A Phase 1b/2 Study of Abemaciclib in Combination With Irinotecan and Temozolomide (Part A) and Abemaciclib in Combination With Temozolomide (Part B) in Pediatric and Young Adult Patients With Relapsed/Refractory Solid Tumors and Abemaciclib in Combination With Dinutuximab, GM-CSF, Irinotecan, and Temozolomide in Pediatric and Young Adult Patients With Relapsed/Refractory Neuroblastoma (Part C)
Phase: PHASE1
Conditions: Relapsed Solid Tumor, Refractory Solid Tumor
Sponsor: Eli Lilly and Company

Pr ot oc ol I 3 Y- M C-J P C S (f)
A P hase 1 b/ 2 St u d y of A be macicli b i n C o m bi nati o n Wit h Iri n oteca n a n d Te m oz ol o mi de ( Part 
A) a n d A be macicli b i n C o m bi nati o n Wit h Te m oz ol o mi de ( Part B) i n Pe diatric a n d Y o u n g
A d ult Patie nts Wit h Rela pse d/ Refract or y S oli d T u m ors a n d A be macicli b i n C o m bi nati o n Wit h
Di n ut u xi ma b, G M- C S F, Iri n oteca n, a n d Te m oz ol o mi de i n Pe diatric a n d Y o u n g A d ult Patie nts
Wit h Rela pse d/ Refract or y Ne ur o blast o ma ( Part C)
N C T 0 4 2 3 8 8 1 9
A p pr o val Date: 1 8 J U L 2 0 2 3

C O N FI D E N TI A L  
I 3 Y-M C -J P C S(f) 
L Y 2 8 3 5 2 1 9  
1  
Title P a ge  
C o nfi d e nti al I nf or m ati o n  
T h e i nf or m ati o n c o nt ai n e d i n t hi s d o c u m e nt i s c o nfi d e nti al a n d i s i nt e n d e d f or t h e u s e of cli ni c al i n v e sti g at or s. It i s t h e pr o p ert y of 
Eli Lill y a n d C o m p a n y or it s s u b si di ari e s a n d s h o ul d n ot b e c o pi e d b y or di stri b ut e d t o p er s o n s n ot i n v ol v e d i n t h e cli ni c al 
i n v e sti g ati o n of a b e m a ci cli b ( L Y 2 8 3 5 2 1 9) , u nl e s s s u c h p er s o n s ar e b o u n d b y a c o nfi d e nti alit y a gr e e m e nt wit h Eli Lill y a n d 
C o m p a n y or it s s u b si di ari e s.   
N ot e t o R e g ul at or y A ut h oriti e s:  T hi s d o c u m e nt m a y c o nt ai n pr ot e ct e d p er s o n al d at a a n d/ or c o m m er ci all y c o nfi d e nti al i nf or m ati o n 
e x e m pt fr o m p u bli c di s cl o s ur e. Eli Li ll y a n d C o m p a n y r e q u e st s c o n s ult ati o n r e g ar di n g r el e a s e/r e d a cti o n pri or t o a n y p u bli c r el e a s e. 
I n t h e U nit e d St at e s, t hi s d o c u m e nt i s s u bj e ct t o Fr e e d o m of I nf or m ati o n A ct ( F OI A) E x e m pti o n 4 a n d m a y n ot b e r e pr o d u c e d or 
ot h er wi s e di s s e mi n at e d wit h o ut t h e w ritt e n a p pr o v al of Eli Lill y a n d C o m p a n y or it s s u b si di ari e s. 
Pr ot oc ol Title : A P has e 1 b / 2 St u d y of A be macicli b i n C o m bi nati o n wit h Iri n oteca n a n d 
Te m oz ol o mi de ( Part A ) a n d A be ma cicli b i n C o m bi nati o n wit h Te m oz ol o mi de ( Part B ) i n 
Pe diatric a n d Y o u n g A d ult Patie nts wit h Rela pse d/ Refract or y S oli d T u m ors  a n d A be ma cicli b i n 
C o m bi nati o n wit h Di n ut u xi ma b, G M -C S F, Iri n ot eca n, a n d Te m oz ol o mi de  i n Pe diatric a n d 
Y o u n g A d ult  Patie nts wit h Rela pse d/ Refract or y Ne ur o blast o ma ( Part C ).  
Pr ot oc ol N u m ber:  I 3 Y-M C -J P C S 
A me n d m e nt N u m ber: (f) 
C o m p o u n d N u m ber:  L Y 2 8 3 5 2 1 9  
St u d y P h ase:  P hase 1 b/ 2  
S h ort Title : A P hase 1 b / 2 St u d y of A be m acicli b Pl us C he m ot hera p y a n d/ or 
C he m oi m m u n ot hera p y i n Pe diatric a n d Y o u n g A d ult Patie nts wit h Rela pse d/ Refract or y S oli d 
T u m ors  
Acr o n y m:  J P C S 
S p o ns or N a me:  Eli Lill y a n d C o m pa n y  
Le g al Re gistere d A d dress:  I n di a na p olis, I n dia na, U S A 4 6 2 8 5  
Re g ul at or y A ge nc y I de ntifier N u m ber(s):  
I N D: 1 3 8 0 2 4  
E u dra C T:  
2 0 1 9 -0 0 2 9 3 1 -2 7  
E U trial n u m ber: 
2 0 2 3 -5 0 6 7 7 8 -1 1 -0 0  
D oc u me nt I D: V V -C LI N -0 9 5 0 0 5  
A p pr o v al D ate: Pr ot oc ol A me n d me nt ( f) Electr o nicall y Si g ne d a n d A p pr o ve d b y Lill y o n date 
pr o vi de d bel o w.  
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
I 3 Y-M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
2  
Pr ot oc ol A me n d me nt S u m m ar y of C h a n ges  T a ble   
D O C U M E N T HI S T O R Y  
D oc u me nt  
D ate  
A m e n d m e nt 
( e) 
1 1 -J ul -2 0 2 2  
A m e n d m e nt 
(d ) 
0 4 -M ar -2 0 2 1  
A m e n d m e nt 
( c) 
1 5 -J a n -2 0 2 1  
A m e n d m e nt 
( b) 
0 8 -J ul -2 0 2 0  
A m e n d m e nt 
( a) 
1 7 -A pr -2 0 2 0  
Ori gi n al 
Pr ot o c ol  
1 4 -D e c -2 0 1 9  
A me n d me nt (f) 
T his a me n d me nt is c o nsi dere d t o be s u bsta ntial 
T he a me n d me nt is c o nsi dere d t o be s u bsta ntial beca use it is li kel y t o ha ve a si g nifica nt i m pact o n 
t he safet y or t he ri g hts of t he st u d y partici pa nts. 
O ver all R ati o n ale f or t he A me n d me nt: 
T he o verall rati o nale f or t his pr ot oc ol a me n d me nt  is t o m o dif y t h e i ncl usi o n criteria t o all o w 
fle xi bilit y relate d t o reti n oi d use , t o all o w I V te m o z ol o mi de (site s o urce d o nl y) i n Part C , a n d t o 
ali g n t he pr ot o c ol f or tr a nsiti o n  t o E U  Cli nical Trial Re g ulati o n ( E U C T R ) 5 3 6/ 2 0 1 4 . A d diti o nal 
c ha n ges i n t he pr ot o c ol  are s u m mariz e d in t he ta ble bel o w.  Mi n or  t y p ogra p hical or f or matti n g  
c ha n ges are n ot liste d.  
Secti o n # a n d N a me  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
1. 1. S y n o psis  
A d de d re g ulat or y a ge n c y i de ntifier n u m bers 
T o ali g n wit h E U C T R  
1. 1. S y n o psis  
A d de d f o ot n ote “a” t o o bjecti ves/e n d p oi nts 
ta ble: “I n Part C, P K is a pri mar y e n d p oi nt f or 
Sta ge 1 o nl y”  
Clarificati o n  
1. 1. S y n o psis  
A d de d esse ntial des cri pti o n of st u d y 
p o p ulati o n  
T o ali g n wit h E U C T R  
1. 1. S y n o psis  
A d de d s u bsecti o n f or et hical c o nsi derati o ns 
of ris k be nefit  
T o ali g n wit h E U C T R  
1. 2. Sc he ma  
U p date d st u d y sc he ma t o i ncl u de C o h ort B 5 
a n d mi n or f or matti n g c ha n ges  
Err or c orrecti o n  
1. 3. 1. Sc he d ule of 
Acti vities f or Par ts A 
I n te xt a b o ve S o A ta ble f or Sc he d ule of O n-
St u d y Treat me nt Acti vities f or Parts A a n d B , 
Clarificati o n  
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
I 3 Y-M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
3  
Secti o n # a n d N a me  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
a n d B 
“( pre g n a nc y res ults are n ot re q uire d t o be 
rec or de d i n t he e C R F)” a d de d i n t he sec o n d 
t o last se nte nce 
1. 3. 1. Sc he d ule of 
Acti vities f or Parts A 
a n d B 
I n O n-St u d y Treat me nt Acti vities f or Parts A 
a n d B, 
 
 
 
 
 
 
Clarificati o n  
1. 3. 1. Sc he d ule of 
Acti vities f or Parts A 
a n d B 
I n O n-St u d y Treat me nt Acti vities f or Parts A 
a n d B, H e mat ol o g y li ne -ite m c o m me nts 
m o difie d a n d a d de d:  
C urre nt c o m me nt e dite d t o: “ ≤7 da ys pri or t o 
C 1 D 1. F or C 2  a n d be y o n d, ≤3 da ys b ef ore  
Da y 1 a n d ± 3 da ys f or Da ys 8 a n d 1 5”  
 
A d de d: “If iri n oteca n h as bee n disc o nti n ue d 
( Part A) or n ot part of t he re gi me n ( Part B), 
a n d cli nicall y si g nifica nt c yt o p e nia is n ot 
o bser ve d after 3 c ycles, C B C ma y b e re d u ce d 
t o Da y 1 (can eli mi nate Da ys 8 a n d/ or 1 5). ”  
T o re d uce partici pa nt 
b ur de n  
1. 3. 1. Sc he d ule of 
Acti vities f or Parts A 
a n d B 
I n O n-St u d y Treat me nt Acti vities f or Parts A 
a n d B, Cli nical C he mistr y li ne -ite m 
c o m me nts m o difie d a n d a d de d:  
C urre nt c o m me nt e dite d t o: ≤7 da ys pri or t o 
C 1 D 1. F or C 2 a n d be y o n d, ≤3 da ys b ef ore  
Da y 1 a n d ± 3 da ys f or Da ys 8 a n d 1 5  
 
A d de d: “If o n st u d y > 3 c ycl es a n d cli nicall y 
si g nifica nt c he mistr y a d v erse e v e nt is n ot 
o bser ve d, fre q ue n c y ma y be re d uce d t o Da y 1 
(can eli mi nate Da ys 8 a n d/ or 1 5).”  
T o re d uce partici pa nt 
b ur de n  
1. 3. 1. Sc he d ule of 
Acti vities f or Parts A 
a n d B 
I n O n-St u d y Treat me nt Acti vities f or Parts A 
a n d B, C ystati n C li ne -ite m c o m me nt 
m o difie d: “ ≤7 da ys pri or t o C 1 D 1. F or C 2 
a n d be y o n d, ≤3  da ys bef o re Da y 1, u nl ess 
m ore fre q u e nt assess me nt is cli nicall y 
i n dicate d. See Secti o n 1 0. 2, A p pe n di x 2.  
T o re d uce partici pa nt 
b ur de n  
1. 3. 1. Sc he d ule of 
Acti vities f or Parts A 
I n P osttreat me nt F oll o w-U p Sc he d ule of 
Acti vities f or Parts A a n d B ,  
 
T o re d uce partici pa nt 
b ur de n  
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T
C CI
C CI

C O N FI D E N TI A L  
I 3 Y-M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
4  
Secti o n # a n d N a me  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
a n d B 
 
 
 
1. 3. 2. Sc he d ule of 
Acti vities f or Part C  
I n te xt f or Secti o n 1. 3. 2, “( pre g n a nc y res ults 
are n ot r e q uire d t o be rec or de d i n t he e C R F)” 
a d de d i n t he sec o n d t o last se nte nce 
Clarificati o n  
1. 3. 2. Sc he d ule of 
Acti vities f or Part C  
I n Sc h e d ule of Bas eli ne a n d Scree ni n g 
Acti vities f or Part C, li ne ite m f or  
 
 
T o re d uce partici pa nt 
b ur de n  
1. 3. 2. Sc he d ule of 
Acti vities f or Part C  
I n Sc h e d ule of Bas eli ne a n d Scree ni n g 
Acti vities f or Part C, li ne ite m f or ser u m or 
uri ne pre g n a nc y test, re m o ve d “ X” fr o m ≤1 4 
c ol u m n a n d a d de d “ X” t o ≤7 c ol u m n  
Clarificati o n  
1. 3. 2. Sc he d ule of 
Acti vities f or Part C  
I n Sc h e d ule of O n-St u d y Treat me nt A cti vities 
f or Part C, delete d t he first para gra p h 
re gar di n g re m ote visits 
Err or c orrecti o n  
1. 3. 2. Sc he d ule of 
Acti vities f or Part C  
I n Sc h e d ule of O n-St u d y Treat me nt A cti vities 
f or Part C,
 
 
Clarificati o n  
1. 3. 2. Sc he d ule of 
Acti vities f or Part C  
I n Sc h e d ule of O n-St u d y Treat me nt A cti viti es 
f or Part C, 
 
 
 
 
 
C larificati o n 
1. 3. 2. Sc he d ule of 
Acti vities f or Part C  
I n Sc h e d ule of O n-St u d y Treat me nt A cti vities 
f or Part C, He mat ol o g y li ne-ite m c o m me nt, 
delete d “If patie nts re m ai n o n st u d y f or > 4 
c ycles a n d cli nicall y si g nifica nt c yt o pe nia is 
n ot o bser ve d, C B C fre q u e nc y ma y be re d uce d 
t o t he start of s u bse q ue nt c ycles a n d as 
cli nicall y i n dicat e d”  
Clarificati o n  
1. 3. 2. Sc he d ule of 
Acti vities f or Part C  
I n Sc h e d ule of O n-St u d y Treat me nt A cti vities 
f or Part C, Bi o mar kers –  plas ma li ne -ite m, 
re d uce d p artici pa nt wei g ht t hres h ol d f or 
sa m pli n g fr o m  
 k g t o  
 k g 
U p date  
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T
C CI
C CI
C CI
C CI
C CI
C CI

C O N FI D E N TI A L  
I 3 Y-M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
5  
Secti o n # a n d N a me  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
1. 3. 2. Sc he d ule of 
Acti vities f or Part C  
I n Sc h e d ule of O n-St u d y Treat me nt A cti vities 
f or Part C, Bi o mar kers-w h ole bl o o d li ne -ite m, 
re d uce d p artici pa nt wei g ht t hres h ol d f or 
sa m pli n g fr o m  
 k g t o  
k g for w h ole 
bl o o d drie d bl o o d s p ot, a n d fr o m  
 k g t o 
 k g f or w h ole bl o o d s a m ple  
U p date  
1. 3. 2. Sc he d ule of 
Acti vities f or Part C  
I n P osttreat me nt F oll o w -U p Sc he d ule of 
Acti vities f or Part C , li ne ite m f or 
 
 
T o re d uce partici pa nt 
b ur de n  
1. 3. 2. Sc he d ule of 
Acti vities f or Part C  
I n P osttreat me nt F oll o w -U p Sc he d ule of 
Acti vities f or Part C, 
 
 
 
T o re d uce partici pa nt 
b ur de n  
1. 3. 2. Sc he d ule of 
Acti vities f or Part C  
I n P osttreat me nt F oll o w -U p Sc he d ule of 
Acti vities f or Part C , Plas ma bi o mar ker 
sa m ple li ne-ite m, a d de d c o m me nts f or 
 partici pa nts  
 k g, w h ole bl o o d 
sa m ple 
 i nitiati o n of s u bse q ue nt t hera p y, a n d  
 o nl y if n ot alrea d y o btai n e d at visit 
w he n partici pa nt disc o nti n ue d st u d y.  
U p date  
1. 3. 2. Sc he d ule of 
Acti vities f or Part C  
I n P osttreat me nt F oll o w -U p Sc he d ule of 
Acti vities f or Part C , Tiss ue s u b missi o n fr o m 
t u m or bi o ps y o btai ne d after pr o gressi o n 
li ne-ite m, e dite d t o: “ O nl y f or patie nts o n 
st u d y treat me nt at least 6 m o nt hs”  
U p date  
1. 3. 2. Sc he d ule of 
Acti vities f or Part C  
I n P osttreat me nt F oll o w -U p Sc he d ule of 
Acti vities f or Part C , C ollecti on of p ostst u d y 
a ntica ncer treat me nt li ne ite m, e dite d 
c o m me nt  
Clarificati o n  
2. 2. 6.  Precli nical a n d 
Cli nical Rati o nale  
A d de d “( K E L L Y a n d I R -3 2)” i n t he t hir d 
para gra p h  
Clarificati o n  
2. 3.  Be nefit/ Ris k 
Assess me nt  
C ha n ge d “strate gi c” t o “effecti ve” i n t he fi rst 
se nte nce 
Clarificati o n  
2. 3. 2. O verall Be nefit 
Ris k C o ncl usi o n  
A d de d s u bsecti o n f or o verall be nefit ris k 
c o ncl usi o n  
T o ali g n wit h E U C T R  
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T
C CI
C CI
C CI
C CI
C CI
C CI
C CI

C O N FI D E N TI A L  
I 3 Y-M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
6  
Secti o n # a n d N a me  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
3. O bjecti ves a n d 
E n d p oi nts  
A d de d f o ot n ote “a” t o o bjecti ves/e n d p oi nts 
ta ble: “I n Part C, P K is a pri mar y e n d p oi nt f or 
Sta ge 1 o nl y”  
Clarificati o n  
4. 1. 2. T w o -sta ge 
Desi g n f or Part C  
Sta ge 1 s u bse cti o n  
 delete d “t he tri al” fr o m R ules A a n d B  
 a d de d “c o m pleti n g” t o R ule B  
 re place d “ mi ni m u m” wit h “ mi n or” i n 
R ule C  
 
Clarificati o n  
Clarificati o n  
C orrecti o n  
4. 1. 2. T w o -sta ge 
Desi g n f or Part C  
I n De-escalati o n d uri n g c o h ort e x pa nsi o n 
s u bsecti o n, re place d “a n d” wit h “ b ut” i n t he 
first se nte nce 
C orrecti o n  
5. 1. I n cl usi o n Criteria  I n cl usi o n criteri o n # 3, f or Part C o nl y, 
defi niti o n of t he first rela pse was e dite d t o 
i ncl u de “ wit h or wit h o ut reti n oi ds”  
T o all o w fle xi bilit y  
5. 1. I n cl usi o n Criteria  I n cl usi o n criteri o n # 3, f or Parts A, B a n d C, 
ite m ii, c ha n ge d “ca n n ot” t o “ca n” 
C orrecti o n  
5. 1. I n cl usi o n Criteria  I n cl usi o n criteri o n # 5, a d de d “a n d/ or h a ve a 
gastri c/ nas o gastric t u be. Refer t o 
Secti o n  6. 1. 2 f or alter nati ve a d mi nistrati o n 
met h o ds”  
Clarificati o n  
5. 1. I n cl usi o n Criteria  I n cl usi o n criteri o n # 6, te xt of t he first 
se nte nce, a d de d “ d ee me d cli nicall y 
i nsi g nifica nt at t he i n vesti gat or’s discreti o n”, 
a n d delete d “ ot her wise n ote d  ( Gra d e ≤2 f or 
al o pecia, d ecrease d te n d o n refle x, a n d 
resi d ual peri p heral se ns or y n e ur o pat h y are 
acce pta ble)”  
F or fle xi bilit y  
5. 2. E x cl usi o n 
Criteria  
E x cl usi o n criteri o n # 2 0 e dite d, n o w rea ds 
“ T he patie nt has acti ve s yste mic i nfecti o ns 
(e. g. bact erial, f un gal, or viral i nfecti o n 
re q uiri n g I V t hera p y). I n di vi d uals wit h sta ble 
HI V, He p atitis B, or C f or w h o m e x p os ure t o 
t he i n vesti gati o nal treat me nt is n ot e x pecte d 
t o e x acer bate t heir c urre nt disease ma y be 
c o nsi dere d eli gi ble. Scree ni n g is n ot re q uir e d 
f or e nr oll me nt.”  
Clarificati o n  
5. 2. E x cl usi o n 
Criteria  
E x cl usi o n criteri o n # 3 1, e dite d t he first 
se nte nce t o r e place “ or” wit h “a n d” a n d a d de d 
“ ne ur ol o gical ”  
Clarificati o n  
5. 2. E x cl usi o n 
E x cl usi o n criteri o n # 3 2 was a d de d: “ P art C 
F or a d diti o nal 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
I 3 Y-M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
7  
Secti o n # a n d N a me  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
Criteria  
o nl y, ha v e recei ve d  pri or a nti -G D 2 t hera p y 
d uri n g i n d ucti o n p has e”  
clarificati o n  
6. 1. St u d y 
I nter ve nti o n(s) 
A d mi nistere d  
C ha n ge d C ycl e “ 4 ” t o C ycle “ 3” i n t he first 
se nte nce of t he f o urt h p ara gra p h 
C orrecti o n  
6. 1. St u d y 
I nter ve nti o n(s) 
A d mi nistere d  
Treat me nt  te xt was e dite d i n s u bsecti o ns f or 
a be maci cli b, te m oz ol o mi de, iri n oteca n, 
di n ut u xi ma b a n d G M -C S F  
Clarificati o n  
6. 1. St u d y 
I nter ve nti o n(s) 
A d mi nistere d  
A d de d E U a ut h orizati o n -relate d te xt f or eac h 
st u d y i nter ve nti o n 
T o ali g n wit h E U C T R  
6. 1. St u d y 
I nter ve nti o n(s) 
A d mi nistere d  
A d de d s u bsecti o n f or pac ka gi n g a n d la beli n g  
T o ali g n wit h E U C T R  
6. 1. 3. Criteria t o 
Be gi n S u bse q ue nt 
C ycles of Treat me nt  
 
 
 
 
Clarificati o n  
6. 1. 3. Criteria t o 
Be gi n S u bse q ue nt 
C ycles of Treat me nt  
A d de d “ u nless dee me d cli nicall y i nsi g nifica nt 
b y t he i n vesti gat or ” at e n d of fi nal b ullet 
p oi nt a n d delete d “ (e x ce pt al o pecia, a n ore xia, 
ast he nia, a n d decrease d t e n d o n refl e x)”  
Clarificati o n  
6. 5. 1. Palliati ve, 
Me dici ne a n d 
S u p p orti ve Care  
I n S u p p orti ve Care s u bsecti o n 
T hir d b ullet: Delete d t he first p orti o n of t he 
se nte nce a n d a d de d “t hr o m b o p oietic gr o wt h 
fact ors” 
Fift h b ullet: Delete d t he s ec o n d se nte nce 
Clarificati o n  
6. 5. 2.  S u p p orti ve 
Ma na ge me nt f or 
Diarr hea  
E dite d t he first, sec o n d, a n d f o urt h para gra p hs Clarificati o n  
6. 6. 1. 1. D ose 
M o dificati o n 
G ui da nce d u e t o 
T o xicities 
C o nsi dere d t o be 
Attri b ute d t o 
A be macicli b  
I n t he Parts A a n d B ta bl e f or a b e maci cli b 
d ose a dj ust me nts a n d s us pe nsi o ns d ue t o 
n o n he mat ol o gic t o xicit y c o nsi dere d t o be 
attri b ute d t o a be maci cli b, a d de d “ u nless 
dee me d cli nicall y i nsi g nifica nt b y t he 
i n vesti gat or ” t o t he li ne f or N o n he mat ol o gic 
T o xicit y (e x ce pt diarr hea, A L T / A S T 
i ncreas e d, a n d I L D/ p n e u m o nitis) 
Clarificati o n  
6. 6. 1. 1. D ose 
M o dificati o n 
I n t he Parts A a n d B ta bl e f or a b e maci cli b 
d ose a dj ust me nts a n d s us pe nsi o ns d ue t o 
C orrecti o n  
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T
C CI

C O N FI D E N TI A L  
I 3 Y-M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
8  
Secti o n # a n d N a me  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
G ui da nce d u e t o 
T o xicities 
C o nsi dere d t o be 
Attri b ute d t o 
A be macicli b  
n o n he mat ol o gic t o xicit y c o nsi dere d t o be 
attri b ute d t o a be maci cli b, a d de d s u perscri pt 
“ b” f o ot n ote refere n ce t o li nes f or  
 
