A Randomised, Open-label, Phase II, Dose/Schedule Optimisation Study of NUC-3373/Leucovorin/Irinotecan Plus Bevacizumab (NUFIRI-bev) Versus 5-FU/Leucovorin/Irinotecan Plus Bevacizumab (FOLFIRI-bev) for the Treatment of Patients With Previously Treated Unresectable Metastatic Colorectal Cancer
Phase: PHASE2
Conditions: Colorectal Cancer, Colorectal Neoplasms, Colorectal Adenocarcinoma, Colorectal Cancer Metastatic, Neoplasm, Colorectal
Sponsor: NuCana plc

N u Ti de: 3 2 3                                                                                                                        Versi o n 2 .1 , 0 6  Fe b  2 0 2 4  
 
 
 
 
 
C LI NI C A L  S T U D Y P R O T O C O L  
 
A r a n d o mis e d, o pe n -l a bel, P h ase II, d ose/sc he d ule o pti misati o n st u d y of 
N U C -3 3 7 3/le uc o v ori n/iri n otec a n pl us be v aciz u m a b  ( N U FI RI-be v ) vers us 
5 -F U/le uc o v ori n/iri n otec a n pl us be v aciz u m a b  ( F O L FI RI-be v ) f or t he 
tre at me nt of p atie nts wit h pre vi o usl y tre ate d u nresect a ble met ast atic 
c ol orect al c a ncer  
 
 
I M P 
N U C -3 3 7 3  
Pr ot oc ol N u m ber  
N u Ti de: 3 2 3  
Pr ot oc ol Versi o n, D ate  
Versi o n 2 .1 , 0 6  Fe b  2 0 2 4  
De vel o p me nt  P h ase  
II 
I N D N u m ber  
1 3 5 2 7 5  
E u dr a C T N u m ber  
2 0 2 2 -0 0 1 4 5 9 -1 7  
Cli nic al Tri als. g o v I D  
N C T 0 5 6 7 8 2 5 7  
S p o ns or:  
N u C a n a plc  
3 L oc hsi de Wa y  
E di n b ur g h, E H 1 2 9 D T, U K  
Tel: + 4 4 ( 0) 1 3 1 3 5 7 1 1 1 1  
E mail: N u Ti de 3 2 3 @ n uca na.c o m  
A p pr o v al:  
 
 
  
S V P,  Cli nical & Me dical 
De vel o p me nt   
 
 
Date  
Me dic al M o nit or:  
 
N u Ca na plc  
3 L oc hsi de Wa y, E di n b ur g h, E H 1 2 9 D T, U K  
Tel: + 4 4 ( 0) 1 3 1 3 5 7 1 1 1 8    
C O N FI D E N TI A LI T Y S T A T E M E N T  
T his c o nfi de nti al d oc u me nt is t he pr o perty of N u C a n a plc. N o u n p u blis he d i nf or m ati o n 
c o nt ai ne d herei n m ay be discl ose d wit h o ut pri or writte n a p pr ov al fr o m N u C a n a.  
Access t o t his d oc u me nt m ust be restricte d t o relev a nt p arties .  

N u Ti de: 3 2 3                                                                                                                        Versi o n 2 .1 , 0 6  Fe b  2 0 2 4  
C o nfi de ntia l                                                            N u Ca na  plc  
1  
 
 
 
 
 
 
 
P RI N CI P A L I N V E S TI G A T O R A G R E E M E N T  
A N D SI G N A T U R E  
 
 
A r a n d o mis e d, o pe n -l a bel, P h ase II, d ose/sc he d ule o pti misati o n st u d y of 
N U C -3 3 7 3/le uc o v ori n/iri n otec a n pl us be v aciz u m a b  ( N U FI RI-be v)  vers us 
5 -F U/le uc o v ori n/iri n otec a n pl us be v aciz u m a b  ( F O L FI RI-be v ) f or t he 
tre at me nt of p atie nts wit h pre vi o usl y tre ate d u nresect a ble met ast atic 
c ol orect al c a ncer  
 
Pr ot oc ol N u m ber  
N u Ti de: 3 2 3  
Pr ot oc ol Versi o n, D ate  
Versi o n 2 .1 , 0 6  Fe b  2 0 2 4  
I M P 
N U C -3 3 7 3  
De vel o p me nt P h ase  
II 
S p o ns or  
N u Ca na plc  
I N D N u m ber 
1 3 5 2 7 5  
E u dr a C T N u m ber  
2 0 2 2 -0 0 1 4 5 9 -1 7  
Cli nic al Tri als. g o v I D  
N C T 0 5 6 7 8 2 5 7  
 
 
T his st u d y will be c o n d ucte d i n c o m plia nce wit h t he cli nical st u d y pr ot oc ol (a n d a me n d me nts), 
I nter nati o nal C ou ncil f or  Har m o nis ati o n g ui deli nes f or c urre nt G o o d Cli nical Practice 
(I C H-G C P) a n d a p plica ble re g ulat or y re q uire me nts . C o m plia nce wit h I C H -G C P sta n dar ds 
pr o vi des ass ura nce t hat t he ri g hts, safet y, a n d well bei n g of st u d y patie nts are pr otecte d, 
c o nsiste nt wit h t he pri nci ples t hat ha ve t heir ori gi n  i n t he Declarati o n of Helsi n ki. 
 
 
 
 
Pri nc i pal I n vesti gat or’s si g nat ure 
 
 
 
 
Date  ( d d-m m m -y y y y)  
Pri nci pal I n vesti gat or’s n a me ( pri nte d)   
 
 
 
 

N u Ti de: 3 2 3                                                                                                                        Versi o n 2 .1 , 0 6  Fe b  2 0 2 4  
C o nfi de ntia l                                                            N u Ca na  plc  
2  
T A B L E O F C O N T E N T S
 
T A B L E O F C O N T E N T S  ........................................................................................... 2  
LI S T O F FI G U R E S  .................................................................................................... 7  
LI S T O F T A B L E S  ...................................................................................................... 7  
P R O T O C O L S Y N O P SI S .............................................................................................. 8  
O V E R A L L S T U D Y D E SI G N  .................................................................................... 1 6  
S U M M A R Y S C H E D U L E O F E V E N T S .................................................................... 1 7  
A B B R E VI A TI O N S  .................................................................................................... 2 1  
1.  
I N T R O D U C TI O N A N D S T UD Y R A TI O N A L E  ................................... 2 4  
1. 1.  
C ol orectal Ca ncer  .................................................................................... 2 4  
1. 2.  
T reat me nt of C ol orectal Ca ncer ............................................................... 2 4  
1. 2. 1  
A dj u va nt Treat me nt  ................................................................................. 2 5  
1. 2. 2  
Treat me nt f or Metastatic Disease  ............................................................ 2 5  
1. 3.  
Li mitati o ns of 5 -F U Treat me nt  ................................................................ 2 6  
1. 4.  
N U C -3 3 7 3  ................................................................................................ 2 7  
1. 4. 1  
N o n -Cli nical Data  .................................................................................... 2 8  
1. 5.  
Cli nical Data  ............................................................................................ 2 8  
1. 5. 1.  
N u T i de: 3 0 1 .............................................................................................. 2 8  
1. 5. 2.  
N u Ti de: 3 0 2  .............................................................................................. 2 9  
1. 6.  
P har mac o ki netics  ..................................................................................... 3 0  
1. 7.  
St u d y Rati o nale  ........................................................................................ 3 1  
2.  
S T U D Y O BJ E C TI V E S A N D  E N D P OI N T S  ........................................... 3 2  
2. 1.  
Pri mar y O bjecti ves  .................................................................................. 3 2  
2. 2.  
Sec o n dar y O bjecti ves  .............................................................................. 3 2  
2. 3.  
E x pl orat or y O bjecti ve  .............................................................................. 3 2  
2. 4.  
Pri mar y E n d p oi nt  ..................................................................................... 3 2  
2. 5.  
S ec o n dar y E n d p oi nts  ............................................................................... 3 2  
2. 5. 1  
Efficac y  .................................................................................................... 3 2  
2. 5. 2  
Safet y  ....................................................................................................... 3 3  
2. 5. 3  
P har mac o ki netics  ..................................................................................... 3 3  
2. 6.  
E x pl orat or y E n d p oi nt  ............................................................................... 3 3  
3.  
I N V E S TI G A TI O N A L P L A N .................................................................. 3 4  
3. 1.  
O verall St u d y Desi g n  ............................................................................... 3 4  
3. 2.  
Rati o nale f or t he D oses Selecte d  ............................................................. 3 4  
3. 2. 1.  
N U FI RI Re gi me n  ..................................................................................... 3 4  

N u Ti de: 3 2 3                                                                                                                        Versi o n 2 .1 , 0 6  Fe b  2 0 2 4  
C o nfi de ntia l                                                            N u Ca na  plc  
3  
3. 2. 2.  
F O L FI RI Re gi me n  ................................................................................... 3 5  
3. 3.  
S t u d y Treat me nt ....................................................................................... 3 5  
3. 4  
D urati o n of Patie nt Partici pati o n  ............................................................. 3 7  
3. 5  
St u d y C o m pleti o n  .................................................................................... 3 7  
4  
P A TI E N T S E L E C TI O N  .......................................................................... 3 9  
4. 1  
I ncl usi o n Criteria ..................................................................................... 3 9  
4. 2  
E xcl usi o n Criteria  .................................................................................... 4 0  
4. 3  
Wai vers t o E ntr y Criteria  ......................................................................... 4 3  
5  
S T U D Y A S S E S S M E N T S A N D P R O C E D U R E S  ................................... 4 4  
5. 1  
I nf or me d C o nse nt .................................................................................... 4 4  
5. 1. 1  
I nf or me d C o nse nt f or T u m o ur Tiss ue C ollecti o n .................................... 4 4  
5. 2  
Patie nt Re gistrati o n a n d Scree ni n g Pr oce d ures  ....................................... 4 4  
5. 3  
Scree ni n g Assess me nts  ............................................................................ 4 5  
5. 4  
Re -Scree ni n g Patie nts w h o Fail Scree ni n g  .............................................. 4 6  
5. 5  
E val uati o ns t o be Perf or me d d uri n g t he St u d y  ........................................ 4 7  
5. 5. 1  
Eac h c ycle, Da y 1 ( ± 2 da ys; All ar ms)  ................................................... 4 7  
5. 5. 2  
Eac h c ycle, Da y 8 ( ± 2 da ys; Ar m A o nl y)  .............................................. 4 8  
5. 5. 3  
Eac h c ycle, Da y 1 5 ( ± 2 da ys; All ar ms)  ................................................. 4 9  
5. 5. 4  
Eac h c ycle, Da y 2 2 ( ± 2 da ys; Ar m A o nl y)  ............................................ 4 9  
5. 5. 5  
E ver y 8 wee ks ( ± 7 da ys) fr o m C ycle 1 Da y 1 u ntil disease pr o gressi o n,  
i nitiati o n of a ne w treat me nt or deat h ...................................................... 5 0  
5. 5. 6  
E n d of Treat me nt Visit ( 3 0 da ys [ + 7 da ys) after last d ose)  ..................... 5 0  
5. 5. 7  
L o n g -Ter m F oll o w -U p  ............................................................................ 5 1  
6  
P A TI E N T WI T H D R A W A L  .................................................................... 5 2  
6. 1  
E n d of Treat me nt  ..................................................................................... 5 2  
6. 2  
F oll o w -u p After Treat me nt Disc o nti n uati o n  ........................................... 5 3  
6. 3  
C o nse nt Wit h dra wal  ................................................................................ 5 3  
7  
S A M P L E S F O R L A B O R A T O R Y A N A L Y SI S  ..................................... 5 4  
7. 1  
Cli nical La b orat or y Tests  ........................................................................ 5 4  
7. 2  
P har mac o ki netics  ..................................................................................... 5 4  
7. 3  
T u m o ur Tiss ue Sa m ple S u b missi o n  ........................................................ 5 4  
7. 4  
La belli n g a n d C o nfi de ntialit y of Bi ol o gical Sa m ples  ............................. 5 4  
7. 5  
Wit h dra wal of C o nse nt f or Bi ol o gical Sa m ple C ollecti o n or Rete nti o n  . 5 5  
8  
I N V E S TI G A TI O N A L M E DICI N A L P R O D U C T S  ................................ 5 6  
8. 1  
N U C -3 3 7 3  ................................................................................................ 5 6  

N u Ti de: 3 2 3                                                                                                                        Versi o n 2 .1 , 0 6  Fe b  2 0 2 4  
C o nfi de ntia l                                                            N u Ca na  plc  
4  
8. 1. 1  
N U C -3 3 7 3 D escri pti o n ............................................................................ 5 6  
8. 1. 2  
N U C -3 3 7 3 S u p plies a n d St u d y Dr u g Pac ka gi n g  ..................................... 5 6  
8. 1. 3  
Ha n dli n g a n d St ora ge of N U C -3 3 7 3  ....................................................... 5 6  
8. 1. 4  
Pre parati o n of N U C -3 3 7 3  ........................................................................ 5 6  
8. 1. 5  
N U C -3 3 7 3 A d mi nistrati o n  ...................................................................... 5 6  
8. 2  
Ot her I M Ps  ............................................................................................... 5 7  
8. 3  
A d mi nistra ti o n of N U C-3 3 7 3 a n d Ot her A ge nts  ..................................... 5 7  
8. 3. 1  
Ar m A  ...................................................................................................... 5 7  
8. 3. 2  
Ar m B  ...................................................................................................... 5 8  
8. 3. 3  
Ar m C  ...................................................................................................... 5 8  
8. 4  
N U C -3 3 7 3 Dr u g Destr ucti o n  ................................................................... 5 9  
8. 5  
Ra n d o misati o n  ......................................................................................... 5 9  
8. 6  
N U C -3 3 7 3 St u d y Dr u g Acc o u nta bilit y  ................................................... 5 9  
8. 7  
Ma na ge me nt of O ver d ose  ........................................................................ 5 9  
8. 8  
I nteracti o n wit h Ot her Dr u gs ................................................................... 6 0  
9  
M A N A G E M E N T O F T O XI CI T Y  .......................................................... 6 1  
9. 1  
Criteria f or C o nti n uati o n of Treat me nt  .................................................... 6 1  
9. 2  
D ose M o dificati o ns  .................................................................................. 6 2  
9. 2. 1  
D ose A da ptati o ns f or Patie nts wit h Partial D P D Deficie nc y  .................. 6 4  
9. 2. 1. 1  
Fra nce  ...................................................................................................... 6 4  
9. 2. 1. 2  
Ot her C o u ntries  ........................................................................................ 6 5  
9. 3  
S u g geste d Ma na ge me nt of T o xicit y  ........................................................ 6 6  
9. 3. 1  
Na usea a n d V o miti n g  .............................................................................. 6 6  
9. 3. 2  
Diarr h oea  ................................................................................................. 6 6  
9. 3. 3  
M uc ositis  .................................................................................................. 6 6  
9. 3. 4  
Pal mar -Pla ntar Er yt hr o d ysest haesia ( ha n d -f o ot s y n dr o me) .................... 6 7  
9. 3. 5  
I nf usi o n Reacti o ns ................................................................................... 6 7  
9. 3. 6  
Oc ular T o xicit y  ........................................................................................ 6 7  
9. 3. 7  
Fati g ue  ..................................................................................................... 6 7  
9. 3. 8  
Car di ot o xicit y  .......................................................................................... 6 7  
9. 3. 9  
Fertilit y  .................................................................................................... 6 7  
9. 3. 1 0  
C o m bi nati o n T hera pies  ............................................................................ 6 8  
1 0  
O T H E R T R E A T M E N T S ( N O N -I M P) .................................................... 6 9  
1 0. 1  
S u p p ort Me dicati o n  ................................................................................. 6 9  
1 0. 2  
Hae mat o p oietic Gr o wt h Fact or S u p p ort  .................................................. 6 9  

N u Ti de: 3 2 3                                                                                                                        Versi o n 2 .1 , 0 6  Fe b  2 0 2 4  
C o nfi de ntia l                                                            N u Ca na  plc  
5  
1 0. 3  
C o nc o mita nt Me dicati o ns  ........................................................................ 6 9  
1 0. 3. 1  
C o ntrace pti o n Met h o ds  ............................................................................ 6 9  
1 0. 3. 2  
Pr o hi bite d T hera p y  .................................................................................. 7 0  
1 0. 3. 3  
T hera pies t o be Use d wit h Ca uti o n  .......................................................... 7 1  
1 0. 3. 4  
C O VI D -1 9 Vacci nati o ns  ......................................................................... 7 1  
1 0. 4  
C o nc o mita nt Pr oce d ures  .......................................................................... 7 2  
1 1  
T U M O U R R E S P O N S E A S S E S S M E N T S  .............................................. 7 3  
1 1. 1  
T u m o ur Meas ure me nts a n d Assess me nt of Disease Res p o nse  ............... 7 3  
1 2  
S A F E T Y R E P O R TI N G  ........................................................................... 7 4  
1 2. 1  
Defi niti o ns  ............................................................................................... 7 4  
1 2. 2  
A d verse E ve nt Re p orti n g  ......................................................................... 7 5  
1 2. 3  
Assess me nt of Ca usalit y t o St u d y Dr u g(s)  .............................................. 7 6  
1 2. 4  
Assess me nt of Se verit y  ............................................................................ 7 6  
1 2. 5  
S A E Re p orti n g  ......................................................................................... 7 6  
1 2. 6  
E x pe dite d Re p orti n g of S A Es  .................................................................. 7 7  
1 2. 7  
S U S A R Re p orti n g  ................................................................................... 7 7  
1 2. 8  
Ter ms a n d Gra di n g of A d verse E ve nts a n d T o xicities  ............................ 7 8  
1 2. 9  
Pre g na nc y  ................................................................................................ 7 8  
1 2. 1 0  
E ve nts E xe m pt fr o m bei n g Re p orte d as A E/ S A Es  .................................. 7 8  
1 2. 1 0. 1  
Pr o gressi o n of U n derl yi n g Disease  ......................................................... 7 8  
1 2. 1 0. 2  
Deat h o n St u d y Attri b ute d t o Mali g na nc y  ............................................... 7 9  
1 2. 1 0. 3  
Electi ve A d missi o ns a n d S u p p orti ve Care  .............................................. 7 9  
1 2. 1 1  
A b n or mal La b orat or y Test Res ult Val ues  ............................................... 7 9  
1 2. 1 2  
A b n or mal Vital Si g n Val ues  .................................................................... 8 0  
1 2. 1 3  
I nf or mi n g I n vesti gat ors of Ne w Safet y I nf or mati o n ............................... 8 0  
1 2. 1 4  
Refere nce Safet y I nf or mati o n f or Assess me nt of E x pecte d ness  ............. 8 0  
1 3  
S T A TI S TI C A L C O N SI D E R A TI O N S  .................................................... 8 2  
1 3. 1  
Sa m ple Size  ............................................................................................. 8 2  
1 3. 2  
Missi n g, U n use d a n d S p uri o us Data  ........................................................ 8 2  
1 3. 3  
A nal ysis P o p ulati o ns  ............................................................................... 8 3  
1 3 . 3. 1 
Safet y P o p ulati o n  ..................................................................................... 8 3  
1 3. 3. 2  
F ull A nal ysis Set  ...................................................................................... 8 3  
1 3. 3. 3  
M o difie d F ull A nal ysis Set  ...................................................................... 8 3  
1 3. 3. 4  
P K A nal ysis Set  ....................................................................................... 8 3  
1 3. 4  
P atie nt Dis p ositi o n  ................................................................................... 8 3  

N u Ti de: 3 2 3                                                                                                                        Versi o n 2 .1 , 0 6  Fe b  2 0 2 4  
C o nfi de ntia l                                                            N u Ca na  plc  
6  
1 3. 5  
Statistical Met h o ds  ................................................................................... 8 4  
1 3. 5. 1  
De m o gra p hics a n d Baseli ne Data  ............................................................ 8 4  
1 3. 5. 2  
C o nc o mita nt Me dicati o ns  ........................................................................ 8 4  
1 3. 5. 3  
E xte nt of E x p os ure  .................................................................................. 8 4  
1 3. 5. 4  
Efficac y A nal ysis  ..................................................................................... 8 4  
1 3. 5. 5  
Safet y A nal ysis  ........................................................................................ 8 7  
1 3. 5. 8  
Pri mar y a n d I nteri m A nal yses  ................................................................. 8 9  
1 3. 5. 9  
C ha n ges t o t he Pla n ne d Statistical Met h o ds  ............................................ 8 9  
1 4  
P A TI E N T D A T A H A N D LI N G A N D C O N FI D E N TI A LI T Y  ................ 9 0  
1 4. 1  
Case Re p ort F or ms  .................................................................................. 9 0  
1 4. 2  
M o nit ori n g of t he St u d y  ........................................................................... 9 0  
1 4. 3  
Patie nt C o nfi de ntialit y  ............................................................................. 9 1  
1 5  
E T HI C A L A N D R E G U L A T O R Y C O N SI D E R A TI O N S  ....................... 9 2  
1 5. 1  
G o o d Cli nical Practice C o m plia nce  ......................................................... 9 2  
1 5. 2  
I nstit uti o nal Re vie w B oar ds/ Et hics C o m mittees .................................... 9 2  
1 5. 3  
Re g ulat or y A ut h orit y A p pr o val  ............................................................... 9 2  
1 5. 4  
Ris k Ma na ge me nt C o nsi derati o ns  ........................................................... 9 2  
1 5. 5  
Pr ot oc ol A me n d me nts  ............................................................................. 9 3  
1 5. 6  
Pr ot oc ol Vi olati o ns a n d De viati o ns  ......................................................... 9 3  
1 5. 7  
Seri o us Breac hes  ...................................................................................... 9 3  
1 5. 8  
St u d y Re p orti n g Re q uire me nts  ................................................................ 9 3  
1 5. 9  
Fi na ncial discl os ure  ................................................................................. 9 4  
1 5 . 1 0 
I n vesti gat or D oc u me ntati o n ..................................................................... 9 4  
1 5. 1 1  
St u d y Rec or ds Rete nti o n  ......................................................................... 9 4  
1 5. 1 2  
A u dit a n d Re g ulat or y I ns pecti o n  ............................................................. 9 4  
1 6  
P U B LI C A TI O N P O LI C Y  ....................................................................... 9 5  
1 6. 1  
C o m m u nicati o n of Res ults b y S p o ns or  ................................................... 9 5  
1 6. 2  
P u blicati o n b y I n vesti gat ors  .................................................................... 9 5  
1 7  
R E F E R E N C E S  ........................................................................................ 9 6  
1 8  
A P P E N DI C E S  ......................................................................................... 9 9  
A P P E N DI X  1.  R E S P O N S E E V A L U A TI O N C R I T E RI A I N S O LI D T U M OU R S 
( R E CI S T) V E R SI O N 1. 1 ......................................................................... 9 9  
A P P E N DI X  2.  E C O G P E R F O R M A N C E S C A L E  ................................................ 1 0 3  
A P P E N DI X  3.  C O N C O MI T A N T M E DI C A TI O N S T H A T M A Y P R O L O N G  Q T C  
I N T E R V A L ........................................................................................... 1 0 4  
A P P E N DI X  4.  M A N A G E M E N T G UI D E F O R  DI A R R H O E A  ........................... 1 0 7  

N u Ti de: 3 2 3                                                                                                                        Versi o n 2 .1 , 0 6  Fe b  2 0 2 4  
C o nfi de ntia l                                                            N u Ca na  plc  
7  
 
LI S T O F FI G U R E S  
Fi g ure 1  
N u Ti de: 3 2 3 st u d y sc he ma  ....................................................................... 1 6  
  
LI S T O F T A B L E S  
Ta ble 1  
St u d y treat me nt i n Ar m A  ........................................................................ 3 6  
Ta ble 2  
St u d y treat me nt i n Ar m B  ........................................................................ 3 6  
Ta ble 3  
St u d y treat me nt i n Ar m C  ........................................................................ 3 7  
Ta ble 4  
D ose re d ucti o n g ui deli nes  ........................................................................ 6 1  
Ta ble 5  
D ose m o dificati o ns f or N U C -3 3 7 3, iri n oteca n a n d 5 -F U  ....................... 6 3  
Ta ble 6  
5 -F U d ose re d ucti o n  g ui deli nes i n patie nts wit h partial D P D deficie nc y  6 5  
Ta ble 7  
I nte nsit y of a d verse e ve nts n ot i ncl u de d i n C T C A E ............................... 7 6  
Ta ble 8  
P har mac o vi gila nce c o ntact details  ........................................................... 7 7  

N u Ti de: 3 2 3                                                                                                                        Versi o n 2 .1 , 0 6  Fe b  2 0 2 4  
C o nfi de ntia l                                                            N u Ca na  plc  
8  
 P R O T O C O L S Y N O P SI S  
St u d y Title  
A ra n d o mise d, o pe n -la bel, P hase II, d ose/ sc he d ule o pti misati o n st u d y of 
N U C -3 3 7 3/le uc o v ori n/iri n oteca n pl us be vaciz u ma b  ( N U FI RI-be v ) vers us 
5 -F U/le uc o v ori n/iri n oteca n pl us be vaciz u ma b  ( F O L FI RI-be v ) f or t he 
treat me nt of patie nts wit h pre vi o usl y treate d u nresecta ble 
m etastatic 
c ol orectal ca ncer  
Pr ot oc ol  
N u Ti de: 3 2 3  
I N D 
1 3 5 2 7 5  
E u dr a C T  
2 0 2 2 -0 0 1 4 5 9 -1 7  
Cli nic al Tri als. g o v  I D 
N C T 0 5 6 7 8 2 5 7  
P h ase  
II 
O bjecti ves  
Pri m ar y O bjecti ves  
•  
T o c o m pare pr o gressi o n free - s ur vi val ( P F S) of N U C-3 3 7 3 i n 
c o m bi nati o n wit h le uc o v ori n ( L V), iri n oteca n a n d be vaciz u ma b 
( N U FI RI-be v) wit h 5 -fl u or o uracil (5 -F U ) i n c o m bi nati o n wit h L V, 
iri n oteca n a n d be vaciz u ma b ( F O L FI RI-be v)  
•  
T o deter mi ne t he o pti mal N U FI RI -be v d osi n g sc he d ule  
Sec o n d ar y O bjecti ves  
•  
T o c o m p a re t he efficac y of N U FI RI-be v t o F O L FI RI -be v i n ter ms 
of:  
o  O bjecti ve res p o nse rate ( O R R)  
o  D urati o n of res p o nse ( D o R)  
o  Disease c o ntr ol rate ( D C R)  
o  Ma xi m u m perce nta ge c ha n ge i n t u m o ur size  
o  O verall s ur vi val ( O S)  
•  
T o assess t he safet y a n d t olera bilit y of N U FI RI -be v c o m pare d t o 
F O L FI RI -be v  
•  
T o assess t he p har mac o ki netics ( P K) of N U FI RI -be v  
E x pl or at or y O bjecti ve  
T o deter mi n e if t here are t u m o ur cell c haracteristics t hat ma y f urt her 
el uci date t he mec ha nis ms t hr o u g h w hic h t he cli nical acti vit y of N U C -3 3 7 3 
is ac hie ve d ( arc hi val tiss ue, w here a vaila ble ).  
St u d y Desi g n  
R a n d o mis e d, o pe n -la bel, d ose/sc he d ule o pti misati o n  st u d y c o m p ari n g 
N U FI RI -be v t o 
F O L FI RI -be v f or t he treat me nt of patie nts 
wit h 
u nresecta ble metastatic c ol orectal ca ncer ( C R C) .  
   
Patie nts will be ra n d o mise d 1: 1: 1 t o eit her N U FI RI -be v base d o n a wee kl y 
( Q 1 W) N U C-3 3 7 3 sc he d ule, N U FI RI -be v base d o n a n  alter nate wee kl y  
( Q 2 W) N U C-3 3 7 3 sc he d ule, or F O L FI RI -be v ( Q 2 W). Ra n d o mis ati o n will 
be stratifie d b y R A S stat us ( wil d -t y pe vs K R A S m ut a nt vs N R A S m uta nt), 
pri or be vaciz u ma b treat me nt ( y es vs n o) a n d d urati o n of pri or li ne of 
t hera p y ( < 6 m o nt hs vs ≥6 m o nt hs).  
St u d y Ce nt res  
T his st u d y will be c o n d ucte d at a p pr o xi matel y 6 1  sites gl o ball y. 

N u Ti de: 3 2 3                                                                                                                        Versi o n 2 .1 , 0 6  Fe b  2 0 2 4  
C o nfi de ntia l                                                            N u Ca na  plc  
9  
E n d p oi nts  
Pri m ar y E n d p oi nt  
•  
P F S, acc or di n g t o R es p o nse E val uati o n C riteria in  S oli d T u m o ur s 
( R E CI S T) v 1. 1, defi ne d as t he ti me fr o m ra n d o misati o n t o t he first 
o bser vati o n of o bjecti ve t u m o ur pr o gressi o n or deat h fr o m a n y 
ca use  
Sec o n d ar y E n d p oi nts  
Effic ac y  
•  
O R R, defi ne d as t he perce nta ge of patie nts ac hie vi n g a c o m plete 
or partial res p o nse t o treat me nt  
•  
D o R, defi ne d as t he ti me fr o m i nitial cli nical res p o nse ( partial 
res p o nse [ P R] or c o m plete res p o nse [ C R]) t o t he first o bser vati o n 
of t u m o ur pr o gressi o n or deat h fr o m a n y ca use  
•  
D C R, defi ne d as t he perce nta ge of patie nts de m o nstrati n g a best 
o verall res p o nse ( B O R) of C R, P R or sta ble disease ( S D)  
•  
Ma xi m u m p erce nta ge c ha n ge fr o m baseli ne i n 
t u m o ur size 
acc or di n g t o R E CI S T v 1. 1  
•  
O S, defi ne d as t he ti me fr o m ra n d o misati o n t o t he ti me of deat h 
fr o m a n y ca use 
S afet y  
Safet y a n d t olera bilit y will be assesse d b y e val uati o n of:  
•  
Treat me nt -e mer ge nt a d verse e ve nts ( T E A Es) a n d seri o us a d verse 
e ve nts ( S A Es; per C o m m o n Ter mi n ol o g y Criteria f or A d verse 
E ve nts [ C T C A E] v 5. 0)  
•  
Deat hs d ue t o T E A Es  
•  
Treat me nt m o dificati o ns  d u e t o T E A Es  
•  
Cli nicall y -si g nifica nt la b orat or y c ha n ges ( per C T C A E v 5. 0) 
•  
Electr ocar di o gra ms ( E C Gs) 
P h ar m ac o ki netics  
T he P K of t he N U FI RI-be v re gi me n will be assesse d, i ncl u di n g:  
•  C o nce ntrati o n at e n d of i nf usi o n ( C i nf) 
•  Ma xi m u m c o nce ntrati o n ( C
ma x ) 
•  Area u n der t he plas ma c o nce ntrati o n-ti me c ur ve (A U C ) 
•  Half -life (t1/ 2) 
•  V ol u me of distri b uti o n ( V d) 
•  
Cleara nce ( C L)  
T he a nal ytes meas ure d i n plas ma will i ncl u de, b ut are n ot li mite d t o:  
•  
N U C -3 3 7 3, C P F -1 0 2 7  α -fl u or o-β -ala ni ne ( F B A L),  iri n oteca n, 
S N -3 8 , S N-3 8 G, A P C  
E x pl or a t or y E n d p oi nt 
•  
P o p ulati o n or t u m o ur c haracteristic s u bt y pes t hat ma y deter mi n e 
be nefit t o N U C -3 3 7 3 treat me nt will be a nal yse d  

N u Ti de: 3 2 3                                                                                                                        Versi o n 2 .1 , 0 6  Fe b  2 0 2 4  
C o nfi de ntia l                                                            N u Ca na  plc  
1 0  
St u d y P o p ul ati o n  
Patie nts 
wit h hist ol o gicall y or c yt ol o gicall y c o nfir me d u nresecta ble 
c ol orectal a de n ocarci n o ma t hat is metastatic a n d meas ura ble. Patie nts m ust 
ha ve pre vi o usl y recei ve d ≥2 m o nt hs of a 1 st-li ne fl u or o p yri mi di ne a n d 
o xali plati n -c o ntai ni n g re gi me n or ha ve rela pse d 
wit hi n 6  m o nt hs of 
c o m pleti n g  
a  
fl u or o p yri mi di ne  
a n d  
o xali plati n -c o ntai ni n g 
ne oa dj u va nt/ a dj u va nt t hera p y . Patie nts w h o starte d o n a fl u or o p yri mi di ne 
a n d o xali plati n -c o ntai ni n g re gi m e n i n a n y setti n g b ut m ust disc o nti n ue t he 
o xali plati n d ue t o t o xicit y or aller g y (a n d are n o w u na ble t o recei v e 
o xali plati n) are c o nsi dere d eli gi ble re gar dless of t he n u m ber of c ycles of 
o xali plati n t he y recei ve d.  
Patie nts m ust als o be B R A F  V 6 0 0 E  wil d -t y pe a n d ha ve a n Easter n 
C o o perati ve O nc ol o g y Gr o u p ( E C O G) perf or ma nce stat us 0 -1, al o n g wit h 
a de q uate h ae mat ol o gic, re nal a n d he patic f u ncti o n. Patie nts wit h M SI -H or 
d M M R are n ot eli gi ble . 
St u d y Tre at me nt  
Patie nts will be ra n d o mise d 1: 1: 1 t o recei ve eit her:  
•  
N U FI RI -be v o n a Q 1 W N U C -3 3 7 3 sc he d ule ( Ar m A)  
•  
N U FI RI -be v o n a Q 2 W N U C -3 3 7 3 sc he d ule ( Ar m B)  
•  
F O L FI RI -be v o n a Q 2 W sc he d ule ( Ar m  C)  
I n Ar m A, be vaciz u ma b will be a d mi nistere d at 5 m g/ k g a n d iri n oteca n 
will be a d mi nistere d at 1 8 0 m g/ m 2, b ot h b y i ntra ve n o us ( I V) i nf usi o n, o n 
Da ys 1 a n d 1 5. L V will be a d mi nistere d at 4 0 0  m g/ m 2 b y I V i nf usi o n o n 
Da ys  1, 8, 1 5 a n d 2 2. F oll o wi n g c o m pleti o n of i nf usi o ns o n Da ys  1 , 8, 1 5 
a n d 2 2, N U C -3 3 7 3 will be a d mi nistere d b y I V i nf usi o n a t 1 5 0 0  m g/ m 2. 
I n Ar m B, be vaciz u ma b will be a d mi nistere d at 5 m g/ k g, iri n oteca n will be 
a d mi nistere d at 1 8 0 m g/ m 2, a n d L V will be a d mi nistere d at 4 0 0 m g/ m 2, all 
b y I V i nf usi o n, o n Da ys 1 a n d 1 5. F oll o wi n g c o m pleti o n of i nf usi o ns o n 
Da ys 1 a n d 1 5, N U C -3 3 7 3 will be a d mi nistere d b y I V i nf usi o n  at 
1 5 0 0  m g/ m 2.  
I n Ar m C, be vaciz u ma b will be a d mi nistere d at 5 m g/ k g, iri n oteca n will be 
a d mi nistere d at 1 8 0 m g/ m 2, a n d L V will be a d mi nistere d at 4 0 0 m g/ m 2, all 
b y I V i nf usi o n, o n Da ys 1 a n d 1 5. F oll o wi n g c o m pleti o n of i nf usi o ns o n 
Da ys  1 a n d 1 5, 5 -F U w ill be a d mi nistere d b y I V b ol us at 4 0 0 m g/ m 2 
f oll o we d b y 2, 4 0 0 m g/ m 2 b y c o nti n u o us I V i nf usi o n o ver 4 6 h o urs.  
Be vaciz u ma b ma y be s u bstit ute d wit h a n y a p pr o ve d bi osi milar c o nsiste nt 
wit h i nstit uti o nal practice. T he s pecific a ge nt a d mi nistere d 
will b e 
rec or de d. T h us, be vaciz u ma b i n t his pr ot oc ol refers t o eit her be vaciz u ma b 
or a lice nse d bi osi milar.  
I ncl usi o n Criteri a 
 
1.  Pr o visi o n of writte n i nf or me d c o nse nt.  
2.  Hist ol o gical or c yt ol o gical c o nfir mati o n of c ol orectal a de n ocarci n o ma  
(e xcl u di n g a p pe n diceal a nd a nal ca nal ca ncers , as well as si g net-ri n g 
cell carci n o ma ) t hat is u nresecta ble a n d metastatic. 
3.  Meas ura ble disease (as defi ne d b y R E CI S T v 1. 1).  
4.  R ecei ve d ≥2 m o nt hs of a first -li ne fl u or o p yri mi di ne a n d o xali plati n-
c o ntai ni n g re gi me n f or metastatic disease or rela pse d wit hi n 6  m o nt hs 
of 
c o m pleti n g 
a 
fl u or o p yri mi di ne 
a n d 
o xali plati n -c o ntai ni n g 
ne o a dj u va nt /a dj u va nt t hera p y. Pre vi o us treat me nt wit h sta n dar d of 
care c he m ot hera p y re gi me ns i n c o m bi nati o n wit h m olec ular tar gete d 
t hera pies (e. g., V E G F a n d E G F R pat h wa y i n hi bit ors a n d i m m u n o -
o nc ol o g y a ge nts) is per mitte d. Pre vi o us treat me nt wit h mai nte na nce 

N u Ti de: 3 2 3                                                                                                                        Versi o n 2 .1 , 0 6  Fe b  2 0 2 4  
C o nfi de ntia l                                                            N u Ca na  plc  
1 1  
t hera p y (e. g., ca pecita bi ne) is als o all o we d.  Patie nts w h o starte d o n a 
fl u or o p yri mi di ne a n d o xali plati n -c o ntai ni n g re gi me n i n a n y setti n g b ut 
m ust disc o nti n ue t he o xali plati n d ue t o t o xicit y or aller g y (a n d are n o w 
u na ble t o recei ve o xali plati n) are c o nsi dere d eli gi ble re gar dless of t he 
n u m ber of c ycles of o xali plati n t he y recei ve d.  
5.  K n o w n R A S  a n d B R A F stat us. Patie nts wit h wil d -t y pe R A S t u m o urs 
m ust ha ve recei ve d pri or treat me nt wit h a n E G F R i n hi bit or,  u nless t his 
was n ot sta n dar d of care acc or di n g t o rele va nt re gi o n -s pecific 
treat me nt rec o m me n dati o ns. 
6.  K n o w n U G T 1 A 1 stat us, or patie nt c o nse nts t o U G T 1 A 1 stat us testi n g 
if u n k n o w n. 
7.  K n o w n D P D acti vit y stat us,  or patie nt c o nse nts t o D P D stat us testi n g 
if u n k n o w n. S ee e xcl usi o n criteri o n 1 .  
8.  A ge ≥1 8 y ears.  
9.  Mi ni m u m l ife e x pecta nc y of ≥1 2 wee ks. 
1 0.  E C O G Perf or ma nce stat us 0 or 1.  
1 1.  A de q uate b o ne marr o w f u nc ti o n as defi ne d b y: a bs ol ute ne utr o p hil 
c o u nt ( A N C) ≥1. 5 × 1 0 9/ L, platelet c o u nt ≥1 0 0 × 1 09/ L, a n d hae m o gl o bi n 
≥9 g/ d L.  Patie nts wit h be ni g n ne utr o pe nia ma y be disc usse d o n a case -
b y -case basis wit h t he me dical m o nit or.  
1 2.  A de q uate li ver f u ncti o n, as defi ne d b y: 
ser u m t otal bilir u bi n 
≤1. 5 × u p per li mit of n or mal ( U L N ; t his t hres h ol d d oes n ot a p pl y t o 
patie nts wit h Gil bert’s s y n dr o me, w h o s h o ul d be disc usse d wit h t he 
M e dical M o nit or ), as partate a mi n otra nsferase ( A S T) a n d ala ni n e 
a mi n otra nsferase ( A L T) ≤2. 5 × U L N ( or ≤5 × U L N if li ver metastases 
are prese nt).  
1 3.  A de q uate re nal f u ncti o n assesse d as ser u m creati ni ne < 1. 5 × U L N a n d  
gl o mer ular filtrati o n rate ≥5 0 m L/ mi n  (calc ulate d b y t he C oc kcr oft-
Ga ult met h o d) . 
1 4.  Ser u m al b u mi n ≥3 g/ d L.  
1 5.  A bilit y t o c o m pl y wit h pr ot oc ol re q uire me nts.  
1 6.  Fe male patie nts of c hil d -beari n g p ote ntial 
m ust ha ve a ne gati ve 
pre g na nc y test 
wit hi n 7 da ys pri or t o t he first st u d y dr u g 
a d mi nistrati o n.  T his criteri o n d oes n ot a p pl y t o patie nts w h o ha ve ha d 
a pre vi o us h ysterect o m y or bilateral o o p h orect o m y. Male patie n ts a n d 
fe male patie nts of c hil d-beari n g p ote ntial m ust a gree t o practice tr ue 
a bsti ne nce or t o use t w o f or ms of c o ntrace pti o n, o ne of w hic h m ust be 
hi g hl y effecti ve . T hese f or ms of c o ntrace pti o n m ust be use d fr o m t he 
ti me of si g ni n g c o nse nt, t hr o u g h o ut t he treat me nt peri o d, a n d f or 6 
m o nt hs f oll o wi n g t he last d ose of a n y st u d y me dicati o n. Oral or 
i njecta ble c o ntrace pti ve a ge nts ca n n ot be t he s ole 
met h o d of 
c o ntrace pti o n.  
1 7.  Patie nts m ust ha ve bee n a d vise d t o ta ke meas ures t o a v oi d or mi ni mize 
e x p os ure  of t he s ki n a n d e y es  t o U V li g ht, i ncl u di n g a v oi di n g 
s u n bat hi n g a n d s olari u m use , f or t he d urati o n of st u d y partici pati o n a n d 
f or a peri o d of 4 wee ks f oll o wi n g t he last d ose of st u d y me dicati o n. 
E xcl usi o n Criteri a  
 
1.  Hist or y of h y perse nsiti vit y or c urre nt c o ntra -i n dicati o ns t o 5-F U , 
F U D R,  or ca pecita bi ne . T his i ncl u des patie nts wit h ge n ot y pic or 
p he n ot y pic  ( bl o o d uracil le vel ≥1 5 0 n g/ m L)  e vi de nce of c o m plete 
D P D deficie nc y  or T Y M P 
m utati o ns ass ociate d wit h t o xicit y t o 

N u Ti de: 3 2 3                                                                                                                        Versi o n 2 .1 , 0 6  Fe b  2 0 2 4  
C o nfi de ntia l                                                            N u Ca na  plc  
1 2  
fl u or o p yri mi di nes. Patie nts w h o t olerat e d pri or 5 -F U at a re d uce d d ose 
le vel ma y be e nr olle d a n d treate d at t hat sa me d ose.  
2.  Hist or y of h y perse nsiti vit y or c urre nt c o ntra -i n dicati o n t o a n y of t he 
c o m bi nati o n a ge nts re q uire d f or t he st u d y.  
3.  Hist or y of aller gic reacti o ns attri b ute d t o c o m p o ne nts of t he N U C -3 3 7 3 
dr u g pr o d uct f or m ulati o n ( su per refi ne d p ol ys or bate 8 0  [ S R P 8 0], 
di met h ylaceta mi de [ D M A]).  
4.  Hist or y of h y perse nsiti vit y t o C hi nese Ha mster O v ar y ( C H O) cell 
pr o d ucts or ot her rec o m bi na nt h u ma n or h u ma nise d a nti b o dies . 
5.  Hist or y of or k n o w n  ce ntral ner v o us s yste m or le pt o me ni n geal 
metastases.  
6.  S y m pt o matic ascites, ascites c urre ntl y re q uiri n g drai na ge pr oce d ures 
or ascites re q uiri n g drai na ge o ver t he pri or 3 m o nt hs.  
7.  M uta nt B R A F V 6 0 0 E stat us.  
8.  M SI hi g h or d M M R.  
9.  Pri or treat me nt wit h iri n oteca n . 
1 0.  C he m ot hera p y, h or m o nal t hera p y, ra di ot hera p y ( ot her t ha n a s h ort 
c ycle of palliati ve ra di ot hera p y [ e. g., f or b o ne pai n] *), i m m u n ot hera p y, 
bi ol o gical a ge nts, or e x p os ure t o a n ot her i n vesti gati o nal a ge nt wit hi n 
2 1  da ys ( or f o ur ti mes t h e half -life f or m olec ular tar gete d a ge nts, 
w hic he ver is s h orter) of first a d mi nistrati o n of st u d y treat me nt:  
a. F or nitr os o ureas a n d mit o m y ci n C wit hi n 6 wee ks of first 
a d mi nistrati o n of st u d y treat me nt  
b.  C o nti n u o us d osi n g 
of ≥1 0 
m g pre d nis ol o ne  ( or ster oi d 
e q ui vale nt)  is n ot all o we d d uri n g t he st u d y. C ortic oster oi d 
treat me nt is all o we d d uri n g scree ni n g b ut s h o ul d be wea ne d t o a 
d ose of ≤1 0 m g pre d nis ol o ne ( or ster oi d e q ui vale nt) b y C y cle 1 
Da y 1  
* P alli ative r a di ot her a py d uri n g p artici p ati o n i n t he st u dy is per mitte d, b ut 
s h o ul d n ot be c o nc urre nt wit h st u dy tre at me nt a n d rec overy s h o ul d be 
all o we d t o preve nt overl a p pi n g t oxicity  (refer t o Secti o n 1 0. 4 ). It s h o ul d 
n ot  i ncl u de a tar get lesi o n.  
1 1.  Resi d ual t o xicities fr o m pri or c he m ot hera p y or ra di ot hera p y w hic h 
ha ve n ot re gresse d t o Gra de ≤1 se verit y ( C T C A E v 5. 0), e xce pt f or 
al o pecia a n d resi d ual Gra de 2 ne ur o pat h y.  
1 2.  Hist or y 
of 
ot her 
mali g na ncies, 
e xce pt 
a de q uatel y 
treate d 
n o n -mela n o ma s ki n ca ncer, c urati vel y treate d i n sit u ca ncer of t he 
cer vi x, s ur gicall y e xcise d or p ote ntiall y c urati vel y treate d d uctal 
carci n o ma i n sit u of t he breast, or l o w -gra de pr ostate ca ncer or patie nts 
after pr ostatect o m y. Patie nts wit h pre vi o us i n vasi v e ca ncers are 
eli gi ble if treat me nt was c o m plete d > 3  y ears pri or t o i nitiati n g t he 
c urre nt st u d y treat me nt, a n d t he patie nt has ha d n o e vi de nce or 
rec urre nce si nce t he n. 
1 3.  Prese nce of a n acti ve bacterial or viral i nfecti o n (i ncl u di n g S A R S -
C o V -2, Her pes Z oste r, Varicella Z oster or c hic ke n p o x), k n o w n H u ma n 
I m m u n o deficie nc y Vir us ( HI V) p ositi ve or k n o w n acti ve he patitis B or 
C.  
1 4.  Prese nce of a n y u nc o ntr olle d c o nc urre nt seri o us ill ness, 
me di cal 
c o n diti o n or ot her me dical hist or y, i ncl u di n g la b orat or y res ults, w hic h, 
i n t he I n vesti gat or’s o pi ni o n, w o ul d be li kel y t o i nterfere wit h t he 
patie nt’s a bilit y t o partici pate i n t he st u d y or wit h t he i nter pretati o n of 
t he res ults, i ncl u di n g t he f oll o wi n g: 

