:RUGLQJ
5HDVRQIRU&KDQJH
2YHUYLHZRI6WXG\
'HVLJQDQG'RVLQJ
5HJLPHQ
$IWHUVFUHHQLQJDQGUHJLVWUDWLRQLQWKHVWXG\
SDWLHQWVZLOOUHFHLYH6HOLQH[RUWZLFHZHHNO\
0RQGD\:HGQHVGD\RU7XHVGD\7KXUVGD\
RUDOO\DWDVWDUWLQJGRVHRIPJPð7KHGRVH
PD\EHWLWUDWHGDVWROHUDWHGZLWKDPD[LPXP
GRVHRIPJPðDQGDPLQLPXPGRVHRI
PJPð
$IWHUVFUHHQLQJDQGUHJLVWUDWLRQLQWKH
VWXG\SDWLHQWVZLOOUHFHLYH6HOLQH[RUWZLFH
ZHHNO\0RQGD\:HGQHVGD\RU
7XHVGD\7KXUVGD\RUDOO\DWDVWDUWLQJGRVH
RIPJPð7KHGRVHPD\EHUHGXFHG
GXHWRDGYHUVHHYHQWVUHODWHGWRVWXG\
GUXJWRDPLQLPXPGRVHRIPJPð
RQFHZHHNO\VHH7DEOH
,GHQWLILHVWKHLQFUHDVHGVWDUWLQJ
GRVHEDVHGRQUHFHQWFOLQLFDO
H[SHULHQFH
6DPHVHFWLRQ
6DPHVHFWLRQ
$PLQLPXP

SDWLHQWVZLOOEHHQUROOHGLQDUP
%,IDUP%LVIXOO\DFFUXHG


$SSUR[LPDWHO\

SDWLHQWV
ZLOOEHHQUROOHGLQ$UP%)RUPDO
VWDWLVWLFDODQDO\VHVIRUHIILFDF\ZLOO
SHUWDLQRQO\WRQRQVXUJLFDO
$UP%SDWLHQWV

&ODULILHVHQUROOPHQWFKDQJHVDQG
WKHVWDWLVWLFDODQDO\VLVSODQQHGIRU
HDFK$UP
6LWHV
$WRWDORIVLWHVZLOOSDUWLFLSDWHLQWKHVWXG\
5HFUXLWPHQWZLOOEHFRPSHWLWLYHZLWKDQ
H[SHFWHGDFFUXDORISDWLHQWVDWHDFKVLWH
XQWLOWKHSODQQHGWRWDOQXPEHURISDWLHQWVLV
UHDFKHG
$WRWDORIVLWHVZLOOSDUWLFLSDWHLQWKH
VWXG\5HFUXLWPHQWZLOOEHFRPSHWLWLYH
ZLWKDQH[SHFWHGDFFUXDORISDWLHQWVDW
HDFKVLWHXQWLOWKHSODQQHGWRWDOQXPEHURI
DSSUR[LPDWHO\SDWLHQWVLVUHDFKHG
&ODULILHVLQFUHDVHGSODQQHG
HQUROOPHQW
,QFOXVLRQ&ULWHULD
«
+HSDWLFIXQFWLRQELOLUXELQWLPHVWKH
XSSHUOLPLWRIQRUPDO8/1$/7WLPHV
8/1>1HZ7H[W@

+HSDWLFIXQFWLRQELOLUXELQWLPHVWKH
XSSHUOLPLWRIQRUPDO8/1$/7
WLPHV8/1$67WLPHV8/1
&ODULILHVHQUROOPHQWHOLJLELOLW\
EDVHGRQ$67OHYHOVREWDLQHGDW
VFUHHQLQJ
7XPRU
$VVHVVPHQW





&KDQJHVWRLGHQWLI\UHVSRQVHIRU
ERWKVWXG\$UPV
5HTXLUHG
3URSK\ODFWLF7KHUDS\
IRU$OO3DWLHQWV
>1HZ7H[W@
3DWLHQWVZLOOUHFHLYHSURSK\ODFWLF
WUHDWPHQWWRSUHYHQWDQRUH[LDDQG
QDXVHDZKLFKLQFOXGHV
3URYLGHVGHWDLOHGLQIRUPDWLRQIRU
LQYHVWLJDWRUVIRUSURSK\ODFWLF
CCI
CCI
CC
I
CCI
CCI
CCI
CCI
CCI

Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 123 of 137 
Version 6.0 
Section 
Previous Wording 
New Wording 
Reason for Change 
•  Megesterol acetate 160-400 mg daily, 
0-3 days before the first dosing day of 
KPT-330  
OR 
• Dexamethasone 2-4 mg (or equivalent 
steroid) on days of dosing and the 
following day. Dexamethasone may be 
given prior to initiation of dosing or 
more frequently as needed 
AND 
•  Olanzapine 5.0 mg qhs or 2.5 mg bid, 
0-3 days before the first dosing day of 
KPT-330  
OR 
•  Mirtazapine 15 mg qd (qpm/phs), 0-3 
days before the first dosing day of KPT-
330  
If the patient is on steroids coming on 
the study, megesterol acetate should be 
added prophylactically to prevent 
anorexia. If an increased risk of adverse 
effects due to olanzapine is anticipated, 
olanzapine can be omitted. However, it is 
recommended that mirtazapine or other 
appetite stimulating serotonergic agent 
be used. Additional standard supportive 
care agents may be used as needed (prn). 
Supportive care may be tapered or 
discontinued in Cycle 2 or later in 
patients who tolerate Selinexor well in 
Cycle 1. 
 
treatment now required in this 
study.  
5.2.2 Screening 
Procedures 
(Ophthalmologic Exam) 
Full ophthalmologic exam: required at 
screening and of clinically indicated.  
Full ophthalmologic exam: required at 
screening and if clinically indicated 
during the treatment phase.  
Clarifies the investigator’s option 
to examine any patient as needed 
while the study is ongoing.  
Same Section 
(Prophylactic therapy)
 
 
[New Text] 
Initiated 0-3 days prior to first Selinexor 
dose (see section 5.2.1) 
 
Identifies the new requirement that 
all patients undergo Prophylactic 
therapy and its timing. 

Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 124 of 137 
Version 6.0 
Section 
Previous Wording 
New Wording 
Reason for Change 
 
6.2.1.1  Drug Name, 
Formulation and 
Storage 
[New Text] 
 
 
Tablets: Selinexor (KPT-330) for oral 
administration will be supplied in two (2) 
tablet strengths: 10 and 25 mg. Bottles of 
50 tablets per bottle will be supplied for 
each of the two strengths.  
 
Describes the tablets by strength 
dispensed. 
6.3 
Dose 
Modifications for 
Selinexor 
Re-escalation of the study drug is allowed as 
outlined in the sections that apply for the 
specific toxicity. If toxicity requires a treatment 
delay of more than 3 weeks the patient is taken 
off protocol treatment.  
 
Based on observations from the ongoing Phase 
1 studies in patients with advanced 
hematological and solid tumors, Selinexor 
(KPT-330) shows a wide therapeutic range, 
with documented anti-cancer activity from 
~12mg/m2 to ≥35mg/m2 orally twice weekly. 
At the present time, we cannot predict which 
patient's tumors will respond to lower doses, 
nor can tolerability be predicted. Therefore, in 
order to individualize and optimize therapeutic 
benefit with this oral SINE XPO1 antagonist, 
initiation of study therapy will be with a 
relatively high dose (35mg/m2 twice weekly by 
mouth) of Selinexor. Although this is a high 
dose, it is below the MTD of oral Selinexor, 
and we believe will maximize early disease 
control with good tolerability in the majority of 
patients. Flexible dose reductions and/or 
schedule modifications will be permitted. In 
patients with tolerability issues on Selinexor, it 
is recommended either: (1) reducing Selinexor 
dose by 30% or (2) reducing Selinexor dosing 
frequency to once weekly. In addition, if a 
patient is experiencing one or more Grade ≤2 
toxicities such as fatigue or anorexia, then 1-2 
Re-escalation of the study drug is only 
allowed as outlined in the sections that 
apply for the specific toxicity. If toxicity 
requires a treatment delay of more than 3 
weeks the patient is taken off protocol 
treatment.  
At the present time, we cannot predict 
which patient's tumors will respond to 
lower doses, nor can tolerability be 
predicted. Therefore, in order to 
individualize and optimize therapeutic 
benefit with this oral SINE XPO1 
antagonist, initiation of study therapy will 
be with a relatively high dose (50mg/m2 
twice weekly by mouth) of Selinexor. 
Although this is a high dose, it is below the 
MTD of oral Selinexor, and we believe will 
maximize early disease control with good 
tolerability in the majority of patients. 
Therefore, in order to optimize specific 
anti-tumor activity and the patient’s 
tolerability, we will allow for dose and/or 
schedule modifications as described below 
(Table 5). Patients should also be treated 
aggressively with supportive care to 
reduce toxicities. 
 
 

Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 125 of 137 
Version 6.0 
Section 
Previous Wording 
New Wording 
Reason for Change 
doses of Selinexor can be held, and then dosing 
resumed at the current dose. In this last 
iteration, dosing for e.g., 3 of every 4 weeks 
may be considered in some patients. In 
addition, given that 35mg/m2 is not the MTD of 
Selinexor (twice weekly 40mg/m2 and 50mg/m2 
are currently under investigation), we will 
allow patients with acceptable tolerability who, 
in the opinion of their treating oncologist, may 
benefit from a dose escalation in order to 
derive additional anti-tumor benefit, to 
increase their dose to 40mg/m2 or, as ongoing 
cohorts allow, to higher doses, twice weekly. In 
conclusion, the wide therapeutic range, lack of 
significant acute toxicity, reversibility of 
common adverse effects (anorexia, nausea, 
fatigue), and the oral dosing regimen of 
Selinexor allows for flexibility in treating 
patients with cancer, and as such, 
individualization of each patient's regimen is 
easily accomplished.  
6.3.1 Dose Adjustment 
Guidelines for Selinexor 
Related Toxicities 
(Table 4)  
[Formerly Table 3] 
[Significant New Text—See Table 4 
(Version 2)] 
This table has been heavily revised 
to reflect more specific dose 
adjustments, assessments, and 
timing of adjustments by adverse 
event class and AE Grade. Too 
extensive to present here. A line-
by-line tracked changes 
comparison of the table is 
available upon request. 
Same section, last 
paragraph 
If the patient tolerates a reduced dose for at 
least four weeks, patients dose may be  
escalated to the dose they received prior to the 
reduction after authorization from the medical 
monitor and Principal Investigator. 
[replaced by New Text] 
For patients whose dose has been 
reduced due to neutropenia, anorexia or 
fatigue, dose re-escalation is permitted if 
the institution of supportive care 
measures has reduced these toxicities to 
Grade ≤1 or to baseline for at least 2 
weeks. Dose re-escalation is only 
permitted for these adverse events when 
This additional text was added in 
conjunction with the prophylactic 
therapy now required by this 
Amendment. 

Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 126 of 137 
Version 6.0 
Section 
Previous Wording 
New Wording 
Reason for Change 
supportive measures have been 
successful. 
6.3.2 Selinexor Dose 
Reduction in the Setting 
of Infection 
Patients with active uncontrolled infections 
should have Selinexor treatment withheld until 
the infection has clinically stabilized or 
resolved.  
After the infection has stabilized clinically, 
treatment may continue at the original dose. 
Missed doses will not be replaced. Patients 
may continue on antibiotics for prolonged 
periods while re-initiating their Selinexor 
regimen at the discretion of the investigator in 
consultation with the Medical Monitor, but the 
infection must be clinically resolved prior to 
restarting Selinexor. Prophylactic antibiotics 
are permitted concurrently with Selinexor 
treatment, but are not required.  
Patients with active uncontrolled infections 
should have Selinexor treatment withheld 
until the infection has resolved or the 
patient is clinically stable.  
After the infection has stabilized clinically 
or resolved, Selinexor treatment may 
continue at the original dose. Missed doses 
will not be replaced. Patients may continue 
on antibiotics for prolonged periods while 
re-initiating their Selinexor regimen at the 
discretion of the investigator. Prophylactic 
antibiotics are permitted concurrently with 
Selinexor treatment, but are not required. 
Opportunistic infections related to 
Selinexor therapy have not been 
reported in >170 patients treated as of 15 
October 2013.  
 