 Diarr hea Gra de 2 t hat persists, a n d  
 I L D / p ne u m o nitis. 
6. 6. 1. 3. Part 
C -S pecific D ose 
M o dificati o ns  
I n t he t a ble f or Part C D ose M o dificati o ns f or 
Diarr hea, a d d e d  
 s u perscri pt “a” f o ot n ote refere nce t o 
li ne f or Gra d e 2 D oes n ot Res ol ve t o 
≤Gra de 1 Wit hi n 2 4 h o urs, 1 st E ve nt 
c ol u m n: “ Persists or rec urs a des pite 
ma xi mal s u p p orti ve meas ures”  
 ne w f o ot n ote “ a Det er mi nati o n of 
persiste nt e ve nts will be at t he 
discreti o n of t he i n vesti gat or. 
Rec urre nt t o xicit y refers t o t he sa me 
e ve nt occ urri n g wit hi n t he ne xt 8 
wee ks (as meas ure d fr o m t he st o p date 
of t he prece di n g e v e nt).”  
Clarificati o n  
6. 6. 1. 3. Part C -
S pecific D ose 
M o dificati o ns  
I n t he t a ble f or Part C Dose M o dificati o ns f or 
He pat ot o xicit y  
 a d de d s u perscri pt “a” f o ot n ote 
refere nce t o li ne title: “ Persiste nt or 
Rec urre nt a Gra de 2 A S T/ A L T 
I n crease” 
 e dite d a n d re or dere d e xisti n g 
s u perscri pt f o ot n ote refere nces 
 a d de d ne w f o ot n ote “ a Deter mi nati o n of 
persiste nt e ve nts will be at t he 
discreti o n of t he i n vesti gat or. 
Rec urre nt t o xicit y refers t o t he sa me 
e ve nt occ urri n g wit hi n t he ne xt 8 
wee ks (as meas ure d fr o m t he st o p 
date of t he prece di n g e ve nt).  
 C ha n ge d f o ot n ote c fr o m “ 3 6” da ys t o 
“3 5”  
Clarificati o n  
6. 6. 1. 3. Part C -
S pecific D ose 
M o dificati o ns  
I n t he t a ble f or Part C D ose M o dificati o ns f or 
Miscella ne o us T o xicit y  
 a d de d s u perscri pt “a” a n d f o ot n ote 
refere nce t o Persiste nt or rec urre nt: 
Clarificati o n  
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
I 3 Y-M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
9  
Secti o n # a n d N a me  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
“ Persiste nt or rec urre nt a Gra de 2 
des pite ma xi mal s u p p orti ve careb” 
 a d de d s u perscri pt “ b” f o ot n ote 
refere nce t o li ne f or N o n he mat ol o gic 
T o xicit y n ot Ot her wise Descri be d 
A b o ve: “ Gra de 2 Persiste nt or 
rec urre nta, b” 
 a d de d ne w f o ot n ote “ a Deter mi nati o n of 
persiste nt e ve nts will be at t he 
discreti o n of t he i n vesti gat or. 
Rec urre nt t o xicit y refers t o t he sa me 
e ve nt occ urri n g wit hi n t he ne xt 8 
wee ks (as meas ure d fr o m t he st o p date 
of t he prece di n g e v e nt).  
 e dite d f or mer f o ot n ote “a” t o “ b” a n d 
m o difie d te xt: “ b D oes n ot res ol ve 
wit h ma xi mal s u p p orti ve meas ures 
wit hi n 7  da ys t o baseli ne or Gra d e 1 
u nless dee me d cli nicall y i nsi g nifica nt 
t he i n vesti gat or. 
8. 3. A d verse E v e nts 
a n d Seri o us A d vers e 
E ve nts  
A d de d secti o ns a n d c o nte nt f or “ Defi niti o n of 
A E” a n d “ E ve nts meeti n g t he A E defi niti o n”  
T o ali g n wit h E U C T R  
8. 3. A d verse E v e nts 
a n d Seri o us A d vers e 
E ve nts  
A d de d “ cli nic all y rele va nt” i n t he sec o n d 
se nte nce of t he ei ght h  para gra p h  
Clarificati o n  
8. 3. 3.  Re g ulat or y 
Re p orti n g 
Re q uire me nts  f or 
S A Es  
E dite d t he sec o n d b ullet a n d delete d t he t hir d 
b ullet  
T o ali g n wit h E U C T R  
8. 8. 1. Bi o mar kers f or 
Part C  
A d de d “f or i nsta nce t o u n dersta n d t he r ole of 
vari o us c o -occ urri n g alterati o ns” t o t he last 
se nte nce of t he sec o n d p ara gra p h 
Clarificati o n  
8 . 8. 1. Bi o mar kers f or 
Part C  
Delete d t he first se nte nce i n t he t hir d 
para gra p h  
C orrecti o n  
8. 8. 1. Bi o mar kers f or 
Part C  
I n t he f o urt h para gra p h, re vise d ti mefra me f or 
st ora ge or rete nti o n of bi o mar ker sa m ples 
fr o m 
 
U p date d  
8. 8. 1. 1. Tiss ue 
Sa m ples f or 
Bi o mar ker Researc h  
Delete d t he f o urt h a n d fift h para gra p hs  
U p date  
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T
C CI

C O N FI D E N TI A L  
I 3 Y-M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 0  
Secti o n # a n d N a me  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
8. 8. 1. 2. Plas ma 
Sa m ples f or 
Bi o mar ker Researc h  
Delete d t he sec o n d para gra p h  
U p date  
9. 4. 6. 2. 1. 2 0 1 7 I N R C  Delete d f o ot n ote “a” f or F D G-P E T i n t he 
s u bsecti o n, Pri mar y t u m or (s oft tiss ue) 
res p o nse 
Clarificati o n  
9. 4. 6. 2. 1. 2 0 1 7 I N R C  Delete d f o ot n ote “a” f or S U V c ollecti o n a n d 
re n u m bere d ot her f o ot n ot es i n t he S oft tiss ue 
a n d b o ne metastatic disease t u m or res p o ns e 
s u bsecti o n 
Clarificati o n  
9. 4. 6. 2. 1. 2 0 1 7 I N R C  Delete d “ S U V will be c ollecte d f or F D G P E T 
a vi d sites” fr o m f o ot n ote b  
 
9. 5. I nteri m A nal yses  M o difie d t he sec o n d a n d t hir d b ullets b y 
a d di n g “treat me nt -relat e d” (treat me nt-relat e d 
A E..) a n d re placi n g “ mi ni mal” wit h " mi n or” 
( mi n or res p o nse), res pecti vel y 
Clarificati o n  
9. 5. I nteri m A nal yses  A d de d “If 5 5 m g/ m 2 is declare d t he M T D, b ut 
eit her R ule A or B is tri g gere d d uri n g c o h ort 
e x pa nsi o n, t he D M C ma y rec o m me n d t hat 
s u bse q ue nt patie nts be tr eate d at 3 0 m g/ m 2. 
See Secti o n 4. 1. 2.”  
Clarificati o n  
1 0. 1. 1. Re g ulat or y 
a n d Et hical 
C o nsi derati o ns  
A d de d ne w f o urt h b ullet p oi nt  
U p date  
1 0. 1. 1. Re g ulat or y 
a n d Et hical 
C o nsi derati o ns  
Mi n or e dit relate d t o E U C T R i n t he fi nal s u b 
b ullet of t he fift h mai n b ullet  
T o ali g n wit h E U C T R  
1 0. 1. 3. Data 
Pr otecti o n  
Re place d secti o n te xt wit h u p date d E U C T R 
te xt 
T o ali g n wit h E U C T R  
1 0. 1. 5. Disse mi nati o n 
of Cli nical St u d y 
Data  
Delete d t he first se nte nce a n d re placed  t he 
secti o n te xt f or “ Data” wit h u p date d E U C T R 
te xt 
T o ali g n wit h E U C T R  
1 0. 2. A p pe n di x 2:  
Cli nical La b orat o r y 
Tests  
I n cli nical la b test ta bles f or Parts A, B, a n d 
C, “ Bl o o d urea nitr o ge n” was e dite d t o 
“ Bl o o d ur ea nitr o ge n ( B U N) or bl o o d ur ea”  
Clarificati o n  
1 0. 6. A p pe n di x 6:  
I n d u cers a n d Str o n g 
I n hi bit ors of 
C Y P 3 A 4  
C ha n ge d “ C Y P 3 A” t o “ C Y P 3 A 4” i n secti o n 
title a n d ta ble hea ders  
Clarificati o n  
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
I 3 Y-M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 1  
Secti o n # a n d N a me  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
1 0. 6. A p pe n di x 6:  
I n d u cers a n d Str o n g 
I n hi bit ors of 
C Y P 3 A 4  
U p d ate d t he ta ble 
U p date  
1 0. 9. A p pe n di x 9: 
C o u ntr y -S pecific 
Re q uire me nts  
C o u ntr y -S pecific A d de n d u m has bee n a d d e d 
as a n a p pe n di x t o t he pr ot oc ol. O nl y s pecific 
f or J P C S sites i n t he E U. 
C o ns oli dati o n of 
Pr ot oc ol as re q uire d b y 
t he E U C T R f or 
Tra nsiti o n  
1 0. 1 0. A p pe n di x 1 0: 
A b bre viati o ns  
U p date d wit h ite ms t hat ali g n wit h E U C T R  
T o ali g n wit h E U C T R  
 
 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
I 3 Y-M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 2  
T a ble of C o nte nts   
Title P a ge  ........................................................................................................................................1  
Pr ot oc ol A me n d me nt S u m m a r y of C h a n ges T a ble  ....................................................................2  
T a ble of C o nte nts  .........................................................................................................................1 2  
1.  
Pr ot oc ol S u m m ar y  ........................................................................................................1 6  
1. 1.  
S y n o psis  ..........................................................................................................................1 6  
1. 2.  
Sc he ma  ............................................................................................................................2 3  
1. 3.  
Sc he d ule of A cti vities ( S o A)  ..........................................................................................2 6  
1. 3. 1.  
Sc he d ule of A cti vities f or Parts A a n d B  ........................................................................2 6  
1. 3. 2.  
Sc he d ule of A cti vities f or Part C  ....................................................................................3 9  
1. 3. 3.  
P har mac o ki netic Sa m pli n g a n d St u d y Dr u g D osi n g Sc he d ul e  .......................................5 0  
2.  
I ntr o d ucti o n ...................................................................................................................5 2  
2. 1.  
St u d y R ati o nale  ...............................................................................................................5 2  
2. 2.  
Bac k gr o u n d  .....................................................................................................................5 2  
2. 2. 1.  
Te m oz ol o mi de  ................................................................................................................5 3  
2. 2. 2.  
Iri n ot eca n ........................................................................................................................5 3  
2. 2. 3.  
A be macicli b  ....................................................................................................................5 4  
2. 2. 4.  
Di n ut u xi ma b  ...................................................................................................................5 4  
2. 2. 5.  
G M -C S F  ..........................................................................................................................5 5  
2. 2. 6.  
Precli nical a n d Cli nical Rati o nale  ...................................................................................5 5  
2. 3.  
Be nefit/ Ris k Assess me nt  ................................................................................................5 9  
2. 3. 1.  
Be nefit/ Ris k Assess me nt of C O VI D -1 9  .........................................................................5 9  
2. 3. 2.  
O verall Be nefit Ris k C o ncl usi o n:  ...................................................................................6 0  
3.  
O bjecti ves a n d E n d p oi nts  ............................................................................................6 1  
4.  
St u d y Desi g n  ..................................................................................................................6 3  
4. 1.  
O verall  Desi g n  ................................................................................................................6 3  
4. 1. 1.  
D ose Escalati o n D esi g n f or Parts A a n d B  .....................................................................6 4  
4. 1. 2.  
T w o -sta ge D esi g n f or Part C...........................................................................................6 5  
4. 1. 3.  
D ose -Li miti n g T o xicit y Deter mi nati o n a n d Ma xi m u m T olerate d 
D ose Defi niti o n  ...............................................................................................................6 7  
4. 2.  
Scie ntific Rati o nale f or St u d y Desi g n  ............................................................................6 9  
4. 3.  
J ustificati o n f or D ose ......................................................................................................6 9  
4. 3. 1.  
A be macicli b  ....................................................................................................................6 9  
4. 3. 2.  
Te m oz ol o mi de  ................................................................................................................7 0  
4. 3. 3.  
Iri n ot eca n ........................................................................................................................7 0  
4. 3. 4.  
Di n ut u xi ma b a n d G M -C S F  .............................................................................................7 1  
4. 4.  
E n d of St u d y Defi niti o n  ..................................................................................................7 1  
5.  
St u d y P o p ul ati o n  ...........................................................................................................7 2  
5. 1.  
I n cl usi o n Criteria ............................................................................................................7 2  
5. 2.  
E x cl usi o n Criteria  ...........................................................................................................7 7  
5. 3.  
Lif est yle C o nsi derati o ns  .................................................................................................7 8  
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
I 3 Y-M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 3  
5. 4.  
Scree n Fail ures  ................................................................................................................7 8  
6.  
St u d y I nter ve nti o n  ........................................................................................................8 0  
6. 1.  
S t u d y I nter v e nti o n(s) A d mi nistere d................................................................................8 0  
6. 1. 1.  
Detaile d A d mi nistrati o n G ui deli nes ( Part C O nl y)  .........................................................8 3  
6. 1. 2.  
Patie nts wit h Diffic ult y S wall o wi n g After I nitiati n g Treat me nt  ....................................8 4  
6. 1. 3.  
Criteria t o Be gi n S u bse q ue nt C ycles of Treat me nt .........................................................8 5  
6. 1. 4.  
Pre me dicati o n  .................................................................................................................8 5  
6. 2.  
Pre parati o n/ Ha n dli n g/ St ora ge/ Acc o u nta bilit y  ................................................................8 5  
6. 3.  
Meas ures t o Mi ni mize Bias:  Ra n d o mizati o n a n d Bli n di n g  ...........................................8 6  
6. 4.  
St u d y I nter v e nti o n C o m plia nce  ......................................................................................8 6  
6. 5.  
C o nc o mita nt T hera p y  .....................................................................................................8 6  
6. 5. 1.  
Palliati ve Me dici ne a n d S u p p orti ve Care  .......................................................................8 8  
6. 5. 2.  
S u p p orti ve Ma na ge me nt f or Diarr hea  ............................................................................8 8  
6. 5. 3.  
S u p p orti ve Ma na ge me nt of A ntici pate d Di n ut u xi ma b -Ass ociate d 
T o xicities ( Part C O nl y)  ..................................................................................................9 0  
6. 6.  
D ose M o dificati o n  ..........................................................................................................9 5  
6. 6. 1.  
D ose M o dificati o n G ui da nce d ue t o  T o xicit y  .................................................................9 7  
6. 7.  
I nter ve nti o n aft er t he E n d of t he St u d y .........................................................................1 0 7  
6. 7. 1.  
Treat me nt after St u d y C o m pleti o n ................................................................................1 0 7  
7.  
Disc o nti n u ati o n of St u d y I nter ve nti o n a n d P artici p a nt 
Disc o nti n u ati o n/ Wit h dr a w al ......................................................................................1 0 9  
7. 1.  
Disc o nti n uati o n of St u d y I nter ve nti o n  ..........................................................................1 0 9  
7. 2.  
Partici pa nt Disc o nti n uati o n/ Wit h dra wal fr o m t he St u d y  ..............................................1 0 9  
7. 3.  
L ost t o F oll o w u p  ..........................................................................................................1 1 0  
8.  
St u d y Assess me nts a n d Pr o ce d ures ...........................................................................1 1 1  
8. 1.  
Efficac y Assess me nts  ...................................................................................................1 1 1  
8. 2.  
Safet y Assess me nts  .......................................................................................................1 1 2  
8. 2. 1.  
Cli nical Safet y La b orat or y Assess me nts  ......................................................................1 1 2  
8. 3.  
A d verse E v e nts a n d Seri o us A d verse E v e nts  ...............................................................1 1 6  
8. 3. 1.  
Ti me Peri o d a n d Fre q ue n c y f or C ollecti n g A E a n d S A E 
Inf or mati o n  ...................................................................................................................1 1 8  
8. 3. 2.  
F oll o w -u p of A Es a n d S A Es  .........................................................................................1 1 9  
8. 3. 3.  
Re g ulat or y Re p orti n g Re q uire me nts f or S A Es  .............................................................1 1 9  
8. 3. 4.  
Pre g n a nc y  ......................................................................................................................1 1 9  
8. 3. 5.  
Car di o vasc ular a n d Deat h E ve nts  .................................................................................1 1 9  
8. 3. 6.  
C o m plai nt Ha n dli n g  ......................................................................................................1 2 0  
8. 4.  
Treat me nt of O v er d ose  .................................................................................................1 2 0  
8. 5.  
P har mac o ki netics  ..........................................................................................................1 2 0  
8. 5. 1.  
Patie nt Diar y  .................................................................................................................1 2 1  
8. 6.  
P har mac o d y na mics  .......................................................................................................1 2 1  
8. 7.  
Ge netics  ........................................................................................................................1 2 1  
8. 7. 1.  
W h ole Bl o o d a n d/ or Sali va Sa m ples f or P har mac o ge n etic 
Researc h  ........................................................................................................................1 2 1  
8. 8.  
Bi o mar kers  ....................................................................................................................1 2 1  
8. 8. 1.  
Bi o mar kers f or Part C  ...................................................................................................1 2 1  
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
I 3 Y-M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 4  
8. 9.  
Me dical Res o urce Utiliz ati o n a n d Healt h Ec o n o mi cs  ..................................................1 2 4  
8. 1 0.  
Pr o d uct Acce pta bilit y a n d Palata bilit y Assess me nts  ....................................................1 2 4  
9.  
St atistic al C o nsi der ati o ns  ...........................................................................................1 2 5  
9. 1.  
Statistical H y p ot heses  ...................................................................................................1 2 5  
9. 2.  
Sa m ple Siz e Deter mi nati o n  ..........................................................................................1 2 5  
9. 3.  
P o p ulati o ns f or A nal ys es  ..............................................................................................1 2 5  
9. 4.  
Statistical A nal yses  .......................................................................................................1 2 6  
9. 4. 1.  
Ge neral Statistical C o nsi derati o ns  ................................................................................1 2 6  
9. 4. 2.  
A nal ysis P o p ulati o n  ......................................................................................................1 2 6  
9. 4. 3.  
Partici pa nt Dis p ositi o n  ..................................................................................................1 2 6  
9. 4. 4.  
Patie nt C haracteristics  ...................................................................................................1 2 7  
9. 4. 5.  
Safet y A nal yses  .............................................................................................................1 2 7  
9. 4. 6.  
Efficac y A nal yses  .........................................................................................................1 2 7  
9. 4. 7.  
P har mac o ki netic/ P har mac o d y n a mic A nal yses  .............................................................1 3 2  
9. 4. 8.  
S u b gr o u p A n al ys es  .......................................................................................................1 3 2  
9. 4. 9.  
Pr o d uct Acce pta bilit y a n d Palata bilit y ..........................................................................1 3 2  
9. 4. 1 0.  Bi o mar ker A nal yses  ......................................................................................................1 3 2  
9. 5.  
I nteri m A nal yses ...........................................................................................................1 3 2  
1 0.  
S u p p orti n g D oc u me nt ati o n a n d O per ati o n al C o nsi der ati o ns  ................................1 3 4  
1 0. 1.  
A p pe n di x 1:  Re g ulat or y, Et hical, a n d St u d y O versi g ht 
C o nsi derati o ns  ..............................................................................................................1 3 4  
1 0. 1. 1.  Re g ulat or y a n d Et hical C o nsi derati o ns  .........................................................................1 3 4  
1 0. 1. 2.  I nf or me d C o nse nt Pr ocess ............................................................................................1 3 5  
1 0. 1. 3.  Data Pr otecti o n ..............................................................................................................1 3 5  
1 0. 1. 4.  C o m mittee Str uct ure  .....................................................................................................1 3 6  
1 0. 1. 5.  Disse mi nati o n of Cli nical St u d y Data ...........................................................................1 3 6  
1 0. 1. 6.  Data Q ualit y Ass ura nce  ................................................................................................1 3 6  
1 0. 1. 7.  S o urce D oc u m e nts  ........................................................................................................1 3 8  
1 0. 1. 8.  St u d y a n d Site Cl os ure  ..................................................................................................1 3 8  
1 0. 1. 9.  P u blicati o n P olic y  .........................................................................................................1 3 8  
1 0. 2.  
A p pe n di x 2:  Cli nical La b orat or y Tests  ........................................................................1 3 9  
1 0. 3.  
A p pe n di x 3:  C o ntrace pti ve G ui da nce a n d C ollecti o n of 
Pre g n a nc y I nf or mati o n  .................................................................................................1 4 2  
1 0. 4.  
A p pe n di x 4:  Li ver Safet y:  S u g geste d Acti o ns a n d F oll o w -u p 
Assess me nts  ..................................................................................................................1 4 5  
1 0. 5.  
A p pe n di x 5:  Creati ni ne Cleara nce F or m ula  ................................................................1 4 7  
1 0. 6.  
A p pe n di x 6:  I n d ucers a n d Str o n g I n hi bit ors of C Y P 3 A 4  ............................................1 4 8  
1 0. 7.  
A p pe n di x 7: Pr o visi o ns f or C ha n ges i n St u d y C o n d uct D uri n g 
E x ce pti o nal Circ u msta nces  ...........................................................................................1 5 0  
1 0 . 7. 1. I nf or me d C o nse nt..........................................................................................................1 5 0  
1 0. 7. 2.  C ha n ges i n St u d y C o n d uct  ............................................................................................1 5 1  
1 0. 7. 3.  D oc u me ntati o n  ..............................................................................................................1 5 3  
1 0. 8.  
A p pe n di x 8: A be macicli b D osi n g C harts  .....................................................................1 5 4  
1 0. 9.  
A p pe n di x 9: C o u ntr y -S p ecific Re q uir e me nts  ...............................................................1 5 7  
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
I 3 Y-M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 5  
1 0. 9. 1.  A d de n d u m 2. 3 ( C o u ntr y -S pecific C o nte nt f or t he E ur o pea n 
U ni o n)  ...........................................................................................................................1 5 7  
1 0. 1 0.  
A p pe n di x 1 0:  A b bre viati o ns a n d Defi niti o ns  ..............................................................1 6 1  
1 0. 1 1.  
A p pe n di x 1 1:  Pr ot oc ol A me n d me nt Hist or y  ...............................................................1 6 6  
1 1.  
Refere nces  ....................................................................................................................1 8 3  
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
I 3 Y-M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 6  
1.  
Pr ot oc ol S u m m ar y   
1. 1.  
S y n o psis   
Pr ot oc ol Title :  A P has e 1 b / 2 St u d y of A be macicli b i n C o m bi nati o n wit h Iri n oteca n a n d 
Te m oz ol o mi de ( Part A) a n d A be ma cicli b i n C o m bi nati o n wit h Te m oz ol o mi de ( Part B) i n 
Pe diatri c a n d Y o u n g A d ult Patie nts wit h Rela pse d/ Refract or y S oli d T u m ors  a n d A be ma cicli b i n 
C o m bi nati o n wit h Di n ut u xi ma b, G M -C S F, Iri n ot eca n, a n d Te m oz ol o mi de  i n Pe diatric a n d 
Y o u n g A d ult  Patie nts wit h Rela pse d/ Refract or y Ne ur o blast o ma ( Part C ).  
S h ort Title :  A P hase 1 b / 2 St u d y of A be macicli b Pl us C he m ot hera p y a n d / or 
C he m oi m m u n ot hera p y i n Pe diatric a n d Y o u n g A d ult Patie nts wit h Rela pse d/ Refract or y S oli d 
T u m ors  
Re g ul at or y A ge nc y I de ntifier N u m ber(s):   
I N D:  1 3 8 0 2 4  
E u dra C T:   2 0 1 9 -0 0 2 9 3 1 -2 7  
E U trial n u m ber:   2 0 2 3 -5 0 6 7 7 8 -1 1 -0 0  
R ati o n ale:   Des pite a d v a nces i n t he treat me nt of p e diatric ca ncers, t here is still a n u n met nee d 
f or efficaci o us a n d t olera ble re gi me ns f or rela ps e d/refract or y s oli d t u m ors. St u d y I 3 Y -M C -J P C S 
(J P C S) is desi g ne d t o ass ess t he p har mac o ki net ics (P K), safet y, a n d t olera bilit y of a be macicli b 
a d de d t o c urre ntl y utilize d c he m ot hera p y a n d c h e m oi m m u n ot hera p y bac k b o ne re gi me ns f or 
pe diatric s oli d t u m ors. J P C S c o nsists of 3  parts : A, B, a n d C . All parts are i nte n de d t o deter mi ne 
t he rec o m me n d e d P hase 2 d ose ( R P 2 D) f or t heir res pecti ve a b e maci cli b c o m bi nati o ns , a n d t he 
sec o n d sta ge of Part C is i nte n de d t o e val uate o bjecti ve res p o nse rate ( O R R)  of  t he a b e macicli b 
c o m bi nati o n wit h R P 2 D deter mi ne d  i n t he first sta ge. 
Parts A a n d B will e nr oll pe diatric a n d y o u n g a d ult patie nts wit h rela ps e d/r efract or y s oli d t u m ors. 
Part C will e x cl usi vel y e nr oll pe diatric a n d y ou n g a d ult  patie nts  wit h rela pse d/refract or y 
ne ur o blast o ma. Part A will c o m bi ne a be macicli b wit h iri n oteca n a n d te m o z ol o mi de a n d will 
i nfl ue nce t he d os es i n Parts B a n d C.  Part B will c o m bi ne a be macicli b a n d te m oz ol o mi de.  Part 
C will c o m bi ne a be macicli b wit h di n ut u xi ma b , G M -C S F,  iri n oteca n, a n d t e m oz ol o mi de. 
 
