An Open-Label, Multi-center, Phase 2 Study of Switch Maintenance With TAS-102 Plus Bevacizumab Following Oxaliplatin or Irinotecan-Based Fluoropyrimidine-Containing Induction Chemotherapy in Patients With Metastatic Colorectal Cancer
Phase: PHASE2
Conditions: Metastatic Colorectal Cancer
Sponsor: Georgetown University

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An Open-label, Multi-center, Phase 2 Study of Switch Maintenance with TAS-102 plus 
Bevacizumab Following Oxaliplatin or irinotecan-based fluoropyrimidine-containing Induction 
Chemotherapy in Patients with Metastatic Colorectal Cancer 
(ALEXANDRIA Study) 

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Principal Investigator: 


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Co- Investigators:  
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Responsible  
Research nurse:
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Investigational Drug:
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Development phase:
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Document Status: 
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IND Number:                       
IND Holder Name 
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Funding Source: 
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Initial version:
0>IM>F;>K
Amended-1:

10 October 2015 
Amended-2:                   25 January 2016 
Amended-3: 
 
09 February 2016 
Amended-4: 
 
18 May 2016 
Amended-5: 
 
17 July 2017 

Research Office 

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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ............................................................................................................. 1 
STUDY SCHEMA ............................................................................................................................. 2 
STUDY SUMMARY .......................................................................................................................... 3 
1.0 
BACKGROUND AND RATIONALE ...................................................................... 3 
 
"BL>:L> :<D@KHNG= 
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2.0 
STUDY OBJECTIVES .......................................................................................... 10 
 
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3.0 
PATIENT ELIGIBILITY ........................................................................................ 11 
 
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4.0 
TREATMENT PLAN ............................................................................................. 12 
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5.0 
STUDY PROCEDURES ....................................................................................... 25 
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6.0 
Measurement of Effect ....................................................................................... 29 
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7.0 
ADVERSE EVENTS ............................................................................................. 32 
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8.0 
DRUG INFORMATION ......................................................................................... 37 
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9.0 
STATISTICAL CONSIDERATIONS .................................................................... 39 
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10.0 
STUDY MANAGEMENT ...................................................................................... 40 
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11.0 
REFERENCES ..................................................................................................... 45 
12.0 
APPENDICES ...................................................................................................... 47 

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STUDY SCHEMA 

 mCRC Pa ents 
with at least SD 
 Pa ents must 
have had first‐
line therapy for 
16 to 20 weeks* 
Repeat TAS 102 plus Bev treatment 
schedule un l pa ent demonstrates 
progression of disease; withdraws 
consent; and/or experiences 
unacceptable toxicity 
Primary end point: PFS 
Safety tests: Blood draw, physical exam, performance status (every  14 days (2 weeks) for the first month and every month therea er) 
CT Scan: Every 8 weeks    
CT Scan 
Safety tests 
Safety tests 
 
Safety tests 
Screening 
CT scan 
Safety tests 
 
Day 56 
Wk 8  
maintenance 
**first‐line therapy: oxalipla n, or irinotecan‐based fluoropyrimidine‐containing chemotherapy and bevacizumab 
5 days 
TAS 102  
treatment 
2 days 
off 
treatment 
Bev 
2 weeks on  
TAS 102 
2 weeks Off 
TAS 102 
Treatment 
 
TAS‐102 plus Bevacizumab (Bev) as Maintenance Therapy in Pa ents with 
Colorectal Cancers 
Day 28 
Wk   4 
Day  1 
Day 14 
Wk  2 
Day 7 
Wk  1 
Bev 
Bev 
TAS‐102: 35 mg/m2 BID PO  d1‐5, 8‐12 every 28 days 
Bevacizumab 5 mg/kg IV administered every 14 days 







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STUDY SUMMARY 
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1.0 
BACKGROUND AND RATIONALE 
1.1 
Disease Background 
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1.1.1 
First-Line Treatment in mCRC 
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1.1.2 
Duration of First-Line Chemotherapy 
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NG:<<>IM:;E>MHQB<BMR1ABLMRIB<:EERF>:GMMA:MI:MB>GMLP>K>MK>:M>=?HK?HNKMHLBQ
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=NK:MBHGH?MA>K:IR

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=>?BG>=GNF;>KH?<R<E>LH?<HF;BG:MBHGBG=N<MBHGMA>K:IRNLN:EERPBMA:M:K@>M>=:@>GM
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1.2 
Maintenance Therapy in Metastatic Colorectal Cancer 
1A>LMK:M>@RH?F:BGM>G:G<>MA>K:IRBLLMBEE:G>OHEOBG@HG>:G=K>F:BGLNG=>K
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F:BGM>G:G<>MA>K:IB>L
1.2.1 
Continuation Maintenance Therapy in mCRC 

1.2.1.1 
Maintenance Therapy with Targeted Agents 
/><>GMLMN=B>LA:O>>O:EN:M>=F:BGM>G:G<>MA>K:IRPBMAHNM<A>FHMA>K:IRPBMAMA>
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1.2.1.2 
Maintenance Therapy with Bevacizumab Alone 
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1.2.1.2.1 MACRO Trial 
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1.2.1.2.2 SAKK 41-06 Trial 
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<HNKL>H?;>O:<BSNF:;IENLHQ:EBIE:MBG<HGM:BGBG@<A>FHMA>K:IR
1.2.1.3 
Maintenance Therapy with Cetuximab Alone 
+:BGM>G:G<>MA>K:IRPBMA<>MNQBF:;:EHG>P:L>O:EN:M>=BGMA>,-/"'!3''LMN=R
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<>MNQBF:;
1.2.1.4 
Maintenance Therapy using Targeted Agents in Combination with Cytotoxic Therapy, 
Compared with Observation Alone 
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1.2.1.4.1 CAIRO-3 Trial 
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1.2.1.4.2 AIO KRK 0207 Trial 
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'G:IK>EBFBG:KRK>IHKMMA>F>=B:G1$0BGMA>?ENHKHIRKBFB=BG>IENL;>O:<BSNF:;
:G=H;L>KO:MBHGL:KFLP:LGHMLB@GB?B<:GMER=B??>K>GM:G=FHGMALK>LI><MBO>ER
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1.3 
Switch Maintenance Therapy 
+:BGM>G:G<>MA>K:IRPBMA:?ENHKHIRKBFB=BG>IENL;>O:<BSNF:;BL:PB=>ER:<<>IM>=
LMK:M>@RA:OBG@;>>GLAHPGMHIKHEHG@IKH@K>LLBHG?K>>LNKOBO:EE:K@>ER;:L>=HGMA>
K>LNEMLH?MA>!'/-LMN=RPAB<AIKHOB=>LMA>;>LM>OB=>G<>LH?:K?HKMA>F:@GBMN=>
H?;>G>?BMMA:MF:BGM>G:G<>MK>:MF>GM<:G;>:<AB>O>=BGF>M:LM:MB<<HEHK><M:E<:G<>K
-GMA>HMA>KA:G=LPBM<AF:BGM>G:G<>PA>G:=B??>K>GM:@>GMBLBGBMB:M>=:?M>K:
IK>=>M>KFBG>=GNF;>KH?<R<E>LH?<HF;BG>=<A>FHMA>K:I>NMB<BG=N<MBHGMA>K:IRBGMA>
:;L>G<>H?=BL>:L>IKH@K>LLBHGBL;>BG@BGO>LMB@:M>=0>O>K:EMA>K:I>NMB<:IIKH:<A>LH?
LPBM<AF:BGM>G:G<>MK>:MF>GM:K><NKK>GMER;>BG@>QIEHK>=BGF!/!$HKBGLM:G<>
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MK>:MF>GM:?M>K?BKLMEBG>MA>K:IR

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1.4 
Study Agent(s) Background and Associated Known Toxicities 
1.4.1 
TAS-102  
10BL:GHO>EGN<E>HLB=>:GMBMNFHK:@>GM<HGLBLMBG@H?MKB?ENKB=BG>:G=MBIBK:<BE
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MKB?ENKB=BG>1ABLF><A:GBLFH?:<MBHGBL=B??>K>GM?KHFMA:MH?:?ENHKHIRKBFB=BG>
HQ:EBIE:MBG:G=BKBGHM><:G

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1.4.2 
Safety in Phase 1-3 Trials 
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1.4.3 
Phase III Study in Colorectal Cancer 
/><>GMERIN;EBLA>=BG,#(+MA>/#!-2/0#MKB:EP:L:@EH;:EK:G=HFBS>==HN;E>;EBG=
IE:<>;H<HGMKHEE>=.A:L><HFI:KBLHGMKB:E>O:EN:MBG@MA>>??B<:<R:G=L:?>MRH?HK:EER
:=FBGBLM>K>=10BGI:MB>GMLPBMAK>?K:<MHKRF!/!1A>MKB:E>GKHEE>=I:MB>GMLBGMA>
20#NKHI>NLMK:EB::G=(:I:GPAHK><>BO>=:ME>:LMMPHIKBHKK>@BF>GLH?LM:G=:K=
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<A>FHMA>K:IR:G:GMB3#%$MA>K:IR:G=:G:GMB#%$/MA>K:IR?HKI:MB>GMLPBMA)/0PBE=
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IE:<>;H78

10MK>:MF>GM=>FHGLMK:M>=LM:MBLMB<:EERLB@GB?B<:GMHO>K:EELNKOBO:E-0:G=IKH@K>LLBHG
?K>>LNKOBO:E.$0;>G>?BMBG:EEIKHLI><MBO>ER=>?BG>=LN;@KHNI:G:ERL>LBG<EN=BG@IKBHKMA>K:IR
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10A:=:LB@GB?B<:GMERAB@A>K=BL>:L><HGMKHEK:M>OL:G=MA>A:S:K=K:MBHL?HK
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1.5 
Rationale 
+:BGM>G:G<>MA>K:IRPBMA:?ENHKHIRKBFB=BG>IENL;>O:<BSNF:;BL:PB=>ER:<<>IM>=
LMK:M>@RA:OBG@;>>GLAHPGMHIKHEHG@IKH@K>LLBHG?K>>LNKOBO:EE:K@>ER;:L>=HGMA>
K>LNEMLH?MA>!'/-LMN=RPAB<AIKHOB=>LMA>;>LM>OB=>G<>LH?:K?HKMA>F:@GBMN=>
H?;>G>?BMMA:MF:BGM>G:G<>MK>:MF>GM<:G;>:<AB>O>=BGF>M:LM:MB<<HEHK><M:E<:G<>K
1ANL!'/-IKHOB=>LO>KRO:EN:;E>@NB=:G<>?HKAHPMHHIMBFBS>:MK>:MF>GM:IIKH:<A
BG<EBGB<:EIK:<MB<>

10:GHK:E<RMHMHQB<:@>GMMA:M<HGLBLMLH?MPH:<MBO>IA:KF:<>NMB<:EBG@K>=B>GML
MA>GN<E>HLB=>:G:EH@MKB?ENKB=BG>MKB?ENHKHMARFB=BG>:<RMHMHQB<:GMBF>M:;HEBM>MA:MA:L
IHM>GMB:E:GMB:G@BH@>GB<>??><MLK>E:M>=MHBGAB;BMBHGH?IE:M>E>M=>KBO>=>G=HMA>EB:E@KHPMA
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F>M:;HEBLFH?MKB?ENKB=BG>

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2.0 
STUDY OBJECTIVES 
2.1 
Primary Objectives 
1H>LMBF:M>MA>>??B<:<RIKH@K>LLBHG?K>>LNKOBO:E7.$08;R/#!'01H?10IENL
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?HEEHPBG@BG=N<MBHG<A>FHMA>K:IR
2.2 
Secondary Objectives 
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MA>K:IR?HEEHPBG@BG=N<MBHG<A>FHMA>K:IRBGI:MB>GMLPBMAF!/!

 1H>LMBF:M>BGI:MB>GMLPBMAF!/!MK>:M>=PBMAF:BGM>G:G<>10IENL
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
-;C><MBO>K>LIHGL>K:M>-//HO>K:EE


"BL>:L><HGMKHEK:M>"!/!/
./
0":MFHGMAL


-O>K:EELNKOBO:E-0


1BF>MH=BL>:L>IKH@K>LLBHG11.


"NK:MBHGH?=BL>:L><HGMKHE""!

0MN=R,NF;>K

99999999999999999999999999999999999999999999999999999999999999999999999


2.3 
Endpoints 
  
2.3.1 
Primary endpoint: 
Progression-Free Survival 
2.3.2 
Secondary endpoints:  
-//"!/-011.""!0:?>MR:G=1HQB<BMR


3.0 
 PATIENT ELIGIBILITY 
3.1.1 
Inclusion Criteria 
0N;C><MLFNLMF>>M:EEH?MA>BG<ENLBHG<KBM>KB:BGHK=>KMHI:KMB<BI:M>BGMABLLMN=R


4KBMM>GBG?HKF>=<HGL>GMBG:<<HK=:G<>PBMA?>=>K:EEH<:E:G=BGLMBMNMBHG:E
@NB=>EBG>L


@>≥R>:KL


.:MB>GMLPBMAABLMHEH@B<:EERIKHO>GNGK>L><M:;E>>O:EN:;E>F>M:LM:MB<<HEHK><M:E
<:G<>K;R/#!'01<KBM>KB:


.:MB>GMLFNLMA:O>A:=MHP>>DLH??BKLMEBG>MA>K:IRPBMAHQ:EBIE:MBG:G=HK
BKBGHM><:G;:L>=?ENKHKIRKBFB=BG><HGM:BGBG@<A>FHMA>K:IRIENL >O:<BSNF:;


.:MB>GMLFNLMA:O>LM:;E>=BL>:L>HK;>MM>K=NKBG@MA>BGBMB:EBG=N<MBHG
<A>FHMA>K:IRPBMA?BKLMEBG><A>FHMA>K:IR


,HIKH@K>LLBO>=BL>:L>:MMA>MBF>H?BGBMB:MBHGH?F:BGM>G:G<>MA>K:IR


#:LM>KG!HHI>K:MBO>-G<HEH@R%KHNI#!-%.>K?HKF:G<>0M:MNLH?MHL>>
II>G=BQ


=>JN:M>HK@:G:G=F:KKHP?NG<MBHG:L=>?BG>=;>EHP
:;LHENM>G>NMKHIABE<HNGM
≥FF
IE:M>E>ML
≥FF
MHM:E;BEBKN;BG
MBF>LMA>NII>KEBFBMH?GHKF:E2*,
>Q<>IMI:MB>GMLPBMA%BE;>KMULLRG=KHF>PAH
FNLMA:O>:MHM:E;BEBKN;BGH?MBF>L2*,
010%-1*10.%1
≤MBF>L2*,
<K>:MBGBG>
F@=*



$HKLN;C><MLPBMAEBO>KF>M:LM:L>L01:G=*1≤5MA>NII>KGHKF:EEBFBMH?
BGLMBMNMBHGLGHKF:EK:G@>:G=,HG?:LMBG@;BEBKN;BG5MA>NII>KGHKF:EEBFBM
H?BGLMBMNMBHGLGHKF:EK:G@>:K>:<<>IM:;E>

 4HF>GH?<ABE=;>:KBG@IHM>GMB:E:G=F>GFNLM:@K>>MHNL>:=>JN:M>
<HGMK:<>IMBHGAHKFHG:EHK;:KKB>KF>MAH=H?;BKMA<HGMKHE:;LMBG>G<>IKBHKMHLMN=R
>GMKR?HKMA>=NK:MBHGH?LMN=RI:KMB<BI:MBHG:G=?HK90=:RL?HEEHPBG@<HFIE>MBHGH?
MA>K:IR0AHNE=:PHF:G;><HF>IK>@G:GMHKLNLI><MLA>BLIK>@G:GMPABE>
I:KMB<BI:MBG@BGMABLLMN=RLA>LAHNE=BG?HKFA>KMK>:MBG@IARLB<B:GBFF>=B:M>ER
 ><:NL>H?MA>IHM>GMB:E?HK@>GHMHQB<BMRF:E>I:MB>GMLPBMA?>F:E>I:KMG>KLH?
K>IKH=N<MBO>IHM>GMB:ELAHNE=;>:=OBL>=MH:OHB=@>MMBG@MA>BKI:KMG>KLIK>@G:GM
=NKBG@MA>MK>:MF>GM:G=?HK:ME>:LMFHGMAL:?M>K?BG:E=HL>

0MN=R,NF;>K

99999999999999999999999999999999999999999999999999999999999999999999999



 .:MB>GMFNLMLM:KMF:BGM>G:G<>MA>K:IR:ME>:LM=:RL:?M>KMA>E:LM:=FBGBLM>K>=
BG=N<MBHG<A>FHMA>K:IR;NMGHE:M>KMA:G=:RL

 .KHOB=>KLFNLMMKRMHIKHOB=>?HKF:EBG?BQ>=I:K:??BG>F;>==>=$$.#MNFHKMBLLN>
;EH<D?HK<>GMK:E<HG?BKF:MBHGH?/0:G= /$FNM:MBHGLM:MNL:G=FHE><NE:K
LN;MRIBG@



3.2 
Exclusion Criteria 
EELN;C><MLF>>MBG@:GRH?MA>>Q<ENLBHG<KBM>KB::M;:L>EBG>PBEE;>>Q<EN=>=?KHFLMN=R
I:KMB<BI:MBHG


.:MB>GMLPAHL>MNFHKLA:O>IKH@K>LL>=HG?BKLMEBG>MK>:MF>GM


.:MB>GMLPBMA:<MBO><HG<NKK>GMF:EB@G:G<RHMA>KMA:GLNI>K?B<B:EGHGBGO:LBO>
LJN:FHNL<>EE<:K<BGHF:H?MA>LDBGHKNM>KBG><>KOBQPBMABGMA>I:LMMAK>>R>:KLG
:<MBO><HG<NKK>GMF:EB@G:G<RPBEE;>=>?BG>=:LHG><NKK>GMERK>JNBKBG@<:G<>K=BK><M>=
MK>:MF>GMHK=>>F>=;RMA>MK>:MBG@IARLB<B:G:LEBD>ERMHK>JNBK>LN<AMK>:MF>GMPBMABG:
LBQFHGMAI>KBH=?KHFMBF>H?L<K>>GBG@


