Clinical trial NCT04256941
Conditions: Anatomic Stage IV Breast Cancer AJCC v8 Metastatic Breast Carcinoma Prognostic Stage IV Breast Cancer AJCC v8
Sponsor: M.D. Anderson Cancer Center
Start date: 2019-05-31; Completion date: 2023-09-22
Enrollment: 4 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This phase II trial studies how well letrozole, anastrozole, or fulvestrant work when given together with ribociclib, palbociclib, and/or abemaciclib in treating patients with hormone receptor (HR) positive breast cancer that has spread to other places in the body (metastatic) and has an ERS1 activating mutation. Letrozole, anastrozole, ribociclib, palbociclib, and abemaciclib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Estrogen can cause the growth of breast cancer cells. Hormone therapy using fulvestrant may fight breast cancer by blocking the use of estrogen by the tumor cells. It is not yet known if giving letrozole, anastrozole, or fulvestrant with ribociclib, palbociclib, and/or abemaciclib will work better in treating patients with breast cancer.

Detailed description:
PRIMARY OBJECTIVE:

I. To assess progression free survival (PFS) with transition to fulvestrant compared with continuing aromatase inhibitor (AI) therapy in patients with emergence of estrogen receptor 1 (ESR1) mutations in plasma.

SECONDARY OBJECTIVES:

I. To assess circulating tumor deoxyribonucleic acid (ctDNA) ESR1 mutant allele fraction (MAF) and kinetics with fulvestrant compared with AI.

II. To assess the prevalence of ESR1 mutations in patients with secondary resistance to endocrine therapy.

III. To correlate ctDNA with cancer antigens (CA) 15-3 tumor marker changes. IV. To assess overall survival (OS) with transition to fulvestrant compared with continuing AI therapy in patients with emergence of ESR1 mutations.

V. To assess PFS and time to next treatment (TTNT) on next line of therapy after progression on fulvestrant versus (vs.) AI in combination with CDKI.

EXPLORATORY OBJECTIVES:

I. Characterize other co-existing actionable genomic alterations of interest in relation to ESR1 and clinical outcomes.

II. To determine frequency of other actionable genomic alterations and frequency of enrollment on genotype-matched therapy.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive ribociclib orally (PO) once daily (QD), palbociclib PO QD on days 1-21, and/or abemaciclib PO twice daily (BID) on days 1-28. Patients also receive fulvestrant intramuscularly (IM) for 2 injections over 1-2 minutes each on days 1 and 15 of cycle 1 and day 2 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive ribociclib orally PO QD, palbociclib PO QD on days 1-21, and/or abemaciclib PO BID on days 1-28. Patients also receive letrozole PO QD or anastrozole PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days.

Arms: arm 1: Patients receive ribociclib PO QD, palbociclib PO QD on days 1-21, and/or abemaciclib PO BID on days 1-28. Patients also receive fulvestrant IM for 2 injections over 1-2 minutes each on days 1 and 15 of cycle 1 and day 2 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. arm 2: Patients receive ribociclib orally PO QD, palbociclib PO QD on days 1-21, and/or abemaciclib PO BID on days 1-28. Patients also receive letrozole PO QD or anastrozole PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Abemaciclib intervention 2: Anastrozole intervention 3: Fulvestrant intervention 4: Letrozole intervention 5: Palbociclib intervention 6: Ribociclib
Intervention descriptions: intervention 1: Given PO intervention 2: Given PO intervention 3: Given IM intervention 4: Given PO intervention 5: Given PO intervention 6: Given PO

Protocol documents:
Prot_SAP_000.pdf: 
3URWRFRO
-DQXDU\
,17(5$&7,17HJUDWHG(YDOXDWLRQRI5HVLVWDQFHDQG$FWLRQDELOLW\XVLQJ
&LUFXODWLQJ7XPRU'1$LQ+5SRVLWLYHPHWDVWDWLFEUHDVWFDQFHUV
3ULQFLSDO,QYHVWLJDWRU6HQWKLO'DPRGDUDQ0'3K'
&RSULQFLSDO,QYHVWLJDWRUV'HEX7ULSDWK\0'6WDF\0RXOGHU0'06&,)XQGD
0HULF%HUQVWDP0'
&ROODERUDWLQJ6WDWLVWLFLDQ%HFN\6ODFN7LGZHOO06
&OLQLFDO&ROODERUDWRUV-HQQLIHU/LWWRQ0'0HJKDQ.DUXWXUL0'5DFKHO/D\PDQ
0'1DRWR8HQR0'3K'
/DERUDWRU\&ROODERUDWRUV,JQDFLR,:LVWXED0'3K'
'HSDUWPHQW
%UHDVW0HGLFDO2QFRORJ\
3KRQH

)D[


3URWRFRO7\SH
6WDQGDUG3URWRFRO
3URWRFRO3KDVH
3KDVH,,
9HUVLRQ6WDWXV

3DJHRI
Proprietary of MD Anderson Cancer Center 


3URWRFRO

-DQXDU\
Table of Contents 
 
,QWURGXFWLRQ 
 
(65PXWDWLRQVDQGHQGRFULQHUHVLVWDQFH 
 
&LUFXODWLQJ7XPRU'1$ 
 
&'.LQKLELWRUV 
 
)XOYHVWUDQW 
 
*XDUGDQW$VVD\ 
 
5DWLRQDOH 
 
7ULDO2EMHFWLYHVDQG(1'32,176 
 
3ULPDU\2EMHFWLYHV 
 
3ULPDU\(QGSRLQWV 
 
6HFRQGDU\2EMHFWLYHV 
 
6HFRQGDU\(QGSRLQWV 
 
([SORUDWRU\2EMHFWLYH 
 
([SORUDWRU\(QGSRLQWV 
 
6WXG\GHVLJQDQG6HOHFWLRQRISDWLHQWV 
 
,QFOXVLRQ&ULWHULD 
 
([FOXVLRQ&ULWHULD 
 
UHJLVWUDWLRQ 
 
3DWLHQWLGHQWLILFDWLRQ(QUROOPHQW 
 
,QVWUXFWLRQVIRUSDWLHQWVZKRGRQRWVWDUWDVVLJQHGSURWRFROWUHDWPHQW 
 
75($70(173ODQ 
 
7UHDWPHQW 
 
'UXJ0RQLWRULQJDQG'RVH0RGLILFDWLRQV 
 
&RQFRPLWDQW7KHUDS\ 
 
$GYHUVH(YHQWV 
 
'XUDWLRQRIWKHUDS\ 
 
VFKHGXOHGHYDOXDWLRQV 
 
3UHWUHDWPHQWHYDOXDWLRQ 
 
(YDOXDWLRQGXULQJVWXG\ 
 
3UHJQDQF\DQGDVVHVVPHQWVRIIHUWLOLW\ 
 
0HDVXUHPHQWRIHIIHFW 
 
5(&,67&ULWHULDLQPHWDVWDWLFGLVHDVH 
 
%,20$5.(5$1'&RUUHODWLYHVWXGLHV 
3DJHRI

Proprietary of MD Anderson Cancer Center 


3URWRFRO

-DQXDU\
 
6WDWLVWLFDO&RQVLGHUDWLRQV 
$SSHQGL[6FKHGXOHRIFOLQLFDODVVHVVPHQWV 






























3DJHRI

Proprietary of MD Anderson Cancer Center 


3URWRFRO
-DQXDU\
,17(5$&7VWXG\6FKHPD
3DWLHQWVZLWKKRUPRQHUHFHSWRUSRVLWLYH0%&ZKRDUHRQILUVWOLQHDURPDWDVHLQKLELWRU
OHWUR]ROHDQDVWUR]ROHZLWK&'.LQKLELWRUSDOERFLFOLEULERFLFOLEDEHPDFLFOLE ZLOOEH
VFUHHQHGIRU(65 PXWDWLRQV 3DWLHQWVZLWK(65 PXWDWLRQVZRXOGEHUDQGRPL]HGWR
FRQWLQXDWLRQRIWUHDWPHQWYHUVXVWUDQVLWLRQWRIXOYHVWUDQW
3DJHRI
Proprietary of MD Anderson Cancer Center 


3URWRFRO

-DQXDU\

,1752'8&7,21
%UHDVWFDQFHULVWKHPRVWFRPPRQLQYDVLYHFDQFHULQZRPHQZLWKDQHVWLPDWHGTXDUWHURIDPLOOLRQQHZ
FDVHV HYHU\ \HDU LQ WKH 86>@ (VWURJHQ SRVLWLYH EUHDVW FDQFHUV DUH WKH PRVW FRPPRQ VXEW\SH DQG
FRQWULEXWH WR WKH PDMRULW\ RI GHDWKV IURP EUHDVW FDQFHUV :KLOH HQGRFULQH WKHUDSLHV WKDW WDUJHW WKH
HVWURJHQVLJQDOLQJSDWKZD\IRUPWKHEDFNERQHRIWUHDWPHQWDQGKDYHVKRZQVLJQLILFDQWLPSURYHPHQWLQ
VXUYLYDOUHVLVWDQFHWRWKHUDS\LVLQHYLWDEOHOLPLWLQJRYHUDOOUHVSRQVH

(65PXWDWLRQVDQGHQGRFULQHUHVLVWDQFH
$FTXLUHGPXWDWLRQVLQ(65KDYHEHHQGHVFULEHGLQPHWDVWDWLFEUHDVWFDQFHU0%&SDWLHQWV
H[SRVHGWRHVWURJHQGHSULYDWLRQZLWKDURPDWDVHLQKLELWRUV$,>@(65PXWDWLRQVDUHXQFRPPRQLQ
SULPDU\ EUHDVW FDQFHUV DQG UDUHO\ REVHUYHG DIWHU DGMXYDQW $, VXJJHVWLQJ FORQDO VHOHFWLRQ>@ 7KRXJK
UHFHQWVWXGLHVKDYHVXJJHVWHGWKDWGHQRYR(65PXWDWLRQVPLJKWEHREVHUYHGDWORZDOOHOHIUHTXHQFLHV
>@&XUUHQWO\WKHXVHRI$,RU$,LQFRPELQDWLRQZLWKF\FOLQGHSHQGHQWNLQDVH&'.LQKLELWRUVDUH
UHFRPPHQGHGIRUILUVWOLQHWUHDWPHQWRI(5SRVLWLYH0%&&RQVWLWXWLYHDFWLYDWLRQWKURXJKPXWDWLRQVLQWKH
OLJDQGELQGLQJGRPDLQHJ<6'*63OHDGVWR$,UHVLVWDQFHDQGSRUWHQGDVKRUWHUVXUYLYDO
>@ 7KRXJK WKHVH PXWDWLRQV PD\ H[KLELW VHQVLWLYLW\ WR VHOHFWLYH HVWURJHQ UHFHSWRU GRZQUHJXODWRUV
6(5'HJIXOYHVWUDQWWKDWWDUJHWPXWDQW(5IRUSURWHDVRPDOGHJUDGDWLRQ>@,QWKH%2/(52VWXG\
ZKLFKWHVWHGWKHXVHRIH[HPHVWDQHDORQHRULQFRPELQDWLRQZLWKHYHUROLPXVLQ0%&ZLWKSULRUH[SRVXUH
WR$,SODVPD(65PXWDWLRQV'*DQG<6RQO\ZHUHLGHQWLILHGLQQHDUO\RISDWLHQWV:KLOH
(65PXWDWLRQVZHUHDVVRFLDWHGZLWKVKRUWHURYHUDOOVXUYLYDOFRPSDUHGWRZLOGW\SHPRQWKV<6
(65PXWDWLRQVPRQWKVZHUHDVVRFLDWHGZLWKDZRUVHRXWFRPHFRPSDUHGWR'*PRQWKV
VXJJHVWLQJGLIIHUHQFHVLQWKHYDULDQWV>@,Q6R)($WULDOZKLFKFRPSDUHGWKHDFWLYLW\RIIXOYHVWUDQWYHUVXV
H[HPHVWDQH DJDLQVW IXOYHVWUDQW LQ FRPELQDWLRQ ZLWK DQDVWUR]ROH LQ KRUPRQHUHFHSWRU +5 SRVLWLYH
PHWDVWDWLF SRVWPHQRSDXVDO ZRPHQ ZKR KDG SURJUHVVHG RQ SULRU QRQVWHURLGDO $, SODVPD (65
PXWDWLRQVZHUHREVHUYHGLQQHDUO\RISDWLHQWV,Q3$/20$VWXG\ZKLFKHYDOXDWHGWKHDGGLWLRQRI
&'.LQKLELWRUSDOERFLFOLEWRIXOYHVWUDQWDSSUR[LPDWHO\RISDWLHQWVZHUHIRXQGWRKDUERU(65
PXWDWLRQVLQSODVPDZKLFKGLGQRWDSSHDUWREHSUHGLFWLYHRISDOERFLFOLEUHVSRQVH7KHORZHUSUHYDOHQFH
RI (65 PXWDWLRQV LQ 3$/20$ OLNHO\ UHIOHFWV WKH LQFOXVLRQ RI SDWLHQWV ZLWK SULPDU\ UHVLVWDQFH WR
HQGRFULQHWKHUDS\DQGSULRUWDPR[LIHQH[SRVXUH

&LUFXODWLQJ7XPRU'1$
,PSURYHGXQGHUVWDQGLQJRIWXPRUHYROXWLRQDQGUHVLVWDQFHKDVKHOSHGWRXQGHUVFRUHWKHLPSRUWDQFHRI
UHSHDWELRSVLHV$PDMRUEDUULHUWRVWXG\JHQRPLFHYROXWLRQDQGPHFKDQLVPVRIUHVLVWDQFHLVWKHFKDOOHQJH
DVVRFLDWHGZLWKREWDLQLQJVHULDOWXPRUELRSVLHV'HSHQGLQJRQWKHRUJDQELRSVLHVDUHDVVRFLDWHGZLWK
SURFHGXUDO FRPSOLFDWLRQV VXFK DV EOHHGLQJ SQHXPRWKRUD[ DQG LQIHFWLRQV ,Q D SURVSHFWLYH VWXG\
HYDOXDWLQJWKHXVHRIELRSVLHVLQDGYDQFHGEUHDVWFDQFHUVRQO\DERXWRISDWLHQWVXQGHUJRLQJELRSV\
KDG VXIILFLHQW WLVVXH IRU UHFHSWRU DQDO\VLV >@ 0RUHRYHU PRUH WKDQ  RI ELRSVLHV IURP ERQH
FRPPRQHVWVLWHRIPHWDVWDVLVLQKRUPRQHUHFHSWRUSRVLWLYHEUHDVWFDQFHUVKDGLQVXIILFLHQWVDPSOH\LHOG
$OVRUDGLRORJLFDODVVHVVPHQWKDVOLPLWHGVHQVLWLYLW\DQGFDQQRWGLVFHUQEHWZHHQFDQFHUFHOOVWKDWDUH
YLDEOHYVQRQYLDEOHRUQRQFDQFHUFHOOVVXFKDVILEUREODVWV
$QDO\VHVRIFLUFXODWLQJWXPRU'1$FW'1$RIIHUDPLQLPDOO\LQYDVLYHEORRGEDVHGDSSURDFKWRPRQLWRU
GLVHDVHDQGWUHDWPHQWUHVSRQVH>@8QOLNHWLVVXHELRSVLHVFW'1$DYRLGVVDPSOLQJELDVGXHWRLQWUDWXPRU
KHWHURJHQHLW\DQGFDQSURYLGHDQREMHFWLYHHVWLPDWHRIWXPRUEXUGHQ4XDQWLWDWLYHFKDQJHVLQFW'1$ZHUH
DVVRFLDWHGZLWKDEHWWHUG\QDPLFUDQJHDQGFRUUHODWLRQZLWKWXPRUEXUGHQFRPSDUHGWRWXPRUPDUNHUVLQ
0%&>@$VVHVVLQJUHVLGXDOFDQFHUEXUGHQZLWKFW'1$KDVEHHQVKRZQLGHQWLI\KLJKULVNSDWLHQWVIRU
UHODSVH >@ FW'1$ DQDO\VLV KDV EHHQ VKRZQ WR LGHQWLI\ (65 PXWDWLRQV QRW GLVFHUQDEOH RQ WLVVXH
VDPSOLQJ >@ $OVR D KLJK SUHYDOHQFH RI SRO\FORQDO (65 PXWDWLRQV KDV EHHQ UHSRUWHG LQ SDWLHQWV
SUHYLRXVO\WUHDWHGZLWKDURPDWDVHLQKLELWRUHQGRFULQHWKHUDS\VXJJHVWLQJWKDWWKHFRPSOH[LWLHVRIUHVLVWDQW
GLVHDVHGXHWRWXPRUHYROXWLRQDQGKHWHURJHQHLW\LVXQOLNHO\WREHFDSWXUHGE\VLQJOHVLWHWLVVXHELRSV\
>@
FW'1$G\QDPLFVKDVEHHQVKRZQWRSUHGLFWUHVSRQVHVEHIRUHVXFKFKDQJHVDUHHYLGHQWRQFRQYHQWLRQDO
DSSURDFKHVVXFKDVLPDJLQJ7KXVHDUO\FW'1$ G\QDPLFVFDQDFWDVDVXUURJDWHIRUDVVHVVPHQWRI
3DJHRI