 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
I 3 Y-M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 7  
O bjecti ves  a n d E n d p oi nt s 
O bjecti ves  
E n d p oi nts  
Pri mar y  
 
T o deter mi ne t he o pti mal R P 2 D f or a be macicli b i n 
patie nts wit h rela pse d/refract or y s oli d t u m ors:  
 Part A:  i n c o m bi nati o n wit h iri n oteca n a n d 
te m oz ol o mi de  
 Part B:  i n c o m bi nati o n wit h te m oz ol o mi de  
 
D L Ts  
 
M T D  
 
P K  (c o nce ntrati o ns of a be macicli b, iri n oteca n, 
a n d te m oz ol o mi de ) 
 
Part C: T o deter mi ne  t he o pti mal R P 2 D , a n d a nti -
t u m or acti vit y of a be macicli b i n c o m bi nati o n wit h 
di n ut u xi ma b, G M -C S F, iri n oteca n, a n d 
te m oz ol o mi de i n patie nts wit h rela psed/refract or y 
ne ur o blast o ma per I N R C  
 
D L Ts  
 
P K (c o nce ntrati o ns of a be macicli b, iri n oteca n, 
a n d te m oz ol o mi de) a 
 
O R R deter mi ne d b y i n vesti gat or  assess me nt  
Sec o n dar y  
 
T o c haracterize t he safet y pr ofile of t he 
c o m bi nati o n t hera pies 
 
Safet y (i ncl u di n g but n ot li mite d t o) :  T E A Es, 
S A Es, deat hs  
 
C li nical la b orat or y a b n or malities per C T C A E 
( versi o n 5. 0), vital si g ns, a n d p h ysical 
e xa mi nati o ns 
 
D ose m o dificati o ns  of all st u d y dr u gs  
T o d oc u me nt t he preli mi nar y a nti -t u m or acti vit y 
of t he c o m bi nati o n t hera p y per R E CI S T v 1. 1 or 
R A N O (f or C N S t u m ors) f or Parts A a n d B, a n d 
per I N R C f or part C.  
 
D o R  
 
C B R  
 
D C R  
 
O R R ( Parts A & B o nl y)  
 
P F S deter mi ne d b y i n vesti gat or assess me nt 
( Part C o nl y) 
T o assess t he acce pta bilit y a n d palata bilit y of t he 
ta blet a n d/ or gra n ule a be macicli b , i ncl u di n g 
dis perse d ta blets a n d/ or gra n ules  
Assess me nt of ta blet, gra n ule, or dis perse d 
a be macicli b  prese ntati o n, i ncl u di n g acce pta bilit y 
a n d palata bilit y 
A b bre viati o ns :  C B R = cli nical b e nefit rate; C T C A E = C o m m o n T er mi n ol o g y Criteria f or A d verse E ve nts; D C R = 
disease c o ntr ol rate; D o R = d urati o n of res p o nse; D L T = d ose -li miti n g t o xicit y; I N R C =  I nter nati o nal 
Ne ur o blast o ma Res p o nse Criteria ; M T D = ma xi m u m t olerate d d ose; O R R = o verall res p o nse rate; P F S  = 
pr o gressi o n -free s ur vi val; P K = p har mac o ki netics; R A N O = Res p o nse Assess me nt i n Ne ur o -O nc ol o g y; R E CI S T 
= Res p o nse E val uati o n Criteri a i n S oli d T u m ors; R P 2 D = rec o m me n de d P hase 2 d ose; S A E = s eri o us a d verse 
e ve nt; T E A E = treat me nt -e mer ge nt a d verse e ve nt.  
a 
In P art C, P K is  a pri mar y e n d p oi nt f or Sta ge 1 o nl y.  
O ver all Desi g n : 
St u d y J P C S is a m ultice nter, n o n -ra n d o mize d, o pe n-la bel, P hase 1b / 2 st u d y t hat will be 
c o m prise d of 3  parts t o e val uate:   
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
I 3 Y-M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 8  
 P art A :  a be ma cicli b  i n c o m bi nati o n wit h iri n oteca n a n d te m oz ol o mi de  
 P art B :  a b e macicli b i n c o m bi nati o n wit h te m oz ol o mi de  
 P art C:   a be ma cicli b i n c o m bi nati o n wit h di n ut u xi ma b , G M -C S F, iri n oteca n, a n d 
te m oz ol o mi de 
i n patie nts wit h rela pse d/refract or y s oli d t u m ors ( Part C: rela pse d/refract or y ne ur o blast o ma o nl y) 
t hat ha ve pr o gresse d o n  sta n dar d treat me nts a n d f or w h o m t he st u d y dr u g c o m bi nati o ns are 
dee me d a p pr o priate . 
Discl os ure St ate me nt : 
T his is a n o pe n -la bel, si n gle-ar m d ose fi n di n g st u d y wit h n o mas ki n g.  
St u d y P o p ul ati o n:  
I n ge neral, a n i n di vi d ual ma y ta k e part i n t his st u d y if t he y  meet t he f oll o wi n g criteria: 
A ge a n d Wei g ht  
 P arts A a n d B o nl y:   
a. Patie nts m ust be ≤1 8 years of a ge at t he ti me of st u d y e nr oll me nt , a n d  
b.  B o d y wei g ht ≥1 0 k g a n d B S A ≥0. 5 m 2.  
 
 P art C o nl y:   
a. Pati e nts m ust be < 2 1  years of a ge at t he ti me of st u d y e nr oll me nt.  
b.  F or patie nts wit h a starti n g a b e maci cli b d ose of 3 0 m g/ m 2 BI D, B S A m ust b e 
≥0. 3  m 2. 
T y pe of  P artici p a nt a n d Dise ase C h ar acteristi cs  
 P arts A a n d B o nl y:  patie nts wit h a n y rela pse d/refract or y m ali g n a nt s oli d t u m ors 
(e x cl u di n g l y m p h o ma), i ncl u di n g C N S t u m ors, t hat ha ve pr o gresse d o n sta n dar d 
t hera pies.  F or sites t hat are acti vel y e nr olli n g Parts B a n d C, patie nts wit h 
ne ur o blast o ma w h o are eli gi ble f or Part C will be e x cl u de d fr o m Part B u nl ess a p pr o ve d 
b y Lill y C R P/ C R S.  
 P art C o nl y:  patie nts wit h first rela pse/r efract or y ne ur o blast o ma.  Refract or y is defi ne d 
as eit her less t ha n p artial res p o nse ( P R ) b y I N R C at t he c o ncl usi o n of at least 4 c ycl es of 
sta n dar d fr o nt-li ne i n d ucti o n c he m ot hera p y or pr o gressi ve diseas e ( P D) d uri n g fr o nt-li ne 
t hera p y.  First rela pse is defi ne d as disease rec urre nce f oll o wi n g c o m pleti o n of 
a g gressi ve m ulti -dr u g c h e m ot hera p y,  s ur ger y, a ut ol o g o us ste m cell tra ns pl a nt a n d 
ra diati o n, wit h or wit h o ut  reti n oi ds.    
N O T E:  F or Part C, fr o nt -li ne c he m ot hera p y m ust ha ve c o m prise d 2 or m ore a ge nts, 
i ncl u di n g a n al k yl ati n g a ge nt a n d a plati n u m-c o nt ai ni n g c o m p o u n d.  
 
 F or P arts A, B, a n d C:   Patie nts m ust ha ve at least o ne meas ura ble or e v al ua ble lesi o n 
as defi ne d b y R E CI S T v 1. 1  or R A N O f or C N S t u m ors .   
 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
I 3 Y-M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 9  
i. 
Meas ura ble is d efi ne d as a n o nl y m p h oi d s oft tiss ue mass ≥1 c m 
(l o n gest di me nsi o n) or l y m p h n o de ≥1. 5 c m (s h ort a xis)  o n a 
M RI or C T sca n   
ii. 
E val ua ble diseas e is defi ne d as  the prese n ce of at least o ne 
lesi o n, wit h n o lesi o n t hat ca n be acc uratel y meas ure d i n at least 
o ne di me nsi o n. S uc h lesi o ns ma y b e e val ua bl e b y n uclear 
me dici ne tec h ni q ues, i m m u n oc yt oc he mistr y t ec h ni q ues, t u m or 
mar kers or ot h er relia ble meas ures.  
iii. 
F or C N S t u m ors: Is olat e d le pt o me ni n geal disease i n 
rela pse d/r efract or y C N S t u m ors t hat is e val ua ble ma y b e eli gi ble 
f or i ncl usi o n after c o ns ultati o n wit h t he Lill y C R P/ C R S. 
F or  Part C:   A  t u m or (eit her meas ura ble  or e val ua ble) t hat is eit her   
 MI B G -a vi d or t hat de m o nstrates i ncrease d F D G u pta ke o n P E T 
sca n (f or MI B G-n o na vi d t u m or), or   
 via ble ne ur o blast o ma c o nfir me d b y bi o ps y  (s u b missi o n of 
pat h ol o g y re p ort is re q uir e d)  
Patie nts wit h i n v ol ve me nt of b o ne marr o w o nl y, wit h o ut a meas ura ble 
or e val ua ble l esi o n, are n ot eli gi ble.  
A N D  
Patie nts m ust ha ve ha d hist ol o gic verifi cati o n of m ali g na n c y at ori gi nal dia g n osis 
or rela pse, e x ce pt:  
a. patie nts wit h C N S ger m cell t u m ors or e xtra-cra ni al ger m -cell t u m ors a n d 
w h o ha ve el e vati o ns of s er u m t u m or mar kers i ncl u di n g al p ha -fet o pr ot ei n 
or beta -H C G , a n d 
b.  patie nts wit h i ntri nsic brai n ste m t u m ors  
 
I n t he j u d g me nt of t he i n vesti gat or, t h e patie nt is a n a p pr o pri ate ca n di date f or t he 
e x peri me ntal t hera p y c o m bi nati o n i n t he st u d y p art t hat is c urre ntl y e nr olli n g.   
 
Ne ur ol o gic deficits i n patie nts wit h C N S t u m ors m ust ha ve bee n sta bl e f or at 
least 7 da ys pri or t o st u d y e nr oll me nt. 
 
A La ns k y sc ore ≥5 0 f or patie nts < 1 6 years of a ge or a Kar n ofs k y sc ore ≥5 0 f or 
patie nts ≥1 6 years of a ge  
 Patie nts w h o are u na bl e t o wal k beca use of paral ysis, b ut are u p i n a 
w heelc h air, will be c o nsi dere d a m b ulat or y f or t he p u r p ose of ass essi n g t he 
perf or ma n ce s c ore.  
 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
I 3 Y-M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
2 0  
N u m ber of P artici p a nt s: 
A p pr o xi matel y 3 0  t o 1 1 7  patie nts  will be e nr olle d i n t his st u d y.   T o e ns ure c o m pre he nsi ve P K 
sa m pli n g i n a pe diatric p o p ulati o n, Parts A a n d B  are desi g n e d t o e val uat e at least 
 
 years of a ge a n d at least 
 years of a ge. A d diti o nall y, i n Part C, 
 
 s h o ul d be i n t he a ge gr o u p of  
 years of a ge, wit h a
 
years of a ge a n d at least
 years of a ge . 
I nter ve nti o n Gr o u ps  a n d D ur ati o n : 
I n Parts A a n d B, patie nts will be  se q ue ntiall y assi g ne d t o o n e d ose le vel of a be maci cli b , 
be gi n ni n g wit h t he a b e m acicli b starti n g d ose of P art A .  N o patie nts will b e assi g n e d t o t he ne xt 
hi g her a be ma cicli b d ose le vel bef ore t he pre vi o us d ose le vel has bee n cleare d.  O nce t h e 
ma xi m u m t olerate d d ose ( M T D ) i n Part A has b ee n deter mi ne d, Part s B  a n d C  will o pe n .  Part B 
will  start at o ne d ose le vel a b o ve t he M T D of a be macicli b deter mi ne d i n P art A.  Part C will use  
t he Part A M T D  a n d will n ot escalate  d osi n g  f or a n y st u d y dr u g. 
A c ycle is defi ne d as 2 1 da ys.  Patie nts will be treate d f or at least 1 c ycl e .  T he d urati o n of 
foll o w -u p will be  at least 3 0 da ys.  Patie nts will c o nti n ue st u d y treat me nt u nti l pr o gressi ve 
disease, u nacce pt a ble t o xicit y, or i n vesti gat or/ pati e nt decisi o n.   C o nti n uati o n o n c he m ot hera p y 
be y o n d C ycl e 1 2 will be u p t o t he i n vesti gat or’s discreti o n a n d t he i n di vi d u al patie nt’s sit uati o n.   
Pri or t o c o nti n ui n g t he patie nt o n c he m ot hera p y b e y o n d C ycle 1 2, t he i n v esti gat or s h o ul d disc uss 
wit h t he Lill y cli nical res earc h p h ysi cia n /cli nical r esearc h scie ntist .   
P art A:  Tri plet C o m bi n ati o n D osi n g  
D ose -Le v el 
C o h ort  
 
A be m acicli b  
Iri n otec a n 
Te m oz ol o mi de  
P atie nts  
D osi n g  
D osi n g  
D osi n g  
A -1  
3 -6  
5 5 m g/ m 2 BI D, P O  
5 0 m g/ m 2/ da y I V  
o n Da ys 1 -5 of a 
2 1 -da y c ycle  
1 0 0 m g/ m 2/ da y P O  
o n D a ys 1 -5 of a  
2 1 -da y c ycle  
A 1  
(st arti n g d ose) 
3 -6  
7 0 m g/ m 2 BI D, P O  
A 2  
3 -6  
9 0 m g/ m 2 BI D, P O  
A 3  
3 -6  
1 1 5 m g/ m 2 BI D, P O  
P art A D ose 
E x pa nsi o n  
6 -1 2 a 
M T D
A  
 
 
A b bre viati o ns:  BI D = t wice dail y; D L T = d ose -li miti n g t o xi cit y; I V = i ntra ve n o us; M T D
A  = P art A ma xi m u m 
t olerate d d ose; P O = orall y . 
a  E x pa nsi o n c o h orts will e nr oll 6 patie nts i nitiall y.  A d diti o nal patie nts  ca n be e nr olle d if nec essar y t o c o nfir m 
safet y.  E xa m ples ma y i ncl u de testi n g a l o wer d ose i n 6 a d diti o nal patie nts if D L Ts are e x perie nce d b y at least 2 
of 6 patie nts i n t he i nitial e x pa nsi o n c o h ort or t o f urt her c o nfir m t olera bilit y of pr ol o n ge d treat me nt.  
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T
C CI
C CI
C CI
C CI
C CI
C CI

C O N FI D E N TI A L  
I 3 Y-M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
2 1  
 
P art B:  D o u blet C o m bi n ati o n D osi n g  
D ose -Le v el 
C o h ort  
 
A be m acicli b  
Te m oz ol o mi de  
P atie nts  
D osi n g  
D osi n g  
B -1  
( or bel o w)a 
3 -6  
D ose will be  de -escalate d 
acc or di n g t o t he d ose 
le vels o utli ne d i n P art A, 
BI D, P O  
1 0 0 m g/ m 2/ da y P O  
o n Da ys 1 -5 of a 2 1 -da y  c ycle  
B 1  
 (st arti n g d ose) b  
3 -6  
O ne d ose le vel a b o ve 
M T D
A , BI D, P O 
B 2 - B 4 a 
3 -6  
D ose will be escalate d 
acc or di n g t o t he d ose 
le vels o utli ne d i n P art A 
B 5 c 
3 -6  
1 1 5 m g/ m 2 BI D, P O  
1 5 0 m g/ m 2/ da y P O  
o n Da ys 1 -5 of a 2 1 -da y c ycle  
P art B D ose 
E x pa nsi o n  
6 -1 2 d  
M T D
B  
te m oz ol o mi de R P 2 D 
( 1 0 0 m g/ m2 or 1 5 0 m g/ m 2) 
A b bre viati o ns :  BI D = t wice dail y; D L T = d ose -li miti n g t o xi cit y; M T D = ma xi m u m t olerate d d ose; M T D
A  =  P art A  
ma xi m u m t olerate d d ose ; M T D
B  =  P art B  ma xi m u m t olerate d d ose; P O  =  orall y; R P 2 D = rec o m me n de d P hase 2 
d ose . 
a  D ose will be escalate d ( C o h orts B 1, B 2, B 3, B 4, B 5) or de -escalate d ( C o h orts B -1, B -2, B -3, B -4) f oll o wi n g d ose 
le vels as o utli ne d i n P art A as nee de d.  It is p ossi ble t hat n ot all d ose le vels will be e nr olle d.  
b  O ne  d ose le vel hi g her t ha n t he M T D of a b e macicli b i n P art A ( or 1 1 5 m g/ m 2 if t his was t he M T D
A ) will ser ve as 
t he starti n g d ose of a b e macicli b i n P art B. 
c  C o h ort B 5 will o nl y ta ke place if t he f oll o wi n g occ ur:  
 
1) T he M T D of a b e macicli b is n ot  reac he d w he n dose d at 1 1 5 m g/ m 2 BI D i n c o m bi nati o n wit h 1 0 0 m g/ m 2/ da y 
te m oz ol o mi de i n P art B; O R  
 
2) If a b e macicli b 1 1 5 m g/ m2 BI D is t he M T D  f or P art A.  I n t his case, P art B will directl y start wit h C o h ort B 5 
usi n g a b e macicli b 1 1 5 m g/ m 2 BI D a n d te m oz ol o mi de 1 5 0 m g/ m 2/ da y.   
d  E x pa nsi o n c o h orts will e nr oll 6 patie nts i nitiall y.  A d diti o nal patie nts ca n be e nr olle d if nec essar y t o c o nfir m 
safet y.  E xa m ples ma y i ncl u de testi n g a l o wer d ose i n 6 a d diti o nal patie nts if D L Ts are e x perie nce d b y at least 2 
of 6 patie nts i n t he i nitial e x pa nsi o n c o h ort or t o f urt her c o nfir m t olera bilit y of pr ol o n ge d treat me nt. 
 
 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
I 3 Y-M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
2 2  
P art  C:  C o m bi n ati o n D osi n g  
E ac h C ycle  
P art C  
A be m acicli b P O BI D  
5 5  m g/ m 2 ( Da ys 1 t o 2 1) a , b 
Di n ut u xi m a b  I V D ail y ×  4  d a ys  
1 7. 5 m g/ m 2/ da y ×  4 da ys  ( Da ys 2  t o 5)  
G M -C S F  S u b Q D ail y ×  7 d a ys  
2 5 0 µ g / m2 ×  7 da ys  (Da ys 6  t o 1 2)  
Iri n otec a n I V D ail y ×  5  d a ys  
5 0 m g/ m 2/ da y ×  5 da ys  ( Da ys 1 t o 5)  
Te m oz ol o mi de P O D ail y ×  5  d a ys  
1 0 0 m g/ m 2/ da y ×  5 da ys  ( Da ys 1 t o 5)  
A b bre viati o ns:  BI D = t wice dail y; G M -C S F = gra n ul oc yte macr o p ha ge c ol o n y -sti m ulati n g fact or; I V = i ntra ve n o us; 
P O  =  orall y; S u b Q = s u b c uta ne o us . 
a 
3 0 m g/ m 2 ma y be e val uate d d ue t o e xcessi ve t o xicities , if ne cessar y, as descri be d i n Secti o n 4. 1. 2  
b 
A n i nter me diate d ose le vel (ie: bet wee n 5 5  m g/ m 2 a n d 3 0  m g/ m 2) ma y be e x pl ore d base d o n e mer gi n g data 
 
Et hic al c o nsi der ati o ns of be nefit/ris k:  
Gi ve n t he o bser ve d safet y pr ofile of a b e macicli b i n a d ults a n d t he k n o w n ris k pr ofiles of 
di n ut u xi ma b, G M -C S F, iri n oteca n, a n d t e m oz ol o mi de, t he ris k f or t he c o m bi nati o ns i n t he 
pr o p ose d st u d y are  e x pecte d t o be ma na gea ble . A d diti o nall y, c o nsi deri n g t h e meas ures ta ke n t o 
e ns ure partici pa nt safet y, t he p ote ntial ris ks are j ustifie d b y t he p ote ntial be nefits f or i n di vi d uals 
wit h  rela pse d mali g na n cies. 
D at a M o nit ori n g C o m mittee:    
 Parts A a n d B: N o  
 Part C: Yes  
 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
L Y 2 8 3 5 2 1 9  
2 3 
1. 2.  
Sc he m a  
 
 
 
 
 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
L Y 2 8 3 5 2 1 9  
2 4 
 
 
A b bre viati o ns:  BI D = t wice dail y; D L T = d ose -li miti n g t o xi cit y; G M -C S F = gra n ul oc yte macr o p ha ge c ol o n y -sti m ulati n g fact or; I V = i ntra ve n o us; M T D = 
ma xi m u m t olerate d d ose; M T D
A  = P art A ma xi m u m t olerat e d d ose; M T D
B  = P art B ma xi m u m t olerate d d ose ; n = n u m b er of partici pa nts; P O = orall y . 
a  Iri n oteca n a d mi nistere d via I V 5 0 m g/ m2/ da y, D a ys 1 -5 of C ycle.  See Secti o n  6. 1 . 
b  Te m oz ol o mi de a d mi nistere d P O 1 0 0 m g/ m 2/ da y, D a ys 1 -5 of C ycle.  See Secti o n 6. 1 . 
c 
O ne d ose le vel hi g her t ha n t he M T D of a b e macicli b i n P art A ( or 1 1 5 m g/ m 2 if t his was t he M T DA ) will ser ve as t he starti n g d ose of a b e macicli b i n P art B. 
d  D ose will be escalate d (C o h orts B 1, B 2, B 3, B 4, B 5) or de -escalate d ( C o h orts B- 1, B -2, B -3, B -4) f oll o wi n g d ose le vels as o utli ne d i n P art A as nee de d .  It is 
p ossi ble t hat n ot all d ose le vels will be e nr olle d. 
e C o h ort B 5 will o nl y ta ke place if  t he f oll o wi n g occ ur: 
 
the M T D of a b e macicli b is n ot  reac he d w he n d ose d at 1 1 5 m g/ m2 BI D i n c o m bi nati o n wit h 1 0 0 m g/ m 2/ da y te m oz ol o mi de i n P art B ; O R  
 
if a b e macicli b 1 1 5 m g/ m2 BI D is t he M T D f or P art A.  I n t his case, P art B will start directl y wit h C o h ort B 5 usi n g a b e macicli b 1 1 5  m g/ m 2 BI D a n d 
te m oz ol o mi de 1 5 0 m g/ m2/ da y. 
f E x pa nsi o n c o h orts will e nr oll 6 patie nts i nitiall y .  A d diti o nal patie nts ca n be e nr olle d if nec essar y t o c o nfir m safet y.  E xa m ples ma y i ncl u de testi n g a l o wer 
d ose i n 6 a d diti o nal patie nts if D L Ts are e x perie nce d b y at l east 2 of 6 patie nts i n t he i niti al e x pa nsi o n c o h ort  or  t o f urt her c o nfir m t olera bilit y of pr ol o n ge d 
treat me nt. 
g 
A be macicli b a d mi nistere d  at 5 5  m g/ m 2 BI D × 2 1 da ys , a n d if nee de d, 3 0 m g/ m 2 BI D  × 2 1 da ys  t o deter mi ne t he M T D f or P art C. S p o ns or ma y elect t o 
e x pl ore a n i nter me diate d ose le vel (ie: bet wee n D L 1 a n d D L-1) base d o n e mer gi n g data.  S ee Secti o n 6. 1 . 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
2 5  
h Di n ut u xi ma b  a d mi nistere d via I V 1 7. 5 m g/ m 2 ×  4 da ys , Da ys 2-5 of C ycle . See Secti o n  6. 1 . 
i 
G M -C S F a d mi nistere d s u bc ut a ne o usl y 2 5 0 µ g/ m 2 ×  7 da ys , Da ys 6-1 2 of C ycle.  See Secti o n  6. 1 . 
 