4HF>GPAH:K>IK>@G:GMHKE:<M:MBG@


2GLM:;E><:K=BHO:L<NE:K?NG<MBHGMA:MBG<EN=>L:G=F:RGHM;>EBFBM>=MH

 0RFIMHF:MB<FRH<:K=B:EBL<A>FB:HK
 2G<HGMKHEE>=<EBGB<:EERLB@GB?B<:GM<HG=N<MBHG:;GHKF:EBMB>L>@O>GMKB<NE:K
M:<AR<:K=B:HG:GMB:KKARMAFB<L:K>>Q<EN=>=:G=LM=>@K>>3;EH<DHK
:LRFIMHF:MB<*$ /   PBEEGHM;>>Q<EN=>=HK
 !HG@>LMBO>A>:KM?:BENK>!&$H?,6&!E:LLHK
 +RH<:K=B:EBG?:K<MBHG+'PBMABGFHGMAL


2G<HGMKHEE>=:<MBO>BG?><MBHGK>JNBKBG@I:K>GM>K:E:GMB;BHMB<L:GMBOBK:ELHK:GMB?NG@:EL
PBMABGHG>P>>DIKBHKMH?BKLM=HL>


.:MB>GMLPBMA:<MBO>!,0F:EB@G:G<RLRFIMHF:MB<LF:EEE>LBHGL:K>GHM<HGLB=>K>=
:<MBO>1K>:M>=E>LBHGLF:R;><HGLB=>K>=BG:<MBO>B?MA>R:K>LM:;E>?HK:ME>:LM
FHGMAL


.>KLBLM>GMIKHM>BGNKB:%K:=>,!'!1!#O@AKLF>:LNK>=;RNKBG>
IKHM>BG<K>:MBGBG>K:MBHHG:K:G=HFNKBG>L:FIE>


.:MB>GMLPBMAH;LMKN<M>=@:LMKHBGM>LMBG:EMK:<MHKNG<HGMKHEE>=OHFBMBG@


.:MB>GMLPBMAL>KBHNLILR<AB:MKB<HKF>=B<:E<HG=BMBHGLMA:M<HNE=BGM>K?>K>PBMAMK>:MF>GM


4.0 
TREATMENT PLAN 

0MN=R,NF;>K

99999999999999999999999999999999999999999999999999999999999999999999999


1A>LMN=RPBEE;><HG=N<M>=:MMA>%>HK@>MHPG*HF;:K=B!HFIK>A>GLBO>!:G<>K
!>GM>K!BMRH?&HI>!HFIK>A>GLBO>!:G<>K!>GM>K:G=MA>-ABH0M:M>2GBO>KLBMR
(:F>L!HFIK>A>GLBO>!:G<>K!>GM>K
4.1 
Treatment Dosage and Administration 
.:MB>GMFNLMLM:KMF:BGM>G:G<>MA>K:IR:ME>:LM=:RL:?M>KMA>E:LM:=FBGBLM>K>=
BG=N<MBHG<A>FHMA>K:IR;NMGHE:M>KMA:G=:RL

0MN=RF>=B<:MBHGLLAHNE=;>:=FBGBLM>K>=:LHNMEBG>=BGMA>IKHMH<HEAHP>O>KMA>
'GO>LMB@:MHK:EP:RLA:LMA>KB@AMMH=>OB:M>?KHFMA>>LM:;EBLA>=KNE>L?HK=HL>K>=N<MBHG
:MABLA>K=BL<K>MBHGB?A>LA>;>EB>O>L:FHK><HGL>KO:MBO>:IIKH:<ABLG>>=>=BGMA>
F:G:@>F>GMH?K>E:M>=HKNGK>E:M>=#L

4.2 
Administration Schedule  
4.2.1 
      Bevacizumab  
   >O:<BSNF:;F@D@'3HO>KFBGNM>LHK:LI>KBGLMBMNMBHG:E@NB=>EBG>L>O>KR
=:RL
1A>=HL>H?;>O:<BSNF:;BLMH;>K><:E<NE:M>=LAHNE=MA>I:MB>GMLP>B@AM<A:G@>;R
HKFHK> 
/>I>:M<R<E>L>O>KR=:RLNGMBEIKH@K>LLBHGNGMBEPBMA=K:P:EH?<HGL>GMHK
NG:<<>IM:;E>MHQB<BMR 
4.2.2 
     TAS-102 
1A>LM:KMBG@=HL>H?10*-,02/$BLF@FNIMH:F:QBFNFH?F@I>K
=HL>;:L>=HGMA>MKB?ENKB=BG><HFIHG>GMHK:EERMPB<>=:BERPBMABGHG>AHNKH?<HFIE>MBHG
H?FHKGBG@:G=>O>GBG@F>:ELHG":RLMAKHN@A:G=":RLMAKHN@AH?>:<A
=:R<R<E>
 

.:MB>GMLPBEE;>BGLMKN<M>=MHLP:EEHPMA>K>JNBK>=GNF;>KH?M:;E>ML:M:IIKHQBF:M>ERMA>
L:F>MBF>HG>:<A=:R.:MB>GMLPBEE;>BGLMKN<M>=MHP:LAMA>BKA:G=L;>?HK>:G=:?M>K
M:DBG@MA>=KN@.:MB>GMLPBEE<HGMBGN>MHM:D>10NGMBEMA>R=>FHGLMK:M>
IKH@K>LLBHGH?=BL>:L>NLBG@LM:G=:K=/#!'01<KBM>KB:HKNGMBEPBMA=K:P:EH?<HGL>GMHK
NG:<<>IM:;E>MHQB<BMR

'?:MMA>;>@BGGBG@H?:GRMK>:MF>GM<R<E>:I:MB>GMUL;H=RP>B@AMA:L=><K>:L>=;R
?KHF;:L>EBG>MA>I:MB>GMUL;H=RLNK?:<>:K>: 0FNLM;>K><:E<NE:M>=:G=MA>
LMN=RF>=B<:MBHG=HL:@>:=CNLM>=

1A>BGBMB:E 0?HK>:<AI:MB>GMPBEE;><:E<NE:M>=NLBG@MA>?HEEHPBG@"N HBL?HKFNE:
:EE 0<:E<NE:MBHGL:K>KHNG=>=MH=><BF:EIE:<>L

 0F7 H=R4>B@AMD@8Q7&>B@AM<F8Q

.E>:L>GHM>MA>?HEEHPBG@


"HL>>L<:E:MBHGLHG:F@F;:LBL:K>GHMK><HFF>G=>=:M:GRMBF>


2IMH=HL>K>=N<MBHGLH?LMN=RF>=B<:MBHG:K>:EEHP>=

0MN=R,NF;>K

99999999999999999999999999999999999999999999999999999999999999999999999




2IMH:=:R=>E:RBGMA>LM:KMH?MA>G>QMMK>:MF>GM<R<E>BL:EEHP>=

0MN=RF>=B<:MBHGLAHNE=;>:=FBGBLM>K>=:LHNMEBG>=BGMA>IKHMH<HE1A>'GO>LMB@:MHK
:EP:RLA:LMA>KB@AMMH=>OB:M>?KHFMA>>LM:;EBLA>=KNE>L?HK=HL>K>=N<MBHG:MABLA>K
=BL<K>MBHGB?A>LA>;>EB>O>L:FHK><HGL>KO:MBO>:IIKH:<ABLG>>=>=BGMA>F:G:@>F>GM
H?K>E:M>=HKNGK>E:M>=#L

'?LMN=RMK>:MF>GM=BL<HGMBGN:MBHG<KBM>KB:A:O>;>>GF>M;NMMA>K>BLLMKHG@>OB=>G<>H?
<EBGB<:E;>G>?BMMHCNLMB?R<HGMBGN:MBHGH?=HLBG@PBMAMA>LMN=RF>=B<:MBHGHGIKHMH<HEMABL
=><BLBHGLAHNE=;>F:=>;RMA>'GO>LMB@:MHKMH@>MA>KPBMAMA>I:MB>GM:G=GHM>=BGMA>
I:MB>GMUL<A:KM

4.2.3 
Study Medication Regimen 

#:<AMK>:MF>GM<R<E>PBEE;>=:RLBG=NK:MBHG-G>MK>:MF>GM<R<E><HGLBLMLH?MA>
?HEEHPBG@

":R:G=":R >O:<BSNF:;F@D@'3HO>KFBGNM>LHK:LI>KBGLMBMNMBHG:E
@NB=>EBG>L

":RLMAKHN@A
10F@F=HL>HK:EERMBF>L=:BERPBMAMA>?BKLM=HL>
:=FBGBLM>K>=BGMA>FHKGBG@H?":RH?>:<A<R<E>:G=MA>E:LM=HL>:=FBGBLM>K>=BGMA>
>O>GBG@H?":R

":RLMAKHN@A
/>LM

":RLMAKHN@A
10F@F=HL>HK:EERMBF>L=:BERPBMAMA>?BKLM=HL>
:=FBGBLM>K>=BGMA>FHKGBG@H?":RH?>:<A<R<E>:G=MA>E:LM=HL>:=FBGBLM>K>=BGMA>
>O>GBG@H?":R

":RLMAKHN@A
10&HEB=:R

.:MB>GMLLAHNE=M:D>LMN=RF>=B<:MBHG10PBMA:@E:LLH?P:M>KPBMABGAHNKH?
<HFIE>MBHGH?MA>BKFHKGBG@:G=>O>GBG@F>:EL 
4.2.4 
Administration 
4.2.4.1 
Bevacizumab  
?BQ>=;>O:<BSNF:;=HL>F@D@PBEE;>@BO>GHG":RL:G=":RLH?>:<A<R<E> 
4.2.4.2 
TAS-102 

1A>LMN=RF>=B<:MBHGM:;E>M<:E<NE:MBHGBLIK>L>GM>=BG1:;E>PAB<ALAHPLMA>GNF;>K
H?M:;E>MLMA:M:K>G>>=>=I>K<:E<NE:M>= 0


10LAHNE=;>@BO>GHGERHG":RLMAKHN@A:G=":RLMAKHN@A
H?>:<A<R<E>>O>GB?=HL>L:K>FBLL>=HKA>E=?HK:GRK>:LHG=NKBG@
":RLMAKHN@AGRBGM>KKNIMBHGLHKFBLL>==HL>LH?=KN@LAHNE=;>
GHM>=;RMA>I:MB>GM:G=HKIARLB<B:G"HGHMM:D>:==BMBHG:E=HL>LMH
F:D>NI?HKFBLL>=HKA>E==HL>L

0MN=R,NF;>K

99999999999999999999999999999999999999999999999999999999999999999999999



#QM>GLBHGH?10MK>:MF>GMBGMH=:RL:G=HKBGMHMA>AHEB=:R
I>KBH=":RLMAKHN@ABLGHMI>KFBMM>=

10*-,02/$BL:<RMHMHQB<=KN@$HEEHP:IIEB<:;E>LI><B:E
A:G=EBG@:G==BLIHL:EIKH<>=NK>L


 
 
 
 
 
 
 
 
 
 
TABLE 1 


4.2.4.3 
 
Instruction to Patients for Handling Study Medication (TAS-102) 

1A>I:MB>GMFNLM;>BGLMKN<M>=BGMA>A:G=EBG@H?LMN=RF>=B<:MBHG:L?HEEHPL


1HLMHK>MA>LMN=RF>=B<:MBHG:MKHHFM>FI>K:MNK>

1HHGERK>FHO>?KHFMA>LMN=RF>=B<:MBHGDBMMA>:FHNGMH?M:;E>ML
G>>=>=:MMA>MBF>H?=HLBG@

,HMMHK>FHO>=HL>LBG:=O:G<>H?MA>G>QML<A>=NE>==HLBG@

1HF:D>>O>KR>??HKMMHM:D>=HL>LHGL<A>=NE>

1HM:D>LMN=RF>=B<:MBHGPBMABGAHNK:?M>K<HFIE>MBG@:F>:EFHKGBG@
:G=>O>GBG@F>:ELPBMA:@E:LLH?P:M>K

'?MA>I:MB>GMOHFBML:?M>KM:DBG@LMN=RF>=B<:MBHGMA>I:MB>GMLAHNE=GHM
M:D>:GHMA>K=HL>

1HD>>ILMN=RF>=B<:MBHGBG:L:?>IE:<>:G=HNMH?K>:<AH?<ABE=K>G

1H;KBG@:EENL>=:G=NGNL>=LMN=RF>=B<:MBHGDBML:M>:<A<EBGB<OBLBM

1HP:LAMA>BKA:G=L;>?HK>:G=:?M>KM:DBG@MA>F>=B<:MBHG

0MN=R,NF;>K

99999999999999999999999999999999999999999999999999999999999999999999999


4.3 
Toxicities and Dosing Delays/Dose Modifications 
GRI:MB>GMPAHK><>BO>LMK>:MF>GMHGMABLIKHMH<HEPBEE;>>O:EN:;E>?HKMHQB<BMR#:<A
I:MB>GMPBEE;>:LL>LL>=I>KBH=B<:EER?HKMA>=>O>EHIF>GMH?:GRMHQB<BMR:<<HK=BG@MHMA>
1BF>:G=#O>GMLM:;E>0><MBHG1HQB<BMRPBEE;>:LL>LL>=:<<HK=BG@MHMA>,!'
!HFFHG1HQB<BMR!KBM>KB:?HK=O>KL>#O>GML!1!#O>KLBHG"HL>:=CNLMF>GML
LAHNE=;>F:=>:<<HK=BG@MHMA>LRLM>FLAHPBG@MA>@K>:M>LM=>@K>>H?MHQB<BMR
4.3.1 
Dose Reduction Doses 
0MN=RF>=B<:MBHG=HL>K>=N<MBHGLMH;>:IIEB>=BG<:L>H?MHQB<BMR:G=MA>GNF;>KH?
M:;E>ML?HK>:<A<:E<NE:M>= 0:K>=>L<KB;>=BG1:;E>/><HFF>G=>==HL>
K>=N<MBHGLH<<NKBGF@FLM>IL



TABLE 2 

0MN=R,NF;>K

99999999999999999999999999999999999999999999999999999999999999999999999




'?=HL>FH=B?B<:MBHG?:BELMHK>LNEMBG:<AB>OBG@FBGBF:E<KBM>KB:MHL:?>ERK>LNF>MK>:MF>GM
MA>'GO>LMB@:MHKF:R=BL<HGMBGN>LMN=RF>=B<:MBHG

0AHNE=MA>MHQB<BMB>LMA:MK>JNBK>=HL>K>=N<MBHGK><NK:?M>K=HL>K>=N<MBHGMHF@F
LMN=RF>=B<:MBHGF:R;>=BL<HGMBGN>=
4.3.2 
Hematological Toxicity Dose Reductions for TAS-102 

,H;>O:<BSNF:;=HL>FH=B?B<:MBHGLHK=>E:RLPBEE;>G><>LL:KR?HKA>F:MHEH@B<
MHQB<BMR&HP>O>K?HKI:MB>GMLU<HGO>GB>G<>:G=L<A>=NEBG@INKIHL>LMA>=><BLBHGH?
PA>MA>KMH<HGMBGN>HKMHAHE=;>O:<BSNF:;PA>G10BLA>E==N>MHA>F:MHEH@B<
MHQB<BMB>LLAHNE=;>F:=>;RMA>'GO>LMB@:MHK

0MN=R,NF;>K

99999999999999999999999999999999999999999999999999999999999999999999999



/><HFF>G=:MBHGL?HK=HL>AHE=:G=K>LNFIMBHGBGK>LIHGL>MHA>F:MHEH@B<MHQB<BMB>L
K>E:M>=MHFR>EHLNIIK>LLBHG:K>=>L<KB;>=BG1:;E>L:G=,HM>MA:M?HK:EEI:MB>GML
PBMA=><K>:L>LBGG>NMKHIABEL:G=HKIE:M>E>MLMA>G>QM<R<E>H?LMN=RMK>:MF>GMLAHNE=
GHM;>LM:KM>=NGMBEMA>K>LNFIMBHG<KBM>KB:BG1:;E>:G=L><MBHG:K>F>M

.:MB>GMLPAH>QI>KB>G<>%K:=>G>NMKHI>GB:HKMAKHF;H<RMHI>GB:MA:MK>LNEMLBG:
P>>D=>E:RH?MA>LM:KMH?MA>G>QM<R<E>LAHNE=LM:KMMA>G>QM<R<E>:M:K>=N<>=;R
LM>I=HL>E>O>E:L=>L<KB;>=BG1:;E>'?MA>=>E:RBLP>>DMA>I:MB>GMLAHNE=LM:KM
MA>G>QM<R<E>:MMA>L:F>=HL>E>O>E

2G<HFIEB<:M>=G>NMKHI>GB:HKMAKHF;H<RMHI>GB:%K:=>=H>LGHMK>JNBK>:K>=N<MBHG
BG=HL>H?LMN=RF>=B<:MBHG.:MB>GMLPAH>QI>KB>G<>NG<HFIEB<:M>=%K:=>
G>NMKHI>GB:HKMAKHF;H<RMHI>GB:LAHNE=;><HGLB=>K>=?HK:=FBGBLMK:MBHGH?
A>F:MHIHB>MB<@KHPMA?:<MHKLHK?HK:=HL>K>=N<MBHGBGMA>G>QM<R<E>HK;HMA=>I>G=BG@
HGMA>L>O>KBMRH?MA><HFIEB<:MBHG1:;E>