N u Ti de: 3 2 3                                                                                                                        Versi o n 2 .1 , 0 6  Fe b  2 0 2 4  
C o nfi de ntia l                                                            N u Ca na  plc  
1 3  
a. C o n gesti ve heart fail ure ( Ne w Y or k Heart Ass ociati o n Class III or 
Class  I V) 
b.  Cli nicall y si g nifica nt c or o nar y heart disease or 
m y ocar dial 
i nfarcti o n wit hi n 6 m o nt hs of t he first d ose of st u d y me dicati o n or 
hi g h ris k of u nc o ntr olle d arr h yt h mia  
c. U nsta ble or p o orl y c o ntr olle d a n gi na pect oris  
d.  C o m plete left b u n dle bra nc h, fasci c ular bl oc k or ot her cli nicall y 
si g nifica nt a b n or mal E C G fi n di n g 
e. Q Tc i nter val > 4 7 0 millisec o n ds  
f. Hist or y of or c urre nt ris k fact or f or t orsa de de p oi ntes ( e. g., heart 
fail ure, h y p o kalae mia, or a fa mil y hist or y of l o n g Q T s y n dr o me)  
g.  Hist or y of se vere s ki n re acti o ns  (e xce pt f or s ki n reacti o ns t hat are a 
c o nse q ue nce 
of 
rece nt 
a nti -ca ncer 
treat me nt, 
i ncl u di n g 
c he m ot hera pies n ot c urre ntl y u n der i n vesti gati o n i n t his st u d y [e. g., 
o xali plati n ] or 
m olec ular tar gete d t hera pies s uc h as 
E G F R 
i n hi bit ors) 
h.  Hist or y of se ve re oc ular dis or ders 
i. I nterstitial p ne u m o nitis or p ul m o nar y fi br osis 
1 5.  A n y 
c o n diti o n ( e. g., k n o w n 
or s us pecte d 
p o or 
c o m plia n ce, 
ps y c h ol o gical i nsta bilit y, ge o gra p hical l ocati o n, etc.) t hat, i n t he 
j u d g me nt of t he I n vesti gat or, ma y affect t he patie nt’s a bilit y t o pr o vi de 
i nf or me d c o nse nt a n d u n der g o st u d y pr oce d ures. 
1 6.  Patie nts wit h a hist or y of h ae m o pt ysis ( 1/ 2 teas p o o n or m ore of re d 
bl o o d) wit hi n 6  m o nt hs pri or t o e nr ol me nt.  
1 7.  W o u n d heali n g c o m plicati o ns or s ur ger y wit hi n 2 8 da ys of starti n g 
be vaciz u ma b ( w o u n d heali n g m ust ha ve bee n f ull y c o m plete d bef ore 
starti n g be vaciz u ma b). I n vesti gat ors ma y all o w patie nts t o i nitiate 
treat me nt wit h t he ot her st u d y dr u gs (i.e., N U C -3 3 7 3/ 5 -F U, L V a n d 
iri n oteca n) o n C 1 D 1 b ut wit h h ol d be vaciz u ma b f or at least 1 5 da ys, 
b ut n o l o n ger t ha n 2 8 da ys, t o all o w c o m pl eti o n of w o u n d heali n g i n 
patie nts w h o w o ul d ot her wise be eli gi ble f or t he st u d y, i n li ne wit h 
sta n dar d l ocal practice a n d after disc ussi o n wit h t he Me dical M o nit or . 
Patie nts w h o ha ve n ot recei ve d be vaciz u ma b b y C 2 D 1 m ust b e 
re place d.   
1 8.  U n heale d w o u n d, acti ve gastric or d u o de nal ulcer, or b o ne fract ure.  
1 9.  Seri o us t hr o m b oe m b olic e ve nt i n t he 6 m o nt hs bef ore i ncl usi o n ( e. g., 
tra nsit or y isc he mic str o ke, str o ke, s u barac h n oi d hae m orr ha ge) . 
Patie nts 
wit h 
n o n -seri o us t hr o m b o e m b olic eve nts  (e. g., n o n -
s y m pt o matic p ul m o nar y e m b olis m or peri p heral dee p vei n t hr o m b osis 
treate d wit h a ntic oa g ula nts) ma y be e nr olle d after disc ussi o n wit h t he 
Me dical M o nit or . 
2 0.  Patie nts wit h a hist or y of hae m orr ha ge  wit hi n 6  m o nt hs pri or t o 
e nr ol me nt.  
2 1.  K n o w n i n herite d or ac q uire d blee di n g dis or ders. 
2 2.  Re d bl o o d cell  ( R B C) tra nsf usi o n de pe n de nce, defi ne d as re q uiri n g 
m or e t ha n 2  u nits of pac ke d R B C tra nsf usi o ns d uri n g t he 4 -wee k 
peri o d pri or t o scree ni n g.  
2 3.  U nc o ntr olle d h y perte nsi o n.  
2 4.  Se vere pr otei n uria or ne p hr otic  s y n dr o me (≥Gra de 3 [ uri ne di pstic k + 4 
or ≥3. 5 g/ da y]) . 
2 5.  Ac ute 
i ntesti nal 
o bstr ucti o n 
or 
s u b -o bstr ucti o n, 
hist or y 
of 
i nfla m mat or y i ntesti nal disease (i ncl u di n g c olitis or Cr o h n’s disease) 

N u Ti de: 3 2 3                                                                                                                        Versi o n 2 .1 , 0 6  Fe b  2 0 2 4  
C o nfi de ntia l                                                            N u Ca na  plc  
1 4  
or e xte n de d resecti o n of t he s mall i ntesti ne. Prese nce of a c oli c 
pr ost hesis.  
2 6.  Hist or y of a b d o mi nal fist ulas, trac hea -oes o p ha geal fist ulas, a n y ot her 
Gra de 4 gastr oi ntesti nal perf orati o ns, n o n -gastr oi ntesti nal fist ulas, or 
i ntra-a b d o mi nal a bscesses 6 m o nt hs pri or t o scree ni n g.  
2 7.  C urre ntl y pre g na nt, lactati n g or breastfee di n g.  
2 8.  Re q uire d c o nc o mita nt use of bri v u di ne , s ori v u di ne a n d a nal o g ues. 
2 9.  Re q uire d c o nc o mita nt use of St J o h n's W ort.  
3 0.  Re q uire d c o nc o mita nt use of dr u gs k n o w n t o pr ol o n g Q T/ Q Tc i nter val.  
3 1.  Re q uire d c o nc o mita nt u se of str o n g C Y P 3 A 4 i n d ucers or str o n g 
C Y P 3 A 4  i n hi bit ors. T he use of str o n g C Y P 3 A 4 i n d ucers wit hi n 2 
wee ks of first recei pt of st u d y dr u g or t he use of str o n g C Y P 3 A 4 
i n hi bit ors wit hi n 1 wee k of first recei pt of st u d y dr u g is als o e xcl u de d. 
3 2.  Use of str o n g U G T 1 A 1 i n hi bit ors wit hi n 1 wee k of first recei pt  of 
st u d y dr u g. 
3 3.  Recei ve d a li ve vacci nati o n wit hi n f o ur wee ks of first pla n ne d d ose of 
st u d y me dicati o n.  
3 4.  Ger m a n y o nl y:  Patie nts w h o ha ve bee n place d i n a n i nstit uti o n b y 
c o urt or official or der.  
St u d y D ur ati o n Per 
P atie nt  
Patie nts ma y c o nti n ue t o recei ve  treat me nt i n t he a bse nce of disease 
pr o gressi o n or u nacce pta ble t o xicit y t hat is n ot a meli orate d b y o pti mal 
me dical or n o n -me dical s u p p orti ve or pr o p h ylactic care , or wit h dra wal of 
c o nse nt . A vera ge ti me o n st u d y is esti mate d at a p pr o xi matel y 7-1 1 m o nt hs 
fr o m start of scree ni n g t o last pr ot oc ol visit, base d o n t he me dia n P F S of 
patie nts wit h u nresecta ble metastatic disease.  
All patie nts will be f oll o we d u p u ntil wit h dra wal of c o nse nt, l ost t o 
f oll o w-u p, deat h, or t he o verall e n d of st u d y, w hic he ver is earli est. 
S a m ple Size a n d 
St atistic al A n al ysis  
Sa m ple Size  
I n t otal, 1 7 1 patie nts will be ra n d o mise d o n a 1: 1: 1 basis ( 5 7 patie nts per 
ar m) t o eit her Q 1 W N U FI RI -be v, Q 2 W N U FI RI -b e v or F O L FI RI -be v 
( Q 2 W).  
T he pri nci pal statistical o bjecti ve of t his st u d y is t o esti mate t he li kel y 
efficac y of t he t w o N U FI RI ar ms as c o m pare d t o t he F O L FI RI c o ntr ol ar m 
t o s u p p ort decisi o n ma ki n g re gar di n g t he f urt her de vel o p me nt of N U FI RI. 
Me dia n P F S is e x pecte d t o be 7 m o nt hs o n t he F O L FI RI c o ntr ol ar m a n d 
at least 9. 9 m o nt hs o n e ac h of t he t w o N U FI RI ar ms. Ass u mi n g a n o n -
li near recr uit me nt pr ofile o ver t he pla n ne d 13 -m o nt h accr ual peri o d ( η = 2; 
Carr oll, 2 0 0 9) a n d wit h a mi ni m u m of 1 7  m o nt hs f oll o w -u p p ost -accr ual, 
a t otal of 1 3 9 P F S e ve nts are e x pecte d acr oss t he t hree ra n d o mise d ar ms. 
Wit h t his a m o u nt of i nf or mati o n, t his st u d y will pr o vi de a n 8 0 % pr o ba bilit y 
of c orrectl y c o ncl u di n g s u peri orit y w he n N U FI RI is tr ul y better t ha n 
F O L FI RI i n ter ms of P F S a n d, si milarl y, a n 8 0 % pr o ba bilit y of c orrectl y 
c o ncl u di n g n o n -s u peri orit y w he n N U FI RI is tr ul y t he sa me as F O L FI RI i n 
ter ms of P F S. T he s mallest o bser ve d i m pr o ve me nt i n me dia n P F S f or eit her 
N U FI RI ar m relati ve t o F O L FI RI t o c o ncl u de N U FI RI is tr ul y better t ha n 
F O L FI RI is 1. 3 m o nt hs.  
F urt her, a n e val uati o n of efficac y ma y be perf or me d 3 m o nt hs after t he last 
patie nt has bee n ra n d o mise d. At t his ti me a t otal of 7 0 P F S e ve nts are 
e x pecte d acr oss t he t hree ra n d o mise d ar ms. 
Wit h t his a m o u nt of 
i nf or mati o n, t he s mallest o bser ve d i m pr o ve me nt i n me dia n P F S f or eit her 

N u Ti de: 3 2 3                                                                                                                        Versi o n 2 .1 , 0 6  Fe b  2 0 2 4  
C o nfi de ntia l                                                            N u Ca na  plc  
1 5  
N U FI RI ar m relati ve t o F O L FI RI t o c o ncl u de N U FI RI is tr ul y better t ha n 
F O L FI RI is 1. 9 m o nt hs.  
Statistical Met h o ds  
Patie nt de m o gra p hics a n d cli nical c haracteristics will be s u m marise d usi n g 
descri pti ve statistics.  
Effic acy A n alysis P o p ul ati o n  
Efficac y e n d p oi nts will be assesse d i n t he F ull A nal ysis Set ( F A S), defi ne d 
as all ra n d o mise d patie nts. A s u p p orti ve a nal ysis of efficac y e n d p oi nt data 
will be perf or me d i n t he m o difie d F A S bei n g defi ne d as t he s u bset of t he 
F A S w h o ha d at least o ne d ose o f ra n d o mise d st u d y treat me nt a n d at least 
o ne f oll o w -u p assess me nt.  
S afety A n alysis P o p ul ati o n  
Safet y will be assesse d i n t he Safet y Set ( S S), defi ne d as all ra n d o mise d 
patie nts w h o recei ve at least o ne d ose ( or partial d ose) of st u d y treat me nt. 
Patie nts w ill be a nal yse d b y t he treat me nt recei ve d, base d o n t heir first 
d ose of ra n d o mise d st u d y dr u g.  
Effic acy A n alysis  
P F S ti me ( defi ne d as t he ti me fr o m ra n d o misati o n t o t he first pr o gressi o n 
or deat h)  will be a nal yse d via C o x re gressi o n m o delli n g  stratifie d f or t he 
ra n d o misati o n stratificati o n fact ors ( R A S stat us, first -li ne treat me nt, a n d 
d urati o n of pri or li ne of t hera p y) a n d i ncl u di n g a fi xe d effect ter m f or 
ra n d o mise d treat me nt . Patie nts free fr o m pr o gressi o n a n d deat h will b e 
ce ns ore d at t hei r last f oll o w-u p visit. T he hazar d rati o will be esti mate d f or 
eac h N U FI RI ar m vers us t he F O L FI RI c o ntr ol ar m, al o n g wit h t he 
ass ociate d c o nfi de nce i nter val ( CI) a n d 2 -si de d p val ue. T he data will als o 
be dis pla y e d usi n g Ka pla n -Meier c ur ves a n d me dia n P F S ti mes will be 
esti mate d.  
T he a nal ysis of sec o n dar y efficac y e n d p oi nts will be detaile d i n t he 
Statistical A n al ysis Pla n.  
S afety A n alysis  
A d verse e ve nts  ( A Es) will be classifie d usi n g t he latest versi o n of t he 
Me dical Dicti o nar y f or Re g ulat or y Acti vities ( Me d D R A) classificati o n 
s yste m. T he se verit y will be gra de d acc or di n g t o C T C A E v 5. 0 w he ne ver 
p ossi ble. All A Es re p orte d fr o m t he first d ose of st u d y dr u g u ntil  3 0  da ys 
after t he last d ose of st u d y dr u g will be c o nsi dere d as treat me nt -e mer ge nt 
A Es ( T E A Es) a n d will be s u m marise d descri pti vel y b y treat me nt, a n d b y 
t he fre q ue nc y of patie nts e x perie nci n g T E A Es c orres p o n di n g t o b o d y 
s yste ms a n d Me d D R A preferre d ter m. Patie nts wit h m ulti ple occ urre nces 
of e ve nts will o nl y be c o u nte d o nce at t he ma xi m u m se verit y/ gra de f or eac h 
Preferre d Ter m, S yste m Or ga n Class ( S O C), a n d o verall. A n y A Es wit h 
missi n g se verit y will be classifie d as se vere. Deat hs t hat occ ur wit hi n 
9 0  da ys after t he last d ose of st u d y dr u g are defi ne d as o n -st u d y deat hs. 
Sc he d ule d p h ysical e xa mi nati o n, vital si g ns, a n d h ae mat ol o g y a n d 
c he mistr y la b orat or y data will be s u m marise d b y treat me nt a n d b y c ycle. 
T he la b orat or y res ults will be gra de d acc or di n g  t o t he C T C A E v 5. 0 se verit y 
gra de. T he fre q ue ncies of t he w orst se verit y gra de o bser ve d will be 
dis pla y e d b y st u d y me dicati o n. S hift ta bles will be pr o vi de d t o e xa mi ne t he 
distri b uti o n of la b orat or y t o xicities. F or para meters f or w hic h a  C T C A E 
v 5. 0 scale d oes n ot e xist, t he fre q ue nc y of patie nts wit h val ues bel o w, 
wit hi n, a n d a b o ve t he n or mal ra n ges will be s u m marise d b y treat me nt.  

N u Ti de: 3 2 3                                                                                                                        Versi o n 2 .1 , 0 6  Fe b  2 0 2 4  
C o nfi de ntia l                                                            N u Ca na  plc  
1 6  
O V E R A L L S T U D Y D E SI G N  
 
 
Fi g ure 1  
N u Ti de: 3 2 3 st u d y sc he m a  
 
A b bre viati o ns: F O L FI RI = 5 -F U + L V + iri n ot eca n; N U FI RI = N U C -3 3 7 3 + L V + iri n oteca n; P F S = pr o gressi o n -free s ur vi val; Q 1 W = wee kl y; Q 2 W = alter nate wee kl y

N u Ti de: 3 2 3                                                                                                                        Versi o n 2 .1 , 0 6  Fe b  2 0 2 4  
C o nfi de ntia l                                                            N u Ca na  plc  
1 8  
Ra n d o misati o n  
 
X 1 7 
 
 
 
 
 
 
 
 
 
 
 
N U C -3 3 7 3 + L V 
a d mi nistrati o n ( Q 1 W)  
 
X  
X  
X  
X  
X  
X  
X  
X  
 
 
 
 
N U C -3 3 7 3 + L V 
a d mi nistrati o n ( Q 2 W)  
 
X  
 
X  
 
X  
 
X  
 
 
 
 
 
5 -F U + L V a d mi nistrati o n  
 
X  
 
X  
 
X  
 
X  
 
 
 
 
 
Iri n oteca n a d mi nistrati o n 
 
X  
 
X  
 
X  
 
X  
 
 
 
 
 
Be vaciz u ma b 
a d mi nistrati o n 
 
X  
 
X  
 
X  
 
X  
 
 
 
 
 
A Es/ S A Es 1 8 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
 
 
P K bl o o d sa m ple 1 9  
 
 
 
 
 
X 1 9 
 
 
 
 
 
 
 
Arc hi ve d sa m ple 2 0 
X  
 
 
 
 
 
 
 
 
 
 
 
 
De ntal e xa mi nati o n 2 1  
X  
 
 
 
 
 
 
 
 
 
 
 
 
F oll o w -u p  
 
O n g oi n g  
 
 
X 2 2 
* D a y 8 a n d D a y 2 2 visits are o nl y t o be perf or me d f or p atie nts recei vi n g Q 1 W N U C -3 3 7 3 ( Ar m  A)  
1  
Assess me nts sc he d ule d o n da ys of d osi n g s h o ul d be d o ne pri or t o a d mi nistrati o n of all i n vesti gati o n me dici nal pr o d ucts (I M Ps), u nless ot her wise 
s pecifie d. La b assess me nts ma y be perf or me d u p t o 7 2 h o urs pri or t o I M P a d mi nistrati o n.  
2  
I ncl u des rec or di n g i nf or mati o n o n t he si de d ness of t he patie nt’s C R C (left-si de d vs ri g ht-si de d). 
3  
A f ull p h ysical assess me nt s h o ul d be c o m plete d at C ycle 1 Da y 1, C ycle 2 Da y 1 a n d at  E n d of Treat me nt. Fr o m C ycle 3 Da y 1 o n war ds, a directe d 
p h ysical assess me nt will be c o m plete d (i n place of t he f ull p h ysical assess me nt), b ut o nl y if cli nicall y i n dicate d.  
4  
Uri nal ysis testi n g f or pr otei n uria s h o ul d be perf or me d pri or t o eac h be vaciz u ma b a d mi nistrati o n.  
5  
D oes n ot nee d t o be re peate d if Scree ni n g assess me nt was perf or me d wit hi n 7 2 h o urs of C 1 D 1.  
6  
Vital si g ns i ncl u de res pirati o n rate, p ulse, te m perat ure a n d bl o o d press ure.  Hei g ht s h o ul d be rec or de d at baseli ne o nl y. Wei g ht s h o ul d be rec or de d 
at baseli ne, Da y 1 of e ver y c ycle a n d at e n d of st u d y visit. If a patie nt’s wei g ht i ncreases or decreases b y ≥1 0 % d uri n g t he c o urse of t he st u d y, t he 
d ose of st u d y treat me nts s h o ul d be recalc ulate d . 
7  
Pre -d ose E C Gs:  Sta n dar d 1 2 -lea d E C G meas ure me nts will be perf or me d pri or t o a d mi nistrati o n of all I M Ps, at t he i n dicate d visits ( Da y 1 of eac h 
c ycle) f or patie nts i n all treat me nt ar ms. 
All 1 2 -lea d E C G meas ure me nts s h o ul d be perf or me d i n tri plic ate ( kee pi n g t he lea ds i n place a n d t he patie nt s u pi ne d uri n g rea di n gs) a n d re vie we d 
b y t he I n vesti gat or or q ualifie d desi g nee f or safet y a n d q ualit y. T he ti mi n g bet wee n t he tri plicate E C Gs is rec o m me n de d t o be a p pr o xi matel y 
1  mi n ute.  

N u Ti de: 3 2 3                                                                                                                        Versi o n 2 .1 , 0 6  Fe b  2 0 2 4  
C o nfi de ntia l                                                            N u Ca na  plc  
1 9  
8  
P ost -d ose E C Gs:  A d diti o nal sta n dar d 1 2-lea d E C G meas ure me nts m ust be ta ke n p ost  a d mi nistrati o n of all I M Ps  o n C 1 D 1, C 1 D 1 5, C 2 D 1 a n d 
C 2 D 1 5 ( wit hi n 1 0 mi n utes of t he e n d of i nf usi o n)  f or patie nts i n t he N U FI RI tre at me nt ar ms  o nl y  ( Ar ms A a n d B). 
9  
Ser u m pre g na nc y assess me nt t o be perf or me d wit hi n 7 da ys of C 1 D 1. Re q uire d o nl y i n w o me n of c hil d beari n g p ote ntial.  I n Fr a nce o nl y: 
Pre g na nc y testi n g m ust c o nti n ue e ver y 4 wee ks f or 6 m o nt hs after t he last d ose of st u d y treat me nt. T his p ost -st u d y treat me nt pre g na nc y testi n g 
m ust n ot be perf or me d wit h a h o me test; h o we ver, i n or der t o a v oi d fre q ue nt h os pital visits, it ma y be perf or me d at a n e xter nal la b orat or y t hat is 
l ocal t o t he patie nt, wit h o versi g ht b y t he st u d y site. If t his occ urs, t he st u d y site m ust n otif y t he S p o ns or. All i nsta nces of p ositi ve pre g na nc y te sts 
m ust be n otifie d b y t he e xter nal la b orat or y t o t he st u d y site, S p o ns or a n d t he patie nt’s treati n g p h ysicia n .  
1 0  
Cli nical c he mistr y (i ncl u di n g he patic pa nel) a n d h ae mat ol o g y will be c o n d ucte d wee kl y i n t he Q 1 W treat me nt ar m a n d alter nate wee kl y  i n t he 
Q 2 W treat me nt ar ms t hr o u g h o ut t he st u d y. I n t he e ve nt of ne utr o pe nia ( A N C < 0. 5 × 1 0 9/ L), t hr o m b oc yt o pe nia ( platelet c o u nt < 5 0 × 1 09/ L), or ≥Gra de 
2 cli nical c he mistr y t o xicit y, t hese assess me nts will be c o n d ucte d m ore fre q ue ntl y as cli nicall y i n dicate d  u ntil t o xicit y res ol ves t o ≤Gra de  1.  
1 1  
C ollect a pre -d ose bl o o d sa m ple f or e val uati o n of carci n oe m br y o nic a nti ge n ( C E A ). 
1 2  
If n ot alrea d y k n o w n, D P D stat us  s h o ul d be teste d d uri n g scree ni n g a n d perf or me d acc or di n g t o l ocal a n d nati o nal g ui deli nes a n d sta n dar d  practice, 
eit her b y ge n ot y pi n g or p he n ot y pic testi n g usi n g bl o o d uracil le vels . Patie nts wit h bl o o d uracil ≥1 5 0 n g/ m L are c o nsi dere d t o be D P D deficie nt 
a n d are e xcl u de d fr o m partici pati o n. Patie nts wit h bl o o d uracil le vels of  ≥1 6 n g/ m L t o < 1 5 0 n g/ m L are c o nsi dere d t o be partiall y D P D deficie nt . 
T he 5 -F U d ose m ust be a da pte d  f or partiall y D P D deficie nt patie nts i n c o u ntries w here t his is sta n dar d practice as per nati o nal a n d/ or l ocal 
g ui deli nes  (refer t o Secti o n 9. 2. 1 ).   
1 3  
If K R A S/ N R A S/ B R A F/ M SI/ M M R stat us is n ot k n o w n , perf or m ge netic testi n g a n d o btai n res ults pri or t o d osi n g o n C 1 D 1.  
1 4  
If U G T 1 A 1 stat us is n ot k n o w n , perf or m ge netic testi n g. Res ults d o n ot nee d t o be o btai ne d pri or t o d osi n g. If a patie nt’s m utati o nal stat us is 
k n o w n pri or t o d osi n g a n d t he y ha ve a m utati o n t hat ma y affect t heir a bilit y t o meta b olise iri n oteca n, a n i nitial d ose re d ucti o n of iri n otec an ma y 
be i m ple me nte d as per t he iri n oteca n S m P C/ Prescri bi n g I nf or mati o n a n d site sta n dar d of care. T his m ust be disc usse d o n a case-b y -case basis wit h 
t he me dical m o nit or.  
1 5  
C o m p ute d t o m o gra p h y ( C T ) / ma g netic res o na nce i ma gi n g ( M RI ) disease assess me nts wil l be perf or me d at Scree ni n g ( wit hi n 2 8 da ys pri or t o 
ra n d o misati o n) a n d e ver y 8 wee ks ( ± 7  da ys) fr o m C 1 D 1 .  
A d diti o nal tests ma y be re q ueste d at t he I n vesti gat or’s discreti o n. T he sa me m o dalit y s h o ul d be use d t hr o u g h o ut.  
1 6  
Patie nts disc o nti n ui n g st u d y treat me nt wit h n o ra di ol o gical e vi de nce of disease pr o gressi o n will re mai n i n t he st u d y a n d rece i ve sca ns e ver y 
8  wee ks ( ± 7 da ys) fr o m C 1 D 1 u ntil disease pr o gressi o n, i nitiati o n of a s u bse q ue nt li ne of t hera p y, or deat h i n or de r t o deter mi ne d urati o n of o verall 
res p o nse a n d P F S .  
1 7  
Ra n d o mis ati o n ta kes place u p t o 3  w or ki n g da y s pri or t o a d mi nistrati o n of st u d y treat me nt o n C 1 D 1.  

N u Ti de: 3 2 3                                                                                                                        Versi o n 2 .1 , 0 6  Fe b  2 0 2 4  
 
C o nfi de ntia l                                                            N u Ca na  plc  
 
2 1  
A B B R E VI A TI O N S  
5 -F U  
5 -fl u or o uracil  
A D R  
A d verse dr u g reacti o n  
A E  
A d verse e ve nt  
A L T  
Ala ni ne a mi n otra nsferase  
A N C  
A bs ol ute ne utr o p hil c o u nt  
A P C  
7 -et h yl-1 0 -[ 4-N -( 5-a mi n o pe nta n oic  aci d) -1 -pi peri di n o]  
car b o n yl o x yca m pt ot heci n  (iri n oteca n meta b olite) 
a P T T 
Acti vate d partial t hr o m b o plasti n ti me  
A S C O  
A merica n S ociet y f or Cli nical O nc ol o g y  
A S T  
As partate a mi n otra nsferase  
A U C  
Area u n der t he plas ma c o nce ntrati o n -ti me c ur ve 
B O R  
Best o verall res p o nse  
B R A F  
v -Raf m uri ne sarc o ma viral o nc o ge ne h o m ol o g B  
B S A  
B o d y  s urface area 
C E A  
Carci n oe m br y o nic a nti ge n  
C F R  
C o de of Fe deral Re g ulati o ns  
C H O  
C hi nese Ha mster O var y (cells)  
CI  
C o nfi de nce i nter val  
C i nf 
C o nce ntrati o n at t he e n d of i nf usi o n  
C L  
A p pare nt cleara nce  
C ma x  
Ma xi m u m plas ma c o nce ntrati o n; pea k plas ma c o nce ntrati o n  
C O VI D -1 9  
C or o na vir us Disease 2 0 1 9  
C R  
C o m plete res p o nse  
C R C  
C ol orectal ca ncer  
C R F  
Case re p ort f or m  
C R O  
Cli nical Researc h Or ga nisati o n  
C S R  
Cli nical st u d y re p ort  
C T  
C o m p ute d t o m o gra p h y  
C T C A E  
C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts  
C Y P  
C yt oc hr o me P 4 5 0  
D C R  
Disease c o ntr ol rate  
D L T  
D ose -li miti n g t o xicit y 
D M A  
Di met h ylaceta mi de  
d M M R  
Deficie nt mis matc h re pair  
D o R  
D urati o n of res p o nse  
D o S D  
D urati o n of sta ble disease  
D P D  
Di h y dr o p yri mi di ne de h y dr o ge nase  
D S U R  
De vel o p me nt safet y u p date re p ort 
d T M P  
De o x yt h y mi di ne m o n o p h os p hate  
d U M P  
De o x y uri di ne m o n o p h os p hate  
E C G  
Electr ocar di o gra m  
E C O G  
Easter n C o o perati ve O nc ol o g y Gr o u p  
e C R F  
Electr o nic Case Re p ort F or m  
E D C  
Electr o nic data ca pt ure  
E G F R  
E pi der mal gr o wt h fact or rece pt or  
E u dra C T  
E ur o pea n U ni o n Dr u g Re g ulati n g A ut h orities Cli nical Trials Data base  
F A S  
F ull a nal ysis set  

N u Ti de: 3 2 3                                                                                                                        Versi o n 2 .1 , 0 6  Fe b  2 0 2 4  
C o nfi de ntia l                                                            N u Ca na  plc  
2 2  
F B A L  
α -fl u or o-β -ala ni ne 
F D A  
( U S) F o o d a n d Dr u g A d mi nistrati o n  
F F P E  
F or mali n -fi xe d paraffi n e m be d de d  
F O L FI RI  
5 -F U + L V + iri n oteca n  
F O L F O X  
5 -F U + L V + o xali plati n  
F O L F O XI RI  
5 -F U + L V + o xali plati n + iri n oteca n  
F U D R  
Fl o x uri di ne ( 5 -fl u or o de o x y uri di ne) 
F U D R -M P 
/ F d U M P 
Fl u or o de o x y uri di ne -m o n o p h os p hate  
F U D R -T P 
/ F d U T P 
Fl u or o de o x y uri di ne -tri p h os p hate 
F U T P  
Fl u or o uri di ne tri p h os p hate  
G -C S F  
Gra n ul oc yte c ol o n y sti m ulati n g fact or  
HI V  
H u ma n I m m u n o deficie nc y Vir us  
I B 
I n vesti gat or’s Br oc h ure 
I C F 
I nf or me d c o nse nt f or m 
I C H-G C P  
I nter nati o nal C o u ncil f or Har m o nisati o n - G o o d Cli nical Practice  
I M P 
I n vesti gati o nal me dici nal pr o d uct 
I N D 
I n vesti gati o nal Ne w Dr u g  
I N R 
I nter nati o nal n or malise d rati o 
I R B/ E C 
I nstit uti o nal re vie w b oar d/ et hics c o m mittee 
I V 
I ntra ve n o us(l y) 
I x R S 
I nteracti ve v oice- or we b -base d res p o nse s yste m  
K R A S  
Kirste n rat sarc o ma vir us  
L D H  
Lactate de h y dr o ge nase  
L V  
Le uc o v ori n  
Me d D R A  
Me dical Dicti o nar y f or Re g ulat or y Acti vities  
m F A S  
M o difie d f ull a nal ysis set  
M H R A  
Me dici nes a n d Healt hcare Re g ulat or y A ge nc y ( U K)  
M RI  
Ma g netic res o na nce i ma gi n g  
M SI -H  
Micr osatellite i nsta bilit y hi g h  
M T D  
Ma xi m u m t olerate d d ose  
N E  
N ot e val ua ble  
N R A S  
Ne ur o blast o ma R A S viral o nc o ge ne h o m ol o g  
N U FI RI  
N U C -3 3 7 3 + L V + iri n oteca n  
N U F O X  
N U C -3 3 7 3 + L V + o xali plati n  
O P R T  
Or otate P h os p h ori b os yl Tra nsferase  
O R R  
O bjecti ve Res p o nse Rate  
O S  
O verall s ur vi val  
P B M C  
Peri p heral bl o o d m o n o n uclear cell  
P F S  
Pr o gressi o n -Free S ur vi val  
P K  
P har mac o ki netics  
P R  
Partial Res p o nse  
P T  
Pr ot hr o m bi n ti me  
Q 1 W  
Wee kl y  
Q 2 W  
Alter nate wee kl y (f ort ni g htl y)  
Q T/ Q Tc  
Q T i nter val / C orrecte d Q T i nter val  
R B C  
Re d bl o o d cells  
R E CI S T  
Res p o nse E val uati o n Criteria i n S oli d T u m o urs  ( versi o n 1. 1) 

N u Ti de: 3 2 3                                                                                                                        Versi o n 2 .1 , 0 6  Fe b  2 0 2 4  
C o nfi de ntia l                                                            N u Ca na  plc  
2 3  
R P 2 D  
Rec o m me n de d P hase II d ose  
R SI  
Refere nce Safet y I nf or mati o n  
S A E  
Seri o us a d verse e ve nt  
S A P  
Statistical a nal ysis pla n  
S A R S -C o V -2  
Se vere ac ute res pirat or y s y n dr o me -relate d c or o na vir us 2 
S D  
Sta ble Disease  
S m P C  
S u m mar y of Pr o d uct C haracteristics  
S N -3 8  
7 -et h yl-1 0 -h y dr o x yca m pt ot heci n  (iri n oteca n acti ve meta b olite) 
S N -3 8 G  
S N -3 8 gl uc ur o ni de  (iri n oteca n i nacti ve meta b olite) 
S O C  
S yste m Or ga n Class  
S R P 8 0  
S u per refi ne d p ol ys or bate 8 0  
S S  
Safet y set  
S U S A R  
S us pecte d U ne x pecte d Seri o us A d verse Reacti o n  
t1/ 2 
Ter mi nal half -life 
T A F  
T e n of o vir alafe na mi de f u marate  
T E A E  
Treat me nt -e mer ge nt a d verse e ve nt  
T K  
T h y mi di ne ki nase  
T P  
T h y mi di ne p h os p h or ylase  
T S  
T h y mi d ylate s y nt hase  
T Y M P  
T h y mi di ne p h os p h or ylase  ( ge ne) 
U G T 1 A 1  
U D P gl uc ur o n os yltra nsferase 1 A 1  
U L N  
U p per li mit of n or mal  
V d 
V ol u me of distri b uti o n  
V E G F  
Vasc ular e n d ot helial gr o wt h fact or  
W B C  
W hite bl o o d cells  
W H O D D  
W orl d Healt h Or ga nisati o n Dr u g Dicti o nar y  
 

N u Ti de: 3 2 3                                                                                                                        Versi o n 2 .1 , 0 6  Fe b  2 0 2 4  
C o nfi de ntia l                                                            N u Ca na  plc  
2 4  
1.  
I N T R O D U C TI O N A N D S T U D Y R A TI O N A L E  
N ucle osi de a nal o gs are a ke y c o m p o ne nt of sta n dar d c he m ot hera p y re gi me ns f or a n u m ber of 
s oli d t u m o urs a n d hae mat ol o gical mali g na ncies. H o we ver, t hese a ge nts are ass ociate d wit h 
li mite d efficac y a n d si g nifica nt t o xicit y d ue t o i n here nt or ac q uire d ca ncer resista nce 
mec ha nis ms, i nefficie nt acti vati o n pat h wa ys, a n d p o or p har mac o ki netic pr ofiles.  
N u Ca na is utilisi n g p h os p h ora mi date c he mistr y t o de vel o p a first -i n-class ra n ge of a nti -ca ncer 
a ge nts calle d Pr o Ti des t hat are s pecificall y desi g ne d t o a d dress t he l i mitati o ns ass ociate d wit h 
c o n ve nti o nal n ucle osi de a nal o gs. Pr o Ti des are s y nt hesise d b y t he a d diti o n of a p h os p hate gr o u p 
o nt o a n ucle osi de a nal o g scaff ol d, t here b y creati n g a pre -acti vate d n ucle oti de a nal o g. T he 
p h os p hate is pr otecte d b y a p h os p h ora mi date  m otif  (c o nsisti n g of a n ar yl, a n ester, a n d a n 
a mi n o aci d) , w hic h sta bilises t he acti ve c o m p o u n d a n d pr otects it a gai nst brea k d o w n. As a 
res ult, Pr o Ti des d o n ot re q uire c o m ple x acti vati o n pat h wa ys, t he y ge nerate hi g her i ntracell ular 
le vels of acti ve a nti-ca ncer meta b olites, a n d t he y are resista nt t o de gra dati o n b y t he e nz y mes 
t hat brea k d o w n t he pare nt n ucle osi de a nal o gs. T his n ot o nl y i m pr o ves t he P K pr ofile b ut als o 
re d uces t he ge nerati o n of t o xic meta b olites a n d is a ntici pate d t o res ult i n greater a nti-ca ncer 
acti vit y c o m pare d t o c o n ve nti o nal n ucle osi de a nal o gs. T he p h os p h ora mi date a p pr oac h has 
bee n well vali date d i n t he a nti -viral fiel d wit h t he de vel o p me nt of s of os b u vir ( S o val di ® ) a n d 
te n of o vir alafe na mi de f u marate ( T A F). 
N U C -3 3 7 3 is a pre -acti vate d a n d  pr otecte d f or m of t he n ucle oti de a nal o g fl o x uri di ne ( F U D R ® ), 
s pecificall y desi g ne d t o o verc o me t he ke y s h ortc o mi n gs t hat li mit t he cli nical utilit y of 
fl u or o p yri mi di nes. T he o verall ai m is t o i m pr o ve t he efficac y a n d safet y pr ofile, w hilst als o 
re d uci n g the d osi n g a d mi nistrati o n b ur de ns, ass ociate d wit h 5 -fl u or o uracil (5 -F U ).  
1. 1.  
C ol orect al C a ncer  
C ol orectal ca ncer ( C R C) is t he t hir d m ost c o m m o n ca ncer  gl o ball y , acc o u nti n g f or 1 0 % of all 
ca ncers. T he i nci de nce w orl d wi de is a p pr o xi matel y 1. 9  milli o n ne w cases per year wit h a 
5 -year s ur vi val rate of 1 4 % f or patie nts dia g n ose d wit h Sta ge 4  disease  (S u n g et al, 2 0 2 1; A C S, 
2 0 2 2 ). I n t he U nite d States, t here are a p pr o xi matel y 1. 5 milli o n pe o ple li vi n g wit h C R C a n d 
a p pr o xi matel y 1 5 5 , 0 0 0 ne w cases of C R C  are dia g n ose d a n n uall y . T he gl o bal b ur de n is 
e x pecte d t o i ncrease b y 6 0 % t o a p pr o xi matel y  3. 1  milli o n ne w cases a n n uall y b y 2 0 4 0.  
T he maj orit y of C R C occ urs i n t he rect u m a n d si g m oi d c ol o n, w hile a s maller pr o p orti o n occ urs 
i n t he caec u m a n d asce n di n g c ol on. A p pr o xi matel y 2 0 % of patie nts ha ve metastatic disease at 
t he ti me of dia g n osis, fre q ue ntl y i n t he li ver, a n d a p pr o xi matel y 3 5 % of patie nts de vel o p 
metastases after a c urati ve i nte nt treat me nt ( De Falc o et al, 2 0 2 0). 
1. 2.  
Tre at me nt of  C ol orect al C a ncer  
S ur ger y is t he mai nsta y of c urati ve treat me nt ( 5 -year s ur vi val rates of 2 0 – 4 5 % re p orte d after 
t he s ur gical resecti o n of R 0 resecta ble c ol orectal li ver metastases); h o we ver, t he ma na ge me nt 
of C R C al m ost al wa ys i n v ol ves a m ulti -m o dal a p pr oac h. I n selecte d pa tie nts, a c o m bi nati o n of 
c he m ot hera p y a n d s ur ger y ca n ac hie ve l o n g -ter m s ur vi val a n d mai ntai ne d q ualit y of life 
(Sc h m oll et al, 2 0 1 2). S yste mic c he m ot hera p y c o nti n ues t o be t he c or nerst o ne of treat me nt f or 
patie nts wit h a d va nce d or metastatic C R C ( Lee & S u n, 2 0 1 6 ). 
M ost s yste mic t hera pies f or C R C i ncl u de t he p yri mi di ne a nal o g 5 -F U, eit her as m o n ot hera p y 
or i n c o m bi nati o n 
wit h a n ot her c he m ot hera pe utic, t y picall y o xali plati n or iri n oteca n. 
Ne vert heless, des pite bei n g t he sta n dar d of care, t he effecti ve ness of  5 -F U as a si n gle -a ge nt is 
m o dest.  

N u Ti de: 3 2 3                                                                                                                        Versi o n 2 .1 , 0 6  Fe b  2 0 2 4  
C o nfi de ntia l                                                            N u Ca na  plc  
2 5  
1. 2. 1  A dj u v a nt T re at me nt 
5 -F U  has bee n t he mai nsta y of a dj u va nt treat me nt f or hi g h -ris k Sta ge II or Sta ge III c ol o n 
ca ncer f or se veral deca des.  A d j u va nt c he m ot hera p y wit h a 5-F U -base d re gi me n has bee n 
s h o w n t o i m pr o ve o verall s ur vi val ( O S) b y 7 % ( 5 % f or t h ose wit h Sta ge II a n d 1 0 % wit h 
Sta ge  III ca ncer; Ra g n ha m mar et al, 2 0 0 1). I n t he a dj u va nt setti n g, 5-F U is gi ve n wit h 
le uc o v ori n (L V ) or c o m bi ne d wit h L V  a n d o xali plati n ( F O L F O X).  T he oral 5 -F U pr o dr u g 
ca pecita bi ne ( Xel o da) ca n be use d i nstea d of 5 -F U, eit her as m o n ot hera p y or i n c o m bi nati o n 
wit h o xali plati n . 
1. 2. 2  Tre at me nt f or M et ast atic D ise ase 
T he c h oice of 1 st-li ne treat me nt f or a d va nce d or metastatic C R C is i nfl ue nce d b y t he cli nical 
prese ntati o n a n d t u m o ur bi ol o g y ( e. g., sites of metastases; d y na mics of pr o gressi o n; prese nt or 
i m mi ne nt s y m pt o ms; pr o g n ostic m olec ular or bi oc he mical mar kers, s uc h as B R A F m utati o n), 
as well as patie nt -relate d fact ors (e. g., c o m or bi dit y a n d p ote ntial t o u n der g o sec o n dar y 
resecti o n) a n d dr u g-relate d fact ors (a vaila bilit y of tar gete d dr u gs; pre dicti ve mar kers, s uc h as 
R A S m utati o n) (Sc h m oll et al, 2 0 1 2). S yste mic t hera p y ma y  i ncl u de a fl u or o p yri mi di ne-base d 
c he m ot hera p y bac k b o ne paire d wit h a bi ol o gic a ge nt (a nti -vasc ular e n d ot helial gr o wt h fact or 
[V E G F ] or a nti -e pi der mal gr o wt h fact or rece pt or [ E G F R ] a nti b o dies). T he a nti -V E G F 
m o n ocl o nal a nti b o d y be vaciz u ma b was t he first bi ol o gic a p pr o ve d f or metastatic C R C a n d 
be nefits all patie nts wit h t his disease (H ur witz et al, 2 0 0 4). C urre ntl y, eit her a nti-V E G F 
( be vaciz u ma b) or a nti-E G F R (cet u xi ma b or pa nit u m u ma b) a ge nts ca n be use d i n 1 st-li ne 
treat me nt f or patie nts wit h left-si de d R A S a n d R A F wil dt y pe metastatic C R C (Hei ne ma n n et 
al , 2 0 1 4; Ve n o o k et al, 2 0 1 7). Ge nerall y, r i g ht-si de d C R Cs or R A S m uta nt C R Cs d o n ot be nefit 
fr o m a nti-E G F R a ge nts i n t he 1 st-li ne metastatic setti n g (Ve n o o k et al, 2 0 1 6; Ar n ol d et al, 
2 0 1 7 ); t heref ore, t hese patie nts t y picall y recei ve a fl u or o p yri mi di ne-base d c he m ot hera p y 
re gi me n i n c o m bi nati o n wit h be vaciz u ma b. Patie nts wit h B RA F -V 6 0 0 E m uta nt C R C ha ve a 
p o orer pr o g n osis (R ot h et al, 2 0 1 0) as t he t u m o urs are a g gressi ve a n d d o n ot res p o n d well t o 
s yste mic t hera p y. F or t hese patie nts, 1 st-li ne tri plet c he m ot hera p y (i.e., F O L F O XI RI) wit h 
be vaciz u ma b is rec o m me n de d a n d, m ore rece ntl y, c o m bi nati o ns wit h B R A F i n hi bit ors a n d 
a nti-E G F R a ge nts ha ve bee n a p pr o ve d as 2 n d-li ne a n d be y o n d o pti o ns f or t his patie nt 
p o p ulati o n (K o petz, 2 0 1 7 ; Va n C utse m 
et al, 2 0 1 9; K o petz 
et al, 2 0 1 9). Alt h o u g h 
i m m u n ot hera pies s uc h as ni v ol u ma b a n d pe m br oliz u ma b ha ve bee n a p pr o ve d f or metastatic 
C R C, o nl y 4 -5 % of patie nts ha ve d M M R or M SI -H t u m o urs; t h us, t he maj orit y of patie nts are 
n ot eli gi ble  f or i m m u n ot hera p y.  
T he c urre nt gl o bal sta n dar d of care for patie nts wit h metastatic C R C is a 5 -F U -c o ntai ni n g 
t hera p y s uc h as F O L F O X ( 5-F U + L V + o xali plati n), F O L FI RI ( 5 -F U + L V + iri n oteca n) or 
F O L F O XI RI ( 5 -F U + L V + o xali plati n + iri n oteca n). T he m ost c o m m o nl y a d mi nistere d 
sta n dar d of care re gi me n f or 1st-li ne metastatic patie nts is a F O L F O X -base d re gi me n, us uall y 
i n c o m bi nati o n wit h be vaciz u ma b or a n a nti-E G F R a nti b o d y. F oll o wi n g pr o gressi o n, m ost 
patie nts recei ve 2 n d-li ne F O L FI RI-base d re gi me ns, wit h or wit h o ut be vaciz u ma b. A P hase III 
st u d y i n vesti gati n g t he se q ue nce of F O L F O X a n d F O L FI RI re gi me ns as 1 st a n d 2 n d-li ne t hera p y 
f or patie nts wit h a d va nce d C R C de m o nstrate d n o si g nifica nt differe nce i n me dia n O S bet wee n 
t he F O L FI RI f oll o we d b y F O L F O X 6 ( 2 0. 4 m o nt hs) a n d F O L F O X 6 f oll o we d b y F O L FI RI 
( 2 1. 5 m o nt hs) re gi me ns (Lee & S u n, 2 0 1 6 ).  
I n t he 2 n d-li ne setti n g, a nti-V E G F t hera p y wit h be vaciz u ma b  was s h o w n t o i m pr o ve o utc o mes 
w he n c o m bi ne d wit h F O L F O X c o m pare d t o F O L F O X al o ne, wit h si g nifica nt differe nces i n 
me dia n O S ( 1 2. 9 m o nt hs vs 1 0. 8 m o nt hs), me dia n pr o gressi o n -free s ur vi val (P F S ) ( 7. 3 m o nt hs 
vs 4. 7  m o nt hs), a n d o bjecti ve res p o nse rate ( O R R ; 2 2. 7 % vs 8. 6 %) ( Gia nt o ni o et al, 2 0 0 7). 