Proprietary of MD Anderson Cancer Center 


3URWRFRO

-DQXDU\
WUHDWPHQW HIILFDF\ ZLWK DELOLW\ WR WUDQVLWLRQ IURP DQ LQHIIHFWLYH WKHUDS\ WR D SRWHQWLDOO\ DFWLYH RQH
)XUWKHUPRUH PXWDWLRQDO DOOHOH IUHTXHQF\ 0$) UHSUHVHQW WXPRU FORQHV KDUERULQJ D PXWDWLRQ WKXV
SURYLGLQJ DQ LQGLFDWRU RI WXPRU EXUGHQ 6HULDO PRQLWRULQJ RI 0$) ZLWK FW'1$ LQ SDWLHQWV WUHDWHG ZLWK
WDUJHWHGWKHUDSLHVKDVEHHQVKRZQWREHDVVRFLDWHGZLWKWLPHWRUDGLRORJLFGLVHDVHSURJUHVVLRQ>@
&ODWRWHWDOUHWURVSHFWLYHO\DQDO\]HG(65PXWDWLRQVLQFW'1$LQSDWLHQWVZKRZHUHWUHDWHGZLWK$,IRU
0%&DVILUVWOLQH>@(65PXWDWLRQVZHUHLGHQWLILHGLQRISDWLHQWVDWSURJUHVVLRQZLWK$,3DWLHQWV
ZLWK(65PXWDWLRQVKDGZRUVHPHGLDQ3)6PRQWKVFRPSDUHGWRSDWLHQWVZLWKRXWDPXWDWLRQ
PRQWKV,QSDWLHQWVZLWK(65PXWDWLRQVRIWKHPKDGGHWHFWDEOHFLUFXODWLQJPXWDWLRQVEHIRUHFOLQLFDO
SURJUHVVLRQ$OVRSDWLHQWVSUHVHQWLQJZLWKLQFUHDVHVLQFLUFXODWLQJ(65DWPRQWKVDIWHUVXEVHTXHQW
WUHDWPHQWZLWKSULRU$,KDGGLVHDVHSURJUHVVLRQ,QWKH)(5*,VWXG\SDWLHQWVZLWKUDGLRORJLFUHVSRQVH
FRPSOHWH RU SDUWLDO GHPRQVWUDWHG VLJQLILFDQW GHFUHDVHV LQ (65 SODVPD 0$) SRVW WUHDWPHQW ZLWK
IXOYHVWUDQWDQGWKHVHZHUHGHWHFWHGHDUO\LQWKHFRXUVHRIUHVSRQVHFW'1$DQDO\VLVRI16&/&SDWLHQWV
WUHDWHGZLWK(*)5LQKLELWRUVVKRZHGWKDW(*)570DFRPPRQPHFKDQLVPRIVHFRQGDU\UHVLVWDQFH
FW'1$ ZDV GHWHFWHG QHDUO\  PRQWKV SULRU WR FOLQLFDO SURJUHVVLRQ DQG WKDW WKH (*)5 70 FW'1$
SRVLWLYHSDWLHQWVKDGVLJQLILFDQWO\VKRUWHUVXUYLYDO>@FW'1$YHORFLW\ZLWKGHFUHDVHLQ0$)DWZHHNV
ZHUHVKRZQWREHSUHGLFWLYHRIUHVSRQVHDQGDVVRFLDWHGZLWKLPSURYHGVXUYLYDOWRGXUYDOXPDELQOXQJ
FDQFHU>@6LPLODUO\LQWKHVWXG\HYDOXDWLQJWKHHIILFDF\RIQHUDWLQLELQDGYDQFHGEUHDVWFDQFHUSDWLHQWV
ZLWK(5%%PXWDWLRQVGHFUHDVHLQ0$)DWZHHNVZDVSUHGLFWLYHRIFOLQLFDOUHVSRQVH>@
FW'1$G\QDPLFVRI3,.&$PXWDWLRQVDVVHVVHGLQ3$/20$VWXG\>@3ODVPDVDPSOHVZHUHFROOHFWHG
DWEDVHOLQH'D\DQGDWSURJUHVVLRQ$UHGXFWLRQLQ&'5FLUFXODWLQJ'1$UDWLRGHILQHGDVWKHUDWLR
RIPXWDQWFRSLHVPODW'D\RQWUHDWPHQWUHODWLYHWREDVHOLQHWRLQ3,.&$ZDVDVVRFLDWHGZLWK
LPSURYHPHQWLQ3)6VHHQZLWKSDOERFLFOLEDQGIXOYHVWUDQW7KXVVHULDOPHDVXUHPHQWVRIFW'1$FDQKHOS
FKDUDFWHUL]HJHQRPLFODQGVFDSHFORQDOHYROXWLRQUHVSRQVHDQGSUHGLFWIRUHDUO\UHFXUUHQFH+RZHYHULW
LVQRWFOHDUZKHWKHUWUHDWPHQWGHFLVLRQVFDQEHPDGHEDVHGRQWKHDSSHDUDQFHRIUHVLVWDQFHPXWDWLRQV
RU 0$) FKDQJHV LQ FW'1$ DQG WKDW ³JHQRPLFDOO\ DGDSWHG WKHUDS\´ FDQ LPSURYH RXWFRPH >@ :H
K\SRWKHVL]HWKDWUHDOWLPHPRQLWRULQJRIFW'1$IRUVHFRQGDU\(65DOWHUDWLRQVFDQLGHQWLI\VXEFOLQLFDO
SURJUHVVLRQDQGHDUO\LQWHUYHQWLRQZLWK(65PXWDWLRQWDUJHWHGDJHQWVFDQLPSURYHVXUYLYDOLQ(5SRVLWLYH
0%&


&'.LQKLELWRUV

&XUUHQWO\&'.LQKLELWRUVHJSDOERFLFOLE,EUDQFHULERFLFOLE.LVTDOLDQG DEHPDFLFOLEYHU]HQLR DUH
DSSURYHGIRUWKHILUVWOLQHWUHDWPHQWRI+5SRVLWLYHDGYDQFHGEUHDVWFDQFHUVLQFRPELQDWLRQZLWKDURPDWDVH
LQKLELWRUVDVZHOODVLQFRPELQDWLRQZLWKIXOYHVWUDQWZLWKGLVHDVHSURJUHVVLRQIROORZLQJSULRUHQGRFULQH
WKHUDS\ )LQDO DSSURYDO RI SDOERFLFOLE LV EDVHG RQ GDWD IURP 3$/20$ ZKLFK UDQGRPL]HG 
SRVWPHQRSDXVDOZRPHQWRSDOERFLFOLESOXVOHWUR]ROHRUSODFHERSOXVOHWUR]ROH>@7KH3)6ZDV
 PRQWKV LQ WKH SDOERFLFOLE SOXV OHWUR]ROH DUP DQG  PRQWKV LQ WKH SODFHER SOXV OHWUR]ROH DUP
+5 &,S3DOERFLFOLELVDOVRDSSURYHGLQFRPELQDWLRQZLWKIXOYHVWUDQW
EDVHGRQ3$/20$ZKLFKUDQGRPL]HGDWRWDORISUHDQGSRVWPHQRSDXVDO+5SRVLWLYHZRPHQ
ZLWK0%&ZLWKGLVHDVHSURJUHVVLRQRQRUDIWHUSULRUDGMXYDQWRUPHWDVWDWLFHQGRFULQHWKHUDS\WRHLWKHU
SDOERFLFOLESOXVIXOYHVWUDQWRUSODFHERSOXVIXOYHVWUDQWXQWLOGLVHDVHSURJUHVVLRQ>@7KHPHGLDQ3)6ZDV
YHUVXVPRQWKVIRUSDWLHQWVWUHDWHGLQWKHSDOERFLFOLESOXVIXOYHVWUDQWDQGSODFHERSOXVIXOYHVWUDQW
DUPV UHVSHFWLYHO\ $SSURYDO RI ULERFLFOLE ZDV EDVHG RQ 021$/((6$ D GRXEOH EOLQG SODFHER
FRQWUROOHGWULDOLQSRVWPHQRSDXVDOZRPHQZLWK+5SRVLWLYHDGYDQFHGEUHDVWFDQFHUVZKRUHFHLYHGQR
SULRUWKHUDS\>@$WRWDORISDWLHQWVZHUHUDQGRPL]HGWRUHFHLYHULERFLFOLESOXVOHWUR]ROHQ RU
SODFHER SOXV OHWUR]ROH Q  7KH HVWLPDWHG PHGLDQ 3)6 KDG QRW EHHQ UHDFKHG LQ WKH ULERFLFOLE
FRQWDLQLQJDUPDQGZDVPRQWKVLQWKHSODFHERFRQWDLQLQJDUP2EMHFWLYHUHVSRQVHUDWH255LQ
SDWLHQWVZLWKPHDVXUDEOHGLVHDVHZDV&,LQWKHULERFLFOLESOXVOHWUR]ROHDUPDQG
  &,   LQ WKH SODFHER SOXV OHWUR]ROH DUP $EHPDFLFOLE ZDV LQLWLDOO\ DSSURYHG LQ
FRPELQDWLRQZLWKIXOYHVWUDQWIRU+5SRVLWLYH0%&SDWLHQWVZKRKDGSURJUHVVHGRQSULRUHQGRFULQHWKHUDS\
7KLV ZDV EDVHG RQ 021$5&+ D GRXEOHEOLQGHG SODFHERFRQWUROOHG VWXG\ WKDW UDQGRPL]HG 
SDWLHQWVWRUHFHLYHIXOYHVWUDQWZLWKRUZLWKRXWDEHPDFLFOLE0HGLDQ3)6ZDVPRQWKVLQSDWLHQWVWDNLQJ
DEHPDFLFOLESOXVIXOYHVWUDQWYVPRQWKVZLWKIXOYHVWUDQWDORQH>@$EHPDFLFOLELVDOVRDSSURYHGLQ
3DJHRI

Proprietary of MD Anderson Cancer Center 


3URWRFRO
-DQXDU\
FRPELQDWLRQZLWKDURPDWDVHLQKLELWRUDVLQLWLDOWKHUDS\IRU+5SRVLWLYH 0%&SDWLHQWVEDVHGRQWKHILQGLQJV
IURP 021$5&+  D UDQGRPL]HG  GRXEOHEOLQGHG SODFHERFRQWUROOHG VWXG\ LQ +5 SRVLWLYH
SRVWPHQRSDXVDO ZRPHQ ZLWK 0%& >@ 7KH HVWLPDWHG PHGLDQ 3)6 ZDV  LQ WKH DEHPDFLFOLE
FRQWDLQLQJ DUP DQG ZDV  PRQWKV LQ WKH SODFHERFRQWDLQLQJ DUP ,Q FRPELQDWLRQ ZLWK HQGRFULQH
WKHUDS\ &'. LQKLELWRUV DUH ZHOO WROHUDWHG ZLWK QHXWURSHQLD LQIHFWLRQV OHXNRSHQLD IDWLJXH QDXVHD
VWRPDWLWLVDQHPLDDORSHFLDGLDUUKHDWKURPERF\WRSHQLDUDVKYRPLWLQJDQGGHFUHDVHGDSSHWLWHEHLQJ
WKHPRVWFRPPRQDGYHUVHUHDFWLRQV

)XOYHVWUDQW
)XOYHVWUDQW)DVORGH[DVHOHFWLYHHVWURJHQUHFHSWRUDQWDJRQLVWZDV LQLWLDOO\LQGLFDWHGIRUWUHDWPHQWRI+5
SRVLWLYH 0%& LQSRVWPHQRSDXVDOZRPHQZLWKGLVHDVHSURJUHVVLRQIROORZLQJ
SULRU
DQWL
HVWURJHQWKHUDS\,WZDVUHFHQWO\DSSURYHGE\)'$DVPRQRWKHUDS\IRUH[SDQGHGXVHLQSRVWPHQRSDXVDO
ZRPHQ ZLWK +5 SRVLWLYH DGYDQFHG EUHDVW FDQFHU ZKR KDYH JRQH WKURXJK PHQRSDXVH DQG KDYH QRW
UHFHLYHGSUHYLRXVHQGRFULQHWKHUDS\ 7KH)'$DSSURYDOLVEDVHGRQGDWDIURPWKH3KDVH,,,)$/&21WULDO
>@7KH)$/&21WULDOLVD3KDVH,,,UDQGRPL]HGGRXEOHEOLQGPXOWLFHQWHU WULDOWKDWFRPSDUHGWKHHIILFDF\
DQG WROHUDELOLW\ RI PJ GRVH RI IXOYHVWUDQW ZLWK DQDVWUR]ROH LQ SRVWPHQRSDXVDO ZRPHQ ZLWK +5
ORFDOO\DGYDQFHGRUPHWDVWDWLFEUHDVWFDQFHUZKRKDYHQRWUHFHLYHGSULRUHQGRFULQHWKHUDS\7KHVWXG\
VKRZHGDVWDWLVWLFDOO\VLJQLILFDQWLQFUHDVHLQPHGLDQ3)6FRPSDUHGWRDQDVWUR]ROHYVPRQWKV
+5S  7KH)$/&21WULDOZDVGHVLJQHGRQWKHEDVLVRIWKH 3KDVH,,),567WULDOZKLFK
GHPRQVWUDWHGDPHGLDQRYHUDOOVXUYLYDOQHDUO\VL[PRQWKVORQJHUZLWK IXOYHVWUDQWFRPSDUHGWRDQDVWUR]ROH
YVPRQWKV+5S >@
&XUUHQWO\WKHPRVWHIIHFWLYHWKHUDS\IRUSDWLHQWVKDUERULQJ(65 PXWDWLRQVLVXQNQRZQ:KLOHSUHFOLQLFDO
VWXGLHVKDYHVKRZQUHGXFHGVHQVLWLYLW\WRIXOYHVWUDQWDWFOLQLFDOO\DFKLHYDEOHFRQFHQWUDWLRQVQRGLIIHUHQFHV
LQ SURJUHVVLRQIUHH VXUYLYDO 3)6 ZHUH QRWHG LQ SDWLHQWV ZLWK SODVPD (65 PXWDWLRQV WUHDWHG ZLWK
IXOYHVWUDQWFRPSDUHGWRZLOGW\SH:7LQ)(5*,VWXG\>@)(5*,VWXG\FRPSDUHGWKHDFWLYLW\RISLFWLOLVLE
DSDQ3,.LQKLELWRUZLWKIXOYHVWUDQWLQ+5SRVLWLYH0%&SDWLHQWVZLWKSULRUH[SRVXUHWR$,>@(65
PXWDWLRQVZHUHREVHUYHGLQDERXWRISDWLHQWVDQGZDVHQULFKHGLQOXPLQDO$VXEW\SHZLWKVLPLODU
3)6LQ(65 PXWDQWDQGZLOGW\SHSDWLHQWVVXJJHVWLQJWKDWPXWDWLRQVDUHQRWDVVRFLDWHGZLWKFOLQLFDO
UHVLVWDQFH WR IXOYHVWUDQW ,Q 3$/20$ VWXG\ DQ LPSURYHPHQW LQ PHGLDQ 3)6 IRU FRPELQDWLRQ RI
IXOYHVWUDQWZLWKSDOERFLFOLELQ0%&SDWLHQWVZKRKDGSURJUHVVHGRQSULRUHQGRFULQHWKHUDS\PRQWKV
YV  PRQWKV IRU IXOYHVWUDQW DORQH 3   ZDV REVHUYHG +RZHYHU WKH XVH RI IXOYHVWUDQW ZLWK
SDOERFLFOLEZDVDVVRFLDWHGZLWKVLPLODULPSURYHPHQWLQSURJUHVVLRQIUHHVXUYLYDO3)6LQERWKZLOGW\SH
DQGPXWDQW(65 VXJJHVWLQJWKDWPXWDWLRQDOVWDWXVGRHVQRWDIIHFWUHVSRQVHWRSDOERFLFOLE>@ ,Q6R)($
WULDOWKRVHZLWK(65 PXWDWLRQVKDGSURORQJHG3)6 ZLWKIXOYHVWUDQWFRPSDUHGZLWKH[HPHVWDQH3  
ZKLOHQR3)6GLIIHUHQFHZDVREVHUYHGLQ:7(65)LJXUH >@&RQVHTXHQWO\SDWLHQWVZLWK(65
PXWDWLRQVZLOOEHUDQGRPL]HGWRIXOYHVWUDQWYHUVXVFRQWLQXDWLRQRI$,
)LJXUH 3)6LQ 6R)($VWXG\EDVHGRQ(65 PXWDWLRQ3DQHO$ 3)6LQSDWLHQWVZLWK(65
PXWDWLRQ WUHDWHGZLWKH[HPHVWDQHYVIXOYHVWUDQWFRQWDLQLQJUHJLPHQ$3DQHO%3)6LQ
SDWLHQWVZLWKRXW(65 PXWDWLRQ
3DJHRI
Proprietary of MD Anderson Cancer Center 