Within a treatment cycle, withhold TAS-102 (LONSURF) for any of the following: 
X
ANC <500/mm3 or febrile neutropenia
X
Platelets <50,000/mm3
X
Grade 3 or 4 non-hematologic adverse reactions


Do not initiate the cycle of TAS-102 (LONSURF) until:
X
Absolute neutrophil count (ANC) ≥1,500/mm3 or febrile neutropenia is 
resolved
X
Platelets ≥75,000/mm3 
X
Grade 3 or 4 non-hematologic adverse reactions are resolved to Grade 0 or 
1

After recovery, resume TAS-102 (LONSURF) after reducing the dose by 5 
mg/m2/dose from the previous dose level, if the following occur: 
X
Febrile neutropenia 
X
Uncomplicated Grade 4 neutropenia (which has recovered to ≥1,500/mm3) 
or thrombocytopenia (which has recovered to ≥75,000/mm3) that results in 
>1 week delay in start of next cycle
X
Non-hematologic Grade 3 or Grade 4 adverse reaction except for Grade 3 
nausea and/or vomiting controlled by antiemetic therapy or Grade 3 
diarrhea responsive to antidiarrheal medication

A maximum of 3 dose reductions are permitted to a minimum dose of  
20 mg/m2 twice daily. Do not escalate TAS-102 (LONSURF) dose after it has been 
reduced 



TABLE 3 

TAS-102 DOSE HOLD CRITERIA FOR HEMATOLOGIC TOXICITIES RELATED TO 
MYELOSUPPRESSION 
 

Hold Criteria 
 
Parameter 
 
Conventional Units 
SI Units 
,>NMKHIABEL
FF
Q*

0MN=R,NF;>K

99999999999999999999999999999999999999999999999999999999999999999999999



.E:M>E>ML

FF
Q*
		 HMA<HGO>GMBHG:E:G=0''GM>KG:MBHG:E0RLM>FNGBML:K>IK>L>GM>=BG,!'!1!#O

TABLE 4 
TAS-102 RESUMPTION CRITERIA FOR HEMATOLOGIC TOXICITIES RELATED TO 
MYELOSUPPRESSION 
 

Resumption Criteria 
 
Parameter 
 
Conventional Units 
SI Units 
,>NMKHIABEL

FF
Q*
.E:M>E>ML

FF
Q*
		 HMA<HGO>GMBHG:E:G=0''GM>KG:MBHG:E0RLM>FNGBML:K>IK>L>GM>=BG,!'!1!#O

4.3.3  Non-hematological Toxicity Dose Reductions (for both study drugs) 
4.3.3.1  Hypertension (Dose delays for bevacizumab only)  






≥
≥


AND 


4.3.3.2  Venous Thrombotic Events  
 

0MN=R,NF;>K

99999999999999999999999999999999999999999999999999999999999999999999999



4.3.3.2.1 Grade 3 venous thrombosis or asymptomatic pulmonary embolism: Hold 
bevacizumab. Bevacizumab may be resumed during the period of full-dose 
anticoagulation if all of the following criteria are met:  
X
1A>I:MB>GMFNLMA:O>:GBGK:G@>',/NLN:EER;>MP>>G:G=HG:
LM:;E>=HL>H?P:K?:KBGHK;>HGLM:;E>=HL>H?EHPFHE><NE:KP>B@AM
A>I:KBGIKBHKMHK>LM:KMBG@;>O:<BSNF:;MK>:MF>GM
X
1A>I:MB>GMFNLMGHMA:O>I:MAHEH@B<:E<HG=BMBHGLMA:M<:KKRAB@AKBLDH?
;E>>=BG@>@MNFHKBGOHEOBG@F:CHKO>LL>EL
X
1A>I:MB>GMFNLMGHMA:O>A:=A>FHKKA:@B<>O>GMLPABE>HGLMN=R

4.3.3.2.2 Grade 4 or for recurrent/worsening venous thromboembolic events despite 
full anticoagulation after resumption of bevacizumab: Discontinue bevacizumab.  
4.3.3.3 
Arterial Thrombotic Events  
 $HK%K:=>:KM>KB:EMAKHF;HMB<>O>GMLGHMIK>L>GM:M;:L>EBG>HKPHKL>G>=LBG<>MA>
BGBMB:MBHGH?IKHMH<HEMA>K:IR=BL<HGMBGN>;>O:<BSNF:;.:MB>GMLF:R<HGMBGN>HMA>K
IKHMH<HEMK>:MF>GM

 $HK%K:=><>K>;KHO:L<NE:KBL<A>FB::G=HKI>KBIA>K:EHKOBL<>K:E:KM>KB:EBL<A>FB:
=BL<HGMBGN>;>O:<BSNF:;.:MB>GMLF:R<HGMBGN>HMA>KIKHMH<HEMK>:MF>GM

 $HK%K:=><:K=B:<BL<A>FB:BG?:K<MBHG=BL<HGMBGN>;>O:<BSNF:;.:MB>GMLF:R
<HGMBGN>HMA>KIKHMH<HEMK>:MF>GM

 $HK:GR%K:=>:KM>KB:EMAKHF;HMB<>O>GMBG<EN=BG@<>K>;KHO:L<NE:KBL<A>FB:
<:K=B:<BL<A>FB:BG?:K<MBHGI>KBIA>K:EHKOBL<>K:E:KM>KB:EBL<A>FB:=BL<HGMBGN>:EE
IKHMH<HEMK>:MF>GM
4.3.3.4 
Left Ventricular Dysfunction 
4.3.3.4.1 %K:=>*3=RL?NG<MBHG0RFIMHF:MB<!&$K>LIHGLBO>MHBGM>KO>GMBHG 
                    X"BL<HGMBGN>;>O:<BSNF:;:G=10
4.3.3.4.2 %K:=>*3=RL?NG<MBHG.HHKER<HGMKHEE>=K>?K:<MHKR!&$BGM>KO>GMBHGLN<A:LO>GMKB<NE:K
:LLBLM=>OB<>HKA>:KMMK:GLIE:GMBLBG=B<:M>= 
             • "BL<HGMBGN>:EEIKHMH<HEMK>:MF>GM 

0MN=R,NF;>K

99999999999999999999999999999999999999999999999999999999999999999999999


4.3.3.5 
Hemorrhage/bleeding  
4.3.3.5.1 $HK%K:=>A>FHKKA:@>;E>>=BG@I>KF:G>GMER=BL<HGMBGN>;>O:<BSNF:;:G=AHE=HMA>K
IKHMH<HEMK>:MF>GMHG<>A>FHKKA:@>HK;E>>=BG@K>LHEO>LHMA>KIKHMH<HEMK>:MF>GMF:R;>
<HGMBGN>=:MMA>MK>:MBG@IARLB<B:GUL=BL<K>MBHG
4.3.3.5.2 $HK%K:=>A>FHKKA:@>;E>>=BG@=BL<HGMBGN>:EEIKHMH<HEMK>:MF>GM 
4.3.3.6 
Proteinuria (Dose delays for bevacizumab only)  
4.3.3.6.1 If nephrotic syndrome (Grade 4 proteinuria) occurs, discontinue bevacizumab. Urine 
protein should be checked every four weeks. 
 
4.3.3.7 
Dose Resumption Timing for TAS-102 

'?MA>I:MB>GMK><HO>KL?KHFMA>MHQB<BMB>LMHMA>K>LNFIMBHG<KBM>KB:=>?BG>=:;HO>=NKBG@
MA>=:RMK>:MF>GMI>KBH=MK>:MF>GM=:RLMAKHN@A:G=MAKHN@APBMAGH=HL>
K>=N<MBHG;>BG@K>JNBK>=10MA>K:IRF:R;>K>LNF>=<HGMBGN>==NKBG@MA:M
<R<E>'?:=HL>K>=N<MBHGBLK>JNBK>=LMN=RF>=B<:MBHGMA>K:IRLAHNE=;>K>LNF>=:MMA>
LM:KMH?MA>G>QM<R<E>:MMA>:IIKHIKB:M>=HL>E>O>E:<<HK=BG@MHMA>BGLMKN<MBHGLBG1:;E>
'?MA>LMN=RF>=B<:MBHG=HL>BLK>=N<>=BMLAHNE=GHM;>BG<K>:L>=?HKLN;L>JN>GM
<R<E>L

'?MA>MHQB<BMB>LMA:M:K>=>?BG>=:;HO>K><HO>K=NKBG@AHEB=:RK>LMI>KBH==:RLMAKHN@A
LM:KMMA>G>QM<R<E>HGL<A>=NE>:MMA>:IIKHIKB:M>=HL>E>O>E:<<HK=BG@MH
BGLMKN<MBHGLIKHOB=>=BG1:;E>'?MA>MHQB<BMB>LMA:M:K>=>?BG>=:;HO>=HGHMK><HO>K
=NKBG@MA>MK>:MF>GMHKAHEB=:RI>KBH=MA>LM:KMH?MA>G>QM<R<E><:G;>=>E:R>=?HK:
F:QBFNFH?=:RL?KHFMA>L<A>=NE>=LM:KM=:M>H?MA>G>QM<R<E>'?K>LNFIMBHG<KBM>KB:
:K>F>M;RMABLF:QBFNF=:R=>E:RMA>G>QM<R<E>LAHNE=;>LM:KM>=:MMA>
:IIKHIKB:M>=HL>E>O>E:<<HK=BG@MHBGLMKN<MBHGLIKHOB=>=BG1:;E>

.:MB>GMLPAHK>JNBK>FHK>MA:G:=:R=>E:RBGMA>L<A>=NE>=LM:KM=:M>H?MA>G>QM
<R<E>PBEEA:O>LMN=RF>=B<:MBHG=BL<HGMBGN>=

4.4 
Supportive Care  
4.4.1 
EELNIIHKMBO>F>:LNK>L<HGLBLM>GMPBMAHIMBF:EI:MB>GM<:K>PBEE;>@BO>GMAKHN@AHNMMA>LMN=R

"B:KKA>:+:G:@>F>GM$HKLRFIMHFLH?=B:KKA>::G=HK:;=HFBG:E<K:FIBG@
MA:MH<<NK:M:GRMBF>=NKBG@MK>:MF>GMI:MB>GMLPBEE;>K><HFF>G=>=MH;>@BG
M:DBG@EHI>K:FB=>*HI>K:FB=>LAHNE=;>NL>=:MMA>=BL<K>MBHG:G=BGLMKN<MBHGL
H?MA>MK>:MBG@IARLB<B:G
4.4.2 
.>@?BE@K:LMBF>IH>MBG:G==:K;>IH>MBG:E?:F:R;>:=FBGBLM>K>=:MMA>MK>:MBG@BGO>LMB@:MHKL
=BL<K>MBHG
4.5 
!HG<HFBM:GM+>=B<:MBHGL1K>:MF>GML
!:NMBHGLAHNE=;>M:D>GPA>GNLBG@=KN@LMA:M:K>ANF:GMARFB=BG>DBG:L>LN;LMK:M>L
>@LM:ON=BG>SB=HON=BG>M>E;BON=BG>0N<A=KN@LB?NL>=<HG<HFBM:GMERPBMA10
F:RMA>HK>MB<:EER<HFI>M>PBMAMA>>??><MHKH?10B>$1"?HK:<MBO:MBHGOB:
MARFB=BG>DBG:L>L1A>K>?HK>PA>GNLBG@:GMBOBK:E=KN@LMA:M:K>ANF:GMARFB=BG>
DBG:L>LN;LMK:M>LFHGBMHK?HKIHLLB;E>=><K>:L>=>??B<:<RH?MA>:GMBOBK:E:@>GM:G=

0MN=R,NF;>K

99999999999999999999999999999999999999999999999999999999999999999999999


<HGLB=>KLPBM<ABG@MH:G:EM>KG:MBO>:GMBOBK:E:@>GMMA:MBLGHM:ANF:GMARFB=BG>DBG:L>
LN;LMK:M>LN<A:LE:FBON=BG>S:E<BM:;BG>=B=:GHLBG>:;:<BO:K>M<

&>F:MHEH@B<0NIIHKM
=FBGBLM>KA>F:MHEH@B<LNIIHKM:LF>=B<:EERBG=B<:M>=>@;EHH=MK:GL?NLBHGL
@K:GNEH<RM><HEHGRLMBFNE:MBG@?:<MHK7%!0$8>KRMAKHIHB>MBG:<<HK=BG@MHMA>
BGLMBMNMBHG:ELBM>LM:G=:K=L

+:G:@>F>GMH?"B:KKA>:
 HMAI:MB>GML:G=<:K>@BO>KLLAHNE=;>>=N<:M>=K>@:K=BG@MA>IHM>GMB:EL>KBHNLG>LLH?
<A>FHMA>K:IRBG=N<>==B:KKA>:1A>RLAHNE=;>BGLMKN<M>=MH<HGM:<MMA><EBGB<:ELBM>
LM:??BFF>=B:M>ER:MMA>?BKLMLB@GH?EHHL>LMHHE

.:MB>GMLLAHNE=;>IKHOB=>=PBMAEHI>K:FB=>HKHMA>KLM:G=:K=:GMB=B:KKA>:EMA>K:IR:G=
MA>I:MB>GMBGLMKN<M>=HGAHPMHNL>MA>MA>K:IR:MMA>?BKLMLB@GH?=B:KKA>:

1A>I:MB>GMUL?ENB=:G=>E><MKHERM>;:E:G<>LAHNE=;>FHGBMHK>=PBMA:IIKHIKB:M>
BGM>KO>GMBHG:L<EBGB<:EERBG=B<:M>=PBMA?ENB=L:G=>E><MKHERM>K>IE:<>F>GM:GMB;BHMB<L:G=
:GMB>F>MB<L

'G?><MBHGIKHIARE:QBLPBMAHK:E:GMB;BHMB<LLAHNE=;><HGLB=>K>=?HKI:MB>GMLPBMAI>KLBLM>GM
=B:KKA>:;>RHG=AHNKLHK<HBG<B=>GMPBMA@K:=>G>NMKHI>GB::L<EBGB<:EERBG=B<:M>=

.:MB>GMLLAHNE=;>IKHOB=>=PBMAIKHIARE:<MB<MK>:MF>GM?HK=B:KKA>::L<EBGB<:EER
BG=B<:M>=

+:G:@>F>GMH?,:NL>:3HFBMBG@.:MB>GMLLAHNE=;>IKHOB=>=PBMA:GMB>F>MB<MA>K:IR:L
<EBGB<:EERBG=B<:M>=

4.6 
Duration of Therapy 
'GMA>:;L>G<>H?MK>:MF>GM=>E:RL=N>MH:=O>KL>>O>GML#LMK>:MF>GMF:R<HGMBGN>
NGMBE

"BL>:L>IKH@K>LLBHG

'GM>K<NKK>GMBEEG>LLMA:MIK>O>GML?NKMA>K:=FBGBLMK:MBHGH?MK>:MF>GM

2G:<<>IM:;E>#L

.:MB>GM=><B=>LMHPBMA=K:P?KHFMA>LMN=ROR 

%>G>K:EHKLI><B?B<<A:G@>LBGMA>I:MB>GMUL<HG=BMBHGK>G=>KMA>I:MB>GMNG:<<>IM:;E>
?HK?NKMA>KMK>:MF>GMBGMA>CN=@F>GMH?MA>BGO>LMB@:MHK
4.7 
Survival Follow-Up 
.:MB>GMLPBEEB=>:EER;>?HEEHP>=NGMBE=>:MA?M>KMK>:MF>GM=BL<HGMBGN:MBHG:M>E>IAHG>
<:EEPBEE;>F:=>MHMA>I:MB>GMHKMA>I:MB>GMUL?:FBER>O>KRFHGMALMHBGJNBK>:;HNM
MA>I:MB>GMUL<HEHG<:G<>KLM:MNL@>G>K:EA>:EMA:G=BG?HKF:MBHGHG:GR:GMBG>HIE:LMB<
MA>K:IB>LNMBEBS>=LBG<>=BL<HGMBGN:MBHGH?LMN=RMK>:MF>GM
4.8 
Removal of Patients from Study  
.:MB>GMLPBEE;>K>FHO>=?KHFLMN=RPA>G:GRH?MA><KBM>KB:EBLM>=BG0><MBHG:IIER
,HMB?RMA>.KBG<BI:E'GO>LMB@:MHK:G==H<NF>GMMA>K>:LHG?HKLMN=RK>FHO:E:G=MA>=:M>
MA>I:MB>GMP:LK>FHO>=BGMA>!:L>/>IHKM$HKF1A>I:MB>GMLAHNE=;>?HEEHP>=NI
I>KIKHMH<HE


0MN=R,NF;>K

99999999999999999999999999999999999999999999999999999999999999999999999


4.9 
Collaboration with other institutions 
1A>LMN=RPBEE;><HG=N<M>=BG<HEE:;HK:MBHGPBMAMA>!BMRH?&HI>!HFIK>A>GLBO>
!:G<>K!>GM>K:G=MA>-ABH0M:M>2GBO>KLBMR(:F>L!HFIK>A>GLBO>!:G<>K!>GM>K
"K(HAG+:KLA:EEBLMA>.KBG<BI:E'GO>LMB@:MHK?HKMA>LMN=R:G=PBEEHO>KL>>MA>LMN=R
BG<EN=BG@MA>=:M:@:MA>KBG@L:?>MR:G=K>IHKMBG@"K+:KP:G$:DBAPBEE;>MA>F:BG
LMN=R<HGM:<M:MMA>!BMRH?&HI>!HFIK>A>GLBO>!:G<>K!>GM>K:G="K0:F>A+BDA:BE
PBEE;>MA>F:BGLMN=R<HGM:<M:MMA>-02(:F>L!:G<>K&HLIBM:E.:MB>GMLPBEE;>
K><KNBM>=:M:EEBGLMBMNMBHGL?HKMA>LMN=R