N u Ti de: 3 2 3                                                                                                                        Versi o n 2 .1 , 0 6  Fe b  2 0 2 4  
C o nfi de ntia l                                                            N u Ca na  plc  
2 6  
F urt her m ore, it has bee n s h o w n t hat c o nti n uati o n of be vaciz u ma b  i n c o m bi nati o n wit h 
c he m ot hera p y i n 2 n d-li ne treat me nt resulte d i n i m pr o ve d O S w he n c o m pare d t o 2 n d-li ne 
c he m ot hera p y al o ne ( me dia n O S: 1 1. 2 m o nt hs vs 9. 8 m o nt hs ; Be n n o u na et al, 2 0 1 3). 
Gi ve n t he gl o bal b ur de n of C R C a n d t he fact t hat t he maj orit y of patie nts prese nt wit h l ocall y 
a d va nce d or metastatic disease re q uiri n g s yste mic t hera p y, a fl u or o p yri mi di ne -base d re gi me n 
i n c o m bi nati o n wit h bi ol o gic a ge nts, m ost fre q ue ntl y be vaciz u ma b, is li kel y t o re mai n t he m ost 
c o m m o nl y a d mi nistere d sta n dar d of care re gi me n f or t he 2n d-li ne treat me nt of patie nts wit h 
metastatic C R C.  
1. 3.  
Li mit ati o ns of 5 -F U T re at me nt  
First i ntr o d uce d i n 1 9 5 7, 5 -F U is still wi del y use d f or t he treat me nt of ma n y ca ncers, i ncl u di n g 
c ol orectal, breast, st o mac h, hea d a n d nec k, a n d pa ncreatic ca ncers.   
T he a nti -ca ncer acti vit y of 5 -F U a n d its ot her f or ms, F U D R a n d ca pecita bi ne ( Xel o da ® ), is 
lar gel y attri b ute d t o t he acti ve a nti-ca ncer meta b olite, fl u or o de o x y uri di ne -m o n o p h os p hate 
( F U D R-M P; F d U M P), w hic h bi n ds t o a n d i n hi bits t h y mi d ylate s y nt hase (T S ), a critical e nz y me 
i n de n ov o  n ucle oti de s y nt hesis a n d cel l s ur vi val (L o n gle y et al, 2 0 0 3 ). T S is re q uire d t o c o n vert 
uri di ne, s pecificall y de o x y uri di ne 
m o n o p h os p hate, or d U M P, t o t h y mi di ne, s pecificall y 
de o x yt h y mi di ne m o n o p h os p hate, or d T M P, o ne of t he f o ur n ucle oti des t hat c o m prise D N A.  
T he i n hi biti o n of T S re s ults i n a n i m bala nce i n t he rati o of t he n ucle oti des d U M P a n d d T M P, 
disr u pti n g D N A s y nt hesis a n d re pair, w hic h ulti matel y lea ds t o ca ncer cell deat h. D ue t o 
m ulti ple li mitati o ns, 5 -F U is n ot efficie ntl y c o n verte d t o t he acti ve a nti -ca ncer meta b olite, 
F U D R -M P, a n d is ofte n deli vere d as a c o nti n u o us i nf usi o n of  u p t o 4 6  h o urs.   
Ke y li mitati o ns i m pacti n g t he brea k d o w n , meta b olis m a n d acti vati o n of 5 -F U ha ve bee n 
ass ociate d wit h p o or pr o g n osis t o treat me nt ( L o n gle y et al, 2 0 0 3; L o n gle y & J o h nst o n , 2 0 0 5 ). 
I n a d diti o n, t he ge nerati o n of cata b olites a n d  meta b olites b y 5 -F U ca uses d ose -li miti n g 
t o xicities ( D L Ts) a n d i m pacts patie nt safet y.  
M ore t ha n 8 5 % of a d mi nistere d 5 -F U is de gra de d b y t he e nz y me di h y dr o p yri mi di ne 
de h y dr o ge nase ( D P D) i n t he li ver, t here f ore m ost of t he dr u g is cata b olise d bef ore it has a n 
o p p ort u nit y t o e nter ca ncer cells, bec o me acti vate d a n d e xert a n y t hera pe utic effect ( Diasi o & 
Harris, 1 9 8 9 ).  D P D is als o prese nt i n ot her tiss ues, s uc h as t he gastr oi ntesti nal tract (Pizz or n o 
et al, 2 0 0 3 ), a n d i n t u m o ur cells, res ulti n g i n a d diti o nal 5-F U cata b olis m. I n a d diti o n t o t he 
re d uce d efficac y, 5-F U cata b olis m b y D P D res ults i n t he ge nerati o n of t o xic b y -pr o d ucts, s uc h 
as α-fl u or o-β -ala ni ne ( F B A L), w hic h has bee n ass ociate d wit h off -tar get t o xicit y i ncl u di n g 
ha n d 
f o ot 
s y n dr o me, 
car di ot o xicit y 
a n d 
ne ur ot o xicit y. 
T heref ore, 
circ u m ve nti n g 
D P D -me diate d de gra dati o n is a ntici pate d t o si g nifica ntl y i m pr o ve t he safet y a n d efficac y of 
fl u or o p yri mi di nes. 
D uri n g meta b olis m, 5 -F U is als o p h os p h or ylate d t o fl u or o uri di ne tri p h os p hate ( F U T P), w hic h 
is k n o w n t o be partiall y res p o nsi ble f or 5-F U -ass ociate d off -tar get t o xicit y t hr o u g h 
i nc or p orati o n i nt o R N A i n healt h y cells (Br utc her et al, 2 0 1 8).  I n dee d, F U T P is t h o u g ht t o be 
t he pri mar y me diat or u n derl yi n g diarr h oea, m uc ositis a n d ne utr o pae nia, w hic h are ke y D L Ts 
i n patie nts treate d wit h 5-F U ( A djei, 1 9 9 9 ).  
O verall, t he b y -pr o d ucts F B A L a n d F U T P pr o d uce d d uri n g meta b olis m of 5 -F U are ass ociate d 
wit h si g nifica nt off -tar get t o xicities t hat li mit t he cli nical utilit y of 5-F U.  

N u Ti de: 3 2 3                                                                                                                        Versi o n 2 .1 , 0 6  Fe b  2 0 2 4  
C o nfi de ntia l                                                            N u Ca na  plc  
2 7  
As 5 -F U is a pr o -dr u g, it nee ds t o be pr ocesse d b y a series of e nz y mes i n ca ncer cells t o ge nerate 
t he pri mar y acti ve a nti-ca ncer meta b olite, F U D R -M P. T he le vels of t w o ke y e nz y mes i n t he 
5 -F U acti vati o n pat h wa y ha ve bee n s h o w n t o c orrelate w it h treat me nt efficac y. Or otate 
p h os p h ori b os yltra nsferase ( O P R T) c o n verts 5 -F U t o fl u or o uri di ne 
m o n o p h os p hate, a n 
i nter me diate i n t he f or mati o n of F U D R-M P. L o w le vels of O P R T i n t u m o ur cells is ass ociate d 
wit h resista nce t o 5 -F U ( Ts uta ni et al, 2 0 0 8). I n ad diti o n, t h y mi di ne p h os p h or ylase ( T P) 
c o n verts 5 -F U t o F U D R, w hic h is t he n f urt her pr ocesse d t o F U D R -M P b y t h y mi di ne ki nase 
( T K). It has bee n s h o w n t hat T K deficie nc y i n h u ma n ca ncer cells di mi nis hes t he acti vit y of 
5 -F U ( Va n de V o or de et al, 2 0 1 1 ). It has als o bee n o bser ve d t hat e x pressi o n of T P c orrelates 
wit h res p o nse t o 5 -F U t hera p y ( Pa ncz y k, 2 0 1 4 ). 
5 -F U is ass ociate d 
wit h si g nifica nt d osi n g a d mi nistrati o n c halle n ges d ue t o p o or 
p har mac o ki netic ( P K) pr o perties. T he plas ma half -life of 5-F U is ver y s h ort at 8 t o 1 4 mi n utes; 
c o nse q ue ntl y, pr ol o n ge d i nf usi o n ti mes o ver 4 6 h o urs are re q uire d t o all o w u pta ke a n d 
acti vati o n of t he pr o -dr u g  a n d t o s hift t he meta b olite pr ofile fr o m F U T P t o F U D R -M P i n or der 
t o li mit t o xicities. T his d osi n g re gi me n a n d t he s u bsta ntial off-tar get t o xicities are b ur de ns o me 
f or pr o vi ders, i nc o n ve nie nces patie nts, a n d c o ntri b utes a d diti o nal c osts t o t he healt hcare 
s yste m. 
1. 4.  
N U C -3 3 7 3  
N U C -3 3 7 3 is specificall y desi g ne d t o o verc o me t he ke y s h ortc o mi n gs t hat li mit t he cli nical 
utilit y of  5 -F U,  t here b y i m pr o vi n g t he efficac y a n d safet y  pr ofile , a n d re d uci n g t he d osi n g 
a d mi nistrati o n b ur de n s, ass ociate d wit h 5 -F U  (Mc G ui ga n et al, 2 0 1 1; Va n de V o or de et al, 
2 0 1 1 ). N U C-3 3 7 3 ge nerates  t he sa me acti ve i ntracell ular a nti-ca ncer meta b olite, F U D R -M P, 
as 5 -F U, b ut at si g nif ica ntl y hi g her c o nce ntrati o ns. 
N U C -3 3 7 3 is a pre -acti vate d a n d pr otecte d f or m of F U D R -M P. T he a d diti o n of t he pr otecti ve 
p h os p h ora mi date gr o u p c ha n ges t he str uct ural c haracteristics of N U C -3 3 7 3 s uc h t hat it is n ot 
a s u bstrate f or , a n d is t heref ore resista nt t o e nz y matic brea k d o w n b y, D P D. T his c o nfers t he 
a d va nta ge of re d uce d e x p os ure t o F B A L  a n d ass ociate d off -tar get t o xicities, s uc h as ha n d f o ot 
s y n dr o me.    
I n a d diti o n, N U C-3 3 7 3 ge nerates m uc h l o wer le vels of F U T P c o m pare d t o 5 -F U, t h u s t he 
i nci de nce of Gra de 3 or hi g her t o xicities ass ociate d wit h off-tar get i nc or p orati o n of t his 
m olec ule i nt o t he R N A of n or mal cells ( e. g., ne utr o pae nia, diarr h oea, m uc ositis) has bee n l o w 
i n cli nical st u dies t o date.   
T he c he mical str uct ure als o alters  t he li p o p hilicit y of t he m olec ule, e na bli n g N U C-3 3 7 3 t o 
e nter ca ncer cells wit h o ut t he nee d f or n ucle o base tra ns p orters ( Mc G ui ga n et al, 2 0 1 1).    
Fi nall y, as N U C -3 3 7 3 directl y deli vers  t he acti ve a nti-ca ncer meta b olite  i ntracell ularl y, t here 
is n o nee d for e nz y matic c o n versi o n t o F U D R a n d s u bse q ue nt p h os p h or ylati o n  t o F U D R-M P , 
t h us o verc o mi n g maj or rate li miti n g pat h wa ys ass ociate d wit h 5-F U.   
T o get her, t hese u ni q ue pr o perties are e x pecte d t o res ult i n e n ha nce d dr u g s yste mic e x p os ure 
a n d a re d ucti o n i n t he release of t o xic b y -pr o d ucts.  O nce i nsi de t he ca ncer cell, t he pr otecti ve 
gr o u p  is clea ve d off wit h release of si g nifica ntl y hi g her le vels of t he acti ve a nti-ca ncer 
meta b olite F U D R -M P.  T his res ults i n e n ha nce d i nteracti o n wit h, a n d i n hi biti o n of, t he tar get 
e nz y me T S, dri vi n g a n i m bala nce i n t he d U M P: d T M P rati o wit h s u bse q ue nt disr u pti o n of D N A 
s y nt hesis a n d re pair a n d, ulti matel y, ca ncer cell deat h. 
Please refer t o t he c urre nt N U C -3 3 7 3 I n vesti gat or’s Br oc h ure (I B) f or f urt her details.  

N u Ti de: 3 2 3                                                                                                                        Versi o n 2 .1 , 0 6  Fe b  2 0 2 4  
C o nfi de ntia l                                                            N u Ca na  plc  
2 8  
1. 4. 1  N o n -C li nic al D at a  
I n n o n-cli nical st u dies, N U C -3 3 7 3 has s h o w n t he a bilit y t o i n hi bit cell gr o wt h acr oss a ra n ge 
of h u ma n t u m o ur cell li nes. I n a pa nel of 9 differe nt h u ma n C R C cell li nes, t he c yt ot o xic 
acti vit y of N U C -3 3 7 3 was i n de pe n de nt of t he basal T S le vel. F urt her m ore, t h y mi di ne 
s u p ple me ntati o n resc ue d N U C-3 3 7 3 -i n d uce d cell deat h, c o nfir mi n g t hat N U C-3 3 7 3 tar gets t he 
de n o v o pat h wa y of d T M P s y nt hesis. I n a d diti o n, p ote nt t u m o ur re gressi o n effects were 
o bser ve d i n h u ma n C R C m o use xe n o graft m o dels, wit h N U C -3 3 7 3 s h o wi n g greater t u m o ur 
i n hi biti o n t ha n 5-F U.  
O ver 
half 
of 
C R C 
cases 
are i nfecte d 
b y 
myc o pl as m a  (H ua n g 
et 
al, 
2 0 0 1).  
Myc o pl as m a -e nc o de d T P re d uces t he acti vit y of se veral c he m ot hera pe utic a ge nts ( Lie ke ns et 
al , 2 0 0 9), i ncl u di n g 5-F U.  I n ca ncer cell li nes, myc o pl as m a  i nfecti o n decreases 5-F U acti vit y 
b y u p t o 1 0 0 -ti mes (Jetté et el, 2 0 0 8). N o n-cli nical st u dies ha ve s h o w n t hat N U C -3 3 7 3 is 
resista nt t o T P-me diate d de gra dati o n, w hereas F U D R is si g nifica ntl y br o ke n d o w n, a n d t hat i n 
h u ma n gli o blast o ma U 8 7 cells c hr o nicall y i nfecte d b y myc o pl as m a hy or hi nis , F U D R mar ke dl y 
l ost its c yt ot o xic acti vit y 4 2 9-f ol d, w hereas N U C-3 3 7 3 acti vit y was u naffecte d ( Va n de V o or de 
et al , 2 0 1 1). 
A n  i n vitr o st u d y i n vesti gati n g t he effect of D P D acti vit y o n t he i ntracell ular c o nce ntrati o ns of 
N U C -3 3 7 3 was c o n d ucte d i n cell l ysate fr o m p o ole d C R C cell li nes ( S W 6 2 0, H C T 1 1 6 a n d 
H T 2 9). It was de m o nstrate d t hat N U C -3 3 7 3 is n ot s usce pti ble t o D P D -me diate d de gra dati o n 
u nli ke 5 -F U, w hic h is ra pi dl y cata b olise d b y D P D.  
I n a series of in vitr o  e x peri me nts i n C R C cell li nes, it was f o u n d t hat N U C -3 3 7 3 ge nerates 
s u bsta ntiall y hi g her le vels of F U D R-M P a n d is a m ore p ote nt i n hi bit or of T S t ha n 5 -F U. 
A d diti o nall y, t he area u n der t he c ur ve ( A U C) f or d U M P was s h o w n t o be u p t o 1 6 2 -ti mes 
hi g her f oll o wi n g N U C-3 3 7 3 treat me nt c o m pare d t o 5 -F U treat me nt, s u g gesti n g a m ore 
pr o n o u nce d effect o n t he d U M P: d T T P rati o. N U C -3 3 7 3’s a bilit y t o ge nerate hi g h i ntracell ular 
le vels of F U D R-M P res ulte d i n t he ge nerati o n of fl u or o de o x y uri di ne-tri p h os p hate (F U D R -T P ; 
als o referre d t o as F d U T P), w hic h was s h o w n t o be i nc or p orate d i nt o t he D N A of C R C cells. 
T his effect was n ot o bser ve d wit h 5 -F U, i n dicati n g t hat N U C -3 3 7 3 is n ot o nl y a m ore p ote nt 
T S i n hi bit or, b ut is als o a 
m ore efficie nt 
D N A -da ma gi n g a ge nt c o m pare d t o 5 -F U. 
F urt her m ore, u nli ke 5 -F U, N U C -3 3 7 3 di d n ot ge nerate t he t o xic meta b olite F U T P i n t hese cell 
li nes.  
M ore details o n t he t o xic ol o g y, p har mac ol o g y a n d t o xic o k i netics ca n be f o u n d i n t he 
N U C -3 3 7 3 I B. 
1. 5.  
Cli nic al D at a  
1. 5. 1.  
N u Ti de: 3 0 1  
N u Ti de: 3 0 1 was a first -i n-h u ma n d ose escalati o n st u d y of N U C -3 3 7 3 m o n ot hera p y i n patie nts 
wit h a d va nce d s oli d t u m o urs ( E u dra C T 2 0 1 5-0 0 2 2 5 0 -1 3; N C T 0 2 7 2 3 2 4 0 ) c o n d ucte d acr oss 
t hree sites i n t he U K (S pili o p o ul o u et al, 2 0 2 1). T his was a t w o-part d ose escalati o n a n d 
e x pa nsi o n st u d y desi g ne d t o e val uate safet y, P K, p har mac o d y na mic, a n d a nti -t u m o ur acti vit y, 
i n a d diti o n t o esta blis hi n g t he ma xi m u m t olerate d d ose ( M T D) a n d rec o m me n de d P hase II d ose 
( R P 2 D) a n d sc he d ule of si n gle-a ge nt i ntra ve n o us (I V) N U C -3 3 7 3 . 
I n Part 1, N U C -3 3 7 3 was a d mi nistere d o n a wee kl y ( Q 1 W) sc he d ule o n Da ys 1, 8, 1 5 a n d 2 2 
of 2 8 -da y c ycles. I n Part 2, N U C -3 3 7 3 was a d mi nistere d o n a n alter nate wee kl y  ( Q 2 W) 
sc he d ule o n Da ys 1 a n d 1 5 of 2 8-da y c ycles. A t otal of 5 9 patie nts wit h metastatic ca nc er, w h o 
ha d e x ha uste d all ot her a vaila ble treat me nt o pti o ns, recei ve d N U C -3 3 7 3 i n t his st u d y, wit h 
4 3  patie nts recei vi n g N U C -3 3 7 3 o n a Q 1 W sc he d ule at d oses ra n gi n g fr o m 1 2 5 m g/ m 2 t o 

N u Ti de: 3 2 3                                                                                                                        Versi o n 2 .1 , 0 6  Fe b  2 0 2 4  
C o nfi de ntia l                                                            N u Ca na  plc  
2 9  
3, 2 5 0  m g/ m 2 a n d 1 6 patie nts recei vi n g N U C -3 3 7 3 o n a Q 2 W sc he d ule at d oses  ra n gi n g fr o m 
1, 5 0 0  m g/ m 2 t o 2, 5 0 0 m g/ m 2. T his hea vil y pre -treate d patie nt p o p ulati o n ( me dia n of 3 pri or 
li nes of c he m ot hera p y; ra n ge: 0 -1 1) ha d a variet y of pri mar y t u m o ur t y pes.  
N U C -3 3 7 3 was well t olerate d a n d, base d o n D L Ts of Gra de 2 hea dac he a n d Gra de  3 tra nsie nt 
h y p ote nsi o n, t he M T D of si n gle -a ge nt N U C -3 3 7 3 was deter mi ne d t o be 2 5 0 0 m g/ m 2 wee kl y. 
T he m ost c o m m o n treat me nt -relate d Gra de 1 -2 a d verse e ve nts ( A Es) re p orte d were fati g ue 
(5 1 %), na usea ( 3 7 %), i nf usi o n reacti o ns ( 3 6 %), diarr h oea ( 3 2 %), v o miti n g ( 1 7 %), a n d a nae mia 
( 1 5 %). T he m ost c o m m o n  treat me nt-relate d Gra de 3 A Es  were  A L T i ncrease d, A S T i ncrease d, 
a n d tra nsa mi nases i ncrease d (eac h i n 3 % of patie nts) . N o Gra de 4 treat me nt -relate d A Es were 
re p orte d. 
E vi de nce of d ura ble a nti -ca ncer acti vit y was  o bser ve d, wit h 1 0 patie nts sta yi n g o n st u d y 
treat me nt f or at least 4 m o nt hs a n d t hree of t hese patie nts ac hie vi n g pr ol o n ge d sta ble disease 
of m ore t ha n ni ne m o nt hs. 
Ma n y of t hese patie nts ha d recei ve d pri or fl u or o p yri di nes as 
sta n dar d of care. 
1. 5. 2.  
N u Ti de: 3 0 2  
N u Ti de: 3 0 2 is a n o n g oi n g  P hase I b/II st u d y of N U C -3 3 7 3 i n c o m bi nati o n wit h sta n dar d a ge nts 
use d f or t he treat me nt of patie nts wit h a d va nce d/ metastatic C R C ( Berli n et al, 2 0 2 1) ( E u dra C T 
2 0 1 7 -0 0 2 0 6 2 -5 3; N C T 0 3 4 2 8 9 5 8 ). I n t his t hree-part st u d y, t he pri mar y o bj ecti ve is t o i de ntif y 
a rec o m me n de d d ose a n d sc he d ule f or N U C -3 3 7 3 w he n a d mi nistere d i n c o m bi nati o ns wit h 
L V, o xali plati n, iri n oteca n, a n d be vaciz u ma b.  
I n Part 1, t he safet y a n d t olera bilit y of N U C-3 3 7 3 w he n c o -a d mi nistere d wit h L V was assesse d  
i n Q 1 W a n d Q 2 W c o h orts . T he P K a n d safet y pr ofile of N U C-3 3 7 3 was n ot affecte d b y 
c o-a d mi nistrati o n wit h L V ; t heref ore, it was deci de d t o a d mi nister N U C -3 3 7 3 i n c o m bi nati o n 
wit h t he sta n dar d d ose of L V ( 4 0 0  m g/ m 2) i n s u bse q ue nt parts of t he st u d y. I n Part 2, t he safet y 
a n d t olera bilit y of differe nt d oses of N U C -3 3 7 3 w he n a d mi nistere d as part of Q 1 W N U F O X 
a n d N U FI RI  re gi me ns i n ≥3r d-li ne patie nts was  assesse d . D ose escalati o n has c o m plete d a n d 
t he Q 1 W M T Ds ha ve bee n deter mi ne d. I n Part 3, 2n d-li ne patie nts are  recei vi n g t he selecte d 
N U F O X a n d N U FI RI re gi me ns  o n a Q 1 W sc he d ule  i n c o m bi nati o n wit h be vaciz u ma b.  
T o date, 3 8 patie nts ha ve bee n treate d i n Part 1, wit h 2 1 patie nts treate d o n a Q 2 W sc he d ule 
a n d 1 7 patie nts treate d o n a Q 1 W sc he d ule. T he m ost c o m m o nl y re p orte d treat me nt -relate d 
A Es i n Part 1 were na usea ( 4 2 %), fati g ue ( 40 %), v o miti n g ( 3 4 %), a n d diarr h oea ( 2 9 %). 
Gra de  3 or 4 treat me nt -relate d A Es occ urre d i n n o m ore t ha n 2 patie nts eac h, wit h t he m ost 
c o m m o n bei n g na usea ( 5 %), ala ni ne a mi n otra nsferase ( A L T) i nc rease d ( 5 %), a n d a nae mia 
( 5 %). I m p orta ntl y, i n vitr o a n d ex viv o data t o date str o n gl y s u g gest t hat N U C-3 3 7 3 d oes n ot 
ge nerate F U T P, a pri mar y ca use of 5 -F U t o xicit y a n d a d ose -li miti n g fact or (A djei et al, 1 9 9 9; 
Br utc her et al, 2 0 1 8). F U T P has n ot bee n detecte d i n C R C cell li nes treate d wit h N U C -3 3 7 3 
n or fr o m t he  peri p heral bl o o d m o n o n uclear cells ( P B M Cs ) of  patie nts treate d wit h N U C -3 3 7 3  
i n t he N u Ti de: 3 0 1 st u d y. Acc or di n gl y, n o  N U C -3 3 7 3 treate d patie nts i n Part 1 of N u Ti de: 3 0 2 
e x perie nce d Gra de 3 or 4 t o xicities ass ociate d wit h F U T P ( diarr h oea, ne utr o pae nia a n d 
m uc ositis).  
Patie nts i n Part 1 of t his st u d y were hea vil y pre -treate d ( me dia n of 4 pri or li nes; ra n ge 2-1 3) 
a n d ha d e x ha uste d all ot her treat me nt o pti o ns. Des pite t his, e nc o ura gi n g efficac y si g na ls ha ve 
bee n o bser ve d i n Part 1 wit h 1 1 patie nts ac hie vi n g sta ble disease of at least 3 m o nt hs. M ost of 
t hese patie nts ac hie ve d peri o ds of P F S t hat matc he d or e xcee de d t h ose ac hie ve d o n pre vi o us 
re gi me ns. I n a d diti o n, n ota ble t u m o ur s hri n ka ge has bee n o bser ve d, i ncl u di n g i n a patie nt w h o 
was refract or y t o all pri or fl u or o p yri mi di ne -c o ntai ni n g re gi me ns . 

N u Ti de: 3 2 3                                                                                                                        Versi o n 2 .1 , 0 6  Fe b  2 0 2 4  
C o nfi de ntia l                                                            N u Ca na  plc  
3 0  
I n Part 2, N U C -3 3 7 3 was  ge nerall y well -t olerate d w he n a d mi nistere d i n t he N U F O X a n d 
N U FI RI re gi me ns. I n t he N U F O X c o h orts, patie nts recei ve d 4 0 0 m g/ m2 L V pl u s 8 5 m g/ m2 
o xali plati n pl us N U C -3 3 7 3 at 1, 5 0 0 m g/ m 2, 1, 8 7 5 m g/ m2, or 2, 2 5 0 m g/ m2. I n t he N U C-3 3 7 3 
2, 2 5 0 m g/ m 2 d ose gr o u p, a t otal of 3 patie nts e x perie nce d D L Ts. T w o patie nts ha d Gra de 3 
fati g ue a n d o ne patie nt ha d raise d li ver f u ncti o n tests p ote ntiall y meeti n g t he criteria f or H y’s 
la w ( A L T/ A S T > 3 ×  u p per li mit of n or mal [ U L N ] a n d bilir u bi n > 2 ×  U L N). T he  N U C -3 3 7 3 
1, 8 7 5 m g/ m 2 d ose gr o u p was e x pa n de d  a n d n o D L Ts were re p orte d; t h us, t he M T D a n d R P 2 D 
f or t he N U F O X re gi me n was deter mi ne d t o be 1, 8 7 5 m g/ m2 N U C -3 3 7 3  Q 1 W  + 4 0 0 m g/ m 2 
L V Q 1 W + 8 5  m g/ m 2 o xali plati n Q 2 W.  
I n t he N U FI RI c o h orts, patie nts recei ve d 4 0 0 m g/ m 2 L V pl us  iri n oteca n pl us N U C -3 3 7 3  as 
f oll o ws: N U C-3 3 7 3 at 1, 5 0 0 m g/ m 2 + iri n oteca n at 1 2 0  m g/ m 2, N U C-3 3 7 3 at 1, 5 0 0 m g/ m 2 + 
iri n oteca n at 1 5 0 m g/ m 2, N U C-3 3 7 3 at 1, 5 0 0 m g/ m 2 + iri n oteca n at 1 8 0  m g/ m 2, a n d N U C-3 3 7 3 
at 1, 8 7 5 m g/ m 2 + iri n oteca n at 1 8 0  m g/ m 2. I n t he N U C-3 3 7 3 1, 8 7 5 m g/ m 2 + iri n oteca n 
1 8 0  m g/ m 2 d ose gr o u p, a t otal of 2 patie nts e x perie nce d D L Ts. O ne patie nt ha d Gra de 3 fati g ue 
a n d o ne pat ie nt ha d Gra de 3 c olitis. As a res ult, t he N U C -3 3 7 3 1, 5 0 0 m g/ m 2 + iri n oteca n 
1 8 0  m g/ m 2 d ose gr o u p was e x pa n de d a n d o ne patie nt e x perie nce d a D L T of Gra de 3 A L T a n d 
A L P i ncrease d . Base d o n t his, t he M T D a n d R P 2 D f or t he N U FI RI re gi me n was deter mi ne d t o 
be 1 5 0 0  m g/ m 2 N U C -3 3 7 3  Q 1 W  + 4 0 0 m g/ m 2 L V Q 1 W + 1 8 0 m g/ m 2 iri n oteca n Q 2 W. 
I n t he N U FI RI c o h orts, t he m ost c o m m o nl y re p orte d treat me nt-relate d T E A Es were  na usea 
( 4 3 %), fati g ue ( 3 0 %), diarr h oea ( 2 6 %), v o miti n g ( 2 6 %), a nae mia ( 2 6 %), A L T i ncrease d 
( 2 2 %), a n d a n ore xia ( 2 2 %). T he maj orit y of t hese e ve nts were Gra de 1 or 2. T he m ost 
c o m m o nl y re p orte d Gra de 3 treat me nt -relate d T E A Es were  fati g ue ( 1 3 %) a n d A L T i ncrease d  
( 9 %). N o Gra de 4 treat me nt-relate d T E A Es ha ve bee n re p orte d.  
Data o btai ne d fr o m 8 patie nts treate d i n t he N U FI RI-be v c o h ort i n Part 3 t o date (c ut -off 1 7  Ja n 
2 0 2 3) s h o w t hat t he re gi me n has bee n well t olerate d. Patie nts recei ve d treat me nt wit h t he R P 2 D 
of 1 5 0 0  m g/ m 2 N U C -3 3 7 3 Q 1 W + 4 0 0 m g/ m 2 L V Q 1 W + 1 8 0 m g/ m 2 iri n oteca n Q 2 W i n 
c o m bi nati o n wit h 5 m g/ k g b e vaciz u ma b Q 2 W . All 8 patie nts c o m plete d C ycle 1 wit h o ut 
T E A Es t hat w o ul d meet D L T criteria i n a d ose -escalati o n desi g n. T he m ost c o m m o nl y re p orte d 
treat me nt-relate d T E A Es ha ve bee n diarr h oea, fati g ue, A L T i ncrease d a n d A S T i ncrease d i n 
2  patie nts eac h. T w o Gra de 3 treat me nt -relate d T E A Es ha ve bee n re p orte d, A L T i ncrease d a n d 
pa ncreatitis. T here ha ve bee n n o Gra de 4 treat me nt -relate d T E A Es t o date.  
1. 6.  
P h ar m ac o ki netics  
Plas ma a n d i ntracell ular P K a nal yses ha ve bee n c o n d ucte d o n 4 5 patie nts fr o m t he N u Ti de: 3 0 1 
(ra n ge: 1 2 5 t o 2 5 0 0 m g/ m2) a n d N u Ti de: 3 0 2 ( 1 5 0 0 m g/ m2) st u dies. T he P K pr ofile of 
N U C -3 3 7 3 c o m pares fa v o ura bl y t o t hat of 5 -F U.  
A d ose -pr o p orti o nal i ncrease i n t he N U C -3 3 7 3 A U C was o bser ve d i n plas ma. O ver t he d ose 
ra n ge st u die d, N U C-3 3 7 3 ha d a mea n plas ma  eli mi nati o n half -life of 5-1 0 h o urs ( vs 8 -1 4 
mi n utes f or 5 -F U). N o acc u m ulati o n was o bser ve d f or N U C -3 3 7 3 or its circ ulati n g meta b olites 
( F U D R a n d F B A L) bet wee n Da y 1 a n d Da y 1 5. 
A d ose -pr o p orti o nal i ncrease i n t he i ntracell ular A U C f or t he acti ve a nti -cancer meta b olite 
F U D R - M P was o bser ve d o ver a d ose ra n ge of 1 2 5 -2 5 0 0 m g/ m 2 i n P B M Cs. T he half-life of 
i ntracell ular F U D R-M P was calc ulate d t o be 1 0 -1 4 h o urs. A p ositi ve li near relati o ns hi p was 
o bser ve d bet wee n i ntracell ular F U D R ‐M P a n d d U M P le vels. T he t o xic  meta b olites F B A L a n d 
F U T P were u n detecta ble i ntracell ularl y at t he d ose le vels teste d.  
Please refer t o t he c urre nt N U C -3 3 7 3 I B f or f urt her details.  

N u Ti de: 3 2 3                                                                                                                        Versi o n 2 .1 , 0 6  Fe b  2 0 2 4  
C o nfi de ntia l                                                            N u Ca na  plc  
3 1  
1. 7.  
St u d y R ati o n ale  
N U C -3 3 7 3 is a pre -acti vate d a n d pr otecte d f or m of t he acti ve a nti -ca ncer a ge nt F U D R t hat is  
bei n g de vel o pe d t o re place fl u or o p yri mi di nes, s uc h as 5 -F U. D ue t o m ulti ple li mitati o ns, 5 -F U 
is n ot efficie ntl y c o n verte d t o t he acti ve a nti-ca ncer meta b olite F U D R -M P, is ass ociate d wit h 
d ose -li miti n g t o xicities d ue t o t he ge nerati o n of s pecific meta b oli tes a n d has a c halle n gi n g 
a d mi nistrati o n sc he d ule d ue t o its p o or P K pr ofile. N U C -3 3 7 3 is a tar gete d T S i n hi bit or 
desi g ne d t o o verc o me t he ke y s h ortc o mi n gs t hat li mit t he cli nical utilit y of 5 -F U.  
T he c urre nt sta n dar d of care f or t he 1 st-li ne a n d 2n d-li ne treat me nt of patie nts wit h a d va nce d or 
metastatic C R C is F O L F O X, F O L FI RI or F O L F O XI RI i n c o m bi nati o n wit h V E G F i n hi bit ors 
or E G F R i n hi bit ors. D uri n g t he patie nt’s treat me nt j o ur ne y, c o m p o ne nts of t he 1 st-li ne re gi me n 
(e. g., o xali plati n or iri n oteca n) will be eit her pa use d a n d re -i nstate d, or s witc he d t o i ntr o d uce a 
ne w c o m bi nati o n a ge nt, f or t he 2 n d-li ne re gi me n. S o me patie nts ma y recei ve mai nte na nce 
t hera p y wit h a fl u or o p yri mi di ne ± be vaciz u ma b. Data i n t he 2n d-li ne setti n g s h o w t hat 
f oll o wi n g F O L F O X fail ure i n t he 1st-li ne, iri n oteca n a n d F O L FI RI are t he m ost a p pr o priate 
o pti o ns f or 2 n d-li ne treat me nt.  
I n n o n-cli nical st u dies , N U C -3 3 7 3 has s h o w n t he a bilit y t o i n hi bit cell gr o wt h acr oss a ra n ge 
of h u ma n t u m o ur cell li nes, i ncl u di n g C R C. I n a d diti o n, si g nifica nt t u m o ur i n hi biti o n effects 
were o bser ve d i n h u ma n C R C m o use xe n o graft m o dels, wit h N U C -3 3 7 3 s h o wi n g greater 
t u m o ur i n hi biti o n t ha n 5-F U. A series of i n vitr o e x peri me nts pr o vi de d pr o of of c o nce pt t hat 
N U C -3 3 7 3 ge nerates s u bsta ntiall y hi g her le vels of  F U D R -M P a n d is a m ore p ote nt i n hi bit or 
of T S t ha n 5 -F U, w hile ge nerati n g m uc h l o wer le vels of t o xic meta b olites.  
T he n o n -cli nical fi n di n gs ha ve bee n s u bsta ntiate d i n patie nts treate d wit h N U C -3 3 7 3 
m o n ot hera p y i n t he N u Ti de: 3 0 1 cli nical st u d y a n d wit h N U C -3 3 7 3 ± L V  ( Part 1), N U F O X a n d 
N U FI RI ( Part 2)  i n t he N u Ti de: 3 0 2 cli nical st u d y. Data fr o m t hese st u dies ha ve c o nfir me d t he 
p ote ntial f or N U C -3 3 7 3 t o ge nerate hi g h i ntracell ular le vels of F U D R -M P. F urt her m ore, 
N U C -3 3 7 3 has bee n 
well -t olerate d, 
wit h a l o wer i nci de nce a n d re d uce d se verit y of 
fl u or o p yri mi di ne-relate d t o xicities s uc h as ne utr o pae nia, diarr h oea a n d ha n d -f o ot s y n dr o me 
c o m pare d t o hist orical data f or 5 -F U. E nc o ura gi n g si g nals of a nti -ca ncer acti vit y ha ve bee n 
o bser ve d i n hea vil y pre -treate d patie nts, wit h t u m o ur s hri n ka ges as well as peri o ds of P F S  
l o n ger t ha n t h ose ac hie ve d o n pre vi o us re gi me ns. O wi n g t o i m pr o ve d P K pr o perties, 
N U C -3 3 7 3 als o offers a m ore c o n ve nie nt a d mi nistrati o n sc he d ule ( 2 -4 h o urs vs 4 6 h o urs f or 
5 -F U).  
T o get her t hese data de m o nstrate t he p ote ntial f or N U C -3 3 7 3 t o o verc o me t he k e y li mitati o ns 
ass ociate d wit h 5 -F U a n d s u g gest t hat N U C-3 3 7 3 mi g ht be a n attracti ve o pti o n t o re place 5 -F U 
i n t he c urre nt sta n dar d of care F O L FI RI re gi me n i n t he 2n d-li ne setti n g f or u nresecta ble 
metastatic C R C .  
 
 
 

N u Ti de: 3 2 3                                                                                                                        Versi o n 2 .1 , 0 6  Fe b  2 0 2 4  
C o nfi de ntia l                                                            N u Ca na  plc  
3 2  
2.  
 S T U D Y O B J E C TI V E S  A N D E N D P OI N T S  
2. 1.  
Pri m ar y O bjecti ve s 
•  T o c o m pare P F S of N U C -3 3 7 3 i n c o m bi nati o n wit h L V, iri n oteca n a n d be vaciz u ma b 
( N U FI RI-be v) wit h 5 -F U i n c o m bi nati o n wit h L V, iri n oteca n a n d be vaciz u ma b 
( F O L FI RI-be v)  
•  T o deter mi ne t he o pti mal N U FI RI -be v d osi n g sc he d ule  
2. 2.  
Sec o n d ar y O bjecti ves  
•  T o c o m pare t he efficac y of N U FI RI -be v t o F O L FI RI -be v i n ter ms of:  
o  O bjecti ve res p o nse rate ( O R R)  
o  D urati o n of res p o nse ( D o R)  
o  Disease c o ntr ol rate ( D C R)  
o  Ma xi m u m perce nta ge c ha n ge i n t u m our  size  
o  O verall s ur vi val ( O S)  
•  T o assess t he safet y a n d t olera bilit y of N U FI RI -be v c o m pare d t o F O L FI RI -be v  
•  T o assess t he P K of N U FI RI -be v  
2. 3.  
E x pl or at or y O bjecti ve  
T o deter mi ne if t here are t u m o ur cell c haracteristics t hat ma y f urt her el uci date t he mec ha nis ms  
t hr o u g h w hic h t he cli nical acti vit y of N U C-3 3 7 3 is ac hie ve d ( arc hi val tiss ue, w here  a vaila ble ). 
2. 4.  
Pri m ar y E n d p oi nt  
•  P F S, acc or di n g t o R es p o nse E val uati o n C riteria in  S oli d T u m o ur s ( R E CI S T) v 1. 1, 
defi ne d as t he ti me fr o m ra n d o misati o n t o t he first o bser vati o n of o bjecti ve t u m o ur 
pr o gressi o n or deat h fr o m a n y ca use  
2. 5.  
Sec o n d ar y E n d p oi nt s 
2. 5. 1  Effic ac y  
O bjecti ve disease assess me nt b y ra di o gra p hic i ma gi n g will be perf or me d e ver y 8 wee ks a n d 
a nal ys e d usi n g R E CI S T v 1. 1 criteria ( A p pe n di x 1 ). A nti -t u m o ur acti vit y will be assesse d o n 
t he basis of: 
•  O R R, defi ne d as t he perce nta ge of patie nts ac hie vi n g a c o m plete or partial res p o nse t o 
treat me nt 
•  D o R, defi ne d as t he ti me fr o m i nitial cli nical res p o nse ( partial res p o nse [ P R] or 
c o m plete res p o nse [ C R] ) t o t he first o bser vati o n of t u m o ur pr o gressi o n or deat h fr o m 
a n y ca use 
•  D C R, defi ne d as t he perce nta ge of patie nts de m o nstrati n g a best o verall res p o nse 
( B O R) of C R, P R or sta ble disease ( S D) 
•  Ma xi m u m perce nta ge c ha n ge fr o m baseli ne i n t u m o ur size acc or di ng t o R E CI S T v 1. 1  
•  O S, defi ne d as t he ti me fr o m ra n d o misati o n t o t he ti me of deat h fr o m a n y ca use  

N u Ti de: 3 2 3                                                                                                                        Versi o n 2 .1 , 0 6  Fe b  2 0 2 4  
C o nfi de ntia l                                                            N u Ca na  plc  
3 3  
2. 5. 2  S afet y  
Safet y a n d t olera bilit y will be assesse d b y e val uati o n of:  
•  T E A Es a n d seri o us a d verse e ve nts ( S A Es; per C o m m o n Ter mi n ol o g y Criteria f or 
A d verse E ve nts [ C T C A E] v 5. 0)  
•  Deat hs d ue t o T E A Es  
•  Treat me nt m o dificati o ns  d ue t o T E A Es  
•  Cli nicall y -si g nifica nt la b orat or y c ha n ges ( per C T C A E v 5. 0) 
•  Electr ocar di o gra ms  ( E C Gs)  
2. 5. 3  P h ar m ac o ki netics   
T he P K of t he N U FI RI-be v re gi me n  will be assesse d, i ncl u di n g:  
•  C o nce ntrati o n at e n d of i nf usi o n ( C i nf) 
•  Ma xi m u m c o nce ntrati o n ( C
ma x ) 
•  A U C  
• 
t1/ 2  
•  V ol u me of distri b uti o n ( V d)  
•  Cleara nce ( C L)  
T he a nal ytes meas ure d i n plas ma will i ncl u de , b ut are n ot li mite d t o: 
•  N U C -3 3 7 3, C P F -1 0 2 7 , F B A L, iri n oteca n, S N -3 8 , S N-3 8 G, A P C  
2. 6.  
E x pl or at or y E n d p oi nt  
•  P o p ulati o n or t u m o ur c haracteristic s u bt y pes t hat ma y deter mi ne be nefit t o N U C -3 3 7 3 
treat me nt will be a nal ys e d  

N u Ti de: 3 2 3                                                                                                                        Versi o n 2 .1 , 0 6  Fe b  2 0 2 4  
C o nfi de ntia l                                                            N u Ca na  plc  
3 4  
3.  
IN V E S TI G A TI O N A L P L A N  
3. 1.  
O ver all S t u d y D esi g n 
N u Ti de: 3 2 3  is a ra n d o mise d, o pe n -la bel, d ose/sc he d ule o pti mi sati o n st u d y of N U FI RI -be v 
vers us F O L FI RI -be v f or t he treat me nt of patie nts wit h  u nresecta ble metastatic C R C . T w o 
N U FI RI -be v d osi n g sc he d ules will be assesse d, wit h a Q 1 W N U C -3 3 7 3  + L V  sc he d ule a n d a 
Q 2 W N U C -3 3 7 3  + L V  sc he d ule.  
T he o verall ai m of t h e st u d y is t o esti mate t he li kel y efficac y of t he t w o N U FI RI ar ms as 
c o m pare d t o t he F O L FI RI c o ntr ol ar m t o s u p p ort decisi o n ma ki n g re gar di n g t he f urt her 
de vel o p me nt of N U FI RI. Deter mi nati o n of t he o pti mal N U FI RI d osi n g sc he d ule will be base d 
o n a c o m paris o n of efficac y, safet y, a n d P K bet wee n t he t w o N U FI RI treat me nt ar ms.  
A t otal of 1 7 1 p atie nts will be ra n d o mise d 1: 1: 1 ( 5 7 patie nts per ar m) t o eit her N U FI RI-be v 
Q 1 W, N U FI RI -be v Q 2 W, or F O L FI RI -be v Q 2 W. Ra n d o mis ati o n will be stratifie d b y R A S 
stat us ( wil d-t y pe vs K R A S m uta nt vs N R A S m uta nt), prior be vaciz u ma b treat me nt ( yes vs n o) 
a n d d urati o n of pri or li ne of t hera p y ( < 6  m o nt hs vs ≥6 m o nt hs).  
Be vaciz u ma b ma y be s u bstit ute d wit h a n y a p pr o ve d bi osi milar c o nsiste nt wit h i nstit uti o nal 
practice. T he s pecific a ge nt a d mi nistere d will be rec or de d.  T h us, be vaciz u ma b i n t his pr ot oc ol 
refers t o eit her be vaciz u ma b or a lice nse d bi osi milar. 
Patie nts 
ma y c o nti n ue t o recei ve treat me nt i n t he a bse nce of disease pr o gressi o n or 
u nacce pta ble t o xicit y t hat is n ot a meli orate d b y o pti mal me dical or n o n -me dical s u p p orti ve or 
pr o p h ylactic care. All patie nts will be f oll o we d u p u ntil wit h dra wal of c o nse nt, l ost t o 
f oll o w-u p, deat h, or t he o verall e n d of st u d y has bee n reac he d ( defi ne d i n Secti o n 3. 5 ), 
w hic he ver occ urs first.  
T he pri mar y efficac y a nal ysis will be perf or me d w he n  a t otal of 1 3 9 P F S e ve nts ha ve occ urre d . 
A n e val uati o n of efficac y ma y als o be perf or me d w he n a t otal of 7 0 P F S e ve nts ha ve occ urre d.  
T he st u d y will be c o nsi dere d c o m plete o nce  t he fi nal patie nt has c o m plete d t heir E n d of 
Treat me nt visit.  
3. 2.  
R ati o n ale f or t he  D ose s S electe d 
3. 2. 1.  
N U FI RI Re gi me n  
Patie nts i n b ot h N U FI RI ar ms will recei ve N U C -3 3 7 3 at a d ose of 1 5 0 0 m g/ m 2 + L V at a d ose 
of 4 0 0 m g/ m 2, o n eit her a Q 1 W sc he d ule ( Ar m A) or a Q 2 W sc he d ule ( Ar m B). T he iri n oteca n 
a n d be vaciz u ma b c o m p o ne nts of t he re gi me n will be a d mi nistere d at t he sta n dar d d oses a n d 
sc he d ules.  
T he safet y of N U C -3 3 7 3 as a si n gle a ge nt  ( wit h o ut L V) at d oses ra n gi n g fr o m 1 2 5  t o 
3 2 5 0  m g/ m 2 a d mi nis tere d o n Da ys 1, 8, 1 5 a n d 2 2  of a 2 8 -da y sc he d ule  ( Q 1 W) has bee n st u die d 
i n t he N u Ti de: 3 0 1 st u d y. T his st u d y als o i ncl u ded  a Q 2 W sc he d ule a n d d oses of 1 5 0 0 t o 
2 5 0 0  m g/ m 2 a d mi nistere d o n Da ys 1 a n d 1 5 of a 2 8 -da y sc he d ule ha ve bee n e val uate d. F o ur  
patie nts e x perie nce d D L Ts. I n t he 5 0 0 m g/ m 2 Q 1 W a n d 1 8 7 5  m g/ m 2 Q 1 W c o h ort s, D L Ts of 
Gra de 3 tra nsa mi n ases i ncrease d  w ere re p orte d. I n t he 3 2 5 0 m g/ m2 Q 1 W  c o h ort, t w o D L Ts  
were re p orte d, o ne D L T  of Gra de 2 hea dac he a n d o ne D L T of Gra de 3 tra nsie nt h y p ote nsi o n 
( dr o p i n bl o o d press ure f or < 5 mi n utes). Base d o n t hese fi n di n gs , the M T D f or si n gle -a ge nt 
N U C -3 3 7 3 was deter mi ne d t o be 2 5 0 0  m g/ m 2 Q 1 W .  