 
Clarifies details of reinitiation of 
study drug and describes the 
Sponsor’s current clinical 
experience with opportunistic 
infections.  
6.4 Concomitant 
Medication and 
Treatment  
Concomitant medication is defined as any 
prescription or over-the-counter preparation, 
including vitamins and supplements. Patients 
may continue their baseline medication(s). All 
concomitant medication(s) must be reported in 
the case report form (CRF). Any diagnostic, 
therapeutic or surgical procedure performed 
during the study period should be recorded, 
including the dates, description of the 
procedure(s) and any clinical findings. Patients 
should minimize the use of products containing 
acetaminophen, which can interfere with the 
metabolism of Selinexor. For combination 
painkillers containing acetaminophen it is 
recommended that single agent opiates or 
aspirin combinations (when clinically 
acceptable) be substituted. 
In vitro studies show that KPT-330 may 
have moderate CYP450 inhibition under 
some circumstances. Concomitant 
sensitive CYP3A4 substrates or CYP3A4 
substrates with a narrow therapeutic 
index should be used with caution as 
Selinexor could increase exposure to 
these substrates. It should be noted, 
however, that in >200 adult patients with 
advanced, relapsed/refractory 
hematologic cancers in ongoing Phase 1 
studies, no restrictions on concomitant 
medications with any CYP3A4 
substrates are required. In addition, 
there are no reports of drug-drug 
interactions in any of the >200 adult 
This text reflected the latest 
information available on CPY 
substrates and caution about using 
these agents in this study. 

Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 127 of 137 
Version 6.0 
Section 
Previous Wording 
New Wording 
Reason for Change 
[Replaced with new text] 
patients with cancers dosed with KPT-
330 as of 8 November 2013. 
6.4.2 Prohibited 
Medications  
Patients should minimize the use of products 
containing acetaminophen [new text]. For 
combination painkillers containing 
acetaminophen it is recommended that single 
agent opiates or aspirin combinations (when 
clinically acceptable) be substituted, 
particularly on the days of Selinexor dosing. 
[new text] 
Concurrent therapy with an approved or 
investigative anticancer therapeutic, other than 
glucocorticoids as specified herein, is not 
allowed.  
Inactivation of Selinexor by glutathione 
conjugation is a significant metabolic pathway 
in vitro and in vivo, including in humans. This 
process can be mediated in the absence of 
proteins, indicating that it is 
thermodynamically favorable.  
 
In vitro studies using human liver microsomes 
confirm in vivo findings that Selinexor 
undergoes minimal CYP450 metabolism. 
Therefore, administration of Selinexor with 
drugs which undergo substantial glutathione 
conjugation should be minimized or avoided. 
These drugs include acetaminophen 
(paracetamol) and ethyl alcohol. It should be 
noted that studies of Selinexor in combination 
with acetaminophen are to begin in late 2013 
and therefore that these recommendations are 
empirical.  
Patients should minimize the use of 
products containing acetaminophen on the 
days of Selinexor dosing. Acetaminophen 
should not be taken within 4 hours 
before or after Selinexor dosing. For 
combination painkillers containing 
acetaminophen it is recommended that 
single agent opiates or aspirin combinations 
(when clinically acceptable) be substituted, 
particularly on the days of Selinexor dosing 
within 4 hours before or after Selinexor 
dosing. 
 
Concomitant sensitive CYP3A4 
substrates or CYP3A4 substrates with a 
narrow therapeutic index should be used 
with caution as Selinexor could increase 
exposure to these substrates. It should be 
noted, however, that in >200 adult 
patients with advanced, 
relapsed/refractory hematologic cancers 
in ongoing Phase 1 studies, no 
restrictions on concomitant medications 
with any CYP3A4 substrates are 
required. In addition, there are no 
reports of drug-drug interactions in any 
of the >200 adult patients with cancers 
dosed with KPT-330 as of 8 November 
2013. 
Concurrent therapy with an approved or 
investigative anticancer therapeutic, 
other than glucocorticoids as specified 
herein, is not allowed.  
 
Inactivation of Selinexor by 
glucuoronidation is the most common 
This information is provided based 
on the most current clinical 
experience and to provide better 
guidance on dose timing if 
required.  

Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 128 of 137 
Version 6.0 
Section 
Previous Wording 
New Wording 
Reason for Change 
metabolic pathway; glutathione 
conjugation is also significant metabolic 
pathway in vitro and in vivo, including 
in humans. 
 
In vitro studies using human liver 
microsomes confirm in vivo findings that 
Selinexor undergoes minimal CYP450 
metabolism. Therefore, administration of 
Selinexor with drugs which undergo 
substantial glutathione conjugation should 
be minimized or avoided. These drugs 
include acetaminophen (paracetamol) and 
ethyl alcohol.  
It should be noted that preliminary studies 
of Selinexor in combination with 
acetaminophen have shown no significant 
changes in adverse events relative to 
Selinexor alone, nor have there been any 
significant increases in liver function 
tests in these adult cancer patients pre-
dosed with 500-1000mg acetaminophen 
prior to dosing of Selinexor as of 8 
November 2013.  
6.5.2 Fatigue  
Patients with Selinexor associated fatigue 
should receive Selinexor no more than twice 
weekly unless the treating physician determines 
that the benefits outweigh the risks. If this does 
not reduce fatigue to an acceptable level, then 
a dose reduction of 30% should be instituted. 
Once-weekly dosing (at the higher dose) can 
also be considered in patients whose disease is 
highly responsive to Selinexor.[Text deleted] 
 