+HGMAER<HG?>K>G<><:EELPBEE;><HG=N<M>=;>MP>>G:EEBGLMBMNMBHGLMH?HEEHPNIHGMA>
IKH@K>LLH?MA>MKB:E"K+:KLA:EEPBEE;>K>LIHGLB;E>?HK<HHK=BG:MBHGH?MA>MKB:E;>MP>>G
:EEBGLMBMNMBHGL0MN=R<HHK=BG:MHKLPBEEGHMB?R"K+:KLA:EENIHGMA>:<<KN:EH?:GRI:MB>GML
BG:GRBGLMBMNMBHG

4.9.1 
Personnel 
M>:<ALBM>I>KLHGG>E=>=B<:M>=MHMABLIKHMH<HEPBEE;>
LMN=R.'
K>L>:K<A<HHK=BG:MHK
=:M:F:G:@>K
'G:==BMBHG:M*HF;:K=B%>HK@>MHPGMA>K>PBEE;>:=>=B<:M>=VFNEMBBGLMBMNMBHG:EW
K>L>:K<A<HHK=BG:MHKPAHPBEEIE:RMA>IKBF:KRKHE>BG<HHK=BG:MBG@MA>MKB:E;>MP>>G
*HF;:K=B%>HK@>MHPG:G=:==BMBHG:ELBM>L1ABL<HHK=BG:MHKPBEE;>MA>F:BGIHBGMH?
<HGM:<M?HK"K+:KLA:EE:G=MA>HMA>KLBM>.'L?HK:GRLMN=RK>E:M>=<HG<>KGL:G=MH
L<K>>G>:<AI:MB>GM;>BG@<HGLB=>K>=?HK>GKHEEF>GM'G<EN=BG@VK>FHM>WL<K>>GBG@?HKMA>
I:MB>GML;>BG@L<K>>G>=:MHMA>KLBM>L1ABL<HHK=BG:MHKPBEE:ELH;>MA>IHBGMH?<HGM:<M
?HKMA>=:M:F:G:@>KL?HK=:M:>GMKRJN>LMBHGL$BG:EERMABL<HHK=BG:MHKPBEEIE:R:F:CHK
KHE>BGK>@NE:MHKR<HHK=BG:MBHGH?MA>LMN=RLI><B?B<:EER;R/>OB>PBG@:G=<HG?BKFBG@
:EELMN=RK>E:M>=:=O>KL>>O>GML0N;FBMMBG@:EE0#K>IHKMLMHMA>%>HK@>MHPG'/ 
1A>K>L>:K<A<HHK=BG:MHKL:MMA>HMA>KLBM>LPBEEIK>I:K>0#K>IHKML?HKI:MB>GMLMK>:M>=
:MMA>BKK>LI><MBO>LBM>L;NMMA>VFNEMBBGLMBMNMBHG:EW<HHK=BG:MHKPBEELN;FBMMA>?BG:E
K>IHKM%:MA>KBG@:G=IK>I:KBG@:EEIKBF:KRLHNK<>=:M:?HKK>OB>P:N=BM;R1A>K:=>Q
'G<

4.9.2 
Patient Enrollment 
#GKHEEF>GM:MMA>LBM>LPBEE;><HFI>MBMBO>'?:I:MB>GMBL;>BG@L<K>>G>=?HK>GKHEEF>GM
MA>EH<:EK>L>:K<A<HHK=BG:MHKFNLML>G=:G>F:BEPBMABGAHNKL<HGM:BGBG@MA>
LN;C><MGNF;>KMHMA>.':G=MHMA>FNEMBBGLMBMNMBHG:E<HHK=BG:MHK'?:I:MB>GMBL
LN<<>LL?NEERL<K>>G>=MA>EH<:EK>L>:K<A<HHK=BG:MHKFNLML>G=:EELNIIHKMBG@
=H<NF>GM:MBHGMHMA>FNEMBBGLMBMNMBHG:EK>L>:K<A<HHK=BG:MHK;R>F:BE
7AD:@>HK@>MHPG>=N8.:MB>GMLLAHNE=GHMLM:KMMA>K:IRNGMBE;HMA.':G=MA>FNEMB
BGLMBMNMBHG:E<HHK=BG:MHKA:O>K>OB>P>=MA>I:MB>GMULK><HK=L:G=<HG?BKF>=MA:MMA>
I:MB>GMBLBG=>>=>EB@B;E>?HK>GKHEEF>GM


4.9.3 
Conference Calls 
FHGMAER<HG?>K>G<><:EEPBEE;>A>E=;>MP>>G*HF;:K=B%>HK@>MHPG:G=MA>HMA>KLBM>L
MHK>OB>PI:MB>GM>GKHEEF>GMMHQB<BMR:G=K>LIHGL>:LL>LLF>GM


0MN=R,NF;>K

99999999999999999999999999999999999999999999999999999999999999999999999


5.0 
STUDY PROCEDURES 
5.1 
 .E>:L>L>>MBF>:G=>O>GMLM:;E>;>EHP
5.2 
Follow-up Procedures 
$HEEHPNI<HGMBGN>L?HK=:RL:?M>KMA>I:MB>GMA:LLMHII>=M:DBG@10
1A>0:?>MR$HEEHPNIOBLBM<:G;><HG=N<M>=BGI>KLHGHK;R:IAHG><:EE1ABLOBLBMPBEE
;><HG=N<M>=:IIKHQBF:M>ER=:RL:?M>KMA>E:LM=HL>H?101A>BGO>LMB@:MHKHK
MKB:ELM:??PBEE:LDMA>I:MB>GMJN>LMBHGL:;HNMAHPA>LA>BL?>>EBG@:G=B?A>LA>A:LA:=
:GRAHLIBM:EBS:MBHGLHK>F>K@>G<RMK>:MF>GMLBG<>MA>E:LMOBLBMMHMA>K>L>:K<ALBM>

0MN=R,NF;>K
999999999999999999999999999999999999999999999999999999999999999999999999










6.0 
STUDY PROCEDURE 
6.1 
Time and Events Table 
 :L>EBG>>O:EN:MBHGL:K>MH;><HG=N<M>=PBMABG=:RLIKBHKMHLM:KMH?IKHMH<HEMA>K:IR2GE>LLHMA>KPBL>GHM>=:LM:G=:K=PBG=HPH?=:RMH

=:RLPBEE;><HGLB=>K>=:<<>IM:;E>?HK:EEM>LMBG@:G=>O:EN:MBHGLPBEEGHM;><HGLB=>K>=LMN=R=>OB:MBHG
 
Study 
 
Study Procedure 
Pre-study 
Treatment 
End of Treatment / Follow-
up 
 
Survival  
Follow-up16 
Treatment 
day -28 
to -1 
All 
Treatment 
Cycles1 
q 2 
Weeks 
(1st 4 
weeks)
Every 4 Weeks 
(week 5 through 
end of treatment)
Every 8 
Weeks 
 
End of 
Treatment14 
Safety 
Follow-
up15 
 
0B@G>='!$
5







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5







+>=B<:E&BLMHKR
5

5
5




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6.2 
Removal of Subjects from Study 

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;>=H<NF>GM>=:G=:IIKHO>=;RMA>":M:+HGBMHKBG@!HFFBMM>>
7.0 
Measurement of Effect 
7.1 
Antitumor Effect- Solid Tumors 
/>LIHGL>:G=IKH@K>LLBHGPBEE;>>O:EN:M>=BGMABLLMN=RNLBG@MA>G>PBGM>KG:MBHG:E
<KBM>KB:IKHIHL>=;RMA>/>LIHGL>#O:EN:MBHG!KBM>KB:BG0HEB=1NFHKL/#!'01
!HFFBMM>>7JNCI8!A:G@>LBGHGERMA>E:K@>LM=B:F>M>K
NGB=BF>GLBHG:EF>:LNK>F>GMH?MA>MNFHKE>LBHGL:K>NL>=BGMA>/#!'01O<KBM>KB:
7.1.1 
Definitions 
#O:EN:;E>?HKMHQB<BMREEI:MB>GMLPBEE;>>O:EN:;E>?HKMHQB<BMR?KHFMA>MBF>H?MA>BK?BKLM
MK>:MF>GMPBMALMN=R=KN@

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IK>L>GM:M;:L>EBG>A:O>K><>BO>=:ME>:LMHG><R<E>H?MA>K:IR:G=A:O>A:=MA>BK
=BL>:L>K>>O:EN:M>=PBEE;><HGLB=>K>=>O:EN:;E>?HKK>LIHGL>1A>L>I:MB>GMLPBEEA:O>
MA>BKK>LIHGL><E:LLB?B>=:<<HK=BG@MHMA>=>?BGBMBHGLLM:M>=;>EHP,HM>.:MB>GMLPAH
>QAB;BMH;C><MBO>=BL>:L>IKH@K>LLBHGIKBHKMHMA>>G=H?<R<E>PBEE:ELH;><HGLB=>K>=
>O:EN:;E>
7.1.2 
Disease Parameters 
+>:LNK:;E>=BL>:L>+>:LNK:;E>E>LBHGL:K>=>?BG>=:LMAHL>MA:M<:G;>:<<NK:M>ER
F>:LNK>=BG:ME>:LMHG>=BF>GLBHGEHG@>LM=B:F>M>KMH;>K><HK=>=:LFFPBMA

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IKH@K>LLBHGH?MA>E>LBHGLBG<>MA><HFIE>MBHGH?K:=B:MBHGMA>K:IR

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EHG@>LM=B:F>M>KFFPBMA<HGO>GMBHG:EM><AGBJN>LHKFFNLBG@LIBK:E!1
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F>:LNK:;E>

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E>LBHGLBGMHM:EK>IK>L>GM:MBO>H?:EEBGOHEO>=HK@:GLLAHNE=;>B=>GMB?B>=:Ltarget 
lesions:G=K><HK=>=:G=F>:LNK>=:M;:L>EBG>1:K@>ME>LBHGLLAHNE=;>L>E><M>=HG
MA>;:LBLH?MA>BKLBS>E>LBHGLPBMAMA>EHG@>LM=B:F>M>K:G=MA>BKLNBM:;BEBMR?HK:<<NK:M>
K>I>:M>=F>:LNK>F>GML>BMA>K;RBF:@BG@M><AGBJN>LHK<EBGB<:EERLNFH?MA>EHG@>LM
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*"1A>;:L>EBG>LNF*"PBEE;>NL>=:LK>?>K>G<>;RPAB<AMH<A:K:<M>KBS>MA>
H;C><MBO>MNFHKK>LIHGL>

,HGM:K@>ME>LBHGLEEHMA>KE>LBHGLHKLBM>LH?=BL>:L>BG<EN=BG@:GRF>:LNK:;E>
E>LBHGLHO>K:G=:;HO>MA>M:K@>ME>LBHGLLAHNE=;>B=>GMB?B>=:Lnon-target lesions 
:G=LAHNE=:ELH;>K><HK=>=:M;:L>EBG>+>:LNK>F>GMLH?MA>L>E>LBHGL:K>GHM
K>JNBK>=;NMMA>IK>L>G<>HK:;L>G<>H?>:<ALAHNE=;>GHM>=MAKHN@AHNM?HEEHPNI

7.1.3 
Methods for Evaluation of Measurable Disease 
EEF>:LNK>F>GMLLAHNE=;>M:D>G:G=K><HK=>=BGF>MKB<GHM:MBHGNLBG@:KNE>KHK
<:EBI>KLEE;:L>EBG>>O:EN:MBHGLLAHNE=;>I>K?HKF>=:L<EHL>ER:LIHLLB;E>MHMA>
;>@BGGBG@H?MK>:MF>GM:G=G>O>KFHK>MA:G=:RL;>?HK>MA>;>@BGGBG@H?MA>
MK>:MF>GM

1A>L:F>F>MAH=H?:LL>LLF>GM:G=MA>L:F>M><AGBJN>LAHNE=;>NL>=MH
<A:K:<M>KBS>>:<AB=>GMB?B>=:G=K>IHKM>=E>LBHG:M;:L>EBG>:G==NKBG@?HEEHPNI
'F:@BG@;:L>=>O:EN:MBHGBLIK>?>KK>=MH>O:EN:MBHG;R<EBGB<:E>Q:FBG:MBHGPA>G;HMA
F>MAH=LA:O>;>>GNL>=MH:LL>LLMA>:GMBMNFHK>??><MH?:MK>:MF>GM

!HGO>GMBHG:E!1:G=+/'1A>L>M><AGBJN>LLAHNE=;>I>K?HKF>=PBMA<NMLH?FFHK
E>LLBGLEB<>MAB<DG>LL<HGMB@NHNLER0IBK:E!1LAHNE=;>I>K?HKF>=NLBG@:FF
<HGMB@NHNLK><HGLMKN<MBHG:E@HKBMAF1ABL:IIEB>LMHMNFHKLH?MA><A>LM:;=HF>G:G=
I>EOBL

!RMHEH@R&BLMHEH@R1A>L>M><AGBJN>L<:G;>NL>=MH=B??>K>GMB:M>;>MP>>GI:KMB:E
K>LIHGL>L./:G=<HFIE>M>K>LIHGL>L!/BGK:K><:L>L>@K>LB=N:EE>LBHGLBG
MNFHKMRI>LLN<A:L@>KF<>EEMNFHKLPA>K>DGHPGK>LB=N:E;>GB@GMNFHKL<:GK>F:BG

1A><RMHEH@B<:E<HG?BKF:MBHGH?MA>G>HIE:LMB<HKB@BGH?:GR>??NLBHGMA:M:II>:KLHK
PHKL>GL=NKBG@MK>:MF>GMPA>GMA>F>:LNK:;E>MNFHKA:LF>M<KBM>KB:?HKK>LIHGL>HK
LM:;E>=BL>:L>BLF:G=:MHKRMH=B??>K>GMB:M>;>MP>>GK>LIHGL>HKLM:;E>=BL>:L>:G
>??NLBHGF:R;>:LB=>>??><MH?MA>MK>:MF>GM:G=IKH@K>LLBO>=BL>:L>


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7.1.4 
Response Criteria 
7.1.4.1 
Evaluation of Target Lesions 
!HFIE>M>/>LIHGL>!/"BL:II>:K:G<>H?:EEM:K@>ME>LBHGL=>M>KFBG>=;RMPH
L>I:K:M>H;L>KO:MBHGL<HG=N<M>=GHME>LLMA:GP>>DL:I:KM1A>K><:G;>GH
:II>:K:G<>H?G>PE>LBHGL

.:KMB:E/>LIHGL>./ME>:LM:=><K>:L>BGMA>LNFH?MA>EHG@>LM=B:F>M>K*"
H?M:K@>ME>LBHGLM:DBG@:LK>?>K>G<>MA>;:L>EBG>LNF*"1A>K><:G;>GH:II>:K:G<>
H?G>PE>LBHGL

.KH@K>LLBO>"BL>:L>."ME>:LM:BG<K>:L>BGMA>LNFH?MA>*"H?M:K@>ME>LBHGL
M:DBG@:LK>?>K>G<>MA>LF:EE>LMLNF*"K><HK=>=LBG<>MA>MK>:MF>GMLM:KM>=HKMA>
:II>:K:G<>H?HG>HKFHK>G>PE>LBHGL

0M:;E>"BL>:L>0",>BMA>KLN??B<B>GMLAKBGD:@>MHJN:EB?R?HK./GHKLN??B<B>GMBG<K>:L>
MHJN:EB?R?HK."M:DBG@:LK>?>K>G<>MA>LF:EE>LMLNF*"LBG<>MA>MK>:MF>GMLM:KM>=
7.1.4.2 
Evaluation of Non-Target Lesions 
!HFIE>M>/>LIHGL>!/"BL:II>:K:G<>H?:EEGHGM:K@>ME>LBHGL:G=GHKF:EBS:MBHGH?
MNFHKF:KD>KE>O>E

'G<HFIE>M>/>LIHGL>0M:;E>"BL>:L>0".>KLBLM>G<>H?HG>HKFHK>GHGM:K@>M
E>LBHGL:G=HKF:BGM>G:G<>H?MNFHKF:KD>KE>O>E:;HO>MA>GHKF:EEBFBML

.KH@K>LLBO>"BL>:L>."II>:K:G<>H?HG>HKFHK>G>PE>LBHGL:G=HKNG>JNBOH<:E
IKH@K>LLBHGH?>QBLMBG@GHGM:K@>ME>LBHGL
7.1.4.3 
Evaluation of Best Overall Response 
1A>;>LMHO>K:EEK>LIHGL>BLMA>;>LMK>LIHGL>K><HK=>=?KHFMA>LM:KMH?MA>MK>:MF>GM
NGMBE=BL>:L>IKH@K>LLBHGK><NKK>G<>M:DBG@:LK>?>K>G<>?HKIKH@K>LLBO>=BL>:L>MA>
LF:EE>LMF>:LNK>F>GMLK><HK=>=LBG<>MA>MK>:MF>GMLM:KM>=1A>I:MB>GML;>LM
K>LIHGL>:LLB@GF>GMPBEE=>I>G=HGMA>:<AB>O>F>GMH?;HMAF>:LNK>F>GM:G=
<HG?BKF:MBHG<KBM>KB:


Target 
Lesions 
Non-
Target 
Lesions 
New Lesions 
Overall 
Response 
Best 
Response for 
this Category 
Also 
Requires: 
!
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7.1.5 
Duration of Response 
"NK:MBHGH?HO>K:EEK>LIHGL>1A>=NK:MBHGH?HO>K:EEK>LIHGL>BLF>:LNK>=?KHFMA>MBF>
F>:LNK>F>GM<KBM>KB::K>F>M?HK!/HK./PAB<A>O>KBL?BKLMK><HK=>=NGMBEMA>?BKLM=:M>
MA:MK><NKK>GMHKIKH@K>LLBO>=BL>:L>BLH;C><MBO>ER=H<NF>GM>=M:DBG@:LK>?>K>G<>?HK
IKH@K>LLBO>=BL>:L>MA>LF:EE>LMF>:LNK>F>GMLK><HK=>=LBG<>MA>MK>:MF>GMLM:KM>=