 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
2 6  
1. 3.  
Sc he d ule of Acti vities  (S o A )  
I n t his se cti o n, the st u d y acti vities f or Parts A a n d B  are pres e nt e d t o get her f or eac h st u d y peri o d ( Secti o n 1. 3. 1 ), w hile the acti vities  
f or Part C are pres e nte d s e parat el y (see Secti o n 1. 3. 2 ). 
1. 3. 1.  
Sc he d ule of Ac ti vities f or P arts A a n d B   
Sc he d ule of Scree ni n g Acti vities  f or P arts A a n d B  
S cree ni n g i nteracti o ns a n d assess me nts  m ust be perf or me d at t he cli nical tri al site , wit h t he e x ce pti o n of  la borat or y assess me nts 
( he mat ol o g y, cli nical c h e mistr y, c ystati n c, a n d pre g n a nc y test), w hic h ma y  be c ollecte d at  a l ocal cli nic i n acc or da nce wit h l ocal la ws 
a n d re g ulati o ns a n d w h e n dee me d a p pr o priate b y t he i n vesti gat or.   A n y scree ni n g pr oce d ures t hat fall o utsi de of t he re q uire d wi n d o ws 
per t he Sc he d ule of Scree ni n g Acti vities m ust be re peate d  s o t hat t he y fall wit hi n t he re q uire d wi n d o w. 
P arts A a n d B  
Rel ati ve D a y Pri or t o C ycle 1 D a y 1  
2 8  
1 4  
7  
I nstr ucti o ns 
Pr o ce d ure  
 
 
I nf or me d c o nse nt/asse nt  
X  
M ust be si g ne d pri or t o c o n d ucti n g a n y pr ot oc ol -s pecific tests/ pr oce d ures.   
I ncl usi o n/ E xcl usi o n e val uati o n 
 
X  
 
De m o gra p hics  
 
X  
I ncl u de race, ge n der, et h nicit y, a n d birt h date per l ocal re g ul ati o ns . 
Pri or a n d c urre nt me dicati o n  
 
X  
I ncl u de pri or ca ncer treat me nts. 
Me dical a n d o nc ol o g y hist or y  
 
X  
I ncl u di n g assess me nt of pree xisti n g c o n diti o ns, hist orical ill nesses, k n o w n 
s o matic alterati o ns, a n d ha bits . 
P h ysical e xa mi nati o n  
 
X  
I ncl u des hei g ht, wei g ht , a n d B S A. 
 
 
 
 
 
 
Vital si g ns  
 
X  
I ncl u des bl o o d press ure, p ulse rate, o x y ge n sat urati o n, a n d te m perat ure. 
La ns k y/ Kar n ofs k y perf or ma n ce stat us  
 
X  
 La ns k y f or a ge < 1 6 years  
 Kar n ofs k y f or a ge ≥1 6 years  
o  
F or patie nts w h o t ur n 1 6 years ol d w hile o n st u d y, Kar n ofs k y s h o ul d be 
use d after t he 1 6 t h birt h da y   
 
He mat ol o g y  
 
X  
See Secti o n 1 0. 2 , A p pe n di x 2.  
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T
C CI
C CI
C CI
C CI C CI

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
2 7  
P arts A a n d B  
Rel ati ve D a y Pri or t o C ycle 1 D a y 1  
2 8  
1 4  
7  
I nstr ucti o ns 
Pr o ce d ure  
 
 
Cli nical c he mistr y  
 
X  
I ncl u de li ver f u ncti o n tests.  S ee Secti o n 1 0. 2 , A p pe n di x 2.  
C ystati n C  
 
X  
See Secti o n 1 0. 2 , A p pe n di x 2.  
Ser u m or uri ne pre g na nc y test  
 
X  
A p plies t o w o me n of c hil d beari n g p ote ntial o nl y.  See Secti o n 1 0. 2 , A p pe n di x 2.  
E C G  
X  
L ocal E C G . 
A nat o mic ra di ol o gic i ma gi n g acc or di n g t o 
R E CI S T v 1. 1  or R A N O  
X  
Baseli ne disease assess me nt per R E CI S T v 1. 1  f or n o n-C N S t u m ors; R A N O 
criteria s h o ul d be use d f or C N S t u m ors .  If perf or me d as part of r o uti ne cli nical 
care, a  7 -da y wi n d o w be y o n d 2 8 da ys is acce pta ble wit h o ut bei n g c o nsi dere d as 
a pr ot oc ol  de viati o n or scree n fail.  
F or patie nts wit h n o n -C N S t u m ors, perf or m C T sca ns of t he c hest, a b d o me n, 
pel vis , a n d t he site of t he k n o w n lesi o n if l ocate d else w here.  F or C N S t u m ors, 
perf or m M RI of t he pri mar y l esi o n i ncl u di n g t he e ntire  brai n  or s pi ne as 
a p plica ble .  F or brai n lesi o n s, als o i ncl u de M RI of t he s pi ne if pre vi o us dr o p 
metastases were prese nt.   I ma gi n g facilit y, ima ge ac q uisiti o n pr ot oc ol , a n d 
i ma gi n g m o dalit y  s h o ul d be c o nsiste nt f or all visits f or a gi ve n patie nt. 
See Secti o n 8. 1 . 
L u m bar p u nct ure  
X  
P erf or m if cli nicall y i n dicate d a n d feasi ble t o assess C S F c yt ol o g y a n d t u m or 
mar kers  (al p ha -fet o pr otei n a n d beta-H C G).  
A d verse e ve nts c ollecti o n/ C T C A E gra di n g  
X  
C T C A E Versi o n 5. 0 . 
C o nc o mita nt me dicati o n n otati o n  
X  
 
A b bre viati o ns :  B S A = b o d y s urface area; C 1 D 1 = C ycle 1 D a y 1; C S F = cere br os pi nal fl ui d; C T C A E = C o m m o n T er mi n ol o g y Criteria f or A d verse E ve nts; 
C N S = ce ntral ner v o us s yste m; E C G = electr ocar di o gra m; 
 R A N O = Res p o nse Assess me nt i n 
Ne ur o -O nc ol o g y;  R E CI S T = Res p o nse E val uati o n Criteria i n S oli d T u m ors.  
 
 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T
C CI

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
2 8  
Sc he d ule of O n -St u d y Tre at me nt Acti vities  fo r P a rts A a n d B  
If t here is a c o ncer n d uri n g a re m ote visit  t hat s u g gests o n-site visit is necessar y, t he partici p a nt s h o ul d ha ve a n o n-site f oll o w-u p visit 
as s o o n as p ossi ble , at t he i n vesti gat or’s discreti o n. F or a p plica ble patie nts, l u m bar p u nct ure s m ust occ ur at t he i n v esti gati ve site. F or 
all patie nts at a n y ti me i n t he st u d y, l a b orat or y a n d pre g na nc y t ests ma y b e c ollecte d at a l o cal cli nic i n acc or da nce wit h l ocal la ws a n d 
re g ulati o ns if dee me d a p pr o priate b y t he i n vesti gat or . All  res ults s h o ul d be re vie we d a n d rec or de d i n t he e C R F (pre g na nc y res ults are 
n ot re q uire d t o be rec or de d i n t he e C R F). A v irt u al visit wit h t he st u d y i n vesti gat or is  n ot re q uir e d f or a l ocal la b dra w or pre g na nc y 
test. 
P art A  
All visits  i n C ycles 1 a n d 2, a n d  Da y s 1 – 5  of all c ycl es  t hereafter s h o ul d occ ur at t he i n v esti gati ve site.  I n e x ce pti o nal circ u msta nces, 
pr oce d ures o n  Da ys 8 a n d 1 5 of C ycl es 1 a n d 2 m a y b e c o n d u cte d re m otel y (see Secti o n 1 0. 7 , A p pe n di x 7) .  Re m ote visits s h o ul d 
i ncl u de a virt ual visit  wit h t he st u d y i n vesti gat or  (i ncl u di n g vi de o) a n d c o ul d als o i ncl u de m o bile healt hcare i n acc or da nce wit h l ocal 
re g ulati o ns if writte n a p pr o val is pr o vi de d b y t he s p o ns or a n d acc or di n g t o t he prefere n ces of t h e partici pa nt a n d st u d y site: 
O n Da ys 8 a n d 1 5  of C ycle 3 a n d be y o n d , t he f oll o wi ng pr oce d ures ma y be c o n d ucte d re m otel y  b y a c o m bi nati o n of virt ual visit a n d 
m o bile healt hcare : 
 P h ysical e x a m  a n d wei g ht  
 Vital si g ns  
 Q uesti o n naires ( w h e n a p plica ble)  
 A E c ollecti o n  
 C o nc o mita nt me dicati o n n otati o n  
P art B  
All visits i n C ycles 1 a n d 2 , al o n g wit h Da y 1 visits of c ycles wit h ra di ol o gi c i ma gi n g , s h o ul d occ ur at t he i n vesti gati ve site u nless 
t here are e x ce pti o nal circ u msta nces (see Secti o n 1 0. 7 , A p pe n di x 7) .  F or C ycl e 3 a n d be y o n d, s o me pr oce d ures ma y be c o n d ucte d 
re m otel y (see g ui d a nce b el o w) b y a c o m bi nati o n of virt ual visit (i ncl u di n g vi de o) a n d c o ul d als o i ncl u de  m o bile healt hcare i n 
acc or da nce wit h l ocal re g ulati o ns if writte n a p pr o val is pr o vi de d b y t h e s p o ns or a n d acc or di n g t o t he prefere n ces of t h e part i ci pa nt a n d 
st u d y site: 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
2 9  
F or C ycles wit h r a di ol o gic i m a gi n g  ( C y cle 3, 5, 8, 1 1, a n d e ver y t hir d c ycle after w ar ds) : 
O n Da ys 8 a n d 1 5, t he f oll o wi n g pr oce d ures ma y be c o n d ucte d re m otel y  b y a c o m bi nati o n of virt ual visit a n d m o bile healt hcare : 
 P h ysical e x a m  a n d wei g ht  
 Vital si g ns  
 Q uesti o n naires ( w h e n a p plica ble)  
 A E c ollecti o n  
 C o nc o mita nt me dicati o n n otati o n  
 
F or C ycles w here r a di ol o gic i m a gi n g d oes n ot occ ur ( C y cles 4, 6, 7, 9, 1 0, 1 2, etc.):  
 All pr oce d ures ma y be c o n d ucte d re m otel y  
 
E ve n u n der e xce pti o n al circ u mst a nc es, p atie nts s h o ul d ne ver g o m ore t h a n 3 c ycles wit h o ut h a vi n g a n  o nsite visit.  
 
 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
3 0  
P arts A a n d B  
Pr o ce d ure  
All Tre at me nt Peri o ds ( C ycl e = 2 1 D a ys)  
N otes  
C ycle 1  
C ycle 2  
C ycle 3  
C ycle 4  
C ycle 5 -n  
Rel ati ve D a y 
wit hi n D osi n g 
C ycle  
1  
8  
1 5  
1  
8  
1 5  
1  
8  
1 5  
1  
8  
1 5  
1  
8  
1 5  
 
P h ysical e xa m 
a n d wei g ht  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
I ncl u des hei g ht ( o nl y Da y 1 of eac h c ycle), wei g ht, a n d 
B S A.  P erf or m wee kl y f or first 4  c ycles.  Fr o m C ycle 5 
o n war d, perf or m o n Da ys  1 a n d 8 o nl y.  P erf or m o n 
sa me da y bef ore  starti n g a ne w c ycle of t hera p y (i.e. 
Da y 1).  If n ot starti n g a ne w c ycle o f t hera p y (i.e. 
Da ys 8 a n d 1 5), a wi n d o w ± 3 da ys is acce pta ble.  
F urt her e val uati o ns f or a n y cli nical c o ncer ns, s uc h as 
b o ne pai n, li m p, a n d ot hers s h o ul d be c o n d ucte d at t he 
i n vesti gat or’s discreti o n.  
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T
C CI

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
3 1  
P arts A a n d B  
Pr o ce d ure  
All Tre at me nt Peri o ds ( C ycl e = 2 1 D a ys)  
N otes  
C ycle 1  
C ycle 2  
C ycle 3  
C ycle 4  
C ycle 5 -n  
Rel ati ve D a y 
wit hi n D osi n g 
C ycle  
1  
8  
1 5  
1  
8  
1 5  
1  
8  
1 5  
1  
8  
1 5  
1  
8  
1 5  
 
Vital si g ns  
See 
N otes  
X  
See 
N otes  
X  
See 
N otes  
X  
See 
N otes  
X  
See 
N otes  
 
 
I ncl u des bl o o d press ure, p ulse rate, o x y ge n sat urati o n, 
a n d te m perat ure.  P erf or m o n sa me da y bef ore  starti n g 
a ne w c ycle of t hera p y (i.e. Da y 1).  If n ot starti n g a 
ne w c ycle of t hera p y (i.e. Da ys 8 a n d 1 5), a wi n d o w ± 3 
da ys is acce pta ble.  
 
F or t he first 4 c ycles , perf or m o n Da ys 1, 8 &  1 5.  
 
F or C ycle 5 a n d o n war ds, perf or m o n Da ys 1 &  8.  
 
F or all c ycles , if recei vi n g st u d y tre at me nt b y 
i nf usi o n, perf or m pri or t o e ver y i nf usi o n (i.e. 
Da ys 1, 2, 3, 4, a n d 5 of a n y c ycle) a n d wit hi n 1 
h o ur after  c o m pleti o n of i nf usi o n.  
La ns k y/  
Kar n ofs k y 
perf or ma nce 
stat us 
X  
 
 
X  
 
 
X  
 
 
X  
 
 
X  
 
 
C o m plete bef ore treat me nt i nitiati o n. 
 La ns k y f or a ge < 1 6 years  
 Kar n ofs k y f or a ge ≥1 6 years  
o  
F or patie nts w h o t ur n 1 6 years ol d w hile o n 
st u d y, Kar n ofs k y s h o ul d be us e d after t he 1 6 t h 
birt h da y  
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
3 2  
P arts A a n d B  
Pr o ce d ure  
All Tre at me nt Peri o ds ( C ycl e = 2 1 D a ys)  
N otes  
C ycle 1  
C ycle 2  
C ycle 3  
C ycle 4  
C ycle 5 -n  
Rel ati ve D a y 
wit hi n D osi n g 
C ycle  
1  
8  
1 5  
1  
8  
1 5  
1  
8  
1 5  
1  
8  
1 5  
1  
8  
1 5  
 
Dr u g pr o d uct 
acce pta bilit y a n d 
palata bilit y 
q uesti o n naire  
X  
 
X  
X  
See N otes  
 
F or patie nts ≤5  years ol d, o nl y t he care gi ver will 
c o m plete t he q uesti o n naires.  
 
F or patie nts ≥6 years ol d t o < 1 2 years ol d, b ot h 
patie nt a n d care gi ver will c o m plete t he 
q uesti o n naires.  
 
F or patie nts ≥1 2 years ol d, o nl y t he patie nt will 
c o m plete t he q uesti o n naires.  
N ote:  F or C ycle 1 Da ys 1 a n d 1 5 a n d C ycle 2 Da y 1, 
perf or m at ti me of d osi n g or wit hi n a p pr o xi matel y 3 0 
mi n utes after d ose.  
If a patie nt c ha n ges t he met h o d of a b e macicli b 
a d mi nistrati o n at a n y p oi nt d uri n g t he trial, t he 
a p pr o priate q uesti o n naire c orres p o n di n g t o t he ne w 
a d mi nistrati o n met h o d s h o ul d be c o m plete d at t he ne xt 
cli nic visit f oll o wi n g t he met h o d c ha n ge.  
Re vie w P atie nt 
Diar y  
X  
X  
X  
X  
X  
X  
X  
 
 
 
 
 
 
 
 
Pr o vi de patie nt diar y at Da y 1 of eac h c ycle.  
P atie nt/care gi ver s h o ul d c o m plete dail y u ntil C ycle 3 
Da y 1. A wi n d o w of  ± 3 da ys is acce pta ble.  
Re vie w patie nt diar y at eac h st u d y visit f or c o m pleti o n 
of date a n d ti me f or eac h d ose.  
P K sa m pli n g  
See Secti o n 1. 3. 3  f or ti me p oi nts 
 
 
 
 
 
 
 
 
 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
3 3  
P arts A a n d B  
Pr o ce d ure  
All Tre at me nt Peri o ds ( C ycl e = 2 1 D a ys)  
N otes  
C ycle 1  
C ycle 2  
C ycle 3  
C ycle 4  
C ycle 5 -n  
Rel ati ve D a y 
wit hi n D osi n g 
C ycle  
1  
8  
1 5  
1  
8  
1 5  
1  
8  
1 5  
1  
8  
1 5  
1  
8  
1 5  
 
He mat ol o g y  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
≤7 da ys pri or  t o C 1 D 1.  
F or C 2 a n d be y o n d,  ≤3  da ys bef ore  Da y 1  a n d ± 3 da ys 
f or Da ys 8 a n d  1 5 . 
Ma y c ollect m ore fre q ue ntl y if cli nicall y i n dicate d.   
If iri n oteca n has bee n disc o nti n ue d ( P art A) or n ot p art 
of t he re gi me n ( P art B), a n d  cli nicall y si g nifica nt 
c yt o pe nia is n ot o bser ve d  after 3  c ycles, C B C ma y be 
re d uce d t o Da y 1  (ca n eli mi nate Da ys 8 a n d / or 1 5).   
See Secti o n 1 0. 2 , A p pe n di x 2.  
Cli nical 
C he mistr y  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
≤7 da ys pri or  t o C 1 D 1.  
F or C 2 a n d be y o n d , ≤3 da ys bef ore  Da y 1  a n d ± 3 da ys  
f or Da ys 8 a n d 1 5.   
Ma y c ollect m ore fre q ue ntl y if cli nicall y i n dicate d.  
I ncl u de li ver f u ncti o n tests.   
If o n st u d y >3  c ycles a n d cli ni call y si g nifica nt 
c he mistr y a d verse e ve nt is n ot o bser ve d, fre q ue nc y 
ma y be re d uce d t o Da y 1  (ca n eli mi nate Da ys 8 a n d/ or 
1 5) .  
See Secti o n 1 0. 2 , A p pe n di x 2.  
C ystati n C  
X  
 
 
X  
 
 
X  
 
 
X  
 
 
X  
 
 
≤7 da ys pri or  t o C 1 D 1.  
F or C 2 a n d be y o n d,  ≤3 da ys bef ore  Da y 1 , u nless m ore 
fre q ue nt assess me nt is cli nicall y i n dicate d.   
See Secti o n  1 0. 2 , A p pe n di x 2.  
Ser u m or uri ne 
pre g na nc y test  
X  
 
 
X  
 
 
X  
 
 
X  
 
 
X  
 
 
F or w o me n of c hil d beari n g p ote ntial o nl y.   
See Secti o n 8. 3. 4  a n d Secti o n 1 0. 2 , A p pe n di x 2.  
N ote :  d uri n g st u d y treat me nt, perf or m at start of eac h 
c ycle ( ≤3 da ys) or as re q uire d per l ocal re g ulati o ns 
a n d/ or i nstit uti o nal g ui deli nes.  
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
3 4  
P arts A a n d B  
Pr o ce d ure  
All Tre at me nt Peri o ds ( C ycl e = 2 1 D a ys)  
N otes  
C ycle 1  
C ycle 2  
C ycle 3  
C ycle 4  
C ycle 5 -n  
Rel ati ve D a y 
wit hi n D osi n g 
C ycle  
1  
8  
1 5  
1  
8  
1 5  
1  
8  
1 5  
1  
8  
1 5  
1  
8  
1 5  
 
Ra di ol o gic 
i ma gi n g 
See N otes  
Sca ns will be perf or me d a n d re vie we d l ocall y;  
 
Sca n after C ycle 2 ( pri or t o a d mi nisteri n g  st u d y 
dr u g f or C 3 D 1)  
 
after C ycle 4 ( pri or t o a d mi nisteri n g st u d y dr u g 
f or C 5 D 1) 
 
t he e n d of e ver y t hir d c ycle t hereafter (after C ycle 
7 [ pri or t o a d mi ni steri n g st u d y dr u g f or C 8 D 1], 
after C ycle 1 0 [ pri or t o a d mi nisteri n g  st u d y dr u g 
f or C 1 1 D 1], etc.) 
C o m pleti o n u p t o 7  da ys bef ore Da y 1 of eac h c ycle 
wit h i ma gi n g is acce pta ble. 
R E CI S T v 1. 1 s h o ul d be use d f or all n o n -C N S t u m ors; 
R A N O criteria s h o ul d be use d f or C N S t u m ors .  F or 
patie nts wit h n o n -C N S t u m ors, perf or m a C T sca n of 
t he k n o w n lesi o n(s) a n d of t he  c hest.  F or C N S t u m ors, 
perf or m M RI of t he pri mar y l esi o n i ncl u di n g t he e ntire 
brai n or s pi ne as a p plica ble. F or brai n lesi o ns, als o 
i ncl u de M RI of t he s pi ne if hist or y o f dr o p metastases 
or if ne w  dr o p metastases were prese nt  at baseli ne 
sca n.  
If i ma ges of b o nes are prese nt i n t he a b o ve sca ns, 
b o nes s h o ul d be assesse d f or gr oss b o ne a b n or malities.  
F or patie nts u na ble t o a d here t o t his sc he d ule d ue t o 
e xce pti o nal circ u ms ta nces, t he i n vesti gat or s h o ul d 
c o ns ult wit h t he Lill y C R P/ C R S.  
I ma gi n g facilit y, i ma ge ac q uisiti o n pr ot oc ol, a n d 
i ma gi n g m o dalit y  s h o ul d be c o nsiste nt f or all visits f or 
a gi ve n patie nt.  
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
3 5  
P arts A a n d B  
Pr o ce d ure  
All Tre at me nt Peri o ds ( C ycl e = 2 1 D a ys)  
N otes  
C ycle 1  
C ycle 2  
C ycle 3  
C ycle 4  
C ycle 5 -n  
Rel ati ve D a y 
wit hi n D osi n g 
C ycle  
1  
8  
1 5  
1  
8  
1 5  
1  
8  
1 5  
1  
8  
1 5  
1  
8  
1 5  
 
L u m bar p u nct ure  
See N otes  
Assess C S F c yt ol o g y a n d t u m or mar kers (al p ha-
fet o pr otei n a n d beta-H C G)  ac c or di n g t o 
i nstit uti o nal/sta n dard  g ui deli nes f or a p plica ble patie nts  
w h o ha d p ositi ve t u m or mar k ers or c yt ol o g y at 
baseli ne .  
A E C ollecti o n / 
C T C A E Gra di n g  
See N otes  
A Es c ollecte d c o nti n u o usl y t hr o u g h o ut st u d y (a n y ti me 
t here is a n A E t o re p ort).  C T C A E Versi o n 5. 0. 
C o nc o mita nt 
Me dicati o n 
N otati o n  
See N otes  
C ollecte d c o nti n u o usl y t hr o u g h o ut st u d y (a n y ti me 
t here is a c o nc o mita nt me dicati o n t o re p ort).  Refer t o 
Secti o n 6. 5  f or m ore i nf or mati o n a b o ut c o nc o mita nt 
me dicati o ns.  
P art A P atie nts:  
A d mi nister 
iri n oteca n 
See N otes  
A d mi nister Da ys 1 -5 of eac h c ycle.  C o nti n uati o n o n 
c he m ot hera p y be y o n d C ycle 1 2 will be u p t o t he 
i n vesti gat or’s discreti o n a n d t he i n di vi d ual patie nt’s 
sit uati o n.  See Secti o n 6. 1 . 
A d mi nister 
te m oz ol o mi de 
See N otes  
A d mi nister Da ys 1 -5 of eac h c ycle.  C o nti n uati o n o n 
c he m ot hera p y be y o n d C ycle 1 2 will be u p t o t he 
i n vesti gat or’s discreti o n a n d t he i n di vi d ual patie nt’s 
sit uati o n.  See Secti o n 6. 1 . 
A d mi nister 
a b e macicli b  
See N otes  
A d mi nister BI D per Secti o n 6. 1 . 
P artici pa nt ret ur ns 
st u d y dr u gs 
 
 
 
X  
 
 
X  
 
 
X  
 
 
X  
 
 
Ret ur n at Da y 1 ( ± 5 da ys) of eac h c ycle starti n g i n 
C ycle 2  t o assess c o m plia nce. 
A b bre viati o ns:  A E = a d verse e ve nt; BI D = t wice dail y; B S A = b o d y s urface area; C N S = ce ntral ner v o us s yste m; C R P/ C R S = cli nical researc h 
p h ysicia n/cli nical researc h sci e ntist ; C T C A E  =  C o m m o n T er mi n ol o g y Criteria f or A d vers e E ve nts; 
 
 P K = p har mac o ki netic; R A N O = Res p o nse Assess me nt i n Ne ur o -O nc ol o g y; R E CI S T = Res p o nse  E val uati o n  Criteria i n S oli d T u m ors . 
 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T
C CI