N u Ti de: 3 2 3                                                                                                                        Versi o n 2 .1 , 0 6  Fe b  2 0 2 4  
C o nfi de ntia l                                                            N u Ca na  plc  
3 5  
I n t he N u Ti de: 3 0 2 st u d y of N UC -3 3 7 3 i n c o m bi nati o n wit h sta n dar d a ge nts f or t he treat me nt 
of patie nts wit h metastatic C R C, patie nts i n Part 2 recei ve d N U FI RI o n a Q 1 W N U C -3 3 7 3 
sc he d ule i n d ose-escalati o n c o h orts . Patie nts recei ve d 4 0 0 m g/ m 2 L V pl us  iri n oteca n pl us 
N U C -3 3 7 3  as f oll o ws:  N U C -3 3 7 3 at 1, 5 0 0 m g/ m 2 + iri n oteca n at 1 2 0  m g/ m 2, N U C-3 3 7 3 at 
1, 5 0 0 m g/ m 2 + iri n oteca n at 1 5 0  m g/ m 2, N U C-3 3 7 3 at 1, 5 0 0 m g/ m 2 + iri n oteca n at 1 8 0  m g/ m 2, 
a n d N U C-3 3 7 3 at 1, 8 7 5 m g/ m 2 + iri n oteca n at 1 8 0  m g/ m 2.  
I n t he N U FI RI c o h orts, 2  patie nts e x perie nce d D L Ts  at t he hi g hest d ose le vel teste d 
( N U C-3 3 7 3 1, 8 7 5 m g/ m 2 + iri n oteca n 1 8 0  m g/ m 2). O ne patie nt ha d Gra de 3 fati g ue a n d o ne 
patie nt ha d Gra de 3 c olitis. As a res ult, t he N U C -3 3 7 3 1, 5 0 0 m g/ m 2 + iri n oteca n 1 8 0  m g/ m 2 
d ose gr o u p was e x pa n de d a n d o ne patie nt e x perie nce d a D L T of Gra de 3 A L T a n d A L P 
i ncrease d. Base d o n t his, t he R P 2 D f or  t he N U FI RI re gi me n was deter mi ne d t o be 1 5 0 0 m g/ m2 
N U C -3 3 7 3  Q 1 W  + 4 0 0 m g/ m 2 L V Q 1 W  +  1 8 0 m g/ m 2 iri n oteca n Q 2 W .  
I n Part 3  of N u Ti de: 3 0 2 , t he selecte d N U FI RI re gi me n is bei n g  a d mi nistere d  o n a Q 1 W 
N U C -3 3 7 3 sc he d ule  i n c o m bi nati o n wit h be vaciz u ma b  ( 5 m g/ k g Q 2 W ) f or t he 2n d-li ne 
treat me nt of patie nts wit h a d va nce d C R C. Data o btai ne d fr o m 8 patie nts treate d i n t he 
N U FI RI -be v c o h ort t o date (c ut-off 1 7 Ja n 2 0 2 3) s h o w t hat t he re gi me n has bee n well t olerate d. 
All 8  patie nts c o m plete d C ycle 1 wit h o ut T E A Es t hat w o ul d meet D L T criteria i n a d ose 
escalati o n desi g n.  T he m ost c o m m o nl y re p orte d treat me nt -relate d T E A Es ha ve bee n diarr h oea, 
fati g ue, A L T i ncrease d a n d A S T increase d i n 2 patie nts eac h. T w o Gra de 3 treat me nt -relate d 
T E A Es ha ve bee n re p orte d, A L T i ncrease d a n d pa ncreatitis. T here ha ve bee n n o Gra de 4 
treat me nt-relate d T E A Es. Base d o n t he T E A E pr ofile o bser ve d t o date, t here d oes n ot a p pear 
t o be a n y o verla p pi n g t o xicit y w he n be vaciz u ma b is a d de d t o t he N U FI RI re gi me n.     
T he selecte d N U C -3 3 7 3 d ose f or t his st u d y is t he M T D a n d R P 2 D deter mi ne d i n t he Q 1 W 
N U FI RI d ose escalati o n c o h orts i n Part 2 of N u Ti de: 3 0 2. T he N U FI RI a n d N U FI RI -be v 
re gi me ns ha ve o nl y bee n a d mi nistere d o n a Q 1 W N U C-3 3 7 3 sc he d ule t o date; t heref ore, o ne 
of t he o bjecti ves of t his st u d y is t o deter mi ne t he o pti mal d osi n g sc he d ule f or t he N U FI RI -be v 
re gi me n. It is a ntici pate d t hat a Q 2 W N U C-3 3 7 3 sc he d ule w o ul d n ot o nl y be well -t olerate d, 
b ut w o ul d als o ease t he treat me nt b ur de n o n t he patie nt a n d ali g n wit h t he sta n dar d 
F O L FI RI -be v d osi n g sc he d ule.  
3. 2. 2.  
F O L FI RI Re gi me n  
I n t he c o m parat or ar m ( Ar m C), patie nts will recei ve t he sta n dar d F O L FI RI-be v re gi me n  
esta blis he d f or t he treat me nt of patie nts wit h metastatic C R C . 
3. 3.  
St u d y T re at me nt 
T his is a t hree-ar m, c o m bi nati o n t hera p y st u d y i n w hic h st u d y treat me nt will be a d mi nistere d 
i n 2 8-da y c ycles .  
Patie nts will be ra n d o mise d 1: 1: 1 t o recei ve eit her:  
•  N U FI RI -be v o n a Q 1 W N U C -3 3 7 3 sc he d ule ( Ar m A)  
•  N U FI RI -be v o n a Q 2 W N U C -3 3 7 3 sc he d ule ( Ar m B)  
•  F O L FI RI -be v o n a Q 2 W sc he d ule ( Ar m  C)  
T he ra n d o misati o n pr ocess is detaile d i n Secti o n 8. 5 .  

N u Ti de: 3 2 3                                                                                                                        Versi o n 2 .1 , 0 6  Fe b  2 0 2 4  
C o nfi de ntia l                                                            N u Ca na  plc  
3 8  
•  T here is e vi de nce of c o nti n ue d cli nical be nefit f or t he patie nt a n d t he patie nt c o nse nts 
t o c o nti n ue wit h treat me nt 
•  T here are n o a p pr o priate alter nati ve treat me nt o pti o ns a vaila ble t o t he patie nt or a 
c ha n ge i n treat me nt w o ul d p ose a ris k t o t he patie nt  
•  T he patie nt a n d his/ her d oct or c o m pl y wit h a n d satisf y a n y le gal or re g ulat or y 
re q uire me nts f or c o nti n uati o n of N U C-3 3 7 3  
A patie nt will n ot be eli gi ble t o recei ve N U C -3 3 7 3 after st u d y c o m pleti o n if a n y of t he 
f oll o wi n g c o n diti o ns are met: 
•  T he S p o ns or has disc o nti n ue d de vel o p me nt of N U C -3 3 7 3 or data s u g gest t hat 
N U C -3 3 7 3 is n ot effecti ve f or metastatic C R C  
•  T he S p o ns or has reas o na ble safet y c o ncer ns re gar di n g N U C -3 3 7 3 as treat me nt f or 
metastatic C R C  
•  Pr o visi o n of N U C -3 3 7 3 is n ot per mitte d u n der t he la ws a n d re g ulati o ns of  t he patie nt’s 
c o u ntr y 
 
 

N u Ti de: 3 2 3                                                                                                                        Versi o n 2 .1 , 0 6  Fe b  2 0 2 4  
C o nfi de ntia l                                                            N u Ca na  plc  
3 9  
4  
P A TI E N T  S E L E C TI O N  
4. 1   
I ncl usi o n C riteri a 
T o be e nr olle d i n t his st u d y, patie nts m ust meet t he f oll o wi n g criteria d uri n g t he Scree ni n g 
peri o d:  
1.  Pr o visi o n of writte n i nf or me d c o nse nt . 
2.  Hist ol o gical or c yt ol o gical c o nfir mati o n of c ol orecta l a de n ocarci n o ma (e xcl u di n g 
a p pe n diceal a n d a nal ca nal ca ncers , as well as si g net-ri n g cell carci n o ma) t hat is 
u nresecta ble a n d metastatic.  
3.  Meas ura ble disease (as defi ne d b y R E CI S T v 1. 1).  
4.  Recei ve d ≥2 m o nt hs of a first -li ne fl u or o p yri mi di ne a n d o xali plati n-c o ntai ni n g re gi me n 
f or metastatic disease or rela pse d wit hi n 6 m o nt hs of c o m pleti n g a fl u or o p yri mi di ne 
a n d o xali plati n -c o ntai ni n g ne oa dj u va nt/ a dj u va nt t hera p y. Pre vi o us treat me nt wit h 
sta ndar d of care c he m ot hera p y re gi me ns i n c o m bi nati o n wit h m olec ular tar gete d 
t hera pies (e. g., V E G F a n d E G F R pat h wa y i n hi bit ors a n d i m m u n o -o nc ol o g y a ge nts) is 
per mitte d. Pre vi o us treat me nt wit h mai nte na nce t hera p y ( e. g., ca pecita bi ne) is als o 
all o we d. Patie nts  w h o starte d o n a fl u or o p yri mi di ne a n d o xali plati n -c o ntai ni n g re gi me n 
i n a n y setti n g b ut m ust disc o nti n ue t he o xali plati n d ue t o t o xicit y or aller g y (a n d are 
n o w u na ble t o recei ve o xali plati n) are c o nsi dere d eli gi ble re gar dless of t he n u m ber of 
c ycles of o xali plati n t he y recei ve d.  
5.  K n o w n R A S a n d B R A F stat us. Patie nts wit h wil d -t y pe R A S t u m o urs m ust ha ve 
recei ve d pri or treat me nt wit h a n E G F R i n hi bit or, u nless t his was n ot sta n dar d of care 
acc or di n g t o rele va nt re gi o n -s pecific treat me nt rec o m me n dati o ns. 
6.  K n o w n U G T 1 A 1 stat us, or patie nt c o nse nts t o U G T 1 A 1 stat us testi n g if u n k n o w n.  
7.  K n o w n D P D acti vit y stat us, or patie nt c o nse nts t o D P D stat us testi n g if u n k n o w n. S ee 
e xcl usi o n criteri o n 1 .  
8.  A ge ≥1 8 years.  
9.  Mi ni m u m l ife e x pecta nc y of ≥1 2 wee ks. 
1 0.  Easter n C o o perati ve O n c ol o g y Gr o u p ( E C O G ) Perf or ma nce stat us 0 or 1.  
1 1.  A de q uate b o ne marr o w f u ncti o n as defi ne d b y: a bs ol ute ne utr o p hil c o u nt ( A N C) ≥1. 5  
×  1 0 9/ L, platelet c o u nt ≥1 0 0 ×  1 0 9/ L, a n d hae m o gl o bi n ≥9 g/ d L.  Patie nts wit h be ni g n 
ne utr o pe nia ma y be disc usse d o n a case -b y -case basis wit h t he me dical m o nit or.  
1 2.  A de q uate li ver f u ncti o n, as defi ne d b y: ser u m t otal bilir u bi n ≤1. 5  ×  U L N  (t his t hres h ol d 
d oes n ot a p pl y t o patie nts wit h Gil bert’s s y n dr o me , w h o s h o ul d be disc usse d wit h t he 
M e dical M o nit or) , A S T a n d A L T ≤2. 5 ×  U L N ( or ≤5  ×  U L N if li ver metastases are 
prese nt).  
1 3.  A de q uate re nal f u ncti o n assesse d as ser u m creati ni ne < 1. 5  ×  U L N a n d  gl o mer ular 
filtrati o n rate ≥5 0 m L/ mi n (calc ulate d b y t he C oc kcr oft-Ga ul t met h o d). 
1 4.  Ser u m al b u mi n ≥3 g/ d L.  
1 5.  A bilit y t o c o m pl y wit h pr ot oc ol re q uire me nts.  

N u Ti de: 3 2 3                                                                                                                        Versi o n 2 .1 , 0 6  Fe b  2 0 2 4  
C o nfi de ntia l                                                            N u Ca na  plc  
4 0  
1 6.  Fe male patie nts of c hil d -beari n g p ote ntial m ust ha ve a ne gati ve ser u m pre g na nc y test 
wit hi n 7 da ys pri or t o t he first st u d y dr u g a d mi nistrati o n.  T his criteri o n d oes n ot a p pl y 
to patie nts w h o ha ve ha d a pre vi o us h ysterect o m y or bilateral o o p h orect o m y. Male 
patie nts a n d fe male patie nts of c hil d-beari n g p ote ntial m ust a gree t o practice tr ue 
a bsti ne nce ( defi ne d i n Secti o n 1 0. 3. 1 ) or t o use t w o f or ms of c o ntrace pti o n, o ne of 
w hic h m ust be hi g hl y effecti ve . T hese f or ms of c o ntrace pti o n m ust be use d fr o m t he 
ti me of si g ni n g c o nse nt, t hr o u g h o ut t he treat me nt peri o d, a n d f or 6 m o nt hs f oll o wi n g 
t he last d ose of a n y st u d y me dicati o n. Oral or i njecta ble c o ntrace pti ve a ge nts ca n n ot be 
t he s ole met h o d of c o ntrace pti o n 
1 7.  Patie nts m ust ha ve bee n a d vise d t o ta ke meas ures t o a v oi d or mi ni mi ze e x p os ure of t he 
s ki n a n d e yes t o U V li g ht, i ncl u di n g a v oi di n g s u n bat hi n g a n d s olari u m use , f or t he 
d urati o n of st u d y partici pati o n a n d f or a peri o d of 4 wee ks f oll o wi n g t he last d ose of 
st u d y me dicati o n 
4. 2  
E xcl usi o n C riteri a 
P ote ntial patie nts w h o meet a n y of t he f oll o wi n g criteria at Scree ni n g will  be e xcl u de d fr o m 
t he st u d y: 
1.  Hist or y of h y perse nsiti vit y or c urre nt c o ntra -i n dicati o ns t o 5-F U , F U D R or 
ca pecita bi ne.  T his i ncl u des patie nts wit h ge n ot y pic or p he n ot y pic ( bl o o d uracil le vel 
≥1 5 0  n g/ m L) e vi de nce of c o m plete D P D deficie nc y or T Y M P m utati o ns ass ociate d 
wit h t o xicit y t o fl u or o p yri mi di nes. Patie nts w h o t olerate d pri or 5 -F U at a re d uce d d ose 
le vel ma y be e nr olle d a n d treate d at t hat sa me d ose. 
2.  Hist or y of h y perse nsiti vit y or c urre nt c o ntra -i n dicati o n t o a n y of t he c o m bi nati o n a ge nts 
re q uire d f or the st u d y.  
3.  Hist or y of aller gic reacti o ns attri b ute d t o c o m p o ne nts of t he N U C -3 3 7 3 dr u g pr o d uct 
f or m ulati o n (su per refi ne d p ol ys or bate 8 0  [ S R P 8 0], di met h ylaceta mi de [ D M A]). 
4.  Hist or y of h y perse nsiti vit y t o C hi nese Ha mster O var y ( C H O) cell pr o d ucts or ot her 
rec o m bi na nt h u ma n or h u ma nise d a nti b o dies.  
5.  Hist or y of or k n o w n  ce ntral ner v o us s yste m or le pt o me ni n geal metastases.  
6.  S y m pt o matic ascites, ascites c urre ntl y re q uiri n g drai na ge pr oce d ures or ascites 
re q uiri n g drai na ge o ver t he pri or 3 m o nt hs. 
7.  M uta nt B R A F V 6 0 0 E stat us.  
8.  M SI hi g h or d M M R.  
9.  Pri or treat me nt wit h iri n oteca n.  
1 0.  C he m ot hera p y, h or m o nal t hera p y, ra di ot hera p y ( ot her t ha n a s h ort c ycle of palliati ve 
ra di ot hera p y [e. g., f or b o ne pai n] *), i m m u n ot hera p y, bi ol o gical a ge nts, or e x p os ure t o 
a n ot her i n vesti gati o nal a ge nt wit hi n 2 1  da ys ( or f o ur ti mes t he half -life f or m olec ular 
tar gete d a ge nts, w hic he ver is s h orter) of first a d mi nistrati o n of st u d y treat me nt: 
a. F or nitr os o ureas a n d mit o m yci n C wit hi n 6 wee ks of first a d mi nistrati o n of st u d y 
treat me nt 
b.  C o nti n u o us d osi n g of ≥1 0 m g pre d nis ol o ne  ( or ster oi d e q ui vale nt) is n ot all o we d 
d uri n g t he st u d y . C ortic oster oi d treat me nt is all o we d d uri n g scree ni n g b ut s h o ul d 
be wea ne d t o a d ose of ≤1 0 m g pre d nis ol o ne ( or ster oi d e q ui vale nt) b y C ycle 1 
Da y 1  

N u Ti de: 3 2 3                                                                                                                        Versi o n 2 .1 , 0 6  Fe b  2 0 2 4  
C o nfi de ntia l                                                            N u Ca na  plc  
4 1  
* P alli ative r a di ot her a py d uri n g p artici p ati o n i n t he st u dy is per mitte d, b ut s h o ul d n ot 
be c o nc urre nt wit h st u dy tre at me nt a n d rec overy s h o ul d be all o we d t o preve nt 
overl a p pi n g t oxicity  (refer t o Secti o n 1 0. 4 ). It s h o ul d n ot i ncl u de a t ar get lesi o n. 
1 1.  Resi d ual t o xicities fr o m pri or c he m ot hera p y or ra di ot hera p y w hic h ha ve n ot re gresse d 
t o Gra de ≤1 se verit y ( C T C A E v 5. 0), e xce pt f or al o pecia a n d resi d ual Gra de 2 
ne ur o pat h y.  
1 2.  Hist or y of ot her mali g na ncies, e xce pt a de q uatel y treate d n o n -mela n o ma s ki n ca ncer, 
c urati vel y treate d i n sit u ca ncer of t he cer vi x, s ur gicall y e xcise d or p ote ntiall y 
c urati vel y treate d d uctal carci n o ma i n sit u of t he breast, or l o w -gra de pr ostate ca ncer or 
patie nts after pr ost atect o m y. Patie nts wit h pre vi o us i n vasi ve ca ncers are eli gi ble if 
treat me nt was c o m plete d > 3 years pri or t o i nitiati n g t he c urre nt st u d y treat me nt, a n d 
t he patie nt has ha d n o e vi de nce or rec urre nce si nce t he n. 
1 3.  Prese nce of a n acti ve bacterial or viral i nfec ti o n (i ncl u di n g S A R S-C o V -2, Her pes 
Z oster, Varicella Z oster or c hic ke n p o x), k n o w n H u ma n I m m u n o deficie nc y Vir us ( HI V) 
p ositi ve or k n o w n acti ve he patitis B or C.  
1 4.  Prese nce of a n y u nc o ntr olle d c o nc urre nt seri o us ill ness, me dical c o n diti o n or ot her 
me dical his t or y, i ncl u di n g la b orat or y res ults, w hic h, i n t he I n vesti gat or’s o pi ni o n, 
w o ul d be li kel y t o i nterfere wit h t he patie nt’s a bilit y t o partici pate i n t he st u d y or wit h 
t he i nter pretati o n of t he res ults, i ncl u di n g t he f oll o wi n g: 
a. C o n gesti ve heart fail ure ( Ne w Y or k Heart Ass ociati o n Class III or Class  I V) 
b.  Cli nicall y si g nifica nt c or o nar y heart disease or m y ocar dial i nfarcti o n wit hi n 
6  m o nt hs of t he first d ose of st u d y me dicati o n or hi g h ris k of u nc o ntr olle d 
arr h yt h mia  
c. U nsta ble or p o orl y c o ntr olle d a n gi na pect ori s 
d.  C o m plete left b u n dle bra nc h, fascic ular bl oc k or ot her cli nicall y si g nifica nt 
a b n or mal E C G fi n di n g  
e. Q Tc i nter val > 4 7 0 millisec o n ds  
f. Hist or y of or c urre nt ris k fact or f or t orsa de de p oi ntes ( e. g., heart fail ure, 
h y p o kal ae mia, or a fa mil y hist or y of l o n g Q T  s y n dr o me) 
g.  Hist or y of se vere s ki n reacti o ns  (e xce pt f or s ki n reacti o ns t hat are a c o nse q ue nce 
of rece nt a nti -ca ncer treat me nt, i ncl u di n g c he m ot hera pies n ot c urre ntl y u n der 
i n vesti gati o n i n t his st u d y [e. g., o xali plati n ] or m olec ular tar gete d t hera pies s uc h  
as E G F R i n hi bit ors)  
h.  Hist or y of se vere oc ular dis or ders  
i. I nterstitial p ne u m o nitis or p ul m o nar y fi br osis 
1 5.  A n y c o n diti o n ( e. g., k n o w n or s us pecte d p o or c o m plia nce, ps yc h ol o gical i nsta bilit y, 
ge o gra p hical l ocati o n, etc.) t hat, i n t he j u d g me nt of t he I n vesti gat or, ma y affect t he 
patie nt’s a bilit y t o pr o vi de i nf or me d c o nse nt a n d u n der g o st u d y pr oce d ures.  
1 6.  Patie nts wit h a hist or y of h ae m o pt ysis ( 1/ 2 teas p o o n or m ore of re d bl o o d) wit hi n 
6  m o nt hs pri or t o e nr ol me nt.  

N u Ti de: 3 2 3                                                                                                                        Versi o n 2 .1 , 0 6  Fe b  2 0 2 4  
C o nfi de ntia l                                                            N u Ca na  plc  
4 2  
1 7.  W o u n d heali n g c o m plicati o ns or s ur ger y wit hi n 2 8 
da ys of starti n g be vaciz u ma b 
( w o u n d heali n g 
m ust ha ve bee n f ull y c o m plete d bef ore starti n g be vaciz u ma b). 
I n vesti gat ors ma y all o w patie nts t o i nitiate treat me nt wit h t he ot her st u d y dr u gs (i.e., 
N U C -3 3 7 3/ 5 -F U, L V a n d iri n oteca n) o n C 1 D 1 b ut wit h h ol d be vaciz u ma b f or at least 
1 5 da ys, b ut n o l o n ger t ha n 2 8 da ys, t o all o w c o m pleti o n of w o u n d heali n g i n patie nts 
w h o w o ul d ot her wise be eli gi ble f or t he st u d y, i n li ne wit h sta n dar d l ocal practice  a n d 
after disc ussi o n wit h t he Me dical M o nit or . Patie nts w h o ha ve n ot recei ve d be vaciz u ma b 
b y C 2 D 1 m ust be re place d.   
1 8.  U n heale d w o u n d, acti ve gastric or d u o de nal ulcer, or b o ne fract ure.  
1 9.  Seri o us t hr o m b oe m b olic e ve nt i n t he 6 m o nt hs bef ore i ncl usi o n ( e. g., tra nsit or y 
isc he mic str o ke, str o ke, s u barac h n oi d hae m orr ha ge) . Patie nts 
wit h n o n -seri o us 
t hr o m b oe m b olic e ve nts (e. g., n o n -s y m pt o matic p ul m o nar y e m b olis m or peri p heral 
dee p vei n t hr o m b osis treate d wit h a ntic oa g ula nts ) ma y be e nr olle d after disc ussi o n wit h 
t he Me dical M o nit or. 
2 0.  Patie nts wit h a hist or y of hae m orr ha ge  wit h i n 6 m o nt hs pri or t o e nr ol me nt.  
2 1.  K n o w n i n herite d or ac q uire d blee di n g dis or ders.  
2 2.  Re d bl o o d cell ( R B C) tra nsf usi o n de pe n de nce, defi ne d as re q uiri n g m ore t ha n 2 u nits 
of pac ke d R B C tra nsf usi o ns d uri n g t he 4 -wee k peri o d pri or t o scree ni n g.  
2 3.  U nc o ntr olle d h y perte nsi o n.  
2 4.  Se vere pr otei n uria  or  ne p hr otic s y n dr o me  (≥Gra de 3 [ uri ne di pstic k + 4 or ≥3. 5 g/ da y]) . 
2 5.  Ac ute i ntesti nal o bstr ucti o n or s u b -o bstr ucti o n, hist or y of i nfla m mat or y i ntesti nal 
disease  (i ncl u di n g c olitis or Cr o h n’s disease) or e xte n de d resecti o n of t he s mall 
i ntesti ne. Prese nce of a c olic pr ost hesis. 
2 6.  Hist or y of a b d o mi nal fist ulas, trac hea -oes o p ha geal fist ulas, a n y ot her 
Gra de 4 
gastr oi ntesti nal perf orati o ns, n o n -gastr oi ntesti nal fist ulas, or i ntra -a b d o mi nal a bscesses 
6 m o nt h s pri or t o scree ni n g. 
2 7.  C urre ntl y pre g na nt, lactati n g or breastfee di n g.  
2 8.  Re q uire d c o nc o mita nt use of bri v u di ne , s ori v u di ne a n d a nal o g ues. 
2 9.  Re q uire d c o nc o mita nt use of St J o h n's W ort.  
3 0.  Re q uire d c o nc o mita nt use of dr u gs k n o w n t o pr ol o n g Q T/ Q Tc i nter val.  
3 1.  Re q uire d c o nc o mita nt u se of str o n g C Y P 3 A 4 i n d ucers or str o n g C Y P 3 A 4  i n hi bit ors. 
T he use of str o n g C Y P 3 A 4 i n d ucers wit hi n 2 wee ks of first recei pt of st u d y dr u g or t he 
use of str o n g C Y P 3 A 4 i n hi bit ors wit hi n 1 wee k of first recei pt of st u d y dr u g  is als o 
e xcl u de d . 
3 2.  Use  of str o n g U G T 1 A 1 i n hi bit ors wit hi n 1 wee k of first recei pt of st u d y dr u g . 
3 3.  Recei ve d a li ve vacci nati o n wit hi n f o ur wee ks of first pla n ne d d ose of st u d y me dicati o n.  
3 4.  Ger m a n y o nl y:  Patie nts w h o ha ve bee n place d i n a n i nstit uti o n b y c o urt or official 
or der.  
Ger m a n y o nl y:  
D uri n g Scree ni n g , all patie nts will be i nter vie we d c o ncer ni n g a n y p ote ntial relati o ns hi p t o t he 
In vesti gat or , t he me dical staff of t he st u d y tea m, t he C o or di nati n g  In vesti gat or , or t he S p o ns or.  

N u Ti de: 3 2 3                                                                                                                        Versi o n 2 .1 , 0 6  Fe b  2 0 2 4  
C o nfi de ntia l                                                            N u Ca na  plc  
4 3  
Patie nts wit h a relati o ns hi p/ de pe n de nc y w h o ma y recei ve p ote ntial be nefit fr o m t he st u d y 
s h o ul d n ot be e xcl u de d; h o we ver, t he patie nt ca n n ot be e nr olle d b y t he pers o n t he y are 
de pe n de nt o n.  
4. 3  
W ai vers t o E ntr y C riteri a 
Wai vers will n ot  be gra nte d f or a pa tie nt w h o d oes n ot satisf y t he eli gi bilit y criteria. 
I n vesti gat ors w h o are u ns ure w het her t he patie nt satisfies all t he e ntr y criteria a n d wis h t o 
clarif y matters of cli nical discreti o n m ust c o ntact t he C R O Me dical M o nit or  w h o will c o ns ult 
t he S p o ns or bef ore res p o n di n g t o t he e n q uir y. 

N u Ti de: 3 2 3                                                                                                                        Versi o n 2 .1 , 0 6  Fe b  2 0 2 4  
C o nfi de ntia l                                                            N u Ca na  plc  
4 4  
5  
S T U D Y A S S E S S M E N T S A N D P R O C E D U R E S  
Data fr o m all pr oce d ures a n d assess me nts m ust be rec or de d i n t he patie nt’s me dical rec or d f or 
e xtracti o n i nt o t he C R F.  R efer t o t he S u m mar y Sc he d ule of  E ve nts  f or f urt her details. 
5. 1  
I nf or me d C o nse nt  
P ote ntial patie nts will be gi ve n t he c urre nt a p pr o ve d versi o n of t he st u d y i nf or mati o n s heet a n d 
i nf or me d c o nse nt f or m (I C F). T he y will als o recei ve clear ver bal i nf or mati o n a b o ut t he st u d y 
detaili n g n o less t h a n: t he nat ure of t he st u d y; t he i m plicati o ns a n d c o nstrai nts of t he pr ot oc ol; 
t he k n o w n si de effects a n d a n y ris ks i n v ol ve d i n ta ki n g part. It will be e x plai ne d t hat t he y will 
be free t o wit h dra w fr o m t he st u d y at a n y ti me, f or a n y reas o n, wit h o ut prej u di ce t o f ut ure care, 
a n d wit h n o o bli gati o n t o gi ve a reas o n f or wit h dra wal. T he y will ha ve at least 2 4  h o urs t o 
c o nsi der t he i nf or mati o n pr o vi de d a n d t he o p p ort u nit y t o q uesti o n t he I n vesti gat or, t heir G P or 
ot her i n de pe n de nt parties bef ore deci di n g w het her  t o partici pate. 
T he I n vesti gat or or desi g nee w h o o btai ns c o nse nt m ust be s uita bl y q ualifie d a n d e x perie nce d. 
All des i g nees m ust be a ut h oris e d b y t he I n vesti gat or t o o btai n c o nse nt. T he I n vesti gat or is 
res p o nsi ble f or e ns uri n g t hat t he st u d y c o nse nt pr oce dures c o m pl y wit h I nter nati o nal C o u ncil 
f or Har m o nisati o n G o o d Cli nical Practice (I C H-G C P ) a n d a n y ot her a d diti o nal l ocal re g ulat or y 
re q uire me nts. I nf or me d c o nse nt disc ussi o ns a n d o utc o mes m ust be well d oc u me nte d i n t he 
me dical rec or d. T he I n vesti gat or m ust  be satisfie d t hat t he patie nt has ma de a n i nf or me d 
d ecisi o n bef ore ta ki n g c o nse nt. T he patie nt a n d t he I n vesti gat or  or a ut h or ise d desi g nee  w h o 
o btai ns c o nse nt m ust pers o nall y si g n a n d date t he c urre nt a p pr o ve d versi o n of t he I C F i n eac h 
ot her’s prese nce.  
A c o p y of t he st u d y i nf or mati o n a n d si g ne d I C F will be gi ve n t o t he patie nt. Writte n i nf or me d 
c o nse nt f or partici pati o n i n t he st u d y m ust be o btai ne d pri or t o  perf or mi n g  a n y st u d y -s pecific 
scree ni n g tests or e val uati o ns. 
5. 1. 1  
I nf or me d C o nse nt f or T u m o u r T iss ue C ollecti o n  
T his st u d y will e val uate bi o mar kers t o p ote ntiall y i de ntif y patie nts t hat are li kel y t o res p o n d t o 
N U C -3 3 7 3 or patie nts w h o ma y be resista nt t o N U C -3 3 7 3. P atie nts will be re q ueste d t o c o nse nt 
t o pr o vi di n g arc hi val t u m o ur tiss ue fr o m t he ti me of dia g n osis, if a vaila ble.  
F or sa m pli n g  pr oce d ures, st ora ge c o n diti o ns  a n d s hi p me nt i nstr ucti o ns, please refer t o  t he 
acc o m pa n yi n g T u m o u r Tiss ue La b orat or y Ma n ual. 
5. 2  
P atie nt R e gistr ati o n a n d S cree ni n g P r oce d ures  
All scree ni n g acti vities m ust be perf or me d wit hi n 2 8  da ys of ra n d o misati o n. A Scree ni n g L o g 
m ust be ke pt of all patie nts c o nsi dere d f or t he st u d y ( i.e., all t h ose t hat are i ncl u de d f or 
scree ni n g a n d a n y t hat are s u bse q uentl y e xcl u de d). T he reas o n f or e xcl usi o n m ust be rec or de d 
o n t his f or m. A c o p y of t he Scree ni n g L o g m ust be retai ne d o n site a n d pr o vi de d t o t he Cli nical 
Researc h Or ga nisati o n ( C R O ) u p o n re q uest, b ut wit h o ut patie nt i de ntifiers.  
Sta n dar d of care assess me nt s t hat were c o m plete d pri or t o i nf or me d c o nse nt b ut are wit hi n t he 
scree ni n g wi n d o w ma y be use d f or scree ni n g assess me nts a n d d o n ot ha ve t o be re peate d. 
I ma gi n g c o m plete d pri or t o i nf or me d c o nse nt f or r o uti ne cli nical practice p ur p oses is 
acce pta ble pr o vi de d it was perf or me d as per R E CI S T v 1. 1 criteria a n d wit hi n 2 8 da ys of 
ra n d o misati o n. All pr ot oc ol -re q uire d assess me nts t hat are n ot dee me d sta n dar d of care s h o ul d 
n ot be perf or me d pri or t o writte n i nf or me d c o nse nt.  

N u Ti de: 3 2 3                                                                                                                        Versi o n 2 .1 , 0 6  Fe b  2 0 2 4  
C o nfi de ntia l                                                            N u Ca na  plc  
4 5  
5. 3  
Scree ni n g A ssess me nts 
Scree ni n g assess me nts of c o nse nte d patie nts will c o m prise t he f oll o wi n g:  
•  Pr o visi o n of writte n i nf or me d c o nse nt  
•  Eli gi bilit y c o nfir mati o n, i ncl u di n g hist ol o gical  or c yt ol o gical  dia g n osis of C R C  t hat 
is u nresecta ble a n d metastatic 
•  Rec or di n g of de m o gra p hic data  
•  Assess me nt of me dical a n d s ur gical hist or y, i ncl u di n g pri or t hera p y f or C R C  as well 
as rec or di n g i nf or mati o n o n t he si de d ness of t he patie nt’s C R C (left-si de d vs 
ri g ht-si de d). 
•  Rec or di n g of c o nc o mita nt me dicati o n  
•  F ull  p h ysical e xa mi nati o n, i ncl u di n g vital s i g ns. F ull p h ysical e xa mi nati o n i ncl u des 
ears, e yes, n ose, hea d, t hr oat, nec k, l u n gs, heart, a b d o me n, e xtre mities, s ki n, 
m usc ul os keletal, ner v o us s yste m, a n d l y m p h n o des . Vital si g ns i ncl u de 
meas ure me nt of p ulse rate, res pirat or y rate, bl o o d press ure a n d t e m perat ure, after 
t he patie nt has bee n seate d or i n t he s u pi ne p ositi o n f or 5 mi n utes 
•  Hei g ht a n d wei g ht  
•  Uri nal ysis: p H, s pecific gra vit y, ket o nes, le u k oc ytes, pr otei n, gl uc ose, bilir u bi n, 
ur o bilir u bi n a n d occ ult bl o o d. Di pstic k testi n g is acce pta ble  
•  E C O G p erf or ma nce s tat us 
•  1 2 -lea d E C G  
o  T he 1 2 -lea d E C Gs s h o ul d be perf or me d i n tri plicate ( kee pi n g t he lea ds i n place 
a n d patie nt s u pi ne d uri n g rea di n gs) a n d re vie we d b y t he I n vesti gat or or a 
q ualifie d desi g nee f or safet y a n d q ualit y . T he ti mi n g bet wee n t he tri plicate 
E C Gs is rec o m me n de d t o be a p pr o xi matel y 1 mi n ute  
o  T he Q Tc i nter val s h o ul d be calc ulate d f or eac h E C G usi n g t he Fri dericia 
f or m ula a n d a vera ge d. 
Ma na ge me nt of Q T/ Q Tc pr ol o n gati o n s h o ul d be 
perf or me d i n acc or da nce wit h i nstit uti o nal sta n dar d of car e at t he discreti o n of 
t he treati n g p h ysicia n 
o  Di gital a n d / or certifie d pa per c o pies s h o ul d be retai ne d at site a n d st ore d as part 
of t he st u d y d oc u me nts i n t he e ve nt t he y nee d t o be use d i n a f ut ure a nal ysis  
•  Bl o o d sa m ples dra w n f or: 
o  Pre g na nc y testi n g:  F or w o me n of c hil d beari n g p ote ntial a ser u m pre g na nc y test 
m ust be perf or me d wit hi n 7 da ys of t he first d ose of st u d y treat me nt  
o  H ae mat ol o g y: w hite bl o o d c ell ( W B C) c o u nt, differe ntial W B C c o u nt, R B C  
c o u nt , h ae m o gl o bi n, h ae mat ocrit a n d platelets  
o  C he mistr y: s o di u m, 
p otassi u m, 
ma g nesi u m, 
urea, creati ni ne, 
gl uc ose, 
p h os p hate, t otal pr otei n, al b u mi n, a dj uste d calci u m, t otal bilir u bi n,  direct 
bilir u bi n, i n direct 
bilir u bi n,  bicar b o nate, c hl ori de, 
uric aci d, al kali ne 
p h os p hatase, A S T, A L T a n d lactate de h y dr o ge nase ( L D H ) 
o  C oa g ulati o n para meters : pr ot hr o m bi n ti me/i nter nati o nal n or malise d rati o 
(P T/I N R ) a n d acti vate d partial t hr o m b o plasti n ti me ( a P T T) 

N u Ti de: 3 2 3                                                                                                                        Versi o n 2 .1 , 0 6  Fe b  2 0 2 4  
C o nfi de ntia l                                                            N u Ca na  plc  
4 6  
o  T u m o ur mar kers (carci n oe m br y o nic a nti ge n [ C E A])  
o  D P D stat us  testi n g, if n ot k n o w n. Perf or me d b y eit her ge n ot y pi n g or p he n ot y pic 
testi n g of bl o o d uracil le vels. Patie nts wit h bl o o d uracil ≥1 5 0  n g/ m L are 
c o nsi dere d t o be D P D deficie nt a n d are e xcl u de d fr o m partici pati o n. Patie nts 
wit h bl o o d uracil le vels of  ≥1 6 n g/ m L t o < 1 5 0  n g/ m L are c o n si dere d t o be 
partiall y D P D deficie nt . T he 5 -F U d ose m ust be a da pte d  f or partiall y D P D 
deficie nt patie nts i n c o u ntries w here t his is sta n dar d practice as per nati o nal 
a n d/ or l ocal g ui deli nes  (refer t o Secti o n 9. 2. 1 ) 
o  B R A F /K R A S/ N R A S/ M SI/ M M R  stat us testi n g, if n ot k n o w n . Res ults m ust be 
o btai ne d pri or t o t he patie nt recei vi n g t he first d ose of st u d y treat me nt   
o  U G T 1 A 1 st at us testi n g, if n ot k n o w n. Res ults d o n ot nee d t o be o btai ne d pri or 
t o t he patie nt recei vi n g t he first d ose of st u d y treat me nt. If a patie nt’s m utati o nal 
stat us is k n o w n pri or t o d osi n g a n d t he y ha ve a m utati o n t hat ma y affect t heir 
a bilit y t o meta b olise iri n oteca n, a n i nitial d ose re d ucti o n of iri n oteca n  ma y be 
i m ple me nte d as per t he iri n oteca n S m P C/ Prescri bi n g I nf or mati o n a n d site 
sta n dar d of care. T his m ust be disc usse d o n a case-b y -case basis wit h t he 
me dical m o nit or  
•  T u m o u r i ma gi n g (c o m p ute d t o m o gra p h y [ C T ] or  ma g netic res o na nce i ma gi n g 
[M RI ] of t h ora x, a b d o me n  a n d pel vis)  –  perf or me d wit hi n 2 8  da ys pri or t o 
ra n d o misati o n. A rece nt pre vi o usl y o btai ne d i ma ge ma y be use d if o btai ne d wit hi n 
2 8  da ys pri or t o ra n d o misati o n a n d i ma ges c ollecte d meet pr ot oc ol re q uire me nts .   
•  A E rec or di n g a n d ca usalit y assess me nt  
•  O btai n a n arc hi val t u m o ur tiss ue bl oc k, if a vaila ble  
•  A d vise t he patie nt t o ta ke meas ures t o a v oi d or mi ni mise e x p os ure to U V li g ht f or 
t he d urati o n of st u d y partici pati o n a n d f or a peri o d of 4 wee ks f oll o wi n g t he last 
d ose of st u d y me dicati o n  
•  A d vise t he patie nt t o c o nsi der cr y o-c o nser vati o n of t heir s per m or e g gs pri or t o 
treat me nt (refer t o Secti o n 9. 3. 9 ) 
•  A de ntal e xa mi nati o n a n d a p p ro p riate pre ve ntati ve de ntistr y s h o ul d be c o nsi dere d 
pri or t o starti n g treat me nt wit h be vaciz u ma b. I n patie nts w h o ha ve pre vi o usl y 
recei ve d or are recei vi n g I V bis p h os p h o nates, i n vasi ve de ntal pr oce d ures s h o ul d be 
a v oi de d if p ossi ble  
•  Patie nt re gistrati o n  
5. 4  
Re -S cree ni n g P atie nts w h o F ail Scree ni n g  
If a patie nt d oes n ot meet t he i ncl usi o n/e xcl usi o n criteria u p o n first assess me nt, t he patie nt ca n 
be reassesse d as nee de d d uri n g t he 2 8 -da y scree ni n g peri o d  wit h o ut bei n g c o nsi dere d a scree n 
fail ure. 
If a patie nt d oes n ot meet t he i ncl usi o n/e xcl usi o n criteria b y t he e n d of t he 2 8 -da y scree ni n g 
peri o d, t he y are c o nsi dere d a scree n fail ur e b ut ma y be re -scree ne d o nce. T hese patie nts will 
be rec o nse nte d.  Patie nts w h o fail at re -scree ni n g are i neli gi ble a n d ma y n ot be e nr olle d . 
All Scree ni n g assess me nts t hat res ult i n a patie nt faili n g t he i nitial scree ni n g pr ocess m ust be 
re peate d a n d c o nfir me d as meeti n g t he i ncl usi o n criteria f or t he st u d y i n a d va nce of C 1 D 1.  

N u Ti de: 3 2 3                                                                                                                        Versi o n 2 .1 , 0 6  Fe b  2 0 2 4  
C o nfi de ntia l                                                            N u Ca na  plc  
4 7  
D uri n g t he re -scree ni n g pr ocess, a n y Scree ni n g assess me nt t hat will be greater t ha n 2 8 da ys 
fr o m t he date ta ke n t o C 1 D 1 m ust als o be re peate d. 
5. 5  
E v al u ati o ns t o b e P erf or me d d uri n g t he S t u d y 
5. 5. 1  E ac h c ycle , D a y 1  (± 2 d a ys; All ar ms)  
All pr oce d ures t o be c o m plete d p ri or t o d osi n g . 
•  Rec or di n g of ne w or c ha n ges t o c o nc o mita nt me dicati o n.  
•  P h ysical e xa mi nati o n  
o  F ull p h ysical e xa mi nati o n (i ncl u di n g ne ur ol o gical e xa mi nati o n) t o be 
perf or me d o n C 1 D 1 a n d C 2 D 1 o nl y . F ull p h ysical e xa mi nati o n i ncl u des ears, 
e yes, n ose, hea d, t hr oat, nec k, l u n gs, heart, a b d o me n, e xtre mities, s ki n, 
m usc ul os keletal, ner v o us s yste m, a n d l y m p h n o des   
o  Directe d p h ysical e xa mi nati o n ( directe d b y cli nical si g ns a n d s y m pt o ms, 
i nclu di n g ne ur ol o gical e xa mi nati o n), o nl y if cli nicall y i n dicate d, t o be 
perf or me d fr o m C ycle  3 o n war ds  
•  Wei g ht  
•  Uri nal ysis: p H, s pecific gra vit y, ket o nes, le u k oc ytes, pr otei n, gl uc ose, bilir u bi n, 
ur o bilir u bi n a n d occ ult bl o o d. Di pstic k testi n g is acce pta ble  
•  E C O G perf or ma nce s tat us 
•  Vital si g ns, i ncl u di n g meas ure me nt of p ulse rate, res pirat or y rate, bl o o d press ure 
a n d te m perat ure, after t he patie nt has bee n seate d or i n t he s u pi ne p ositi o n f or 
5  mi n utes  
•  Pre -d ose E C Gs:  1 2 -lea d E C Gs s h o ul d be perf or me d pri or t o i nf usi o n of all 
i n vesti gati o nal me dici nal pr o d ucts (I M Ps) f or patie nts i n all treat me nt ar ms 
•  P ost -d ose E C Gs:  1 2 -lea d E C Gs s h o ul d be perf or me d p ost  i nf usi o n of all I M Ps 
( wit hi n 1 0 mi n utes of t he e n d of i nf usi o n) o n C 1 D 1 a n d C 2 D 1  f or patie nts i n t he 
N U FI RI treat me nt ar ms o nl y ( Ar ms A a n d B)  
o  T he E C Gs s h o ul d be perf or me d i n tri plicate ( kee pi n g t he lea ds i n place a n d 
patie nt s u pi ne d uri n g rea di n gs) a n d re vie we d b y t he I n vesti gat or or a q ualifie d 
desi g nee f or safet y a n d q ualit y . T he ti mi n g be twee n t he tri plicate E C Gs is 
rec o m me n de d t o be a p pr o xi matel y 1 mi n ute 
o  T he Q Tc i nter val s h o ul d be calc ulate d f or eac h E C G usi n g t he Fri dericia 
f or m ula a n d a vera ge d. 
Ma na ge me nt of Q T/ Q Tc pr ol o n gati o n s h o ul d be 
perf or me d i n acc or da nce wit h i nstit uti o nal sta n dar d of car e at t he discreti o n of 
t he treati n g p h ysicia n 
o  Di gital a n d / or certifie d pa per c o pies s h o ul d be retai ne d at site a n d st ore d as part 
of t he st u d y d oc u me nts i n t he e ve nt t he y nee d t o be use d i n a f ut ure a nal ysis  
•  Uri ne pre g na nc y test f or w o me n of c hil d -beari n g p ote ntial. If a n y uri ne test res ult 
is p ositi ve, patie nt d osi n g will be p ost p o ne d u ntil t he res ult is c o nfir me d b y a ser u m 
pre g na nc y test. A n y patie nt wit h a p ositi ve ser u m test will n ot be all o we d t o recei ve 
a n y st u d y treat me nt  

N u Ti de: 3 2 3                                                                                                                        Versi o n 2 .1 , 0 6  Fe b  2 0 2 4  
C o nfi de ntia l                                                            N u Ca na  plc  
4 8  
•  Bl o o d sa m ples dra w n f or: 
o  H ae mat ol o g y: W B C  c o u nt, differe ntial W B C c o u nt, R B C  c o u nt, h ae m o gl o bi n, 
h ae mat ocrit a n d platelets  
o  C he mistr y: s o di u m, 
p otassi u m, 
ma g nesi u m, 
urea, creati ni ne, 
gl uc ose, 
bicar b o nate, c hl ori de, uric aci d, p h os p hate, t otal pr otei n, al b u mi n, a dj uste d 
calci u m, t ot al  bilir u bi n, direct bilir u bi n, i n direct bilir u bi n, al kali ne p h os p hatase, 
A S T, A L T a n d L D H  
o  C oa g ulati o n para meters : P T/I N R a n d a P T T  
o  Fr o m C ycle 2 D a y 1 o n w ar ds:  T u m o ur mar kers ( C E A)  
•  Ra n d o mis ati o n (ca n be perf or me d 3  w or ki n g da y s pri or t o C 1 D 1)  
•  I V a d mi nistrati o n of st u d y dr u g:  
o  Ar m A: Be vaciz u ma b + L V + iri n oteca n + N U C -3 3 7 3  
o  Ar m B: Be vaciz u ma b + L V + iri n oteca n + N U C -3 3 7 3  
o  Ar m C: Be vaciz u ma b + L V + iri n oteca n + 5 -F U  
•  A E rec or di n g a n d ca usalit y assess me nt  
•  Bl o o d sa m ples f or P K  meas ure me nts  o n C 2 D 1 o nl y  - Refer t o Secti o n  7 . 2 f or m ore 
details  
5. 5. 2  E ac h c ycle, D a y 8 (± 2 d a ys; Ar m A  o nl y)  
All pr oce d ures t o be c o m plete d pri or t o d osi n g : 
•  Rec or di n g of ne w or c ha n ges t o c o nc o mita nt me dicati o ns  
•  Vital si g ns , i ncl u di n g meas ure me nt of p ulse rate, res pirat or y rate, bl o o d press ure 
a n d te m perat ure, after t he patie nt has bee n seate d or i n t he s u pi ne p ositi o n f or 
5  mi n utes  
•  Bl o o d sa m ples dra w n  f or: 
o  H ae mat ol o g y: W B C c o u nt, differe ntial W B C c o u nt, R B C  c o u nt, h ae m o gl o bi n, 
h ae mat ocrit a n d platelets  
o  C he mistr y: s o di u m, 
p otassi u m, 
ma g nesi u m, 
urea, creati ni ne, 
gl uc ose, 
bicar b o nate, c hl ori de, uric aci d, p h os p hate, t otal pr otei n, al b u mi n, a dj uste d 
calci u m, t otal bilir u bi n, direct bilir u bi n, i n direct bilir u bi n, al kali ne p h os p hatase, 
A S T, A L T a n d L D H  
•  I V a d mi nistrati o n of st u d y dr u g: 
o  Ar m A: N U C -3 3 7 3 + L V  
•  A E rec or di n g a n d ca usalit y assess me nt  