1A>=NK:MBHGH?HO>K:EE!/BLF>:LNK>=?KHFMA>MBF>F>:LNK>F>GM<KBM>KB::K>?BKLMF>M
?HK!/NGMBEMA>?BKLM=:M>MA:MK><NKK>GM=BL>:L>BLH;C><MBO>ER=H<NF>GM>=


"NK:MBHGH?LM:;E>=BL>:L>0M:;E>=BL>:L>BLF>:LNK>=?KHFMA>LM:KMH?MA>MK>:MF>GM
NGMBEMA><KBM>KB:?HKIKH@K>LLBHG:K>F>MM:DBG@:LK>?>K>G<>MA>LF:EE>LMF>:LNK>F>GML
K><HK=>=LBG<>MA>MK>:MF>GMLM:KM>=
7.1.6 
Progression-Free Survival 
.KH@K>LLBHG?K>>LNKOBO:E.$0BL=>?BG>=:LMA>=NK:MBHGH?MBF>?KHFLM:KMH?MK>:MF>GM
10IENL;>O:<BSNF:;MHMBF>H?IKH@K>LLBHGHKI:MB>GMUL=>:MA?KHF:GR<:NL>
7.2 
Safety/tolerability 
G:ERL>LPBEE;>I>K?HKF>=?HK:EEI:MB>GMLA:OBG@K><>BO>=:ME>:LMHG>=HL>H?LMN=R
=KN@1A>LMN=RPBEENL>MA>!1!#O>KLBHG?HKK>IHKMBG@H?GHGA>F:MHEH@B<#L
http://ctep.cancer.gov/reporting/ctc.html:G=FH=B?B>=<KBM>KB:?HKA>F:MHEH@B<#L
II>G=BQ!-MA>K#??B<:<R.:K:F>M>KL
8.0 
ADVERSE EVENTS 
8.1 
Adverse Event Monitoring 
=O>KL>>O>GM=:M:<HEE><MBHG:G=K>IHKMBG@PAB<A:K>K>JNBK>=:LI:KMH?>O>KR<EBGB<:E
MKB:E:K>=HG>MH>GLNK>MA>L:?>MRH?0N;C><ML>GKHEE>=BGMA>LMN=B>L:LP>EE:LMAHL>
PAHPBEE>GKHEEBG?NMNK>LMN=B>LNLBG@LBFBE:K:@>GML=O>KL>>O>GML:K>K>IHKM>=BG:
KHNMBG>F:GG>K:ML<A>=NE>=MBF>L=NKBG@:MKB:E==BMBHG:EER<>KM:BG#LFNLM;>
.
GR
6>LHK
."

GHIKBHK0"
./HK!/
G
."	
6>LHK
."
G
GR
6>L
."
	
'G>Q<>IMBHG:E<BK<NFLM:G<>LNG>JNBOH<:EIKH@K>LLBHGBGGHGM:K@>M
E>LBHGLF:R;>:<<>IM>=:L=BL>:L>IKH@K>LLBHG

,HM>
.:MB>GMLPBMA:@EH;:E=>M>KBHK:MBHGH?A>:EMALM:MNLK>JNBKBG@
=BL<HGMBGN:MBHGH?MK>:MF>GMPBMAHNMH;C><MBO>>OB=>G<>H?
=BL>:L>IKH@K>LLBHG:MMA:MMBF>LAHNE=;>K>IHKM>=:L
Vsymptomatic deterioration”#O>KR>??HKMLAHNE=;>F:=>MH
=H<NF>GMMA>H;C><MBO>IKH@K>LLBHG>O>G:?M>K=BL<HGMBGN:MBHGH?
MK>:MF>GM

0MN=R,NF;>K
9999999999999999999999999999999999999999999999999999999999999999999999


K>IHKM>=BG:G>QI>=BM>=F:GG>KMH:EEHP?HKHIMBF:EFHGBMHKBG@H?I:MB>GML:?>MR:G=
<:K>

EEI:MB>GML>QI>KB>G<BG@:G#K>@:K=E>LLH?BMLK>E:MBHGLABIMHLMN=R=KN@PBEE;>FHGBMHK>=NGMBE
 MA>#K>LHEO>LHKMA>LRFIMHFLHKLB@GLMA:M<HGLMBMNM>MA>#K>MNKGMH;:L>EBG>:G=
K>F:BG:M;:L>EBG>?HK=:RL
 :GR:;GHKF:EE:;HK:MHKRO:EN>LA:O>K>MNKG>=MH;:L>EBG>?HK:ME>:LM=:RL
 LM:KMH?G>P:GMBMNFHKMA>K:IR
 MA>K>BL:L:MBL?:<MHKR>QIE:G:MBHGHMA>KMA:GMA>LMN=R=KN@?HKMA><A:G@>LH;L>KO>=HK
 =>:MA

8.2 
Definitions 
8.2.1 
Definition of Adverse Event 
G:=O>KL>>O>GMBL:GRNG=>LBK:;E>>QI>KB>G<>:LLH<B:M>=PBMAMA>NL>H?:F>=B<:E
IKH=N<MBG:I:MB>GMG#<:GMA>K>?HK>;>:GRNG?:OHK:;E>:G=NGBGM>G=>=LB@G
BG<EN=BG@:G:;GHKF:EE:;HK:MHKR?BG=BG@LRFIMHFHK=BL>:L>M>FIHK:EER:LLH<B:M>=
PBMAMA>NL>H?:G>QI>KBF>GM:EBGM>KO>GMBHGPA>MA>KHKGHMK>E:M>=MHMA>BGM>KO>GMBHG
8.2.2 
Severity of Adverse Events 
EE#LPBEE;>@K:=>=:<<HK=BG@MHMA>,!'!HFFHG1>KFBGHEH@R!KBM>KB:?HK=O>KL>
#O>GML!1!#O>KLBHG1A>!1!#OBL:O:BE:;E>:M
AMMI<M>I<:G<>K@HOK>IHKMBG@<M<AMFE

8.2.3 
Serious Adverse Events 
VL>KBHNLW#0#BL=>?BG>=BGK>@NE:MHKRM>KFBGHEH@R:L:GRNGMHP:K=F>=B<:E
H<<NKK>G<>MA:M

8.2.3.1 
Results in death. 
'?=>:MAK>LNEML?KHFIKH@K>LLBHGH?MA>=BL>:L>BMLAHNE=;>K>IHKM>=:L>O>GM0#
BML>E?

8.2.3.2 
Is life-threatening. 
MA>I:MB>GMP:L:MKBLDH?=>:MA:MMA>MBF>H?MA>>O>GMBM=H>LGHMK>?>KMH:G>O>GMMA:M
ARIHMA>MB<:EERFB@AMA:O><:NL>==>:MAB?BMP>K>FHK>L>O>K>

0MN=R,NF;>K
9999999999999999999999999999999999999999999999999999999999999999999999


8.2.3.3 
Requires in-patient hospitalization or prolongation of existing hospitalization. 
8.2.3.4 
Results in persistent or significant disability or incapacity. 
8.2.3.5 
Is a congenital anomaly/birth defect 
8.2.3.6 
Is an important medical event 
GR>O>GMMA:M=H>LGHMF>>MMA>:;HO><KBM>KB:;NMMA:MBGMA>CN=@F>GMH?MA>
BGO>LMB@:MHKC>HI:K=BS>LMA>I:MB>GMF:R;><HGLB=>K>=?HKK>IHKMBG@:L:G0#1A>
>O>GMF:RK>JNBK>F>=B<:EHKLNK@B<:EBGM>KO>GMBHGMHIK>O>GMHG>H?MA>HNM<HF>LEBLM>=
BGMA>=>?BGBMBHGH?V0>KBHNL=O>KL>#O>GMV
$HK>Q:FIE>:EE>K@B<;KHG<AHLI:LFK>JNBKBG@BGM>GLBO>MK>:MF>GMBG:G>F>K@>G<RKHHF
HK:MAHF><HGONELBHGLMA:MF:RGHMK>LNEMBGAHLIBM:EBS:MBHG=>O>EHIF>GMH?=KN@:;NL>
HK=KN@=>I>G=>G<R
8.3 
Steps to Determine If an Adverse Event Requires Expedited Reporting 

0M>I '=>GMB?RMA>MRI>H?#NLBG@MA>,!'!HFFHG1>KFBGHEH@R!KBM>KB:?HK=O>KL>
#O>GML!1!#O

0M>I%K:=>MA>#NLBG@MA>,!'!1!#O

0M>I">M>KFBG>PA>MA>KMA>#BLK>E:M>=MHMA>IKHMH<HEMA>K:IR
MMKB;NMBHG<:M>@HKB>L:K>:L?HEEHPL
-
">?BGBM>Y1A>#is clearly relatedMHMA>LMN=RMK>:MF>GM:G=HG>H?MA>
?HEEHPBG@<HG=BMBHGLBLMKN>

IHLBMBO>=><A:EE>G@>F>:GBG@MA>>O>GMK>LHEO>LPA>GMA>
=KN@BLLMHII>=

IHLBMBO>K><A:EE>G@>F>:GBG@MA>>O>GMK>:II>:KLPA>GMA>
=KN@BLK>LM:KM>=

1A>>O>GM<:GGHM;>K>:LHG:;E>>QIE:BG>=;RMA>I:MB>GMUL
<EBGB<:ELM:M>:G=HKHMA>K:=FBGBLM>K>=MA>K:IB>L
-
.KH;:;E>Y1A>#is likely related MHMA>LMN=RMK>:MF>GM
-
.HLLB;E>Y1A>#may be relatedMHMA>LMN=RMK>:MF>GM
-
2GK>E:M>=Y1A>#is clearly NOT relatedMHMA>LMN=RMK>:MF>GM1A>K>
BLGH>OB=>G<>MHLN@@>LM:<:NL:EK>E:MBHGLABI;>MP>>GMA>=KN@:G=MA>
#

,HM>1ABLBG<EN=>L:EE>O>GMLMA:MH<<NKPBMABG=:RLH?MA>E:LM=HL>H?IKHMH<HE
MK>:MF>GMGR>O>GMMA:MH<<NKLFHK>MA:G=:RL:?M>KMA>E:LM=HL>H?MK>:MF>GM:G=
BL:MMKB;NM>=IHLLB;ERIKH;:;ERHK=>?BGBM>ERMHMA>:@>GMLFNLM:ELH;>K>IHKM>=
:<<HK=BG@ER

0M>I
">M>KFBG>MA>IKBHK>QI>KB>G<>H?MA>#
#QI><M>=>O>GML:K>MAHL>MA:MA:O>;>>GIK>OBHNLERB=>GMB?B>=:LK>LNEMBG@?KHF
:=FBGBLMK:MBHGH?MA>:@>GMG#BL<HGLB=>K>=NG>QI><M>=?HK>QI>=BM>=K>IHKMBG@
INKIHL>LHGERPA>G>BMA>KMA>MRI>H?>O>GMHKMA>L>O>KBMRH?MA>>O>GMBLGHMEBLM>=BG

MA><NKK>GMDGHPG#LEBLM>=BGMA>@>GM'G?HKF:MBHG0><MBHGH?MABL
IKHMH<HE

MA>=KN@I:<D:@>BGL>KM

MA><NKK>GM'GO>LMB@:MHKUL KH<ANK>

0MN=R,NF;>K
9999999999999999999999999999999999999999999999999999999999999999999999


8.4 
Reporting Requirements for Adverse Events 

1A>BGO>LMB@:MHKLPBEE?HEEHPLM:G=:K=@NB=>EBG>L!1!#O?HKK>IHKMBG@H?#L
0>KBHNL#BG?HKF:MBHGPA>MA>KHKGHMK>E:M>=MH10:LP>EE:LK>IHKMLH?
IK>@G:G<RHO>K=HL>HKF>=B<:MBHG>KKHKPBEE;>K>IHKM>='G:==BMBHG:EE@K:=>LH?
:=O>KL>=KN@K>:<MBHGL"/L#LK>E:M>=MHLMN=RF>=B<:MBHG:G=:GR#MA:MK>LNEML
BGMK>:MF>GM=BL<HGMBGN:MBHGPBEE;>K><HK=>=:LLMN=R=:M:HG!/$L
8.4.1 
Expedited Reporting 

1A>.KBG<BI:E'GO>LMB@:MHKFNLM;>GHMB?B>=PBMABGAHNKLH?E>:KGBG@H?:GRL>KBHNL#L
K>@:K=E>LLH?:MMKB;NMBHGH<<NKKBG@=NKBG@MA>LMN=RHKPBMABG=:RLH?MA>E:LM:=FBGBLMK:MBHGH?
MA>LMN=R=KN@

'GO>LMB@:MBHG:E@>GML10

!HFF>K<B:E@>GML >O:<BSNF:;

4A>G:GBGO>LMB@:MBHG:E:@>GMLBLNL>=BG<HF;BG:MBHGPBMA:<HFF>K<B:E:@>GMLMA>
<HF;BG:MBHGBL<HGLB=>K>=MH;>BGO>LMB@:MBHG:E:G=>QI>=BM>=K>IHKMBG@H?:=O>KL>>O>GML?HEEHP
MA>@NB=>EBG>L?HKBGO>LMB@:MBHG:E:@>GML

*:M>.A:L>:G=.A:L>0MN=B>L
#QI>=BM>=/>IHKMBG@/>JNBK>F>GML?HK=O>KL>#O>GMLMA:M-<<NKHG0MN=B>LNG=>K:G',"
PBMABG":RLH?MA>*:LM=FBGBLMK:MBHGH?MA>'GO>LMB@:MBHG:E@>GM'GM>KO>GMBHG


1A>'/ FNLM;>GHMB?B>=PBMABG;NLBG>LL=:RLH?V:GRNG:GMB<BI:M>=IKH;E>FLBGOHEOBG@KBLDMH
LN;C><MLHKHMA>KLW2./2./L:K>=>?BG>=:L:GRIKH;E>FHK>O>GMMA:MBL<HGLB=>K>=
L>KBHNLNG>QI><M>=:G=:ME>:LMIHLLB;ERK>E:M>=MHLMN=RI:KMB<BI:MBHG


1A>$"LAHNE=;>GHMB?B>=PBMABG<:E>G=:K=:RLH?:GRNG>QI><M>=?:M:EHKEB?>MAK>:M>GBG@#
PBMAIHLLB;E>K>E:MBHGLABIMHLMN=R=KN@:G=<:E>G=:K=:RLH?:GR>O>GMMA:MBL<HGLB=>K>=
L>KBHNLNG>QI><M>=:G=:ME>:LMIHLLB;ERK>E:M>=MHLMN=RI:KMB<BI:MBHG
8.4.2 
Routine Reporting 

EEHMA>K#LLN<A:LMAHL>MA:M:K>>QI><M>=HK:K>NGEBD>ERHK=>?BGBM>ERGHMK>E:M>=MH
MA>LMN=RI:KMB<BI:MBHG:K>MH;>K>IHKM>=:GGN:EER:LI:KMH?K>@NE:K=:M:LN;FBLLBHG
8.5 
Premature termination of the study 
 '?KBLD;>G>?BMK:MBH;><HF>LNG:<<>IM:;E>HPBG@MH?HK>Q:FIE>
o
0:?>MR?BG=BG@L?KHFMABLLMN=R>@0#L
o
/>LNEMLH?:GRBGM>KBF:G:ERLBL
o
/>LNEMLH?I:K:EE>E<EBGB<:ELMN=B>L
o
/>LNEMLH?I:K:EE>E:GBF:ELMN=B>L
HG>@MHQB<BMRM>K:MH@>GB<BMR<:K<BGH@>GB<BMRHKK>IKH=N<MBHGMHQB<BMR

'?MA>LMN=R<HG=N<M>@K><KNBMF>GMK:M>=KHIHNMK:M>=:M:JN:EBMRIKHMH<HE<HFIEB:G<>=H>L
GHMLN@@>LM:IKHI>K<HFIE>MBHGH?MA>MKB:EPBMABG:K>:LHG:;E>MBF>?K:F>
1A>BGO>LMB@:MHKA:LMA>KB@AMMH<EHL>ABLA>K<>GM>K:M:GRMBF>

0MN=R,NF;>K
9999999999999999999999999999999999999999999999999999999999999999999999


$HK:GRH?MA>:;HO><EHLNK>LMA>?HEEHPBG@:IIEB>L

!EHLNK>LLAHNE=H<<NKHGER:?M>K<HGLNEM:MBHG;>MP>>GBGOHEO>=I:KMB>L

EE:??><M>=BGLMBMNMBHGL>@'#!L'/ L<HFI>M>GM:NMAHKBMRB>LLMN=R<>GM>KA>:=H?LMN=R
<>GM>KFNLM;>BG?HKF>=:L:IIEB<:;E>:<<HK=BG@MHEH<:EE:P

'G<:L>H?:I:KMB:ELMN=R<EHLNK>HG@HBG@LN;C><MLBG<EN=BG@MAHL>BGIHLMLMN=R?HEEHPNIFNLM
;>M:D>G<:K>H?BG:G>MAB<:EF:GG>K

0MN=R,NF;>K
9999999999999999999999999999999999999999999999999999999999999999999999



9.0 
DRUG INFORMATION 
9.1 
TAS-102 

Other names for the drug:  MKB?ENKB=BG>$1":G=MBIBK:<BEAR=KH<AEHKB=> 


!E:LLB?B<:MBHGMRI>H?:@>GMGMBMNFHKGN<E>HLB=>


+H=>H?:<MBHG

10BL:GHO>EGN<E>HLB=>:GMBMNFHK:@>GM<HGLBLMBG@H?MKB?ENKB=BG>$1":G=MBIBK:<BE
AR=KH<AEHKB=>1.'$1"BLMA>:<MBO><HFIHG>GMH?10:G=BL=BK><MERBG<HKIHK:M>=
BGMH",E>:=BG@MH",=RL?NG<MBHG&HP>O>KPA>G$1"BLM:D>GHK:EERBMBLE:K@>ER
=>@K:=>=MH:GBG:<MBO>?HKF1.'IK>O>GMLMA>=>@K:=:MBHGH?$1"