Patients with Selinexor associated fatigue 
should receive Selinexor no more than 
twice weekly unless the treating physician 
determines that the benefits outweigh the 
risks. If this does not reduce fatigue to an 
acceptable level, then a dose reduction of 
one level (see Table 3) should be 
instituted.  
This section was changed to be 
consistent with the dose reduction 
schedule outlined in Table 3 of this 
Amendment.  
6.5.5 Thrombocytopenia 
Physicians should consider the use of 
Intravenous immune globulin in patients with 
enlarged spleens and thrombocytopenia. 
Physicians should consider the use of 
Intravenous immune globulin in patients 
with enlarged spleens and 
thrombocytopenia. 
This section was changed to be 
consistent with the dose reduction 
in response to specific adverse 
events displayed in Table 4. These 

6HOLQH[RU.37
.DU\RSKDUP7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO.&3
1RYHPEHU

&RQILGHQWLDO
3DJHRI
9HUVLRQ
6HFWLRQ
3UHYLRXV:RUGLQJ
1HZ:RUGLQJ
5HDVRQIRU&KDQJH
3DWLHQWVZLWK6HOLQH[RUDVVRFLDWHG*UDGH
WKURPERF\WRSHQLDVKRXOGUHFHLYH6HOLQH[RUQR
PRUHWKDQWZLFHZHHNO\SULRUWRDQ\GRVH
UHGXFWLRQ'RVHUHGXFWLRQRIVKRXOGWKHQ
EHFRQVLGHUHG2QFHZHHNO\GRVLQJFDQDOVREH
FRQVLGHUHGLQSDWLHQWVZKRVHGLVHDVHLVKLJKO\
UHVSRQVLYHWR6HOLQH[RU>7H[WGHOHWHG@


UHFRPPHQGDWLRQVDUHEDVHGRQWKH
ODWHVWFOLQLFDOGDWDDYDLODEOHIURP
WKH3KDVHWULDOV
5HSRUWLQJRI6$(V
$Q\FOLQLFDODGYHUVHHYHQWRUDEQRUPDO
ODERUDWRU\WHVWYDOXHWKDWLVVHULRXVRFFXUULQJ
GXULQJWKHFRXUVHRIWKHVWXG\IURPWKHGDWHRI
VLJQLQJWKHLQIRUPHGFRQVHQWLUUHVSHFWLYHRI
WKHWUHDWPHQWUHFHLYHGE\WKHSDWLHQWPXVWEH
UHSRUWHGWRWKHVSRQVRUZLWKLQRQHZRUNLQJGD\
RINQRZOHGJHH[SHGLWHGUHSRUWLQJ
$Q\FOLQLFDODGYHUVHHYHQWRUDEQRUPDO
ODERUDWRU\WHVWYDOXHWKDWLVVHULRXV
RFFXUULQJGXULQJWKHFRXUVHRIWKHVWXG\
IURPWKHGDWHRIVLJQLQJWKHLQIRUPHG
FRQVHQWLUUHVSHFWLYHRIWKHWUHDWPHQW
UHFHLYHGE\WKHSDWLHQWPXVWEHUHSRUWHGWR
WKHVSRQVRUZLWKLQKRXUVH[SHGLWHG
UHSRUWLQJ
7KLVFKDQJHFODULILHVWKHKRXU
UHSRUWLQJGHDGOLQH7KHSULRUWH[W
PD\KDYHFDXVHGVRPHVLWHVWR
GHOD\UHSRUWLQJEH\RQGWKH
UHTXLUHGWLPHZLQGRZ
3UHJQDQF\
3UHJQDQFLHVRFFXUULQJXSWRPRQWKVDIWHUWKH
FRPSOHWLRQRIWKHODVWWUHDWPHQWF\FOHPXVWDOVR
EHUHSRUWHGWRWKHLQYHVWLJDWRU7KHLQYHVWLJDWRU
PXVWUHSRUWDOOSUHJQDQFLHVZLWKLQRQHZRUNLQJ
GD\WR*62PE+*62PE+ZLOOIRUZDUGDOO
SUHJQDQF\UHSRUWVWRWKHVSRQVRUZLWKLQRQH
ZRUNLQJGD\7KHSDWLHQWVKRXOGEHPRQLWRUHG
XQWLOWKHFRQFOXVLRQRIWKHSUHJQDQF\
3UHJQDQFLHVRFFXUULQJXSWRPRQWKVDIWHU
WKHFRPSOHWLRQRIWKHODVWWUHDWPHQWF\FOH
PXVWDOVREHUHSRUWHGWRWKHLQYHVWLJDWRU
7KHLQYHVWLJDWRUPXVWUHSRUWDOO
SUHJQDQFLHVZLWKLQKRXUV*62PE+
ZLOOIRUZDUGDOOSUHJQDQF\UHSRUWVWRWKH
VSRQVRUZLWKLQKRXUV
7KLVWH[WKDVEHHQFKDQJHGWR
UHIOHFWWRPRUHVSHFLILFODQJXDJH
IRU6$(UHSRUWLQJDQGRWKHU
LPSRUWDQWUHTXLUHGQRWLILFDWLRQV
GHVFULEHGLQWKLV$PHQGPHQW
7ULDO'HVLJQDQG
+\SRWKHVHV
7KLVWULDOKDVEHHQGHVLJQHGDVDQRSHQODEHO
QRQUDQGRPL]HGDUPPXOWLFHQWUH3KDVH,,
VWXG\


DQGSDWLHQWVZKRGRQRWUHTXLUH
VXUJHU\ZLOOEHWUHDWHGZLWK6HOLQH[RUDORQH
$UP%XQWLOGLVHDVHSURJUHVVLRQ

7KLVK\SRWKHVLVZLOOEHWHVWHGXVLQJWKHGDWD
IURP
$UP%


7KLVWULDOKDVEHHQGHVLJQHGDVDQRSHQ
ODEHOQRQUDQGRPL]HGDUPPXOWLFHQWUH
3KDVH,,VWXG\



3DWLHQWVLQ0HGLFDO$UP$UP%ZLOOEH
WUHDWHGZLWK6HOLQH[RUDORQH[ZHHN





6DPHVHFWLRQ6HFRQGDU\
REMHFWLYHV
>1HZWH[W@

CCI
CCI
CCI
CCI
CCI
CCI

6HOLQH[RU.37
.DU\RSKDUP7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO.&3
1RYHPEHU