N u Ti de: 3 2 3                                                                                                                        Versi o n 2 .1 , 0 6  Fe b  2 0 2 4  
C o nfi de ntia l                                                            N u Ca na  plc  
4 9  
5. 5. 3  E ac h cycle, D a y 1 5  (± 2 d a ys; All ar ms ) 
All pr oce d ures t o be c o m plete d p ri or t o d osi n g : 
•  Rec or di n g of ne w or c ha n ges t o c o nc o mita nt me dicati o ns  
•  Vital si g ns, i ncl u di n g meas ure me nt of p ulse rate, res pirat or y rate, bl o o d press ure 
a n d te m perat ure, after t he patie nt has bee n seate d or i n t he s u pi ne p o siti o n f or 
5  mi n utes  
•  Uri nal ysis: p H, s pecific gra vit y, ket o nes, le u k oc ytes, pr otei n, gl uc ose, bilir u bi n, 
ur o bilir u bi n a n d occ ult bl o o d. Di pstic k testi n g is acce pta ble  
•  Pre -d ose E C Gs:  1 2 -lea d E C Gs s h o ul d be perf or me d pri or t o i nf usi o n of all 
i n vesti gati o nal me dici nal pr o d ucts (I M Ps)  o n C 1 D 1 5 a n d C 2 D 1 5  f or patie nts i n all 
treat me nt ar ms.  
•  P ost -d ose E C Gs:  1 2 -lea d E C Gs s h o ul d be perf or me d p ost  i nf usi o n of all I M Ps 
( wit hi n 1 0 mi n utes of t he e n d of i nf usi o n) o n C 1 D 1 5  a n d C 2 D 1 5  f or patie nts i n t he 
N U FI RI treat me nt ar ms o nl y ( Ar ms A a n d B)  
o  T he E C Gs s h o ul d be perf or me d i n tri plicate ( kee pi n g t he lea ds i n place a n d 
patie nt s u pi ne d uri n g rea di n gs) a n d re vie we d b y t he I n vesti gat or or a q ualifie d 
desi g nee f or safet y a n d q ualit y . T he t i mi n g bet wee n t he tri plicate E C Gs is 
rec o m me n de d t o be a p pr o xi matel y 1 mi n ute 
o  T he Q Tc i nter val s h o ul d be calc ulate d f or eac h E C G usi n g t he Fri dericia 
f or m ula a n d a vera ge d. 
Ma na ge me nt of Q T/ Q Tc pr ol o n gati o n s h o ul d be 
perf or me d i n acc or da nce wit h i nstit uti o n al sta n dar d of care at t he discreti o n of 
t he treati n g p h ysicia n 
o  Di gital a n d / or certifie d pa per c o pies s h o ul d be retai ne d at site a n d st ore d as part 
of t he st u d y d oc u me nts i n t he e ve nt t he y nee d t o be use d i n a f ut ure a nal ysis  
•  Bl o o d sa m ples dra w n f or:  
o  H ae mat ol o g y: W B C c o u nt, differe ntial W B C c o u nt, R B C  c o u nt, h ae m o gl o bi n, 
h ae mat ocrit a n d platelets  
o  C he mistr y: s o di u m, 
p otassi u m, 
ma g nesi u m, 
urea, creati ni ne, 
gl uc ose, 
bicar b o nate, c hl ori de, uric aci d, p h os p hate, t otal pr otei n, al b u mi n, a dj uste d 
calci u m, t ot al bilir u bi n, direct bilir u bi n, i n direct bilir u bi n, al kali ne p h os p hatase, 
A S T, A L T a n d L D H  
•  I V a d ministrati o n of st u d y dr u g:  
o  Ar m A: Be vaciz u ma b + L V + iri n oteca n + N U C -3 3 7 3  
o  Ar m B: Be vaciz u ma b + L V + iri n oteca n + N U C -3 3 7 3  
o  Ar m C: Be vaciz u ma b + L V + iri n oteca n + 5 -F U  
•  A E rec or di n g a n d ca usalit y assess me nt  
5. 5. 4  E ac h cycle, D a y 2 2  (± 2 d a ys; Ar m A  o nl y)   
All pr oce d ures t o be c o m plete d pri or t o d osi n g:  
•  Rec or di n g of ne w or c ha n ges t o c o nc o mita nt me dicati o ns  

N u Ti de: 3 2 3                                                                                                                        Versi o n 2 .1 , 0 6  Fe b  2 0 2 4  
C o nfi de ntia l                                                            N u Ca na  plc  
5 0  
•  Vital si g ns, i ncl u di n g meas ure me nt of p ulse rate, res pirat or y rate, bl o o d press ure 
a n d te m perat ure, after t he patie nt has bee n seate d or i n t he s u pi ne p ositi o n f or 
5  mi n utes  
•  Bl o o d sa m ples dra w n f or:  
o  Hae mat ol o g y: W B C c o u nt, differe ntial W B C c o u nt, R B C  c o u nt, hae m o gl o bi n, 
hae mat ocrit a n d platelets  
o  C he mistr y: s o di u m, 
p otassi u m, 
ma g nesi u m, 
urea, creati ni ne, 
gl uc ose, 
bicar b o nate, c hl ori de, uric aci d, p h os p hat e, t otal pr otei n, al b u mi n, a dj uste d 
calci u m, t otal bilir u bi n, direct bilir u bi n, i n direct bilir u bi n, al kali ne p h os p hatase, 
A S T, A L T a n d L D H  
•  I V a d mi nistrati o n of st u d y dr u g: 
o  Ar m A: N U C -3 3 7 3 + L V  
•  A E rec or di n g a n d ca usalit y assess me nt  
5. 5. 5  E ver y 8  w ee ks ( ± 7 d a ys) f r o m C ycle 1 D a y 1  u ntil dise ase p r o gressi o n, i niti ati o n 
of a ne w tre at me nt or d e at h  
•  T u m o u r i ma gi n g ( C T, or M RI  of t h ora x, a b d o me n  a n d pel vis)  
o  A d diti o nal tests ma y be re q ueste d at t he I n vesti gat or’s discreti o n. T he sa me 
m o dalit y s h o ul d be use d t hr o u g h o ut  
5. 5. 6  E n d of T re at me nt V isit ( 3 0 d a ys [ + 7 d a ys) after l ast d ose) 
T he a ssess me nts t o be perf or me d o n disc o nti n uati o n d ue t o ra di ol o gical disease pr o gressi o n or 
earl y treat me nt disc o nt i n uati o n f or ot her reas o ns (e. g., wit h dra wal of c o nse nt)  are s u m maris e d 
bel o w . T he E n d of Treat me nt  v isit s h o ul d occ ur wit hi n a mi ni m u m of 3 0 da ys t o a ma xi m u m 
of 3 7 da ys f oll o wi n g t he last a d mi nistrati o n of a n y st u d y me dicati o n . D uri n g t he E n d of 
Treat me nt  visit, t he  f oll o wi n g ite ms will be assesse d:  
•  Rec or di n g of ne w or c ha n ges t o c o nc o mita nt me dicati o n  
•  F ull  p h ysical e xa mi nati o n , i ncl u di n g vital si g ns. F ull p h ysical e xa mi nati o n i ncl u des 
ears, e yes, n ose, hea d, t hr oat, nec k, l u n gs, heart, a b d o me n, e xtre mities, s ki n, 
m usc ul os keletal, ner v o us s yste m, a n d l y m p h n o des. 
Vital si g ns i ncl u de  
meas ure me nt of p ulse rate, res pirat or y rate, bl o o d press ure  a n d te m perat ure , after 
t he patie nt has bee n seate d or i n t he s u pi ne p ositi o n f or 5 mi n utes, a n d te m perat ure  
•  Wei g ht  
•  Uri nal ysis: p H, s pecific gra vit y, ket o nes, le u k oc ytes, pr otei n, gl uc ose, bilir u bi n, 
ur o bilir u bi n a n d occ ult bl o o d. Di pstic k testi n g is acce pta ble  
•  E C O G perf or ma nce stat us  
•  1 2 -lea d E C G  
o  T he 1 2 -lea d E C Gs s h o ul d be perf or me d i n tri plicate ( kee pi n g t he lea ds i n place 
a n d patie nt s u pi ne d uri n g rea di n gs) a n d re vie we d b y t he I n vesti gat or or a 
q ualifie d desi g nee f or safet y a n d q ualit y . T he ti mi n g bet wee n t he tri plicate 
E C Gs is rec o m me n de d t o be a p pr o xi matel y 1 mi n ute   

N u Ti de: 3 2 3                                                                                                                        Versi o n 2 .1 , 0 6  Fe b  2 0 2 4  
C o nfi de ntia l                                                            N u Ca na  plc  
5 1  
o  T he Q Tc i nter val s h o ul d be calc ulate d f or eac h E C G usi n g t he Fri dericia 
f or m ula a n d a vera ge d. 
Ma na ge me nt of Q T/ Q Tc pr ol o n gati o n s h o ul d be 
perf or me d i n acc or da nce wit h i nstit uti o nal sta n dar d of care at t he discreti o n of 
t he treati n g p h ysicia n 
o  Di gital a n d / or certifie d pa per c o pies s h o ul d be retai ne d at site a n d st ore d as part 
of t he st u d y d oc u me nts i n t he e ve nt t he y nee d t o be use d i n a f ut ure a nal ysis  
•  Bl o o d sa m ples dra w n f or: 
o  Pre g na nc y testi n g  f or w o me n of c hil d-beari n g p ote ntial  
o  H ae mat ol o g y: W B C c o u nt, differe ntial W B C c o u nt, R B C  c o u nt, h ae m o gl o bi n, 
h ae mat ocrit a n d platelets  
o  C he mistr y: s o di u m, 
p otassi u m, 
ma g nesi u m, 
urea, creati ni ne, 
gl uc ose, 
bicar b o nate, c hl ori de, uric aci d, p h os p hate, t otal pr otei n, al b u mi n, a dj uste d 
calci u m, t ot al bilir u bi n, direct bilir u bi n, i n direct bilir u bi n, al kali ne p h os p hatase, 
A S T, A L T a n d L D H  
o  C oa g ulati o n para meters : P T/I N R a n d  a P T T 
o  T u m o ur mar kers C E A  
•  A E rec or di n g a n d ca usalit y assess me nt  
5. 5. 7  L o n g -Ter m F oll o w -U p  
I n Fr a nce o nl y: Pre g na nc y testi n g m ust c o nti n ue i n w o me n of c hil d beari n g p ote ntial e ver y 
4  wee ks f or 6 m o nt hs after t he last d ose of st u d y treat me nt. T his p ost-st u d y treat me nt 
pre g na nc y testi n g m ust n ot be perf or me d wit h a h o me test; h o we ver, i n or der t o a v oi d fre q ue nt 
h os pital visits, it ma y be perf or me d at a n e xter nal la b orat or y t hat is l ocal t o t he patie nt, wit h 
o versi g ht b y t he st u d y site . If t his occ urs, t he st u d y site m ust n otif y t he S p o ns or. All i nsta nces 
of p ositi ve pre g na nc y tests m ust be n otifie d b y t he e xter nal la b orat or y t o t he st u d y site, S p o ns or 
a n d t he patie nt’s treati n g p h ysicia n . 
Patie nts w h o st o p treat me nt wit h n o e vi de nce of  ra di ol o gical disease pr o gressi o n  as defi ne d b y 
R E CI S T  v 1. 1 criteria  will c o nti n ue t o recei ve sca ns at re g ular i nter vals ( e ver y 8 wee ks 
[± 7  da ys ] fr o m C 1 D 1 ) u ntil disease pr o gressi o n , i nitiati o n of a ne w treat me nt f or C R C , or deat h 
( w hic he ver c o mes first) t o deter mi ne d urati o n of o verall res p o nse a n d P F S . 
All patie nts  will be f oll o we d u p e ver y 1 2  wee ks ( ± 1 4 da ys)  fr o m C 1 D 1 u ntil wit h dra wal of 
c o nse nt, l ost t o f oll o w -u p, deat h, or t he o verall e n d of st u d y has bee n reac he d ( de fi ne d i n 
Secti o n 3. 5 ), w hic he ver occ urs first. Patie nts i n f oll o w -u p w h o ha ve n ot e x perie nce d disease 
pr o gressi o n s h o ul d c o nti n ue t o atte n d t he cli nic f or pla n ne d ra di ol o gic sca ns; h o we ver, ot her 
f oll o w-u p data c a n be c ollecte d re m otel y.  

N u Ti de: 3 2 3                                                                                                                        Versi o n 2 .1 , 0 6  Fe b  2 0 2 4  
C o nfi de ntia l                                                            N u Ca na  plc  
5 2  
6  
P A TI E N T WI T H D R A W A L  
6. 1  
E n d of T re at me nt 
Patie nts ma y c o nti n ue o n st u d y u nt il o ne of t he f oll o wi n g occ urs: 
•  Pr o gressi ve Disease as defi ne d b y R E CI S T  v 1. 1 criteria . Patie nts s h o ul d n ot 
disc o nti n ue st u d y treat me nt d ue t o  cli nical si g ns of  pr o gressi ve disease  u ntil it has 
bee n c o nfir me d b y R E CI S T  v 1. 1  
•  U n ma na gea ble t o xicit y defi ne d as a n A E t hat is c o nsi dere d b y t he I n vesti gat or t o 
warra nt per ma ne nt disc o nti n uati o n of st u d y treat me nt i ncl u di n g t he f oll o wi n g: 
o  A E res ulti n g i n a d osi n g dela y of m ore t ha n 2 8  da ys i n starti n g t he ne xt c ycle  
u nless t he patie nt is recei vi n g cli nical be nefit  
o  Cli nicall y -si g nifica nt treat me nt-relate d A E t hat rec urs des pite d ose 
re d ucti o n i n t w o c o nsec uti ve c ycles. Patie nts ma y c o nti n ue t o recei ve 
treat me nt if t he Pri nci pal I n vesti gat or a n d Me dical M o nit or a gree t hat t he 
patie nt is recei vi n g a cli nical be nefit a n d t he t o xicit y is ma na gea ble, 
re versi ble or tra nsie nt 
•  R ec urre nt r a di ol o gicall y c o nfir me d p ne u m o nitis , w hich d oes n ot res p o n d t o ster oi ds 
•  Ra di ol o gicall y c o nfir me d p osteri or re versi ble e nce p hal o pat h y s y n dr o me ( P R E S)  
•  Lac k of f urt her cli nical be nefit or u nfa v o u ra ble ris k/ be nefit pr ofile as j u d ge d b y t he 
I n vesti gat or 
•  I nter-c urre nt ill ness t hat pre ve nts f urt her a d mi nistrati o n of st u d y treat me nt 
•  Patie nt wit h dra ws c o nse nt fr o m f urt her treat me nt or f or f urt her data c ollecti o n  
o  If t he patie nt wit h dra ws c o nse nt f or f urt her treat me nt, f oll o w-u p visits 
s h o ul d c o nti n ue 
o  If t he patie nt wit h dra ws c o nse nt f or f urt her treat me nt a nd data c ollecti o n, n o 
a d diti o nal st u d y visits or data c ollecti o n s h o ul d occ u r 
•  Patie nt re q uires use of a pr o hi bite d c o nc o mita nt me dicati o n or t hera p y  
•  Pre g na nc y  
•  C ha n ges i n t he patie nt’s c o n diti o n , w hic h i n t he o pi ni o n of t he I n vesti gat or, ma ke 
t he patie nt u n s uita ble f or a n y f urt her treat me nt u n der t he pr ot oc ol  
•  Patie nt n o n -c o m plia nce  
•  L os t t o f oll o w-u p  
•  Patie nt wit h dra wal of c o nse nt  
•  S p o ns or re q uest  
All st u d y  pr oce d ures o utli ne d f or t he E n d of Treat me nt  visit are t o be c o m plete d 3 0  da ys  
(+ 7  da ys)  after  t he last d ose of st u d y dr u g. T he pri mar y reas o n f or st u d y dr u g disc o nti n uati o n 
is t o be rec or de d i n t he C R F . 

N u Ti de: 3 2 3                                                                                                                        Versi o n 2 .1 , 0 6  Fe b  2 0 2 4  
C o nfi de ntia l                                                            N u Ca na  plc  
5 3  
6. 2  
F oll o w -u p After Tre at me nt Disc o nti n u ati o n  
Patie nts w h o ha ve d oc u me nte d disease pr o gressi o n defi ne d b y R E CI S T v 1. 1 criteria w hile 
recei vi n g st u d y treat me nt will disc o nti n ue treat me nt b ut will e nter t he f oll o w-u p peri o d. 
Treat me nt s h o ul d n ot be disc o nti n ue d beca use of raise d t u m o ur mar ker le vels or ot her cli nical 
si g ns of pr o gressi ve disease  u ntil disease stat us has bee n assesse d b y o bjecti ve meas ures  a n d 
disease pr o gressi o n  has bee n deter mi ne d b y R E CI S T v 1. 1 criteria.  
Patie nts w h o st o p treat me nt wit h n o e vi de nce of disease pr o gressi o n will e nter t he f oll o w -u p 
peri o d a n d s h o ul d atte n d cli nic at least e ver y 8 wee ks ( ± 7 da ys) f or f oll o w -u p sca ns, a n d 
i nf or mati o n re gar di n g s u bse q ue nt a nti-ca ncer me dicati o ns prescri be d. T his f oll o w -u p s h o ul d 
c o nti n ue u ntil disease pr o gressi o n per R E CI S T v 1. 1, i nitiati o n of a ne w a nti -ca ncer me dicati o n, 
or deat h. Patie nts w h o n o l o n ger atte n d cli nic e ver y 8  wee ks f or a n y reas o n s h o ul d c o nti n ue t o 
be f oll o we d f or pr o gressi o n stat us ( u nless pr o gressi o n has alrea d y bee n d oc u me nte d), f or 
details o n a n y ne w a nti -ca ncer treat me nts, a n d f or s ur vi val stat us e ver y 1 2  wee ks ( ± 1 4 da ys). 
If a patie nt bec o mes u nc o ntacta ble, t he n t he I nvesti gat or s h o ul d f oll o w u p o n t heir stat us b y 
ot her mea ns (s uc h as G P c o ntact, ne xt of ki n c o ntact, h os pital n ote re vie w , or nati o nal 
re gistries/ data bases), i n li ne wit h patie nt c o nse nt. A t otal of t hree atte m pts s h o ul d be ma de 
bef ore t he patie nt is c o nsi dere d as l ost t o f oll o w -u p . 
6. 3  
C o nse nt W it h dr a wa l 
Patie nts will be i nf or me d t hat t he y ha ve t he ri g ht t o wit h dra w fr o m t he s t u d y at a n y ti me f or 
a n y reas o n  wit h o ut prej u dice t o t heir me dical care .  
Patie nts ma y deci de t o disc o nti n ue fr o m f urt her st u d y treat me nt or fr o m f urt her partici pati o n 
i n t he st u d y, as descri be d bel o w. 
Decisi o n t o disc o nti n ue st u d y tre at me nt  
If a patie nt deci des t o disc o nti n ue a n y  f urt her st u d y treat me nt, it s h o ul d be c o nfir me d wit h t he m 
w het her t he y a gree t o c o m plete t he  f oll o w-u p  visits . 
Decisi o n t o disc o nti n ue st u d y p artici p ati o n  
D ue t o t he i m p orta nce of c ollecti o n of P F S a n d s ur vi val data, if a patie nt deci des  t o disc o nti n ue 
st u d y partici pati o n, it s h o ul d be c o nfir me d wit h t he m w het her t he y a gree f or t he I n vesti gat or 
t o f oll o w up o n t heir stat us b y ot her mea ns (s uc h as G P c o ntact, ne xt of ki n c o ntact, re vie w of 
me dical n otes  or nati o nal re gistries/ data bases ) or if t he y tr ul y wis h t o wit h dra w s o t hat n o 
f urt her data is c ollecte d o n t heir stat us. C o nfir mati o n of t his will be rec or de d i n s o urce data at 
site. 
If a patie nt wit h dra ws c o nse nt f or f urt her treat me nt a n d partici pati o n i n t he st u d y , t he n n o 
a d diti o nal st u d y visits or data c ollecti o n s h o ul d occ ur . U n der t hese circ u msta nces, t he site 
pers o n nel s h o ul d  d oc u me nt all rele va nt disc ussi o ns i n t he patie n t n otes a n d mar k all f ut ure 
C R F pa ges  as n ot a p plica ble . U n der t hese c o n diti o ns, I n vesti gat ors are still res p o nsi ble t o 
f oll o w-u p  a n y S A Es u ntil res ol uti o n.  

N u Ti de: 3 2 3                                                                                                                        Versi o n 2 .1 , 0 6  Fe b  2 0 2 4  
C o nfi de ntia l                                                            N u Ca na  plc  
5 5  
7. 5  
Wit h dr a w al of C o nse nt f or B i ol o gic al S a m ple  C ollecti o n or R ete nti o n 
A patie nt ma y wit h dra w c o nse nt t o pr o vi de sa m ples or all o w t heir sa m ples t o be use d f or 
researc h at a n y ti me wit h o ut gi vi n g a reas o n. T he I n vesti gat or m ust e ns ure t hat t heir wis hes are 
rec or de d i n t he me dical rec or d a n d C R F. T he cli nical researc h ass ociate s h o ul d be i nf or me d 
acc or di n gl y. T he I n vesti gat or s h o ul d disc uss wit h patie nts t he val ua ble use of sa m ples t hat 
ha ve alrea d y bee n pr o vi de d a n d u n der circ u msta nces w here t hese sa m ples ha ve alrea d y bee n 
pr ocesse d a n d a n o n y mise d, it w o ul d n ot be p ossi ble t o destr o y s uc h sa m ples.  

N u Ti de: 3 2 3                                                                                                                        Versi o n 2 .1 , 0 6  Fe b  2 0 2 4  
C o nfi de ntia l                                                            N u Ca na  plc  
5 6  
8  
IN V E S TI G A TI O N A L M E DI C I N A L P R O D U C TS  
8. 1  
N U C -3 3 7 3  
8. 1. 1  N U C -3 3 7 3  D escri pti o n 
T he Dr u g Pr o d uct is calle d ‘ N U C -3 3 7 3 f or i nf usi o n’ a n d is prese nte d as a si n gle -d ose sterile 
li q ui d f or m ulati o n f or I V i njecti o n of N U C -3 3 7 3  i n a clear glass vial. 
8. 1. 2  N U C -3 3 7 3  S u p plies a n d S t u d y D r u g P ac k a gi n g  
‘N U C -3 3 7 3  f or i nf usi o n’ will be s u p plie d t o t he p har mac y of t he i n vesti gati ve cli nical site i n 
1 0 m L  clear glass vials . T he vials are pac ka ge d i n a  la belle d car d b oar d o uter cart o n.  
N U C -3 3 7 3 sali ne -base d f or m ulati o n is pre pare d b y  wit h dra wi n g  t he re q uire d v ol u me of 
‘N U C -3 3 7 3  f or i nf usi o n’ fr o m t he vial  a n d a d di n g it directl y  t o t he sali ne i nf usi o n ba g. Please 
refer t o t he d ose pre parati o n g ui da nce  i n t he c urre nt versi o n of t he P har mac y Ma n ual f or f urt her 
i nf or mati o n o n t he pre parati o n of N U C -3 3 7 3  sali ne-base d f or m ulati o ns .  
8. 1. 3  H a n dli n g a n d S t or a ge of N U C -3 3 7 3  
‘N U C -3 3 7 3  f or i nf usi o n’ m ust be st ore d i n a n a p pr o priatel y sec ure i n vesti gati o nal p har mac y 
at all ti mes u ntil dis pe nse d f or a d mi nistrati o n t o patie nts o n pr ot oc ol. ‘ N U C -3 3 7 3 f or i nf usi o n’ 
m ust be st ore d bet wee n 2 -8° C  ( 3 6-4 6° F)  i n a te m perat ure-m o nit ore d refri gerate d u nit. O nl y 
a de q uatel y trai ne d p har mac y staff are per mitte d t o ha n dle ‘ N U C -3 3 7 3 f or i nf usi o n’. T he st u d y 
me dicati o n s h o ul d n ot be re m o ve d fr o m t he p har mac y e xce pt f or t he p ur p oses of dis pe nsi n g t o 
t he patie nt f or t his pr ot oc ol. St u d y dr u g t hat has bee n q uara nti ne d f or a n y reas o n m ust n ot be 
dis pe nse d or a d mi nistere d t o patie nts.  
If ‘ N U C-3 3 7 3 f or i nf usi o n’ c o ntacts t he s ki n or t he m uc o us me m bra nes, it s h o ul d be was he d 
i m me diatel y a n d t h or o u g hl y. Please refer t o t he g uida nce i n t he c urre nt versi o n of t he P har mac y 
Ma n ual f or f urt her i nf or mati o n o n t he pre parati o n of N U C -3 3 7 3  sali ne-base d f or m ulati o ns .  
8. 1. 4  Pre p ar ati o n  of N U C -3 3 7 3  
As wit h ot her c yt ot o xic s u bsta nces, a p plica ble l ocal pr oce d ures s h o ul d be use d i n t he 
pre parati o n  a n d a d mi nistrati o n of ‘ N U C-3 3 7 3 f or i nf usi o n’. Please refer t o t he a d mi nistrati o n 
g ui da nce i n t he c urre nt versi o n of t he P har mac y  Ma n ual  f or f urt her i nf or mati o n o n t he 
pre parati o n of N U C -3 3 7 3  sali ne-base d f or m ulati o n . 
D ue t o k n o w n iss ues re gar di n g D M A a n d  c o m pat ibilit y wit h p ol ycar b o nate, d o n ot  use 
p ol ycar b o nate s yri n ges or p ol ycar b o nate filter nee dles t o wit h dra w ‘ N U C-3 3 7 3 f or i nf usi o n’.  
8. 1. 5  N U C -3 3 7 3 A d mi nistr ati o n  
‘ N U C-3 3 7 3 f or i nf usi o n’ will be a d mi nistere d t o eac h patie nt base d o n b o d y s urface area ( B S A ; 
calc ulate d f or m patie nt’s hei g ht a n d wei g ht ) at baseli ne a n d/ or hei g ht at baseli ne a n d wei g ht at 
Da y 1 of eac h c ycle base d o n l ocal sta n dar d o perati n g practises. If a patie nt’s wei g ht i ncreases 
or decreases b y ≥1 0 % d uri n g t he c o urse of t he st u d y, t he d ose of ‘ N U C -3 3 7 3 f or i nf usi o n’ 
s h o ul d be re-calc ulate d. T he D u b ois & D u b ois B S A calc ulati o n is t he preferre d met h o d, 
h o we ver ot her sta n dar d calc ulati o ns ca n als o be use d. Sites s h o ul d d oc u me nt t he met h o d use d 
i n t he C R F . 
D u b ois & D u b ois B S A c alc ul ati o n:  
B S A ( m 2) = 0. 0 0 7 1 8 4 × Hei g ht (c m)0. 7 2 5 × Wei g ht ( k g) 0. 4 2 5  

N u Ti de: 3 2 3                                                                                                                        Versi o n 2 .1 , 0 6  Fe b  2 0 2 4  
C o nfi de ntia l                                                            N u Ca na  plc  
5 7  
8. 2  Ot her I M Ps  
All of t he a ge nts t o be use d i n t his st u d y  (iri n oteca n, be vaciz u ma b, 5-F U a n d L V)  are 
c o m merciall y a vaila ble a n d s h o ul d be s o urce d l ocall y b y t he I n vesti gati ve sites w here p ossi ble; 
h o we ver, t he y ma y be pr o vi de d ce ntrall y s h o ul d t his be dee me d necessar y b y t he S p o ns or .  
Descri pti ve i nf or mati o n f or t hese a ge nts ca n be f o u n d i n t he pac ka ge i nserts. T hese a ge nts 
s h o ul d be st ore d acc or di n g t o t he ma n ufact urer’s i nstr ucti o ns. F urt her i nf or mati o n ca n be f o u n d 
i n t he P har mac y M a n ual.  
Refer  t o t he S m P Cs/ Prescri bi n g I nf or mati o n of t he se a ge nts f or t he ma na ge me nt of patie nts, 
partic ularl y  c o ncer ni n g c o ntrai n dicati o ns, s pecial 
war ni n gs a n d preca uti o ns, p os ol o g y 
a da ptati o n i n case of t o xicit y, m o nit ori n g, a n d me dicati o ns t hat are c o ntrai n dicate d or t hat m ust 
be use d wit h ca uti o n . C o pies of t hese S m P Cs/ Prescri bi n g I nf or mati o n will be pr o vi de d t o eac h 
site.   
Be vaciz u ma b ma y be s u bstit ute d wit h a n y a p pr o ve d bi osi milar c o nsiste nt wit h i nstit uti o nal 
practice. T he s pecific a ge nt a d mi nistere d will be rec or de d.   
8. 3     A d mi nistr ati o n  of N U C -3 3 7 3 a n d Ot her  A ge nts  
T he secti o ns bel o w pr o vi de a d mi nistrati o n ti mes a n d or der f or eac h of t he c o m bi nati o n a ge nts  
i n eac h ar m of t he st u d y. D ose a dj ust me nts or d ose dela ys are t o be i m ple me nte d wit hi n or 
bet wee n c ycles base d o n dr u g -relate d t o xicities. T he d ose m o dificati o n sc he me t o be e m pl o ye d 
is detaile d i n Secti o n 9  of t hi s pr ot oc ol. 
T here s h o ul d be n o c ha n ges t o t he treat me nt sc he d ules o utli ne d bel o w. H o we ver, i n t he e ve nt 
of A Es occ urri n g d uri n g i nf usi o n of a n y of t he st u d y dr u gs, a dela y i n d osi n g of 1 da y 
( ma xi m u m) ma y be per mitte d f or s u bse q ue nt st u d y dr u gs n ot yet i nfuse d, after disc ussi o n wit h 
t he C R O Me dical M o nit or.  
8. 3. 1  Ar m A  
I n Ar m A, be vaciz u ma b will be a d mi nistere d at a d ose of 5 m g/ k g a n d iri n oteca n will be 
a d mi nistere d at a d ose of 1 8 0 m g/ m 2, b ot h b y I V i nf usi o n, o n Da ys 1 a n d 1 5 ( Q 2 W). L V will 
be a d mi nistere d at a d ose of 4 0 0  m g/ m 2 b y I V i nf usi o n o n Da ys  1, 8, 1 5 a n d 2 2  ( Q 1 W). 
F oll o wi n g c o m pleti o n of i nf usi o ns o n Da ys  1 a n d 1 5 ( be vaciz u ma b, iri n oteca n a n d L V) a n d 
Da ys 8 a n d 2 2 ( L V), N U C -3 3 7 3 will be a d mi nistere d b y I V i nf usi o n at a d ose of 1 5 0 0  m g/ m 2  
( Q 1 W). 
St u d y treat me nt will be a d mi nistere d i n 2 8-da y c ycles as f oll o ws:  
1.  Be vaciz u ma b 5 m g/ k g  o n Da ys 1 a n d 1 5:  
o  9 0 mi n utes f or t he first d ose  
o  6 0 mi n utes f or t he sec o n d d ose (if first d ose is t olerate d)  
o  3 0 mi n utes f or s u bse q ue nt d oses (if sec o n d d ose is t olerate d)  
N ote:  patie nts w h o ha ve pre vi o usl y t olerate d be vaciz u ma b i nf usi o ns well ma y recei ve all 
i nf usi o ns o ver 3 0 mi n utes fr o m t he first d ose. 
2.  L V 4 0 0 m g/ m 2 o ver 1 2 0 mi n utes o n Da ys 1, 8, 1 5, a n d 2 2  
3.  Iri n oteca n 1 8 0 m g/ m 2 o ver 9 0 mi n utes (c o nc urre ntl y wit h t he L V i nf usi o n) o n Da ys  1 
a n d 1 5 
4.  N U C -3 3 7 3  1 5 0 0 m g/ m 2 o ver 1 2 0  mi n utes o n Da ys 1, 8 , 1 5 , a n d 2 2 

N u Ti de: 3 2 3                                                                                                                        Versi o n 2 .1 , 0 6  Fe b  2 0 2 4  
C o nfi de ntia l                                                            N u Ca na  plc  
5 8  
N ote:  the i nf usi o n or der a n d/ or d urati o ns ma y be u p date d base d o n e mer gi n g data fr o m t he 
N u Ti de: 3 0 2 st u d y.  
8. 3. 2  Ar m B  
I n Ar m B, be vaciz u ma b will be a d mi nistere d at a d ose of 5 m g/ k g, iri n oteca n will be 
a d mi nistere d at a d ose of 1 8 0 m g/ m 2, a n d L V will be a d mi nistere d at a d ose of 4 0 0 m g/ m 2, all 
b y I V i nf usi o n, o n Da ys 1 a n d 1 5  ( Q 2 W). F oll o wi n g c o m pleti o n of i nf usi o ns o n Da ys 1 a n d 
1 5, N U C -3 3 7 3 will be a d mi nistere d b y I V i nf usi o n at a d ose of 1 5 0 0 m g/ m 2  ( Q 2 W).  
St u d y treat me nt will be a d mi nistere d i n 2 8 -da y c ycles as f oll o ws:  
1.  Be vaciz u ma b 5 m g/ k g o n Da ys 1 a n d 1 5:  
o  9 0 mi n utes f or t he first d ose  
o  6 0 mi n utes f or t he sec o n d d ose (if first d ose is t olerate d)  
o  3 0 mi n utes f or s u bse q ue nt d ose s (if sec o n d d ose is t olerate d) 
N ote:  patie nts w h o ha ve pre vi o usl y t olerate d be vaciz u ma b i nf usi o ns well ma y recei ve all 
i nf usi o ns o ver 3 0 mi n utes fr o m t he first d ose. 
2.  L V 4 0 0 m g/ m 2 o ver 1 2 0 mi n utes o n Da ys 1 a n d 1 5  
3.  Iri n oteca n 1 8 0 m g/ m2 o ver 9 0 mi n utes (c o nc urre ntl y wit h t he L V i nf usi o n) o n Da ys 1 
a n d 1 5 
4.  N U C -3 3 7 3 1 5 0 0 m g/ m 2 o ver 1 2 0 mi n utes o n Da ys 1 a n d 1 5  
N ote:  the i nf usi o n or der a n d/ or d urati o ns ma y be u p date d base d o n e mer gi n g data fr o m t he 
N u Ti de: 3 0 2 st u d y.  
8. 3. 3  Ar m C  
I n Ar m C, be vaciz u ma b will be a d mi nistere d at a d ose of 5 m g/ k g, iri n oteca n will be 
a d mi nistere d at a d ose of 1 8 0 m g/ m 2, a n d L V will be a d mi nistere d at a d ose of 4 0 0 m g/ m 2, all 
b y I V i nf usi o n, o n Da ys 1 a n d 1 5  ( Q 2 W). F oll o wi n g c o m pleti o n of i nf usi o ns o n Da ys 1 a n d 
1 5, 5 -F U will be a d mi nistere d b y I V b ol us at 4 0 0  m g/ m 2 f oll o we d b y c o nti n u o us I V i nf usi o n 
at 2, 4 0 0  m g/ m 2 o ver 4 6 h o urs  (Q 2 W) .  
St u d y treat me nt will be a d mi nistere d i n 2 8 -da y c ycles as f oll o ws:  
1.  Be vaciz u ma b 5 m g/ k g o n Da ys 1 a n d 1 5:  
o  9 0 mi n utes f or t he first d ose  
o  6 0 mi n utes f or t he sec o n d d ose (if first d ose is t olerate d) 
o  3 0 mi n utes f or s u bse q ue nt d oses (if sec o n d d ose is t olerate d)  
N ote:  patie nts w h o ha ve pre vi o usl y t olerate d be vaciz u ma b i nf usi o ns well ma y recei ve all 
i nf usi o ns o ver 3 0 mi n utes fr o m t he first d ose. 
2.  L V 4 0 0 m g/ m 2 o ver 1 2 0 mi n utes o n Da ys 1 a n d 1 5  
3.  Iri n oteca n 1 8 0 m g/ m2 o ver 9 0 mi n utes (c o nc urre ntl y wit h t he L V i nf usi o n) o n Da ys  1 
a n d 1 5 
4.  5 -F U 4 0 0 m g/ m 2 b ol us o n Da ys 1 a n d 1 5  
5.  5 -F U 2 4 0 0 m g/ m 2 i nf usi o n o ver 4 6 h o urs o n Da ys 1 a n d 1 5 

N u Ti de: 3 2 3                                                                                                                        Versi o n 2 .1 , 0 6  Fe b  2 0 2 4  
C o nfi de ntia l                                                            N u Ca na  plc  
5 9  
8. 4     N U C -3 3 7 3 Dr u g D estr ucti o n  
Use d vials  of N U C -3 3 7 3 s h o ul d be destr o ye d i n acc or da nce wit h l ocal pr oce d ures a n d 
d oc u me nte d i n t he dr u g acc o u nta bilit y a n d dr u g destr ucti o n l o g . A c o p y of t he dis p osal 
certificates s h o ul d be ke pt i n t he st u d y file.  
8. 5   
R a n d o mis ati o n  
Patie nts ma y be ra n d o mise d u p t o 3  w or ki n g da y s pri or t o C 1 D 1 usi n g a n i n de pe n de nt 
i nteracti ve v oice- or we b -base d res p o nse s yste m ( I x R S). At t his ti me, t he I n vesti gat or will e nter 
i nt o t he I x R S t heir site i nf or mati o n, R A S stat us ( wil d-t y pe vs K R A S m uta nt vs N R A S m uta nt), 
pri or b e vaciz u ma b treat me nt ( yes vs n o) , a n d d urati o n of pri or li ne of t hera p y ( < 6  m o nt hs vs 
≥6 m o nt hs). T he I x R S will t he n i n dicate t o w hic h treat me nt ar m t he patie nt has bee n 
ra n d o mise d a n d t he st u d y site will o btai n t he patie nt’s i de ntificati o n n u m ber fr o m t he  I x R S. 
T he ra n d o misati o n will be i n a 1: 1 : 1 rati o t o recei ve treat me nt i n Ar m A (N U FI RI -be v Q 1 W ), 
Ar m B ( N U FI RI -be v Q 2 W ), or Ar m C ( F O L FI RI-be v Q 2 W) . Ra n d o misati o n will be stratifie d 
b y t he f oll o wi n g 3  fact ors: 
•  R A S stat us ( wil d -t y pe vs K R A S m uta nt vs N R A S m uta nt)  
•  P ri or be vaciz u ma b treat me nt ( yes vs n o) 
•  D urati o n of pri or li ne of t hera p y ( < 6  m o nt hs vs ≥6 m o nt hs)  
8. 6    
N U C -3 3 7 3 St u d y D r u g A cc o u nt a bilit y  
T he U S F o o d a n d Dr u g A d mi nistrati o n ( F D A ) a n d ot her a p plica ble re g ulat or y a ut h orities 
re q uire acc o u nti n g of all st u d y dr u g recei ve d b y eac h st u d y ce ntre. Rec or ds of dr u g dis p ositi o n 
re q uire d i ncl u de t he date recei ve d b y t he ce ntre, date a d mi nistere d, q ua ntit y a d mi nistere d, a n d 
t he patie nt t o w h o m st u d y dr u g was a d mi nistere d. T he I n vesti gat or is res p o nsi ble f or t he 
acc o u nta bilit y of all use d a n d u n use d st u d y dr u g c o ntai ners a n d u n use d st u d y dr u g . Eac h st u d y 
ce ntre is t o use a st u d y dr u g acc o u nta bilit y l o g t o d oc u me nt st u d y dr u g dis p ositi o n. All ite ms 
o n t his f or m are t o be c o m plete d i n f ull.  
T he I n vesti gat or i de ntificati o n n u m ber a n d patie nt i nitials (as all o we d b y l ocal re g ulati o ns) a n d 
i de ntificati o n n u m ber are t o be rec or de d o n eac h st u d y dr u g acc o u nta bilit y l o g. Eac h ti me st u d y 
pers o n nel dis pe nse st u d y dr u g f or a patie nt, he or s he is t o rec or d t he date di s pe nse d, a m o u nt 
of st u d y dr u g dis pe nse d, L ot n u m ber, a n d the  dis pe nser ’s i nitials. St u d y pers o n nel are t o 
m o nit or t he i n ve nt or y of cli nical s u p plies a n d mai ntai n a c o u nt of all use d a n d u n use d st u d y 
dr u g . T he S p o ns or’s desi g nate d site m o nit or will re vie w st u d y dr u g acc o u nta bilit y rec or ds a n d 
re mai ni n g dr u g s u p plies d uri n g r o uti ne m o nit ori n g visits. 
8. 7    
M a n a ge me nt of O ver d ose   
T he d ose of N U C -3 3 7 3  i nte n de d f or use o n t his pr ot oc ol is 1 5 0 0  m g/ m 2. I n t he P hase I 
( N u Ti de: 3 0 1), first-i n-h u ma n st u d y, t he 
M T D was 2 5 0 0 
m g/ m 2 wee kl y a n d d oses of 
N U C -3 3 7 3 s h o ul d n ot e xcee d t his d ose le vel.  S h o ul d a  s u bsta ntial o ver d ose occ ur, t here is n o 
k n o w n a nti d ote .  
I n t he e ve nt of a s u bsta ntial o ver d ose of a n y of t he a ge nts use d i n t he prescri be d  c o m bi nati o ns 
( L V, iri n oteca n, be vaciz u ma b , 5 -F U ), ma na ge me nt s h o ul d f oll o w g ui da nce  i n t he 
S m P C/ P rescri bi n g Inf or mati o n  a n d sta n dar d l ocal practice. 
A n y patie nt  w h o i na d verte ntl y recei ves a d ose  of a n y a ge nt i n t his st u d y hi g her  t ha n i nte n de d 
s h o ul d be m o nit ore d cl osel y, ma na ge d wit h a p pr o priate s u p p orti ve care, i ncl u di n g tra nsf usi o n 

N u Ti de: 3 2 3                                                                                                                        Versi o n 2 .1 , 0 6  Fe b  2 0 2 4  
C o nfi de ntia l                                                            N u Ca na  plc  
6 0  
a n d hae mat o p oietic gr o wt h fact ors as nee de d, u ntil rec o ver y . S uc h o ver d oses s h o ul d be 
rec or de d as f oll o ws: 
1.  If a n o ver d ose occ urs i n t he c o urse of t he st u d y, site pers o n nel m ust i nf or m t he 
I n vesti gat or a n d m o nit or i m me diatel y u p o n disc o ver y of t he e ve nt. A n o ver d ose will 
be rec or de d o n t he treat me nt C R F pa ge a n d a n y ass ociate d A Es/ S A Es will be rec or de d 
as t he A E dia g n osis/s y m pt o ms o n t he rele va nt A E/ S A E pa ge i n t he C R F. A n o ver d ose 
wit h n o ass ociate d s y m pt o ms is o nl y re p orte d o n t he treat me nt C R F.  
2.  All o ver d oses s h o ul d be trac ke d as a vi olati o n. 
8. 8    
I nter acti o n wit h Ot her Dr u gs 
Patie nts recei vi n g N U C -3 3 7 3 s h o ul d be caref ull y ma na ge d f or p ote ntial dr u g i nte racti o ns 
acc or di n g t o l ocal practice. Refer t o Secti o n 1 0  f or i nf or mati o n re gar di n g t he use of pr o hi bite d 
t hera pies a n d t hera pies t o be use d wit h ca uti o n.  
I nteracti o ns bet wee n t he pr ot oc ol s pecifie d c o m bi nati o n a ge nts ( L V, iri n oteca n, be vaciz u ma b) 
or 5 -F U a n d a n y c o nc o mita nt 
me dicati o ns s h o ul d be c hec ke d 
wit h t he res pecti ve 
S m P Cs/ Prescri bi n g I nf or mati o n  i n acc or da nce wit h l ocal practice. L ocal practice g ui deli nes 
s h o ul d be f oll o we d f or t he 
ma na ge me nt of a n y p ote ntial st u d y treat me nt/c o nc o mita nt 
me di cati o n i nteracti o ns.  

N u Ti de: 3 2 3                                                                                                                        Versi o n 2 .1 , 0 6  Fe b  2 0 2 4  
C o nfi de ntia l                                                            N u Ca na  plc  
6 2  
•  Rec o ver y fr o m all cli nicall y si g nifica nt t o xicities t o ≤Gra de 2 or t o baseli ne gra de 
prese nt at st u d y e ntr y  
If a patie nt fails t o meet a n y of t hese criteria, ad mi nistrati o n o f st u d y dr u g s h o ul d be hel d u ntil 
all of t he re -treat me nt criteria are met. T he st u d y dr u gs ca n be wit h hel d f or a ma xi m u m of 
2 8  da ys; i f t he dela y is >2 8  da ys, t he patie nt m ust be wit h dra w n fr o m treat me nt, u nless t he 
patie nt is recei vi n g a cli nical be nefit .   
9. 2  
D ose M o dific ati o ns  
Treat me nt bet wee n c ycles ca n be dela ye d f or u p t o 2 8  da ys f or patie nt s t o meet t he re-treat me nt 
criteria bef o re starti n g t heir ne xt c ycle. Patie nts w h o fail t o meet t hese re q uire me nts after t his 
a d diti o nal ti me will n ot be all o we d t o recei ve f urt her c ycles of t hera p y wit hi n t he st u d y, u nless 
t he y are recei vi n g cli nical be nefit i n t he o pi ni o n of t he I n vesti gat or. If a patie nt e x perie nces 
m ulti ple t o xicities, d ose a dj ust me nts will be base d  o n t he m ost se vere t o xicit y . 
A n y patie nt w h o e x perie nces o ne or m ore rec urre nt, cli nicall y si g nifica nt t o xicit y  after t he 
i nitial per ma ne nt d ose re d ucti o n ma y ha ve o ne f urt her per ma ne nt d ose re d ucti o n . Patie nts w h o 
c o nti n ue t o e x perie nce cli nicall y si g nifica nt t o xicit y des pite t w o d ose re d ucti o ns wil l be 
disc o nti n ue d fr o m st u d y treat me nt.  A patie nt recei vi n g cli nical be nefit will n ot re q uire 
disc o nti n uati o n a n d treat me nt g ui deli nes f or s uc h patie nt will be deci de d i n disc ussi o n wit h t he 
I n vesti gat or, C R O M e dical M o nit or a n d S p o ns or base d o n all data c urre ntl y a vaila ble f or 
N U C -3 3 7 3 at t he ti me.  
Ge neral g ui da nce f or d ose m o dificati o ns  of N U C -3 3 7 3 , iri n oteca n a n d 5-F U  is pr o vi de d i n 
Ta ble 5 . At t he discreti o n of t he I n vesti gat or, t he d oses of b ot h dr u gs ( N U C -3 3 7 3/iri n oteca n or 
5 -F U/iri n oteca n) ma y be m o difie d or t he d ose of t he dr u g s us pecte d t o be t he mai n u n derl yi n g 
ca use of t h e t o xicit y ma y be re d uce d.  T he d ose of L V s h o ul d be mai ntai ne d.  
If t he pla n ne d d ose(s) o n a partic ular visit ca n n ot be a d mi nistere d d uri n g t hat pla n ne d visit f or 
a n y reas o n a n d nee ds t o be dela ye d, t he dr u g(s) ma y s u bse q ue ntl y be a d mi nistere d wit hi n t he 
n e xt 2 4 h o urs. If t he dela y nee ds t o be l o n ger t ha n 2 4 h o urs,  t he n t he pla n ne d d ose(s) s h o ul d 
be s ki p pe d  a n d treat me nt s h o ul d be dela ye d u ntil t he ne xt pla n ne d d ose.  
If a patie nt’s U G T 1 A 1 m utati o nal stat us is k n o w n pri or t o d osi n g a n d t he y ha ve a m utati o n t hat 
ma y affect t heir a bilit y t o meta b olise iri n oteca n, a n i nitial d ose re d ucti o n of iri n oteca n ma y be 
i m ple me nte d as per t he iri n oteca n S m P C/ Prescri bi n g I nf or mati o n a n d site sta n dar d of care. 
T his m ust be disc usse d o n a case -b y -case basis wit h t he me dical m o nit or.  
Be vaciz u ma b d ose re d ucti o ns are n ot per mitte d; h o we ver, d osi n g 
ma y be dela ye d or 
disc o nti n ue d t o ma na ge t o xicities t hat are s us pecte d t o be relate d t o be vaciz u ma b  (see 
Secti o n  9. 3. 1 0 ). Patie nts w h o disc o nti n ue be vaciz u ma b ca n re mai n o n t he st u d y as l o n g as t he y 
are still recei vi n g treat me nt wit h N U C -3 3 7 3  or 5 -F U .  
Refer  t o t he S m P Cs/ Prescri bi n g I nf or mati o n of L V, iri n oteca n, be vaciz u ma b a n d 5 -F U f or t he 
ma na ge me nt of patie nts, partic ularl y  c o ncer ni n g c o ntrai n dicati o ns, s pecial war ni n gs a n d 
preca uti o ns, p os ol o g y a da ptati o n i n case of t o xicit y, m o nit ori n g, a n d me dicati o ns t hat are 
c o ntrai n di cate d or t hat m ust be use d wit h ca uti o n . C o pies of t hese S m P Cs / Prescri bi n g 
I nf or mati o n will be pr o vi de d t o eac h site.    
  