$1":G:GMBG>HIE:LMB<:GMBF>M:;HEBM>BL:MARFB=RE:M>LRGMA:L>10BGAB;BMHK :L>=HG
IK><EBGB<:E=:M:$1":ELH:II>:KLMH;>BG<HKIHK:M>=BGMH=>HQRKB;HGN<E>B<:<B=",
.K>EBFBG:KRK>LNEMLLN@@>LMMA:MPA>G$1"BLBG<N;:M>=PBMA<:G<>K<>EEL:M:AB@A
<HG<>GMK:MBHG?HKLAHKMMBF>I>KBH=LBMBLI:LLBO>ERBG<HKIHK:M>=BGMHMA>",?K:<MBHGH?
MA><>EE:G=MA:MLN<A;>A:OBHKH?$1"BL=B??>K>GM?KHFMA>IKBF:KR<RMHMHQB<F><A:GBLF
H?$2:G=U=>HQR?ENHKHNKB=BG>$=2K=B>BGAB;BMBHGH?10



Storage and stability:  10BL?HKFNE:M>=:L:GBFF>=B:M>K>E>:L>?BEF
<H:M>=M:;E>MPAB<ABLLNIIEB>=BGLMK>G@MAL>QIK>LL>=:L$1"<HGM>GM


1A>F@PABM>KHNG=M:;E><HGM:BGLF@$1":G=F@1.':L:<MBO>
BG@K>=B>GML


1A>F@I:E>K>=KHNG=M:;E>M<HGM:BGLF@$1":G=F@1.':L:<MBO>
BG@K>=B>GML


 HMAM:;E>MLMK>G@MAL<HGM:BGE:<MHL>FHGHAR=K:M>IK>@>E:MBGBS>=LM:K<ALM>:KB<
:<B=AERIKHF>EEHL>MBM:GBNF=BHQB=>IHER>MARE>G>@ER<HE:G=F:@G>LBNF
LM>:K:M>1A>F@M:;E>M:ELH<HGM:BGLK>=?>KKB<HQB=>


0MHK>;>EHP\!\$


.KHMH<HE=HL>F@F=HL>


/HNM>H?:=FBGBLMK:MBHG?HKMABLLMN=RHK:E


Incompatibilities: .:MB>GMLLAHNE=GHMK><>BO>:GRHMA>KBGO>LMB@:MBHG:EHK:GR
HMA>K:GMB<:G<>KMA>K:IRBG<EN=BG@<A>FHMA>K:IRBFFNGHMA>K:IR;BHEH@B<:E
K>LIHGL>FH=B?B>KLHK>G=H<KBG>MA>K:IRPABE>K><>BOBG@10 


O:BE:;BEBMRIKHOB=>=;RLIHGLHKLI><B?RB?IKHOB=>=?K>>H?<A:K@>:LMABLA:L
BFIEB<:MBHGL?HKMA><HGL>GM?HKF


Side effects: />?>KMHMA>I:<D:@>BGL>KM?HK:<HFIK>A>GLBO>EBLMH?#L
!HFFHGLB=>>??><MLBG<EN=>MA>?HEEHPBG@,:NL>:OHFBMBG@=B:KKA>:
E>NDHI>GB:G>NMKHI>GB::G>FB:?:MB@N>EHLLH?:II>MBM>BG?><MBHG<HGLMBI:MBHG

0MN=R,NF;>K
9999999999999999999999999999999999999999999999999999999999999999999999


MAKHF;H<RMHI>GB::EHI><B:K:LAIKHM>BGNKB:A>:=:<A>:KMAK:E@B:
ARIH:E;NFBG>FB::GQB>MR>E>O:M>=EBO>K>GSRF>L
9.1.1 
Return and Retention of Study Drug (TAS-102) 
1A>=KN@PBEE;>=>LMKHR>=:<<HK=BG@MHMA>BGLMBMNMBHGULIHEB<R:G=BGLMKN<MBHGL


9.2 
Bevacizumab 

 >O:<BSNF:;O:LMBG%>G>GM><A0HNMA0:G$K:G<BL<H!20BL:K><HF;BG:GM
FHGH<EHG:E:GMB;H=RF;'@%:GMB;H=RMA:MA:L;>>G=>O>EHI>=?HKANF:GL?KHF
FNKBG>:GMB3#%$F;1A>FNKBG>F;BLLI><B?B<?HKANF:G3#%$
;BG=BG@MH:EEH?MA>DGHPGBLH?HKFLH?MA>EB@:G=>@3#%$3#%$3#%$
3#%$'MBL?HKF>=MAKHN@A:EM>KG:MBO>@>G>LIEB<BG@IK>O>GMBG@BM?KHF;BG=BG@MH
3#%$/LHGO:L<NE:K>G=HMA>EB:E<>EEL
 >O:<BSNF:;BL:LM:G=:K=$":IIKHO>=MK>:MF>GM?HK<HEHK><M:E<:G<>KMK>:MF>GM


a. Very Common Side Effects (reported in ≥10% of patients): 

Epistaxis 

Headache 

Hypertension 

Rhinitis 

Proteinuria 

Dry skin 

Rectal hemorrhage 

Taste alteration 

Lacrimation disorder 

Back pain 

Exfoliative dermatitis 




;+HLML>KBHNLLB=>>??><MLGHMEBD>ER7GHM<HFFHG8;NMLHF>MBF>L?:M:E


%'I>K?HK:MBHG0>KBHNL:G=LHF>MBF>L?:M:E%'I>K?HK:MBHGH<<NKL:M:AB@A>KBG<B=>G<>BG
O:LMBGMK>:M>=I:MB>GML<HFI:K>=MH<HGMKHEL1A>BG<B=>G<>LH?%'I>K?HK:MBHGK:G@>=
?KHFMH:<KHLL<EBGB<:ELMN=B>L


1A>BG<B=>G<>H?PHNG=A>:EBG@:G=LNK@B<:E<HFIEB<:MBHGLBG<EN=BG@L>KBHNL:G=?:M:E
<HFIEB<:MBHGLBLBG<K>:L>=BGO:LMBGMK>:M>=I:MB>GML


0>O>K>HK?:M:EA>FHKKA:@>BG<EN=BG@A>FHIMRLBL%';E>>=BG@A>F:M>F>LBL<>GMK:E
G>KOHNLLRLM>FA>FHKKA:@>>IBLM:QBL:G=O:@BG:E;E>>=BG@H<<NKK>=NIMH?HE=FHK>
?K>JN>GMERBGI:MB>GMLK><>BOBG@O:LMBG<KHLLBG=B<:MBHGLMA>BG<B=>G<>H?@K:=>≥
A>FHKKA:@B<>O>GML:FHG@I:MB>GMLK><>BOBG@O:LMBGK:G@>=?KHFMH

<-MA>KIHLLB;E>L>KBHNLLB=>>??><ML

0MN=R,NF;>K
9999999999999999999999999999999999999999999999999999999999999999999999



==BMBHG:EL>KBHNL:=O>KL>>O>GMLPBMABG<K>:L>=BG<B=>G<>BGMA>O:LMBGMK>:M>=:KFOL
<HGMKHEBG<EN=>=
o
%'O:@BG:E?BLMNE:>H<<NKK>=BGH?I:MB>GMLBG:<>KOB<:E<:G<>KMKB:E
o
&RI>KM>GLBHG@K:=>YY
o
.HLM>KBHKK>O>KLB;E>>G<>IA:EHI:MARLRG=KHF>./#0


'G?NLBHGK>:<MBHGLBG?NLBHGK>:<MBHGLPBMAMA>?BKLM=HL>H?O:LMBGP>K>NG<HFFHG
:G=L>O>K>K>:<MBHGLH<<NKK>=BGH?I:MB>GML

,HG%'?BLMNE:>BGMKB:EL:<KHLLO:KBHNLBG=B<:MBHGLBG:<>KOB<:E<:G<>KMKB:E

%'?BLMNE:>NIMHBGF>M:LM:MB<<HEHK><M:E<:G<>K:G=HO:KB:G<:G<>KI:MB>GML

KM>KB:EMAKHF;H>F;HEB<>O>GML@K:=>≥

.KHM>BGNKB:G>IAKHMB<LRG=KHF>








10.0 STATISTICAL CONSIDERATIONS 
10.1 
Study Design/Study Endpoints 

1ABLBL:GHI>GE:;>ELBG@E>:KFIKHLI><MBO>.A:L>''LMN=R0MN=R>G=IHBGML:K>
=>?BG>=:L?HEEHPL

.KH@K>LLBHG?K>>LNKOBO:E.$0.$0PBEE;>=>?BG>=:LMA>MBF>BG=:RL?KHFLMN=R>GMKR
NGMBEIKH@K>LLBHGHK=>:MA?KHF:GR<:NL>.:MB>GMLPAH:K>:EBO>:G=?K>>H?IKH@K>LLBHG
HGMA>=:M>H?<EHLBG@?HEEHPNIPBEE;><>GLHK>=HGMA>=:M>H?MA>E:LMMNFHK
:LL>LLF>GM

/>LIHGL>K:M>-;C><MBO>K>LIHGL>PBEEBG<EN=>/#!'01<KBM>KB:PBMA<HG?BKF>=
<E:LLB?B<:MBHGH?<HFIE>M>K>LIHGL>!/HKI:KMB:EK>LIHGL>./.:MB>GMLPAH:K>EHLM
MH?HEEHPNIPBMAHNM:O:EB=K>LIHGL>:LL>LLF>GMPBEE;><E:LLB?B>=:LGHM;>G>?BMBG@

!EBGB<:E;>G>?BM!E:LLB?B<:MBHGPBEE?HEEHPMA>/#!'01<KBM>KB::G=PBEE;>=>?BG>=:L
LN<<>LL?NE<HG?BKF>=<E:LLB?B<:MBHGH?LM:;E>=BL>:L>0"./HK!/.:MB>GMLPAH:K>
EHLMMH?HEEHPNIPBMAHNM:O:EB=K>LIHGL>:LL>LLF>GMPBEE;><E:LLB?B>=:LGHM;>G>?BMBG@

-O>K:EELNKOBO:E-0-0PBEE;>=>?BG>=:LMA>MBF>BG=:RL?KHFLMN=R>GMKRNGMBE=>:MA
.:MB>GMLPAH:K>:EBO>HGMA>=:M>H?<EHLBG@?HEEHPNIPBEE;><>GLHK>=HG=:M>H?E:LM
<HGM:<M

1BF>MHIKH@K>LLBHG11.11.PBEE;>=>?BG>=:LMA>MBF>BG=:RL?KHFLMN=R>GMKRNGMBE
IKH@K>LLBHG.:MB>GMLPAH:K>?K>>H?IKH@K>LLBHGHGMA>=:M>H?<EHLBG@?HEEHPNIPBEE;>
<>GLHK>=HGMA>=:M>H?MA>E:LMMNFHK:LL>LLF>GM.:MB>GMLPAH=B>=PBMAHNM
IKH@K>LLBHGPBEE;><>GLHK>=HGMA>BK=:M>H?=>:MA

"NK:MBHGH?=BL>:L><HGMKHE""!""!PBEE;>=>?BG>=:LMA>MBF>BG=:RL?KHFMA>=:M>
?BKLMGHM>=H?LM:;E>=BL>:L>HK;>MM>KNGMBEIKH@K>LLBHGHK=>:MA.:MB>GMLPAH:K>?K>>H?
IKH@K>LLBHGHGMA>=:M>H?<EHLBG@?HEEHPNIPBEE;><>GLHK>=HGMA>=:M>H?MA>E:LMMNFHK

0MN=R,NF;>K
9999999999999999999999999999999999999999999999999999999999999999999999


:LL>LLF>GM.:MB>GMLPAH=B>=PBMAHNMIKH@K>LLBHGPBEE;><>GLHK>=HGMA>BK=:M>H?
=>:MA

-;C><MBO>K>LIHGL>K:M>-//HO>K:EE-//PBEE;>=>?BG>=:LMA>LNFH?I:KMB:E
K>LIHGL>L./IENL<HFIE>M>K>LIHGL>L!/4A>G=>?BG>=BGMABLF:GG>K-//BL:
=BK><MF>:LNK>H?=KN@:GMBMNFHK:<MBOBMRPAB<A<:G;>>O:EN:M>=BG:LBG@E>:KFLMN=R

!HFIE>M>K>LIHGL>!/"BL:II>:K:G<>H?:EEM:K@>ME>LBHGLGRI:MAHEH@B<:EERFIA
GH=>LFNLMA:O>K>=N<MBHGBGLAHKM:QBLMHFF

.:KMB:EK>LIHGL>./ME>:LM:=><K>:L>BGMA>LNFH?=B:F>M>KLH?M:K@>ME>LBHGL
M:DBG@:LK>?>K>G<>MA>;:L>EBG>LNF=B:F>M>KL

"BL>:L><HGMKHEK:M>"!/"!/BL=>?BG>=:L<HFIE>M>K>LIHGL>
I:KMB:EK>LIHGL>

LM:;E>=BL>:L>:MFHGMAL:?M>KMK>:MF>GMBGBMB:MBHG

-O>K:EEK>LIHGL>K:M>-//$"A:L=>?BG>=-//:LMA>LNFH?I:KMB:EK>LIHGL>L
IENL<HFIE>M>K>LIHGL>L4A>G=>?BG>=BGMABLF:GG>K-//BL:=BK><MF>:LNK>H?=KN@
:GMBMNFHK:<MBOBMR
10.2 
Sample Size and Accrual 
1A>IKBF:KR>??B<:<R>G=IHBGMH?MABLLBG@E>:KFLMN=RBLIKH@K>LLBHG?K>>LNKOBO:E.$0
H?LPBM<AF:BGM>G:G<>PBMA10IENL >O:<BSNF:;?HEEHPBG@BG=N<MBHG
<A>FHMA>K:IR1A>GNEEARIHMA>LBLBLMA:MMA>F>=B:G.$0PBMAH;L>KO:MBHG:EHG>BLE>LL
MA:GFHGMALMA><AHB<>H?:F>=B:GH?FHGMAL?HKMA>F>=B:GH?H;L>KO:MBHGP:L
E:K@>ER;:L>=HGMA>K>LNEMH?!'/-MKB:E0BFD>GL*&>M:EE:G<>MPAB<ABL;R?:KMA>
;>LM:G=LMKHG@>LM>OB=>G<>P>A:O>BGMABLL>MMBG@'GMA>!'/-MKB:EMA>
H;L>KO:MBHG:KFA:=:F>=B:G.$0H?FHGMAL1A>FHGMALBL<AHL>GMH;>
<HGL>KO:MBO>BG<:E<NE:MBG@MA>L:FIE>LBS>LHMA:MMA>=B??>K>G<>H?MA>MK>:MF>GM>??><M
PBEE;>LF:EE>KPAB<APBEEK>LNEMBG:E:K@>KL:FIE>LBS>
1A>:EM>KG:MBO>ARIHMA>LBLBLMA:MMA>G>PMK>:MF>GMPBEE;>:;E>MHBG<K>:L>MA>.$0MH
FHGMA1A>L:FIE>LBS><:E<NE:MBHGBL;:L>=HGMA>:LLNFIMBHGH?:G>QIHG>GMB:E
=BLMKB;NMBHGH?MA>.$0MBF>.:MB>GML>GM>KBG@MA>MKB:E:K>:LLNF>=MH?HEEHP:.HBLLHG
=BLMKB;NMBHGMHM:EH?I:MB>GMLPBEE;>G>>=>=:M:LB@GB?B<:G<>E>O>EMHIKHOB=>:M
E>:LMIHP>KMHM>LMMA>F>=B:G.$0=B??>K>G<>H?FHGMAOLFHGMA?HK:LB=>=
M>LM:LLNFBG@MA:MMA>:<<KN:EMBF>BLFHGMAL:G=FBGBFNF?HEEHPNIMBF>BL
FHGMAL1A>K>?HK>LMN=R=NK:MBHGPBEEKNG?HK:FBGBFNFH?FHGMAL'?P>:<<HNGM?HK:
H?I:MB>GM=KHIHNMK:M>MA>GI:MB>GMLPBEE;>G>>=>=MH>GKHEEMHMA>LMN=R
.:MB>GMLPBEE;>?HEEHP>=?HK:F:QBFNFH?R>:KLFHGMALHKNGMBEI:MB>GM=>:MA
10.3 
Data Analyses Plans 
">L<KBIMBO>LM:MBLMB<LPBEE;>NL>=MHLNFF:KBS>I:MB>GMLU=>FH@K:IAB<L:G=:EEE:;HK:MHKR
I:K:F>M>KL1HQB<BMR:G=#LPBEE;>LNFF:KBS>=;RMA>@K:=>:G=?K>JN>G<R:<<HK=BG@
MHMA>!1!#?HK:EEMK>:M>=LN;C><ML$HKI:MB>GMLPAHPBEE;>K>FHO>=?HKMHQB<BMRMA>R
PBEE;>BG<EN=>=?HKLNFF:KRH?MA>#;NMGHM?HKMA>.$0>O:EN:MBHG1HM>LMMA>GNEE
ARIHMA>LBLH?FHGMAOLMA>:EM>KG:MBO>H?:ME>:LMFHGMAH?F>=B:G.$0:HG>
L:FIE>EH@K:GDM>LMPBEE;>NL>=BGPAB<AMA>M>LMLM:MBLMB<PBEE?HEEHP:<ABLJN:K>
=BLMKB;NMBHGPBMA=>@K>>H??K>>=HF1A>MBF>MH>O>GM>G=IHBGML.$0-011.:G=
""!PBEE;>>LMBF:M>=NLBG@MA>):IE:G+>B>KF>MAH=#LMBF:M>LH?MA>K:M>L-//:G=
"!/PBEE;>IK>L>GM>=PBMAMA>BK<HG?B=>G<>BGM>KO:EL