&RQILGHQWLDO
3DJHRI
9HUVLRQ
6HFWLRQ
3UHYLRXV:RUGLQJ
1HZ:RUGLQJ
5HDVRQIRU&KDQJH
CCI
CCI

6HOLQH[RU.37
.DU\RSKDUP7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO.&3
1RYHPEHU

&RQILGHQWLDO
3DJHRI
9HUVLRQ
6HFWLRQ
3UHYLRXV:RUGLQJ
1HZ:RUGLQJ
5HDVRQIRU&KDQJH
,QWHQWWR7UHDW
3RSXODWLRQ
7KHWUHDWHGSRSXODWLRQ,77ZLOOFRQVLVWRIDOO
SDWLHQWVZKRUHFHLYHDWOHDVWRQHGRVHRIVWXG\
PHGLFDWLRQDQGKDYHSRVWEDVHOLQHHIILFDF\
IROORZXSLQIRUPDWLRQ7KLVSRSXODWLRQZLOO
LQFOXGHSDWLHQWVZLWKDWOHDVWRQHGRVHRIVWXG\
GUXJZKRKDYHGLVFRQWLQXHGWKHUDS\GXHWR
WR[LFLW\RUGLVHDVHSURJUHVVLRQDQGSDWLHQWV
ZKRKDYHWDNHQDWOHDVWRQHGRVHRIVWXG\GUXJ
DQGKDYHGLHGIURPDQ\FDXVHUHODWHGWRVWXG\
GUXJRUGLVHDVH3DWLHQWVZKRGLHGXHWRFDXVHV
FOHDUO\XQUHODWHGWRVWXG\GUXJRUGLVHDVHZLOO
EHFHQVRUHGDWWKHWLPHRIGHDWK6LPLODUO\
SDWLHQWVZKRGLHGXULQJVXUJHU\

7KLVSRSXODWLRQZLOOEHXVHGIRU
VXSSRUWLYHDQDO\VHVRIHIILFDF\DGGLWLRQDO
VHQVLWLYLW\DQDO\VHVZLOOEHSHUIRUPHGRQWKLV
SRSXODWLRQDVGHVFULEHGLQ6HFWLRQ
7KHWUHDWHGSRSXODWLRQ,77ZLOOFRQVLVWRI
DOO$UP%SDWLHQWVZKRUHFHLYHDWOHDVW
RQHGRVHRIVWXG\PHGLFDWLRQDQGKDYH
SRVWEDVHOLQHHIILFDF\IROORZXS
LQIRUPDWLRQ


7KLVSRSXODWLRQZLOOLQFOXGH
SDWLHQWVZLWKDWOHDVWRQHGRVHRIVWXG\GUXJ
ZKRKDYHGLVFRQWLQXHGWKHUDS\GXHWR
WR[LFLW\RUGLVHDVHSURJUHVVLRQDQGSDWLHQWV
ZKRKDYHWDNHQDWOHDVWRQHGRVHRIVWXG\
GUXJDQGKDYHGLHGIURPDQ\FDXVHUHODWHG
WRVWXG\GUXJRUGLVHDVH7KLVSRSXODWLRQ
ZLOOEHXVHGIRUSULPDU\DQDO\VHVRI
HIILFDF\DGGLWLRQDOVHQVLWLYLW\DQDO\VHVZLOO
EHSHUIRUPHGRQWKLVSRSXODWLRQDV
GHVFULEHGLQ6HFWLRQ
7KLVWH[WKDVEHHQFKDQJHGWREH
FRQVLVWHQWZLWKWKHGHVLJQDWLRQRI
WKH0HGLFDO$UP$UP%DVWKH
,77SRSXODWLRQIRUWKLVVWXG\
CCI
C
C
I

6HOLQH[RU.37
.DU\RSKDUP7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO.&3
1RYHPEHU

&RQILGHQWLDO
3DJHRI
9HUVLRQ
6HFWLRQ
3UHYLRXV:RUGLQJ
1HZ:RUGLQJ
5HDVRQIRU&KDQJH
3HU3URWRFRO
3RSXODWLRQ
7KHSHUSURWRFROSRSXODWLRQZLOOFRQVLVWRIDOO
SDWLHQWVZKRKDYHEHHQDGPLQLVWHUHGDWOHDVW
PRQWKVRIVWXG\GUXJWUHDWPHQWZKRDUH
FRPSOLDQWZLWKVWXG\DVVHVVPHQWVDQGKDYH
UHFHLYHGDWOHDVWRIWKHLUSUHVFULEHGVWXG\
PHGLFDWLRQDQGZKRKDYHQRPDMRUSURWRFRO
YLRODWLRQVWKDWZRXOGFRPSURPLVHWKH
DVVHVVPHQWRIHIILFDF\0DMRUYLRODWLRQVZLOOEH
GHWHUPLQHGLQGHSHQGHQWO\RINQRZOHGJHRI
UHVSRQVHWRWKHUDS\





7KLV
SRSXODWLRQZLOOEHXVHGIRUSULPDU\LQIHUHQFHV
FRQFHUQLQJHIILFDF\KRZHYHULIWKHUHDUH
PDMRUGLIIHUHQFHVEHWZHHQWKHUHVXOWVLQWKLV
SRSXODWLRQDQGWKRVHREWDLQHGLQWKH,77
SRSXODWLRQWKLVZLOOEHWDNHQLQWRFRQVLGHUDWLRQ
LQWKHGHFLVLRQWRFRQWLQXHWRODWHUSKDVH
VWXGLHVRULQWKHGHVLJQRIIXUWKHUVWXGLHV,WLV
DQWLFLSDWHGWKDWWKH3HUSURWRFROSRSXODWLRQ
ZLOOSURYLGHWKHEDVLVIRUWKH6LPRQWZRVWDJH
DQDO\VLV>'HOHWHGWH[W@
7KHSHUSURWRFROSRSXODWLRQZLOOFRQVLVWRI
DOO$UP%SDWLHQWVZKRKDYHEHHQ
DGPLQLVWHUHGDWOHDVWPRQWKVRIVWXG\
GUXJWUHDWPHQWZKRDUHFRPSOLDQWZLWK
VWXG\DVVHVVPHQWVDQGKDYHUHFHLYHGDW
OHDVWRIWKHLUSUHVFULEHGVWXG\
PHGLFDWLRQDQGZKRKDYHQRPDMRU
SURWRFROYLRODWLRQVWKDWZRXOGFRPSURPLVH
WKHDVVHVVPHQWRIHIILFDF\