3URWRFRO
-DQXDU\

*XDUGDQW$VVD\
FW'1$
DQDO\VLV ZRXOG EH SHUIRUPHG XVLQJ WKH *XDUGDQW  DVVD\V *XDUGDQW +HDOWK 5HGZRRG &LW\ &$
*XDUGDQWLVD&/,$FHUWLILHG&$3DFFUHGLWHG1HZ<RUN6WDWH'HSDUWPHQWRI+HDOWKDSSURYHGGLJLWDO
VHTXHQFLQJWHFKQRORJ\IRUFOLQLFDOFI'1$WHVWLQJ7KHDVVD\ WHVWV IRU619VVLQJOHQXFOHRWLGHYDULDWLRQV
LQXSWRJHQHVDVZHOODVLQGHOV&19VFRS\QXPEHUYDULDWLRQVDQGJHQHIXVLRQVLQVHOHFWJHQHV
/LVWRIJHQHVDFFHVVHGE\*XDUGDQWLVOLVWHGLQ7DEOH3DWLHQWVZLWKDFWLYDWLQJ(65 PXWDWLRQV
LGHQWLILHGRQWKH*XDUGDQWSDQHOZLOO EHUDQGRPL]HGLQWRWKHVWXG\

5DWLRQDOH
1HDUO\ WZRWKLUGV RIEUHDVWFDQFHUVRYHUH[SUHVVHVWURJHQUHFHSWRU(5 DQGHVWURJHQEORFNDGHLVDQ
LQWHJUDOSDUWRIWUHDWPHQW&XUUHQWO\WKHXVHRI$,LQFRPELQDWLRQZLWKD&'.LQKLELWRULVUHFRPPHQGHG
IRUILUVWOLQHWUHDWPHQWRI(5SRVLWLYH0%&0XWDWLRQVLQWKHOLJDQGELQGLQJGRPDLQRI(65KDYHEHHQ
GHVFULEHG LQ 0%& SDWLHQWV H[SRVHG WR HVWURJHQ GHSULYDWLRQ ZLWK $, 7KHVH PXWDWLRQV KDYH EHHQ
GHPRQVWUDWHG WR PHGLDWH UHVLVWDQFH WR $, WKHUDS\ OLPLWLQJ WKHLU FOLQLFDO DFWLYLW\ DQG SRUWHQG D VKRUWHU
VXUYLYDO3UHVHQWO\WKHPRVWHIIHFWLYHWKHUDS\IRUSDWLHQWVKDUERULQJ(65PXWDWLRQVLVXQNQRZQ3UH
FOLQLFDO VWXGLHV KDYH VXJJHVWHG WKDW IXOYHVWUDQW D 6(5' LV DFWLYH LQ (65 PXWDQW EUHDVW FDQFHUV
$QDO\VHVRIFLUFXODWLQJWXPRU'1$FW'1$RIIHUDPLQLPDOO\LQYDVLYHDSSURDFKWRPRQLWRUGLVHDVHDQG
WUHDWPHQWUHVSRQVH&XUUHQWO\WUHDWPHQWGHFLVLRQVDUHEDVHGRQFOLQLFDOGLVHDVHSURJUHVVLRQDQGWKXVDW
WKH WLPH RI KLJK GLVHDVH EXUGHQ 5HDO WLPH PRQLWRULQJ ZLWK FW'1$ FDQ LGHQWLI\ SDWLHQWV ZKR H[KLELW
VXEFOLQLFDOUHFXUUHQFHRUSURJUHVVLRQ(DUO\GHWHFWLRQDQGLQWHUYHQWLRQZLWKDOWHUQDWHWKHUDS\WRRYHUFRPH
UHVLVWDQFHDWPLQLPDOGLVHDVHEXUGHQSURJUHVVLRQFRXOGKDYHDODUJHULPSDFWWKDQWUHDWLQJKLJKHUEXUGHQ
GLVHDVHDWFOLQLFDOSURJUHVVLRQ+RZHYHULWLVQRWFOHDUZKHWKHUWUHDWPHQWGHFLVLRQVFDQEHPDGHEDVHG
RQWKHDSSHDUDQFHRIUHVLVWDQFHPXWDWLRQVLQFW'1$DQGWKDW³JHQRPLFDOO\DGDSWHGWKHUDS\´FDQLPSURYH
RXWFRPH 7KH SUHVHQW VWXG\ K\SRWKHVL]HV WKDW UHDOWLPH PRQLWRULQJ RI FW'1$ IRU VHFRQGDU\ (65
DOWHUDWLRQVFDQLGHQWLI\SDWLHQWVZLWKVXEFOLQLFDOSURJUHVVLRQDQGHDUO\LQWHUYHQWLRQZLWK(65PXWDWLRQ
WDUJHWHGDJHQWVDWPLQLPDO
GLVHDVHEXUGHQSURJUHVV
7KLV
VWUDWHJ\DOVRSUHFOXGHVSDWLHQWVIURPEHLQJH[SRVHGWRWUHDWPHQWV NQRZQWREHDVVRFLDWHGZLWKUHVLVWDQFH
DQGXQOLNHO\WRRIIHUFOLQLFDOEHQHILW
7DEOH *XDUGDQWFW'1$SDQHO
3DJHRI
Proprietary of MD Anderson Cancer Center 


3URWRFRO

-DQXDU\

75,$/2%-(&7,9(6$1'(1'32,176

3ULPDU\2EMHFWLYHV
x
7R DVVHVV SURJUHVVLRQ IUHH VXUYLYDO 3)6 ZLWK WUDQVLWLRQ WR IXOYHVWUDQW FRPSDUHG ZLWK
FRQWLQXLQJ$,WKHUDS\LQSDWLHQWVZLWKHPHUJHQFHRI(65PXWDWLRQVLQSODVPD

3ULPDU\(QGSRLQWV
x
3URJUHVVLRQIUHHVXUYLYDODVDVVHVVHGE\.DSODQ0HLHUDQDO\VLV

6HFRQGDU\2EMHFWLYHV
x
7RDVVHVVFW'1$(65PXWDQWDOOHOHIUDFWLRQ0$)DQGNLQHWLFVZLWKIXOYHVWUDQWFRPSDUHG
ZLWK$,
x
7RDVVHVVWKHSUHYDOHQFHRI(65PXWDWLRQVLQSDWLHQWVZLWKVHFRQGDU\UHVLVWDQFHWR
HQGRFULQHWKHUDS\
x
7RFRUUHODWHFW'1$ZLWK&$WXPRUPDUNHUFKDQJHV
x
7R DVVHVV RYHUDOO VXUYLYDO 26 ZLWK WUDQVLWLRQ WR IXOYHVWUDQW FRPSDUHG ZLWK FRQWLQXLQJ $,
WKHUDS\LQSDWLHQWVZLWKHPHUJHQFHRI(65PXWDWLRQV
x
7RDVVHVV3)6DQGWLPHWRQH[WWUHDWPHQW7717RQQH[WOLQHRIWKHUDS\DIWHUSURJUHVVLRQ
RQIXOYHVWUDQWYV$,LQFRPELQDWLRQZLWK&'.,

6HFRQGDU\(QGSRLQWV
x
0$)
x
&$
x
26
x
3)6
x
7717

([SORUDWRU\2EMHFWLYH
x
&KDUDFWHUL]HRWKHUFRH[LVWLQJDFWLRQDEOHJHQRPLFDOWHUDWLRQVRILQWHUHVWLQUHODWLRQWR(65
DQGFOLQLFDORXWFRPHV
x
7RGHWHUPLQHIUHTXHQF\RIRWKHUDFWLRQDEOHJHQRPLFDOWHUDWLRQVDQGIUHTXHQF\RIHQUROOPHQW
RQJHQRW\SHPDWFKHGWKHUDS\

([SORUDWRU\(QGSRLQWV
x
&RQFRPLWDQWJHQRPLFDOWHUDWLRQVZLOOEHH[SORUHGLQUHODWLRQWRFOLQLFDORXWFRPHVRILQWHUHVW
DQGLQSDUWLFXODULQUHODWLRQWRWKHSULPDU\HQGSRLQWRI3)6
3DJHRI

Proprietary of MD Anderson Cancer Center 


3URWRFRO

-DQXDU\

678'<'(6,*1$1'6(/(&7,212)3$7,(176
:KLOHWKHHVWLPDWHVRI(65PXWDWLRQVLQDGYDQFHGEUHDVWFDQFHUVKDYHYDULHGDFURVVVWXGLHVGDWDIURP
6R)($ DQG 3$/20$ VKRZ WKDW (65 PXWDWLRQV ZHUH W\SLFDOO\ DVVRFLDWHG ZLWK VHQVLWLYLW\ WR SULRU
HQGRFULQHWKHUDS\DQGVHFRQGDU\UHVLVWDQFH6HFRQGDU\RUDFTXLUHGUHVLVWDQFHLVGHILQHGDVUHODSVHZKLOH
RQDGMXYDQWHQGRFULQHWKHUDS\DIWHUDWOHDVW\HDUVRUUHODSVHZLWKLQPRQWKVRIFRPSOHWLRQRIDGMXYDQW
HQGRFULQHWKHUDS\ RUUHODSVHDIWHUPRQWKVRIHQGRFULQHWKHUDS\IRU 0%&>@6R)($WULDOHQUROOHG
SDWLHQWVZLWKQRGLVHDVHSURJUHVVLRQRUUHODSVHRQQRQVWHURLGDO$,IRUDWOHDVWPRQWKVLQWKHDGMXYDQW
VHWWLQJRUDWOHDVWPRQWKVLQWKHPHWDVWDWLFVHWWLQJDVILUVWOLQHWUHDWPHQW,Q6R)($WULDOQHDUO\RI
(65PXWDWLRQVREVHUYHGLQ0%&SDWLHQWVZKRKDGUHFHLYHG$,IRUDWOHDVWPRQWKV:KLOH3$/20$
VWXG\HQUROOHGDPRUHYDULHGSRSXODWLRQRI(65PXWDWLRQVZHUHREVHUYHGLQSDWLHQWVZKRZHUH
GHHPHGVHQVLWLYHWRSULRUHQGRFULQHWKHUDS\VXJJHVWLQJWKDW(65PXWDWLRQVDUHVHOGRPDVVRFLDWHGZLWK
SULPDU\UHVLVWDQFH>@&RQVHTXHQWO\WRLGHQWLI\(65PXWDWLRQV+5SRVLWLYH(5!0%&SDWLHQWV
ZKRDUHRQ$,ZLWK&'.LQKLELWRUSDOERFLFOLEULERFLFOLERUDEHPDFLFOLEDVILUVWOLQHWKHUDS\IRUDWOHDVW
PRQWKVZRXOGEHVFUHHQHGIRUFW'1$DQDO\VLV3DWLHQWVZLWK(65DOWHUDWLRQVLQFW'1$ZRXOGEH
HQUROOHGDQGUDQGRPL]HG
,WLVDQWLFLSDWHGWKDWDSSUR[LPDWHO\0%&SDWLHQWVZKRDUHRQ$,ZLWK&'.DVILUVWOLQHWKHUDS\IRU
DWOHDVWPRQWKVZLOOEHVFUHHQHGIRUFW'1$DQDO\VLVLQRUGHUWRLGHQWLI\DSSUR[LPDWHO\HOLJLEOH
SDWLHQWVZLWK(65DOWHUDWLRQVLQFW'1$)RUVFUHHQLQJDSSUR[LPDWHO\P/RISHULSKHUDOEORRGZLOOEH
FROOHFWHGLQ6WUHFNWXEHVVHH7DEOH7KHUHVXOWVIURPWKHVFUHHQLQJFW'1$WHVWVZLOOEHUHSRUWHGWR
WUHDWLQJSK\VLFLDQV3DWLHQWVPXVWPHHWDOOLQFOXVLRQDQGH[FOXVLRQFULWHULDSULRUWRWUHDWPHQW7KHZULWWHQ
LQIRUPHGFRQVHQWPXVWEHREWDLQHGIURPWKHSDWLHQWSULRUWRVFUHHQLQJ7KHIROORZLQJFULWHULDDSSO\WRDOO
SDWLHQWVHQUROOHGRQWRWKHVWXG\XQOHVVRWKHUZLVHVSHFLILHG

,QFOXVLRQ&ULWHULD
 $JH\HDUV
 (&2*SHUIRUPDQFHVWDWXVRIRU
 $GHTXDWHERQHPDUURZIXQFWLRQDVVKRZQE\$1&[/3ODWHOHWV[/+EJG/
 $GHTXDWHOLYHUIXQFWLRQDVVKRZQE\
7RWDOVHUXPELOLUXELQPJG/
$/7DQG$67[8/1[8/1LQSDWLHQWVZLWKOLYHUPHWDVWDVHV
$GHTXDWHUHQDOIXQFWLRQVHUXPFUHDWLQLQH[8/1
 $FWLYDWLQJ (65 PXWDWLRQ HJ '* <61 63 LGHQWLILHG RQ FW'1$ 1RYHO (65
DOWHUDWLRQVDOORZHGDVSHUGLVFUHWLRQRI3,
 2Q$,ZLWK&'.LQKLELWRUSDOERFLFOLEULERFLFOLERUDEHPDFLFOLEDVILUVWOLQHWKHUDS\IRU0%&
IRUDWOHDVWPRQWKVZLWKRXWHYLGHQFHRIFOLQLFDOSURJUHVVLRQ
 3DWLHQWVZLWKKLVWRORJLFDOO\FRQILUPHG+5SRVLWLYH(5DQGRU35!0%&

6LQFH SDWLHQWV DUH DOUHDG\ RQ $, DQG &'. LQKLELWRUV DW WKH WLPH RI HQUROOPHQW LQWR WKH VWXG\ DQG
IXOYHVWUDQWLVWKHLQWHUYHQWLRQDOGUXJWUHDWPHQWFDQEHDGPLQLVWHUHGDVSHUVWDQGDUGRIFDUHSDUDPHWHUV
DQGDWWKHGLVFUHWLRQRIWUHDWLQJSK\VLFLDQ
3DJHRI

Proprietary of MD Anderson Cancer Center 


3URWRFRO

-DQXDU\

([FOXVLRQ&ULWHULD
 3UHJQDQWRUODFWDWLQJZRPHQ
 5HFHLYHGSULRUWKHUDS\IRU0%&H[FHSWIRU$,XVHIRUXSWRZHHNVSULRUWRLQLWLDWLRQRI&'.
LQKLELWRU
 3ULRUWKHUDS\ZLWKIXOYHVWUDQWLQWKHPHWDVWDWLFVHWWLQJ
 +(5SRVLWLYH0%&DVGHILQHGE\$6&2&$3JXLGHOLQHV
 47FLQWHUYDO!PVHF%UXJDGDV\QGURPHRUNQRZQKLVWRU\RI47FSURORQJDWLRQRU7RUVDGHGH
3RLQWHV
 3V\FKLDWULFLOOQHVVZKLFKZRXOGOLPLWLQIRUPHGFRQVHQW
 3DWLHQWVZKRKDYHDQ\VHYHUHDQGRUXQFRQWUROOHGPHGLFDOFRQGLWLRQVVXFKDV
x
XQVWDEOHDQJLQDSHFWRULVV\PSWRPDWLFFRQJHVWLYHKHDUWIDLOXUHP\RFDUGLDOLQIDUFWLRQ
PRQWKVSULRUWRHQUROOPHQWVHULRXVXQFRQWUROOHGFDUGLDFDUUK\WKPLDRUDQ\RWKHUFOLQLFDOO\
VLJQLILFDQWFDUGLDFGLVHDVH
x
DFWLYHDFXWHRUFKURQLFRUXQFRQWUROOHGVHYHUHLQIHFWLRQOLYHUGLVHDVHVXFKDVFLUUKRVLV
GHFRPSHQVDWHGOLYHUGLVHDVHDQGDFWLYHDQGFKURQLFKHSDWLWLVLHTXDQWLILDEOH+%9'1$
DQGRUSRVLWLYH+EV$JTXDQWLILDEOH+&951$
x
VHYHUHKHSDWLFLPSDLUPHQW&KLOG3XJK&
 +,9SRVLWLYHSDWLHQWVRQFRPELQDWLRQDQWLUHWURYLUDOWKHUDS\
 ([SHFWHGVXUYLYDOPRQWKV
$Q\VHULRXVPHGLFDOLOOQHVVRWKHUWKDQWKDWWUHDWHGE\WKLVVWXG\ZKLFKZRXOGOLPLWVXUYLYDOWROHVV
WKDQPRQWK
3DWLHQWVZLWKDKLVWRU\RIQRQFRPSOLDQFHWRPHGLFDOUHJLPHQVRUZKRDUHFRQVLGHUHGSRWHQWLDOO\
XQUHOLDEOHRUZLOOQRWEHDEOHWRFRPSOHWHWKHHQWLUHVWXG\
3DWLHQWVZKRDUHFXUUHQWO\SDUWRIRUKDYHSDUWLFLSDWHGLQDQ\FOLQLFDOLQYHVWLJDWLRQZLWKDQ
LQYHVWLJDWLRQDOGUXJZLWKLQPRQWKSULRUWRGRVLQJ
:RPHQRIFKLOGEHDULQJSRWHQWLDO:2&%3GHILQHGDVDOOZRPHQSK\VLRORJLFDOO\FDSDEOHRI
EHFRPLQJSUHJQDQWPXVWXVHKLJKO\HIIHFWLYHPHWKRGVRIFRQWUDFHSWLRQGXULQJWKHVWXG\DQG
ZHHNVDIWHUWKHHQGRIWUHDWPHQW+LJKO\HIIHFWLYHFRQWUDFHSWLRQPHWKRGVLQFOXGHFRPELQDWLRQRI
DQ\WZRRIWKHIROORZLQJ