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9. 3  
S u g geste d M a n a ge me nt of T o xicit y  
9. 3. 1  N a use a a n d V o miti n g  
•  C o nsi der a nti -e metic me dicati o ns, e. g., gra nisetr o n, de xa met has o ne, c yclizi ne  
•  Mai ntai n a de q uate h y drati o n, i ncl u di n g use of I V fl ui ds if i n dicate d 
•  S u p ple me nt electr ol ytes, partic ularl y p otassi u m a n d ma g nes i u m, t o rec o m me n de d 
le vels 
•  Disc o nti n ue a n y c o nc o mita nt me dicati o ns t hat c o ul d c o ntri b ute t o na usea a n d 
v o miti n g  
•  R ule o ut ot her p ote ntial aeti ol o gies ( e. g., gast r oi ntesti nal tract o bstr ucti o n) 
•  C o nsi der pr o p h y lactic a nti-e metic 
me dicati o ns per 
A S C O g ui deli nes f or 
c he m ot hera p y r e gi me ns of m o derate e metic ris k  pri or t o ne xt sc he d ule d treat me nt 
9. 3. 2  Di arr h oe a  
•  All a vaila ble a nti -diarr h oeal 
me dicati o ns, i ncl u di n g l o pera mi de a n d o pi u m 
pre parati o ns etc, s h oul d be c o nsi dere d f or treat me nt  
•  Mai ntai n a de q uate h y drati o n, i ncl u di n g use of I V fl ui ds if i n dicate d 
•  S u p ple me nt electr ol ytes, partic ularl y p otassi u m a n d m a g nesi u m, t o rec o m me n de d 
le vels 
•  A v oi d oral s u p ple me nt ati o n of electr ol ytes si nce diarr h oea c o ul d be e xacer bate d i n 
s o me cases 
•  R ule o ut ot her p ote ntial ca uses, i ncl u di n g i nfec ti o us aeti ol o gies 
•  Disc o nti n ue a n y c o nc o mita nt me dicati o ns t hat c o ul d e xacer bate diarr h oea 
•  A v oi d t he use of di uretics a n d la xati ves  
•  Refer t o A p pe n di x 4  f or f urt her g ui da nce 
9. 3. 3  M uc ositis  
•  E nc o ura ge g o o d oral h y gie ne, i ncl u di n g clea ni n g teet h after eac h meal a n d at 
be dti me, us i n g s oft-bristle d t o ot h br us h  
•  Ri nse m o ut h usi n g c hl or he xi di ne ( or si milar) m o ut h was h after br us hi n g teet h, afte r 
mealti mes a n d i n t he e ve ni n gs  
•  Caref ul de ntal fl ossi n g o nce dail y; a v oi d visits t o de ntal h y gie nist d uri n g treat me nt  
•  De nt ures clea ne d after eac h meal a n d s oa ke d  o ver ni g ht i n clea ni n g s ol uti o n  
•  A v oi da nce o f s pic y, r o u g h or cr u nc h y f o o ds 
•  Ma na ge pai n fr o m m uc ositis wit h be nz y da mi ne m o ut h was h ( Diffla m), s yste mic 
a nal gesics s uc h as dispersi ble paraceta m ol or as piri n  
•  F or ulcers, l ocal a nal gesia i ncl u di n g M ucai ne e q ui vale nt 1 0  m L  q ds, li d ocai ne 1 % 
gel, t o pical B o njela u p t o e ver y 3 h o urs, b uccal h y dr oc ortis o ne ( 2. 5  m g) ta blet s 4 x 
dail y or ora base oi nt me nts  

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•  S ucralfate s us pe nsi o n 5  m L  q ds ri nse d ar o u n d t he m o ut h  
•  F or patie nts  wit h G ra de 3/ 4 m uc ositis, use l o w d ose o piates; c o nsi der ri nsi n g wit h 
Gelcair oral gel ( 1 5  m L  sac hets) 
9. 3. 4  P al m ar -P l a nt ar E r yt hr o d ysest h a esi a (h a n d -f o ot s y n dr o me) 
•  F or Gra de 1 or a b o ve, c o nsi der starti n g p yri d o xi ne 5 0  m g t ds  
9. 3. 5  I nf usi o n R e acti o ns 
I nf usi o n reacti o ns s h o ul d be ma na ge d as f oll o ws:  
•  
Re d uce i nf usi o n rate b y 5 0 % i n patie nts e x perie nci n g a mil d or m o derate ( G ra de 1 
or 2) i nf usi o n reacti o n f or t he d urati o n of t hat i nf usi o n  
•  
Ter mi nate t he i nf usi o n i n patie nts e x peri e nci n g se vere i nf usi o n reacti o ns. 
De pe n di n g o n t he se verit y a n d/ or persiste nce of t he reacti o n, per ma ne ntl y 
disc o nti n ue t he c o m bi nati o n a ge nt.  
9. 3. 6  Oc ul ar T o xicit y  
Patie nts prese nti n g wit h si g ns or s y m pt o ms s u g gesti ve of e ye dis or ders s uc h as ac ute or 
w orse ni n g e ye i nfla m mati o n, lacri mati o n, li g ht se nsiti vit y, bl urre d visi o n, e ye pai n a n d/ or re d 
e ye s h o ul d be referre d pr o m ptl y t o a n o p ht hal m ol o g y s pecialist f or e val uati o n.  
9. 3. 7  F ati g ue  
Fati g ue is a n e x pecte d A E  f or patie nts wit h pre-treate d a d va nce d ca ncer w h o will be e nr olle d 
t o t his st u d y. As cli nical be nefit is m ost li kel y t o be reali se d o nl y wit h c o nti n ue d treat me nt, 
best eff orts t hat i ncl u de s u p p orti ve care a n d caref ull y c o nsi dere d d ose re d ucti o ns of all or s o me 
of t he a ge nts wit hi n a treat me nt re gi me n ca n be c o nsi dere d. C ha n ges i n d ose f or a n y a ge nt 
s h o ul d be disc usse d wit h t he M e dical M o nit or pri or t o i m ple me ntati o n.  
9. 3. 8  C ar di ot o xicit y  
Car di ot o xicit y has bee n ass ociate d wit h fl u or o p yri mi di ne t hera p y, i ncl u di n g m y ocar dial 
i nfarcti o n, a n gi na, arr h yt h mias, 
m y ocar ditis, car di o ge nic s h oc k, s u d de n deat h, stress 
car di o m y o pat h y (ta k ots u b o s y n dr o me) a n d electr ocar di o gra p hic c ha n ges (i ncl u di n g ver y rare 
cases of Q T pr ol o n gati o n). Pri or hist or y of c or o nar y arter y disease ma y be a ris k fact or f o r 
s o me car diac a d verse reacti o ns. Care s h o ul d t heref ore be e xercise d i n treati n g patie nts w h o 
e x perie nce d c hest pai n d uri n g c o urses of treat me nt, or patie nts wit h a hist or y of heart disease. 
Caref ul c o nsi derati o n s h o ul d be gi ve n t o re -a d mi nistrati o n of 5 -F U or N U C -3 3 7 3  after a 
d oc u me nte d car di o vasc ular reacti o n (arr h yt h mia, a n gi na, S T se g me nt c ha n ges) as t here is a 
ris k of s u d de n deat h.  
I n case of se vere car di ot o xicit y, treat me nt wit h 5 -F U or N U C -3 3 7 3  s h o ul d be disc o nti n ue d. 
9. 3. 9  Fertilit y  
I n acc or da nce wit h the 5 -F U a n d be vaciz u ma b pac ka ge i nserts , ge netic c o ns ultati o n is 
rec o m me n de d if t he patie nt wis hes t o ha ve c hil dre n after e n di n g treat me nt. Si nce treat me nt 
wit h 5 -F U ma y ca use irre versi ble i nfertilit y i n males a n d be vaciz u ma b ma y ca use a d verse 
effects o n f ertilit y i n fe males, it is rec o m me n de d t hat patie nts w h o wis h t o bec o me pare nts i n 
t he f ut ure as k f or a d vice re gar di n g cr y o-c o nser vati o n of t heir s per m or e g gs pri or t o treat me nt.  

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9. 3. 1 0  C o m bi n ati o n T her a pies  
F or a n  o ver vie w of A Es  a n d t o xicities relate d t o eac h of t he c o m bi nati o n a ge nts o r 5 -F U , refer 
t o t he rele va nt S m P C/ Prescri bi n g I nf or mati o n.  
T o xicities t hat are s us pecte d t o be relate d t o be vaciz u ma b s h o ul d be ma na ge d t hr o u g h d osi n g 
dela ys or disc o nti n uati o n. Be vaciz u ma b treat me nt m ust be per ma ne ntl y disc o nti n ue d i n 
patie nts w h o de vel o p a n y of t he f oll o wi n g:  
•  G astr oi ntesti nal perf orati o n  
•  N ecr otisi n g fasciitis  
•  P osteri or R e versi ble E nce p hal o pat h y S y n dr o me “ P R E S”  
•  N e p hr otic s y n dr o me  
•  A rterial t hr o m b oe m b olic reacti o ns 
•  L ife-t hreate nin g ( Gra de 4) t hr o m b oe m b olic reacti o ns, i ncl u di n g p ul m o nar y e m b olis m  
( N CI-C T C A E v 3) . Patie nts wit h t hr o m b oe m b olic reacti o ns ≤Gra de 3 nee d t o be cl osel y 
m o nit ore d ( N CI-C T C A E v 3)  
•  Gra de 3 or 4 blee di n g d uri n g be vaciz u ma b t hera p y ( N CI -C T C A E v 3)  
 
 

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1 0  
O T H E R T R E A T M E N T S ( N O N -I M P) 
All prescri pti o n a n d n o n -prescri pti o n me dicati o ns a n d t hera pies, i ncl u di n g p har mac ol o gic 
d oses of vita mi ns, her bal me dici nes or ot her n o n -tra diti o nal me dici nes, ta ke n fr o m 3 0  da ys 
pri or t o t he first d ose of st u d y treat me nt t hr o u g h t he E n d of Treat me nt  Visit m ust be rec or de d 
i n t he C R F. All pri or a nti-ca ncer t hera pies fr o m i nitial dia g n osis u p u ntil e nr ol me nt m ust be 
rec or de d i n t he C R F. 
1 0. 1  
S u p p ort M e dic ati o n  
Patie nts ma y recei ve 
pr o p h ylactic 
me dical treat me nt  at t he I n vesti gat or’s discreti o n t o 
pre ve nt  A E s c o m m o n t o t he a d mi nistrati o n of a nti-ca ncer a ge nts  i ncl u di n g, b ut n ot restricte d 
t o, a na p h yla xis, na usea a n d v o miti n g. All s u p p ort me dicati o n s m ust be rec or de d i n t he C R F.  
S u p p ort me dicati o ns s h o ul d be a d mi nistere d acc or di n g t o t he S m P Cs/ Prescri bi n g I nf or mati o n 
a n d sta n dar d l ocal practice f or t he rele va nt c o m bi nati o n a ge nts. T he f oll o wi n g s u p p ort 
me dicati o ns 
are rec o m me n de d: 
a nti-e metics ( pal o n osetr o n, 
gra nisetr o n, 
a pre pita nt, 
de xa met has o ne, met ocl o pra mi de,  c yclizi ne ); a nti-hista mi nes ; atr o pi ne; s u nscree n of ≥S P F 3 0 ; 
a n d t o pical c ortic oster oi ds (e. g., h y dr oc ortis o ne 2. 5 %, alcl o metas o ne) .  
1 0. 2  
H ae m at o p oietic G r o wt h F act or S u p p ort  
T he I n vesti gat or ma y prescri be  hae mat o p oietic gr o wt h fact or s u p p ort  (e. g., G -C S F)  acc or di n g 
t o l ocal pr ot oc ols a n d as pr o p h yla xis after a n y fe brile ne utr o pe nic e pis o de t o e na ble t he patie nt 
t o c o nti n ue o n st u d y. C o nc o mita nt treat me nt wit h hae mat o p oietic gr o wt h fact or s u p p ort  a n d 
st u d y treat me nt s h o ul d be a v oi de d. All hae mat o p oietic gr o w t h fact ors use d fr o m 3 0 da ys pri or 
t o date of c o nse nt u ntil 3 0 da ys after a d mi nistrati o n of last d ose of st u d y treat me nt m ust be 
rec or de d i n t he C R F. A n y bl o o d a n d platelet tra nsf usi o ns s h o ul d als o be rec or de d i n t he C R F. 
1 0. 3  
C o nc o mit a nt M e dic ati o ns 
M a y be gi ve n as me dicall y i n dicate d u nless pr o hi bite d as o utli ne d i n Secti o n 1 0. 3. 2 . All 
c o nc o mita nt me dicati o n s use d fr o m 3 0  da ys pri or t o date of c o nse nt u ntil 3 0 da ys after 
a d mi nistrati o n of last a d mi nistrati o n  of N U C -3 3 7 3 m ust be rec or de d i n t he C R F.  
1 0. 3. 1  C o ntr ace pti o n M et h o ds  
As defi ne d bel o w, m ale patie nts a n d fe male patie nts of c hil d -beari n g p ote ntial m ust a gree t o 
practice tr u e a bsti ne nce or t o use t w o f or ms of c o ntrace pti o n , o ne of w hic h m ust be hi g hl y 
effecti ve . Fe male patie nts are c o nsi dere d t o be of c hil d -beari n g p ote ntial  f oll o wi n g me narc he 
a n d u ntil bec o mi n g  p ost -me n o pa usal ( 1 2 m o nt hs of a me n orr hea) u nless  per ma ne ntl y  sterile. 
Per ma ne nt sterilisati o n met h o ds i ncl u de h ysterect o m y, bilateral sal pi n gect o m y a n d bilateral 
o o p h orect o m y.  
Tr ue a bsti ne nce is defi ne d as refrai ni n g fr o m se x ual i nterc o urse. Tr ue a bsti ne nce is o nl y 
acce pta ble if t his practice is i n li ne wit h t he patie n t’s prefere nce a n d us ual lifest yle. Peri o dic 
a bsti ne nce ( e. g., cale n dar, o v ulati o n, s y m pt ot her mal, p ost -o v ulati o n met h o ds), declarati o n of 
a bsti ne nce f or t he d urati o n of e x p os ure t o t he i n vesti gati o nal dr u g, a n d wit h dra wal are n ot 
acce pta ble met h o ds of c o n trace pti o n.  
Hi g hl y effecti ve f or ms of c o ntrace pti o n i ncl u de:  
•  Bilateral t u bal occl usi o n  
•  Vasect o mise d part ner  

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•  I ntra uteri ne de vice or i ntra uteri ne s yste m 
•  C o m bi ne d ( oestr o ge n a n d pr o gest o ge n c o ntai ni n g) h or m o nal  c o ntrace pti o n  ass ociate d 
wit h i n hi biti o n of o v ulati o n:  
o  Oral  
o  I ntra va gi nal 
o  Tra ns der mal  
•  Pr o gest o ge n -o nl y h or m o nal  c o ntrace pti o n ass ociate d wit h i n hi biti o n of o v ulati o n:  
o  Oral  
o  I njecta ble 
o  I m pla nta ble 
Acce pta ble f or ms of c o ntrace pti o n t hat are n ot c o nsi dere d hi g hl y effecti ve i ncl u de:  
•  Pr o gest o ge n -o nl y h or m o nal c o ntrace pti o n, w here i n hi biti o n of o v ulati o n is n ot t he 
pri mar y m o de of acti o n  
•  M ale or fe male c o n d o m wit h or wit h o ut  s per mici de 
•  Ca p, dia p hra g m or s p o n ge wit h s per mici de  
T w o  f or ms of c o ntrace pti o n ( o ne of w hic h m ust be hi g hl y effecti ve) m ust be us e d fr o m t he 
ti me of si g ni n g c o nse nt, t hr o u g h o ut t he treat me nt peri o d, a n d f or 6 m o nt hs f oll o wi n g t he last 
d ose of a n y st u d y me dicati o n. Oral or i njecta ble c o ntrace pti ve a ge nts ca n n ot be t he s ole met h o d 
of c o ntrace pti o n. Fe male p atie nts of c hil d beari n g p ote ntial m ust ha ve a ne gati ve pre g na nc y test 
wit hi n se ve n da ys pri or t o t he first st u d y dr u g a d mi nistrati o n.  
1 0. 3. 2  Pr o hi bite d T her a p y  
E xce pt as i ncl u de d i n t he s pecific ar ms of t his st u d y, use of t he f oll o wi n g t hera pies is pr o hi bite d 
(at a n y d ose) at a n y ti me d ur i n g t he st u d y: 
•  Ot her c yt ot o xic c he m ot hera p y  
•  Ra di ot hera p y , e xcl u di n g a s h ort c ycle of palliati ve ra di ot hera p y (e. g., f or b o ne pai n) 
•  I m m u n ot hera p y i ncl u di n g i m m u n os u p pressi ve t hera p y 
•  Ra di oi m m u n ot hera p y  
•  H or m o ne t hera p y ( ot her t ha n 
c o ntrace pti ves, 
h or m o ne -re place me nt t hera p y, 
a nti-h or m o nal t hera p y f or patie nts wit h pr ostate ca ncer, or me gestr ol acetate)  
•  Ot her bi ol o gic a ge nts i nte n de d f or t he treat me nt of C R C  ( ot her t ha n hae mat o p oietic 
gr o wt h fact ors, w hic h  are all o we d if cli nicall y i n dicate d a n d use d i n acc or da nce wit h 
i nstr ucti o ns pr o vi de d i n t he pac ka ge i nserts. C o nc o mita nt d osi n g wit h st u d y treat me nts 
s h o ul d be a v oi de d) 
•  A n y t hera pies i nte n de d f or t he treat me nt of C R C , w het her a p pr o ve d b y l ocal re g ulat or y 
a ut h orities or i n vesti gati o nal  
•  Dr u gs t hat are k n o w n t o pr ol o n g Q Tc i nter val (refer t o A p pe n di x 3 ) 
•  Str o n g i n d ucers of C Y P 3 A 4,  i ncl u di n g b ut n ot li mite d t o p he n yt oi n, p he n o bar bital, 
car ba maze pi ne, rifa m pi n, rifa b uti n or St. J o h n’s w ort  

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•  Str o n g i n hi bit ors 
of 
C Y P 3 A 4,  i ncl u di n g 
b ut 
n ot li mite d t o 
ket oc o naz ole, 
clarit hr o m yci n, i n di na vir, itrac o naz ole, l o pi na vir, nefaz o d o ne, nelfi na vir, rit o na vir, 
sa q ui na vir, or  ataza na vir  
•  Bri v u di ne , s ori v u di ne a n d a nal o g ues 
•  Li ve vacci nes ( m ust als o be a v oi de d f or si x m o nt hs  after last d ose of st u d y me dicati o n ) 
1 0. 3. 3  T her a p ies t o be Use d wit h C a uti o n 
T he f oll o wi n g war ni n gs a n d preca uti o ns re gar di n g c o nc o mita nt me dicati o ns a p pl y:  
•  Str o n g i n hi bit ors of U G T 1 A 1 , i ncl u di n g b ut n ot li mite d t o ket oc o naz ole, i n di na vir, 
itrac o naz ole, l o pi na vir, nelfi na vir, rit o na vir, sa q ui na vir, ataza na vir, or ge mfi br ozil, 
s h o ul d n ot be a d mi nistere d wit h iri n oteca n.  Str o n g i n hi bit ors of U G T 1 A 1 s h o ul d be 
disc o nti n ue d at least 1 wee k pr i or t o starti n g iri n oteca n. D o n ot a d mi nister str o n g 
i n hi bit ors of U G T 1 A 1 wit h iri n oteca n u nless t here are n o ot her t hera pe utic alter nati ves.  
Ple ase c o nt act t he Me dic al M o nit or bef ore c o nc o mit a nt a d mi nistr ati o n of str o n g 
U G T 1 A 1 i n hi bit ors a n d iri n otec a n  
•  In vitr o  st u dies ha ve s h o w n t he p ote ntial f or N U C-3 3 7 3 dr u g -dr u g i nteracti o n wit h 
c o nc o mita nt me dicati o ns t hat are meta b olise d b y C Y P 3 A 4 a n d C Y P 2 C 8. T he cli nical 
i m pact of t hese i n vitr o o bser vati o ns is n ot k n o w n a n d t he use of c o nc o mita nt 
me dicati o ns t hat are cleare d b y t hese C Y P e nz y mes is per mitte d wit h ca uti o n i n patie nts 
recei vi n g N U C-3 3 7 3.  
•  I nteracti o n bet wee n iri n oteca n a n d ne ur o m usc ular bl oc ki n g a ge nts ca n n ot be r ule d o ut. 
Iri n oteca n has a nti-c h oli nesterase acti vit y, w hic h ma y pr ol o n g t he ne ur o m usc ula r 
bl oc ki n g effects of s u xa met h o ni u m a n d t he ne ur o m usc ular bl oc ka de of n o n -
de p olarisi n g dr u gs 
ma y be a nta g o nise d. 
Ca uti o n s h o ul d be use d 
w he n usi n g 
ne ur o m usc ular bl oc ki n g a ge nts wit h iri n oteca n  
•  Patie nts recei vi n g w arfari n or  ot her t y pes of l o n g -acti n g a nti -c oa g ula nts (s uc h as 
p he n pr oc o u m o n a n d a nti‑ Xa i n hi bit ors wit h a half‑life of > 1 2 h o urs) m ust be re g ularl y 
m o nit ore d f or I N R , w hic h s h o ul d be c hec ke d wee kl y  u ntil a sta ble warfari n d ose is 
esta blis he d . F oll o wi n g t his, I N R s h o ul d be c hec ke d pre -d ose o n Da y 1  of eac h c ycle 
a n d t he val ue m ust be wit hi n t he n or mal ra n ge bef ore a d mi nisteri n g st u d y treat me nt.  
H o we ver, if p ossi ble, patie nts s h o ul d s witc h t o l o w m olec ular wei g ht he pari n or a nti‑ Xa 
i n hi bit ors wit h a half‑life of ≤1 2 h o urs.  
Refer t o t he N U C -3 3 7 3 I B f or c urre nt i nf or mati o n o n p ote ntial dr u g i nteracti o ns. F or 
c o m bi nati o n a ge nts, please refer t o t he res pecti ve S m P C / Prescri bi n g I nf or mati o n. 
1 0. 3. 4  C O VI D -1 9 V acci n ati o ns  
A ris k assess me nt perf or me d i n acc or da nce wit h t he U K Me dici nes a n d  Healt hcare pr o d ucts 
Re g ulat or y A ge nc y ( M H R A) g ui da nce ‘ Ma na gi n g cli nical trials d uri n g C O VI D -1 9’ ( M H R A, 
2 0 2 1 ) c o ncl u de d t hat t here is n o s pecific scie ntific c o ntrai n dicati o n a n d a C O VI D-1 9 vacci ne 
gi ve n t o a st u d y patie nt is c o nsi dere d a si m ple c o nc o mita n t me dicati o n. 
N o acti o n is re q uire d i n relati o n t o C O VI D -1 9 vacci nati o n ti mi n g wit h res pect t o a d mi nistrati o n 
of N U C -3 3 7 3 a n d t he ot her c o m bi nati o n a ge nts use d i n t his st u d y.  

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1 0. 4  
C o nc o mit a nt Pr oce d ures  
Palliati ve ra di ot hera p y d uri n g partici pati o n i n t he st u d y is per mitte d, b ut it s h o ul d n ot be 
c o nc urre nt wit h st u d y treat me nt. C he m ot hera p y s h o ul d be st o p pe d at least 7 da ys bef ore t he 
start of ra di ot hera p y a n d ca n be restarte d after all t o xicities ha ve res ol ve d or ret ur ne d t o 
baseli ne, b ut n ot earlier t ha n 7 da ys  after c o m pleti n g ra di ot hera p y. If t he ra diati o n fiel d is ver y 
s mall or f or a n y ot her reas o ns, e xce pti o ns t o t his r ule ca n be disc usse d o n a case -b y -case basis 
wit h t he Me dical M o nit or.  
A d diti o nal ca uti o n m ust be a p plie d wit h re gar ds t o gastr oi ntesti nal p erf orati o ns/fist ulae f or 
patie nts recei vi n g pel vic ra di ot hera p y.  
Treat me nt dela ys f or palliati ve ra di ot hera p y are c o nsi dere d se paratel y fr o m treat me nt 
m o dificati o ns f or a d verse e ve nts.   
Patie nts s h o ul d n ot recei ve treat me nt wit h be vaciz u ma b  u ntil a n y w o u n ds are f ull y heale d, e. g., 
f or at least 2 8 da ys bef ore or after s ur ger y.  
All c o nc o mita nt pr oce d ures  perf or me d  fr o m 3 0 da ys pri or t o date of c o nse nt u ntil 3 0 da ys after 
a d mi nistrati o n of last a d mi nistrati o n of N U C -3 3 7 3 m ust be rec or de d i n t h e C R F.  
 

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1 1  
T U M O U R R E S P O N S E A S S E S S M E N T S  
1 1. 1  
T u m o u r M e as ure me nts a n d A ssess me nt of D ise ase R es p o nse  
Patie nts m ust ha ve at least o ne lesi o n t hat ca n be acc uratel y assesse d at baseli ne b y C T  or M RI  
a n d w hic h  is s uita ble f or re peate d assess me nt i n or der t o be eli gi ble  f or t his st u d y. All k n o w n 
or s us pecte d disease sites m ust be assesse d at b aseli ne b y eit her C T  or M RI sca n . T he sa me 
ra di ol o gical met h o d use d at baseli ne m ust be use d t o f oll o w lesi o ns t hr o u g h o ut t he st u d y . 
A d diti o nal a nat o mical areas  s h o ul d be assesse d by C T or M RI i n case of s us pici o n of prese nce 
of metastases base d o n si g ns, s y m pt o ms, bi oc he mical res ults a n d/ or as sta n dar d of care i ma gi n g 
of patie nts ( i.e., n o n -st u d y relate d).   
Disease stat us m ust be assesse d  acc or di n g t o R E CI S T v 1. 1 criteria , wit h target a n d n o n -tar get 
lesi o ns i de ntifie d, meas ure d a n d f oll o we d t hr o u g h o ut t he st u d y (A p pe n di x 1 ).  Bi o psie d lesi o ns 
s h o ul d n ot be desi g nate d as tar get lesi o ns f or t he p ur p oses of R E CI S T v 1. 1  a n d a tar get lesi o n 
s h o ul d n ot be bi o psie d d uri n g t he st u d y u nless me dicall y necessar y. 
W he ne ver p ossi ble, t he sa me q ualifie d p h ysicia n will i nter pret res ults t o re d uce varia bilit y. 
Ra di o gra p hic i ma ges will be mai ntai ne d at t he st u d y ce ntre a n d I n vesti gat or’s assess me nts  will 
be file d i n t he patie nt’s s o urce d oc u me nts.  
T u m o u r meas ure me nts a n d disease res p o nse assess me nts are t o be perf or me d e ver y 8  wee ks 
(± 7 da ys) fr o m C 1 D 1 . If t he patie nt st o ps st u d y treat me nt f or reas o ns ot her t ha n ra di ol o gicall y -
c o nfir me d pr o gressi ve disease , t u m ou r meas ure me nts a n d disease res p o nse assess me nts s h o ul d 
c o nti nue e ver y 8 wee ks  (± 7 da ys ) fr o m C 1 D 1  u ntil  pr o gressi ve disease  is ra di ol o gicall y 
c o nfir me d.  
T u m o u r meas ure me nts a n d disease res p o nse assess me nts s h o ul d be perf or me d a n y ti me disease 
pr o gressi o n is s us pecte d . Patie nts s h o ul d n ot disc o nti n ue treat me nt beca use of cli nical si g ns of 
pr o gressi o n  u ntil it has bee n c o nfir me d b y ra di ol o gic assess me nt. 
I n t he case of S D, meas ure me nts m ust ha ve met t he S D criteria at least o nce after st u d y e ntr y 
at a mi ni m u m i nter val of n ot less t ha n 7  wee ks  after t he start of st u d y treat me nt . 

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1 2  
S A F E T Y R E P O R TI N G  
T his st u d y e val uates N U FI RI -be v a n d F O L FI RI -be v c o m bi nati o n re gi me ns. I n c o nsi deri n g 
safet y assess me nts a n d re p orti n g, it is a ntici pate d t hat s o me safet y fi n di n gs ma y be attri b uta ble 
t o a s pecific a ge nt i n a c o m bi nati o n re gi me n , w hile ot hers ma y n ot be attri b uta ble t o a s pecific 
a ge nt.  I n t his secti o n, t he ter m “st u d y dr u g(s)” refers t o a n y of t he a ge nts a d mi nistere d t o t he 
patie nt i n t he ar m of t he st u d y t o w hic h he/s he was e nr olle d.  
1 2. 1  
Defi niti o ns  
T he I n vesti gat or is res p o nsi ble f or re p orti n g all A Es t hat are o bser ve d or re p orte d d uri n g  t he 
st u d y, re gar dless of relati o ns hi p t o st u d y dr u g(s) o r cli nical si g nifica nce.  
A n A E  is defi ne d as a n y u nt o war d me dical occ urre nce i n a patie nt e nr olle d i nt o t his st u d y 
re gar dless of its ca usal relati o ns hi p t o st u d y dr u g(s). Pa tie nts or t heir le gall y a ut h orise d 
re prese ntati ves will be i nstr ucte d t o c o ntact t he I n vesti gat or or S u b-In vesti gat or at a n y ti me 
after si g ni n g t he I C F if a n y s y m pt o ms de vel o p. 
A T E A E  is defi ne d as a n y e ve nt n ot prese nt bef ore e x p os ure t o st u d y dr u g(s) or a n y e ve nt 
alrea d y prese nt t hat w orse ns i n eit her i nt e nsit y or fre q ue nc y after e x p os ure t o st u d y dr u g (s). 
A S A E  is defi ne d as a n y e ve nt t hat: 
•  Res ults i n deat h  
•  Is i m me diatel y life-t hreate ni n g 
•  Re q uires i n patie nt h os pitalis ati o n or pr o l o n gati o n of e xisti n g h os pitalisati o n 
•  Res ults i n persiste nt or si g nifica nt disa bilit y/i nca pacit y  
•  Is a c o n ge nital a n o mal y/birt h  defect  
•  Is a si g nifica nt me dical e ve nt i n t he I n vesti gat or's j u d g me nt (e. g., ma y je o par d ise 
t he patie nt or ma y re q uire me dical/s ur gical i nter ve nti o n t o pre ve nt o ne of t he 
o utc o mes liste d a b o ve)  
Disease pr o gressi o n  a n d disease -relate d deat h will n ot  be c o nsi dere d a n A E or S A E.  
A  si g nifica nt me dical e ve nt t hat ma y n ot res ult i n deat h, be life -t hreate ni n g, or re q uire 
h os pitalisati o n ma y be c o nsi dere d a n S A E w he n, base d u p o n a p pr o priate me dical j u d g me nt, it 
ma y  je o par dise t he patie nt a n d ma y re q uire me dical or s ur gical i nter ve nti o n t o pre ve nt o ne of 
t he o utc o mes liste d i n t his defi niti o n. E xa m ples of s uc h me dical e ve nts i ncl u de aller gic 
br o nc h os pas m re q uiri n g i nte nsi ve treat me nt i n a n e mer ge nc y r o o m or at h o me, bl o o d 
d yscrasias, c o n v ulsi o ns t hat d o n ot res ult i n i n patie nt h os pitalisati o n, or t he de vel o p me nt of 
dr u g de pe n de nc y or dr u g a b use. Please c o ns ult Secti o n 1 2. 5  f or t he s pecific mec ha nis m b y 
w hic h S A Es are t o be re p orte d.  
A n  a d verse dr u g r e acti o n ( A D R)  is a n A E w hic h is c o nsi dere d t o be ca usall y relate d t o a n y 
d ose of st u d y dr u g(s). T his mea ns t hat a ca usal relati o ns hi p bet wee n st u d y dr u g(s) a n d t he A E 
is at least a reas o na ble p ossi bilit y, i.e., t he relati o ns hi p ca n n ot be r ule d o ut. 
A n  u ne x pecte d dr u g r e acti o n is a n A D R , t he nat ure or se verit y of w hic h is n ot c o nsiste nt wit h 
a p plica ble pr o d uct i nf or mati o n . F or N U C-3 3 7 3 , please refer t o t he I B Refere nce Safet y 
I nf or mati o n (R SI ). F or t he ot her a ge nts, please refer t o t he a p plica ble S m P C / Prescri bi n g 
I nf or mati o n, w hic h ser ve as t heir R SI. Re prese ntati ve S m P Cs f or eac h a ge nt are pr o vi de d i n 
t he N U C-3 3 7 3 I B ( Secti o n 8. 1) f or ease of refere nce.  

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A  s us pecte d u ne x pecte d seri o us a d verse re acti o n ( S U S A R)  is a seri o us A D R , t he nat ure or 
se verit y of w hic h is n ot c o nsiste nt wit h t he a p plica ble pr o d uct i nf or mati o n ( e. g., I B f or a n 
u na p pr o ve d I M P). 
1 2. 2  
A d verse E ve nt R e p orti n g  
At e ver y st u d y visit, patie nts will be as ke d n o n directi ve q uesti o ns t o elicit a n y me dicall y -
relate d c ha n ges i n t heir well-bei n g . T he y will als o be as ke d if t he y ha ve bee n h os pita lise d, ha d 
a n y acci de nts, use d a n y ne w me dicati o ns, or c ha n ge d c o nc o mita nt me dicati o n re gi me ns ( b ot h 
prescri p ti o n a n d o ver-t he-c o u nter me dicati o ns) . I n a d diti o n t o patie nt o bser vati o ns, A Es will 
be d oc u me nte d fr o m a n y data c ollecte d o n t he C R F or ot her d oc u me nts t hat are rele va nt t o 
patie nt safet y . A n y aller gic reacti o n t o t he a ge nts a d mi nistere d  as st u d y dr u g tr eat me nt m ust be 
re p orte d as a n A E. 
A Es a n d S A Es will be re p orte d fr o m t he p oi nt t hat i nf or me d c o nse nt has bee n o btai ne d 
o n war ds . T hereafter, all A E s occ urri n g u p t o a n d i ncl u di n g 3 0  da ys after t he last d ose of st u d y 
dr u g  has bee n a d mi nistere d  m ust be re p or te d i n detail o n t he A E C R F . Disease pr o gressi o n i n 
t he me dical o pi ni o n of t he p h ysicia n a n d/ or disease-relate d m or bi dit y a n d m ortalit y as a st u d y 
e n d p oi nt will n ot be c o nsi dere d a n A E or S A E b ut s h o ul d be ca pt ure d o n t he Deat h C R F . 
I nf or mati o n t o be c ollecte d f or eac h A E i ncl u des o nset date, t y pe of e ve nt, aeti ol o g y , 
I n vesti gat or-s pecifie d assess me nt of se verit y a n d relati o ns hi p t o st u d y dr u g, seri o us ness, a n y 
re q uire d treat me nt or e val uati o ns, o utc o me a n d date of res ol uti o n. A Es res ulti n g fr o m 
c o nc urre nt ill nesses, reacti o ns t o c o nc urre nt ill nesses, reacti o ns t o c o nc urre nt me dicati o ns, or 
pr o gressi o n of disease states m ust als o be re p orte d . All A Es will be f oll o we d f or 3 0 da ys after 
t he patie nt’s last d ose  or u ntil res ol uti o n, w hic he ver c o mes first.  
Pre -e xisti n g c o n diti o ns ( prese nt bef ore t he start of t he A E c ollecti o n peri o d) are c o nsi dere d 
c o nc urre nt me dical c o n diti o ns a n d s h o ul d n ot be rec or de d as A Es . H o we ver, if t he patie nt 
e x perie nces a w orse ni n g or c o m plicati o n of s uc h a c o nc urre nt c o n diti o n, t he w or se ni n g or 
c o m plicati o n s h o ul d be rec or de d as a n A E . Pre -e xisti n g A Es t hat w orse n s h o ul d be f oll o we d 
u ntil  3 0 da ys after t he patie nt’s last d ose or res ol uti o n t o t he gra de or  le vel prese nt at st u d y 
e ntr y. I n vesti gat ors s h o ul d e ns ure t hat t he A E ter m rec or ded ca pt ures t he c ha n ge i n t he 
c o n diti o n ( e. g., “ w orse ni n g of [c o n diti o n]”).  
I ns ufficie nt cli nical res p o nse, efficac y, or p har mac ol o gical acti o n s h o ul d N O T be rec or de d as 
a n A E. T he I n vesti gat or m ust ma ke t he disti ncti o n bet wee n e xacer bati o n of pre -e xisti n g ill ness 
a n d lac k of t hera pe utic efficac y . P r o gressi ve disease is N O T a n A E; h o we ver, s o me se q uelae 
of pr o gressi ve disease  (i.e., pai n, ne ur ol o gic i m pair me nt) ma y be re p orte d as A Es ( ge nerall y 
n ot relate d t o st u d y dr u g(s)). 
A b n or mal la b orat or y val ues or test res ults c o nstit ute A Es o nl y if t he y i n d uce cli nical si g ns or 
s y m pt o ms, are c o nsi dere d cli nicall y si g nifica nt, re q uire t hera p y or f urt her dia g n osis be y o n d 
re peat testi n g f or c o nfir mati o n, or (if n ot ass ociate d wit h cli nical si g ns or s y m pt o ms) re mai n at 
le vels c o nsiste nt wit h se vere a b n or malities des pite a p pr o priate me dical i nter ve nti o n. It is 
re q ueste d t hat w he n re p orti n g A Es f or w hic h p ote ntiall y re d u n da nt C T C A E ter ms e xist, t he 
I n vesti gat or uses  t he 
m ore cli nicall y-orie nte d ter mi n ol o g y (f or e xa m ple, ‘ a nae mia’ is 
prefera ble t o ‘ h ae m o gl o bi n decrease d’).  
It is als o re q ueste d t hat i n t he setti n g of a n aller gic reacti o n or s us pecte d aller gic reacti o n 
c o nsi dere d b y t he I n vesti gat or t o be relate d t o st u d y dr u g(s), t he I n vesti gat or re p orts b ot h t he 
s pecific s ym pt o ms ass ociate d wit h t he reacti o n ( i.e., ‘ urticaria’, ‘d ys p n oea ’) a n d als o re p ort t he 
a p pr o priate ter m i n dicati n g t he aller gic reacti o n (‘aller gic reacti o n’ or ‘a na p h yla xis’ if 
a p pr o priate [I m m u ne S yste m Dis or ders; C T C A E v 5. 0 ]). 

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•  All ot her S U S A Rs will be re p orte d wit hi n 1 5 da ys of r ecei pt. 
I n a d diti o n, ot her safet y iss ues q ualif y f or e x pe dite d re p orti n g w here t he y mi g ht materiall y 
alter t he c urre nt ris k assess me nt of N U C -3 3 7 3  or be s ufficie nt t o c ha n ge N U C -3 3 7 3  
a d mi nistrati o n or t he o verall c o n d uct of t he st u d y.  
T he S p o ns or  will n oti f y a p pr o priate re g ulat or y a ut h orities of a n y fatal  or life -t hreate ni n g 
e x perie nce t hat is deter mi ne d t o be relate d t o t he use of t he st u d y dr u g (s) (e x pe dite d re p ort) as 
s o o n as p ossi ble b ut n o later t ha n 7 cale n dar da ys after t he i nitial recei pt of t he i nf or mati o n . 
I nitial n otificati o n will be f oll o we d b y a writte n re p ort wit hi n 1 5 cale n dar da ys.  
F or u ne x pecte d e ve nts ass ociate d wit h t he use of t he st u d y dr u g (s) w hic h are n ot fatal or life 
t hreate ni n g, t he S p o ns or will n otif y t he re g ulat or y a ut h orities as s o o n as p ossi ble a n d n o later 
t ha n 1 5 da ys of t he i nitial recei pt of i nf or mati o n .  
T he I n vesti gat or is res p o nsi ble f or i nf or mi n g t he I R B/ E C.  C o pies of S A E c orres p o n d e nce wit h 
all I n vesti gat ors or S u b -In vesti gat ors, re g ulat or y a ut h orities, I R Bs/ E Cs a n d t he S p o ns or m ust 
be s u b mitte d f or fili n g. 
1 2. 8   Ter ms a n d G r a di n g of A d verse E ve nts a n d T o xicities  
All A Es a n d t o xicities m ust be gra de d acc or di n g t o C T C A E v 5. 0 . 
1 2. 9   Pre g n a nc y  
A w o ma n w h o bec o me s pre g na nt d uri n g t he c o urse of t he st u d y s h o ul d be wit h dra w n fr o m 
st u d y treat me nt i m me diatel y. Pre g na nc y occ urri n g i n a patie nt or part ner  d uri n g t he st u d y 
re q uire e x pe dite d re p orti n g. A p re g na nc y n otificati o n re p ort s h o ul d be e ntere d directl y i n t he 
E D C s yste m. If t he E D C is u na vaila ble, t he pre g na nc y n otificati o n re p ort ma y be c o m plete d 
a n d e maile d usi n g t he c o ntact details i n Ta ble 8  wit hi n t he sa me ti meli nes as a n S A E . All 
re p orte d pre g na ncies s h o ul d be f oll o we d a n d t he o utc o me re p orte d usi n g t he p re g na nc y foll o w -
u p re p ort . If t he o utc o me of t he pre g na nc y meets a n y of t he criteria f or seri o us ness, it m ust als o 
be re p orte d as a n S A E .  
E xa m ples of pre g na nc y o utc o mes t hat are S A Es i ncl u de re p orts of:  
•  C o n ge nital a n o ma lies or de vel o p me ntal dela y, i n t he f oet us or t he c hil d  
•  F oetal  deat h a n d  s p o nta ne o us a b orti o n 
•  S us pecte d a d verse reacti o ns i n t he ne o nate  t hat are classifie d as seri o us 
1 2. 1 0  E ve nts E xe m pt fr o m bei n g R e p orte d as A E/ S A Es  
1 2. 1 0. 1   Pr o gressi o n of U n derl y i n g D ise ase 
Disease  pr o gressi o n a n d res ulta nt deat h will be ca pt ure d o n t he C R F . A Es i ncl u di n g 
h os pitalis ati o n t hat are clearl y c o nsiste nt wit h disease pr o gressi o n will n ot be re p orte d as 
i n di vi d ual A E/ S A Es. Cli nical s y m pt o ms of disease pr o gressi o n will o nl y be re p orte d as A Es if 
t he s y m pt o m ca n n ot be determi ne d as e xcl usi vel y d ue t o pr o gressi o n of t he u n derl yi n g 
mali g na nc y  or d oes n ot fit t he e x pecte d patter n of pr o gressi o n f or t he disease u n der st u d y.  
E ver y eff ort s h o ul d be ma de t o d oc u me nt t he o bjecti ve pr o gressi o n of u n de rl yi n g mali g na nc y. 
I n s o me cases, t he deter mi nati o n of cli nical pr o gressi o n ma y be base d o n s y m pt o matic 
deteri orati o n. F or e xa m ple, pr o gressi o n ma y be  e vi de nt fr o m cli nical s y m pt o ms  b ut is n ot 
s u p p orte d b y t u m ou r meas ure me nts. Or t he disease pr o gressi o n is s o e vi de nt t hat t he 
In vesti gat or ma y elect n ot t o perf o r m f urt her disease assess me nts. 