7KHVHFKDQJHVKDYHEHHQPDGHWR
FRQILUPWKDW$UP%ZLOOFRPSULVH
WKH33SRSXODWLRQ







CCI
CCI
CCI
CCI

6HOLQH[RU.37
.DU\RSKDUP7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO.&3
1RYHPEHU

&RQILGHQWLDO
3DJHRI
9HUVLRQ
6HFWLRQ
3UHYLRXV:RUGLQJ
1HZ:RUGLQJ
5HDVRQIRU&KDQJH
6DIHW\3RSXODWLRQ
7KHVDIHW\SRSXODWLRQZLOOFRQVLVWRIDOO
SDWLHQWVZKRKDYHUHFHLYHGDQ\DPRXQWRI
VWXG\PHGLFDWLRQ
>1HZWH[W@
7KHVDIHW\SRSXODWLRQZLOOFRQVLVWRIDOO
SDWLHQWVZKRKDYHUHFHLYHGDQ\DPRXQWRI
VWXG\PHGLFDWLRQ7KHVDIHW\SRSXODWLRQ
ZLOOLQFOXGHERWKWKHQRQVXUJLFDODQG
VXUJLFDOSDWLHQWJURXSVDQDO\VHVRI
VDIHW\ZLOOEHSURGXFHGIRUERWKWKHSRRO
RIVXUJLFDODQGQRQVXUJLFDOSDWLHQWVDV
ZHOODVHDFKJURXSVHSDUDWHO\
7KLVWH[WFKDQJHFODULILHVWKH
DQDO\VLVRIVDIHW\IRUERWK$UPV
VHSDUDWHO\DQGWRJHWKHU
*HQHUDO6WDWLVWLFDO
&RQVLGHUDWLRQV
>1HZWH[W@

)RUPDOVWDWLVWLFDODQDO\VHVIRUHIILFDF\
DVGHVFULEHGLQWKHIROORZLQJVHFWLRQVDQG
FRQVLVWHQWZLWKWKH6LPRQWZRVWDJH
GHVLJQZLOOSHUWDLQRQO\WRWKHSULPDU\
SDWLHQWSRSXODWLRQV,77DQG33WKDW
LQFOXGHQRQVXUJLFDOSDWLHQWV
'HVFULSWLYHVWDWLVWLFVRQO\ZLOOEH
SUHVHQWHGIRUWKHVXUJLFDOJURXS

7KLVQHZWH[WSURYLGHVWKHSODQQHG
HIILFDF\DQDO\VLVDVOLPLWHGWRWKH
,77DQG33SRSXODWLRQV



'HPRJUDSKLFVDQG
%DVHOLQH&KDUDFWHULVWLFV
%DVHOLQHFKDUDFWHULVWLFVLQFOXGH3HUIRUPDQFH
6WDWXVGXUDWLRQIURPLQLWLDOGLDJQRVLVUHVSRQVH
WRSUHYLRXVWKHUDS\<1>1HZWH[WDGGHG@

%DVHOLQHFKDUDFWHULVWLFVLQFOXGH
3HUIRUPDQFH6WDWXVGXUDWLRQIURPLQLWLDO
GLDJQRVLVUHVSRQVHWRSUHYLRXVWKHUDS\
<1'HPRJUDSKLFVDQGEDVHOLQH
FKDUDFWHULVWLFVZLOOEHVXPPDUL]HG
VHSDUDWHO\IRUQRQVXUJLFDODQGVXUJLFDO
SDWLHQWV

7KLVWH[WZDVDGGHGWRLGHQWLI\WKH
GLIIHUHQFHLQWKHSODQQHGDQDO\VLV
RIWKLVSDUDPHWHUIRUWKHWZRVWXG\
$UPV
CCI

6HOLQH[RU.37
.DU\RSKDUP7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO.&3
1RYHPEHU

&RQILGHQWLDO
3DJHRI
9HUVLRQ
6HFWLRQ
3UHYLRXV:RUGLQJ
1HZ:RUGLQJ
5HDVRQIRU&KDQJH
(IILFDF\
(YDOXDWLRQ
7KHDQDO\VLVRIPRQWK3)6ZLOOEHSHUIRUPHG
E\FDOFXODWLQJWKHSRLQWHVWLPDWHRIWKH
SHUFHQWDJHRISDWLHQWVZKRKDYHQHLWKHU
SURJUHVVHGQRUGLHGDWPRQWKVIROORZLQJWKH
VWDUWRIWKHUDS\ZKHUHSURJUHVVLRQZLOOEH
GHWHUPLQHGE\WKH5$12FULWHULD7REH
FRQVLVWHQWZLWKWKH6LPRQGHVLJQDORZHURQH
VLGHG&,ZLOOEHSUHVHQWHGRQUDWHRI
PRQWK3)6DGGLWLRQDOO\IRUGHVFULSWLYH
SXUSRVHVDWZRVLGHG&,ZLOODOVREH
FDOFXODWHGXVLQJH[DFWPHWKRGV7KHPRQWK
3)6UHVXOWVZLOOEHSUHVHQWHGIRUWKHILUVWVWDJH
RIWKHVWXG\DQGIRUERWKVWDJHVFRPELQHG
FRQVLVWHQWZLWKWKH6LPRQGHVLJQDQDGGLWLRQDO
SUHVHQWDWLRQRIUHVXOWVIURPERWKVWDJHV
FRPELQHGZLOOVXPPDUL]HWKHGDWDIURP