3ODFHPHQWRIDQLQWUDXWHULQHGHYLFH,8'RULQWUDXWHULQHV\VWHP,86

%DUULHUPHWKRGVRIFRQWUDFHSWLRQFRQGRPRURFFOXVLYHFDSGLDSKUDJPRUFHUYLFDOYDXOW
FDSVZLWKVSHUPLFLGDOIRDPJHOILOPFUHDPYDJLQDOVXSSRVLWRU\

7RWDODEVWLQHQFHRU

0DOHIHPDOHVWHULOL]DWLRQ
0DOHSDWLHQWVZKRVHVH[XDOSDUWQHUVDUH:2&%3ZKRDUHQRWZLOOLQJWRXVHDGHTXDWH
FRQWUDFHSWLRQGXULQJWKHVWXG\DQGIRUZHHNVDIWHUWKHHQGRIWUHDWPHQW
3DJHRI

Proprietary of MD Anderson Cancer Center 


3URWRFRO

-DQXDU\

5(*,675$7,21

3DWLHQWLGHQWLILFDWLRQ(QUROOPHQW
+5 SRVLWLYH (5 ! 0%& SDWLHQWV ZKR DUH RQ $, ZLWK &'. LQKLELWRU SDOERFLFOLE ULERFLFOLE RU
DEHPDFLFOLEDVILUVWOLQHWKHUDS\IRUDWOHDVWPRQWKVZRXOGEHVFUHHQHGIRUFW'1$DQDO\VLV3DWLHQWV
ZLWKSRVLWLYH(65PXWDWLRQVLGHQWLILHGRQFW'1$ZRXOGEHUDQGRPL]HGWRIXOYHVWUDQWYHUVXVFRQWLQXDWLRQ
RI$,WKDWWKH\VWDUWHGRQ
3DWLHQWVPXVWPHHWDOORIWKHHOLJLELOLW\UHTXLUHPHQWVOLVWHGLQ6HFWLRQ


,QVWUXFWLRQVIRUSDWLHQWVZKRGRQRWVWDUWDVVLJQHGSURWRFRO
WUHDWPHQW
,IDSDWLHQWGRHVQRWUHFHLYHDQ\DVVLJQHGSURWRFROWUHDWPHQWEDVHOLQHDQGIROORZXSGDWDZLOOVWLOOEH
FROOHFWHG'RFXPHQWWKHUHDVRQIRUQRWVWDUWLQJSURWRFROWUHDWPHQWRQRQHRIWKHEDVHOLQHIRUPV$OVR
UHSRUWWKHGDWHDQGW\SHRIWKHILUVWQRQSURWRFROWUHDWPHQWWKDWWKHSDWLHQWUHFHLYHV

3DJHRI

Proprietary of MD Anderson Cancer Center 


3URWRFRO

-DQXDU\

75($70(173/$1

7UHDWPHQW


)XOYHVWUDQWPJVKRXOGEHDGPLQLVWHUHGLQWUDPXVFXODUO\GD\VLQWRWKHEXWWRFNVVORZO\
PLQXWHVSHULQMHFWLRQDVWZRP/LQMHFWLRQVRQHLQHDFKEXWWRFNRQGD\VRI&\FOH
DQGWKHQ'D\RI&\FOHVDQGEH\RQG&\FOH GD\V

5LERFLFOLE WDEOHWV VKRXOG EH WDNHQ RUDOO\ LQ FRPELQDWLRQ ZLWK 16$, QRQVWHURLGDO DURPDWDVH
LQKLELWRURUIXOYHVWUDQW6WDUWLQJGRVH±PJRUDOO\WDNHQRQFHGDLO\IRUFRQVHFXWLYHGD\V
IROORZHGE\GD\VRIIWUHDWPHQW

3DOERFLFOLEFDSVXOHVVKRXOGEHWDNHQRUDOO\ZLWKIRRGLQFRPELQDWLRQZLWKDQ16$,RUIXOYHVWUDQW
6WDUWLQJGRVH±PJRUDOO\WDNHQRQFHGDLO\IRUFRQVHFXWLYHGD\VIROORZHGE\GD\VRII
WUHDWPHQW

$EHPDFLFOLEWDEOHWVVKRXOGEHWDNHQRUDOO\LQFRPELQDWLRQZLWK16$,RUIXOYHVWUDQW6WDUWLQJGRVH
±PJWZLFHGDLO\

/HWUR]ROHPJRUDQDVWUR]ROHPJRUDOO\VKRXOGEHWDNHQRUDOO\GDLO\

3UH3HULPHQRSDXVDOZRPHQWUHDWHGZLWK&'.,SOXV16$,RUIXOYHVWUDQWWKHUDS\VKRXOGEHWUHDWHG
ZLWKOXWHLQL]LQJKRUPRQHUHOHDVLQJKRUPRQH/+5+DJRQLVWVDFFRUGLQJWRFXUUHQWFOLQLFDOSUDFWLFH
VWDQGDUGV
6LQFHWUHDWPHQWLQYROYHVVWDQGDUGRIFDUHDJHQWVSDWLHQWVFDQSXUVXHWUHDWPHQWRXWVLGHRI0'
$QGHUVRQXQGHUWKHVXSHUYLVLRQRIWKHORFDORQFRORJLVW+RZHYHUFOLQLFDOGRFXPHQWVWRFRQILUP
DGPLQLVWUDWLRQVKRXOGEHVHQWIRUUHYLHZ$GGLWLRQDOO\FOLQLFDODVVHVVPHQWVWRFRQILUPUHVSRQVH
HJVWDJLQJVFDQVVKRXOGEHSHUIRUPHGDW0'$QGHUVRQ

'UXJ0RQLWRULQJDQG'RVH0RGLILFDWLRQV

$GPLQLVWUDWLRQRISDOERFLFOLEULERFLFOLERUDEHPDFLFOLEVKRXOGIROORZVWDQGDUGSURFHGXUHDVRXWOLQHGLQWKH
SDFNDJH LQVHUW 'RVH LQWHUUXSWLRQ PRGLILFDWLRQ RU GLVFRQWLQXDWLRQ EDVHG RQ LQGLYLGXDO VDIHW\ DQG
WROHUDELOLW\FDQEHFDUULHGRXWDVSHULQYHVWLJDWRU¶VRUWUHDWLQJSK\VLFLDQ¶VGLVFUHWLRQ

3DOERFLFOLE
7KHSDOERFLFOLESUHVFULELQJLQIRUPDWLRQUHFRPPHQGVPRQLWRULQJFRPSOHWHEORRGFRXQWVSULRUWRVWDUWLQJ
WKHUDS\DQGDWWKHEHJLQQLQJRIHDFKF\FOHDVZHOODVRQGD\RIWKHILUVWF\FOHV
%DVHG RQ SKDUPDFRNLQHWLF DQDO\VLV IURP SULRU VWXGLHV PLOG KHSDWLF LPSDLUPHQW KDG QR HIIHFW RQ WKH
H[SRVXUHRISDOERFLFOLEELOLUXELQ8/1DQG$67!8/1RUWRWDOELOLUXELQ!WRî8/1DQGDQ\$67
7KHSKDUPDFRNLQHWLFVRISDOERFLFOLEKDYHQRWEHHQVWXGLHGLQSDWLHQWVZLWKPRGHUDWHRUVHYHUHKHSDWLF
LPSDLUPHQWWRWDOELOLUXELQ!î8/1DQGDQ\$67
%DVHGRQSKDUPDFRNLQHWLFDQDO\VLVPLOG&U&OPOPLQRUPRGHUDWHUHQDOG\VIXQFWLRQ&U&O
POPLQKDGQRHIIHFWRQWKHH[SRVXUHRISDOERFLFOLE7KHSKDUPDFRNLQHWLFVRISDOERFLFOLEKDYHQRWEHHQ
VWXGLHGLQSDWLHQWVZLWKPRGHUDWHRUVHYHUHUHQDOG\VIXQFWLRQ
0RVW FRPPRQ DGYHUVH UHDFWLRQV LQFLGHQFH  ZLWK SDOERFLFOLE ZHUH QHXWURSHQLD LQIHFWLRQV
OHXNRSHQLD IDWLJXH QDXVHD VWRPDWLWLV DQHPLD DORSHFLD GLDUUKHD WKURPERF\WRSHQLD UDVK YRPLWLQJ
GHFUHDVHGDSSHWLWHDVWKHQLDDQG͒S\UH[LD

7DEOH5HFRPPHQGHG'RVH0RGLILFDWLRQIRU3DOERFLFOLE
3DJHRI

Proprietary of MD Anderson Cancer Center 


3URWRFRO

-DQXDU\
'RVH/HYHO
'RVH
6WDUWLQJGRVH
PJGD\
)LUVWGRVHUHGXFWLRQ

PJGD\
6HFRQGGRVHUHGXFWLRQ
PJGD\
7KLUGGRVHUHGXFWLRQ
PJGD\
7ZRZHHNVRQWZRZHHNVRII,IIXUWKHUGRVHUHGXFWLRQLVUHTXLUHGGLVFRQWLQXHSDOERFLFOLE

5LERFLFOLE
7KHULERFLFOLESUHVFULELQJLQIRUPDWLRQUHFRPPHQGVPRQLWRULQJFRPSOHWHEORRGFRXQWVDQGOLYHUIXQFWLRQ
WHVWV/)7VSULRUWRVWDUWLQJWKHUDS\DQGDWWKHEHJLQQLQJRIHDFKVXEVHTXHQWF\FOHVDQGDVFOLQLFDOO\
LQGLFDWHGDVZHOODVRQGD\RIWKHILUVWF\FOHV$GGLWLRQDOO\(.*VSULRUWRLQLWLDWLQJWKHUDS\'D\
RIILUVWF\FOHDQGWKHEHJLQQLQJRIVHFRQGF\FOHDUHUHTXLUHG(OHFWURO\WHVDWWKHEHJLQQLQJRIHDFKF\FOH
IRUF\FOHVDUHDOVRUHFRPPHQGHG
1R GRVH DGMXVWPHQW LV QHFHVVDU\ LQ SDWLHQWV ZLWK PLOG KHSDWLF LPSDLUPHQW &KLOG3XJK FODVV $ 7KH
UHFRPPHQGHGVWDUWLQJGRVHLVPJRQFHGDLO\IRUSDWLHQWVZLWKPRGHUDWH&KLOG3XJKFODVV%DQG
VHYHUHKHSDWLFLPSDLUPHQW&KLOG3XJKFODVV&
5LERFLFOLEVKRXOGEHDYRLGHGLQSDWLHQWVZKRDUHDWULVNRIGHYHORSLQJ47FSURORQJDWLRQHJORQJ47
V\QGURPHHOHFWURO\WHDEQRUPDOLWLHVXQVWDEOHDQJLQDRUDUUK\WKPLDV
0RVW FRPPRQ DGYHUVH UHDFWLRQV LQFLGHQFH   DUH QHXWURSHQLD QDXVHD IDWLJXH GLDUUKHD
OHXNRSHQLDDORSHFLDYRPLWLQJFRQVWLSDWLRQKHDGDFKHDQGEDFNSDLQ

7DEOH5HFRPPHQGHG'RVH0RGLILFDWLRQIRU5LERFLFOLE
'RVH/HYHO
'RVH
6WDUWLQJGRVH
PJGD\
)LUVWGRVHUHGXFWLRQ

PJGD\
6HFRQGGRVHUHGXFWLRQ
PJGD\
,IIXUWKHUGRVHUHGXFWLRQEHORZPJGD\LVUHTXLUHGWUHDWPHQWVKRXOGEHGLVFRQWLQXHG

$EHPDFLFOLE
7KHDEHPDFLFOLESUHVFULELQJLQIRUPDWLRQUHFRPPHQGVPRQLWRULQJFRPSOHWHEORRGFRXQWVDQGOLYHUIXQFWLRQ
WHVWV/)7VSULRUWRVWDUWLQJWKHUDS\HYHU\ZHHNVIRUWKHILUVWPRQWKVPRQWKO\IRUWKHQH[WPRQWKV
DQGDVFOLQLFDOO\LQGLFDWHG
1RGRVDJHDGMXVWPHQWVDUHQHFHVVDU\LQSDWLHQWVZLWKPLOGRUPRGHUDWHKHSDWLFLPSDLUPHQW&KLOG3XJK
$RU%7KHUHFRPPHQGHGVWDUWLQJGRVHIRUSDWLHQWVZLWKVHYHUHKHSDWLFLPSDLUPHQW&KLOG3XJK&LV
PJGDLO\
$EHPDFLFOLEFDQLQFUHDVHVHUXPFUHDWLQLQHGXHWRLQKLELWLRQRIUHQDOWXEXODUVHFUHWLRQWUDQVSRUWHUVZLWKRXW
DQ\HIIHFWRQJORPHUXODUIXQFWLRQ7\SLFDOHOHYDWLRQVKDSSHQGXULQJWKHILUVWF\FOHEXWWKH\UHPDLQHGVWDEOH
WKURXJK WKH WUHDWPHQW SHULRG DQG ZHUH UHYHUVLEOH ZLWK GLVFRQWLQXDWLRQ 1R GRVDJH DGMXVWPHQW LV
UHFRPPHQGHG IRU SDWLHQWV ZLWK PLOG RU PRGHUDWH UHQDO LPSDLUPHQW &U&O   P/PLQ 7KH
3DJHRI

Proprietary of MD Anderson Cancer Center 


3URWRFRO

-DQXDU\
SKDUPDFRNLQHWLFVRIDEHPDFLFOLEKDVLQSDWLHQWVZLWKVHYHUHUHQDOLPSDLUPHQW&U&OP/PLQGLDO\VLV
RUHQGVWDJHUHQDOGLVHDVHLVXQNQRZQ
0RVWFRPPRQDGYHUVHUHDFWLRQVLQFLGHQFHZHUHGLDUUKHDQHXWURSHQLDQDXVHDDEGRPLQDOSDLQ
LQIHFWLRQV IDWLJXH DQHPLD OHXNRSHQLD GHFUHDVHG DSSHWLWH YRPLWLQJ KHDGDFKH DORSHFLD DQG
WKURPERF\WRSHQLD

7DEOH5HFRPPHQGHG'RVH0RGLILFDWLRQIRU$EHPDFLFOLE
'RVH/HYHO
'RVH
6WDUWLQJGRVH
PJWZLFHGDLO\
)LUVWGRVHUHGXFWLRQ

PJWZLFHGDLO\
6HFRQGGRVHUHGXFWLRQ
PJWZLFHGDLO\

)XOYHVWUDQW
)XOYHVWUDQWLVDGPLQLVWHUHGLQWUDPXVFXODUO\PJRQGD\VRI&\FOHDQGRQFHPRQWKO\WKHUHDIWHU
&\FOH GD\V)RUSDWLHQWVZLWKPRGHUDWHKHSDWLFLPSDLUPHQWIXOYHVWUDQWVKRXOGEHDGPLQLVWHUHGDW
PJRQGD\VDQGRQFHPRQWKO\WKHUHDIWHU0RGHUDWHKHSDWLFLPSDLUPHQWLVGHILQHGDV&KLOG3XJK
FODVV%
7KH PRVW FRPPRQ FOLQLFDOO\ VLJQLILFDQW DGYHUVH UHDFWLRQV RFFXUULQJ LQ   RI SDWLHQWV UHFHLYLQJ
IXOYHVWUDQWDUHSDLQDWWKHVLWHRILQMHFWLRQQDXVHDYRPLWLQJERQHSDLQDUWKUDOJLDKHDGDFKHIDWLJXHKRW
IODVKHVDQRUH[LDDVWKHQLDPXVFXORVNHOHWDOSDLQFRXJKG\VSQHDDQGFRQVWLSDWLRQ,QFUHDVHLQKHSDWLF
HQ]\PHVWUDQVDPLQDVHVDQGDONDOLQHSKRVSKDWHVZHUHREVHUYHGLQPRUHWKDQRISDWLHQWVDQGZDV
LQGHSHQGHQWRIWKHGRVH
)RUGHWDLOHGLQIRUPDWLRQRQGRVHPRGLILFDWLRQIRUIXOYHVWUDQWVHH3DFNDJLQJ,QVHUW