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
3 6  
P ost tre at me nt F oll o w -U p Sc he d ule of Acti vities  f or P arts A a n d B 
P osttreat me nt F oll o w -U p i nteracti o ns a n d ass ess me nts  s h o ul d be c o n d ucte d at t he site, e x ce pt i n e x ce pti o nal circ u msta nces (see 
Secti o n 1 0. 7 , A p pe n di x 7 ).  
 a n d l u m bar p u nct ur e  are n ot per mitte d t o be perf or me d re m otel y e v e n i n 
e x ce pti o nal circ u msta nces.  
P arts A a n d B  
 
S h ort -Ter m F oll o w -U p 
( 3 0 ± 7 D a ys) a 
C o m me nts  
Visit  
8 0 1  
 
P h ysical e xa mi nati o n  
X  
I ncl u des hei g ht, wei g ht, a n d B S A. 
Vital si g ns  
X  
I ncl u des bl o o d press ure, p ulse rate, o x y ge n sat urati o n, a n d te m perat ure. 
La ns k y/ Kar n ofs k y 
perf or ma nce stat us  
X  
 La ns k y f or a ge < 1 6 years  
 Kar n ofs k y f or a ge ≥1 6 years  
F or patie nts w h o t ur n 1 6 years ol d w hile o n st u d y or i n f oll o w -u p, 
Kar n ofs k y s h o ul d be use d after t he 1 6 t h birt h da y  
A d verse e ve nts 
c ollecti o n/ C T C A E gra di n g  
X  
C T C A E Versi o n 5. 0.  After Visit 8 0 1, o nl y st u d y treat me nt -relate d 
seri o us e ve nts are re p orte d. 
C o nc o mita nt me dicati o n  
X  
 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T
C CI
C CI

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
3 7  
P arts A a n d B  
 
S h ort -Ter m F oll o w -U p 
( 3 0 ± 7 D a ys) a 
C o m me nts  
Visit  
8 0 1  
 
Ra di ol o gic i ma gi n g  
X  
R E CI S T v 1. 1 s h o ul d be use d f or all n o n -C N S  t u m ors; R A N O s h o ul d be 
use d f or C N S t u m ors . F or patie nts wit h n o n -C N S t u m ors, perf or m a C T 
sca n of t he k n o w n lesi o n(s) a n d of t he c hest.  F or C N S t u m ors, perf or m 
M RI of t he pri mar y lesi o n i ncl u di n g t he e ntire brai n  or s pi ne as 
a p plica ble. F or brai n lesi o ns, als o i ncl u de M RI of t he s pi ne if hist or y of 
dr o p metastases or if ne w dr o p metastases were prese nt at b aseli ne sca n. 
I ma gi n g is not re q u ire d if partici pa nt has disc o nti n ue d d ue t o 
pr o gressi ve disease . F or patie nts w h o disc o nti n ue d f or a n y r eas o n ot her 
t ha n pr o gressi ve disease, sca ns s h o ul d c o nti n ue per t he o n-tr eat me nt 
sc he d ule f or ra di ol o gic i ma gi n g. I ma gi n g facilit y, i ma ge ac q uisiti o n 
pr ot oc ol, a n d i ma gi n g m o dalit y  s h o ul d be c o nsiste nt f or all visits f or a 
gi ve n patie nt.  
L u m bar p u nct ure  
X  
Assess C S F c yt ol o g y a n d t u m or mar kers (al p ha -fet o pr otei n a n d beta-
H C G) acc or di n g t o i nstit uti o nal/sta n dar d g ui deli nes f or a p plica ble 
patie nts w h o ha d p ositi ve t u m or mar kers or c yt ol o g y at baseli ne  a n d  
w h o are off st u d y treat me nt f or reas o ns ot her t ha n disease pr o gressi o n . 
He mat ol o g y  
X  
See Secti o n 1 0. 2 , A p pe n di x 2.  
Cli nical c he mistr y  
X  
I ncl u de li ver f u ncti o n tests.  S ee Secti o n 1 0. 2 , A p pe n di x 2.  
C ollecti o n of p ostst u d y 
a ntica ncer treat me nt  
X  
T ele p h o ne assess me nt is acce pta ble.  F or all patie nts, details o n 
s u bse q ue nt a ntica ncer treat me nt (start/st o p dates a n d treat me nts 
a d mi nistere d).  
A b bre viati o ns:  B S A = b o d y s urface area; C T C A E = C o m m o n T er mi n ol o g y Criteria f or A d verse E ve nts;  
 
 R A N O = Res p o nse Assess me nt i n Ne ur o -O nc ol o g y; R E CI S T = Res p o nse E val uati o n Criteria i n S oli d T u m ors . 
a S h ort -ter m f oll o w-u p be gi ns w he n t he patie nt a n d i n vesti gat or a gree t hat t he patie nt will n o l o n ger c o nti n ue st u d y treat me nt a n d lasts a p pr o xi m atel y 3 0 da ys  
fr o m t he last a d mi nistrati o n of st u d y dr u gs. 
 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T
C CI

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
3 8  
 
C o nti n ue d Access Sc he d ul e of Acti vities  f or P arts A a n d B 
P arts A a n d B  
Visit  
St u d y 
Tre at me nt  
F oll o w -
U p  
N otes  
5 0 1 -5 X X  
9 0 1  
Pr o ce d ure  
 
 
A E 
c ollecti o n/ C T C A E 
gra di n g  
X  
X  
P er C T C A E Versi o n  5. 0.   C ollect all A Es/ S A Es .  P er sta n dar d of care , m o nit or vital si g ns a n d perf or m 
sta n dar d la b orat or y tests ( he mat ol o g y, c he mistr y, a n d pre g na nc y testi n g).  See Secti o n s 6. 7. 1. 1  a n d 
Secti o n  1 0. 2 , A p pe n di x 2.  
A d mi nister 
a b e macicli b  
X  
 
See Secti o n 6. 1 . 
A d mi nister 
te m oz ol o mi de (if 
a p plica ble) 
X  
 
A d mi nister Da ys 1 -5 of eac h c ycle.  C o nti n uati o n o n c he m ot hera p y be y o n d C ycle 1 2 will be u p t o t he 
i n vesti gat or’s discreti o n a n d t he i n di vi d ual patie nt’s sit uati o n.  See Secti o n 6. 1 . 
P art A P atie nts:  
A d mi nister 
iri n oteca n (if 
a p plica ble) 
X  
 
A d mi nister Da ys 1 -5 of eac h c ycl e.  C o nti n uati o n o n c he m ot hera p y be y o n d C ycle 1 2 will be u p t o t he 
i n vesti gat or’s discreti o n a n d t he i n di vi d ual patie nt’s sit uati o n.  See Secti o n 6. 1 . 
A b bre viati o ns:  A E = a d verse e ve nt; C T C A E = C o m m o n T er mi n ol o g y Criteria f or A d vers e E ve nts ; S A E = seri o us a d verse e ve nt. 
 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
3 9  
1. 3. 2.  
Sc he d ule of Acti vities f or P art C   
At a n y ti me i n t he st u d y, la b orat or y a n d pre g na n c y tests ma y be c ollecte d at a l ocal cli nic i n acc or da nce wit h l ocal la ws a n d 
re g ulati o ns if dee me d a p pr o priate b y t he i n vesti gat or . All res ults s h o ul d be re vie we d a n d rec or de d i n t he e C R F ( pre g na nc y res ults are 
n ot re q uire d t o  be rec or de d) . A virt ual visit wit h t he st u d y i n vesti gat or is n ot re q uire d f or a l ocal la b dra w or pre g na n c y test. All ot her 
scree ni n g i nteracti o ns a n d assess me nts m ust be perf or me d at t he cli nical tri al site .   
Sc he d ule of B aseli ne a n d  Scree ni n g Acti vities f or P a rt C 
A n y s cree ni n g pr oce d ures t hat fall o utsi de of t he re q uire d wi n d o ws per t he Sc he d ule of Scree ni n g Acti vities m ust be re peate d s o t hat 
t he y fall wit hi n t he re q uir e d wi n d o w. 
P art C  
Rel ati ve D a y Pri or t o C ycle 1 D a y 1  
2 8  
1 4 
7  
I nstr ucti o ns 
Pr o ce d ure  
 
 
I nf or me d c o nse nt/asse nt 
X  
  
M ust be si g ne d pri or t o c o n d ucti n g a n y pr ot oc ol -s pecific 
tests/ pr oce d ures. 
I ncl usi o n/e xcl usi o n e val uati o n  
 
X  
 
De m o gra p hics  
 
X  
I ncl u de race, ge n der, et h nicit y, a n d birt h date per l ocal re g ul ati o ns. 
Pri or ca ncer treat me nts  
 
X  
 
Me dical a n d o nc ol o g y hist or y  
 
X  
I ncl u di n g assess me nt of pree xisti n g c o n diti o ns, hist orical ill nesses, 
k n o w n s o matic alterati o ns, a n d ha bits.  
P h ysical e xa mi nati o n  
 
X  
I ncl u des hei g ht, wei g ht, a n d B S A. 
Vital si g ns  
 
X  
I ncl u des bl o o d press ure, p ulse rate, o x y ge n sat urati o n, a n d 
te m perat ure. 
La ns k y/ Kar n ofs k y perf or ma n ce stat us 
 
X  
 La ns k y f or a ge < 1 6 years  
 Kar n ofs k y f or a ge ≥1 6 years  
F or patie nts w h o t ur n 1 6 years ol d w hile o n st u d y, Kar n ofs k y 
s h o ul d be use d after t he 1 6 t h birt h da y  
He mat ol o g y  
 
X  
 See Secti o n 1 0. 2 , A p pe n di x 2.  
Cli nical c he mistr y  
 
X  
 See Secti o n 1 0. 2 , A p pe n di x 2.  
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T
C CI

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
4 0  
P art C  
Rel ati ve D a y Pri or t o C ycle 1 D a y 1  
2 8  
1 4 
7  
I nstr ucti o ns 
Pr o ce d ure  
 
 
Ser u m or uri ne pre g na nc y test  
 
 
X  
 W o me n of c hil d beari n g p ote ntial o nl y.   
 See Secti o n 1 0. 2 , A p pe n di x 2.  
Pr ot hr o m bi n ti me 
X  
 
Ec h ocar di o gra m or M U G A  
X  
 
T u m or assess me nt 
C T or M RI  
 
X  
  
 If perf or me d as part of r o uti ne cli nical care, a 7 -da y wi n d o w be y o n d 
2 8 da ys is acce pta ble wit h o ut bei n g c o nsi dere d as a pr ot oc ol  
de viati o n or scree n fail.  
 C T sca ns of t he c hest, a b d o me n, pel vis, a n d t he site of t he k n o w n 
lesi o n if l ocate d else w here. 
 T he C T p orti o n of a P E T -C T ma y be use d f or res p o nse a ssess me nt if 
t he site ca n d oc u me nt t hat t he C T is of i de ntical q ualit y t o a 
dia g n ostic C T.   
 I ma gi n g facilit y, i ma ge ac q uisiti o n pr ot oc ol, a n d i ma gi n g m o dalit y 
s h o ul d be c o nsiste nt f or all visits f or a gi ve n patie nt.  
 See Secti o n 8. 1 . 
T u m or assess me nt 
MI B G or P E T C T  
 
X  
 If perf or me d as part of r o uti ne cli nical care, a 7 -da y wi n d o w be y o n d 
2 8 da ys is acce pta ble wit h o ut bei n g c o nsi dere d as a pr ot oc ol  
de viati o n or scree n fail.  
 MI B G sca ns f or all patie nts wit h MI B G a vi d disease, i ncl u di n g t h ose 
wit h disease als o detecta ble b y C T or M RI.  
 F D G -P E T ma y be use d  i n pati e nts w h ose t u m ors are MI B G n o n-a vi d.  
B o ne marr o w assess me nt  
X  
 Bilateral b o ne marr o w as pirat es a n d bi o psies . 
 If perf or me d as part of r o uti ne cli nical care, a 7 -da y wi n d o w be y o n d 
2 8 da ys is acce pta ble wit h o ut bei n g c o nsi dere d as a pr ot oc ol  
de viati o n or scree n fail.  
Bi o mar kers  –  T u m or Tiss ue  
X  
 Arc hi val or fres h t u m or sa m pl e s will be c ollecte d, w he n  a vaila ble.  
 
 or  
 sa m ple, w he n a vaila ble , is preferre d.  
 T he m ost rece nt sa m ple is desire d.   
 T u m or sa m ples i n t he f or m of a f or mali n -fi xe d, paraffi n -e m b e d de d 
bl oc k  are preferre d . If t his is n ot p ossi ble,   sli des of fres hl y 
pre pare d , u nstai ne d , 5 -micr o n secti o ns ma y be pr o vi de d.  
 Sa m ples ca n be se nt at a n y ti me d uri n g st u d y if n ot s u b mitt e d at 
scree ni n g. 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T
C CI
C CI
C CI

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
4 1  
P art C  
Rel ati ve D a y Pri or t o C ycle 1 D a y 1  
2 8  
1 4 
7  
I nstr ucti o ns 
Pr o ce d ure  
 
 
A d verse e ve nts c ollecti o n a n d  
C T C A E gra di n g  
X  
C T C A E Versi o n 5. 0.  
C o nc o mita nt me dicati o n  
X  
 
A b bre viati o ns:  B S A = b o d y s urface area; C T C A E = C o m m o n T er mi n ol o g y Criteria f or A d verse E ve nts; C T = c o m p ute d t o m o gra p h y;  F D G = 
fl u or o de o x y gl uc ose; 
 MI B G = metai o d o be nz yl g ua ni di ne ; M RI = ma g netic res o na nc e 
i ma gi n g; M U G A = m ulti gate d ac q uisiti o n; P E T = p ositr o n e missi o n t o m o gra p h y . 
 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T
C CI

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
4 2  
Sc he d ule  of O n -St u d y Tre at me nt Acti vities  f o r P a rt C  
T he start of a c ycle ( Da y 1) is defi ne d as t he first da y t h at t he c o m bi nati o n of iri n oteca n, te m oz ol o mi de , a n d a b e macicli b are 
a d mi nistere d f or t hat c ycle.  
All visits i n C ycle 1 a n d Da ys 1  t hr o u g h 6 of all c ycl es t hereafter s h o ul d occ ur at t he i n v esti gati ve site. G M -C S F ma y be a d mi nistere d 
i n a n o ut-patie nt setti n g p er l ocal sta n d ar ds of care.  All visits t hat  i ncl u de ra di ol o gic i ma gi n g s h o ul d occ ur at t he i n v esti gati ve site 
(see Secti o n 1 0. 7 ).  
P art C  
Pr o ce d ures  
D uri n g C ycle 1  
C ycle 2 o n w ar d  
I nstr ucti o ns 
P h ysical assess me nt 
i ncl u di n g vital si g ns  
X  
X  
 U p t o 3  da ys bef ore  D a y 1 of eac h c ycle  
 Dail y pri or t o eac h di n ut u xi ma b i nf usi o n.  See Secti o n 6. 1. 1. 1   
 O nl y Da y 1  val ues  of eac h c ycle m ust b e  rec or de d i n t he E D C s yste m  
Hei g ht, wei g ht, B S A , 
a n d 
 
X  
X  
 U p t o 3  da ys bef ore Da y 1 of eac h c ycle  
 Dail y wei g ht pri or t o eac h di n ut u xi ma b i nf usi o n  
 O nl y t he Da y 1 val ues of eac h c ycle m ust  be  rec or de d i n t he E D C s yste m 
 
 
P erf or ma nce stat us  
 
X  
 U p t o  3 da ys bef ore  Da y 1 of eac h c ycle  
 La ns k y f or a ge < 1 6 years  
 Kar n ofs k y f or a ge ≥1 6 years  
o  
F or patie nts w h o t ur n 1 6 years ol d w hile o n st u d y, Kar n ofs k y s h o ul d 
be use d after t he 1 6 t h birt h da y  
He mat ol o g y  
W ee kl y  
Wee kl y  
 See Secti o n 1 0. 2 , A p pe n di x 2  
 U p t o 3 da ys bef ore Da y 1 of eac h c ycle  
 Wee kl y = Da y s 1, 8, a n d 1 5  
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T
C CI
C CI
C CI

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
4 3  
P art C  
Pr o ce d ures  
D uri n g C ycle 1  
C ycle 2 o n w ar d  
I nstr ucti o ns 
Cli nical c he mistr y  
W ee kl y  
X  
 See Secti o n 1 0. 2 , A p pe n di x 2.  N ote t he a d diti o n of P O 4 - a n d M g + +  
 U p t o 3 da ys pri or t o Da y 1 of eac h c ycle  
 Wee kl y = Da y s 1, 8, a n d 1 5  
A b bre viate d  c he mistr y 
pa nel (electr ol ytes a n d 
creati ni ne) 
D ail y d uri n g 
di n ut u xi ma b 
a d mi nistrati o n  
D ail y d uri n g di n ut u xi ma b 
a d mi nistrati o n  
 See Secti o n 1 0. 2 , A p pe n di x 2  
 Da ys 2, 3, 4, a n d 5 of eac h c ycle d uri n g di n ut u xi ma b a d mi nistrati o n  
 If d i n ut u xi ma b is n ot a d mi nist ere d, dail y la bs are  n ot re q uire d  
Ser u m or u ri ne 
p re g na nc y test  
X  
X  
 A p plies t o w o me n of c hil d beari n g p ote ntial o nl y  
 U p t o 3 da ys pri or t o Da y 1 of eac h c ycle or as re q uire d per l ocal 
re g ulati o ns a n d/ or i nstit uti o nal g ui deli nes 
T u m or e val uati o n:  
C T  or M RI  
 
E n d of C ycle s 2, 4 , a n d  6, t he n  
 at t he e n d e ver y 4t h c ycle  
 U p t o 1 wee k pri or t o t he start of t he ne xt pla n ne d c ycle of t hera p y  
 Re peat assess me nt ≥4 wee ks after i nitial res p o nse f or patie nts wit h 
c o m plete res p o nse, partial res p o nse, a n d mi n or res p o nse  
 Use sa me m o dalit y t hr o u g h o ut t he st u d y  
 Sca ns will be perf or me d a n d re vie we d l ocall y  
T u m or e val uati o n:  
MI B G or P E T C T  
 
E n d of C ycle s 2, 4 , a n d  6, t he n 
at t he e n d e ver y 4t h c ycle  
 U p  t o 1 wee k pri or t o t he start of t he ne xt pla n ne d c ycle of t hera p y 
 P E T C T o nl y f or patie nts wit h n o n -MI B G a vi d lesi o ns  
 Re peat assess me nt ≥4 wee ks after i nitial res p o nse f or patie nts wit h 
c o m plete res p o nse, partial res p o nse, a n d mi n or res p o nse  
 Sca ns will be perf or me d a n d re vie we d l ocall y  
Bilateral b o ne marr o w 
as pirates/ bi o psies  
 
E n d of C ycle s 2, 4, 6 a n d  t he n 
after e ver y 4t h c ycle - o nl y f or 
patie nts wit h marr o w disease  
a n d  all patie nts (e ve n if n o 
marr o w disease) f oll o wi n g 
C ycle 6  
U p t o 1 wee k pri or t o t he start of t he ne xt pla n ne d c ycle of t hera p y  
Bi o mar kers –  p las ma 
X  
X  
 C ollect pre -d ose at C 1 D 1 o n partici pa nts 
 o nl y  
 C ollect at disease pr o gressi o n a n d/ or st u d y disc o nti n uati o n  o n partici pa nts 
 
Bi o mar kers -  
w h ole bl o o d  
X  
 
 F or partici pa nts 
 w h ol e bl o o d drie d bl o o d s p ot  
 F or partici pa nts 
 w h ol e bl o o d sa m ple  
 If n ot c ollecte d d uri n g scree ni n g/ baseli ne, t he n o btai n at C 1 D 1  
 If bl o o d v ol u me restricti o ns pre ve nt c ollecti o n d uri n g scree ni n g/ baseli ne 
a n d C 1 D 1 , t he n sa m ple ca n be c ollecte d at a s u bse q ue nt ti me p oi nt  
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T
C CI
C CI
C CI
C CI

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
4 4  
P art C  
Pr o ce d ures  
D uri n g C ycle 1  
C ycle 2 o n w ar d  
I nstr ucti o ns 
 O nl y o ne sa m ple is nee de d per patie nt  
 See Secti o n 8. 8  
Dr u g pr o d uct 
acce pta bilit y a n d 
palata bilit y 
q uesti o n naire  
Da ys 1 a n d  1 5   
C ycle 2 Da y 1  o nl y  
 F or patie nts ≤5 years ol d, o nl y t he care gi ver will c o m plete  
 F or patie nts ≥6 t o < 1 2 years ol d, patie nt a n d care gi ver will c o m plete  
 F or patie nts ≥1 2 years ol d, o nl y t he patie nt will c o m plete  
 P erf or m at ti me of d osi n g or wit hi n a p pr o xi matel y 3 0 mi n utes after d ose  
 If met h o d of a be macicli b a d mi nistrati o n or f or m ulati o n (ta blets t o gra n ules 
o r vice versa)  c ha n ges,  t he a p pr o priate q uesti o n naire c orres p o n di n g t o t he 
ne w a d mi nistrati o n met h o d a n d f or m ulati o n s h o ul d be c o m plete d at t he 
cli nic visit f oll o wi n g t h is c ha n ge  
Re vie w P atie nt Diar y  
See N otes  
 Pr o vi de patie nt diar y at Da y 1 of eac h c ycle.  P atie nt/care gi ver s h o ul d 
c o m plete dail y u ntil C ycle 3 Da y 1. A wi n d o w of ± 3 da ys is acce pta ble.  
 Re vie w patie nt diar y at eac h st u d y visit f or c o m pleti o n of date a n d ti me f or 
eac h d ose.  
P K sa m pli n g  
See  N otes  
See Secti o n 1. 3. 3  
A E collecti o n a n d  
C T C A E gra di n g  
See N otes  
A Es c ollecte d c o nti n u o usl y t hr o u g h o ut st u d y (a n y ti me t her e is a n A E t o 
re p ort) per C T C A E Versi o n 5. 0.  C ollect all A Es/ S A Es  
Dis pe nse a b e macicli b  
See N otes  
P O BI D  pe r detaile d a d mi nistrati o n g ui deli nes, see Secti o n 6. 1 .  
A d mi nister 
te m oz ol o mi de 
See N otes  
F or detaile d a d mi nistrati o n g ui deli nes, see Secti o ns 6. 1 , a n d 6. 4 . 
A d mi nister iri n oteca n  
See N otes  
F or detaile d a d mi nistrati o n g ui deli nes, s ee Secti o n s 6. 1 , a n d 6. 4 . 
A d mi nister di n ut u xi ma b  
See N otes  
 F or detaile d a d mi nistrati o n g ui deli nes, see Secti o ns 6. 1 , a n d 6. 4 . 
 I m p ort a nt N ote : M o nit or patie nts  per g ui d eli nes i n Secti o n 6. 1. 1. 1 . 
Dis pe nse/ ad mi nister 
G M -C S F  
See N otes  
 F or detaile d a d mi nistrati o n g ui deli nes, see Secti o ns 6. 1  a n d 6. 4  
P artici pa nts ret ur n  st u d y 
dr u gs  
See N otes  
 Ret ur n at Da y 1 ( ± 5 da ys) of eac h c ycle starti n g i n C ycle 2 t o assess 
c o m plia nce . Refer t o secti o n 6. 4 . 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
4 5  
P art C  
Pr o ce d ures  
D uri n g C ycle 1  
C ycle 2 o n w ar d  
I nstr ucti o ns 
C o nc o mita nt m e dicati o n 
n otati o n  
See N otes  
 C ollecte d c o nti n u o usl y t hr o u g h o ut st u d y (a n y ti me t here is a c o nc o mita nt 
me dicati o n t o re p ort).  Refer t o Secti o n 6. 5  f or m ore i nf or mati o n a b o ut 
c o nc o mita nt me dicati o ns  
A b bre viati o ns:  A E = a d verse e ve nt; BI D = t wice dail y; B S A = b o d y s urface area; C 1 D 1 = C ycle 1 Da y 1; C B C = c o m plete bl o o d c o u nt; C T C A E = C o m m o n 
T er mi n ol o g y Criteria f or A d verse E ve nts;  C T  =  c o m p ute d t o m o gra p h y; E D C = electr o nic data ca pt ure s yste m; 
 G M -C S F 
= gra n ul oc yte macr o p ha ge c ol o n y -sti m ulati n g fact or;
 M g + +  = ma g nesi u m; MI B G = metai o d o be nz yl g ua ni di ne; M RI = ma g netic 
res o na nce i ma gi n g; 
 P E T = p ositr o n e missi o n t o m o gra p h y; P K = p har mac o ki neti c; P O = orall y; P O 4 - = p h os p h or us ; 
S A E =  seri o us a d verse e ve nt; V M A = va nill yl ma n delic aci d.  
 