$UP%VHSDUDWHO\ZLWKRXWVWDWLVWLFDO
LQIHUHQFH>'HOHWHGWH[W@

7KHDQDO\VLVRIPRQWK3)6ZLOOEH
SHUIRUPHGE\FDOFXODWLQJWKHSRLQWHVWLPDWH
RIWKHSHUFHQWDJHRIQRQVXUJLFDOSDWLHQWV
ZKRKDYHQHLWKHUSURJUHVVHGQRUGLHGDW
PRQWKVIROORZLQJWKHVWDUWRIWKHUDS\
ZKHUHSURJUHVVLRQZLOOEHGHWHUPLQHGE\
WKH5$12FULWHULD7REHFRQVLVWHQWZLWK
WKH6LPRQGHVLJQDORZHURQHVLGHG
&,ZLOOEHSUHVHQWHGRQUDWHRIPRQWK
3)6DGGLWLRQDOO\IRUGHVFULSWLYHSXUSRVHV
DWZRVLGHG&,ZLOODOVREHFDOFXODWHG
XVLQJH[DFWPHWKRGV7KHPRQWK3)6
UHVXOWVZLOOEHSUHVHQWHGIRUWKHILUVWVWDJH
RIWKHVWXG\DQGIRUERWKVWDJHVFRPELQHG
FRQVLVWHQWZLWKWKH6LPRQGHVLJQ

7KLV$PHQGPHQWLQFOXGHVRQO\
0HGLFDO$UP$UP%SDWLHQWVLQ
WKLVDQDO\VLV
6DPHVHFWLRQ
6HFRQGDU\$QDO\VHV
$OOVHFRQGDU\HIILFDF\DQDO\VHVZLOOEH
SHUIRUPHGRQWKHUHVSHFWLYHFRPSOHWHDQDO\VLV
SRSXODWLRQWKDWLVQRSUHVHQWDWLRQRIUHVXOWV
RQHDFKRIWKHWZRVWXG\VWDJHVLVSODQQHG
+RZHYHUUHVXOWVZLOOEHSUHVHQWHGLQD
EUHDNGRZQE\
$UP%DQGWRWDO
>'HOHWHGWH[W@

7KH$PHQGPHQWGHVFULEHVD
FKDQJHGDQDO\VLVSODQ7KLVWH[W
KDVEHHQGHOHWHGEHFDXVHLWQR
ORQJHUUHIOHFWVWKHSODQQHG
DQDO\VLV
CCI
CCI

6HOLQH[RU.37
.DU\RSKDUP7KHUDSHXWLFV,QF
&OLQLFDO6WXG\3URWRFRO.&3
1RYHPEHU

&RQILGHQWLDO
3DJHRI
9HUVLRQ
6HFWLRQ
3UHYLRXV:RUGLQJ
1HZ:RUGLQJ
5HDVRQIRU&KDQJH
,QWHULPDQG)LQDO
$QDO\VLV
7KHILQDODQDO\VLVZLOOWDNHSODFHDIWHUWKHUH
DUHSDWLHQWVHYDOXDEOHIRUDQDO\VLVRI
PRQWK3)6$GGLWLRQDOGDWDVXPPDUL]DWLRQ
PD\WDNHSODFHDIWHUDOODYDLODEOHVXUYLYDOGDWD
DUHFROOHFWHGRUDIWHU6SRQVRUGHFLVLRQDV
DSSURSULDWH>7H[WGHOHWHG@