&RQFRPLWDQW7KHUDS\
3DWLHQWVPXVWEHLQVWUXFWHGQRWWRWDNHDQ\PHGLFDWLRQVRYHUWKHFRXQWHURURWKHUSURGXFWVGXULQJWKH
SURWRFROWUHDWPHQWSHULRGZLWKRXWSULRUFRQVXOWDWLRQZLWKWKHLQYHVWLJDWRU$OOPHGLFDWLRQVRWKHUWKDQVWXG\
GUXJWDNHQZLWKLQGD\VRIVWDUWLQJVWXG\WUHDWPHQWWKURXJKWKHGD\VDIHW\IROORZXSYLVLWVKRXOGEH
UHSRUWHGRQWKH&5)
$OO VXSSRUWLYH PHDVXUHV FRQVLVWHQW ZLWK RSWLPDO SDWLHQW FDUH VKRXOG EH JLYHQ WKURXJKRXW WKH VWXG\
([FHSWLRQVLQFOXGHWKHXVHRIJURZWKIDFWRUVWRWUHDWDQHPLDRUWKURPERF\WRSHQLDDVVXFKXVHKDVEHHQ
DVVRFLDWHGZLWKGHFUHDVHGVXUYLYDODQGLQFUHDVHGWKURPERWLFHYHQWVLQSDWLHQWVZLWKEUHDVWFDQFHU7KH
XVH RI P\HORLG JURZWK IDFWRUV LQ WKH IRUP RI *&6) VKRXOG IROORZ $6&2 JXLGHOLQHV *&6) FDQ EH
DGPLQLVWHUHGWRWUHDW&'.LQKLELWRULQGXFHGQHXWURSHQLDDVGHWHUPLQHGE\WKHWUHDWLQJSK\VLFLDQ
'RVH0RGLILFDWLRQVIRU8VHZLWK6WURQJ&<3$,QKLELWRUV
&RQFRPLWDQWXVHRIVWURQJ&<3$LQKLELWRUVVKRXOGEHDYRLGHGZLWKSDOERFLFOLE,ISDWLHQWVPXVWWKHFR
DGPLQLVWHUHGZLWKDVWURQJ&<3$LQKLELWRUGRVHRI3DOERFLFOLEVKRXOGEHUHGXFHGWRPJGDLO\$YRLG
FRQFXUUHQWRISDOERFLFOLEZLWKVWURQJ&<3$LQGXFHUV7KHGRVHRIVHQVLWLYH&<3$VXEVWUDWHVZLWK
QDUURZWKHUDSHXWLFLQGLFHVPD\QHHGWREHUHGXFHGZKHQJLYHQFRQFXUUHQWO\ZLWKSDOERFLFOLE
&RQFRPLWDQWXVHRIVWURQJ&<3$LQKLELWRUVVKRXOGEHDYRLGHGZLWKULERFLFOLE,ISDWLHQWVPXVWWKHFR
DGPLQLVWHUHGZLWKDVWURQJ&<3$LQKLELWRUGRVHRIULERFLFOLEVKRXOGEHUHGXFHGWRPJGDLO\$YRLG
3DJHRI

Proprietary of MD Anderson Cancer Center 


3URWRFRO

-DQXDU\
FRQFRPLWDQWXVHRIULERFLFOLEZLWKVWURQJ&<3$LQGXFHUV7KHGRVHRIVHQVLWLYH&<3$VXEVWUDWHVZLWK
QDUURZWKHUDSHXWLFLQGLFHVPD\QHHGWREHUHGXFHGZKHQJLYHQFRQFXUUHQWO\ZLWKULERFLFOLE
&RQFRPLWDQW XVH RI NHWRFRQD]ROH VKRXOG EH DYRLGHG ZLWK DEHPDFLFOLE ,I SDWLHQWV PXVW WKH FR
DGPLQLVWHUHGZLWKDVWURQJ&<3$LQKLELWRUGRVHRIDEHPDFLFOLEVKRXOGEHUHGXFHGWRPJWZLFHGDLO\
$YRLGFRQFRPLWDQWXVHRIDEHPDFLFOLEZLWKVWURQJ&<3$LQGXFHUV
3DWLHQWVVKRXOGDYRLGSRPHJUDQDWHVRUSRPHJUDQDWHMXLFHJUDSHIUXLWDOORIZKLFKDUHNQRZQWRLQKLELW
F\WRFKURPH&<3$HQ]\PHVDQGPD\LQFUHDVHWKHH[SRVXUHWRSDOERFLFOLEDQGULERFLFOLE
$YRLGFRQFRPLWDQWXVHRIGUXJVNQRZQWRSURORQJ47LQWHUYDOVXFKDVDQWLDUUK\WKPLFVLQFOXGLQJEXWQRW
OLPLWHG WR DPLRGDURQH GLVRS\UDPLGH SURFDLQDPLGH TXLQLGLQH DQG VRWDORO DQG RWKHU GUXJV NQRZQ WR
SURORQJWKH47LQWHUYDOLQFOXGLQJEXWQRWOLPLWHGWRFKORURTXLQHKDORIDQWULQHFODULWKURP\FLQKDORSHULGRO
PHWKDGRQHPR[LIOR[DFLQEHSULGLOSLPR]LGHDQGRQGDQVHWURQ
7KHUHDUHQRNQRZQGUXJGUXJLQWHUDFWLRQVZLWKIXOYHVWUDQW
&\WRFKURPH3LQKLELWRUVLQGXFHUVVXEVWUDWHV

$OLVWRIGUXJVWKDWDUHVWURQJLQGXFHUVRULQKLELWRUVRI&<3$DQGVHQVLWLYHVXEVWUDWHVRI&<3$ZLWKD
QDUURZWKHUDSHXWLFZLQGRZLVSURYLGHGKHUH

&<3
HQ]\PHV
6WURQJLQKLELWRU
6WURQJ
LQGXFHU
6HQVLWLYHVXEVWUDWH
6XEVWUDWHZLWK
QDUURZWKHUDSHXWLF
UDQJH
&<3$
%RFHSUHYLU
FODULWKURP\FLQ
FRQLYDSWDQ
JUDSHIUXLWMXLFH
LQGLQDYLU
LWUDFRQD]ROH
NHWRFRQD]ROH
ORSLQDYLUULWRQDYLU
PLEHIUDGLO
QHID]RGRQH
QHOILQDYLU
SRVDFRQD]ROH
ULWRQDYLU
VDTXLQDYLU
WHODSUHYLU
WHOLWKURP\FLQ
YRULFRQD]ROH
$YDVLPLEH
FDUEDPD]HSLQ
HSKHQ\WRLQ
ULIDPSLQ6W
-RKQ¶VZRUW
$OIHQWDQLODSUHSLWDQW
EXGHVRQLGH
EXVSLURQH
FRQLYDSWDQ
GDULIHQDFLQGDUXQDYLU
GDVDWLQLE
GURQHGDURQH
HOHWULSWDQ
HSOHUHQRQH
HYHUROLPXV
IHORGLSLQHLQGLQDYLU
IOXWLFDVRQHORSLQDYLU
ORYDVWDWLQOXUDVLGRQH
PDUDYLURF
PLGD]RODP
QLVROGLSLQH
TXHWLDSLQH
VDTXLQDYLUVLOGHQDILO
VLPYDVWDWLQVLUROLPXV
WROYDSWDQWLSUDQDYLU
WULD]RODPWLFDJUHORU
YDUGHQDILO
$OIHQWDQLO
DVWHPL]ROH
FLVDSULGH
F\FORVSRULQH
GLK\GURHUJRWDPLQH
HUJRWDPLQHIHQWDQ\O
SLPR]LGHTXLQLGLQH
VLUROLPXVWDFUROLPXV
WHUIHQDGLQH


$GYHUVH(YHQWV

,QIRUPDWLRQ DERXW FRPPRQ VLGH HIIHFWV DUH DOUHDG\ NQRZQ DERXW WKH DJHQWV SDOERFLFOLE ULERFLFOLE
DEHPDFLFOLEOHWUR]ROHDQDVWUR]ROHIXOYHVWUDQW

$QDGYHUVHHYHQW$(LVWKHDSSHDUDQFHRUZRUVHQLQJRIDQ\XQGHVLUDEOHVLJQV\PSWRPRUPHGLFDO
FRQGLWLRQRFFXUULQJDIWHUVWDUWLQJWKHVWXG\GUXJHYHQLIWKHHYHQWLVQRWFRQVLGHUHGWREHUHODWHGWRVWXG\
3DJHRI

Proprietary of MD Anderson Cancer Center 


3URWRFRO

-DQXDU\
GUXJ0HGLFDOFRQGLWLRQVGLVHDVHVSUHVHQWEHIRUHVWDUWLQJVWXG\GUXJDUHRQO\FRQVLGHUHGDGYHUVHHYHQWV
LIWKH\ ZRUVHQDIWHUVWDUWLQJVWXG\GUXJ$EQRUPDOODERUDWRU\YDOXHVRUWHVWUHVXOWVFRQVWLWXWH DGYHUVH
HYHQWV RQO\ LI WKH\ LQGXFH FOLQLFDO VLJQV RU V\PSWRPV DUH FRQVLGHUHG FOLQLFDOO\ VLJQLILFDQW RU UHTXLUH
WKHUDS\

$GYHUVHHYHQWVLQFOXGLQJODEDEQRUPDOLWLHVWKDWFRQVWLWXWH$(VVKRXOGEHGHVFULEHGXVLQJDGLDJQRVLV
ZKHQHYHUSRVVLEOHUDWKHUWKDQLQGLYLGXDOXQGHUO\LQJVLJQVDQGV\PSWRPV:KHQDFOHDUGLDJQRVLVFDQQRW
EHLGHQWLILHGHDFKVLJQRUV\PSWRPVKRXOGEHUHSRUWHGDVDVHSDUDWH$(

$VIDUDVSRVVLEOHHDFKDGYHUVHHYHQWVKRXOGEHHYDOXDWHGWRGHWHUPLQH
 7KHVHYHULW\JUDGH&7&$(*UDGH
 ,WVGXUDWLRQ6WDUWDQGHQGGDWHVRULIFRQWLQXLQJDWWKH6DIHW\)ROORZXS9LVLW
 ,WVUHODWLRQVKLSWRWKHVWXG\WUHDWPHQW5HDVRQDEOHSRVVLELOLW\WKDW$(LVUHODWHG1R<HV
 $FWLRQ WDNHQ ZLWK UHVSHFW WR VWXG\ RU LQYHVWLJDWLRQDO WUHDWPHQW QRQH GRVH DGMXVWHG WHPSRUDULO\
LQWHUUXSWHGSHUPDQHQWO\GLVFRQWLQXHGKRVSLWDOL]HGXQNQRZQQRWDSSOLFDEOH
 :KHWKHUPHGLFDWLRQRUWKHUDS\ZDVJLYHQQRFRQFRPLWDQWPHGLFDWLRQQRQGUXJWKHUDS\FRQFRPLWDQW
PHGLFDWLRQQRQGUXJWKHUDS\
 2XWFRPHQRWUHFRYHUHGQRWUHVROYHGUHFRYHUHGUHVROYHGUHFRYHULQJUHVROYLQJUHFRYHUHGUHVROYHG
ZLWKVHTXHODHIDWDOXQNQRZQ
 :KHWKHULWLVVHULRXVZKHUHDVHULRXVDGYHUVHHYHQW6$(LVGHILQHGDVLQWKH6HULRXV$GYHUVH
(YHQWVVXEVHFWLRQ

$OODGYHUVHHYHQWVVKRXOGEHWUHDWHGDSSURSULDWHO\6XFKWUHDWPHQWPD\LQFOXGHFKDQJHVLQVWXG\GUXJ
WUHDWPHQWLQFOXGLQJSRVVLEOHLQWHUUXSWLRQRUGLVFRQWLQXDWLRQVWDUWLQJRUVWRSSLQJFRQFRPLWDQWWUHDWPHQWV
FKDQJHV LQ WKH IUHTXHQF\ RU QDWXUH RI DVVHVVPHQWV KRVSLWDOL]DWLRQ RU DQ\ RWKHU PHGLFDOO\ UHTXLUHG
LQWHUYHQWLRQ2QFHDQDGYHUVHHYHQWLVGHWHFWHGLWVKRXOGEHIROORZHGXQWLOLWVUHVROXWLRQDQGDVVHVVPHQW
VKRXOGEHPDGHDWHDFKYLVLWRUPRUHIUHTXHQWO\LIQHFHVVDU\RIDQ\FKDQJHVLQVHYHULW\WKHVXVSHFWHG
UHODWLRQVKLSWRWKHVWXG\GUXJWKHLQWHUYHQWLRQVUHTXLUHGWRWUHDWLWDQGWKHRXWFRPH

7KHLQYHVWLJDWRURUSK\VLFLDQGHVLJQHHLVUHVSRQVLEOHIRUYHULI\LQJDQGSURYLGLQJVRXUFHGRFXPHQWDWLRQ
IRUDOODGYHUVHHYHQWVDQGDVVLJQLQJWKHDWWULEXWLRQIRUDOODGYHUVHHYHQWVIRUVXEMHFWVHQUROOHG
3URWRFROZLOOEHPRQLWRUHGE\WKH0'$QGHUVRQ([WHUQDO'DWDDQG6DIHW\0RQLWRULQJ%RDUG
('60%

/DERUDWRU\WHVWDEQRUPDOLWLHV
/DERUDWRU\ DEQRUPDOLWLHV WKDW FRQVWLWXWH DQ DGYHUVH HYHQW LQ WKHLU RZQ ULJKW DUH FRQVLGHUHG FOLQLFDOO\
VLJQLILFDQWLQGXFHFOLQLFDOVLJQVRUV\PSWRPVUHTXLUHFRQFRPLWDQWWKHUDS\RUUHTXLUHFKDQJHVLQVWXG\
WUHDWPHQWVKRXOGEHUHFRUGHGRQWKH$GYHUVH(YHQWV&5):KHQHYHUSRVVLEOHDGLDJQRVLVUDWKHUWKDQ
DV\PSWRPVKRXOGEHSURYLGHGHJDQHPLDLQVWHDGRIORZKHPRJORELQ/DERUDWRU\DEQRUPDOLWLHVWKDW
PHHWWKHFULWHULDIRU$GYHUVH(YHQWVVKRXOGEHIROORZHGXQWLOWKH\KDYHUHWXUQHGWRQRUPDORUDQDGHTXDWH
H[SODQDWLRQRIWKHDEQRUPDOLW\LVIRXQG/DERUDWRU\DEQRUPDOLWLHVWKDWGRQRWPHHWWKHGHILQLWLRQRIDQ
DGYHUVHHYHQWVKRXOGQRWEHUHSRUWHGDVDGYHUVHHYHQWV$*UDGHRUHYHQWVHYHUHDVSHU&7&$(
GRHVQRWDXWRPDWLFDOO\LQGLFDWHD6$(XQOHVVLWPHHWVWKHGHILQLWLRQRIVHULRXVDVGHILQHGEHORZDQGRUDV
SHU LQYHVWLJDWRU¶V GLVFUHWLRQ *UDGH  RU  QHXWURSHQLD LV DQ H[SHFWHG RQWDUJHW $( ZLWK &'.
LQKLELWRUV7KXVGRVHPRGLILFDWLRQVIRUQHXWURSHQLDVKRXOGIROORZVSHFLILFSUHVFULELQJLQIRUPDWLRQEURFKXUH
JXLGHOLQHV



5HFRPPHQGHG$GYHUVH(YHQW5HFRUGLQJ*XLGHOLQHV
 
$WWULEXWLRQ
*UDGH
*UDGH
*UDGH
*UDGH
*UDGH
8QUHODWHG
3KDVH,
3KDVH,
3KDVH,
3KDVH,
3KDVH,
3DJHRI

Proprietary of MD Anderson Cancer Center 


3URWRFRO

-DQXDU\
3KDVH,,

3KDVH,,
3KDVH,,,
3KDVH,,
3KDVH,,,
8QOLNHO\
3KDVH,
3KDVH,
3KDVH,
3KDVH,,
3KDVH,
3KDVH,,
3KDVH,,,
3KDVH,
3KDVH,,
3KDVH,,,
3RVVLEOH
3KDVH,
3KDVH,,
3KDVH,
3KDVH,,
3KDVH,,,
3KDVH,
3KDVH,,
3KDVH,,,
3KDVH,
3KDVH,,
3KDVH,,,
3KDVH,
3KDVH,,
3KDVH,,,
3UREDEOH
3KDVH,
3KDVH,,