 
 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T
C CI
C CI
C CI

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
4 6  
P osttre at me nt  F oll o w -U p Sc he d ule of Acti vities  f or P art C 
P art C  
 
S h ort -Ter m F oll o w -U p 
( 3 0 ± 7 D a ys)  
L o n g -Ter m F oll o w -U p ( 9 0 ± 1 4 D a ys)  
C o m me nts  
Visit  
8 0 1  
8 0 2 -X  
Rel ati ve D a y wit hi n 
C ycle  
B e gi ns w he n t he patie nt a n d 
t he i n vesti gat or a gree t hat 
t he patie nt will n o l o n ger 
c o nti n ue st u d y treat me nt a n d 
lasts a p pr o xi matel y 3 0 da ys. 
Be gi ns  w he n s h ort -ter m f oll o w-u p 
peri o d is c o m plete a n d c o nti n ues u ntil 
deat h, st u d y wit h dra wal, or t he patie nt 
is l ost t o f oll o w-u p. I n all cases, n o 
f oll o w-u p pr oce d ures will be perf or me d 
f or a patie nt w h o wit h dra ws 
c o nse nt/asse nt u nless he or s he has 
e x plicitl y pr o vi de d per missi o n a n d 
c o nse nt/asse nt.  
Cli nicall y directe d p h ysical 
e xa mi nati o n  
X  
 
E val uati o ns per e xa mi ner’s discreti o n a n d 
patie nts’ s y m pt o ms  
Vital si g ns  
X  
 
I ncl u des hei g ht, wei g ht, bl o o d press ure, p ulse, 
te m perat ure, a n d res pirat or y rate 
P erf or ma nce stat us  
X  
 
 La ns k y f or a ge < 1 6 years  
 Kar n ofs k y f or a ge ≥1 6 years  
F or patie nts w h o t ur n 1 6 years ol d w hile o n 
st u d y, Kar n ofs k y s h o ul d be us e d after t he 
1 6 t h birt h da y  
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T
C CI

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
4 7  
P art C  
 
S h ort -Ter m F oll o w -U p 
( 3 0 ± 7 D a ys)  
L o n g -Ter m F oll o w -U p ( 9 0 ± 1 4 D a ys)  
C o m me nts  
Visit  
8 0 1  
8 0 2 -X  
Rel ati ve D a y wit hi n 
C ycle  
B e gi ns w he n t he patie nt a n d 
t he i n vesti gat or a gree t hat 
t he patie nt will n o l o n ger 
c o nti n ue st u d y treat me nt a n d 
lasts a p pr o xi matel y 3 0 da ys. 
Be gi ns  w he n s h ort -ter m f oll o w-u p 
peri o d is c o m plete a n d c o nti n ues u ntil 
deat h, st u d y wit h dra wal, or t he patie nt 
is l ost t o f oll o w-u p. I n all cases, n o 
f oll o w-u p pr oce d ures will be perf or me d 
f or a patie nt w h o wit h dra ws 
c o nse nt/asse nt u nless he or s he has 
e x plicitl y pr o vi de d per missi o n a n d 
c o nse nt/asse nt.  
T u m or resta gi n g 
e val uati o n  
C T or M RI  
a n d  
MI B G or P E T C T  
X  
X   
 Use sa me m o dalit y t hr o u g h o ut t he st u d y   
 P E T C T o nl y f or patie nts wit h  n o n -MI B G 
a vi d lesi o ns   
 N ot re q uire d if P D  is d oc u me nte d w hile o n 
treat me nt, or if sta gi n g has be e n perf or me d 
wit h i n t he past 3 wee ks 
 P erf or m d uri n g e ver y l o n g -ter m f oll o w-u p 
visit if P D  has n ot o cc urre d  
 Sca ns will be perf or me d a n d re vie we d 
l ocall y  
A d verse e ve nts 
c ollecti o n/ C T C A E gra di n g  
X  
X  
 C T C A E Versi o n 5. 0  
 After Visit 8 0 1, o nl y st u d y tre at me nt -relate d 
seri o us e ve nts are re p orte d 
C o nc o mita nt me dicati o n  
X  
 
 
He mat ol o g y  
X  
 
 L ocal testi n g  
 See Secti o n 1 0. 2 , A p pe n di x 2 
Cli nical che mistr y  
X  
 
 L ocal testi n g  
 See Secti o n 1 0. 2 , A p pe n di x 2 
Plas ma bi o mar ker sa m ple  
X  
 
 F or partici pa nts
 w h ol e bl o o d sa m ple  
 Bef ore i nitiati o n of s u bse q ue nt t hera p y  
 O nl y if  n ot alrea d y o btai ne d at visit w he n 
partici pa nt disc o nti n ue d  st u d y  
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T
C CI

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
4 8  
P art C  
 
S h ort -Ter m F oll o w -U p 
( 3 0 ± 7 D a ys)  
L o n g -Ter m F oll o w -U p ( 9 0 ± 1 4 D a ys)  
C o m me nts  
Visit  
8 0 1  
8 0 2 -X  
Rel ati ve D a y wit hi n 
C ycle  
B e gi ns w he n t he patie nt a n d 
t he i n vesti gat or a gree t hat 
t he patie nt will n o l o n ger 
c o nti n ue st u d y treat me nt a n d 
lasts a p pr o xi matel y 3 0 da ys. 
Be gi ns  w he n s h ort -ter m f oll o w-u p 
peri o d is c o m plete a n d c o nti n ues u ntil 
deat h, st u d y wit h dra wal, or t he patie nt 
is l ost t o f oll o w-u p. I n all cases, n o 
f oll o w-u p pr oce d ures will be perf or me d 
f or a patie nt w h o wit h dra ws 
c o nse nt/asse nt u nless he or s he has 
e x plicitl y pr o vi de d per missi o n a n d 
c o nse nt/asse nt.  
Tiss ue s u b missi o n fr o m 
t u m or bi o ps y o btai ne d 
after pr o gressi o n  
X  
 
O pti o nal  
O nl y f or patie nts o n st u d y treat me nt at least 6 
m o nt hs  
C ollecti o n of p ostst u d y 
a ntica ncer treat me nt  
X  
X  
T ele p h o ne assess me nt is acce pta ble .  
D etails o f s u bse q ue nt a ntica nc er treat me nt 
(i ncl u di n g ra di ot hera p y, s ur geries, s yste mic, 
a n d l oc ore gi o nal t hera pies i ncl u di n g start/st o p 
dates)  
S ur vi val assess me nt  
X  
X  
T ele p h o ne assess me nt is acce pta ble  
A b bre viati o ns:  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 T er mi n ol o g y Criteria f or A d verse E ve nts; MI B G  =  metai o d o be nz yl g ua ni di ne; M RI =  
ma g netic res o na nce i ma gi n g; P E T = p ositr o n e missi o n t o m o gra p h y . 
 
 
 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
4 9  
C o nti n ue d  Access Sc he d ule of Acti vities  f or P art C 
P art C  
Visit  
St u d y 
Tre at me nt  
F oll o w -U p  
N otes  
 
5 0 1 -5 X X  
9 0 1  
Pr o ce d ure  
 
 
A E c ollecti o n/ C T C A E 
gra di n g  
X  
X  
 P er C T C A E Versi o n 5. 0  
 C ollect all A Es/ S A Es  
 P er sta n dar d of care, m o nit or vital si g ns a n d perf or m sta n dar d la b orat or y tests ( he mat ol o g y, 
c he mistr y, a n d pre g na nc y testi n g)  
 See Secti o n 6. 7. 1. 1  a n d  Secti o n 1 0. 2 , A p pe n di x 2  
A d mi nister 
a b e macicli b  
X  
 
See Secti o n 6. 1  
C o nti n uati o n o n c he m ot hera p y be y o n d C ycle 1 2 will be u p t o t he i n vesti gat or’s discreti o n a n d t he 
i n di vi d ual patie nt’s sit uati o n   
  
A d mi nister 
te m oz ol o mi de  
X  
 
A d mi nister iri n oteca n  
X  
 
A d mi nister 
d i n ut u xi ma b 
X  
 
A d mi nister G M -C S F  
X  
 
A b bre viati o ns:  A E = a d verse e ve nt; C T C A E = C o m m o n T er mi n ol o g y Criteria f or A d vers e E ve nts; G M -C S F = gra n ul oc yte macr o p ha ge c ol o n y -sti m ul ati n g 
fact or; S A E = seri o us a d verse e ve nt.  
 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
5 0  
1. 3. 3.  P h ar m a c o ki netic S a m pli n g a n d St u d y Dr u g D osi n g Sc he d ule    
T he dail y d osi n g sc h e d ul e f or eac h st u d y dr u g a n d t he p har mac o ki n etic ( P K) sa m pli n g  s c he d ule 
is s u m marized i n t he ta ble  a n d fi g ures bel o w.  
A be macicli b d osi n g dates a n d ti mes are re q uire d t o be c ollecte d 3 da ys pri or t o t he P K sa m ples.  
Iri n ot eca n a n d te m oz ol o mi de  d osi n g dates a n d ti mes s h o ul d als o be rec or de d.   T he date a n d 
e x act ti me of c ollecti o n of eac h v e n o us bl o o d sa m ple m ust be rec or de d o n t he la b orat or y 
re q uisiti o n.  Be y o n d t he first d ose, P K sa m ples ma y be ali g n e d t o c oi nci de wit h sta n dar d 
la b orat ories w h e n a p plica ble , wit h t he f oll o wi n g c ollecti o n dates/ti mes t o be use d as a g ui d e. 
T here will be n o P K a n al ysis of d i n ut u xi ma b or G M -C S F.  
F or patie nts i n Part A a n d Part B, a n d p atie nts i n Part C w h o wei g h
 at e nr ol me nt, all 
pla n ne d P K sa m ples will be ta ke n b y ve n o us bl o o d dra w a n d pr ocess e d i nt o plas ma.  
F or patie nts i n Part C w h o wei g h  
 at enr ol me nt, pla n ne d P K sa m ples will be ta ke n f or 
a be maci cli b (a n d its meta b olites) o nl y b y a v ol u metric a bs or pti ve micr osa m pli n g de vice. N o P K 
sa m ples f or iri n oteca n (a n d S N-3 8) or te m oz ol o mi de will be dra w n. 
 
D a y  
P K Sc he d ule a ,c 
  
C ycle 1  
C ycle 2  
C ycle 3  
1  
See P K Ti mec o urse a n d D osi n g 
Sc he d ule Fi g ures  
See P K Ti mec o urse a n d D osi n g 
Sc he d ule Fi g ures  
Pre -d ose b: 
A be macicli b P K sa m ple o nl y  
2  
  
Pre -d ose b: 
P K sa m ple f or eac h st u d y dr u g   
(e xce pt di n ut u xi ma b a n d G M-C S F)  
 
1 5  
Pre -d ose b: 
A be macicli b P K sa m ple o nl y  
 
 
A b bre viati o ns:  G M -C S F = gra n ul oc yte macr o p ha ge c ol o n y -sti m ulati n g fact or; P K = p har mac o ki netic.  
a P K sa m pli n g will i ncl u de  a b e macicli b , M 2 a n d M 2 0 (acti ve meta b olites of a be macicli b) , iri n oteca n, S N -3 8 
(acti ve meta b olite of iri n oteca n ), a n d te m oz ol o mi de.  N o P K sa m ples will be c ollecte d f or di n ut u xi ma b or G M -
C S F.  
b Pre -d ose P K sa m ples s h o ul d be dra w n pri or t o ta ki n g st u d y dr u gs.  
c F or patie nts i n P art C w h o wei g h  
 at e nr ol me nt, a be macicli b P K sa m ples s h o ul d be  ta ke n b y v ol u metric 
a bs or pti ve micr osa m pli n g rat her t ha n ve n o us bl o o d dra w. N o te m oz ol o mi de or iri n oteca n sa m ples s h o ul d be 
ta ke n fr o m t hese patie nts. 
 
 
 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T
C CI
C CI
C CI

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
5 1  
 
 
A b bre viati o ns:  hr  = h o ur; I V = i ntra ve n o us; P K = p har mac o ki netic.  
 a Dra w P K sa m ple pri or t o a d mi nisteri n g a n y st u d y dr u gs.  
b Dra w P K sa m ples pri or t o iri n oteca n i nf usi o n.  At least 1 h o ur s h o ul d se parate t he te m oz ol o mi de d ose a n d t he 
start of t he iri n oteca n i nf usi o n. 
c Re fer t o l ocal la bel a n d/ or sta n dar d of care f or i nf usi o n d urati o n. 
d Dra w P K sa m ples i m me diatel y after iri n oteca n i nf usi o n.   
e Sec o n d a b e macicli b d ose s h o ul d n ot b e a d mi nistere d u ntil after last P K sa m ple has bee n dra w n .   
f   F or patie nts i n P art C w h o we i g h  
 at e nr ol me nt, a be macicli b P K sa m ples s h o ul d be ta ke n b y v ol u metric 
a bs or pti ve micr osa m pli n g  rat her t ha n ve n o us bl o o d dra w. No te m oz ol o mi de or iri n oteca n sa m ples s h o ul d be 
ta ke n fr o m t hese patie nts. 
 
 
  
  
 
A b bre viati o ns:  hr = h o ur; P K = p har mac o ki netic.  
 a Dra w P K sa m ple pri or t o a d mi nisteri n g a n y st u d y dr u gs.  
b Sec o n d a b e macicli b d ose s h o ul d n ot b e a d mi nistere d u ntil after last P K sa m ple has bee n dra w n .   
 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T
C CI
C CI
C CI
C CI
C CI

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
5 2  
2.  
I ntr o d ucti o n  
2. 1.  
St u d y  R ati o n ale   
Des pite a d va n ces i n t he treat me nt of p e diatric ca n cers, t here is still a n u n met nee d f or efficaci o us 
an d t olera ble re gi me ns f or rela pse d/refract or y s oli d t u m ors. A be macicli b is a selecti ve a n d p ote nt 
s mall-m olec ule c ycli n-d e pe n de nt ki nase 4 a n d c ycli n -de p e n de nt ki nase 6 ( C D K 4  & 6) i n hi bit or, 
fa v ori n g C D K 4 i n hi biti o n 1 4-f ol d o ver C D K 6 i n hi biti o n i n e nz y matic assa ys (T orres -G uz m án  et 
al. 2 0 1 7 ). Base d u p o n precli nical data  a n d t he r ol e of C D K 4 & 6 i n m ulti ple pe diatric t u m or 
t y pes, Eli Lill y a n d C o m pa n y ( Lill y) h y p ot h esiz e s t hat a be macicli b a d mi nistere d i n c o m bi nati o n 
wit h te m oz ol o mi de, i n c o m bi nati o n wit h iri n oteca n a n d te m oz ol o mi de, a n d/ or i n c o m bi nati o n 
wit h di n ut u xi ma b, G M -C S F, iri n oteca n, a n d t e m oz ol o mi de will be s ufficie ntl y t olera ble wit h 
e vi de nce of cli nical a cti vit y t o s u p p ort f urt her de v el o p me nt.  
St u d y J P C S is desi g ne d t o e val uate : 
 t he rec o m me n d e d P hase 2 d ose ( R P 2 D ) f or a b e macicli b i n pe diatric patie nts wit h 
rela pse d/r efract or y s oli d t u m ors 
▪ i n c o m bi nati o n wit h iri n oteca n a n d t e m oz ol o mi de (Part A ), 
▪ i n c o m bi nati o n wit h te m oz ol o mi de (Part B ), a n d 
▪ i n c o m bi nati o n wit h di n ut uxi ma b , G M-C S F, iri n oteca n, a n d te m oz ol o mi de i n 
patie nts wit h rela pse d/r efract or y n e ur o blast o ma ( P art C).   
 t he a nti-t u m or acti vit y of a be maci cli b i n c o m bi nati o n wit h di n ut uxi ma b, G M -C S F, 
iri n oteca n, a n d te m oz ol o mi de i n patie nts wit h rela pse d/refract or y n e ur o blast o ma ( Part 
C).  
2. 2.  
B ac k gr o u n d   
Pe diatric ca n cer re prese nts a s pectr u m of rare m ali g na n cies wit h  ap pr o xi matel y 1 5, 0 0 0 patie nts 
a ged  0 t o 1 9  years  dia g n ose d i n t he U nite d States i n 2 0 1 8  ( N CI 2 0 1 8). P e diatric patie nts wit h 
rela pse d/r efract or y s oli d t u m ors t y picall y ha v e a p o or  pr o g n osis .  Treat me nt i n t his setti n g 
t y picall y res ults i n o nl y mi ni mal i m pr o ve me nts i n efficac y, wit h 5 -year p ost -rela pse s ur vi v al 
rates ofte n less t ha n 3 0 % f or pediatric s oli d t u m ors, s uc h as E wi n g’s sarc o ma, ne ur o blast o ma, 
ce ntral ner v o us s yste m ( C N S ), oste osarc o ma, a n d r ha b d o m y osarc o ma ( Ces c hel et al. 2 0 0 6; 
Da nt o nell o et al. 2 0 0 8; L o n d o n et al. 2 0 1 1; Sta hl et al. 2 0 1 1 ; Lear y et al. 2 0 1 3). I n t he 
rela pse d/r efract or y dise ase setti n g , fe w treat me nt o pti o ns e xist a n d fre q ue ntl y c o nsist of m ulti ple 
r o u n ds of c yt ot o xic c he m ot hera pies, s uc h as iri n oteca n a n d te m oz ol o mi de.   
Ne w t hera pe utic strat e gies are nee de d t o s y ner gize wit h c he m ot hera p y t o effecti ve l y i n d uce 
ca ncer cell deat h . Cell c ycle i n hi biti o n wit h a be macicli b, a p ote nt a n d selecti ve C D K 4 & 6 
i n hi bit or, is o ne s uc h strate g y t o p ote ntiate t he effects c he m ot hera p y. G e n etic a berrati o ns i n t he 
C ycli n D/ C D K 4 & 6 pat h wa y ha ve b ee n o bs er ve d i n pe diatric t u m ors, p ote ntiall y ma ki n g t he m 
se nsiti ve t o C D K 4 & 6 i n hi biti o n  ( Saa b et al. 2 0 0 6; M ole naar et al. 2 0 1 2 ; Ra der et al. 2 0 1 3; Z h u 
et al. 2 0 1 6; C o o k Sa n gar et al . 2 0 1 7; Ge oer ger et al . 2 0 1 7; St ur m et al. 2 0 1 7; D o wless et al. 
2 0 1 8) . Precli nical e vi d e n ce has de m o nstr ate d  a d diti ve acti vit y of a be macicli b i n c o m bi nati o n 
wit h te m oz ol o mi de wit h a n d wit h o ut iri n oteca n (see Secti o n 2. 2. 6 ). 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
5 3  
M ore  s pecifi call y, ne ur o blast o ma acc o u nts f or 1 2 % of c hil d h o o d ca n cer deat hs. Des pite 
a g gressi ve m ulti m o dal t hera p y, o ver 5 0 % of patie nts wit h hi g h -ris k disease will s uffer diseas e 
rela pse.  S ur vi val after rela pse of  hi g h -ris k ne ur o blast o ma i n c hil dre n o ver 1 8 m o nt hs of a ge 
re mai ns p o or  (La u a n d L o n d o n 2 0 1 2 ). A d diti o nall y, a n ot h er 5 % t o 2 0 % of ne wl y di a g n ose d l o w-
, i nter me diate-, a n d hi g h-ris k patie nts will be refract or y t o i nitial t hera p y (Z h o u et al. 2 0 1 5;  T wist 
et al. 2 0 1 9; Li u et al. 2 0 2 0 ). T hese  p atie nts wit h eit her rela ps e d or  refract ory  ne ur o blast o ma  
warra nt a d diti o nal i n vesti gati o ns.   
Treat me nt of rela pse d/refract or y n e ur o blast o ma  has e v ol ve d t o  tar get t he disial o ga n gli osi de G D 2 
t hat is e x presse d o n ne ur o blast o ma cells. D i n ut u xi ma b, t he first a nti-G D 2 m o n ocl o nal a nti b o d y, 
was  a d de d t o G M -C S F i n a mai nte na nce setti n g  aft er i nte nsi ve c h e m ot hera p y, ra diati o n t hera p y, 
s ur gic al res ecti o n, m yel o a blati ve c he m ot hera p y, a n d a ut ol o g o us ste m -cell resc ue bas e d o n  t he 
A N B L 0 0 3 2 st u d y res ults de m o nstrati n g a  2 0 %  E F S a n d 1 1 % O S i m pr o ve me nt w he n c o m pare d 
t o sta n dar d t hera pi es wit h o ut di n ut u xi ma b  ( Y u et al. 2 0 1 0 ). S u bse q ue nt de vel o p me nt of 
di n ut u xi ma b -beta, a si milar a nti -G D 2 m o n ocl o n al a nti b o d y, f oll o we d di n ut u xi ma b.   
A d diti o nal  researc h has pr o vi de d e vi de nce of t he r ole of di n ut u xi ma b, G M -C S F,  iri n oteca n, a n d 
te m oz ol o mi de i n patie nts wit h i nitial ne ur o blast o ma rela pse. I n st u d y A N B L 1 2 2 1, t he 
c o m bi nati o n of di n ut u xi ma b, G M -C S F, iri n oteca n , a n d te m oz ol o mi de  de m o nstrate d si g nifica nt 
a nti-t u m or acti vit y a n d ac hie ve d a n o v erall res p o nse rate of 4 1. 5 % , a o n e -year P F S of 6 7. 9 %  a n d 
o ne -year O S of 8 4. 9 % .  Des pite t hese a d v a nces, t here re mai ns a si g nifica nt u n met nee d f or 
c hil dre n wit h rele ase d a n d refract or y n e ur o blast o ma  ( M o d y et al. 2 0 2 0) . 
2. 2. 1.  
Te m o z ol o mi de   
Te m oz ol o mi de is a D N A-al k yl ati n g a ge nt wit h a d ult i n dicati o ns f or gli o blast o ma a n d refract or y 
a na plastic astr o c yt o m a .  I n pe diatric patie nts , it is c o m m o nl y use d i n C N S t u m ors s uc h as 
hi g h -gra de gli o mas (W orl d Healt h Or ga nizati o n  Gra de s III/I V) i n t he fr o nt-li ne setti n g a n d i n 
me d ull o blast o ma/ pri miti ve ne ur oect o der m al t u m ors i n t he rec urre nt setti n g  ( De Si o et al. 2 0 0 6; 
C o he n et al. 2 0 1 1 ; Cefal o et al. 2 0 1 4 ; G uerra-García et al. 2 0 2 0 ; Le T e uff et al. 2 0 2 0). 
Te m oz ol o mi de is als o wi del y us e d i n c o m bi nati o n wit h iri n oteca n i n pe diatric s oli d t u m ors (see 
Secti o n 2. 2. 2 ).  T he safet y pr ofile of te m oz ol o mi de is well esta blis he d a n d pre dicta ble a n d is 
k n o w n t o ca use m yel os u p pressi o n a n d he p at ot o xicit y  ( Te m oz ol o mi de U S Pac ka ge I ns ert 2 0 1 7 ). 
2. 2. 2.  
Iri n otec a n  
Iri n ot eca n is a t o p ois o merase I i n hi bit or t hat is i n dicated f or m etastatic c ol o n ca ncer i n a d ults, 
b ut is fre q ue ntl y us e d i n c o m bi nati o n wit h te m oz ol o mi de f or treat me nt of p e diatric 
rela pse d/r efract or y s oli d t u m ors, i ncl u di n g b ut n ot li mite d t o ne ur o blast o ma, E wi n g’s sarc o ma, 
oste osarc o ma, r ha b d o m y osarc o ma, a n d o t hers d ue t o t he n o n-o verla p pi n g t o xicit y pr ofile a n d t he 
acti vit y t hat has b ee n o bs er ve d i n pr ecli nical a n d cli nical st u dies ( H o u g ht o n et al. 2 0 0 0; Wa g ner 
et al. 2 0 0 4; K us h ner et al. 2 0 0 6; Case y et al. 2 0 0 9; Wa g ner et al. 2 0 0 9; Ba gatell et al. 2 0 1 1 ,  
2 0 1 4 ; K ur uc u et al. 2 0 1 5; Pal meri ni et al. 2 0 1 8 ).  T he iri n oteca n a d verse e ve nt ( A E) pr ofile  is 
well d oc u me nte d a n d pre dicta ble.  N ota bl y, i ri n oteca n ca n ca use m yel os u p pressi o n a n d earl y a n d 
late f or ms of diarr hea; earl y diarr hea ma y be acc o m pa nie d b y c h oli ner gic s y m pt o ms (Iri n oteca n 
U S Pac ka ge I ns ert 2 0 2 0 ). 
 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
5 4  
2. 2. 3.  
A be m acicli b   
A be macicli b is a n orall y a d mi nistere d, p ote nt , a n d selecti ve i n hi bit or of C D K 4 & 6 t hat is 
c urre ntl y a p pr o ve d f or t he treat me nt of h or m o ne rece pt or p ositi ve ( H R + ) / h u ma n e pi der mal 
gr o wt h fact or rece pt or 2 ne gati ve  (H E R 2 -) a d va n ce d breast ca ncer as m o n ot hera p y a n d i n 
c o m bi nati o n w it h e n d ocri ne t hera pies ( Dic kler et al. 2 0 1 7; G oetz et al. 2 0 1 7; Sle d ge et al. 2 0 1 7; 
J o h nst o n et al. 2 0 1 9).  Fr o m a t hera pe utic st a n d p oi nt, t he g oal of i n hi biti n g C D K 4 & 6 is t o 
pre ve nt c ell c ycle pr o gressi o n t hr o u g h t he G 1 restri cti o n p oi nt, t h us arresti n g t u m or gr o wt h.  
C ycli n -de p e n de nt ki nases 4 & 6 partici p ate i n a c o m ple x wit h D -t y pe c ycli ns t o i nitiate t he 
tra nsiti o n t hr o u g h t he G 1 restricti o n p oi nt, w hic h c o ntr ols e ntr y i nt o S p hase a n d is esse ntial f or 
mai ntai ni n g c o ntr ol o f cell di visi o n ( S herr 1 9 9 6; Orte ga et al. 2 0 0 2) t hr o u g h p h os p h or ylati o n of 
t he reti n o blast o ma ( R B) t u m or s u p press or pr otei n.  Alterati o ns i n t his pat h wa y o cc ur fre q u e ntl y 
i n h u ma n ca ncers a n d i n v ol ve: 
 l oss of e n d o ge n o us c ycli n -de pe n de nt ki nas e ( C D K) i n hi bit ors b y m utati o n or e pi ge netic 
sile nci n g, 
 m utati o n/ o vere x pressi o n of eit her C D K 4 & 6 or C ycli n D, or  
 i nacti vati o n of R B . 
T hese alterati o ns re n der cells less de pe n de nt o n mit o ge nic si g nali n g f or pr oliferati o n.   Wit h t he 
p ossi ble e x ce pti o n of t h ose t u m ors wit h c o m plete i nacti vati o n of R B , w hic h f u ncti o ns 
d o w nstrea m of t he C ycli n D/ C D K 4 & 6  c o m ple x, ca ncers t hat i n v ol ve C D K m utati o ns or o ver -
e x pressi o n are p ote ntiall y se nsiti ve t o p har m ac ol o gic i n hi biti o n of C D K 4 & 6.  
2. 2. 4.  
Di n ut u xi m a b   
I n h u ma ns, G D 2 e x press i o n is al m ost e x cl usi vel y li mite d t o ne ur o blast o ma cells  a n d ne ur o ns , 
ma ki n g G D 2 a s uita ble tar get f or i m m u n ot hera p y  (Y u et al . 2 0 1 0). A nti -G D 2 m o n ocl o nal 
a nti b o dies, i ncl u di n g di n ut u xi ma b a n d di n ut u xi ma b-beta, rel y o n i m m u ne effect or f u n cti o ns li ke 
c o m ple me nt -de pe n d e nt c yt ot o xicit y  a n d A D C C , w hic h are e n ha n ce d w he n c o m bi ne d wit h G M -
C S F .  A nti-G D 2 t hera pi es ha ve dra m ati call y i m pr o v e d ne ur o blast o ma tr eat me nt o utc o mes .   
T he a nti -G D 2 a nti b o d y d i n ut u xi ma b was first  a p pr o ve d i n 2 0 1 5 b y t he F D A f or i nitial treat me nt 
of ne ur o blast o ma f oll o wi n g i nte nsi ve m ulti m o dal t hera p y .  A p pr o v al was gra nte d bas e d o n t he 
res ults fr o m t he pr os pecti ve, ra n d o mize d A N B L 0 3 2 st u d y i n w hic h d i n ut u xi ma b was c o m bi ne d 
wit h  G M -C S F, i nterle u ki n 2 (I L -2), a n d cis -reti n oic aci d (is otreti n oi n) f or t he treat me nt of 
pe diatric patie nts wit h hi g h -ris k ne ur o blast o ma w h o ac hie ve at least a p artial res p o nse t o i nitial 
m ulti m o dalit y t hera p y.   I n Eur o pe, di n ut u xi ma b -beta  is t he a p pr o ve d a nti-G D 2 m o n ocl o nal 
anti b o d y.  I L-2 has bee n re m o ve d fr o m t he st a n dar d c o m bi nati o n base d o n t he ris k -be nefit 
pr ofile as de m o nstrat e d b y La d e nstei n et al. (2 0 1 8 , 2 0 1 9).      
After  s h o wi n g dra matic i m pr o ve me nts w he n a d d e d t o t he mai nte na nce s etti n g i n first-li ne 
treat me nt, a nti-G D 2 t h era p y h as si nce b ee n s h o w n t o a d d be nefit i n patie nts wit h rela pse d or 
refract or y dise ase, i ncl u di n g i n patie nts w h o e x perie nce d diseas e rel a pse after pre vi o us e x p os ure 
t o di n ut u xi ma b i n t he fr o nt-li ne mai nte na nce s etti n g.  Di n ut u xi ma b wit h G M -C S F, iri n oteca n, 
a n d te m oz ol o mi de s h o we d a n O R R  of 4 1. 5 %  ( 9 5 % CI: 2 8. 2 %,  5 4. 8 %)  i n t he A N B L 1 2 2 1 trial 
lea di n g t o a d o pti o n of t his re gi me n as sta n dar d of care f or first r ela pse wit hi n t he U S  a n d 
pr o m pti n g trials of di n ut u xi ma b -beta  as rela pse d/refract or y t hera p y  i n E ur o pe ( M o d y et al. 
2 0 2 0) .    
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
5 5  
J P C S Part C ai ms t o i m pr o ve t he o utc o mes  of di n ut u xi ma b , G M -C S F, iri n oteca n , a n d 
te m oz ol o mi de i n t he first rela psed /r efract or y setti n g.  
2. 2. 5.  
G M -C S F   
T he  c yt o ki ne G M -C S F is a n i m p orta nt c o m p o ne nt of c he m oi m m u n ot hera p y i n ne ur o blast o ma .  
G M -C S F a m plifies t he A D C C effects  o f a nti-G D 2  a nti b o dies via acti vati o n  a n d sti m ulati o n  of 
gra n ul oc ytes a n d m acr o p ha ges  t o f u ncti o n as a nti ge n -pres e nti n g cells  t o pr o m ote a h ost a nti-
t u m or res p o nse ( Y u et al. 20 1 0 ).  T he a d diti o n  of G M -C S F wit h  d i n ut u xi ma b t o c he m ot hera p y 
has bee n  de m o nstr ate d t o be effi caci o us i n m ulti ple st u dies  (M o d y et al. 2 0 2 0; Y u et al. 2 0 1 0 ), 
a n d t he c o m bi nati o n of a nti-G D 2 a nti b o dies wit h G M -C S F  n o w ser ves as part of t he sta n dar d of  
care. 
2. 2. 6.  
Precli nic al  a n d Cli nic al R ati o n ale   
Pe diatric ca n cers ofte n h ar b or ge n etic a b errati o ns i n t he C ycli n D/ C D K 4 & 6 pat h wa y , ma ki n g 
t he m l o gical c a n di dates f or se nsiti vit y t o a be macicli b.  I n a pa nel of 3 9 cell li nes deri ve d fr o m 
patie nts a ge d ≤2 1 years a n d e nc o m passi n g a wi de s pectr u m of hist ol o gies, t he a bs ol ute I C 5 0 of 
a be maci cli b was wit hi n a cli nicall y rele va nt r a n ge ( < 2 µ M ; wit hi n  2 -f ol d of a vera ge patie nt 
c o nce ntr ati o ns [ G o n g et al. 2 0 1 7 ; D o wless et al. 2 0 1 8]) i n a p pr o xi matel y h alf of t he cell li nes, 
w hic h warra nte d a d diti o nal st u dies of a be macicli b i n pe diatric m o dels.  
E wi n g’s s arc o m a has bee n re p orte d t o ha ve deleti o n of C D K N 2 A  (e nc o des t he p 1 6I N K 4a t u m or 
s u p press or t hat bi n ds t o C D K 4 & 6) i n a p pr o xi matel y 1 0  t o 3 0 % of pri mar y t u m ors a n d nearl y 
5 0 % of E wi n g’s sarc o ma cell li nes ( D o wless et al 2 0 1 8).  I n t he cell -deri ve d x e n o graft E wi n g’s 
sarc o ma m o del A 6 7 3 ( deri ve d fr o m a 1 5 -year -ol d  patie nt), of t he 6 a ni mals treate d wit h t he 
tri plet c om bi nati o n of a be macicli b, iri n oteca n, a n d te m oz ol o mi de, 1 ha d a partial re gressi o n a n d 
5 ha d sta ble disease, w hile t he 6 a ni mals treate d wit h iri n oteca n a n d te m oz ol o mi de e x perie nce d 
pr o gressi ve dise ase ( D o wless et al. 2 0 1 8).   I n a d diti o n, d ura ble res p o nses wit h a be macicli b i n 
c o m bi nati o n wit h iri n oteca n a n d te m oz ol o mi de ha ve bee n re p orte d i n ot her E wi n g’s sarc o ma 
m o dels ( D o wless et al. 2 0 1 8).  
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
5 6 
A 6 7 3 
s s arc o m a C D X m o del i n mi ce tre ate d wit h ve hicle, a be m acicli b ( d ail y f or 2 8 
d a ys), iri n otec a n a n d te m o z ol o mi de ( d ail y f or 5 d a ys, rest f or 1 6 d a ys, t he n d ail y f or 5 
d a ys), or a be m acicli b, iri n otec a n, a n d te m oz ol o mi de, (s a me sc he d ules f or e ac h dr u g as 
a b o ve).  Tre at me nt st arte d o n a p pr o xi m atel y D a y 1 5. ( A) T u m o r v ol u me o ver ti me ( B) 
T u m or res p o nse assess me nt at D a y 3 1 ( M o difie d fr o m D o wless et al. [ 2 0 1 8] ). 
 