7KHGHOHWHGWH[WQRORQJHUUHIOHFWV
WKHSODQQHGDQDO\VLVRXWOLQHGLQ
WKLV$PHQGPHQW


CCI
CCI

Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 136 of 137 
Version 6.0 
17 REFERENCES 
1 
Wen PY, Kesari S. Malignant gliomas in adults. N Engl J Med 2008;359:492-507. 
2 
Stupp R, Mason WP, van den Bent MJ et al. Radiotherapy plus Concomitant and Adjuvant 
Temozolomide for Glioblastoma. N Engl J Med 2005;352:987-96. 
3 
Mirimanoff RO, Gorlia T, Mason W et al. Radiotherapy and Temozolomide for Newly Diagnosed 
Glioblastoma: Recursive Partitioning Analysis of the EORTC 26981/22981 – NCIC CE3 Phase III 
Randomized Trial. J Clin Oncol 2006;24:1563-2569. 
4 
Hart MG, Garside R, Rogers G, Stein K, Grant R. Temozolomide for high grade glioma. Cochrane 
Database Syst Rev 2013;4:CD007415. 
5 
Eftimov TN, Ivanov ID, Petkov AP, Nakov E. Management of recurrent high-grade gliomas. Cancer 
Therapy 2007;5:243-252. 
6 
Happold C, Roth P, Wick W, Steinbach JP, Linnebank M, Weller M, Eisele G. ACNU-based 
chemotherapy for recurrent glioma in the temozolomide era. J Neurooncol 2009;92(1):45-8. 
7 
Westphal M, Hilt DC, Bortey E, Delavault P et al. A phase 3 trial of local chemotherapy with 
biodegradable carmustine (BCNU) wafers (Gliadel wafers) in patients with primary malignant glioma. 
Neuro Oncology 2002;5:79-88. 
8 
Brandes AA, Tosoni A, Basso U, Reni M et al. Second-Line Chemotherapy With Irinotecan Plus 
Carmustine in Glioblastoma Recurrent or Progressive After First-Line Temozolomide Chemotherapy: 
A Phase II Study of the Gruppo Italiano Cooperativo di Neuro-Oncologia (GICNO). J Clin Oncol 
2004;22:4779-4786. 
9 
Kappelle AC, Postma TJ, Taphoorn MJB et al. PCV chemotherapy for recurrent glioblastoma 
multiforme. Neurology 2001;56:118-120. 
10 Perry JR, Bélanger K, Mason WP, Fulton D et al. Phase II trial of Continuous Dose-Intense 
Temozolomide in Recurrent Malignant Glioma: RESCUE Study. J Clin Oncol 2010;29:2051-2057. 
11 Omuro A, Chan TA, Abrey LE et al. Phase II trial of continuous low-dose temozolomide for patients 
with recurrent malignant glioma. Neuro Oncol 2013;15(2): 242-50. 
12 Gil-Gil MJ, Mesia C, Rey M, Bruna J. Bevacizumab for the Treatment of Glioblastoma. Clin Med 
Insights Oncol 2013;7:123-135. 
13 Bokstein F, Shpigel S, Blumenthal ST. Treatment with bevacizumab and irinotecan for recurrent high-
grade glial tumors. Cancer 2008;112:2267-2273. 
14 Vredenburgh JJ, Desjardins A, Herndon JE et al. Bevacizumab plus irinotecan in recurrent 
glioblastoma multiforme. J Clin Oncol 2007;25:4722-4729. 
15 Poulsen HS, Grunnet K, Sorensen M et al. Bevacizumab plus irinotecan in the treatment of patient 
with progressive recurrent malignant brain tumors. Acta Oncol 2009;48:52-58. 
16 Batchelor TT, Sorensen AG, di Tomaso E et al. AZD2171, a pan-VEGF receptor tyrosine kinase 
inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 
2007;11:83-95. 
17 Kesselheim JC, Norden AD, Wen PY, Joffe S. Discontinuing bevacizumab in patients with 
glioblastoma: an ethical analysis. Oncologist 2011;16(10):1435-9. 
18 Chinot OL. Bevacizumab-based therapy in relapsed glioblastoma: rationale and clinical experience to 
date. Expert Rev Anticancer Ther 2012;12(11):1413-27. 
19 Wen PY, Lee EQ, Reardon DA, Ligon KL, Alfred Yung WK. Current clinical development of PI3K 
pathway inhibitors in glioblastoma. Neuro Oncol 2012;14(7):819-29. 
20 Lassen U, Sorensen M, Gaziel TB et al. Phase II study of bevacizumab and temsirolimus combination 
therapy for recurrent glioblastoma multiforme. Anticancer Res 2013;33(4):1657-60. 
21 Van den Bent MJ, Brandes AA, Rampling R et al. Randomized Phase II Trial of Erlotinib Versus 
Temozolomide or Carmustine in Recurrent Glioblastoma: EORTC Brain Tumor Group Study 26034. 
J Clin Oncol 2009;27:1268-1274. 

Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 137 of 137 
Version 6.0 
22 Bode U, Massimino M, Bach F et al. Nimotuzumab treatment of malignant gliomas. Expert Opin Biol 
Ther 2012;12(12):1649-59. 
23 Muhic A, Poulsen HS, Sorensen M et al. Phase II open-label study of nintedanib in patients with 
recurrent glioblastoma multiforme. J Neurooncol 2013;111(2):205-12. 
24 Kreisl TN, McNeill KA, Sul J et al. A phase I/II trial of vandetanib for patients with recurrent 
malignant glioma. Neuro Oncol 2012;14(12):1519-26. 
25 Reardon DA, Dresemann G, Taillibert S et al. Multicentre phase II studies evaluating imatinib plus 
hydroxyurea in patients with progressive glioblastoma. Br J Cancer 2009;101(12):1995-2004. 
26 Hu J, Wen PY, Abrey LE et al. A phase II trial of oral gimatecan for recurrent glioblastoma. J 
Neurooncol 2013;111(3):347-53. 
27 Grossmann KF, Colman H, Akerley WA et al. Phase I trial of verubulin (MPC-6827) plus carboplatin 
in patients with relapsed glioblastoma multiforme. J Neurooncol 2012;110(2):257-64. 
28 Reardon DA, Groves MD, Wen PY et al. A phase I/II trial of pazopanib in combination with lapatinib 
in adult patients with relapsed malignant glioma. Clin Cancer Res 2013;19(4):900-8. 
29 Shen A, Wang Y, Zhao Y, Zou L, Sun L, Cheng C. Expression of CRM1 in human gliomas and its 
significance in p27 expression and clinical prognosis. Neurosurgery 2009;65(1): 153-9. 
30 Wang D, He F, Zhang L et al. The role of p27 (Kip1) phosphorylation at serine 10 in the migration of 
malignant glioma cells in vitro. Neoplasma 2011;58(1):65-73. 
31 National Comprehensive Cancer Network®. NCCN Clinical Practice Guidelines in Oncology (NCCN 
Guidelines®): Fatigue. Available at http://www.nccn.org/professionals/physician_gls/pdf/fatigue.pdf. 
32 National Comprehensive Cancer Network®. NCCN Clinical Practice Guidelines in Oncology (NCCN 
Guidelines®): Palliative Care, version 1.2014. Fort Washington, NY. April 2014. Available at: 
http://www.lls.org/content/nationalcontent/resourcecenter/freeeducationmaterials/generalcancer/pdf/fa
cts.pdf. 
33 National Comprehensive Cancer Network®. NCCN Clinical Practice Guidelines in Oncology (NCCN 
Guidelines®): Antiemesis, version 2.2014. Fort Washington, NY. April 2014. Available at: 
http://www.nccn.org/professionals/physician_gls/PDF/antiemesis.pdf. 
34 Benson AB, Ajani JA, Catalano RB, et al. Recommended guidelines for the treatment of cancer 
treatment-induced diarrhea. J Clin Onc 2004; 22:2918. 
35 Green AL, Ramkissoon SH, McCauley D, et al. Preclinical antitumor efficacy of selective exportin 1 
inhibitors in glioblastoma. Neuro-Oncology 2014;0:1–11, doi:10.1093/neuonc/nou303. 
36 Simon R. Optimal Two-Stage Designs for Phase II Clinical Trials. Controlled Clinical Trials 
1989;10:1-10. 
37 Wen PY, Macdonald DR, Reardon DA et al., Updated Response Assessment Criteria for High-Grade 
Gliomas: Response Assessment in Neuro-Oncology (RANO) Working Group. J Clin Oncol 
2010:28(11);1963-72. Available at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3631110/.