3KDVH,
3KDVH,,
3KDVH,,,
3KDVH,
3KDVH,,
3KDVH,,,
3KDVH,
3KDVH,,
3KDVH,,,
3KDVH,
3KDVH,,
3KDVH,,,
'HILQLWLYH
3KDVH,
3KDVH,,

3KDVH,
3KDVH,,
3KDVH,,,
3KDVH,
3KDVH,,
3KDVH,,,
3KDVH,
3KDVH,,
3KDVH,,,
3KDVH,
3KDVH,,
3KDVH,,,

3UHJQDQF\
%DVHGRQDQLPDOVWXGLHVSDOERFLFOLEULERFLFOLERUDEHPDFLFOLEFDQFDXVHIHWDOKDUPZKHQDGPLQLVWHUHG
WRSUHJQDQWZRPHQ,QDQLPDOUHSURGXFWLRQVWXGLHVDGPLQLVWUDWLRQRISDOERFLFOLEGXULQJRUJDQRJHQHVLV
UHVXOWHGLQHPEU\RIHWDOWR[LFLW\DWPDWHUQDOH[SRVXUHVWKDWZHUHWLPHVWKHKXPDQFOLQLFDOH[SRVXUH
EDVHG RQ DUHD XQGHU WKH FXUYH $8& ,Q DQLPDO UHSURGXFWLRQ VWXGLHV DGPLQLVWUDWLRQ RI ULERFLFOLE WR
SUHJQDQWUDWVDQGUDEELWVGXULQJRUJDQRJHQHVLVFDXVHGHPEU\RIHWDOWR[LFLWLHVDWPDWHUQDOH[SRVXUHVWKDW
ZHUHDQGWLPHVWKHKXPDQFOLQLFDOH[SRVXUHUHVSHFWLYHO\EDVHGRQDUHDXQGHUWKHFXUYH$8&
,QDQLPDOUHSURGXFWLRQVWXGLHVDGPLQLVWUDWLRQRIDEHPDFLFOLEGXULQJRUJDQRJHQHVLVZDVWHUDWRJHQLFDQG
FDXVHGGHFUHDVHGIHWDOZHLJKWDWPDWHUQDOH[SRVXUHVVLPLODUWRKXPDQFOLQLFDOH[SRVXUHEDVHGRQ$8&
DWWKHPD[LPXPUHFRPPHQGHGKXPDQGRVH3UHJQDQWZRPHQVKRXOGEHDGYLVHGRISRWHQWLDOULVNWRIHWXV
DQGVKRXOGXVHHIIHFWLYHFRQWUDFHSWLRQGXULQJDQGIRUDWOHDVWZHHNVDIWHUWKHODVWGRVHRISDOERFLFOLE
ULERFLFOLERUDEHPDFLFOLE
/DFWDWLRQ
7KHUHLVQRLQIRUPDWLRQUHJDUGLQJWKHSUHVHQFHRISDOERFLFOLEULERFLFOLERUDEHPDFLFOLELQKXPDQPLON
WKHLUHIIHFWVRQPLONSURGXFWLRQRUWKHEUHDVWIHGLQIDQW%HFDXVHRIWKHSRWHQWLDOIRUVHULRXVDGYHUVHHIIHFWV
LQEUHDVWIHGLQIDQWVZLWKSDOERFLFOLEULERFLFOLERUDEHPDFLFOLEODFWDWLQJZRPHQVKRXOGQRWEUHDVWIHHG
GXULQJWUHDWPHQWDQGIRUZHHNVDIWHUWKHODVWGRVH
6HULRXV$GYHUVH(YHQW6$(5HSRUWLQJ
$Q DGYHUVH HYHQW RU VXVSHFWHG DGYHUVH UHDFWLRQ LV FRQVLGHUHG ³VHULRXV´ LI LQ WKH YLHZ RI HLWKHU WKH
LQYHVWLJDWRURUWKH:HVWHUQ,QVWLWXWLRQDO5HYLHZ%RDUG:,5%LWUHVXOWVLQDQ\RIWKHIROORZLQJRXWFRPHV

'HDWK

$OLIHWKUHDWHQLQJDGYHUVHGUXJH[SHULHQFH±DQ\DGYHUVHH[SHULHQFHWKDWSODFHVWKHSDWLHQWLQ
WKH YLHZ RI WKH LQLWLDO UHSRUWHU DW LPPHGLDWH ULVN RI GHDWK IURP WKH DGYHUVH H[SHULHQFH DV LW
RFFXUUHG,WGRHVQRWLQFOXGHDQDGYHUVHH[SHULHQFHWKDWKDGLWRFFXUUHGLQDPRUHVHYHUHIRUP
PLJKWKDYHFDXVHGGHDWK

,QSDWLHQWKRVSLWDOL]DWLRQRUSURORQJDWLRQRIH[LVWLQJKRVSLWDOL]DWLRQ

$SHUVLVWHQWRUVLJQLILFDQWLQFDSDFLW\RUVXEVWDQWLDOGLVUXSWLRQRIWKHDELOLW\WRFRQGXFWQRUPDOOLIH
IXQFWLRQV

$FRQJHQLWDODQRPDO\ELUWKGHIHFW
,PSRUWDQWPHGLFDOHYHQWVWKDWPD\QRWUHVXOWLQGHDWKEHOLIHWKUHDWHQLQJRUUHTXLUHKRVSLWDOL]DWLRQPD\
EHFRQVLGHUHGDVHULRXVDGYHUVHGUXJH[SHULHQFHZKHQEDVHGXSRQDSSURSULDWHPHGLFDOMXGJPHQWWKH\
PD\MHRSDUGL]HWKHSDWLHQWRUVXEMHFWDQGPD\UHTXLUHPHGLFDORUVXUJLFDOLQWHUYHQWLRQWRSUHYHQWRQHRI
3DJHRI

Proprietary of MD Anderson Cancer Center 


3URWRFRO

-DQXDU\
WKHRXWFRPHVOLVWHGLQWKLVGHILQLWLRQ([DPSOHVRIVXFKPHGLFDOHYHQWVLQFOXGHDOOHUJLFEURQFKRVSDVP
UHTXLULQJLQWHQVLYHWUHDWPHQWLQDQHPHUJHQF\URRPRUDWKRPHEORRGG\VFUDVLDVRUFRQYXOVLRQVWKDWGR
QRWUHVXOWLQLQSDWLHQWKRVSLWDOL]DWLRQRUWKHGHYHORSPHQWRIGUXJGHSHQGHQF\RUGUXJDEXVH&)5

x
,PSRUWDQWPHGLFDOHYHQWVDVGHILQHGDERYHPD\DOVREHFRQVLGHUHGVHULRXVDGYHUVHHYHQWV$Q\
LPSRUWDQWPHGLFDOHYHQWFDQDQGVKRXOGEHUHSRUWHGDVDQ6$(LIGHHPHGDSSURSULDWHE\WKH
3ULQFLSDO,QYHVWLJDWRU

x
$OOOLIHWKUHDWHQLQJRUIDWDOHYHQWVWKDWDUHXQH[SHFWHGDQGUHODWHGWRWKHVWXG\GUXJPXVWKDYH
DZULWWHQUHSRUWVXEPLWWHGZLWKLQKRXUVQH[WZRUNLQJGD\RINQRZOHGJHRIWKHHYHQWWRWKH
:,5%
x
$OOHYHQWVRFFXUULQJGXULQJWKHFRQGXFWRIDSURWRFRODQGPHHWLQJWKHGHILQLWLRQRID6$(PXVW
EHUHSRUWHGWRWKH:,5%LQDFFRUGDQFHZLWKWKHWLPHIUDPHVDQGSURFHGXUHVRXWOLQHGLQWKH
:,5%UHSRUWLQJUHTXLUHPHQWVXVLQJWKH:,5%3URPSWO\5HSRUWDEOH,QIRUPDWLRQIRUPWRUHSRUW
WKHIROORZLQJLQIRUPDWLRQWRZLWKLQGD\V

1HZRULQFUHDVHGULVN

3URWRFROGHYLDWLRQWKDWKDUPHGDVXEMHFWRUSODFHGVXEMHFWDWULVNRIKDUP

3URWRFROGHYLDWLRQPDGHZLWKRXWSULRU,5%DSSURYDOWRHOLPLQDWHDQLPPHGLDWHKD]DUGWRDVXEMHFW

$XGLWLQVSHFWLRQRULQTXLU\E\DIHGHUDODJHQF\

:ULWWHQUHSRUWVRIIHGHUDODJHQFLHVHJ)'$)RUP

$OOHJDWLRQRI1RQFRPSOLDQFHRU)LQGLQJRI1RQFRPSOLDQFH

%UHDFKRIFRQILGHQWLDOLW\

8QUHVROYHGVXEMHFWFRPSODLQW

6XVSHQVLRQRUSUHPDWXUHWHUPLQDWLRQE\WKHVSRQVRULQYHVWLJDWRURULQVWLWXWLRQ

,QFDUFHUDWLRQRIDVXEMHFWLQDUHVHDUFKVWXG\QRWDSSURYHGWRLQYROYHSULVRQHUV

$GYHUVHHYHQWVRU,1'VDIHW\UHSRUWVWKDWUHTXLUHDFKDQJHWRWKHSURWRFRORUFRQVHQW

6WDWHPHGLFDOERDUGDFWLRQV

8QDQWLFLSDWHGDGYHUVHGHYLFHHIIHFW
,QIRUPDWLRQZKHUHWKHVSRQVRUUHTXLUHVSURPSWUHSRUWLQJWRWKH,5%,QIRUPDWLRQQRWOLVWHGDERYH
GRHVQRWUHTXLUHSURPSWUHSRUWLQJWR:,5%

,QIRUPDWLRQQRWOLVWHGDERYHGRHVQRWUHTXLUHSURPSWUHSRUWLQJWR:,5%3OHDVHQRWHFRQVLVWHQWZLWK
$$+533¶VUHTXLUHPHQWVLQFRQQHFWLRQZLWKLWVDFFUHGLWDWLRQRI,5%VWKHLQGLYLGXDODQGRURUJDQL]DWLRQ
VXEPLWWLQJUHVHDUFKIRUUHYLHZVKDOOSURPSWO\FRPPXQLFDWHRUSURYLGHDQGZKHUHQHFHVVDU\FDXVHHDFK
LQYHVWLJDWRUWRSURPSWO\FRPPXQLFDWHRUSURYLGHWKHIROORZLQJLQIRUPDWLRQUHOHYDQWWRWKHSURWHFWLRQRI
KXPDQVXEMHFWVWR:,5%LQDWLPHO\PDQQHU

D8SRQUHTXHVWRIWKH,5%DFRS\RIWKHZULWWHQSODQEHWZHHQVSRQVRURU&52DQGVLWHWKDWDGGUHVVHV
ZKHWKHUH[SHQVHVIRUPHGLFDOFDUHLQFXUUHGE\KXPDQVXEMHFWUHVHDUFKVXEMHFWVZKRH[SHULHQFH
UHVHDUFKUHODWHGLQMXU\ZLOOEHUHLPEXUVHGDQGLIVRZKRLVUHVSRQVLEOHLQRUGHUWRGHWHUPLQH
FRQVLVWHQF\ZLWKWKHODQJXDJHLQWKHFRQVHQWGRFXPHQW

E$Q\VLWHPRQLWRULQJUHSRUWWKDWGLUHFWO\DQGPDWHULDOO\DIIHFWVVXEMHFWVDIHW\RUWKHLUZLOOLQJQHVVWR
FRQWLQXHSDUWLFLSDWLRQ6XFKUHSRUWVZLOOEHSURYLGHGWRWKH,5%ZLWKLQGD\V

F5HSRUWVIURPDQ\GDWDPRQLWRULQJFRPPLWWHHGDWDDQGVDIHW\PRQLWRULQJERDUGRUGDWDDQGVDIHW\
PRQLWRULQJFRPPLWWHHLQDFFRUGDQFHZLWKWKHWLPHIUDPHVSHFLILHGLQWKHUHVHDUFKSURWRFRO
G$Q\ILQGLQJVIURPFORVHGUHVHDUFKZKHQWKRVHILQGLQJVPDWHULDOO\DIIHFWWKHVDIHW\DQGPHGLFDOFDUHRI
SDVWVXEMHFWV)LQGLQJVZLOOEHUHSRUWHGIRU\HDUVDIWHUWKHFORVXUHRIWKHUHVHDUFK


3DJHRI

Proprietary of MD Anderson Cancer Center 


3URWRFRO

-DQXDU\
x
6HULRXVDGYHUVHHYHQWVZLOOEHFDSWXUHGIURPWKHWLPHRIWKHILUVWSURWRFROVSHFLILFLQWHUYHQWLRQ
XQWLOGD\VDIWHUWKHODVWGRVHRIGUXJXQOHVVWKHSDUWLFLSDQWZLWKGUDZVFRQVHQW6HULRXVDGYHUVH
HYHQWVPXVWEHIROORZHGXQWLOFOLQLFDOUHFRYHU\LVFRPSOHWHDQGODERUDWRU\WHVWVKDYHUHWXUQHGWR
EDVHOLQHSURJUHVVLRQRIWKHHYHQWKDVVWDELOL]HGRUWKHUHKDVEHHQDFFHSWDEOHUHVROXWLRQRIWKH
HYHQW

5HSRUWLQJWR)'$
,WLVWKHUHVSRQVLELOLW\RIWKH3,DQGWKHUHVHDUFKWHDPWRHQVXUHVHULRXVDGYHUVHHYHQWVDUHUHSRUWHG
DFFRUGLQJ WR WKH &RGH RI )HGHUDO 5HJXODWLRQV *RRG &OLQLFDO 3UDFWLFHV WKH SURWRFRO JXLGHOLQHV DQG
:HVWHUQ,QVWLWXWLRQDO5HYLHZ%RDUGSROLF\

7KH*XDUGDQW$VVD\LVDOLTXLGEDVHGELRSV\WHVWZLWKFOLQLFDOO\PLQLPDOULVNV

'HYLFH)DLOXUH
,WLVWKHUHVSRQVLELOLW\RIWKH3,DQGWKHUHVHDUFKWHDPWRHQVXUHXQDQWLFLSDWHGDGYHUVHGHYLFHHIIHFWVDUH
UHSRUWHGDFFRUGLQJWRWKH&RGHRI)HGHUDO5HJXODWLRQV*RRG&OLQLFDO3UDFWLFHVWKHSURWRFROJXLGHOLQHV
DQG:HVWHUQ,QVWLWXWLRQDO5HYLHZ%RDUGSROLF\




'XUDWLRQRIWKHUDS\
3DWLHQWVZLOOUHFHLYHSURWRFROWKHUDS\XQOHVV

3DWLHQWZLWKGUDZVFRQVHQW

3DWLHQWKDVSURJUHVVLRQRIGLVHDVHDVGHILQHGLQVHFWLRQ

3DWLHQWH[SHULHQFHVXQDFFHSWDEOHGUXJWR[LFLW\

'XUDWLRQRI)ROORZXS
)RUWKLVSURWRFRODOOSDWLHQWVLQFOXGLQJWKRVHZKRGLVFRQWLQXHSURWRFROWKHUDS\HDUO\ZLOOEHIROORZHGXQWLO
PRQWKDIWHUGLVFRQWLQXDWLRQRIWKHUDS\IRUPHWDVWDWLFGLVHDVH'DWHRIODVWIROORZXSFOLQLFYLVLWVKRXOGEH
ZLWKLQGD\VRIHQGRIWUHDWPHQWGD\V
3DJHRI

Proprietary of MD Anderson Cancer Center 


3URWRFRO

-DQXDU\

6&+('8/('(9$/8$7,216

3UHWUHDWPHQWHYDOXDWLRQ
%DVHOLQHODERUDWRU\DVVHVVPHQWVVKRXOGEHSHUIRUPHGDVSHUVWDQGDUGRIFDUHIRUSDOERFLFOLEULERFLFOLE
DEHPDFLFOLEDQGIXOYHVWUDQW6FKHGXOHRIFOLQLFDODVVHVVPHQWVLVOLVWHGLQ$SSHQGL[

+LVWRU\DQGSK\VLFDOH[DPLQDWLRQ

5DGLRORJLFHYDOXDWLRQZLWKLQZHHNVSULRUWR&\FOH

3DWLHQWPXVWVLJQ,5%DSSURYHGLQIRUPHGFRQVHQWSULRUWRDQ\VWXG\VSHFLILFSURFHGXUHVXQOHVV
VXFKSURFHGXUHVDUHSDUWRIWKHVWDQGDUGRIFDUH

6FUHHQLQJFW'1$%ORRGGUDZ*XDUGDQW6WUHFN70FHOOSUHVHUYDWLRQWXEHVP/[SHU
EORRGGUDZ

(YDOXDWLRQGXULQJVWXG\
)ROORZXSODERUDWRU\DVVHVVPHQWVVKRXOGEHSHUIRUPHGDVSHUVWDQGDUGRIFDUHIRUSDOERFLFOLEULERFLFOLE
DEHPDFLFOLEDQGIXOYHVWUDQW