A b bre viati o ns:  C D X = cell -deri ve d xe n o graft; P D = pr o gressi ve  disease; P R = partial res p o nse; S D = sta ble 
disease; T/ C = treate d t u m or size di vi de d b y c o ntr ol t u m or size; T M Z = te m oz ol o mi de.  
A d diti o nall y, ne ur o blast o ma has bee n re p orte d t o ha ve dere g ulati o n of t he C D K pat h wa y 
t hr o u g h a m plificati o n of C D K 4  a n d C C N D 1  ( C ycli n D 1) a n d deleti o n of C D K N 2 A  ( M ole naar et 
al. 2 0 1 2; Ra der et al. 2 0 1 3).  I n a pa n el of 9 ne ur o blast o ma cell li nes, all 9 wer e s e nsiti ve t o 
a be maci cli b at cli nicall y rele va nt c o n ce ntr ati o ns. A be macicli b ( 5 0 m g/ k g/ oral/ o nce dail y [ Q D]) 
was als o e val u ate d as a si n gle a ge nt i n 2 cell- d eri v e d x e n o graft m o dels ( K E L L Y a n d I R- 3 2) of 
pe diatric ne ur o blast o ma.  I n b ot h m o dels, a b e maci cli b ha d a statisticall y si g nifica nt t u m or 
gr o wt h re d ucti o n w h e n c o m pare d t o t he ve hicl e, res ulti n g i n a Res p o nse E val uati o n Criteria i n 
S oli d T u m ors ( R E CI S T) of sta ble disease f or K E L L Y a n d partial r e gressi o n f or I M R- 3 2.  I M R-
3 2 is k n o w n t o ha ve a F B X 0 3 1  l oss of f u ncti o n, a feat ure li n ke d t o C ycli n D 1 acti vati o n, a n d 
t heref ore ma y be a t he m ore se nsiti ve m o del ( Ri ha ni et al. 2 0 1 5; G o n g et al. 2 0 1 7).  T here were 
n o si g nifica nt c o ncer ns f or t olera bilit y as assesse d b y t wice- wee kl y meas ure me nts of b o d y 
wei g ht a n d dail y o bser vati o n of ge n eral a p peara nce.   
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
5 7  
E v al u ati o n of A be m acicli b i n Cell -Deri ve d Ne ur o bl ast o m a Xe n o gr aft M o dels  
M o del  
n  
% T/ C or 
Re gressi o n  
P -v al ue  
R E CI S T  
% c h a n ge b o d y wei g ht 
fr o m b aseli ne 
P -v al ue  
I M R-3 2  
6  
-6 9. 5  
< 0. 0 0 1  
partial re gressi o n  
-6. 9  
0. 0 1 3  
K E L L Y  
5  
1 3. 5  
< 0. 0 0 1  
sta ble disease 
-6. 8  
< 0. 0 0 1  
A b bre viati o ns:  R E CI S T = Res p o nse E val uati o n Criteria i n S oli d T u m ors; T/ C = treate d t u m or size di vi de d b y 
c o ntr ol t u m or size.  
Pe diatric hi g h -gra d e gli o ma ca n als o har b or ge n etic a berrati o ns s uc h as C C N D/ C D K 
a m plificati o n a n d C D K N 2 A/ B  deleti o n ( St ur m et al. 2 0 1 7). I n a patie nt -d eri ve d x e n o gra ft m o del  
of  pe diatric hi g h -gra de gli o ma , ra di ot hera p y, a dj u va nt  te m oz ol o mi de a n d a be macicli b  
si g nifica ntl y e xte n de d s ur vi val c o m pare d t o b ot h ra di ot hera p y al o n e a n d t o ra di ot hera p y pl us  
te m oz ol o mi de i n t he m o del s h o w n bel o w . T hree ot her m o dels di d n ot s h o w c o nsiste nt res ults.  
 
C N X F 4 2 0 4 pe di atric hi g h -gr a de gli o m a p atie nt -deri ve d xe n o gr aft m o del  ( n =8 per gr o u p). 
Mice w ere tre ate d  wit h 1 G y  x 1 d a y  r a di ot her a p y , te m oz ol o mi de d ail y ( a p pr o xi m atel y 5 
d a ys per c ycle x 2 c y cles de pe n di n g o n t oler a bilit y), a n d a be m acicli b d ail y o n d a ys 1 -6 6 or 
1 1 -6 6 as i n dic ate d . 
 
A d diti o nall y , a be m acicli b m o n ot hera p y a n d a b e m acicli b c o m bi ne d wit h te m oz ol o mi de ha ve 
bee n e v al uate d i n a n a d ult gli o blast o ma  m o dels .  Usi n g a rat ort h ot o pic U 8 7 M G x e n o graft 
m o del, a be macicli b m o n ot hera p y res ulte d i n a si g nifica nt l y i m pr o ved  s ur vi val c o m pare d t o t he 
c o ntr ol ( ve hicle -treat e d) ( Ra u b et al. 2 0 1 5).  F urt h er m ore , i n r ats wit h i ntracra nial U 8 7 M G 
t u m ors, a be macicli b c o m bi n e d wit h te m oz ol o mi de was , at mi ni m u m, a d diti ve c o m pare d t o eit her 
as m o n ot hera p y ( Ra u b et al. 2 0 1 5).  T hese a n d ot her st u dies i n dicate d t hat a be macicli b ca n cr oss 
t he bl o o d-brai n barrier wit h  u n b o u n d brai n le vels e x pecte d t o i n hi bit C D K 4 & 6 ( Ra u b et  al. 
2 0 1 5).  
 
 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
5 8  
U 8 7 M G o rt h ot o pic gli o m a m o del ( n = 8 per gr o u p) .  R ats w ere tre ate d st arti n g o n d a y 6 at 
t he i n dic ate d sc he d ule i n t a ble ( gre y h oriz o nt al b ar a b o ve x-a xis i n dic ates tre at me nt 
peri o d) ( M o difie d f r o m R a u b et al. [2 0 1 5 ]). 
 
A b bre viati o ns :  Q D = o n ce dail y; Q 2 D = t wice dail y; T M Z = te m oz ol o mi de.  
A be macicli b w as als o i n vesti gate d i n a gli o blast o ma c o h ort of a d ult patie nts i n t he P hase 1 St u d y 
I 3 Y-M C -J P B A.  Of 1 7 e nr olle d, 3 patie nts e x hi bite d sta ble disease at t he ti me of t he pri ma r y 
e n d p oi nt ( Pat nai k et al. 2 0 1 6).  T w o patie nts c o nti n ue d t o recei ve a b e macicli b wit h o ut disease 
pr o gressi o n f or 1 9 a n d 2 3 c ycles, a n d t he y re mai n e d o n treat me nt at t he ti me of data c ut off.  I n  
t he P hase 2 St u d y I 3 Y-M C -J P B O of a be macicli b i n patie nts wit h brai n metastases t here was  
e vi de nce t o s u p p ort t hat a be maci cli b ac hie ved t h era pe utic c o n ce ntr ati o ns i n brai n metastases 
( T ola ne y et al. 2 0 2 0 ). 
Ot her pe diatri c s oli d t u m ors, s uc h as ost e osarc o m a, mali g n a nt r ha b d oi d t u m ors, 
me d ull o blast o ma, a n d r ha b d o m y os arc o ma, ha ve b ee n re p orte d t o c o ntai n ge netic a b errati o ns t hat 
ma y c o nfer se nsiti vit y t o a be maci cli b, alt h o u g h s ufficie nt st u dies ha ve n ot bee n perf or me d t o 
vali date acti vit y ( Saa b et al.  2 0 0 6;  Z h u et al. 2 0 1 6;  Ge oer ger et al. 2 0 1 7; C o o k Sa n gar et al. 
2 0 1 7).  Ot her C D K 4 & 6 i n hi bit ors ( pal b ocicli b a n d ri b ocicli b) ha ve b ee n e val uate d i n 
precli nical or cli nical st u dies wit h se veral of t h ese t u m or t y pes, b ut res ults are li mite d base d o n 
s mall n u m bers a n d a lac k of c o nfir mat or y st u dies ( Has hiz u me et al. 2 0 1 6; C o o k Sa n gar et al. 
2 0 1 7 ; Ge oer ger et al. 2 0 1 7).   
I m p ort a ntl y, alt h o u g h St u d y J P C S is t he first Lill y-s p o ns or e d pe diatric cli nical trial of 
a be maci cli b, a n e x pl orat or y i n vesti gat or -s p o ns ore d P hase 1 cli nical trial e val uati n g t he 
si n gle-a ge nt a cti vit y of a be macicli b i n c hil dre n a n d y o u n g a d ults is c urre ntl y o n g oi n g i n t he 
U nite d States (Cas h et al. 2 0 1 9 ).  T he 1 3 0 m g/ m 2 BI D d os e le vel ( e q ui vale nt t o a p pr o xi matel y 
2 0 0 m g BI D f or a n a d ult), is  re p orte d t o be well t olerate d i n pe diatri c patie nts wit h 
rec urre nt/refract or y s oli d t u m ors, i ncl u di n g mali g na nt brai n t u m ors ( Cas h et al. 2 0 1 9).  
T o get h er, t he mec ha nis m of acti o n of a b e macicli b, t he n o ncli nical data s u p p orti n g i n v ol ve me nt 
of t he C ycli n D / C D K 4 & 6 pat h wa y i n pe diatric ca ncers, as well as t he great u n met me dical nee d 
ha ve pr o m pte d St u d y J P C S. 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
5 9  
2. 3.  
Be nefit / Ris k Assess me nt  
T here is a n ur ge nt ne e d f or ne w effecti ve c o m bi nati o ns of tar gete d t hera pies t o treat rela ps e d 
mali g na n cies .  T he a d diti o n of a be ma cicli b will b uil d u p o n sta n dar d bac k b o ne c he m ot hera p y t o 
e val uate safet y a n d t olera bilit y a n d will i nf or m effi cac y assess me nts i n f ut ure a p pr o pri atel y 
p o were d t u m or -specific st u dies.   T he st u d y desi g n e ns ure s t hat t he c o m m o nl y use d dise ase -
s pecific t hera pies (te m oz ol o mi de ±  iri n oteca n f or ma n y s oli d t u m ors a n d a nti-G D 2 a nti b o dies 
wit h G M -C S F , te m oz ol o mi de, a n d iri n oteca n f or ne ur o blast o ma) will n ot be wit h hel d.  Gi ve n t he 
o bser ve d safet y pr ofile of a be ma cicli b i n a d ults a n d t he k n o w n ris k pr ofile of di n ut u xi ma b, G M -
C S F, iri n oteca n, a n d te m oz ol o mi de, t he ris k f or t he c o m bi nati o ns i n t he pr o p ose d st u d y 
p o p ulati o n is e x pecte d t o be ma na gea ble.  
E xtra p olati n g fr o m a d ult cli nical safet y dat a wit h a be macicli b, diarr h ea, n e utr o pe nia, a n d al a ni ne 
a mi n otra nsferase ( A L T) i ncreas e d, all of w hic h ha ve de m o nstrate d re versi bilit y wit h r e d ucti o n or 
disc o nti n uati o n of a be ma cicli b, are c o nsi dere d p ot e ntial areas of o verla p pi n g t o xicit y w he n gi ve n 
i n c o m bi nati o n wit h iri n oteca n a n d t e m oz ol o mi de a n d wit h di n ut u xi ma b .  T hese e ve nts are 
rea dil y m o nit ore d a n d m a na gea ble.   
A d diti o nal details o n t he ma na ge me nt of diarr hea are i n Secti o n 6. 5. 2 ; a d diti o nal details o n d ose 
m o dificati o ns f or diarr hea, he mat ol o gic t o xicit y, h e pa t ot o xicit y, a n d ot her t o xicities are i n 
Secti o n 6. 6 ; a n d a d diti o nal details of he patic m o nit ori n g are i n Secti o n 8. 2. 1. 1 . 
T he m olec ular p at h o p h ysi ol o g y t hat pr o m otes gr o wt h i n  ma n y pe di atric mali g na nci es a n d t he 
e xisti n g precli nical data s u p p ort t he e val uati o n of a be maci cli b i n rela pse d/r efract or y pe diatric 
s olid t u m ors i n c o m bi nati o n wit h c yt ot o xic t hera p y ( i.e. t e m oz ol o mi de, iri n oteca n). I m p orta ntl y, 
t he C D K 4 & 6 p at h wa y ca n als o be  dere g ulate d i n ne ur o blast o ma, a n d t he a d diti o n of 
a be maci cli b  t o c he m oi m m u n ot hera p y pr o vi des a n o vel strate g y t o p ote ntiall y i m pr o ve o utc o mes 
f or patie nts wit h rela ps e d/refract or y ne ur o blast o ma. 
M ore i nf or mati o n a b o ut t he k n o w n a n d e x pecte d be nefits, ris ks, seri o us a d v erse e v e nts ( S A Es) , 
a n d reas o n a bl y a ntici pate d A Es of a be m acicli b are t o be f o u n d i n t he I n vesti gat or’s Br oc h ure 
(I B). 
M ore detaile d i nf or mati o n a b o ut t he k n o w n a n d e x pecte d be nefits a n d ris ks of di n ut u xi ma b, 
G M -C S F,  iri n oteca n, a n d  te m oz ol o mi de, ma y b e f o u n d i n t he Patie nt I nf or mati o n Leaflet, 
Pac ka ge I ns ert , a n d/ or S u m mar y of Pr o d uct C haracteristics. 
2. 3. 1.  
Be nefit/ Ris k Assess me nt of C O VI D -1 9   
E ns uri n g t he h ealt h a n d s afet y of researc h p artici p a nts, re d uci n g t he b ur d e n o n t he healt hcare 
s yste m, a n d u p h ol di n g t h e i nte grit y of cli nical trial data are of t he ut m ost i m p orta nce.  Bas e d o n 
t he p o or s ur vi val a n d lac k of t hera p e utic o pti o ns f or pe diatric p atie nts wit h rela pse d/r efract or y 
s oli d t u m ors, t he p ote ntial be nefits st u d y patie nts ma y recei ve o ut wei g h t h e ris ks t he y ma y 
e nc o u nter b y b ei n g o n -site at t he facilit y t o recei ve treat me nt d uri n g t he C O VI D-1 9 pa n d e mic.  
W het her t hese patie nts see k treat me nt i n a cli nical trial setti n g or i n a sta n d ar d healt hcare setti n g, 
t he ris k of C O VI D-1 9 i nfecti o n will be prese nt.  Acti vities i n t his trial were desi g ne d t o reflect 
t he sta n dar d of care acti vities f or t his patie nt p o p ulati o n.  H o we ver, t here are s o me ad diti o nal 
visits (s uc h as o n da ys wit h P K assess me nts) t o e ns ure patie nt safet y a n d t o meet t he trial 
o bjecti ves.  T hese a d diti o nal visits are n ot c o nsi dere d t o p ose a si g nifica nt i ncreas e i n ris k, si nce 
sta n dar d l ocal h os pital/cli nic pr oce d ures t o pre v e nt t he s prea d of C O VI D-1 9 will be i n place.   
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
6 0  
I n or der t o mai ntai n r e g ular visits a n d treat me nt a d mi nistrati o n, fle xi bilit y meas ures, s uc h as 
all o wi n g re m ote visits, ha ve bee n i nte grate d i nt o t his cli nical trial pr ot oc ol as o utli ne d i n 
Secti o n  1 0. 7 , A p pe n di x 7, t h us mi ni mizi n g i nter pers o nal c o ntact.  T h ese fle xi bilit y meas ures will 
all o w f or c o m plia nce wit h t his pr ot oc ol, t here b y e ns uri n g p atie nt safet y a n d data relia bilit y.  
Wit h t he fle xi bilit y meas ures i n place a n d t he hi g h u n met nee d of t he p atie nts partici pati n g i n 
St u d y J P C S, t he p ote ntial be nefits of St u d y J P C S o ut wei g h t he p ot e ntial ris ks of starti n g t he tri al 
d uri n g t he C O VI D -1 9 p a n d e mic. 
2. 3. 2.  
O ver all Be nefit R is k C o ncl usi o n:  
Gi ve n t he o bser ve d safet y pr ofile of a b e macicli b i n a d ults a n d t he k n o w n ris k pr ofile s of 
di n ut u xi ma b, G M -C S F, iri n oteca n, a n d t e m oz ol o mi de , t he ris k f or t he c o m bi nati o ns i n t he 
pr o p ose d st u d y are e x pecte d t o be ma na gea ble . A d diti o nall y, c o nsi deri n g t h e meas ures ta ke n t o 
e ns ure partici pa nt safe t y, t he p ote ntial ris ks are j ustifie d b y t he p ote ntial be nefits f or i n di vi d uals 
wit h  rela pse d mali g na n cies. 
 