11.0 STUDY MANAGEMENT 

0MN=R,NF;>K
9999999999999999999999999999999999999999999999999999999999999999999999


11.1 
Conflict of Interest 

GRBGO>LMB@:MHKPAHA:L:<HG?EB<MH?BGM>K>LMPBMAMABLLMN=RI:M>GMHPG>KLABIKHR:EMB>L
HK?BG:G<B:E@:BG@K>:M>KMA:GMA>FBGBFNF:EEHP:;E>;RMA>BKBGLMBMNMBHG>M<FNLMA:O>
MA><HG?EB<MK>OB>P>=;R'/ EEBGO>LMB@:MHKLPBEE?HEEHPMA>2GBO>KLBMR<HG?EB<MH?BGM>K>LM
IHEB<R
11.2 
Institutional Review Board (IRB) Approval and Consent 
'MBL>QI><M>=MA:MMA>'/ PBEEA:O>MA>IKHI>KK>IK>L>GM:MBHG:G=?NG<MBHGBG:<<HK=:G<>
PBMA?>=>K:EERF:G=:M>=K>@NE:MBHGL1A>'/ LAHNE=:IIKHO>MA><HGL>GM?HKF:G=
IKHMH<HE

'GH;M:BGBG@:G==H<NF>GMBG@BG?HKF>=<HGL>GMMA>BGO>LMB@:MHKLAHNE=<HFIERPBMAMA>
:IIEB<:;E>K>@NE:MHKRK>JNBK>F>GML:G=LAHNE=:=A>K>MH%HH=!EBGB<:E.K:<MB<>%!.
:G=MH>MAB<:EIKBG<BIE>LMA:MA:O>MA>BKHKB@BGBGMA>"><E:K:MBHGH?&>ELBGDB


 >?HK>K><KNBMF>GM:G=>GKHEEF>GMHGMHMABLLMN=RMA>I:MB>GMPBEE;>@BO>G:?NEE
>QIE:G:MBHGH?MA>LMN=R:G=PBEE;>@BO>GMA>HIIHKMNGBMRMHK>OB>PMA><HGL>GM?HKF
#:<A<HGL>GM?HKFFNLMBG<EN=>:EEMA>K>E>O:GM>E>F>GML<NKK>GMERK>JNBK>=;RMA>$"
/>@NE:MBHGL:G=EH<:EHKLM:M>K>@NE:MBHGL-G<>MABL>LL>GMB:EBG?HKF:MBHGA:L;>>G
IKHOB=>=MHMA>I:MB>GM:G=MA>BGO>LMB@:MHKBL:LLNK>=MA:MMA>I:MB>GMNG=>KLM:G=LMA>
BFIEB<:MBHGLH?I:KMB<BI:MBG@BGMA>LMN=RMA>I:MB>GMPBEE;>:LD>=MH@BO><HGL>GMMH
I:KMB<BI:M>BGMA>LMN=R;RLB@GBG@:G'/ :IIKHO>=<HGL>GM?HKF

.KBHKMH:I:MB>GMULI:KMB<BI:MBHGBGMA>MKB:EMA>PKBMM>GBG?HKF>=<HGL>GM?HKFLAHNE=;>
LB@G>=:G=I>KLHG:EER=:M>=;RMA>I:MB>GM:G=;RMA>I>KLHGPAH<HG=N<M>=MA>
BG?HKF>=<HGL>GM=BL<NLLBHG
11.3 
Required Documentation 
 >?HK>MA>LMN=R<:G;>BGBMB:M>=:M:GRLBM>MA>?HEEHPBG@=H<NF>GM:MBHGFNLM;>
IKHOB=>=MHMA>/>L>:K<A-??B<>


<HIRH?MA>H??B<B:E'/ :IIKHO:EE>MM>K?HKMA>IKHMH<HE:G=BG?HKF>=<HGL>GM

'/ F>F;>KLABIEBLM

!3L:G=F>=B<:EEB<>GLNK>?HKMA>IKBG<BI:EBGO>LMB@:MHK:G=:GR:LLH<B:M>
BGO>LMB@:MHKLPAHPBEE;>BGOHEO>=BGMA>LMN=R

$HKF$":IIKHIKB:M>ER?BEE>=HNM:G=LB@G>=PBMA:IIKHIKB:M>=H<NF>GM:MBHG

<HIRH?MA>'/ :IIKHO>=<HGL>GM?HKF

!.:G=!*'*:;HK:MHKR<>KMB?B<:MBHGGNF;>KL:G=BGLMBMNMBHGE:;GHKF:EO:EN>L

#Q><NM>=<EBGB<:EK>L>:K<A<HGMK:<M
11.4 
Registration Procedures 
EEI:MB>GMLFNLM;>K>@BLM>K>=PBMAMA>%>HK@>MHPG!/+-!EBGB<:E/>L>:K<A
+:G:@>F>GM-??B<>;>?HK>>GKHEEF>GMMHLMN=R.KBHKMHK>@BLMK:MBHG>EB@B;BEBMR<KBM>KB:
FNLM;><HG?BKF>=PBMAMA>%>HK@>MHPG2GBO>KLBMR+NEMB0BM>0MN=R!HHK=BG:MHK
EELMN=R=H<NF>GMLPBEE;>K>=:<M>=;RMA>EH<:ELBM>MHK>FHO>.KHM><M>=&>:EMA
'G?HKF:MBHG:L=>?BG>=;R&'.:G=PBEE;>E:;>E>=PBMALN;C><MBGBMB:EL:G=GNF;>K
1A>L>F:M>KB:ELPBEE;>NIEH:=>=;RMA>EH<:ELBM>MH:L><NK>I:LLPHK=IKHM><M>=<EHN=
;:L>=%>HK@>MHPG HQIHKM:E<<>LLMH HQPBEE;>IKHOB=>=;R%>HK@>MHPG*!!!
LM:??PAHPBEEK><>BO>:G=K>OB>PMA>LHNK<>=H<NF>GML:G=<HG?BKF>EB@B;BEBMR1A>EH<:E
LBM>PBEEK><>BO>PKBMM>GGHMB?B<:MBHG?KHF%>HK@>MHPG*!!!K>@:K=BG@>EB@B;BEBMR

0MN=R,NF;>K
9999999999999999999999999999999999999999999999999999999999999999999999



11.5 
 Data Management  
1A>%>HK@>MHPG*HF;:K=B!HFIK>A>GLBO>!:G<>K!>GM>KPBEE;>K>LIHGLB;E>?HKMA>
=:M::G=L:?>MRFHGBMHKBG@H?MABLFNEMBLBM>MKB:ELMABLLMN=RBL:GBGO>LMB@:MHKBGBMB:M>=
LMN=R.A:L>''LMN=RNMBEBSBG@:GHG$":IIKHO>==KN@?HKPAB<AMA>.'AHE=LMA>',"BM
BL<HGLB=>K>=:FH=>K:M>KBLDLMN=RPAB<AK>JNBK>LK>:EMBF>FHGBMHKBG@;RMA>.':G=
LMN=RM>:F:G=L>FB:GGN:EK>OB>PL;RMA>*!!!":M::G=0:?>MR+HGBMHKBG@
!HFFBMM>>"0+!

1A>.KBG<BI:E'GO>LMB@:MHK:G=MA>!H'GO>LMB@:MHKLPBEEK>OB>PMA>=:M:BG<EN=BG@L:?>MR
FHGBMHKBG@:MMA>BKP>>DERBGLMBMNMBHG;:L>==BL>:L>@KHNIF>>MBG@L:G=HGFHGMAER
=BL>:L>@KHNIM>E><HG?>K>G<>L

0>KBHNL=O>KL>#O>GML0#L:K>K>JNBK>=MH;>K>IHKM>=MHMA>'/ :LI>KMA>EH<:E
IHEB<R :L>=HG0#LMA>'/ K>M:BGLMA>:NMAHKBMRMHLNLI>G=?NKMA>K:<<KN:EI>G=BG@
FHK>=>M:BE>=K>IHKMBG@:G=HKFH=B?B<:MBHGLMH?NKMA>KK>=N<>KBLD:G=F:QBFBS>MA>
L:?>MRH?I:KMB<BI:MBG@I:MB>GML

.KH@K>LLHGMA>MKB:E:G=MA>MHQB<BMB>L>QI>KB>G<>=PBEE;>K>OB>P>=;RMA>*!!!":M:
:G=0:?>MR+HGBMHKBG@!HFFBMM>>>O>KRFHGMAL?KHFMA>MBF>MA>?BKLMI:MB>GMBL
>GKHEE>=HGMA>LMN=R/>LNEMLH?MA>"0+!F>>MBG@LPBEE;>?HKP:K=>=MHMA>'/ PBMA
K><HFF>G=:MBHGLK>@:K=BG@G>>=?HKLMN=R<EHLNK>

"0+!K><HFF>G=:MBHGLLAHNE=;>;:L>=GHMHGERHGK>LNEML?HKMA>MKB:E;>BG@
FHGBMHK>=:LP>EE:LHG=:M::O:BE:;E>MHMA>"0+!?KHFHMA>KLMN=B>L'MBLMA>
K>LIHGLB;BEBMRH?MA>.'MH>GLNK>MA:MMA>"0+!BLD>IM:IIKBL>=H?GHG<HG?B=>GMB:E
K>LNEML?KHFK>E:M>=LMN=B>LMA:M;><HF>:O:BE:;E>'MBLMA>K>LIHGLB;BEBMRH?MA>"0+!MH
=>M>KFBG>MA>>QM>GMMHPAB<AMABLBG?HKF:MBHGBLK>E>O:GMMHBML=><BLBHGLK>E:M>=MHMA>
LI><B?B<MKB:E;>BG@FHGBMHK>=

PKBMM>G<HIRH?MA>"0+!K><HFF>G=:MBHGLPBEE;>@BO>GMHMA>MKB:E.':G=MA>'/ '?
MA>"0+!K><HFF>G=L:LMN=R<A:G@>?HKI:MB>GML:?>MRHK>??B<:<RK>:LHGLMA>MKB:E.'
FNLM:<MMHBFIE>F>GMMA><A:G@>:L>QI>=BMBHNLER:LIHLLB;E>'GMA>NGEBD>ER>O>GMMA:M
MA>MKB:E.'=H>LGHM<HG<NKPBMAMA>"0+!K><HFF>G=:MBHGLMA>GMA>*!!!LLH<B:M>
"BK><MHKH?!EBGB<:E/>L>:K<AFNLM;>BG?HKF>=H?MA>K>:LHG?HKMA>=BL:@K>>F>GM1A>
MKB:E.'"0+!!A:BK:G=MA>*!!!"?HK!EBGB<:E/>L>:K<APBEE;>K>LIHGLB;E>?HK
K>:<ABG@:FNMN:EER:<<>IM:;E>=><BLBHG:;HNMMA>LMN=R:G=IKHOB=BG@=>M:BELH?MA:M
=><BLBHGMHMA>'/ !HG?B=>GMB:EBMRFNLM;>IK>L>KO>==NKBG@MA>L>=BL<NLLBHGL
&HP>O>KBGLHF><:L>LK>E>O:GM=:M:F:R;>LA:K>=PBMAHMA>KL>E><M>=MKB:E
BGO>LMB@:MHKL:G=LM:??MHL>>D:=OB<>MH:LLBLMBGK>:<ABG@:FNMN:EER:<<>IM:;E>
=><BLBHG

'?:K><HFF>G=:MBHGBLF:=>MH<A:G@>:MKB:E?HKK>:LHGLHMA>KMA:GI:MB>GML:?>MRHK
>??B<:<RMA>"0+!PBEEIKHOB=>:G:=>JN:M>K:MBHG:E>?HKBML=><BLBHG'?MA>"0+!
K><HFF>G=LMA:MMA>MKB:E;><EHL>=?HK:GRK>:LHGMA>K><HFF>G=:MBHGPBEE;>K>OB>P>=
;RMA>LLH<B:M>"BK><MHK?HK!EBGB<:E/>L>:K<A:M%*!!!NMAHKBMRMH<EHL>:MKB:E?HK
L:?>MRK>:LHGLEB>LPBMAMA>'/ PBMAMA>:;HO>=>L<KB;>=BGINM?KHF"0+!:G=MA>"
?HK!EBGB<:E/>L>:K<A




0MN=R,NF;>K
9999999999999999999999999999999999999999999999999999999999999999999999


11.6 
Adherence to the Protocol 
#Q<>IM?HK:G>F>K@>G<RLBMN:MBHGBGPAB<AIKHI>K<:K>?HKMA>IKHM><MBHGL:?>MR:G=
P>EE;>BG@H?MA>LMN=RI:MB>GMK>JNBK>L:EM>KG:MBO>MK>:MF>GMMA>LMN=RLA:EE;>
<HG=N<M>=>Q:<MER:L=>L<KB;>=BGMA>:IIKHO>=IKHMH<HE
11.6.1 Emergency Modifications 
'GO>LMB@:MHKLF:RBFIE>F>GM:=>OB:MBHG?KHFHK:<A:G@>H?MA>IKHMH<HEMH>EBFBG:M>
:GBFF>=B:M>A:S:K=LMHMKB:ELN;C><MLPBMAHNMIKBHK'/ :IIKHO:E

$HK:GRLN<A>F>K@>G<RFH=B?B<:MBHGBFIE>F>GM>=:'/ FH=B?B<:MBHG?HKFFNLM;>
<HFIE>M>=PBMABG?BO>;NLBG>LL=:RLH?F:DBG@MA><A:G@>
11.6.2 Single Patient/Subject Exceptions 
GRK>JN>LMMH>GKHEE:LBG@E>LN;C><MPAH=H>LGHMF>>M:EEMA>>EB@B;BEBMR<KBM>KB:H?MABL
LMN=RK>JNBK>LMA>:IIKHO:EH?MA>.KBG<BI:E'GO>LMB@:MHK:G=MA>'/ 
11.6.3 Other Protocol Deviations/Violations 
EEHMA>KIE:GG>==>OB:MBHGL?KHFMA>IKHMH<HEFNLMA:O>IKBHK:IIKHO:E;RMA>.KBG<BI:E
'GO>LMB@:MHK:G=MA>'/ <<HK=BG@MHMA>'/ :IKHMH<HE=>OB:MBHGBL:GRNGIE:GG>=
O:KB:G<>?KHF:G'/ :IIKHO>=IKHMH<HEMA:M

'L@>G>K:EERGHM>=HKK><H@GBS>=:?M>KBMH<<NKL

&:LGHLN;LM:GMBO>>??><MHGMA>KBLDLMHK>L>:K<AI:KMB<BI:GML

&:LGHLN;LM:GMBO>>??><MHGMA>L<B>GMB?B<BGM>@KBMRH?MA>K>L>:K<AIE:GHKMA>O:EN>
H?MA>=:M:<HEE><M>=

"B=GHMK>LNEM?KHFPBEE?NEHKDGHPBG@FBL<HG=N<MHGMA>I:KMH?MA>BGO>LMB@:MHKL

GNGIE:GG>=IKHMH<HEO:KB:G<>BL<HGLB=>K>=:OBHE:MBHGB?MA>O:KB:G<>

&:LA:KF>=HKBG<K>:L>=MA>KBLDH?A:KFMHHG>HKFHK>K>L>:K<AI:KMB<BI:GML

&:L=:F:@>=MA>L<B>GMB?B<BGM>@KBMRH?MA>=:M:<HEE><M>=?HKMA>LMN=R

/>LNEML?KHFPBEE?NEHKDGHPBG@FBL<HG=N<MHGMA>I:KMH?MA>BGO>LMB@:MHKL

">FHGLMK:M>LL>KBHNLHK<HGMBGNBG@GHG<HFIEB:G<>PBMA?>=>K:EK>@NE:MBHGL0M:M>
E:PLHK2GBO>KLBMRIHEB<B>L

'?:=>OB:MBHGHKOBHE:MBHGH<<NKLPBMAHNMIKBHK:IIKHO:E?KHFMA>.KBG<BI:E'GO>LMB@:MHK
IE>:L>?HEEHPMA>@NB=>EBG>L;>EHP


Protocol Deviations: .>KLHGG>EPBEEK>IHKMMH:GRLIHGLHKHK=:M::G=L:?>MRFHGBMHKBG@
<HFFBMM>>BG:<<HK=:G<>PBMAMA>BKIHEB<B>L">OB:MBHGLLAHNE=;>LNFF:KBS>=:G=
K>IHKM>=MHMA>'/ :MMA>MBF>H?<HGMBGNBG@K>OB>P

Protocol Violations: 3BHE:MBHGLLAHNE=;>K>IHKM>=;RLMN=RI>KLHGG>EPBMABGHG>
P>>DH?MA>BGO>LMB@:MHK;><HFBG@:P:K>H?MA>>O>GMNLBG@MA>L:F>'/ HGEBG>
F><A:GBLFNL>=MHK>IHKM2G:GMB<BI:M>=.KH;E>FL


Protocol Deviations: #:<A<>GM>KLAHNE=>GM>KIHEB<R

Protocol Violations: 3BHE:MBHGLLAHNE=;>K>IHKM>=;RLMN=RI>KLHGG>EPBMABGHG>
P>>DH?MA>BGO>LMB@:MHK;><HFBG@:P:K>H?MA>>O>GMNLBG@MA>L:F>'/ HGEBG>
F><A:GBLFNL>=MHK>IHKM2G:GMB<BI:M>=.KH;E>FL