3K\VLFDOH[DPLQDWLRQLQFOXGLQJYLWDOVLJQVZHLJKWSHUIRUPDQFHVWDWXV

3DWLHQWVZLOOXQGHUJRUHVWDJLQJZLWKFRPSOHWHLPDJLQJ&7&$3DQGERQHVFDQDSSUR[LPDWHO\
HYHU\  F\FOHV RI WKHUDS\ IRU WKH ILUVW  PRQWKV DQG HYHU\  PRQWKV WKHUHDIWHU XQWLO
SURJUHVVLRQ

([SORUDWRU\FW'1$EORRGGUDZV*XDUGDQW6WUHFN70FHOOSUHVHUYDWLRQWXEHVP/[SHU
EORRGGUDZZLOOSHUIRUPHGDW&\FOH&\FOHDQG&\FOH7KHVHZLOOEHEDQNHGDW0'$&&
FW'1$ZLOOEHGUDZQRQWKHVDPHGDWHDVVWDQGDUGRIFDUHODEVDVVHVVPHQWV

(QGRI7UHDWPHQW3URJUHVVLRQFW'1$%ORRGGUDZ*XDUGDQW6WUHFN70FHOOSUHVHUYDWLRQWXEHV
P/[SHUEORRGGUDZ

3UHJQDQF\DQGDVVHVVPHQWVRIIHUWLOLW\
%DVHGRQDQLPDOVWXGLHV&'.LQKLELWRUVFDQSRWHQWLDOO\FDXVHIHWDOKDUPZKHQDGPLQLVWHUHGWRSUHJQDQW
ZRPHQ,QDQLPDOUHSURGXFWLRQVWXGLHVDGPLQLVWUDWLRQRI&'.LQKLELWRUVGXULQJRUJDQRJHQHVLVUHVXOWHGLQ
HPEU\RIHWDOWR[LFLW\
:RPHQRIFKLOGEHDULQJSRWHQWLDOGHILQHGDVDOOZRPHQSK\VLRORJLFDOO\FDSDEOHRIEHFRPLQJSUHJQDQW
PXVWXVHKLJKO\HIIHFWLYHFRQWUDFHSWLRQGXULQJWKHVWXG\DQGIRUDWOHDVWZHHNVDIWHUVWRSSLQJWUHDWPHQW
+LJKO\HIIHFWLYHFRQWUDFHSWLRQLVGHILQHGDVHLWKHU
x
7RWDODEVWLQHQFH:KHQWKLVLVLQOLQHZLWKWKHSUHIHUUHGDQGXVXDOOLIHVW\OHRIWKHVXEMHFW>3HULRGLF
DEVWLQHQFHHJFDOHQGDURYXODWLRQV\PSWRWKHUPDOSRVWRYXODWLRQPHWKRGVDQGZLWKGUDZDODUHQRW
DFFHSWDEOHPHWKRGVRIFRQWUDFHSWLRQ@
x
6WHULOL]DWLRQKDYHKDGVXUJLFDOELODWHUDORRSKRUHFWRP\ZLWKRUZLWKRXWK\VWHUHFWRP\RUWXEDOOLJDWLRQ
DW OHDVW VL[ ZHHNV EHIRUH WDNLQJ VWXG\ WUHDWPHQW ,Q FDVH RI RRSKRUHFWRP\ DORQH RQO\ ZKHQ WKH
UHSURGXFWLYHVWDWXVRIWKHZRPDQKDVEHHQFRQILUPHGE\IROORZXSKRUPRQHOHYHODVVHVVPHQW
x
0DOH SDUWQHU VWHULOL]DWLRQ ZLWK WKH DSSURSULDWH SRVWYDVHFWRP\ GRFXPHQWDWLRQ RI WKH DEVHQFH RI
VSHUPLQWKHHMDFXODWH
x
8VHRIDFRPELQDWLRQRIWKHIROORZLQJ
D 3ODFHPHQWRIDQLQWUDXWHULQHGHYLFH,8'RULQWUDXWHULQHV\VWHP,86
3DJHRI

Proprietary of MD Anderson Cancer Center 


3URWRFRO

-DQXDU\
E %DUULHUPHWKRGVRIFRQWUDFHSWLRQ&RQGRPRU2FFOXVLYHFDSGLDSKUDJPRUFHUYLFDOYDXOWFDSV
ZLWKVSHUPLFLGDOIRDPJHOILOPFUHDPYDJLQDOVXSSRVLWRU\
0DOH&RQWUDFHSWLRQ
x
6H[XDOO\DFWLYHPDOHVPXVWXVHDFRQGRPGXULQJLQWHUFRXUVHZKLOHWDNLQJWKHGUXJDQGIRUZHHNV
DIWHUVWRSSLQJWUHDWPHQWDQGVKRXOGQRWIDWKHUDFKLOGLQWKLVSHULRG
x
$FRQGRPLVUHTXLUHGWREHXVHGDOVRE\YDVHFWRPL]HGPHQLQRUGHUWRSUHYHQWGHOLYHU\RIWKH
GUXJYLDVHPLQDOIOXLG
x
)HPDOHSDUWQHUVRIPDOHSDWLHQWVPXVWDOVREHDGYLVHGWRXVHRQHRIWKHIROORZLQJFRQWUDFHSWLRQ
PHWKRGV 8VH RI  RUDO LQMHFWHG LPSODQWHG RU RWKHU KRUPRQDO PHWKRGV RI FRQWUDFHSWLRQ RU 
LQWUDXWHULQHGHYLFH,8'RULQWUDXWHULQHV\VWHP,86RUSULRUPDOHIHPDOHVWHULOL]DWLRQ


3DJHRI

Proprietary of MD Anderson Cancer Center 


3URWRFRO

-DQXDU\

0($685(0(172)())(&7

5(&,67&ULWHULDLQPHWDVWDWLFGLVHDVH
7XPRUUHVSRQVHIRUSDWLHQWVZLWKPHDVXUDEOHOHVLRQVVKRXOGEHDVVHVVHGXVLQJ5(&,67>@3DWLHQWV
ZLWKPHDVXUDEOHOHVLRQVVKRXOGEHDVVHVVHGXVLQJFRQWUDVWHQKDQFHG&7RIWKHFKHVWDEGRPHQDQGRU
05,VFDQRIWKHFKHVWDEGRPHQDQGSHOYLVDSSUR[LPDWHO\GD\VHYHU\WKUHHF\FOHVF\FOHOHQJWKLV
GD\VIURPWKHGDWHRIILUVWGRVHRIIXOYHVWUDQWXQWLOWKHGD\IROORZXSYLVLW$OWKRXJKSURJUHVVLRQ
PD\EHGHWHUPLQHGE\WKHLQYHVWLJDWRUEDVHGXSRQFOLQLFDOGHWHULRUDWLRQHYHU\HIIRUWVKRXOGEHPDGHWR
GRFXPHQWSURJUHVVLRQXVLQJUDGLRJUDSKLFPHWKRGV7KHEDVLVIRUGHWHUPLQDWLRQRISURJUHVVLRQSHUFOLQLFDO
GHWHULRUDWLRQVKRXOGEHGRFXPHQWHG
1RWH,WLVYHU\LPSRUWDQWWKDWWKHVDPHPHWKRGRIUDGLRORJLFDVVHVVPHQWEHXVHGWKURXJKRXWWKHVWXG\
DQGWKDWWKHVDPHOHVLRQVDUHIROORZHG

5HVSRQVH&ULWHULD
&KDQJHVLQWKHODUJHVWGLDPHWHURIWKHWXPRUOHVLRQVDQGWKHVKRUWHVWGLDPHWHULQWKHFDVHRIPDOLJQDQW
O\PSKQRGHVVKRXOGEHXVHGLQ5(&,67DVVHVVPHQW
&RPSOHWH5HVSRQVH&5'LVDSSHDUDQFHRIDOOWDUJHWOHVLRQV$Q\SDWKRORJLFDOO\PSKQRGHVZKHWKHU
WDUJHWRUQRQWDUJHWPXVWKDYHUHGXFWLRQLQVKRUWD[LVWRPP
3DUWLDO5HVSRQVH35$WOHDVWDGHFUHDVHLQWKHVXPRIWKHGLDPHWHUVRIWDUJHWOHVLRQVWDNLQJDV
UHIHUHQFHWKHEDVHOLQHVXPGLDPHWHUV
3URJUHVVLYH'LVHDVH3'$WOHDVWDLQFUHDVHLQWKHVXPRIWKHGLDPHWHUVRIWDUJHWOHVLRQVWDNLQJ
DVUHIHUHQFHWKHVPDOOHVWVXPRQVWXG\WKLVLQFOXGHVWKHEDVHOLQHVXPLIWKDWLVWKHVPDOOHVWRQVWXG\,Q
DGGLWLRQWRWKHUHODWLYHLQFUHDVHRIWKHVXPPXVWDOVRGHPRQVWUDWHDQDEVROXWHLQFUHDVHRIDWOHDVW
PP1RWHWKHDSSHDUDQFHRIRQHRUPRUHQHZOHVLRQVLVDOVRFRQVLGHUHGSURJUHVVLRQV
6WDEOH'LVHDVH6'1HLWKHUVXIILFLHQWVKULQNDJHWRTXDOLI\IRU35QRUVXIILFLHQWLQFUHDVHWRTXDOLI\IRU3'
WDNLQJDVUHIHUHQFHWKHVPDOOHVWVXPGLDPHWHUVZKLOHRQVWXG\

3DJHRI

Proprietary of MD Anderson Cancer Center 


3URWRFRO
-DQXDU\

%,20$5.(5$1'&255(/$7,9(678',(6
FW'1$DQDO\VLV
7R LGHQWLI\ (65 DOWHUDWLRQVSDWLHQWV ZLOO KDYH PDQGDWRU\ FW'1$ DVVHVVPHQW SULRU WR UDQGRPL]DWLRQ,Q
DGGLWLRQWR DVVHVV PXWDQW DOOHOH IUDFWLRQVRPDWLF DOOHOH EXUGHQ6$%SODVPD IRU FW'1$ ZRXOG EH REWDLQHG
DWZHHNVDQG DW SURJUHVVLRQ%ORRGGUDZIRUFW'1$ZRXOGEHVWRUHGLQ*XDUGDQW6WUHFN70FHOO
SUHVHUYDWLRQWXEHVP/[SHUEORRGGUDZ :KHUH SRVVLEOHEORRG VDPSOHV IRUFW'1$ZLOO EH GUDZQ
IURP SDWLHQWV VFKHGXOHG WR KDYH YHQLSXQFWXUH IRU VWDQGDUGRIFDUHODEVDVVHVVPHQWV IRUFOLQLFDOFDUH
3DWLHQWV ZLWK DFWLYDWLQJ (65 PXWDWLRQV ZLOO EH WUHDWHG XQWLO UDGLRORJLFDO GLVHDVH SURJUHVVLRQ 7R
FKDUDFWHUL]H FDQGLGDWH PHFKDQLVPV RI UHVLVWDQFH*XDUGDQW FW'1$ DQDO\VHV ZLOO EH SHUIRUPHG DW
GLVHDVH SURJUHVVLRQ DQG FRPSDUHG ZLWK SUHWUHDWPHQW FW'1$ DQDO\VHV 6SHFLILFDOO\ ZH ZLOO HYDOXDWH
DOWHUDWLRQVLQ73 DQG3,.&$ DQGFRUUHODWHZLWK3)6:HZLOO DOVRHYDOXDWHIRUDFTXLUHG5% PXWDWLRQV
DVZHOODVRWKHUHPHUJHQWJHQRPLFDOWHUDWLRQVZLWKH[SRVXUHWR&'.LQKLELWRUV:HZLOOFRUUHODWHFW'1$
G\QDPLFVZLWKFKDQJHVLQ&$WXPRUPDUNHU:HZLOODOVRFRUUHODWHFW'1$G\QDPLFVDQGYHORFLW\ZLWK
UHVSRQVHVVHHQRQLPDJLQJ

)RU SDWLHQWVZLWKWXPRUVLWHVDPHQDEOHWRELRSV\UHSHDWWXPRUELRSVLHV DWWKHWLPHRIGLVHDVHSURJUHVVLRQ
PD\ EH SHUIRUPHG DV VWDQGDUG RI FDUH DQG VXEMHFWHG WR WXPRU JHQRPLF DQDO\VLV E\ QH[W JHQHUDWLRQ
VHTXHQFLQJ1*67XPRUJHQRPLFDQDO\VLVZRXOGEHSHUIRUPHGXVLQJ2QFRPLQH6ROLG7XPRU*HQRPLFV
$VVD\67*$9LQWKH0ROHFXODU'LDJQRVWLFV/DERUDWRU\DW0'$&&7LVVXHEDVHGWXPRU
JHQRPHVHTXHQFLQJ LVDSSURYHG LQVWDQGDUGFDUHIRUSDWLHQWVZLWKPHWDVWDWLFEUHDVWFDQFHUV DW0'$&&
E\WKH0ROHFXODU7HVWLQJ(YDOXDWLRQ&RPPLWWHH07(&*HQRPLFDOWHUDWLRQVLGHQWLILHGE\WLVVXHEDVHG
3DJHRI
Proprietary of MD Anderson Cancer Center 


3URWRFRO

-DQXDU\
1*6 ZLOO EH FRUUHODWHG ZLWK JHQRPLF DOWHUDWLRQV LGHQWLILHG E\ FW'1$ DQDO\VLV *HQRPLF DOWHUDWLRQV
DVVHVVHGE\67*$DUHOLVWHGDERYH
3DJHRI

Proprietary of MD Anderson Cancer Center 


3URWRFRO

-DQXDU\

67$7,67,&$/&216,'(5$7,216

3ULPDU\6HFRQGDU\2EMHFWLYHV
7KLVLVDUDQGRPL]HGRSHQODEHO3KDVH,,IRU+5SRVLWLYHDGYDQFHGEUHDVWFDQFHUSDWLHQWVZKRKDYH
EHHQWUHDWHGZLWK$,DQG&'.DVILUVWOLQHLQWKHPHWDVWDWLFVHWWLQJIRUDWOHDVWPRQWKVDQGZKRKDYH
(65PXWDWLRQVLGHQWLILHGWKURXJKFW'1$DVVD\
%HFN\6ODFN7LGZHOO06'HSDUWPHQWRI%LRVWDWLVWLFVDW0'$QGHUVRQ&DQFHU&HQWHUZLOORYHUVHHWKH
LPSOHPHQWDWLRQRIWKHVWDWLVWLFDODQDO\VLV7KHSULPDU\HQGSRLQWLV3)6ZKLFKLVPHDVXUHGIURPWKHGDWH
RIVWXG\UDQGRPL]DWLRQWRWKHGDWHRIHYHQWLHGHDWKDQGRUGLVHDVHSURJUHVVLRQRUWKHGDWHRIODVWIROORZ
XSLIQRHYHQWKDVRFFXUUHG6XUYLYDOFXUYHVIRU3)6ZLOOEHDQDO\]HGXVLQJWKH.DSODQ0HLHUPHWKRGDQG
VXUYLYDOGLIIHUHQFHDFURVVJURXSVZLOOEHH[DPLQHGE\ORJUDQNWHVW3DWLHQWVDOLYHDQGGLVHDVHIUHHDWWKH
ODWHVWFOLQLFDOHYDOXDWLRQ ZLOOEHFHQVRUHGIRU3)6DWWKHGDWHRIWKDWHYDOXDWLRQ:HZLOOHVWLPDWHWKH
WUHDWPHQW FRPSDULVRQ ZLWK  FRQILGHQFH LQWHUYDOV DQG SYDOXH XVLQJ &R[ SURSRUWLRQDO KD]DUGV
UHJUHVVLRQDQGZHZLOODVVHVVWKHSURSRUWLRQDOKD]DUGDVVXPSWLRQXVLQJJUDSKVRIUHVFDOHG6FKRHQIHOG
UHVLGXDOVDQGUHODWHGWHVWV:HZRXOGDWWHPSWWRLGHQWLI\LQGHSHQGHQWSUHGLFWRUVRI3)6XVLQJPXOWLYDULDEOH
&R[ 3+ UHJUHVVLRQ DQDO\VLV $QDO\VLV IRU 26 DQG 3)6 IURP WKH VWDUW RI QH[W OLQH RI WKHUDS\ ZLOO EH
SHUIRUPHGDVGHVFULEHGIRU3)6IURPWKHGDWHRIUDQGRPL]DWLRQ5DQGRPL]DWLRQZLOOEHSHUIRUPHGXVLQJ
&RUH 6WUDWLILFDWLRQ IDFWRUV LQFOXGH UHFXUUHQFH IUHH LQWHUYDO   \HDUV YV !  \HDUV SULRU DGMXYDQW
HQGRFULQHWKHUDS\WDPR[LIHQYVDURPDWDVHLQKLELWRUDQGVLWHRIPHWDVWDVLVERQHYVYLVFHUDO
7RGHWHFWDFKDQJHLQPHGLDQ3)6IURPPRQWKVIRU$,DUPWRPRQWKVZLWKIXOYHVWUDQWDUPZRXOG
UHTXLUHDERXWSDWLHQWVDVVXPLQJSDWLHQWVSHUPRQWKDFFUXDOPRQWKVSRVWDFFUXDOIROORZXS
WZRVLGHGDOSKDSRZHUORJUDQNWHVWLQJ3)6HYHQWVDUHH[SHFWHGXQGHUWKHDOWHUQDWLYH
K\SRWKHVLV,QWHULPDQDO\VLVZLOOEHSHUIRUPHGZKHQ3)6HYHQWVDUHREVHUYHG8VLQJ2
%ULHQ)OHPLQJ
VWRSSLQJERXQGDULHVZHZLOOVWRSIRUIXWLOLW\LIWKHORJUDQNWHVWSYDOXH!DQGVWRSIRUVXFFHVVLILWLV
'HVFULSWLYHVWDWLVWLFVDQGJUDSKLFDODQDO\VLVZLOOEHXVHGWRVXPPDUL]HSDWLHQWV¶GHPRJUDSKLFDQG
FOLQLFRSDWKRORJLFDO FKDUDFWHULVWLFV DQG HIILFDF\ RXWFRPHV :H ZLOO XVH PHDQ VWDQGDUG GHYLDWLRQ RU
PHGLDQUDQJHWRVXPPDUL]HFRQWLQXRXVYDULDEOHVDQGIUHTXHQF\SHUFHQWDJHVIRUFDWHJRULFDOYDULDEOHV
*UDSKLFDODQDO\VLVVXFKDVVFDWWHUSORWVZLWK/RZHVVVPRRWKHUVZLOOEHXVHGWRDVVHVVWKHFRUUHODWLYH
VWUXFWXUH RI RXWFRPHV DQG FRPSDUH 0$) EHWZHHQ IXOYHVWUDQW DQG $, WUHDWHG JURXSV 7KH 3HDUVRQ
FRUUHODWLRQRULWVQRQSDUDPHWULFDQDORJXHWKH6SHDUPDQFRUUHODWLRQZLOOEHXVHGWRHVWLPDWHWKHOLQHDU
FRUUHODWLRQDPRQJYDULDEOHV5DGLRJUDSKLFUHVSRQVHUDWHSDUWLDOUHVSRQVHFRPSOHWHFOLQLFDOUHVSRQVH
ZLOOEHHVWLPDWHGDQGUHSRUWHGZLWKD&,