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1 2. 1 0. 2   De at h o n S t u d y A ttri b ute d t o M ali g n a nc y  
Deat h d ue t o disease u n der st u d y is t o be rec or de d o n t he Deat h C R F f or m,  pr o vi de d t hat t he 
deat h is e x pecte d a n d n o ca usal relati o ns hi p is s us pecte d. T he I n vesti gat or m ust clearl y state 
w het her t he deat h was e x pecte d or u ne x pecte d a n d w het her a ca usal relati o ns hi p t o N U C -3 3 7 3  
or ot her pr ot oc ol treat me nt i nter ve nti o n is s us pecte d . 
1 2. 1 0. 3   Electi ve A d missi o ns a n d S u p p orti ve C a re 
Electi ve a d missi o ns t o h os pital f or patie nt c o n ve nie nce or f or pla n ne d pr oce d ures or 
i n vesti gati o ns or treat me nt as s pecifie d i n t his pr ot oc ol a n d sta n dar d s u p p orti ve care are n ot 
S A Es  a n d d o n ot re q uire S A E re p orti n g .  
1 2. 1 1  A b n or m al L a b or at or y Test Res ult V al ues  
T he I n vesti gat or will i de ntif y a n d rec or d cli nicall y si g nifica nt la b orat or y test res ults.  N ot e ver y 
la b orat or y test res ult a b n or malit y q ualifies as a n A E; h o we ver, a la b orat or y test res ult m ust be 
re p orte d as a n A E if it meets a n y of t he f oll o wi n g criteria: 
•  Is acc o m pa nie d b y cli nical s y m pt o ms 
•  Res ults i n a c ha n ge i n st u d y treat me nt ( e. g., d osa ge m o dificati o n, treat me nt i nterr u pti o n, 
or treat me nt disc o nti n uati o n)  
•  Res ults i n a me dical i nter ve nti o n ( e. g., p otassi u m s u p ple me ntati o n f or h y p o kalae mia) or a 
c ha n ge i n c o nc o mita nt t hera p y  
•  Is cli nicall y si g nifica nt i n t he I n vesti gat or’s j u d ge me nt 
It is t he I n vesti gat or’s res p o nsi bilit y t o re vie w all la b orat or y test res ult fi n di n gs. Me dical a n d 
scie ntific j u d ge me nt s h o ul d be e xercise d i n deci di n g w het her a n is olate d la b orat or y test res ult 
a b n or malit y s h o ul d be classifie d as a n A E.  
If a cli nicall y si g nifica nt la b orat or y test res ult a b n or malit y is a si g n of a disease or s y n dr o me 
(e. g., al kali ne p h os p hatase a n d bilir u bi n 5 × U L N ass ociate d wit h c h olestasis), t he dia g n osis 
(i.e., c h olestasis) s h o ul d be rec or de d o nl y o n t he A E C R F.  
If a cli nicall y si g nifica nt la b orat or y test res ult a b n or malit y is n ot a si g n of a disease or 
s y n dr o me, t he a b n or malit y itself s h o ul d be rec or de d o n t he A E C R F, al o n g wit h a descri pt or 
i n dicati n g w het her t he test res ult is a b o ve or bel o w t he n or mal ra n ge (e. g., “ele vate d 
p otassi u m,” as o p p ose d t o “a b n or mal p otassi u m”). If t he la b orat or y test res ult a b n or malit y ca n 
be c haracterise d b y a precise cli nical ter m per sta n dar d defi niti o ns, t he cli nical ter m s h o ul d be 
rec or de d as t he A E. F or e xa m ple, a n ele vate d ser u m p otassi u m le vel of 7. 0 m E q/ L s h o ul d be 
rec or de d as “ h y per kalae mia.”  
Cases of p ote ntial dr u g -i n d uce d li ver i nj ur y ( DI LI) t hat i ncl u de a n ele vate d A L T or A S T i n 
c o m bi nati o n wit h eit her a n ele vate d bilir u bi n or I N R m ust be rec or de d  (F D A, 2 0 0 9 ).  
T reat me nt i nterr u pti o n/ disc o nti n uati o n s h o ul d be c o nsi dere d if a n y of t he  f oll o wi n g criteria are 
met : 
•  Treat me nt -e mer ge nt A L T or A S T > 8 × U L N  
•  Treat me n t-e mer ge nt A L T or A S T > 5 × U L N f or m ore t ha n 2 wee ks  
•  Treat me nt -e mer ge nt A L T or A S T > 3 × U L N wit h  t otal bilir u bi n > 2 × U L N or I N R > 1. 5   

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•  Treat me nt -e mer ge nt A L T or A S T > 3 × U L N wit h t he a p peara nce of fati g ue, na usea, 
v o miti n g, ri g ht u p per q ua dra nt pai n or te n der ness, fe ver, ras h, a n d/ or e osi n o p hilia ( > 5 %)  
H y’s La w cases, acc or di n g t o F D A g ui da nce o n DI LI ( F D A, 2 0 0 9 ), s h o ul d be c o nsi dere d if t he 
criteria a b o ve are met a n d a d diti o nall y t he f oll o wi n g fi n di n gs are re p orte d : 
•  N o i nitial fi n di n g of c h olestasis (ele va te d ser u m A L P) 
•  N o ot her reas o n ca n be f o u n d t o e x plai n t he i ncrease s i n A L T/A S T a n d bilir u bi n or I N R , 
s uc h as viral he patitis A, B, or C; pre-e xisti n g or ac ute li ver disease; biliar y d uct 
o bstr ucti o n ; or a n ot her dr u g ca pa ble of ca usi n g t he o bser ve d i nj ur y  
F or p atie nts meeti n g H y’s la w criteria d ue t o dr u g -relate d t o xicit y, c o nsi der  disc o nti n uati o n of 
treat me nt or, if t he patie nt is deri vi n g be nefit i n t he o pi ni o n of I n vesti gat or, c o nsi der h ol di n g 
treat me nt u ntil val ues are < 3 ×  U L N f or A S T a n d/ or A L T a n d < 2  ×  U L N f or t otal bilir u bi n, 
t he n restart treat me nt at a re d uce d d ose (as per Ta ble 4 ). La b orat or y val ues m ust be cl osel y 
m o nit ore d a n d st u d y treat me nt m ust be disc o nti n u e d if patie nts meets criteria f or a sec o n d ti me 
des pite d ose re d ucti o n.   
1 2. 1 2  A b n or m al Vit al Si g n V al ues  
T he  I n vesti gat or will i de ntif y a n d rec or d cli nicall y si g nifica nt vital si g n res ults.  
N ot e ver y vital si g n a b n or malit y q ualifies as a n A E; h o we ver, a vital si g n res ult m ust be 
re p orte d as a n A E if it meets a n y of t he f oll o wi n g criteria: 
•  Is acc o m pa nie d b y cli nical s y m pt o ms 
•  Res ults i n a c ha n ge i n st u d y treat me nt ( e. g., d osa ge m o dificati o n, treat me nt i nterr u pti o n, or 
treat me nt disc o nti n uati o n) 
•  Res ults i n a me dical i nter ve nti o n or a c ha n ge i n c o nc o mita nt t hera p y  
•  Is cli nicall y si g nifica nt i n t he I n vesti gat or’s j u d ge me nt 
It is t he I n vesti gat or’s res p o nsi bilit y t o re vie w all vital si g n res ult fi n di n gs. Me dical a n d 
scie ntific j u d ge me nt s h o ul d be e xercise d i n decidi n g w het her a n is olate d vital si g n val ue 
a b n or malit y s h o ul d be classifie d as a n A E.  
If a cli nicall y si g nifica nt vital si g n val ue a b n or malit y is a si g n of a disease or s y n dr o me (e. g., 
hi g h bl o o d press ure), t he dia g n osis ( i.e., h y perte nsi o n) s h o ul d be rec o r de d o nl y o n t he A E C R F. 
1 2. 1 3  I nf or mi n g I n vesti g at ors of N e w S afet y Inf or m ati o n  
T he s p o ns or  will e n s ure t hat all I n vesti gat ors are i nf or me d i n a ti mel y ma n ner of  ne w safet y 
i nf or mati o n re gar di n g N U C-3 3 7 3  t hat bec o mes a vaila ble . I n vesti gat ors are res p o nsi ble f or 
briefi n g t heir st u d y tea m as a p pr o priate.  
1 2. 1 4  Refere nce S af et y Inf or m ati o n f or A ssess me nt of E x pecte d ness  
1 2. 1 4. 1     N U C -3 3 7 3  
T he I B s u p plie d b y t he S p o ns or f or N U C-3 3 7 3 c o ntai ns t he N U C -3 3 7 3 R SI f or t his st u d y.  
O nl y t he I B versi o n wit h c urre nt re g ulat or y a n d I R B/ E C a p pr o val f or use i n t he st u d y will be 
use d t o assess S A E re p orts t o i de ntif y S U S A Rs.  

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•  Si g nific a nt C h a n ges t o t he R SI : If patie nt safet y or t he ris k/ be nefit assess me nt has 
c ha n ge d or ne w e x pecte d reacti o ns ha ve bee n a d de d, t he n a p pr o val of t he u p date d  I B 
b y a p plica ble Re g ulat or y A ut h orities a n d I R Bs/ E Cs will be s o u g ht . If ne w e x pecte d 
reacti o ns ha ve bee n a d de d t o t he I B or e ve nts ha ve bee n d o w n -gra de d t o ‘e x pecte d’, a 
j ustificati o n f or t he c ha n ges will be i ncl u de d i n t he a me n d me nt re q uest. C ha n ges t o the 
I B t hat i m pact o n patie nt safet y or alter t he ris k/ be nefit assess me nt ma y re q uire c ha n ges 
t o st u d y d oc u me ntati o n, s uc h as t he I C F. T he s p o ns or will i de ntif y a n y  re q uire d c ha n ges 
a n d e ns ure I C F re visi o ns are ma de a n d a p pr o ve d b y a p plica ble Re g ulat or y A ut h orities 
a n d I R Bs/ E Cs , a n d patie nts re-c o nse nte d as a p plica ble . Si g nifica nt u p dates t o t he I B 
s hall be attac he d t o t he de vel o p me nt safet y u p date re p ort ( D S U R ) ( o nce a p pr o ve d b y 
a p plica ble Re g ulat or y A ut h orities a n d I R Bs/ E Cs ); h o we ver , t he I B i n effect at t he start 
of t he D S U R re p orti n g peri o d ser ves at t he R SI  d uri n g t he re p orti n g peri o d .  
•  N o n -Si g nific a nt C h a n ges t o t he I B: If c ha n ges t o t he I B are mi n or a n d d o n ot i ncl u de 
ne w /re m o ve d e x pecte d reacti o ns, d o n ot i m pact o n patie nt safet y  or alter t he be nefit/ris k 
assess me nt, t he n sites will n ot recei ve t he u p date d I B u ntil t he e n d of t he D S U R 
re p orti n g peri o d. 
If t he n o n-si g nifica nt u p date d I B is t o be i m ple me nte d i n t he ne w D S U R re p orti n g peri o d, t he n 
Re g ulat or y A ut h orit y a n d I R B/ E C s h o u l d be i nf or me d of t he i nte nti o n t o i m ple me nt t he 
u p date d I B after t he D S U R re p orti n g peri o d e n ds . T he u p date d I B will be attac he d t o t he 
D S U R . If ne w e x pecte d reacti o ns ha ve bee n a d de d t o t he I B or e ve nts ha ve d o w n gra de d t o 
‘e x pecte d’, t he n t he u p date d I B m ust recei ve a p pr o val bef ore it is i m ple me nte d . T he I B will be 
se nt t o t he st u d y sites wit h a c o veri n g letter d oc u me nti n g t he c ha n ges . T his will be circ ulate d 
after t he D S U R has bee n s u b mitte d at t he start of t he ne w D S U R re p orti n g peri o d.  
1 2. 1 4. 2     Ot her A ge nts  t o be Use d i n C o m bi n ati o n wit h N U C-3 3 7 3  
T he res pecti ve S m P C / Prescri bi n g I nf or mati o n of eac h c o m bi nati o n a ge nt a d mi nistere d i n 
c o nj u n cti o n wit h N U C-3 3 7 3 i n t his st u d y will ser ve as t heir o w n R SI .  Re prese ntati ve  S m P C s 
of t hese a ge nts  are pr o vi de d i n t he N UC -3 3 7 3 I B ( Secti o n 8. 1) f or ease of refere nce .  

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S T A TI S TI C A L C O N SI D E R A TI O N S  
A Statistical A nal ysis P la n ( S A P) will be fi nalis e d bef ore data base l oc k a n d c o n d uct of t he 
fi nal a nal ysis is u n derta ke n. O nl y t he mai n feat ures of t he pla n ne d statistical a nal ysis are 
i ncl u de d bel o w. 
All statistical a nal yses will be perf or me d usi n g S A S ® , Versi o n 9. 3 or hi g her.  
T he st u d y data base will be l oc ke d pri or t o t he pri mar y a nal yses f or i ncl usi o n i n t he cli nical 
st u d y re p ort (C S R ).  
1 3. 1  
S a m ple S ize 
I n t otal, 1 7 1 patie nts will be ra n d o mise d o n a 1: 1: 1 basis ( 5 7 patie nts per ar m) t o eit her Q 1 W 
N U FI RI -be v, Q 2 W N U FI RI -be v or F O L FI RI -be v ( Q 2 W).  
T he pri nci pal statistical o bjecti ve of t his st u d y is t o esti mate t he li kel y efficac y of t he t w o 
N U FI RI ar ms as c o m pare d t o t he F O L FI RI c o ntr ol ar m t o s u p p ort decisi o n ma ki n g re gar di n g 
t he f urt her de vel o p me nt of N U FI RI. Me dia n P F S is e x pecte d t o be 7 m o nt hs o n t he F O L FI RI 
c o ntr ol ar m a n d at least 9. 9 m o nt hs o n eac h of t he t w o N U FI RI ar ms. Ass u mi n g a n o n -li near 
recr uit me nt pr ofile o ver t he pla n ne d 1 3 -m o nt h accr ual peri o d ( η = 2; Carr oll, 2 0 0 9 ) a n d wit h a 
mi ni m u m of 1 7  m o nt hs f oll o w -u p p ost -accr ual, a t otal of 1 3 9 P F S e ve nts are e x pecte d acr oss 
t he t hree ra n d o mise d ar ms. Wit h t his a m o u nt of i nf or mati o n, t his st u d y will pr o vi de a n 8 0 % 
pr o ba bilit y of c orrectl y c o ncl u di n g s u peri orit y w he n N U FI RI is tr ul y better t ha n F O L FI RI i n 
ter ms of P F S a n d, si milarl y, a n 8 0 % pr o ba bilit y of c orrectl y c o ncl u di n g n o n -s u peri orit y w he n 
N U FI RI is tr ul y t he sa me as F O L FI RI i n ter ms of P F S. T he s mallest o bser ve d i m pr o v e me nt i n 
me dia n P F S f or eit her N U FI RI ar m relati ve t o F O L FI RI t o c o ncl u de N U FI RI is tr ul y better 
t ha n F O L FI RI is 1. 3 m o nt hs. 
F urt her, a n e val uati o n of efficac y ma y be perf or me d 3 m o nt hs after t he last patie nt has bee n 
ra n d o mise d. At t his ti me a t otal of 7 0 P F S e ve nts are e x pecte d acr oss t he t hree ra n d o mise d 
ar ms. Wit h t his a m o u nt of i nf or mati o n , t he s mallest o bser ve d i m pr o ve me nt i n me dia n P F S f or 
eit her N U FI RI ar m relati ve t o F O L FI RI t o c o ncl u de N U FI RI is tr ul y better t ha n F O L FI RI is 
1. 9  m o nt hs.  
1 3. 2  
Missi n g, U n use d  a n d S p uri o us D at a  
I n ge neral, missi n g data will re mai n missi n g a n d will n ot be i ncl u de d i n data s u m maries.   
E xce pti o ns are descri be d bel o w.  
Missi n g b aseli ne d ata  
If a baseli ne val ue is n ot a vaila ble a n d a scree ni n g val ue is a vaila ble f or t he sa me para meter, 
t he n t he last scree ni n g val ue will be use d as baseli ne. T his val ue will als o be use d f or 
calc ulati o ns of c ha n ges fr o m baseli ne. U nless ot her wise defi ne d, baseli ne will be defi ne d as 
C 1 D 1 . 
Missi n g t u m o ur assess me nt data  
Patie nts w h o wit h dra w c o nse nt t o f oll o w -u p ma y d o s o pri or t o ha vi n g e x perie nce d pr o gressi ve 
disease.  T he i m pact of s uc h patie nts o n t he efficac y a nal ysis will be e x pl ore d via m ulti ple 
i m p utati o n a n d ti p pi n g p oi nt a nal yses.  
Patie nts w h o ha ve missi n g t u m o ur assess me nt data lea di n g t o missi n g o bjecti ve res p o nse data 
will be i ncl u de d i n t he O R R a nal ysis as n o n -res p o n ders. 

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1 3. 3  
A n al ysis P o p ul ati o ns  
T he a nal ysis p o p ulati o ns defi ne d f or t his st u d y are detaile d bel o w. I n a d diti o n, a n d as dee me d 
warra nte d  b y t he data, efficac y ma y als o  be assesse d i n s u b -p o p ulati o ns  as defi ne d b y t he 
s p o ns or. S u b gr o u p a nal yses will assess c o nsiste nc y of treat me nt effect acr oss p ote ntial  or 
e x pecte d pr o g n ostic fact ors  or bi o mar kers. A nal yses will n ot be perf or me d if t here are t o o fe w 
e ve nts a vaila ble f or a mea ni n gf ul a nal ysis of a partic ular s u b -gr o u p.  
1 3. 3. 1  S afet y P o p ul ati o n  
Safet y will be assesse d i n t he Safet y Set ( S S), defi n e d as all ra n d o mise d patie nts w h o recei ve 
at least o ne d ose ( or partial d ose) of st u d y treat me nt. Patie nts will be a nal yse d b y t he treat me nt 
recei ve d, base d o n t heir first d ose of ra n d o mise d st u d y dr u g.  
1 3. 3. 2  F ull A n al ysis S et 
T he  F ull A nal ysis S et ( F A S) is base d o n t he i nte nti o n -t o-treat pri nci ples a n d i ncl u des all 
ra n d o mise d patie nts . 
T he F A S  will be t he pri nci pal p o p ulati o n use d t o assess efficac y e n d p oi nts . Patie nts will be 
a nal yse d base d o n ra n d o mise d treat me nt.  
1 3. 3. 3  M o difie d F ull A n al ysis Set  
T he  M o difie d F ull A nal ysis Set  (m F A S ) is defi ne d as a s u bset of t he F A S w h o ha d at least o ne 
d ose of ra n d o mise d st u d y treat me nt a n d at least o ne f oll o w -u p assess me nt.  
T he m F A S  will be use d t o perf or m a s u p p orti ve a nal ysis of efficac y e n d p oi nt data . Patie nts 
w ill be a nal yse d base d o n ra n d o mise d treat me nt. 
1 3. 3. 4  P K A n al ysis S et 
T he P K P o p ulati o n c o ntai ns all patie nts w h o recei ve d N U C -3 3 7 3 as per pr ot oc ol ( i.e., i nte n de d 
d ose) a n d pr o vi de d at least o ne usa ble P K pr o file. All P K data will be a nal yse d acc or di n g t o 
treat me nt recei ve d.   
T his p o p ulati o n will c o m prise all data fr o m patie nts w h o recei ve d st u d y treat me nt as per 
pr ot oc ol (i.e., i nte n de d d ose) a n d di d n ot vi olate or de viate fr o m t he pr ot oc ol a n d pla n ne d 
d osi n g re gi me n i n wa ys t hat w o ul d si g nifica ntl y affect t he P K a nal yses (f or e xa m ple s ki p pi n g 
d oses, or ta ki n g re d uce d d oses or ta ki n g c o nc o mita nt me dicati o ns wit h t he p ote ntial t o ca use a 
dr u g -dr u g i nteracti o n) d uri n g t he P K sa m pli n g peri o d. Patie nts w h o di d de viate fr o m t he 
pla n ne d d osi n g re gi me n  ma y still pr o vi de s o me d ata f or i ncl usi o n i n t he P K set  if t he y ha ve at 
least o ne usa ble P K pr ofile. T he p o p ulati on  a n d decisi o ns re ga r di n g w hic h pr ofiles are usa ble 
will be defi ne d b y t he st u d y tea m, p har mac o ki neticist a n d statisticia n pri or t o a n y a nal yses 
bei n g perf or me d.  
1 3. 4  
P atie nt D is p ositi o n 
T he dis p ositi o n of patie nt s will be s u m marise d prese nti n g t he n u m ber of patie nts scree ne d, t he 
n u m ber of patie nts ra n d o mise d, t he n u m ber of patie nts treate d, a n d t he n u m ber of patie nts 
i ncl u de d i n eac h st u d y p o p ulati o n.  
I n a d diti o n, t he n u m ber a n d perce nta ge of patie nts w h o c o m plete t he st u d y a n d w h o disc o nti n ue 
t he st u d y earl y, i ncl u di n g a brea k d o w n of t he pri mar y reas o ns f or st u d y disc o nti n uati o n, will 
be prese nte d f or t he F A S p o p ula ti o n. Si milarl y, patie nts w h o c o m plete or pre mat urel y 

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disc o nti n ue ra n d o mi se d treat me nt will be s u m mari se d, i ncl u di n g a brea k d o w n of t he pri mar y 
reas o ns f or disc o nti n uati o n. 
Patie nts wit h i m p orta nt pr ot oc ol de viati o ns or ot her si g nifica nt de viati o ns as defi ne d i n t he 
S A P will be liste d a n d s u m marise d.  
1 3. 5  
St atistic al M et h o ds 
1 3. 5. 1  De m o gr a p hics a n d B aseli ne D at a  
De m o gra p hic a n d baseli ne disease c haracteristic data will be prese nte d base d o n t he F A S.  
Baseli ne de m o gra p hic a n d bac k gr o u n d data, i ncl u di n g, b ut n ot li mite d  t o a ge, ge n der, wei g ht, 
hei g ht, race, et h nicit y a n d E C O G st at us will be liste d a n d s u m maris e d usi n g a p pr o priate 
descri pti ve statistics.  
Baseli ne disease c haracteristics i ncl u di n g, b ut n ot li mite d t o, pri mar y dia g n osis, pri mar y 
t u m ou r l ocati o n a n d disease stat us at baseli ne will als o be liste d a n d s u m maris e d usi n g 
a p pr o priate descri pti ve statistics.  
Rele va nt me dical hist or y a n d pri or treat me nt f or C R C, i ncl u di n g, b ut n ot li mite d t o s yste mic 
t hera pies, ra diati o n a n d s ur geries, will be liste d a n d s u m marise d usi n g a p pr o priate descri pti ve 
statistics. F ull details will be pr o vi de d i n t he S A P. 
1 3. 5. 2  C o nc o mit a nt M e dic ati o ns  
C o nc o mita nt me dicati o n s c o de d usi n g W orl d Healt h Or ga nisati o n Dr u g Dicti o nar y ( W H O 
D D ) b y W H O D D a nat o mical, t hera pe utic, c he m ical class a n d preferre d ter m will be liste d.  
S u m maries ma y be pr o d uce d f or c o nc o mita nt me dicati o ns of s pecific i nterest, as deter mi ne d 
b y t he st u d y tea m p h ysicia n, f or e xa m ple use of hae mat o p oietic  gr o wt h fact ors a n d 
tra nsf usi o ns. 
1 3. 5. 3  E xte nt of E x p os ure  
Desc ri pti ve statistics f or patie nts treate d, i ncl u di n g t he n u m ber of i nf usi o ns recei ve d, t otal d ose 
gi ve n, a n d i nf usi o ns dela ye d or misse d, will be prese nte d.  
T o u n dersta n d t he i m pact of d ose re d ucti o ns o n t he i nte n de d d osi n g re gi me n, d ose i nte nsit y 
will als o be liste d a n d s u m maris e d. D ose i nte nsit y will be defi ne d i n t he S A P.  
1 3. 5. 4  Effic ac y A n al ysis  
T he efficac y e n d p oi nts a n d met h o ds of a nal ysis are defi ne d bel o w . 
1 3. 5. 4. 1  
Pri m ar y Effic ac y A n al ysis  
T he pri mar y efficac y e n d p oi nt is P F S, defi ne d as t he ti me fr o m ra n d o misati o n u ntil t he date of 
o bjecti ve disease pr o gressi o n or deat h ( b y a n y ca use i n t he a bse nce of disease pr o gressi o n). 
Patie nts w h o start a n ot her a nti -ca ncer t hera p y pri or t o pr o gressi o n will be ce ns ore d at t he date 
of t he last a vaila ble R E CI S T v 1. 1 assess me nt.  
P atie nts w h o ha ve n ot e x perie nce d disease pr o gressi o n or die d at t he ti me of a nal ysis will be 
ce ns ore d at t he ti me of t he latest date of assess me nt fr o m t heir last e val ua ble R E CI S T v 1. 1 
assess me nt.   
T he P F S ti me will al wa ys be deri ve d base d o n t he sca n/ass ess me nt dates rat her t ha n visit dates 
a n d t he f oll o wi n g r ules will be a p plie d:  

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•  Date of disease pr o gressi o n will be deter mi ne d base d o n t he earliest of t he dates of 
t he c o m p o ne nt t hat tri g gere d t he disease pr o gressi o n, i.e., if b ot h t he tar get lesi o ns 
a n d t he n o n -tar get lesi o ns i n dicate disease pr o gressi o n b ut were sca n ne d o n 
differe nt da ys, t he earlier of t he 2 dates w o ul d be a p plie d   
•  W he n ce ns ori n g a patie nt f or P F S t he patie nt will be ce ns ore d at t he latest of t he 
assess me nt dates c o ntri b uti n g t o a parti c ular o verall visit assess me nt  
P F S will be a nal yse d via C o x re gressi o n 
m o delli n g  stratifie d f or t he ra n d o misati o n 
stratificati o n fact ors ( R A S stat us, first-li ne treat me nt, a n d d urati o n of pri or li ne of t hera p y) a n d 
i ncl u di n g a fi xe d effect ter m f or ra n d o mise d treat me nt. T he hazar d rati o will be esti mate d f or 
eac h N U FI RI ar m vers us t he F O L FI RI c o ntr ol ar m, al o n g wit h t he ass ociate d c o nfi de nce 
i nter val ( CI) a n d 2-si de d p-val ue. T he data will als o be dis pla ye d usi n g Ka pla n -Meier c ur ves 
a n d me dia n P F S ti mes wil l be esti mate d. 
1 3. 5. 4. 2  
Sec o n d ar y Effic ac y A n al ysis  
1 3. 5. 4. 2. 1  C h a n ge fr o m B aseli ne i n T u m o ur Size  
T he perce nta ge c ha n ge fr o m baseli ne i n t u m o ur size at 8 -wee k i nter vals ( % Δ T S ti me p o oi nt) will 
be defi ne d as f oll o ws:  
•  Baseli ne t u m o ur size ( T S b aseli ne): s u m of l o n gest dia meters of tar get lesi o ns at 
baseli ne  
•  O n -st u d y T S ( T S ti me p oi nt): s u m of l o n gest dia meters of tar get lesi o ns at a p ost-
treat me nt disease assess me nt ti me p oi nt 
 
% ∆T S 𝑡𝑖𝑚𝑒𝑝𝑜𝑖𝑛𝑡= T S 𝑡𝑖𝑚𝑒𝑝𝑜𝑖𝑛𝑡− T S 𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒
T S 𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒
 ×  1 0 0  
 
T he best perce nta ge c ha n ge fr o m baseli ne i n t u m o ur size ( % Δ T S best) acr oss all ti me p oi nts will 
be calc ulate d a n d prese nte d usi n g waterfall pl ots.   
T he % Δ T S best will be defi ne d as f oll o ws:  
•  Baseli ne t u m o ur size ( T S b aseli ne): s u m of l o n gest dia meters of tar get lesi o ns at 
baseli ne  
•  Best T S ( T S best):  s mallest s u m of l o n gest dia meters of tar get lesi o ns o bser ve d at 
a n y ti me p oi nt, re gar dless of w het her t he assess me nt was sc he d ule d or u nsc he d ule d, 
after first d ose a n d pri or t o disease pr o gressi o n  
 
% ∆𝑇𝑆𝑏𝑒𝑠𝑡= T S 𝑏𝑒𝑠𝑡− T S 𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒
T S 𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒
 ×  1 0 0  
 
If a patie nt wit h meas ura ble disease has n o e val ua ble p ost-d ose tar get lesi o n data, t he n t he y 
will be e xcl u de d fr o m t he waterfall pl ot of % Δ T S best.  
T u m o ur size ( % Δ T S W k 8  a n d % Δ T S best) will be prese nte d gra p hicall y usi n g waterfall pl ots f or 
prese nti n g eac h patie nt’s perce nta ge c ha n ge i n t u m o ur size as a se parate bar wit h t he bars 

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or dere d fr o m t he lar gest i ncrease t o t he lar gest decrease. Refere nce li nes at t he + 2 0 % a n d –
3 0 % c ha n ge i n t u m o ur size le vels will be a d de d t o t he pl ots, w hic h c orres p o n d wit h t he 
defi niti o ns of disease pr o gressi o n a n d P R, res pecti vel y. S pi der pl ots will als o be prese nte d.   
1 3. 5. 4. 2. 2  O bjecti ve Res p o nse R ate  
O R R is defi ne d as t he n u m ber of patie nts ac hie vi n g a res p o nse ( C R or P R), defi ne d i n 
acc or da nce wit h R E CI S T v 1. 1 (see A p pe n di x 1 ). T he n u m ber a n d perce nta ge of patie nts i n 
eac h R E CI S T v 1. 1 o verall res p o nse cate g or y ( C R, P R, S D, pr o gressi ve disease or n ot eval ua ble 
[ N E]), as well as t he O R R will be prese nte d. All data will be liste d. 
1 3. 5. 4. 2. 3  Dise ase C o ntr ol R ate  
D C R is defi ne d as t he n u m ber of patie nts ac hie vi n g res p o nse ( C R a n d P R) or S D as a best 
o verall res p o nse. D C R will be s u m marise d a n d liste d.  
1 3. 5. 4. 2. 4  D ur ati o n of Re s p o nse  
D o R is defi ne d f or t he s u bset of t he F A S p o p ulati o n cate g orise d as res p o n ders f or t he 
assess me nt of O R R. D o R is defi ne d as t he ti me, i n m o nt hs , fr o m t he ti me meas ure me nt criteria 
are first met f or C R or P R ( w hic he ver is first rec or de d) u ntil t he fi rst date t hat pr o gressi ve 
disease is o bjecti vel y d oc u me nte d (ta ki n g as refere nce f or pr o gressi ve disease t he s mallest 
meas ure me nts rec or de d si nce t he treat me nt starte d). F or patie nts w h o were l ost t o f oll o w -u p 
wit h o ut pr o gressi o n or reac he d t he ti me p oi nt of a nal ysis wit h o ut a k n o w n rec or d of deat h or 
pr o gressi o n, t he D o R will be ce ns ore d at t he date of last t u m o ur assess me nt.  D o R will be 
s u m marise d a n d liste d. 
1 3. 5. 4. 2. 5  D ur ati o n of St a ble Dise ase  
S D is defi ne d f or t he s u bset of t he F A S p o p ulati o n cate g orise d as ha v i n g neit her s ufficie nt 
s hri n ka ge t o q ualif y f or P R n or s ufficie nt i ncrease t o q ualif y f or pr o gressi ve disease. D urati o n 
of S D is defi ne d as t he ti me, i n m o nt hs , fr o m t he ti me meas ure me nt criteria are first met f or 
S D u ntil t he first date t hat pr o gressi ve d isease is o bjecti vel y d oc u me nte d (ta ki n g as refere nce 
f or pr o gressi ve disease t he s mallest meas ure me nts rec or de d si nce t he treat me nt starte d). F or 
patie nts w h o were l ost t o f oll o w -u p wit h o ut pr o gressi o n or reac he d t he ti me p oi nt of a nal ysis 
wit h o ut a k n o w n  rec or d of deat h or pr o gressi o n, t he d urati o n of S D will be ce ns ore d at t he date 
of last t u m o ur assess me nt.  D urati o n of S D will be s u m marise d a n d liste d.  
1 3. 5. 4. 2. 6  O ver all S ur vi v al  
O S  is defi ne d as t he ti me fr o m ra n d o misati o n t o t he ti me of deat h d ue t o a n y ca use. F or patie nts 
w h o are ali ve at t he ti me of a nal ysis, or are per ma ne ntl y l ost t o f oll o w -u p, d urati o n of O S will 
be ce ns ore d at t he date at w hic h t he y were last k n o w n t o be ali ve.  
T he date at w hic h t he patie nt is last k n o w n t o be ali ve is defi ne d as t he lates t date of: (i) last 
site visit; (ii) last date at w hic h t he patie nt ha d a ra di o gra p hic sca n; a n d (iii) last date at w hic h 
t he patie nt, t he st u d y i n vesti gat or, t heir ot her p h ysicia ns, or a fa mil y me m ber c o nfir me d t hat 
t he patie nt was ali ve. 
T he n u m ber of o v erall ce ns ore d patie nts, n u m ber of patie nts wit h e ve nts a n d Ka pla n -Meier 
esti mates wit h 9 5 % c o nfi de nce i nter vals will be prese nte d.  

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1 3. 5. 5  S afet y A n al ysis  
Safet y a nal yses i n a d diti o n t o t h ose descri be d i n t he f oll o wi n g s u bsecti o ns ma y be deter mi ne d 
at a n y ti me wit h o ut prej u dice  i n or der t o m ost clearl y e n u merate rates of t o xicities a n d t o defi ne 
f urther t he safet y pr ofile of N U C -3 3 7 3  wit hi n  t he pr o p ose d c o m bi nati o ns. 
1 3. 5. 5. 1  
A d verse E ve nts  
A Es will be c o nsi dere d treat me nt -e mer ge nt ( T E A E) if t he y start o n or after t he ti me of t he first 
d ose of st u d y treat me nt a n d u p t o 3 0 da ys after t he last d ose of st u d y treat me nt. A Es will be 
s u m marise d b y Me dical Dicti o nar y f or Re g ulat or y Acti vities ( Me d D R A )™ S yste m Or ga n 
Class ( S O C) a n d preferre d ter m , t he latest versi o n of Me d D R A will al wa ys be use d. T he 
se verit y of A Es will als o be s u m marise d b y C T C A E v 5. 0  ( or hi g her), g ra de. N o n-treat me nt-
e mer ge nt A Es will be i ncl u de d i n t he patie nt listi n gs a n d fla g ge d as s uc h b ut will n ot be 
i ncl u de d i n t he s u m mar y ta bles. W here a n A E date is partial or missi n g, a n d it is u nclear 
w het her t he A E is treat me nt -e mer ge nt, t he A E will be ass u me d t o be treat me nt -e mer ge nt.  A n y 
A Es wit h missi n g se verit y will be classifie d as se vere. Deat hs t hat occ ur wit hi n 9 0  da ys after 
t he last d ose of st u d y dr u g are define d as o n -st u d y deat hs. 
T he f oll o wi n g s u m maries will be pr o d uce d:  
•  A n o ver vie w ta ble of t he i nci de nce of T E A Es, G ra de 3 + T E A Es, S A Es, treat me nt-
relate d T E A Es, T E A Es lea di n g t o treat me nt disc o nti n uati o n , T E A Es lea di n g t o 
treat me nt i nterr u pti o n, a n d T E A Es lea di n g t o deat h, f or eac h treat me nt gr o u p 
•  S u m mar y of T E A Es b y S O C a n d preferre d ter m: B ot h t he n u m ber a n d perce nta ge 
of patie nts i n eac h cate g or y ( patie nt -le vel s u m mar y) a n d t he n u m ber of epis o des 
(e pis o de-le vel s u m mar y) 
•  S u m mar y of treat me nt -relate d T E A Es b y S O C a n d preferre d ter m 
•  S u m mar y of T E A Es occ urri n g i n at least 1 0 % of patie nts, s orte d  b y all gra des a n d 
Gra de 3 -4 a n d  i n desce n di n g or der of fre q ue nc y (i.e., m ost fre q ue nt e ve nt s h o w n 
first). T he or der of fre q ue nc y will be deter mi ne d b y t he m ost fre q ue nt preferre d 
ter m acr oss all c o h orts. 
•  S u m mar y of C T C A E G ra de 3 a nd a b o ve T E A Es b y preferre d ter m  
•  S u m mar y of T E A Es lea di n g t o treat me nt i nterr u pti o ns b y S O C a n d preferre d ter m 
•  S u m mar y of T E A Es lea di n g t o treat me nt disc o nti n uati o n b y S O C a n d prefe rre d 
ter m f or eac h st u d y treat me nt 
•  S u m mar y of T E A Es b y S O C, preferre d ter m a n d ma xi m u m se verit y  
•  S u m mar y of T E A Es b y S O C, preferre d ter m a n d w orst -case relati o ns hi p attri b uti o n  
•  S u m mar y of H y’s la w cases  
•  S u m mar y of S A Es b y S O C a n d preferre d ter m  
•  S u m mar y of S A Es b y preferre d ter m s orte d i n desce n di n g or der of fre q ue nc y 
•  S u m mar y of T E A Es lea di n g t o deat h b y S O C a n d preferre d ter m  

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A d diti o nall y, t he f oll o wi n g will be liste d:  
•  All A Es, liste d wit h date of o nset, st u d y da y, d ose at o nset, treat me nt stat us  at o nset 
( pre-treat me nt, o n g oi n g or p ost-treat me nt), I n vesti gat or’s assess me nt of se verit y 
a n d relati o ns hi p t o st u d y dr u g , a n d o utc o me. 
•  A Es wit h o utc o me of deat h al o n g wit h t he date of o nset, st u d y da y, d ose at o nset, 
treat me nt stat us at o nset ( pre-treat me nt, o n g oi n g or p ost -treat me nt) a n d 
I n vesti gat or’s assess me nt of se verit y a n d relati o ns hi p t o st u d y dr u g  
•  All S A Es al o n g wit h t he date of o nset, st u d y da y, d ose at o nset, treat me nt stat us at 
o nset ( pre -treat me nt, o n g oi n g or p ost-treat me nt), date of res ol utio n (if S A E is 
res ol ve d), I n vesti gat or’s assess me nt of se verit y a n d relati o ns hi p t o st u d y dr u g (s) 
•  A Es lea di n g t o disc o nti n uati o n of ra n d o mise d treat me nt, liste d al o n g wit h t he date 
of o nset, st u d y da y, d ose at o nset, treat me nt stat us at o nset ( pre -treat me nt, o n g oi n g 
or p ost -treat me nt) a n d I n vesti gat or’s assess me nt of se verit y a n d relati o ns hi p t o 
st u d y dr u g 
•  A Es lea di n g t o treat me nt i nterr u pti o ns, liste d al o n g wit h t he date of o nset, st u d y 
da y, d ose at o nset, treat me nt stat us at o nset ( pre -treat me nt, o n g oi n g or p ost-
treat me nt) a n d I n vesti gat or’s assess me nt of se verit y a n d relati o ns hi p t o st u d y dr u g 
If a n A E is re p orte d m ore t ha n o nce d uri n g t he st u d y peri o d t he greatest se verit y a n d t he 
w orst -case attri b uti o n will be prese nte d i n s u m mar y ta bles. A n y A Es c o m me nc i n g > 3 0 da ys 
after disc o nti n uati o n of st u d y treat me nt will n ot be i ncl u de d i n t he ta b ulati o ns of A E da ta. 
1 3. 5. 5. 2  
L a b or at or y P ar a meters  
Cli nical la b orat or y data (act ual a n d c ha n ge fr o m baseli ne) f or c o nti n u o us para meters at eac h 
sc he dule d assess me nt will be s u m marise d usi n g descri pti ve statistics i ncl u di n g n u m ber of 
o bser vati o ns, mea n, sta n dar d de viati o n, i nter q uartile ra n ge (f or o verall o nl y), mi ni m u m, 
me dia n a n d ma xi m u m val ues. F or cate g orical la b orat or y assess me nts, s hift fr o m baseli ne will 
be s u m marise d u si n g fre q ue nc y a n d pr o p orti o n at eac h sc he d ule d assess me nt ti me. 
A d diti o nall y, data ma y be dis pla ye d gra p hicall y. F ull details will be pr o vi de d i n t he S A P.  
All cli nical la b orat or y data f or i n di vi d ual patie nts will be liste d.  
1 3. 5. 5. 3  
Vit al S i g ns 
Act ual val ues at baseli ne a n d eac h sc he d ule d visit a n d c ha n ge fr o m baseli ne at eac h p ost -
baseli ne sc he d ule d visit of vital si g ns (i ncl u di n g p ulse, res pirati o n, s yst olic a n d diast olic bl o o d 
press ure, oral te m perat ure, a n d wei g ht) will be s u m marise d wit h descri pti ve statisti cs b y d ose 
c o h ort a n d ti me p oi nt. A ll data will als o be liste d.  
1 3. 5. 5. 4  
E C O G P erf or m a nce S t at us 
E C O G perf or ma nce stat us will be s u m marise d a n d liste d. T he E C O G Perf or ma nce Scale is 
pr o vi de d i n A p pe n di x 2 . 
1 3. 5. 5. 5  
P h ysic al E x a mi n ati o n  
Listi n gs  will be pr o vi de d f or p h ysical e xa mi nati o n para meters.  

N u Ti de: 3 2 3                                                                                                                        Versi o n 2 .1 , 0 6  Fe b  2 0 2 4  
C o nfi de ntia l                                                            N u Ca na  plc  
8 9  
1 3. 5. 5. 6  
E C Gs  
E C G para meters will be descri be d at eac h ti me p oi nt. T he site will be re q uire d t o re vie w E C Gs 
as a safet y c hec k. T his will be d o ne i m me diatel y b y a q ualifie d I n vesti gat or or car di ol o gist at 
t he stu d y site. E C G assess me nts ma y be retai ne d f or re vie w ce ntrall y, w here res ults will be 
pr o vi de d t o t he st u d y site a n d retai ne d as s o urce data.  
T he tri plicate val ues at eac h ti me p oi nt f or a patie nt will be a vera ge d, a n d t he a vera ge val ue will 
be use d i n t he s u m maries. Act ual val ues at baseli ne a n d eac h sc he d ule d visit a n d c ha n ge fr o m 
baseli ne at eac h p ost -baseli ne sc he d ule d visit i n E C G e n d p oi nts will be s u m marise d. 
A d diti o nall y, a b n or mal res ults will be s u m marise d b y  treat me nt gr o u p at eac h  ti me p oi nt i n 
terms of fr e q ue nc y c o u nts a n d perce nta ges . All E C G data will be dis pla ye d i n a data listi n g. 
1 3. 5. 6  P h ar m ac o ki netics  A n al ysis  
T he P K of t he N U FI RI-be v re gi me n  will be assesse d, i ncl u di n g:  
•  C i nf 
•  C ma x  
•  A U C  
•  t1/ 2 
•  V d 
•  C L  
T he a nal ytes meas ure d i n plas ma will i ncl u de , b ut are n ot li mite d t o : 
•  N U C -3 3 7 3, F B A L , C P F -1 0 2 7,  iri n oteca n, S N -3 8 , S N-3 8 G, A P C  
All P K para meters will be a nal ys e d i n t he P K p o p ulati o n.  
1 3. 5. 7  E x pl or at or y E n d p oi nts  
P ote ntial  bi o mar kers of bi ol o gical acti vit y will be a nal yse d i n arc hi val  t u m o ur sa m ples fr o m 
patie nts i n t he F A S  p o p ulati o n. T he S A P will s pecif y ca n di date bi o mar kers , w here k n o w n , as 
well as t he e x pl orat or y nat ure of t he bi o mar ker st u dies t o be c o n d ucte d a n d e x pl orati o n of 
p ossi ble relati o ns hi ps, if e vi de nt, bet wee n bi o mar ker s a n d cli nical acti vit y.  
1 3. 5. 8    Pri m ar y a n d Interi m  A n al yses    
T he pri mar y efficac y a nal ysis will ta ke place after a t otal of 1 3 9 P F S e ve nts ha ve occ urre d .  
A n e val uati o n of efficac y ma y als o be perf or me d after a t otal of 7 0 P F S e ve nts ha ve occ urre d .  
T he st u d y will be c o nsi dere d c o m plete w he n  t he fi nal patie nt has c o m plete d t heir E n d of 
Treat me nt visit.  
1 3. 5. 9    C h a n ges t o t he P l a n ne d S t atistic al M et h o ds 
Pla n ne d statistical a nal yses will be d oc u me nte d i n t he fi nal S A P bef ore data base l oc k . A n y 
c ha n ges t o t he pla n ne d statistical met h o ds will be d oc u me nte d i n t he C S R .  

N u Ti de: 3 2 3                                                                                                                        Versi o n 2 .1 , 0 6  Fe b  2 0 2 4  
C o nfi de ntia l                                                            N u Ca na  plc  
9 0  
1 4  
P A TI E N T  D A T A H A N D LI N G A N D C O N FI D E N TI A LI T Y  
1 4. 1  
C ase R e p ort F or ms  
As part of t he res p o nsi bilities ass u me d b y partici pati n g i n t he st u d y, t he In vesti gat or or 
S u b -In vesti gat or a grees t o mai ntai n a de q uate case hist ories f or t he patie nts  e nr olle d as part of 
t he researc h u n der t his pr ot oc ol. T he In vesti gat or a grees t o mai ntai n acc urate C R Fs a n d s o urce 
d oc u me ntati o n as part of t he case hist ories . T hese s o urce d oc u me nts i ncl u de la b orat or y re p orts 
a n d M RI or C T sca ns . 
A n electr o nic C R F ( e C R F) will be use d , please refer t o  t he eC R F C o m pleti o n G ui deli nes f or 
f urt her i nf or mati o n. T he I n vesti gat or m ust re vie w eac h c o m plete d e C R F i n a ti mel y ma n ner. 
T he I n vesti gat or will be re q uire d t o re vie w a n d electr o nicall y si g n a n d date t he C R Fs o nce t he 
patie nt’s data is c o m plete.  
1 4. 2   M o nit ori n g of t he S t u d y 
M o nit ori n g a n d a u diti n g pr oce d ures de vel o pe d b y t he S p o ns or or desi g nee will be f oll o we d  i n 
or der t o c o m pl y wit h I C H -G C P g ui deli nes . Bef ore a st u d y ce ntre ca n e nter a patie nt i nt o t he 
st u d y, a re prese ntati ve of t he S p o ns or or desi g nee will visit t he st u d y ce ntre t o: 
•  Deter mi ne  t he a de q uac y of t he facilities 
•  Disc uss wit h t he I n vesti gat or(s) a n d ot her pers o n nel t heir res p o nsi bilities wit h 
re gar d t o pr ot oc ol a d here nce, a n d t he res p o nsi bilities of t he S p o ns or or its 
re prese ntati ves. T his will be d oc u me nte d i n a Cli nical St u d y A gree me nt bet wee n 
t he S p o ns or a n d t he I n vesti gat or  
D uri n g t he st u d y, a m o nit or fr o m t he S p o ns or or a p p oi nte d C R O wil l ha ve re g ular c o ntacts 
wit h t he st u d y ce ntre, f or t he f oll o wi n g: 
•  Pr o vi de i nf or mati o n a n d s u p p ort t o t he I n vesti gat ors  
•  C o nfir m t h at facilities re mai n acce pta ble  
•  C o nfir m t hat t he i n vesti gati o nal tea m is a d heri n g t o t he pr ot oc ol, t hat data are bei n g 
acc urate l y rec or de d i n t he s o urce d oc u me nts a n d e C R Fs, a n d t hat dr u g  
acc o u nta bi lit y c hec ks are bei n g perf or me d 
•  Perf or m s o urce data verificati o n. T his i ncl u des a c o m paris o n of t he data i n t he 
e C R Fs wit h t he patie nt’s me dical rec or ds at t he h os pital or practice, a n d  ot her 
rec or ds rele va nt t o t he st u d y. T his will re q uire direct access t o all ori gi nal rec or ds 
f or eac h patie nt (e. g., cli nic c harts)  
•  Rec or d a n d re p ort a n y pr ot oc ol de viati o ns n ot pre vi o usl y se nt t o t he S p o ns or 
•  C o nfir m A Es a n d S A Es ha ve bee n pr o perl y d oc u me nte d i n t he e C R Fs a n d c o nfir m 
a n y S A Es ha ve bee n f or war de d t o t he S p o ns or or desi g nee, a n d t h ose S A Es t hat 
met criteria f or re p orti n g ha ve bee n f or war de d t o t he I R B/ E C  
T he m o nit or will be a vaila ble bet wee n visits if t he I n vesti gat or or ot her staff nee ds i n f or mati o n 
or g ui da nce .  
N ote : if re q uire d d ue t o c o u ntr y or site-le vel healt h/i nfecti o n c o ntr ol relate d restricti o ns (e. g., 
t he C O VI D-1 9 pa n de mic ), re m ote visits ma y re place o n-site visits f or as s h ort a peri o d of ti me 
as p ossi ble. 

N u Ti de: 3 2 3                                                                                                                        Versi o n 2 .1 , 0 6  Fe b  2 0 2 4  
C o nfi de ntia l                                                            N u Ca na  plc  
9 1  
1 4. 3  
 P atie nt C o nfi de nti alit y  
Pers o nal data rec or de d o n all d oc u me nts will be re gar de d as hi g hl y c o nfi de ntial . T o preser ve 
eac h patie nt’s a n o n y mit y, o nl y t heir patie nt st u d y n u m ber a n d date of birt h ( or ot her i de ntifie d 
as a p pr o priate t o c o u ntr y re g ulati o ns a n d a gree d wit h t he S p o ns or) will be rec or de d o n t he 
eC R Fs.  
T he I n vesti gat or site m ust mai ntai n t he patie nt’s a n o n y mit y i n all c o m m u nicati o ns a n d re p orts 
relate d t o t he researc h. T he I n vesti gat or site tea m m ust kee p a se parate l o g of e nr olle d patie nts’ 
pers o nal i de ntificati o n detai ls as necessar y t o e na ble t he m t o be trac ke d. T hese d oc u me nts m ust 
be retai ne d sec urel y, i n strict c o nfi de nce. T he y f or m part of t he I n vesti gat or Site File a n d are 
n ot t o be release d e xter nall y.   