0MN=R,NF;>K
9999999999999999999999999999999999999999999999999999999999999999999999


11.7 
Amendments to the Protocol 
-GERMA>*>:=.'F:R:F>G=MA>IKHMH<HE1A>K>BLHGERHG>O>KLBHGH?MA>IKHMH<HE
:<MBO>:M:GRHG>MBF>0AHNE=:F>G=F>GMLMHMA>IKHMH<HE;>K>JNBK>=MA>
:F>G=F>GMLPBEE;>HKB@BG:M>=:G==H<NF>GM>=;RMA>*>:=.KBG<BI:E'GO>LMB@:MHK:M
%>HK@>MHPG2GBO>KLBMR'MLAHNE=:ELH;>GHM>=MA:MPA>G:G:F>G=F>GMMHMA>IKHMH<HE
LN;LM:GMB:EER:EM>KLMA>LMN=R=>LB@GHKMA>IHM>GMB:EKBLDMHMA>I:MB>GM:K>OBL>=<HGL>GM
?HKFFB@AM;>K>JNBK>=

1A>PKBMM>G:F>G=F>GM:G=B?K>JNBK>=MA>:F>G=>=<HGL>GM?HKFFNLM;>:IIKHO>=;R
MA>'/ H?K><HK=:MLMN=RLBM>IKBHKMHBFIE>F>GM:MBHG
11.8 
Record Retention 
0MN=R=H<NF>GM:MBHGBG<EN=>L:EE!:L>/>IHKM$HKFL=:M:<HKK><MBHG?HKFLHKJN>KB>L
LHNK<>=H<NF>GML0IHGLHK'GO>LMB@:MHK<HKK>LIHG=>G<>FHGBMHKBG@EH@LE>MM>KL:G=
K>@NE:MHKR=H<NF>GML>@IKHMH<HE:G=:F>G=F>GML'/ <HKK>LIHG=>G<>:G=
:IIKHO:ELB@G>=I:MB>GM<HGL>GM?HKFL

0HNK<>=H<NF>GMLBG<EN=>:EEK><HK=BG@LH?H;L>KO:MBHGLHKGHM:MBHGLH?<EBGB<:E:<MBOBMB>L
:G=:EEK>IHKML:G=K><HK=LG><>LL:KR?HKMA>>O:EN:MBHG:G=K><HGLMKN<MBHGH?MA><EBGB<:E
K>L>:K<ALMN=R

%HO>KGF>GM:@>G<RK>@NE:MBHGL:G==BK><MBO>LK>JNBK>MA:M:EELMN=R=H<NF>GM:MBHG
I>KM:BGBG@MHMA><HG=N<MH?:<EBGB<:EMKB:EFNLM;>K>M:BG>=;RMA>LMN=RBGO>LMB@:MHK'G
MA><:L>H?:LMN=RPBMA:=KN@L>>DBG@K>@NE:MHKR:IIKHO:E:G=F:KD>MBG@MA>L>
=H<NF>GMLLA:EE;>K>M:BG>=?HK:ME>:LMMPHR>:KL:?M>KMA>E:LM:IIKHO:EH?F:KD>MBG@
:IIEB<:MBHGBG:G'GM>KG:MBHG:E!HG?>K>G<>HG&:KFHGBS:MBHG'!&K>@BHG'G:EEHMA>K
<:L>LLMN=R=H<NF>GMLLAHNE=;>D>IMHG?BE>NGMBEMAK>>R>:KL:?M>KMA><HFIE>MBHG:G=
?BG:ELMN=RK>IHKMH?MABLBGO>LMB@:MBHG:ELMN=R
11.9 
Obligations of Investigators 
1A>.KBG<BI:E'GO>LMB@:MHKBLK>LIHGLB;E>?HKMA><HG=N<MH?MA><EBGB<:EMKB:E:MMA>LBM>BG
:<<HK=:G<>PBMA1BME>!$/I:KML:G=H?MA>!H=>H?$>=>K:E/>@NE:MBHGL:G=HK
MA>"><E:K:MBHGH?&>ELBGDB1A>.KBG<BI:E'GO>LMB@:MHKFNLM:LLNK>MA:M:EELMN=RLBM>
I>KLHGG>EBG<EN=BG@LN;BGO>LMB@:MHKL:G=HMA>KLMN=RLM:??F>F;>KL:=A>K>MHMA>
LMN=RIKHMH<HE:G=:EE$"%!.,!'K>@NE:MBHGL:G=@NB=>EBG>LK>@:K=BG@<EBGB<:EMKB:EL
;HMA=NKBG@:G=:?M>KLMN=R<HFIE>MBHG

1A>.KBG<BI:E'GO>LMB@:MHK:M>:<ABGLMBMNMBHGHKLBM>PBEE;>K>LIHGLB;E>?HK:LLNKBG@MA:M:EE
MA>K>JNBK>==:M:PBEE;><HEE><M>=:G=>GM>K>=HGMHMA>!:L>/>IHKM$HKFL'GO>LMB@:MHK
HO>KLB@AM:<KHLLFNEMBIE>LBM>LPBEE;><HG=N<M>=OB:K>@NE:KERH<<NKKBG@<HG?>K>G<><:EEL
MHBG<EN=>K>OB>PH?>GKHEEF>GM:G=L:?>MR=:M:MMA><HFIE>MBHGH?MA>LMN=R:EE<:L>
K>IHKM?HKFLPBEE;>K>OB>P>=;RMA>.KBG<BI:E'GO>LMB@:MHK:G=PBEEK>JNBK>ABLA>K?BG:E
LB@G:MNK>MHO>KB?RMA>:<<NK:<RH?MA>=:M: 

0MN=R,NF;>K
9999999999999999999999999999999999999999999999999999999999999999999999



12.0 REFERENCES 

(>F:E0BF:K=#."HK>EE!>M:EGGN:E/>IHKMMHMA>,:MBHGHGMA>0M:MNLH?!:G<>K
 ?>:MNKBG@ MA> ;NK=>G :G= MK>G=L BG ANF:G I:IBEEHF:OBKNL &.3:LLH<B:M>= <:G<>KL :G= &.3
O:<<BG:MBHG<HO>K:@>E>O>EL(,:ME!:G<>KBGLM

KGHE= " 0M>BG  ,>P =>O>EHIF>GML BG MA> L><HG=EBG> MK>:MF>GM H? F>M:LM:MB< <HEHK><M:E
<:G<>KIHM>GMB:EIE:<>BGMA>K:IR"KN@L

0<A>BMA:N>K 4 /HL>G & )HKG>D %3 >M :E /:G=HFBL>= <HFI:KBLHG H? <HF;BG:MBHG
<A>FHMA>K:IR IENL LNIIHKMBO> <:K> PBMA LNIIHKMBO> <:K> :EHG> BG I:MB>GML PBMA F>M:LM:MB< <HEHK><M:E
<:G<>K +(

,HK=B<%:LMKHBGM>LMBG:E1NFHK=CNO:GM1A>K:IR%KHNI#QI><M:G<RHKIKBF:KR<A>FHMA>K:IRBG
I:MB>GMLPBMA:=O:G<>=:LRFIMHF:MB<<HEHK><M:E<:G<>K:K:G=HFBS>=MKB:E(!EBG-G<HE


0BFFHG=L .! .:EEB:MBO> <A>FHMA>K:IR ?HK :=O:G<>= <HEHK><M:E <:G<>K LRLM>FB< K>OB>P :G=
F>M::G:ERLBL!HEHK><M:E!:G<>K!HEE:;HK:MBO>%KHNI +(

%KHMA>R  3:G !NML>F # 0H;K>KH  >M :E />@HK:?>GB; FHGHMA>K:IR ?HK IK>OBHNLER MK>:M>=
F>M:LM:MB<<HEHK><M:E<:G<>K!-//#!1:GBGM>KG:MBHG:EFNEMB<>GMK>K:G=HFBL>=IE:<>;H<HGMKHEE>=
IA:L>MKB:E*:G<>M(:G

">%K:FHGM$B@>K0>RFHNK+>M:E*>N<HOHKBG:G=?ENHKHNK:<BEPBMAHKPBMAHNM-Q:EBIE:MBG
:L?BKLMEBG>MK>:MF>GMBG:=O:G<>=<HEHK><M:E<:G<>K(!EBG-G<HE

%HE=;>K@/+0:K@>GM"(+HKMHG/$>M:E/:G=HFBS>=<HGMKHEE>=MKB:EH?K>=N<>==HL>;HENL
?ENHKHN:<BEIENLE>N<HOHKBG:G=BKBGHM><:GHKBG?NL>=?ENHKHNK:<BEIENLE>N<HOHKBG:G=-Q:EBIE:MBGBGI:MB>GML
PBMAIK>OBHNLERNGMK>:M>=F>M:LM:MB<<HEHK><M:E<:G<>K:,HKMAF>KB<:G'GM>K@KHNI1KB:E(!EBG-G<HE


"B:S/N;BH # 1:;>KG>KH ( %_F>S#LI:^:  >M :E .A:L> ''' LMN=R H? <:I><BM:;BG> IENL
HQ:EBIE:MBG<HFI:K>=PBMA<HGMBGNHNLBG?NLBHG?ENHKHNK:<BEIENLHQ:EBIE:MBG:L?BKLMEBG>MA>K:IRBGF>M:LM:MB<
<HEHK><M:E<:G<>K?BG:EK>IHKMH?MA>0I:GBLA!HHI>K:MBO>%KHNI?HKMA>1K>:MF>GMH?"B@>LMBO>1NFHKL
1KB:E(!EBG-G<HEY

1HNKGB@:G=!G=K>1<ABEE>#>M:E$-*$'/'?HEEHP>=;R$-*$-5HKMA>K>O>KL>L>JN>G<>
BG:=O:G<>=<HEHK><M:E<:G<>K:K:G=HFBS>=%#/!-/LMN=R(!EBG-G<HEY

"HNBEE:K=(6!NGGBG@A:F"/HMA">M:E'KBGHM><:G<HF;BG>=PBMA?ENHKHNK:<BE<HFI:K>=PBMA
?ENHKHNK:<BE:EHG>:L?BKLMEBG>MK>:MF>GM?HKF>M:LM:MB<<HEHK><M:E<:G<>K:FNEMB<>GM>KK:G=HFBL>=MKB:E
*:G<>MY

$N<AL !0 +:KLA:E (* +BM<A>EE # >M :E  K:G=HFBS>= <HGMKHEE>= MKB:E H? BKBGHM><:G IENL
BG?NLBHG:E;HENLHKHK:E?ENHKHIRKBFB=BG>LBG?BKLMEBG>MK>:MF>GMH?F>M:LM:MB<<HEHK><M:E<:G<>KK>LNEML
?KHFMA> '!!!LMN=R(!EBG-G<HEY

$:E<HG>/B<<B0 KNG>MMB'>M:E.A:L>'''MKB:EH?BG?NLBHG:E?ENHKHNK:<BEE>N<HOHKBGHQ:EBIE:MBG
:G=BKBGHM><:G$-*$-5'/'<HFI:K>=PBMABG?NLBHG:E?ENHKHNK:<BEE>N<HOHKBG:G=BKBGHM><:G$-*$'/'
:L?BKLMEBG>MK>:MF>GM?HKF>M:LM:MB<<HEHK><M:E<:G<>KMA>%KNIIH-G<HEH@B<H,HK=-O>LM(!EBG-G<HE


%KHMA>R  &><KB<D ## +:LL /" >M :E />LIHGL>BG=>I>G=>GM LNKOBO:E ;>G>?BM BG F>M:LM:MB<
<HEHK><M:E<:G<>K:<HFI:K:MBO>:G:ERLBLH?,:G=3$(!EBG-G<HE

0B>G:0.>>M>KL+3:G!NML>F#>M:ELLH<B:MBHGH?IKH@K>LLBHG?K>>LNKOBO:EPBMAI:MB>GM
K>IHKM>=HNM<HF>L:G=LNKOBO:EK>LNEML?KHF:K:G=HFBL>=IA:L>MKB:EH?I:GBMNFNF:; K(!:G<>K


%B>LL>G!*:N;>G=>K/.GD>KLM".>M:E.KH@K>LLBHG?K>>LNKOBO:E:L:LNKKH@:M>>G=IHBGM
?HKF>=B:GHO>K:EELNKOBO:EBGF>M:LM:MB<<HEHK><M:E<:G<>KEBM>K:MNK>;:L>=:G:ERLBL?KHFK:G=HFBS>=
?BKLMEBG>MKB:EL!EBG!:G<>K/>L

6:E<BG02LEN/":G>$>M:E >O:<BSNF:; #3IENL<:I><BM:;BG>:LF:BGM>G:G<>MA>K:IR
:?M>K BGBMB:E MK>:MF>GM PBMA  #3 IENL 5#*-5 BG IK>OBHNLER NGMK>:M>= I:MB>GML PBMA F>M:LM:MB< <HEHK><M:E
<:G<>K F:MNK> =:M: ?KHF 01-. :G= %- : IA:L> ''' K:G=HFBS>= FNEMB<>GM>K LMN=R ( !EBG -G<HE 
LNIIE:;LMK

0MN=R,NF;>K
9999999999999999999999999999999999999999999999999999999999999999999999



"]:S/N;BH#%_F>S#LI:^:+:LLNM] >M:E$BKLMEBG>5#*-5IENL;>O:<BSNF:;?HEEHP>=
;R 5#*-5 IENL ;>O:<BSNF:; HK LBG@E>:@>GM ;>O:<BSNF:; :L F:BGM>G:G<> MA>K:IR BG I:MB>GML PBMA
F>M:LM:MB<<HEHK><M:E<:G<>KMA>IA:L>'''+!/-11"LMN=R-G<HEH@BLM

)H>;>KE>" >MMB<A>K"!3HG+HHL/>M:E >O:<BSNF:;<HGMBGN:MBHGO>KLNLGH<HGMBGN:MBHG
:?M>K ?BKLMEBG> <A>FH;>O:<BSNF:; MA>K:IR BG I:MB>GML PBMA F>M:LM:MB< <HEHK><M:E <:G<>K : K:G=HFBS>=
IA:L>'''GHGBG?>KBHKBMRMKB:E0))(!EBG-G<HELNIIE:;LMK

1O>BM)+%NK>G1%EBF>EBNL >M:E.A:L>'''MKB:EH?<>MNQBF:;PBMA<HGMBGNHNLHKBGM>KFBMM>GM
?ENHKHNK:<BE E>N<HOHKBG :G= -Q:EBIE:MBG ,HK=B< $*-5 O>KLNL $*-5 :EHG> BG ?BKLMEBG> MK>:MF>GM H?
F>M:LM:MB<<HEHK><M:E<:G<>KMA>,-/"'!3''LMN=R(!EBG-G<HE

)HHIF:G + >M :E $BG:E K>LNEML :G= LN;@KHNI :G:ERL>L H? MA> IA:L>  !'/- LMN=R
+:BGM>G:G<>MK>:MF>GMPBMA<:I><BM:;BG>:G=;>O:<BSNF:;O>KLNLH;L>KO:MBHG:?M>KBG=N<MBHGMK>:MF>GM
PBMA <A>FHMA>K:IR :G= ;>O:<BSNF:; BG F>M:LM:MB< <HEHK><M:E <:G<>K F!/! :;LMK:<M ( !EBG -G<HE
LNIIE:;LMK* 

KGHE="%K:>O>G2*>K<A>GFNEE>K!>M:E+:BGM>G:G<>LMK:M>@RPBMA?ENHKHIRKBFB=BG>L$.
IENL >O:<BSNF:; >O >O:EHG>HKGHMK>:MF>GM?HEEHPBG@:LM:G=:K=<HF;BG:MBHGH?$.HQ:EBIE:MBG
-Q:G= >O:L?BKLMEBG>MK>:MF>GM?HKI:MB>GMLPBMAF>M:LM:MB<<HEHK><M:E<:G<>KF!/!:IA:L>'''
GHGBG?>KBHKBMRMKB:E'-)/):;LMK:<M(!EBG-G<HELLNIIE:;LMK

6HLABGH 1 +BSNGNF: , 6:F:S:DB ) >M :E 10 FHGHMA>K:IR ?HK IK>MK>:M>= F>M:LM:MB<
<HEHK><M:E<:G<>K:=HN;E>;EBG=K:G=HFBS>=IE:<>;H<HGMKHEIA:L>MKB:E*:G<>M-G<HE


/H;>KM ( +:R>K #KB< 3:G !NML>F E?K>=H $:E<HG> >M :E /:G=HFBS>= 1KB:E H? 10 ?HK
/>?K:<MHKR+>M:LM:MB<!HEHK><M:E!:G<>K,#G@E(+>=


"N HBL""N;HBL#$?HKFNE:MH>LMBF:M>MA>:IIKHQBF:M>LNK?:<>:K>:B?A>B@AM:G=P>B@AM;>
DGHPGArch Intern Med. 




0MN=R,NF;>K
9999999999999999999999999999999999999999999999999999999999999999999999



13.0 APPENDICES 

APPENDIX A  ECOG PERFORMANCE STATUS 
.KHMH<HE,H
 
GRADE 

ECOG 

$NEER:<MBO>:;E>MH<:KKRHG:EEIK>=BL>:L>I>K?HKF:G<>PBMAHNMK>LMKB<MBHG

/>LMKB<M>=BGIARLB<:EERLMK>GNHNL:<MBOBMR;NM:F;NE:MHKR:G=:;E>MH<:KKRHNMPHKDH?:EB@AMHK
L>=>GM:KRG:MNK>>@EB@AMAHNL>PHKDH??B<>PHKD

F;NE:MHKR:G=<:I:;E>H?:EEL>E?<:K>;NMNG:;E>MH<:KKRHNM:GRPHKD:<MBOBMB>L2I:G=:;HNMFHK>
MA:GH?P:DBG@AHNKL

!:I:;E>H?HGEREBFBM>=L>E?<:K><HG?BG>=MH;>=HK<A:BKFHK>MA:GH?P:DBG@AHNKL

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