&RQWURO
([SHULPHQWDO
0HGLDQ
0HGLDQ
3RZHU















































3DJHRI

Proprietary of MD Anderson Cancer Center 


3URWRFRO

-DQXDU\
5()(5(1&(6


6LHJHO5/0LOOHU.'-HPDO$&DQFHUVWDWLVWLFV&$&DQFHU-&OLQ


(OOLV0-'LQJ/6KHQ'HWDO:KROHJHQRPHDQDO\VLVLQIRUPVEUHDVWFDQFHUUHVSRQVH
WRDURPDWDVHLQKLELWLRQ1DWXUH

5RELQVRQ'5:X<09DWV3HWDO$FWLYDWLQJ(65PXWDWLRQVLQKRUPRQHUHVLVWDQW
PHWDVWDWLFEUHDVWFDQFHU1DW*HQHW

2HVWHUUHLFK6'DYLGVRQ1(7KHVHDUFKIRU(65PXWDWLRQVLQEUHDVWFDQFHU1DW*HQHW


7R\:6KHQ<:RQ+HWDO(65OLJDQGELQGLQJGRPDLQPXWDWLRQVLQKRUPRQH
UHVLVWDQWEUHDVWFDQFHU1DW*HQHW

6FKLDYRQ*+UHELHQ6*DUFLD0XULOODV,HWDO$QDO\VLVRI(65PXWDWLRQLQ
FLUFXODWLQJWXPRU'1$GHPRQVWUDWHVHYROXWLRQGXULQJWKHUDS\IRUPHWDVWDWLFEUHDVWFDQFHU6FL
7UDQVO0HGUD

:DQJ3%DKUHLQL$*\DQFKDQGDQL5HWDO6HQVLWLYH'HWHFWLRQRI0RQRDQG
3RO\FORQDO(650XWDWLRQVLQ3ULPDU\7XPRUV0HWDVWDWLF/HVLRQVDQG&HOO)UHH'1$RI
%UHDVW&DQFHU3DWLHQWV&OLQ&DQFHU5HV

7DNHVKLWD7<DPDPRWR<<DPDPRWR,EXVXNL0HWDO'URSOHWGLJLWDOSRO\PHUDVH
FKDLQUHDFWLRQDVVD\IRUVFUHHQLQJRI(65PXWDWLRQVLQEUHDVWFDQFHUVSHFLPHQV7UDQVO
5HVH

)ULEEHQV&2
/HDU\%.LOEXUQ/HWDO3ODVPD(650XWDWLRQVDQGWKH7UHDWPHQWRI
(VWURJHQ5HFHSWRU3RVLWLYH$GYDQFHG%UHDVW&DQFHU-&OLQ2QFRO

&KDQGDUODSDW\6&KHQ'+H:HWDO3UHYDOHQFHRI(650XWDWLRQVLQ&HOO)UHH'1$
DQG2XWFRPHVLQ0HWDVWDWLF%UHDVW&DQFHU$6HFRQGDU\$QDO\VLVRIWKH%2/(52&OLQLFDO
7ULDO-$0$2QFRO

$PLU(0LOOHU1*HGGLH:HWDO3URVSHFWLYHVWXG\HYDOXDWLQJWKHLPSDFWRIWLVVXH
FRQILUPDWLRQRIPHWDVWDWLFGLVHDVHLQSDWLHQWVZLWKEUHDVWFDQFHU-&OLQ2QFRO


0XUWD]D0'DZVRQ6-7VXL':HWDO1RQLQYDVLYHDQDO\VLVRIDFTXLUHGUHVLVWDQFHWR
FDQFHUWKHUDS\E\VHTXHQFLQJRISODVPD'1$1DWXUH

'DZVRQ6-7VXL':0XUWD]D0HWDO$QDO\VLVRIFLUFXODWLQJWXPRU'1$WRPRQLWRU
PHWDVWDWLFEUHDVWFDQFHU1(QJO-0HG

*DUFLD0XULOODV,6FKLDYRQ*:HLJHOW%HWDO0XWDWLRQWUDFNLQJLQFLUFXODWLQJWXPRU
'1$SUHGLFWVUHODSVHLQHDUO\EUHDVWFDQFHU6FL7UDQVO0HGUD

&KX'3DROHWWL&*HUVFK&HWDO(650XWDWLRQVLQ&LUFXODWLQJ3ODVPD7XPRU'1$
IURP0HWDVWDWLF%UHDVW&DQFHU3DWLHQWV&OLQ&DQFHU5HV

)UHQHO-6&DUUHLUD6*RRGDOO-HWDO6HULDO1H[W*HQHUDWLRQ6HTXHQFLQJRI&LUFXODWLQJ
&HOO)UHH'1$(YDOXDWLQJ7XPRU&ORQH5HVSRQVH7R0ROHFXODUO\7DUJHWHG'UXJ
$GPLQLVWUDWLRQ&OLQ&DQFHU5HV





3DJHRI

Proprietary of MD Anderson Cancer Center 


3URWRFRO

-DQXDU\

&ODWRW)3HUGUL[$$XJXVWR/HWDO.LQHWLFVSURJQRVWLFDQGSUHGLFWLYHYDOXHVRI(65
FLUFXODWLQJPXWDWLRQVLQPHWDVWDWLFEUHDVWFDQFHUSDWLHQWVSURJUHVVLQJRQDURPDWDVHLQKLELWRU
2QFRWDUJHW

=KHQJ'<H;=KDQJ0=HWDO3ODVPD(*)570FW'1$VWDWXVLVDVVRFLDWHGZLWK
FOLQLFDORXWFRPHLQDGYDQFHG16&/&SDWLHQWVZLWKDFTXLUHG(*)57.,UHVLVWDQFH6FL5HS


0LFKDHO$.X]LRUD%:+3KLOLS%URKDZQ5DMLY5DMD.RXVWXEK5DQDGH&LUFXODWLQJ
WXPRU'1$FW'1$YDULDQWDOOHOHIUHTXHQFLHVDUHUHGXFHGLQUHVSRQGHUVWRGXUYDOXPDEDQG
ORZEDVHOLQHYDULDQWDOOHOHIUHTXHQFLHVDUHDVVRFLDWHGZLWKLPSURYHGRYHUDOOVXUYLYDOLQ16&/&
SDWLHQWV$$&5$QQXDO0HHWLQJ

0D&;%RVH5*DR)HWDO1HUDWLQLE(IILFDF\DQG&LUFXODWLQJ7XPRU'1$'HWHFWLRQ
RI+(50XWDWLRQVLQ+(51RQDPSOLILHG0HWDVWDWLF%UHDVW&DQFHU&OLQ&DQFHU5HV


2
/HDU\%+UHELHQ60RUGHQ-3HWDO(DUO\FLUFXODWLQJWXPRU'1$G\QDPLFVDQG
FORQDOVHOHFWLRQZLWKSDOERFLFOLEDQGIXOYHVWUDQWIRUEUHDVWFDQFHU1DW&RPPXQ

.DUORYLFK&*ROGPDQ-:6XQ-0HWDO$VVHVVPHQWRI(*)50XWDWLRQ6WDWXVLQ
0DWFKHG3ODVPDDQG7XPRU7LVVXHRI16&/&3DWLHQWVIURPD3KDVH,6WXG\RI5RFLOHWLQLE
&2&OLQ&DQFHU5HV

)LQQ560DUWLQ05XJR+6HWDO3DOERFLFOLEDQG/HWUR]ROHLQ$GYDQFHG%UHDVW
&DQFHU1(QJO-0HG

7XUQHU1&5R-$QGUH)HWDO3DOERFLFOLELQ+RUPRQH5HFHSWRU3RVLWLYH$GYDQFHG
%UHDVW&DQFHU1(QJO-0HG

+RUWREDJ\L*16WHPPHU60%XUULV+$HWDO5LERFLFOLEDV)LUVW/LQH7KHUDS\IRU
+53RVLWLYH$GYDQFHG%UHDVW&DQFHU1(QJO-0HG

6OHGJH*:-U7RL01HYHQ3HWDO021$5&+$EHPDFLFOLELQ&RPELQDWLRQ
:LWK)XOYHVWUDQWLQ:RPHQ:LWK+5+(5$GYDQFHG%UHDVW&DQFHU:KR+DG3URJUHVVHG
:KLOH5HFHLYLQJ(QGRFULQH7KHUDS\-&OLQ2QFRO

*RHW]037RL0&DPSRQH0HWDO021$5&+$EHPDFLFOLE$V,QLWLDO7KHUDS\IRU
$GYDQFHG%UHDVW&DQFHU-&OLQ2QFRO

5REHUWVRQ-)5%RQGDUHQNR,07ULVKNLQD(HWDO)XOYHVWUDQWPJYHUVXV
DQDVWUR]ROHPJIRUKRUPRQHUHFHSWRUSRVLWLYHDGYDQFHGEUHDVWFDQFHU)$/&21DQ
LQWHUQDWLRQDOUDQGRPLVHGGRXEOHEOLQGSKDVHWULDO/DQFHW

(OOLV0-/ORPEDUW&XVVDF$)HOWO'HWDO)XOYHVWUDQWPJ9HUVXV$QDVWUR]ROH
PJIRUWKH)LUVW/LQH7UHDWPHQWRI$GYDQFHG%UHDVW&DQFHU2YHUDOO6XUYLYDO$QDO\VLV)URP
WKH3KDVH,,),5676WXG\-&OLQ2QFRO

6SRHUNH-0*HQGUHDX6:DOWHU.HWDO+HWHURJHQHLW\DQGFOLQLFDOVLJQLILFDQFHRI
(65PXWDWLRQVLQ(5SRVLWLYHPHWDVWDWLFEUHDVWFDQFHUSDWLHQWVUHFHLYLQJIXOYHVWUDQW1DW
&RPPXQ







3DJHRI

Proprietary of MD Anderson Cancer Center 


3URWRFRO

-DQXDU\

&DUGRVR)&RVWD$1RUWRQ/HWDO(62(602QGLQWHUQDWLRQDOFRQVHQVXVJXLGHOLQHV
IRUDGYDQFHGEUHDVWFDQFHU$%&%UHDVW

(LVHQKDXHU($7KHUDVVH3%RJDHUWV-HWDO1HZUHVSRQVHHYDOXDWLRQFULWHULDLQVROLG
WXPRXUVUHYLVHG5(&,67JXLGHOLQHYHUVLRQ(XU-&DQFHU

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 










3DJHRI

Proprietary of MD Anderson Cancer Center 


3URWRFRO

-DQXDU\

Appendix 1   Schedule of clinical assessments  


Evaluation 
Screening 
Cycle 1 
Cycle 2 
Cycle 4 
Cycle 
12 
End of 
treatment/ 
Progression 
Physical exam, 
Vital Signs 
Xa 
 
 
 
 
 
ECOG PS 
Xa 
 
 
 
 
 
Hematology and 
Chemistry 
Z 
 
 
 
 
 
Coagulation 
(PT/PTT/INR) 
Z 
 
 
 
 
 
Pregnancy Test 
(urine)* 
X 
 
 
 
 
 
Liquid Biopsy ** 
X** 
 
X*** 
X*** 
X*** 
X** 
Concomitant 
medications 
Xa 
 
 
 
 
 
Fulvestrant d 
administration 
 
X 
X 
X 
X 
 
Imaging 
Xb 
 
 
X 
X 
X 
Tumor marker 
X 
 
X 
Xc 
X 
 

)RUZRPHQRIFKLOGEHDULQJDJH5HSHDWHGDWWKHGLVFUHWLRQRIWUHDWLQJSK\VLFLDQ
=/DEVDQGFOLQLFDOPRQLWRULQJVKRXOGEHSHUIRUPHGDVSHUVWDQGDUGRIFDUHIRU&'.ZLWK$,IXOYHVWUDQW
XVH
 *XDUGDQW FW'1$ DVVHVVPHQWV DUH FROOHFWHG DW VFUHHQLQJ IRU EDVHOLQH (65 DVVHVVPHQW DW
SURJUHVVLRQ
([SORUDWRU\VDPSOHVIRUFW'1$DVVHVVPHQWZLOOEHFROOHFWHGDW&\FOH&\FOHDQG&\FOHDQGZLOO
EHEDQNHGDW0'$&&DQGSURFHVVHGDW*XDUGDQW+HDOWKDWWKHWLPHRIVWXG\FRQFOXVLRQ
D$OOPHGLFDWLRQVRWKHUWKDQVWXG\GUXJWDNHQZLWKLQGD\VRIVWDUWLQJVWXG\WUHDWPHQWWKURXJKWKH
GD\VDIHW\IROORZXSYLVLWVKRXOGEHUHSRUWHGRQWKH&5)
E7XPRULPDJLQJ&7%RQHVFDQZLOOEHSHUIRUPHGDSSUR[LPDWHO\HYHU\F\FOHVRIWKHUDS\IRUWKHILUVW
PRQWKVDQGHYHU\PRQWKVWKHUHDIWHUXQWLOSURJUHVVLRQ7XPRULPDJLQJVKRXOGEHSHUIRUPHGDW0'
$QGHUVRQ
F7XPRUPDUNHUV&$SHUIRUPHGDSSUR[LPDWHO\HYHU\F\FOHVZHHNVXQWLOGLVHDVHSURJUHVVLRQ
LQFRRUGLQDWLRQZLWKURXWLQHODEVDQGLPDJLQJ
G)XOYHVWUDQWDGPLQLVWUDWLRQIRUSDWLHQWVUDQGRPL]HGWRWKHIXOYHVWUDQWDUPRQO\GD\V6HFRQGGRVH
RI IXOYHVWUDQW WR EH DGPLQLVWHUHG DW &' &RQWURO SDWLHQWV ZRXOG FRQWLQXH WKH WUHDWPHQW WKH\ ZHUH
DOUHDG\RQ&'.LQKLELWRULQFRPELQDWLRQZLWKDURPDWDVHLQKLELWRUV)XOYHVWUDQWFDQEHDGPLQLVWHUHGXQGHU
WKHVXSHUYLVLRQRIWUHDWLQJSK\VLFLDQORFDOO\
3DJHRI

Proprietary of MD Anderson Cancer Center 


3URWRFRO

-DQXDU\
 
 
 
 
3DJHRI

Proprietary of MD Anderson Cancer Center