N u Ti de: 3 2 3                                                                                                                        Versi o n 2 .1 , 0 6  Fe b  2 0 2 4  
C o nfi de ntia l                                                            N u Ca na  plc  
9 2  
1 5  
E T HI C A L A N D R E G U L A T O R Y C O N SI D E R A TI O N S  
1 5. 1  
G o o d C li nic al P r actice C o m pli a nce  
T he S p o ns or, I n vesti gat ors a n d a n y t hir d part y t o w h o m as pects of t he st u d y ma na ge me nt or 
m o nit ori n g ha ve bee n dele gate d will u n derta ke t heir assi g ne d r oles f or t his st u d y i n c o m plia nce 
wit h I C H-G C P, U S 2 1 C o de of Fe deral Re g ulati o ns ( C F R) 1 1, 2 1 C F R  5 0, 2 1  C F R  5 4, 
2 1  C F R  5 6, 2 1  C F R  3 1 2 a n d  all ot her a p plica ble re g ulati o ns. 
1 5. 2  
I nstit uti o n al R e vie w B o ar d s/ E t hics C o m mittees  
T he a p plica ble I R Bs/ E Cs will re vie w all a p pr o priate st u d y d oc u me ntati o n t o safe g uar d t he 
ri g hts, safet y, a n d well -bei n g  of t he patie nts.  
T he fi nal st u d y pr ot oc ol  a n d I C F m ust be a p pr o ve d i n writi n g b y t he a p plica ble I R Bs/ E Cs f or 
eac h site . Writte n I R B/ E C a p pr o val m ust be recei ve d b y  t he S p o ns or or a p p oi nte d C R O bef ore 
a st u d y ce ntre ca n e nr ol  a n y patie nt s i nt o t he st u d y. I n a d diti o n, t he I R B/ E C m ust a p pr o ve all 
a d vertisi n g use d t o recr uit patie nts f or t he st u d y .  
I n t he 
U S, the pr ot oc ol (a n d ass ociate d d oc u me nts, i ncl u di n g a me n d me nts) 
m ust be 
re-a p pr o ve d b y t he I R B/ E C s a n n uall y, as l ocal re g ulati o ns re q uire . Pr o gress re p orts will be 
pr o vi de d t o t he I R B/ E C acc or di n g t o l oc al re g ulati o ns a n d g ui deli nes.  
1 5. 3  
Re g ul at or y A ut h orit y A p pr o v al  
A ut h oris ati o n t o c o n d uct t he st u d y will be o btai ne d fr o m t he a p plica ble Re g ulat or y A ut h orities 
pri or t o i nitiati n g t he st u d y i n eac h partici pat i n g c o u ntr y. 
1 5. 4  
Ris k M a n a ge me nt C o nsi der ati o ns  
T his st u d y c o m plies wit h t he E ur o pea n Me dici nes A ge nc y g ui deli ne o n strate gies t o i de ntif y 
a n d 
miti gate 
ris ks 
f or 
first -i n-h u ma n 
a n d 
earl y 
cli nical 
st u dies 
wit h 
I M Ps 
(E M E A/ C H M P/ S W P/ 2 8 3 6 7/ 0 7 Re v. 1, E M A 0 1 Fe b 2 0 1 8 ).  
T his st u d y will e nr ol patie nts wit h a d va nce d c ol orectal ca ncer  w h o ha ve e x perie nce d disease 
pr o gressi o n o n pri or a nti -ca ncer t hera pies . Patie nts will be ra n d o mi se d t o recei ve t he sta n dar d 
of care F O L FI RI -be v re gi me n or t he N U FI RI -be v re gi me n . T he o nl y differe nce bet wee n t he 
re gi me ns is t he s u bstit uti o n of t he 5-F U c o m p o ne nt i n F O L FI RI wit h t he N U C -3 3 7 3 
c o m p o ne nt i n N U FI RI. T he sites t hat ha ve bee n selecte d f or partici pati o n i n t his st u d y ha ve 
e x perie nce i n treati n g t h e patie nt p o p ulati o n  wit h t he st a n dar d of care re gi me ns, i ncl u di n g 
F O L FI RI -be v, a n d i n c o n d ucti n g P hase II  cli nical st u dies.   
As descri be d i n Secti o n 3. 2 , t he d ose of N U C -3 3 7 3  has bee n a p pr o priatel y deter mi ne d fr o m 
t he a vaila ble n o ncli nical a n d cli nical data. T he N U FI RI treat me nt c o m bi nati o n has bee n 
e val uate d i n d ose -escalati o n c o h orts i n t he N u Ti de: 3 0 2 cli nical st u d y, a n d t he rec o m me n de d 
d ose was selecte d f or f urt her i n vesti g ati o n i n t he N u Ti de: 3 2 3 cli nical st u d y. T his st u d y i ncl u des 
t w o N U FI RI sc he d ules, wee kl y a n d alter nate wee kl y, t o all o w f urt her o pti misati o n of t he d ose 
sc he d ule.  
T o e ns ure patie nt safet y, d ose m o dificati o n criteria a n d s u g geste d ma na ge me nt pr oce d ures f or  
dr u g -relate d t o xicities are pr o vi de d f or eac h of t he st u d y dr u gs i n Secti o n 9 . 
E C Gs are bei n g r o uti nel y m o nit ore d t hr o u g h o ut t he st u d y f or a n y ac ute car diac effect s (see 
S u m mar y Sc he d ule of E ve nts).  

N u Ti de: 3 2 3                                                                                                                        Versi o n 2 .1 , 0 6  Fe b  2 0 2 4  
C o nfi de ntia l                                                            N u Ca na  plc  
9 3  
Patie nt safet y will be m o nit ore d cl osel y o n a n o n g oi n g basis t hr o u g h rec or di n g a n d re p orti n g 
of A Es, r o uti ne la b orat or y tests, a n d p h ysical e xa mi nati o n/ vital si g ns m o nit ori n g.  Pr oce d ures 
f or safet y re p orti n g are clearly o utli ne d i n Secti o n 1 2  a n d p ost -st u d y f oll o w-u p of patie nts is 
descri be d i n Secti o n 3. 4 .   
1 5. 5  
Pr ot oc ol  A me n d me nts  
All pr ot oc ol a me n d me nts (a n d a me n d me nts t o relate d st u d y d oc u me ntati o n) will be  a p pr o ve d 
b y t he a p plica ble I R B s/ E Cs a n d Re g ulat or y A ut h orities  pri or t o i m ple me ntati o n.  
1 5. 6  
Pr ot oc ol V i ol ati o ns a n d D e vi ati o ns  
T he I n vesti gat or, 
or desi g nee , m ust d oc u me nt a n d e x plai n i n t he patie nt’s s o urce 
d oc u me ntati o n a n y de viat i o n fr o m t he a p pr o ve d pr ot oc ol. 
A de viati o n fr o m t he pr ot oc ol is a n u ni nte n de d a n d/ or u na ntici pate d de part ure fr o m t he 
pr oce d ures a n d/ or pr ocesses a p pr o ve d b y t he S p o ns or a n d t he I R B / E C a n d a gree d t o b y t he 
I n vesti gat or or S u b-In vesti gat or. De viati o ns us uall y ha ve a n i m pact o n i n di vi d ual patie nts or a 
s mall gr o u p of patie nts a n d d o n ot i n v ol ve i ncl usi o n/ or pri mar y e n d p oi nt criteria . De viati o ns 
will be trac ke d b y t he C R O al o n g wit h t he c orrecti ve a n d pre ve ntati ve acti o ns b y res p o nsi ble 
part y .  
A pr ot oc ol vi olati o n occ urs w he n t here is n o na d here nce t o t he pr ot oc ol t hat res ults i n a 
si g nifica nt, a d diti o nal ris k t o t he patie nt, w he n t he patie nt or I n vesti gat or has faile d t o a d here 
t o si gnific a nt pr ot oc ol re q uire me nts ( e. g., i ncl usi o n/ criteria a n d t he patie nt was e nr olle d 
wit h o ut pri or S p o ns or a p pr o val ), or w he n t here is n o na d here nce t o t he F D A or ot her a p plica ble 
I C H-G C P g ui deli nes . 
T he cli nical m o nit or will d oc u me nt pr ot oc ol vi olati o ns a n d de viati o ns t hr o u g h o ut t he c o urse 
of m o nit ori n g visits. T he m o nit or wi ll n otif y t he I n vesti gat ors d uri n g a visit a n d  i n writi n g of 
all vi olati o ns a n d de viati o ns. T he I R B / E C s h o ul d be n otifie d of all pr ot oc ol vi olati o ns a n d 
de viati o ns i n a ti mel y ma n ner.  
1 5. 7  
Seri o us B re ac hes  
A seri o us breac h is defi ne d as a breac h of I C H -G C P or t he st u d y pr ot oc ol w hic h is li kel y t o 
effect t o a si g nifica nt de gree t he  safet y a n d ri g hts of a patie nt or t he relia bilit y a n d r o b ust ness 
of t he data ge nerate d i n t he cli nical st u d y.   
I n vesti gat ors will n otif y t he C R O wit hi n o ne w or ki n g da y if a n y seri o us breac h of I C H-G C P 
or t he pr ot oc ol is s us pecte d . U p o n c o nfir mati o n of a seri o us breac h, t he C R O will n otif y t he 
a p plica ble Re g ulat or y A ut h orities . T y picall y, seri o us breac h n otificati o ns s h o ul d be ma de 
wit hi n se ve n da ys of t he C R O bec o mi n g a ware; h o we ver, t his ti meli ne ma y differ as s pecifie d 
b y a p plica ble l ocal re g ulat or y re q uire me nts.  
1 5. 8  
St u d y R e p orti n g R e q uire me nts  
T he I n vesti gat or a grees t o s u b mit pr o gress  re p orts t o t heir I R B/ E C as a p pr o priate. T he 
I n vesti gat or als o a grees t o pr o vi de t he S p o ns or wit h a n a de q uate re p ort s h ortl y after c o m pleti o n 
of t heir partici pati o n i n t he st u d y.  

N u Ti de: 3 2 3                                                                                                                        Versi o n 2 .1 , 0 6  Fe b  2 0 2 4  
C o nfi de ntia l                                                            N u Ca na  plc  
9 4  
1 5. 9   Fi n a nci al d iscl os ure 
T he I n vesti gat ors a n d S u b -In vesti gat ors are re q uire d t o pr o vi de fi na nci al discl os ure 
i nf or mati o n t o all o w t he s p o ns or t o s u b mit t he c o m plete a n d acc urate certificati o n or discl os ure 
state me nts re q uire d u n der 2 1 C F R 5 4. I n a d diti o n, t he I n vesti gat or a n d S u b -In vesti gat ors m ust 
pr o vi de t he s p o ns or wit h a c o m mit me nt t o u p date t hi s i nf or mati o n pr o m ptl y if a n y rele va nt 
c ha n ges occ ur d uri n g t he i n vesti gati o n a n d f or o ne year after st u d y c o m pleti o n. 
Neit her t he s p o ns or n or t he C R O is fi na nciall y res p o nsi ble f or f urt her testi n g/treat me nt of a n y 
me dical c o n diti o n w hic h ma y be detecte d d uri n g t he scree ni n g pr ocess. I n a d diti o n, i n t he 
a bse nce of s pecific arra n ge me nts, neit her t he s p o ns or n or t he C R O  is fi na nciall y res p o nsi ble 
f or f urt her treat me nt of t he patie nt’s disease. 
1 5. 1 0    
I n vesti g at or D oc u me nt ati o n  
Bef ore be gi n ni n g t he st u d y, eac h i n vesti gati ve site will ha ve all a p plica ble esse ntial d oc u me nts 
a vaila ble, i n acc or da nce  wit h I C H -G C P  secti o n 8. 2. 
1 5. 1 1  St u d y R ec or ds R ete nti o n 
Esse ntial d oc u me nts s h o ul d be retai ne d u ntil at least 1 0  years after t he last a p pr o val of a 
mar keti n g a p plicati o n i n a n I C H re gi o n a n d u ntil t here are n o pe n di n g or c o nte m plate d 
mar keti n g a p plicati o ns i n a n I C H re gi o n, or at least 1 0  years ha ve ela pse d si nce t he f or mal 
disc o nti n uati o n of N U C -3 3 7 3  cli nical de vel o p me nt . T hese d oc u me nts s h o ul d be retai ne d f or a 
l o n ger peri o d, h o we ver, if re q uire d b y t he a p plica ble re g ulat or y re q uire me nts or b y a n 
a gree me nt wit h t he s p o ns or. It is t he res p o nsi bilit y of t he s p o ns or t o i nf or m t he I n vesti gat or or 
S u b -I n vesti gat or or i nstit uti o n as t o w he n t hese d oc u me nts n o l o n ger nee d t o be retai ne d. 
If t he I n vesti gat or bec o mes u na ble f or a n y reas o n t o c o nti n ue t o retai n st u d y rec or ds f or t he 
re q uire d peri o d, t he s p o ns or s h o ul d be pros pecti vel y n otifie d . T he st u d y rec or ds m ust be 
tra nsferre d t o a desi g nee acce pta ble t o t he s p o ns or, s uc h as a n ot her I n vesti gat or, a n ot her 
i nstit uti o n, or t o a n i n de pe n de nt t hir d part y arra n ge d b y t he s p o ns or. T he I n vesti gat or m ust 
o btai n writte n per missi o n fr o m t he s p o ns or bef ore dis p osi n g of a n y rec or ds, e ve n if rete nti o n 
re q uire me nts ha ve bee n met. Rete nti o n a n d st ora ge of ce ntral la b orat or y rec or ds s u p p orti n g P K 
e n d p oi nts a n d t he dis p ositi o n of sa m ples d o nate d via t he st u d y m ust als o c o m pl y wit h 
a p plica ble le gislati o n.  
1 5. 1 2   A u dit a n d R e g ul at or y Ins pecti o n  
T he I n vesti gat or, S u b -I n vesti gat ors, a n d i nstit uti o ns i n v ol ve d i n t he st u d y will per mit 
st u d y-relate d m o nit ori n g, a u dits, I R B/ E C re vie w, a n d re g ulat or y i ns pecti o n(s) b y pr o vi di n g 
direct access t o all st u d y rec or ds. I n t he e ve nt of a n a u dit, t he I n vesti gat or or S u b -I n vesti gat or 
a grees t o all o w t he s p o ns or re prese ntati ves of t he s p o ns or, t he F D A, or ot her re g ulat or y a ge nc y 
access t o all st u d y rec or ds.  
T he I n vesti gat or s h o ul d pr o m ptl y n otif y t he s p o ns or a n d t he a p p oi nte d C R O of a n y a u dits 
sc he d ule d b y a n y re g ulat or y a ut h orities a n d pr o m ptl y f or war d c o pies of a n y a u dit re p orts 
recei ve d t o t he s p o ns or.  

N u Ti de: 3 2 3                                                                                                                        Versi o n 2 .1 , 0 6  Fe b  2 0 2 4  
C o nfi de ntia l                                                            N u Ca na  plc  
9 5  
1 6  
P U B LI C A TI O N P O LI C Y  
A n I C H E 3 -c o m plia nt C S R will be ge nerate d base d o n t he fi nal data listi n gs of t his st u d y . T he 
fi nal C S R will be s u b mitte d t o Re g ulat or y A ut h orities a n d I R Bs/ E Cs i n acc or da nce wit h t he 
sti p ulate d ti meli nes. 
1 6. 1  
C o m m u nic ati o n of R es ults b y S p o ns or  
T he s p o ns or  s hall p u blicl y discl ose st u d y res ults t hr o u g h p osti n g o n all a p plica ble p u blic 
re gistries i n acc or da nce wit h l ocal la ws a n d re g ulati o ns. 
Fi nal st u d y res ults ma y be s u b mitte d t o Cli nical Trials. g o v wit hi n o ne year of t he pri mar y 
c o m pleti o n date, w hic h is defi ne d as ‘t he date t hat t he fi nal patie nt was e xa mi ne d or recei ve d 
a n i nter ve nti o n f or t he p ur p oses of fi nal c ollecti o n of data f or t he pri mar y o utc o me, w het her 
t he cli nical st u d y c o ncl u de d acc or di n g t o t he pre-s pecifie d pr ot oc ol or was ter mi nate d’. Fi nal 
st u d y res ults ma y  be p oste d t o E u dra C T wit hi n o ne year of t he e n d of st u d y . 
 
1 6. 2  
P u blic ati o n b y I n vesti g at ors 
I n vesti gat ors ma y n ot p u blis h or discl ose res ults u ntil t he st u d y is c o m plete d. I n a d diti o n, 
I n vesti gat ors s hall ac k n o wle d ge t hat, d ue t o t he li mite d patie nt p o p ulati o n i n i n di vi d ual ce ntres, 
t he data ge nerate d fr o m t heir i n di vi d ual ce ntres  ma y n ot be s ufficie nt fr o m w hic h t o dra w a n y 
mea ni n gf ul scie ntific c o ncl usi o n.  
T he s p o ns or  will pr o vi de a ut h ors hi p ri g hts t o I n vesti gat ors i n or de r of greatest c o ntri b uti o n of 
e val ua ble patie nts t o t he st u d y . P u blicati o n of st u d y res ults ma y als o be descri be d i n t he 
a gree me nt bet wee n t he s p o ns or a n d eac h I nstit uti o n . I n a d diti o n, t he S p o ns or ma y f or m a 
p u blicati o n c o m mittee t o e val uate a n d gi ve fi nal a p pr o val of p u blicati o n s u b missi o n.  
T he pr o p ose d p u blicati o n ( ma n uscri pt, a bstract or p oster) or prese ntati o n will be pr o vi de d t o 
t he s p o ns or b y t he I n vesti gat or f or re vie w a n d c o m me nt at least 6 0 da ys pri or t o t he pla n ne d 
s u b missi o n. T he I n vesti gat or u n dersta n ds a n d a grees t hat partici pati o n i n t he st u d y ma y i n v ol ve 
a c o m mit me nt t o p u blis h t he st u d y res ults i n a c o o perati ve p u blicati o n wit h ot her I n vesti gat ors . 
N o p u blicati o n of c o nfi de ntial i nf o r mati o n s hall be ma de wit h o ut t he s p o ns or’s pri or writte n 
a p pr o val .  
T he I n vesti gat or a grees, u p o n s p o ns or’s re q uest, t o delete a n y c o nfi de ntial i nf or mati o n t hat 
ma y i m pact i ntellect ual pr o pert y pr otecti o n fr o m t he pr o p ose d p u blicati o n . I n vesti gat ors will 
c o m pl y wit h rec o g nis e d et hical p u blicati o ns a n d a ut h ors hi p sta n dar ds, i ncl u di n g Secti o n II of 
t he Rec o m me n dati o ns f or t he C o n d uct, Re p orti n g, E diti n g, a n d P u blicati o n of Sc h olarl y W or k 
i n Me dical J o ur nals (htt p:// w w w.ic mje. or g/ic mje -rec o m me n dati o ns. p df). 
 
 

N u Ti de: 3 2 3                                                                                                                        Versi o n 2 .1 , 0 6  Fe b  2 0 2 4  
C o nfi de ntia l                                                            N u Ca na  plc  
9 6  
1 7  
R E F E R E N C E S  
A merica n  
Ca ncer  
S ociet y : 
C ol orectal  
Ca ncer  
2 0 2 2 .  
A vaila ble  
fr o m: 
htt ps:// w w w.ca ncer. or g/ca ncer/c ol o n -rectal-ca ncer. ht ml  
A djei A A.  A re vie w of t he p har mac ol o g y a n d cli nical acti vit y of ne w c he m ot hera p y a ge nts 
f or t he treat me nt of c ol orectal ca ncer.  J Cli n P h ar m ac ol  1 9 9 9; 4 8: 2 6 5 -2 7 7.  
Ar n ol d D, et al. Pr o g n ostic a n d pre dicti ve val ue of pri mar y t u m o ur si de i n patie nts wit h R AS 
wil d -t y pe 
metastatic c ol orectal ca ncer treate d 
wit h c he m ot hera p y a n d E G F R directe d 
a nti b o dies i n si x ra n d o mise d trials. A n n O nc ol  2 0 1 7; 2 8: 1 7 1 3 – 2 9.  
Be n n o u na J et al; M L 1 8 1 4 7 St u d y I n vesti gat ors. C o nti n uati o n of be vaciz u ma b  after first 
pr o gressi o n i n meta static c ol orectal ca ncer ( M L 1 8 1 4 7): a ra n d o mise d p hase 3 trial. L a ncet 
O nc ol  2 0 1 3; 1 4: 2 9 -3 7.  
Berli n J et al. A P hase I b st u d y of N U C-3 3 7 3, a tar gete d i n hi bit or of t h y mi d ylate s y nt hase, i n 
c o m bi nati o n wit h sta n dar d t hera pies i n patie nts wit h a d va nce d c ol ore ctal ca ncer ( N u Ti de: 3 0 2). 
E S M O 2 0 2 1 ; A bstract 4 7 5 P.  
Br utc her E et al. 5-Fl u or o uracil a n d ca pecita bi ne: Assess me nt a n d treat me nt of u nc o m m o n 
earl y-o nset se vere t o xicities ass ociate d wit h a d mi nistrati o n. Cli n J O nc ol N urs  2 0 1 8; 2 2: 6 2 7 -
6 3 4.  
Carr oll KJ. Bac k t o basics: e x plai ni n g sa m ple size i n o utc o me trials, are statisticia ns d oi n g a 
t h or o u g h j o b. P h ar m St at  2 0 0 9; 8: 3 3 3 -3 4 5.  
De Falc o V, et al . H o w we treat metastatic c ol orectal ca ncer. E S M O O pe n 2 0 2 0; 4:e 0 0 0 8 1 3.  
Diasi o R B & Harris B E.  Cli nical p har mac ol o g y of 5 -fl u or o uracil.  Cli n P h ar m ac oki net 1 9 8 9 , 
1 6 : 2 1 5– 2 3 7.  
Eise n ha uer E A et al. Ne w res p o nse e val uati o n criteria i n s oli d t u m o urs: re vise d R E CI S T 
g ui deli ne ( versi o n 1. 1) . E ur J C a ncer  2 0 0 9;  4 5:  2 2 8 – 2 4 7.  
E M A. G ui deli ne o n strate gies t o i de ntif y a n d miti gate ris ks f or first -i n-h u ma n a n d earl y cli nical 
trials wit h i n vesti gati o nal me dici nal pr o d ucts. E M E A/ C H M P/ S W P/ 2 8 3 6 7/ 0 7 Re v. 1, E M A 0 1 
Fe b 2 0 1 8.  
F D A G ui da nce f or I n d ustr y: Dr u g -I n d uce d Li ver I nj ur y: Pre mar keti n g Clinical E val uati o n. 
J ul y 2 0 0 9. A vaila ble fr o m: htt ps:// w w w.f da. g o v/ me dia/ 1 1 6 7 3 7/ d o w nl oa d .  
Gia nt o ni o BJ et al; Easter n C o o perati ve O nc ol o g y Gr o u p St u d y E 3 2 0 0. be vaciz u ma b  i n 
c o m bi nati o n wit h o xali plati n, fl u or o uracil, a n d le uc o v ori n ( F O L F O X 4) f or pre vi o usl y treate d 
metastatic c ol orectal ca ncer: res ults fr o m t he Easter n C o o perati ve O nc ol o g y Gr o u p St u d y 
E 3 2 0 0. J Cli n O nc ol  2 0 0 7; 2 5: 1 5 3 9 -1 5 4 4.  
H A S. Rec herc he de Déficit e n Di h y dr o p yri mi di ne Dés h y dr o ge nase e n V ue de Pré ve nir 
Certai nes T o xicités Sé vères S ur ve na nt S o us Traite me nt  C o m p orta nt des Fl u or o p yri mi di nes ( 5 -
Fl u or o uracile), Rec o m ma n dati o ns et Référe ntiels; I N Ca: B o ul o g ne -Billa nc o urt, Fra nce; H A S:  
Sai nt -De nis, Fra nce, 2 0 1 8.  
Hei ne ma n n V, et al. F O L FI RI pl us cet u xi ma b vers us F O L FI RI pl us be vaciz u ma b as first-li ne 
treat me nt f or patie nts wit h metastatic c ol orectal ca ncer ( FI R E-3): a ra n d o mise d, o pe n -la bel, 
p hase 3 trial. L a ncet O nc ol  2 0 1 4; 1 5: 1 0 6 5 – 7 5.  
H ua n g S 
et al.  
M yc o plas ma infecti o ns a n d differe nt h u ma n carci n o mas.  W orl d J 
G astr oe nter ol  2 0 0 1, 7: 2 6 6 – 2 6 9.  

N u Ti de: 3 2 3                                                                                                                        Versi o n 2 .1 , 0 6  Fe b  2 0 2 4  
C o nfi de ntia l                                                            N u Ca na  plc  
9 7  
H ur witz H, et al. Be vaciz u ma b pl us iri n oteca n, fl u or o uracil, a n d le uc o v ori n f or metastatic 
c ol orectal ca ncer. N E n gl J Me d  2 0 0 4; 3 5 0: 2 3 3 5 – 4 2.  
Jetté L et al.  Resista nce of col orectal ca ncer cells t o 5 -F U d R a n d 5 -F U ca use d b y M yc o plas ma 
i nfecti o n.  A ntic a ncer Res  2 0 0 8, 2 8: 2 1 7 5 – 2 1 8 0.  
K o petz S. Ra n d o mis e d trial of iri n oteca n a n d cet u xi ma b wit h or wit h o ut ve m urafe ni b i n 
B R A F -m uta nt metastatic c ol orectal ca ncer ( S W O G S 1 4 0 6). J Cli n O nc ol 2 0 1 7; 3 5: 3 5 0 5.  
K o petz S, et al. E nc orafe ni b, bi ni meti ni b, a n d cet u xi ma b i n B R A F V 6 0 0 E– m utate d c ol orectal 
ca ncer. N E n gl J Me d  2 0 1 9; 3 8 1: 1 6 3 2 -1 6 4 3.  
La ures et al. Im pact of g ui deli nes re gar di n g di h y dr o p yri mi di ne  de h y dr o ge nase ( D P D ) 
deficie nc y scree ni n g usi n g uracil -base d p he n ot y pi n g o n t he re d ucti o n of  se vere si de effect of 
5 -fl u or o uracil-base d  c he m ot hera p y: a pr o pe nsi o n sc ore a nal ysis . P h ar m ace utics  2 0 2 2; 
1 4: 2 1 1 9.  
Lee JJ & S u n W. O pti o ns f or sec o n d -li ne treat me nt i n metastatic c ol orectal ca ncer. Cli n A dv 
He m at a n d O nc ol  2 0 1 6; 1 4.  
Lie ke ns S et al.  I m pr o ve me nt of p uri ne a n d p yri mi di ne a nti meta b olite-base d a ntica ncer 
treat me nt b y selecti ve s u p pressi o n of m yc o plas ma-e nc o de d cata b olic e nz y mes.  L a ncet O nc ol  
2 0 0 9; 1 0: 6 2 8 – 6 3 5.  
L o n gle y  D B et al. 5-fl u or o uracil: mec ha nis ms of acti o n a n d cli nical strate gies. N at Rev C a ncer 
2 0 0 3, 3: 3 3 0 – 3 3 8.  
L o n gle y  D B & J o h nst o n P G. M olec ular mec ha nis ms of dr u g resista nce. J P at h ol 2 0 0 5 , 2 0 5: 
2 7 5 – 2 9 2.  
Mc G ui ga n C et al.  P h os p h ora mi date Pr o Ti des of t he a ntica ncer a ge nt F U D R s uccessf ull y 
deli ver t he pref or me d bi oacti ve m o n o p h os p hate i n cells a n d c o nfer a d va nta ge o ver t he pare nt 
n ucle osi de. J Me d C he m 2 0 1 1, 2 7: 7 2 4 7 – 7 2 5 8.  
M H R A G ui da nce: Ma na gi n g cli nical trials d uri n g c or o na vir us ( C O VI D -1 9). Marc h 2 0 2 1. 
A vaila ble fr o m : htt ps:// w w w. g o v. u k/ g ui da nce/ ma na gi n g-cli nical-trials-d uri n g -c or o na vir us -
c o vi d -1 9  
Pa ncz y k M.  P har mac o ge netics researc h o n c he m ot hera p y resista nce i n c ol orectal ca ncer o ver 
t he last 2 0 years. W orl d J G astr oe nter ol  2 0 1 4; 2 0: 9 7 7 5 – 9 8 2 7.  
Pizz or n o G et al . P yri mi di ne a nal o gs. H oll a n d -Frei C a ncer Me dici ne . 6t h e diti o n. 2 0 0 3. 
Ra g n ha m mar P et al.  A s yste matic o ver vie w of c he m ot hera p y effects i n c ol orectal ca ncer.  
Act a O nc ol  2 0 0 1; 4 0: 2 8 2 -3 0 8.  
R ot h A D, et al. Pr o g n ostic r ole of K R A S a n d B R A F i n sta ge II a n d III r esecte d c ol o n ca ncer: 
res ults of t he tra nslati o nal st u d y o n t he P E T A C C-3, E O R T C 4 0 9 9 3, S A K K 6 0 – 0 0 trial. J Cli n 
O nc ol  2 0 1 0; 2 8: 4 6 6 – 7 4.  
Sc h m oll HJ, et al. E S M O C o nse ns us G ui deli nes f or ma na ge me nt of patie nts wit h c ol o n a n d 
rectal ca ncer. a pers o nalize d a p proac h t o cli nical decisi o n ma ki n g. A n n O nc ol  2 0 1 2; 2 3: 2 4 7 9 -
5 1 6.  
S pili o p o ul o u P et al. Fi nal res ults of first-i n-h u ma n st u d y of t he Pr o Ti de t h y mi d ylate s y nt hase 
i n hi bit or N U C-3 3 7 3 i n patie nts wit h a d va nce d s oli d t u m o urs ( N u Ti de: 3 0 1). E S M O 2 0 2 1 ; 
A bstract 5 4 9 P.  
S u n g H et al. Gl o bal ca ncer statistics 2 0 2 0: G L O B O C A N esti mates of i nci de nce a n d m ortalit y 
w or l d wi de f or 3 6 ca ncers i n 1 9 5 c o u ntries. C a C a ncer J Cli n  2 0 2 1; 7 1: 2 0 9 -2 4 9.  

N u Ti de: 3 2 3                                                                                                                        Versi o n 2 .1 , 0 6  Fe b  2 0 2 4  
C o nfi de ntia l                                                            N u Ca na  plc  
9 8  
Ts uta ni Y et al.  Decrease d or otate p h os p h ori b os yltra nsferase acti vit y pr o d uces 5-fl u or o uracil 
resista nce i n a h u ma n gastric ca ncer cell li ne.  O nc ol Re p  2 0 0 8, 2 0: 1 5 4 5 -1 5 5 1.  
Va n C utse m E, et al. Bi ni meti ni b, e nc orafe ni b, a n d cet u xi ma b tri plet t hera p y f or patie nts wit h 
B R A F V 6 0 0 E -m uta nt metastatic c ol orectal ca ncer: safet y lea d -i n res ults fr o m t he p hase III 
B E A C O N c ol orectal ca ncer st u d y. J Cli n O nc ol  2 0 1 9; 3 7: 1 4 6 0 – 6 9.  
Va n de V o or de J et al .  T he c yt ostatic acti vit y of N U C -3 0 7 3, a p h os p h ora mi date pr o dr u g of 5 -
fl u or o-2' -de o x y uri di ne, is i n de pe n de nt of acti vati o n b y t h y mi di ne ki nase a n d i ns e nsiti ve t o 
de gra dati o n b y p h os p h or ol ytic e nz y mes. Bi oc he m P h ar m ac ol 2 0 1 1, 8 2: 4 4 1 – 4 5 2.  
Ve n o o k A P, et al. I m pact of pri mar y ( 1°) t u m o ur l ocati o n o n o verall s ur vi val ( O S) a n d 
pr o gressi o n -free s ur vi val ( P F S) i n patie nts ( pts) wit h metastatic c ol orectal ca ncer ( m C R C): 
a nal ysis of C A L G B/ S W O G 8 0 4 0 5 ( Allia nce). J Cli n O nc ol  2 0 1 6; 3 4: 3 5 0 4 (a bstract).  
Ve n o o k A P, et al. Effect of first-li ne c he m ot hera p y c o m bi ne d wit h cet u xi ma b or be vaciz u ma b 
o n o verall s ur vi val i n patie nts wit h K R A S wil d -t y pe a d va nce d or metastatic c ol orectal ca ncer: 
a ra n d o mise d cli nical trial. J A M A 2 0 1 7; 3 1 7: 2 3 9 2 – 4 0 1.  
W o osle y, R L a n d R o mer o, K A,  w w w. Cre di ble me ds. or g , Q T dr u gs List, [ Accesse d Fe br uar y 
2 0 2 4 ], A Z C E R T, I nc. 1 8 2 2 I n n o vati o n Par k Dr., Or o Valle y, A Z  8 5 7 5 5, U S A.  

N u Ti de: 3 2 3                                                                                                                        Versi o n 2 .1 , 0 6  Fe b  2 0 2 4  
C o nfi de ntia l                                                            N u Ca na  plc  
9 9  
1 8  A P P E N DI C E S  
A P P E N DI X  1.  R E S P O N S E 
E V A L U A TI O N 
C RI T E RI A 
I N 
S O LI D 
T U M O U R S ( R E CI S T) V E R SI O N 1. 1  
T he f oll o wi n g para gra p hs are a q uic k refere nce t o t he R E CI S T criteria (v 1. 1) . T he c o m plete 
criteria are a vaila ble at htt p:// w w w.e ortc. be/ R E CI S T  a n d are i ncl u de d i n t he p u blis he d R E CI S T 
d oc u me nt:  
Eise n ha uer et al. Ne w res p o nse e val uati o n criteria i n s oli d t u m o urs: re vise d R E CI S T g ui deli ne 
( versi o n 1. 1). E ur J C a ncer  2 0 0 9;  4 5:  2 2 8 – 2 4 7.  
 
Me as ur a bilit y of T u m o u r Lesi o ns at B aseli ne  –  Defi niti o ns  
Me as ur a ble dise ase  –  t he prese nce of at least o ne meas ura ble lesi o n. If t he meas ura ble disease 
is restricte d t o a s olitar y lesi o n, its ne o plastic nat ure s h o ul d be c o nfir me d b y 
c yt ol o g y/ hist ol o g y.  
Me as ur a ble lesi o ns  –  t u m ou r lesi o ns t hat ca n be acc uratel y meas ure d i n at least o ne di me nsi o n 
(l o n gest dia meter t o be rec or de d) as ≥2 0 m m wit h c hest x -ra y, a n d as ≥1 0 m m wit h C T sca n or 
cli nical e xa mi nati o n [ usi n g calli pers] . B o ne lesi o ns are c o nsi dere d meas ura ble o nl y if assesse d 
b y C T sca n a n d ha ve a n i de ntifia ble s oft tiss ue c o m p o ne nt t hat meets t hese re q uire me nts (s oft 
tiss ue c o m p o ne nt ≥1 0 m m b y C T sca n). M ali g n a nt ly m p h n o des  m ust be ≥1 5 m m i n t he s h ort 
a xis t o be c o nsi dere d meas ura ble; o nl y t he s h ort a xis will be meas ure d a n d f oll o we d . All 
t u m ou r meas ure me nts m ust be rec or de d in milli metres  ( or deci mal fracti o ns of ce nti metres ) b y 
use of a r uler or calli pers. T u m o u r lesi o ns sit uate d i n a pre vi o usl y irra diate d area, or i n a n area 
s u bjecte d t o ot her l oc o-re gi o nal t hera p y, are us uall y n ot c o nsi dere d meas ura ble u nless t here 
has bee n  de m o nstrate d pr o gressi o n i n t he lesi o n.  
N o n -me as ur a ble lesi o ns  –  all ot her lesi o ns ( or sites of disease), i ncl u di n g s mall lesi o ns are 
c o nsi dere d n o n -meas ura ble disease . B o ne lesi o ns wit h o ut a meas ura ble s oft tiss ue c o m p o ne nt, 
le pt o me ni n geal disease, ascites, ple ural/ pericar dial eff usi o ns, l y m p ha n gitis c utis/ p ul m o nis, 
i nfla m mat or y breast disease, l y m p ha n gitic i n v ol ve me nt of l u n g or s ki n a n d a b d o mi nal masses 
f oll o we d b y cli nical e xa mi nati o n are all n o n-meas ura ble. N o des t hat ha ve a s h ort a xis < 1 0 m m 
at basel i ne are c o nsi dere d n o n-pat h ol o gical a n d s h o ul d n ot be rec or de d or f oll o we d.  
T ar get lesi o ns –  w he n m ore t ha n o ne meas ura ble t u m o u r lesi o n or mali g na nt l y m p h n o de is 
prese nt at baseli ne all lesi o ns u p t o a m axi m u m of 5  lesi o ns t ot al (a n d a ma xi m u m of 2 lesi o ns 
per or g a n ) re prese ntati ve of all i n v ol ve d or ga ns s h o ul d be i de ntifie d as tar get lesi o ns a n d will 
be rec or de d a n d meas ure d at baseli ne. Tar get lesi o ns s h o ul d be selecte d o n t he basis of t heir 
size (lesi o ns wit h t he l o n gest dia meter), be re prese ntati ve of all i n v ol ve d or ga ns, b ut i n a d diti o n 
s h o ul d be t h ose t hat le n d t he msel ves t o re pr o d uci ble re pe ate d me as ure me nts. N ote t hat 
pat h ol o gical n o des m ust meet t he criteri o n of a s h ort a xis of ≥1 5 m m b y C T sca n a n d o nl y t he 
s h ort a xis of t hese n o des will c o ntri b u te t o t he baseli ne s u m.  
At baseli ne, t he s u m of t he tar get lesi o ns (l o n gest dia meter of t u m o u r lesi o ns pl us s h ort a xis of 
l y m p h n o des: o verall ma xi m u m of 5) is t o be calc ulate d a n d rec or de d. 
N o n -t ar get lesi o ns –  all n o n-meas ura ble lesi o ns ( or sites of dis ease) i ncl u di n g pat h ol o gical 
n o des (t h ose wit h s h ort a xis ≥1 0 m m b ut < 1 5 m m), pl us a n y meas ura ble lesi o ns o ver a n d a b o ve 
t h ose liste d as tar get lesi o ns are c o nsi dere d n o n -t ar get lesi o ns. Meas ure me nts are n ot re q uire d 
b ut t hese lesi o ns s h o ul d be n ote d at ba seli ne a n d s h o ul d be f oll o we d as “ prese nt” or “a bse nt”. 

N u Ti de: 3 2 3                                                                                                                        Versi o n 2 .1 , 0 6  Fe b  2 0 2 4  
C o nfi de ntia l                                                            N u Ca na  plc  
1 0 0  
All baseli ne e val uati o ns s h o ul d be perf or me d as cl osel y as p ossi ble t o t he be gi n ni n g of 
treat me nt a n d ne ver m ore t ha n 4 wee ks bef ore t he be gi n ni n g of t he treat me nt. 
Met h o ds of Me as ure me nts  
T he sa me me t h o d of assess me nt a n d t he sa me tec h ni q ue s h o ul d be use d t o c haracterise eac h 
i de ntifie d a n d re p orte d lesi o n at baseli ne a n d d uri n g f oll o w-u p . Assess me nts s h o ul d be 
i de ntifie d o n a cale n dar sc he d ule a n d s h o ul d n ot be affecte d b y dela ys i n t hera p y, w hic h ma y 
be treat me nt ar m de pe n de nt . W hile o n st u d y, all tar get lesi o ns rec or de d at baseli ne s h o ul d ha ve 
t heir act ual meas ure me nts rec or de d o n t he C R F at eac h s u bse q ue nt e val uati o n, e ve n w he n ver y 
s mall (e. g., 2  m m) . If it is t he o pi ni o n of t he ra di ol o gist t hat t he lesi o n has li kel y disa p peare d, 
t he meas ure me nt s h o ul d be rec or de d as 0 m m. If t he lesi o n is belie ve d t o be prese nt a n d is 
fai ntl y see n b ut t o o s mall t o meas ure, a defa ult val ue of 5 m m s h o ul d be assi g ne d. F or lesi o ns 
w hic h fra g me nt/s plit a d d t o get her t he l o n gest dia meters of t he fra g me nte d p orti o ns; f or lesi o ns 
w hic h c oalesce, meas ure t he ma xi mal l o n gest dia meter f or t he “ mer ge d lesi o n”.  
Cli nic al lesi o ns  –  cli nical lesi o ns will o nl y be c o nsi dere d meas ura ble w he n t he y are s u perficial 
a n d ≥1 0 m m as asses se d usi n g calli pers (e. g., s ki n n o d ules). F or t he case of s ki n lesi o ns, 
d oc u me ntati o n b y c ol o ur p h ot o gra p h y i ncl u di n g a r uler t o esti mate t he size of t he lesi o n is 
rec o m me n de d. If feasi ble, i ma gi n g is preferre d. 
C hest X -r a y –  c hest C T is preferre d o ver c he st X-ra y, partic ularl y w he n pr o gressi o n is a n 
i m p orta nt e n d p oi nt, si nce C T is m ore se nsiti ve t ha n X-ra y, partic ularl y i n i de ntif yi n g ne w 
lesi o ns. H o we ver, lesi o ns ≥2 0 m m o n c hest X -ra y ma y be c o nsi dere d meas ura ble if t he y are 
clearl y defi ne d a n d s urr o u n de d  b y aerate d l u n g.  
C T, M RI  –  C T is t he best c urre ntl y a vaila ble a n d re pr o d uci ble met h o d t o meas ure lesi o ns 
selecte d f or res p o nse assess me nt. T his g ui deli ne has defi ne d meas ura bilit y of lesi o ns o n C T 
sca n base d o n t he ass u m pti o n t hat C T slice t hic k ness is 5 m m or less. W he n C T sca ns ha ve 
slice t hic k ness greater t ha n 5 m m, t he mi ni m u m size f or a meas ura ble lesi o n s h o ul d be t wice 
t he slice t hic k ness. M RI is als o acce pta ble i n certai n sit uati o ns (e. g., f or b o d y sca ns). W hile 
P E T sca ns are n ot c o nsi dere d a de q uate  t o meas ure lesi o ns, P E T-C T sca ns ma y be use d 
pr o vi di n g t hat t he meas ures are o btai ne d fr o m t he C T sca n a n d t he C T sca n is of i de ntical 
dia g n ostic q ualit y t o a dia g n ostic C T ( wit h I V a n d oral c o ntrast).  
Ultr as o u n d  –  ultras o u n d is n ot usef ul i n assess me nt o f lesi o n size a n d s h o ul d n ot be use d as a 
met h o d of meas ure me nt. If ne w lesi o ns are i de ntifie d b y ultras o u n d i n t he c o urse of t he st u d y, 
c o nfir mati o n b y C T s h o ul d be o btai ne d.  
E n d osc o p y, L a p ar osc o p y  –  t he utilisati o n of t hese tec h ni q ues f or o bjecti ve t u m o u r e val uati o n 
is n ot a d vise d. H o we ver, t he y ca n be usef ul t o c o nfir m c o m plete pat h ol o gical res p o nse w he n 
bi o psies are o btai ne d or t o deter mi ne rela pse i n st u dies w here rec urre nce f oll o wi n g c o m plete 
res p o nse or s ur gical resecti o n is a n e n d p oi nt. 
T u m o u r m ar kers  –  t u m ou r mar kers al o ne  ca n n ot be use d t o assess o bjecti ve t u m o u r res p o nse. 
If mar kers are i nitiall y a b o ve t he u p per n or mal li mit, h o we ver, t he y m ust n or malise f or a patie nt 
t o be c o nsi dere d i n c o m plete res p o nse. 
C yt ol o g y, Hist ol o g y  –  t hese tec h ni q ues ca n be use d t o differe ntiate bet wee n P R a n d C R i n rare 
cases if re q uire d b y pr ot oc ol (f or e xa m ple, resi d ual lesi o ns i n t u m o u r t y pes s uc h as ger m cell 
t u m ou rs, w here k n o w n resi d ual be ni g n t u m ou rs ca n re mai n). W he n eff usi o ns are k n o w n t o be 
a p ote ntial a d verse effect of treat me nt ( e. g. wit h certai n ta xa ne c o m p o u n ds or a n gi o ge nesis 
i n hi bit ors), t he c yt ol o gical c o nfir mati o n of t he ne o plastic ori gi n of a n y eff usi o n t hat a p pears or 
w orse ns d uri n g treat me nt w he n t he meas ura ble t u m o u r has met criteria f or res p o nse or sta ble 
disease is a d vise d t o differe ntiate bet wee n res p o nse or sta ble disease a n d pr o gressi ve disease.  

N u Ti de: 3 2 3                                                                                                                        Versi o n 2 .1 , 0 6  Fe b  2 0 2 4  
C o nfi de ntia l                                                            N u Ca na  plc  
1 0 2  
A n y  
P D  
A n y  
P D  
 
A n y  
A n y  
Yes  
P D  
 
N ote : Patie nts wit h a gl o bal deteri orati o n of healt h stat us re q uiri n g disc o nti n uati o n of treat me nt 
wit h o ut o bjecti ve e vi de nce of disease pr o gressi o n ( or e vi de nce of u ne q ui v ocal disease pr o gressi o n) 
at t hat ti me s h o ul d be re p orte d as “ sy m pto m atic deteri or ati o n ” . T his is a reas o n f or st o p pi n g t hera p y, 
b ut is N O T o bjecti ve P D . E ver y eff ort s h o ul d be ma de t o d oc u me nt t he o bjecti ve pr o gressi o n e ve n 
after disc o nti n uati o n of treat me nt.  
 
Fre q ue nc y of T u m o u r Re-E v al u ati o n  
T u m o u rs s h o ul d be assesse d at t he e n d of e ver y 2 n d c ycle. 
D ate of Pr o gressi o n  
T his is defi ne d as t he first da y w he n t he R E CI S T ( v 1. 1) criteria f or P D are met.  
Re p orti n g of T u m o u r Res p o nse  
All patie nts i ncl u de d i n t he st u d y m ust be assesse d f or res p o nse t o treat me nt, e ve n if t here i s a 
maj or pr ot oc ol treat me nt de viati o n or if t he y are i neli gi ble, or n ot f oll o we d/re -e val uate d. Eac h 
patie nt will be assi g ne d o ne of t he f oll o wi n g cate g ories: c o m plete res p o nse, partial res p o nse, 
sta ble disease, pr o gressi ve disease, or n ot e val ua ble . 

N u Ti de: 3 2 3                                                                                                                        Versi o n 2 .1 , 0 6  Fe b  2 0 2 4  
C o nfi de ntia l                                                            N u Ca na  plc  
1 0 8  
 
•  persists f or m ore t ha n 2 4 h o urs.   T he d ose is 4 m g t o start, f oll o we d b y 2 m g e ver y 2 
h o urs ( or 4 m g e ver y 4 h o urs at ni g ht t o all o w slee p). L o pera mi de s h o ul d be c o n ti n ue d 
f or 1 2 h o urs f oll o wi n g res ol uti o n of t he diarr h oea a n d re-esta blis h me nt of a n or mal diet.  
Hi g h -d ose l o pera mi de ( 4 m g f oll o we d b y 2 m g e ver y 2 h o urs) is als o rec o m me n de d at 
t he o nset of a ny diarr h oea i n patie nts recei vi n g iri n oteca n c he m ot hera p y.  
•  Atr o p hi ne -di p he n o x yl ate  
At t he discreti o n of t he treati n g p h ysicia n, it 
ma y be usef ul t o a d d atr o pi ne - 
di p he n o x ylate 1 t o 2 ta blets, e ver y 6 -8 h o urs, t o l o pera mi de t hera p y f or Gra de 1 or 2 
diarr h oea.  It s h o ul d n ot be e x pecte d t hat t his w o ul d be s ufficie nt f or t he ma na ge me nt 
of Gra de 3 or 4 diarr h oea.  
 
•  Octre oti de  
F or Gra des 1 a n d 2 diarr h oea lasti n g m ore t ha n 2 4 h o urs des pite hi g h -d ose l o pera mi de 
+ atr o p hi ne -di p he n o x ylate, octre oti de 1 0 0 -1 5 0 mc g S C TI D ma y be c o nsi dere d.  F or 
Gra des 3 a n d 4 diarr h oea, octre ot i de 1 5 0 mc g S C TI D is i n dicate d; t hese patie nts 
us uall y re q uire h os pitalisati o n. If t here is n o i m pr o ve me nt i n t he diarr h oea after 2 4 
h o urs, t he d ose of octre oti de s h o ul d be i ncrease d t o 3 0 0 -5 0 0 mc g S C TI D. T he d urati o n 
of octre oti d e t hera p y s h o ul d be i n di vi d ualis e d, b ut ca n be disc o nti n ue d 2 4 h o urs after 
t he e n d of diarr h oea a n d re-esta blis h me nt of a n or mal diet.  Alter nati vel y, octre oti de 
ma y  be a d mi nistere d  via a s yri n g e dri ver wit h i nf usi o n o ver 2 4 h o urs of 6 0 0 mc g 
octre oti de. If n ot c o ntr olle d eac h da y,  i ncrease t he d ose t o 1 2 0 0 mc g , t he n 1 8 0 0 mc g , 
t he n 2 4 0 0 mc g, b ut n ot be y o n d t his dail y d ose. If diarr h oea is c o ntr olle d , t he n octre oti de 
ca n be de -escalate d . 
 
•  A nti bi otics  
I n t he prese nce of c o nc o mita nt ne utr o pae nia ( gra n ul oc ytes < 1 × 1 0 6/ L), a nti bi otics  
s h o ul d be c o nsi dere d u ntil res ol uti o n of diarr h oea a n d rec o ver y of t he gra n ul oc yte 
c o u nts. I n a d diti o n, oral a nti bi otics ( mi n oc ycli ne, d o x yc ycli ne, or a nti bi otics c o veri n g 
s ki n fl ora) s h o ul d be gi ve n t o pre ve nt or treat E G F R i n hi bit or-relate d ras h. 
 
A v oi d t he use of di uretics, la xati ves a n d ot her a ge nts k n o w t o e xacer bate diarr h oea.