 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
6 1  
3.  
O bjecti ves  a n d E n d p oi nts   
O bjecti ves  
E n d p oi nts  
Pri mar y  
 
T o deter mi ne t he o pti mal R P 2 D f or a be macicli b i n 
patie nts wit h rela pse d/refract or y s oli d t u m ors: 
 Part A:  i n c o m bi nati o n wit h iri n oteca n a n d 
te m oz ol o mi de  
 Part B:  i n c o m bi nati o n wit h te m oz ol o mi de  
 
D L Ts  
 
M T D  
 
P K (c o nce ntrati o ns of a be macicli b, iri n oteca n, 
a n d te m oz ol o mi de)  
Part C: T o deter mi ne t he o pti mal R P 2 D, a n d a nti -
t u m or acti vit y of a be macicli b i n c o m bi nati o n wit h 
di n ut u xi ma b, G M -C S F, iri n oteca n, a n d 
te m oz ol o mi de i n patie nts wit h rela pse d/refract or y 
ne ur o blast o ma per I N R C  
 
D L Ts  
 
P K (c o nce ntrati o ns of a be macicli b, iri n oteca n, 
a n d te m oz ol o mi de) a 
 
O R R deter mi ne d b y i n vesti gat or  assess me nt 
Sec o n dar y  
 
T o c haracterize t he safet y pr ofile of t he 
c o m bi nati o n t hera pies 
 
Safet y (i ncl u di n g b ut n ot li mite d t o):  T E A Es, 
S A Es, deat hs  
 
Cli nical la b orat or y a b n or malities per C T C A E 
( versi o n 5. 0), vital si g ns, a n d p h ysical 
e xa mi nati o ns 
 
D ose m o dificati o ns of all st u d y dr u gs 
T o d oc u me nt t he preli mi nar y a nti -t u m or acti vit y 
of t he c o m bi nati o n t hera p y per R E CI S T v 1. 1 or 
R A N O (f or C N S t u m ors) f or Parts A a n d B, a n d 
per I N R C f or part C.  
 
D o R  
 
C B R  
 
D C R  
 
O R R ( Parts A & B o nl y)  
 
P F S deter mi ne d b y i n vesti gat or assess me nt 
(Part C o nl y)  
T o assess t he acce pta bilit y a n d palata bilit y of t he 
ta blet a n d/ or gra n ule a be macicli b, i ncl u di n g 
dis perse d ta blets a n d/ or gra n ules  
Assess me nt of ta blet, gra n ule, or dis perse d 
a be macicli b prese ntati o n, i ncl u di n g acce pta bilit y 
a n d palata bilit y 
Tertiar y/ E x pl orat or y  
 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T
C CI

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
6 2  
A b bre viati o ns:  C B R = cli nical b e nefit rate; C T C A E = C o m m o n T er mi n ol o g y Criteria f or A d verse E ve nts; D C R = 
disease c o ntr ol rate; D o R = d urati o n of res p o nse; D L T = d ose -li miti n g t o xicit y; G M -C S F  = gra n ul oc yte 
macr o p ha ge c ol o n y -sti m ulati n g fact or; 
 M T D = 
ma xi m u m t olerate d d ose; O R R = o verall res p o nse rate; 
 P F S = pr o gressi o n -free s ur vi val; 
P K = p har mac o ki netics; R A N O = Res p o nse Assess me nt i n Ne ur o -O nc ol o g y; R E CI S T = Res p o nse E val uati o n 
Criteria i n S oli d T u m ors; R P 2 D = rec o m me n de d P hase 2 d ose; S A E = seri o us a d verse e ve nt; T E A E = treat me nt -
e mer ge nt a d verse e ve nt.  
a 
I n P art C, P K is a pri mar y e n d p oi nt f or Sta ge 1 o n l y.  
 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T
C CI
C CI
C CI

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
6 3  
4.  
St u d y Desi g n   
4. 1.  
O ver all  Desi g n   
Secti o n 1. 2  ill ustrates t he st u d y sc he m a. 
St u d y  J P C S is a m ultice nter P hase 1 b / 2 st u d y wit h 3 parts. Parts A a n d B are i n patie nts wit h a n y 
rela pse d/r efract or y s oli d t u m or t hat ha s pr o gresse d o n  sta n dar d treat me nts a n d f or w h o m 
e x peri me ntal t hera p y wit h a be maci cli b i n c o m bi nati o n wit h te m oz ol o mi de or i n c o m bi nati o n 
wit h te m oz ol o mi de a n d  iri n oteca n is dee me d me dicall y a p pr opriate b y t he i n vesti gat or. Part C 
will  e x cl usi vel y e nr oll partici pa nts wit h rela pse d/r efract or y ne ur o blast o ma a n d f or w h o m 
e x peri me ntal t hera p y wit h a be maci cli b i n c o m bi nati o n wit h di n ut u xi ma b, G M -C S F, iri n oteca n , 
a n d te m oz ol o mi de  is dee me d me dicall y a p pro priate b y t he i n v esti gat or.   D ue t o gl o bal 
differe n ces i n t he sta n d ar d of care f or t his p o p ulati o n, t he trial will e nr oll patie nts t o Part C o nl y 
i n N ort h A merica a n d A ustralia.    
T he t otal sa m ple siz e f or t he  st u d y is de pe n d e nt o n t he i nci de nce of D L Ts in all parts  a n d 
res p o nses i n P art C. T he  st u d y will e nr oll a p pr o xi matel y 3 0  t o 1 1 7  patie nts  (see Secti o n 9. 2 ). 
Patie nts i n Parts A a n d B m ust be  ≤1 8 years of a ge a n d wei g h ≥1 0 k g  (wit h b o d y s urface area 
[B S A ] ≥0. 5  m 2). Patie n ts i n Part C m ust be < 2 1 years of a ge (f or patie nts wit h a starti n g 
a be maci cli b d ose of  3 0 m g/ m 2  BI D , B S A m ust b e ≥0. 3 m 2). T he trial will be c o n d ucte d 
f oll o wi n g a 3 + 3 d ose es calati o n  sc he me f or P arts A a n d B a n d Si m o n’s t w o -sta ge desi g n (Si m o n 
1 9 8 9)  wit h a d ose fi n di n g c o m p o n e nt f or Part C: 
 Part A:  a be maci cli b i n c o m bi nati o n wit h iri n oteca n a n d te m oz ol o mi de  
 Part B:  a be m acicli b i n c o m bi nati o n wit h te m oz ol o mi de  
 Part C:   a be macicli b i n c o m bi nati o n wit h di n ut u xi ma b,  G M -C S F, iri n oteca n , a n d 
te m oz ol o mi de. 
Part A will be e x ec ute d  first t o c o nfir m t he M T D of a be macicli b i n c o m bi nati o n wit h iri n oteca n 
a n d te m oz ol o mi de .  T he  M T D is defi ne d as t he hi g hest d ose l e vel at w hic h less t ha n 3 3 % of 
patie nts e x perie nce a D L T d uri n g C ycle 1.  After t he M T D of a b e macicli b i n Part A has bee n 
deter mi ne d, Part s B  a n d C  will o pe n .  As  Part B re d uces c u m ulati ve e x p os ure t o 
m yel os u p pressi ve a ge nts , it will e nr oll at a starti n g d ose o ne le vel hi g her t ha n t he a be m acicli b 
M T D  i n Part A ( n ot t o e xcee d 1 1 5 m g/ m2).  Si nce Part B will n ot start at t he l o west d ose le vel  
(u nless t he l o west d ose l e vel of Part A is n ot t olerate d) , t his se q ue ntial desi g n has p ote ntial  t o 
mi ni mize t he n u m ber of patie nts necessar y t o c o m plete Part B.   T he d os e escalati o n/ de -
escalati o n met h o d f or a b e macicli b i n Parts A a n d B is descri b e d i n detail i n Secti o n 4. 1. 1 . Part  C 
will utilize  t he M T D  f or t he c o m bi nati o n of a be m acicli b , iri n oteca n, a n d t e m oz ol o mi de  
i de ntifie d i n Part A a n d t he sta n dar d d osi n g of di n ut u xi ma b a n d G M-C S F  ( M o d y et al. 2 0 20)  as 
t he starti n g d ose.  Part C  c o nsists of t w o sta ges t hat will e val uate ( 1) safet y a n d t olera bilit y a n d 
( 2) a nti-t u m or acti vit y of t he c o m bi nati o n ( details i n Secti o n 4. 1. 2 ).  
D ose -li miti n g t o xicities will be e val uate d d uri n g t he 2 1 da ys of treat me nt  i n C ycle 1.  After t he 
M T D has bee n i d e ntifie d , a n e x pa nsi o n c o h ort f or eac h p art will be e nr olle d  t o f urt her i nf or m 
safet y a n d P K a n d t o c o nfir m t he t olera bilit y i n a d diti o nal patie nts .  
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
6 4  
T he c ycle l e n gt h is 2 1 da ys .  Patie nts will c o nti n ue st u d y tr eat me nt u ntil at least o ne of t he 
disc o nti n uati o n criteria is met  ( Secti o n 7 ).  C o nti n uati o n  o n c he m ot hera p y be y o n d C ycl e 1 2 will 
be u p t o t he i n vesti gat or’s discreti o n a n d t he i n di vi d ual patie nt’s sit uati o n .  Pri or t o c o nti n ui n g 
t he patie nt o n c he m ot hera p y b e y o n d C ycle 1 2, t he i n vesti gat or s h o ul d disc uss wit h t he Lill y 
cli nical researc h p h ysi cia n/cli nical researc h sci e ntist ( C R P/ C R S ). 
T he  pri mar y o bje cti ve  i n Parts A a n d B is t o deter mi ne t he R P 2 D of a be macicli b i n c o m bi nati o n 
wit h iri n oteca n a n d te m o z ol o mi de (Part A ), a n d a be macicli b i n c o m bi nati o n wit h te m oz ol o mi de 
(Part B ) i n p atie nts wit h rela pse d/refract or y s oli d t u m ors. T he sec o n d ar y o bjecti ves i ncl u de t he 
assess me nt of t he safet y pr ofile, preli mi nar y a nti-t u m or acti vit y, a n d a be macicli b  acce pta bilit y 
a n d palata bilit y. 
 
T he c o-pri mar y o bjecti ve s i n Part C are t o e val uat e t he safet y, t olera bilit y, a n d a nti-t u m or 
acti vit y of a be ma cicli b i n c o m bi n ati o n wit h di n ut u xi ma b,  G M -C S F,  iri n oteca n, a n d 
tem oz ol o mi de i n patie nts wit h rela pse d/refract or y ne ur o blast o ma.  T he s ec o n dar y o bjecti ves 
i ncl u de t he assess me nt of D o R, C B R, D C R, a n d  P F S b y i n vesti gat or  assess me nt , a n d e val uati o n 
of d r u g pr o d uct acce pta bilit y a n d palata bilit y. 
 
 
4. 1. 1.  
D ose  Esc al ati o n Desi g n  f or P arts A a n d B  
T he d ose will be escalate d f oll o wi n g ass ess me nt of t o xicit y usi n g t he sta n d ar d sc ori n g s yste m, 
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 ) Versi o n 5. 0, esta blis he d b y t h e 
Nati o nal Ca ncer I nstit ute ( N CI).  
I n Part A, patie nts  will be gi n a be ma cicli b at D ose Le v el 1 ( 7 0  m g/ m 2).  After t he d ose escalati o n 
of Part A  is c o m plete d, o ne d ose le vel hi g her t ha n t he M T D of a b e macicli b i n Part A  will be 
use d as t he starti n g d ose i n t he d ose escal ati o n of Part B, b ut  will  n ot e xcee d 1 1 5 m g/ m 2 BI D.   
T hree p atie nts are pla n ne d f or treat me nt at eac h d ose le vel; h o we ver, t he e x act n u m ber of 
patie nts treate d at a s pecific d ose le vel d e pe n ds o n t he n u m ber of patie nts wit hi n t he c o h ort w h o 
e x perie nce d a D L T.  
Patie nts will be c o ns i dere d D L T-e v al ua ble i f t h e y ha ve eit her c o m plete d t h e D L T-o bser vati o n 
peri o d a n d recei v e d at least 7 5 % of pla n ne d d os es of eac h st u d y dr u g i n C ycle 1  or  ha v e 
disc o nti n ue d st u d y treat me nt or st u d y partici pati o n bef ore c o m pleti n g C ycle 1 d ue t o a D L T or  
recei v e d less t ha n 7 5 % of pla n ne d C ycle 1 d oses d ue t o dr u g -rel ate d t o xicit y.  N o n -e val ua ble 
patie nts ma y b e re pl ace d t o e ns ure t hat e n o u g h p atie nts c o m plete 1 c ycle u nless  accr ual t o t hat 
c o h ort has st o p pe d d ue t o a D L T.  
F oll o wi n g t he 3 + 3 d ose escalati o n sc he me, if 0 of 3 patie nts at a gi ve n d ose le vel e x perie nce first 
c ycle D L T, t h e s u bse q ue nt c o h ort will e nr oll at t he ne xt hi g her  d ose l e vel.  
 If 0 of 3 e v al ua ble patie nts e x perie nce a D L T, b ut safet y c o n cer ns are prese nt, 3 
a d diti o nal patie nts ma y b e a d de d  t o t he sa m e d ose le vel  c o h ort t o pr o vi de a d diti o nal 
data f oll o wi n g dis c ussi o n bet wee n t he i n v esti gat ors a n d t he s p o ns or. 
If 1 of 3 e v al ua ble patie nts i n a c o h ort e x perie nce a D L T, t he c o h ort will be e x pa n de d t o i ncl u de 
6 patie nts.  
 T he d ose escalati o n ca n pr ocee d if < 2 o ut of 6 e v al ua ble patie nts e x perie n ce a D L T.  
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T
C CI
C CI

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
6 5  
 If a D L T is o bser ve d i n ≥2 o ut of a ma xi m u m of 6 e val ua ble p atie nts at a n y gi ve n 
d ose, a safet y re vie w will be tri g gere d, d os e escalati o n will cease, a n d t he ne xt l o wer 
d os e will be c o nsi dere d t he M T D.  
If t he starti n g d ose le v el of a be ma cicli b 7 0 m g/ m2 BI D is n ot t olerat e d i n Part A , t he A−1 d ose 
le vel of 5 5 m g/ m 2 BI D of a be ma cicli b will be e x pl ore d.   If 5 5 m g/ m2 of a b e macicli b is n ot 
t olerate d i n Part A, a t h or o u g h safet y re vie w will be c o n d ucte d i n c olla b orati o n wit h 
i n vesti gat ors t o wei g h t h e be nefits a n d ris ks of starti n g Part B.  If t he c o m bi nati o n is dee me d t o 
be n ot t olera ble d ue t o o v erla p pi n g t o xicit y of a be macicli b pl us te m oz ol o mi de or a be macicli b 
al o ne, t he st u d y will n ot pr ocee d t o Part s B  or C .  H o we ver, if t he c o m bi nati o n was n ot t olera ble 
d ue t o o verla p pi n g t o xicit y of a b e maci cli b pl us iri n oteca n (e. g.  D L Ts of di arr hea), Part B usi n g 
5 5 m g/ m 2 of a be maci cli b as t he starti n g d os e ma y pr ocee d.  
I n t his st u d y, i ntrapatie nt d ose escal ati o n is n ot per mitte d .  
T he R P 2 D of a be ma cicli b will be defi ne d bas e d o n t he t otalit y of safet y, t olera bilit y, a n d P K 
res ults.  D ose -li miti n g t o xicities a n d d ose selecti o n decisi o ns will be ma de after disc ussi o n 
bet wee n t he i n v esti gat ors  a n d t he s p o ns or.  
T he R P 2 D fr o m eac h part will be c o nfir me d i n e x pa nsi o n c o h orts f or eac h c o m bi nati o n.   
E x pa nsi o n c o h orts will e nr oll 6 patie nts.   I n b ot h  st u d y parts, up o n c o m pleti o n of a t h or o u g h 
safet y re vi e w, ad diti o nal patie nts ca n be e nr olle d if necess ar y t o c o nfir m safet y.  E x a m ples ma y 
i ncl u de testi n g a l o w er d ose i n 6 a d diti o nal patie nts if D L Ts are e x perie nce d b y at least 2 of 6 
patie nts i n t he i nitial e x pa nsi o n c o h ort t o f urt her c o nfir m t olera bilit y of pr ol o n ge d tr eat me nt.  
4. 1. 2.  
T w o -st a ge D esi g n f o r P art C  
Part C c o nsists of t w o sta ges t o first e val uate t h e safet y a n d t olera bilit y a n d t he n t he a nti -t u m or 
acti vit y of a be ma cicli b i n c o m bi nati o n wit h c he m oi m m u n ot hera p y . T h e desi g n is briefl y 
descri be d b el o w wit h a fi g ure i m me diatel y f oll o wi n g .  
St a ge 1  
Sta ge 1 starts wit h a d ose o pti mizati o n  t o i de ntif y M T D. S pecificall y, it will i nitiall y e nr oll 3 
patie nts at 5 5 m g/ m 2  (i.e., t he M T D f or a b e maci cli b  i n c o m bi nati o n wit h  iri n oteca n a n d 
te m oz ol o mi de i n Part A  pl us di n ut u xi ma b  a n d G M -C S F ) a n d use 3 + 3 r ules t o g ui de d ose 
decisi o n. D uri n g M T D i d e ntificati o n, if 5 5 m g / m2 is dee me d i nt olera bl e, t he n a l o wer 
a be maci cli b d ose of 3 0 m g / m2 ( kee pi n g t he ot her dr u gs t he s a me) will be e x pl ore d . If t his l o wer 
d ose le vel is dee me d i nt olera ble, Ar m C will be ter mi nate d d ue t o i nt olera bilit y.  
I n a d diti o n t o t he safet y assess me nt, t he a nti-t u m or acti vit y will be  meas ure d b y o bjecti ve t u m or 
res p o nse. If M T D is decl are d, a n e x pa nsi o n c o h ort will e nr oll at t he M T D t o c o nfir m t he 
t olera bilit y w hile e v al uati n g t he preli mi nar y a nti-t u m or acti vit y.  I n t h e e x pa nsi o n c o h ort, u p t o  
patie nts ma y b e si m ulta ne o usl y e nr olle d.  Sta ge 1 will e nr oll u p t o 
 D L T -e val ua ble p atie nts  at 
t he i de ntifie d M T D.  If n o ne of t he f oll o wi n g st o p pi n g r ules are tri g gere d, t he M T D will be  
c o nfir me d as R P 2 D a n d Part C will m o ve t o Sta ge 2 .  
• 
R ule A: st o p f or t o xicit y if 
 of t he D L T -e val u a ble patie nts e x perie nce D L T . 
• 
R ule B: st o p f or i nt olera bilit y if 
 p atie nts disc o nti n ue d ue t o treat me nt-relate d A E 
bef ore c o m pleti n g  c ycl es. 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T
C CI
C CI
C CI
C CI
C CI

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
6 6  
• 
R ule C: st o p f or  i ns ufficie nt e vi de nce of a nti-t u m or acti vit y if <
 of  
patie nts are 
res p o n ders (i.e., ha v e o bjecti ve t u m or res p o ns e, i ncl u di n g a b est o verall res p o nse of 
c o m plete res p o nse [ C R], partial res p o nse [ P R] or mi n or res p o nse [M R ] per I N R C) . 
De -es c al ati o n d uri n g c o h ort e x p a nsi o n:  If 5 5 m g/ m 2 is declare d t he M T D, b ut eit her st o p pi n g 
R u le A or B  is tri g gere d i n t he c o h ort e x pa nsi o n, s u bse q ue nt patie nts will be treate d at 3 0 m g / m2 
a n d t h ose at t he 5 5  m g/ m 2 d ose ma y be dr o p pe d  t o 3 0  m g / m2 u p o n i n vesti gat or’s discreti o n. Part 
C will  c o nti n ue t o e nr oll u ntil t here are 
t otal patie nts treate d at 3 0  m g / m2 wit h a mi ni m u m of 
 ne wl y e nr olle d D L T -e v al ua ble 3 0 m g/ m 2 patie nts.  If n o  st o p pi n g rul es are tri g gere d, t he d ose 
c o m bi nati o n wit h a be ma cicli b at 3 0  m g/ m 2 is the R P 2 D a n d Part C will m o ve t o Sta ge 2.  
St a ge 2  
A n  a d diti o nal 
 patie nts will be e nr olle d  at t he R P 2 D  i n Sta ge 2. A m o n g t he 
 e val ua bl e 
patie nts treate d i n Sta ges 1 a n d 2 at t he R P 2 D , if t here are 
 res p o n d ers, t he n t here is 
i ns ufficie nt e vi de nce of a nti -t u m or acti vit y. If  
 of t he patie nts are res p o n ders, t he n it is 
reas o na bl e t o c o ncl u de t h at t he dr u g c o m bi nati o n has pr o misi n g  a nti-t u m or acti vit y t hat c o ul d 
warra nt f urt her s t u d y. 
T he fi g ure b el o w ill ustrates t he Part C  desi g n . 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
6 7  
Statistical  details f or t he t w o -sta ge desi g n are pr o vi de d i n Secti o n 9 . 
4. 1. 3.  
D ose -Li miti n g T o xicit y Deter mi n ati o n a n d M a xi m u m T oler ate d D ose Defi niti o n   
A D L T is defi ne d as a n y of t he e ve nts a cc or di n g t o t he N CI C T C A E v ersi o n 5. 0 bel o w if b ot h 
t he f oll o wi n g criteria are met: 
 T he e ve nt oc c urs d uri n g t he D L T o bser vati o n peri o d of C ycl e 1, bet wee n Da ys 1 a n d 2 1,  
a n d, 
 T he e ve nt is cli nicall y si g nifica nt a n d eit her defi nitel y, pr o ba bl y, or p ossi bl y rel ate d t o 
a be maci cli b or t he c o m bi nati o n treat me nt f oll o wi n g disc ussi o n bet w ee n t he i n vesti gat or 
a n d Lill y C R P/ C R S . 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T
C CI

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
6 8  
I n v esti gat ors, t o get her wit h t he Lill y C R P/ C R S, ca n declare a D L T if  a pati e nt e x perie nc es a 
si g nifica nt t o xicit y dee m e d t o be d ose-li miti n g. 
I n t he e ve nt of a n y Gra de 5 A E, e nr oll me nt will be s us pe n de d, a n d a t h or o u g h safet y re vi e w will 
be perf or me d pri or t o r es u mi n g e nr oll me nt.  
If a patie nt recei ves < 7 5 % of a n y pla n ne d C ycl e 1 st u d y dr u g d oses d u e t o dr u g -relat e d t o xicit y, 
t he t o xicit y will be decl are d a D L T.  
N o n he mat ol o gi cal e v e nts:  
Wit h t he e x ce pti o ns liste d bel o w, all  G ra d e ≥3 n o n he mat ol o gical A E s will be c o nsi dere d a D L T .   
E xce pti o ns :  
 Gra de 3 diarr hea c o ntr oll e d wit h s u p p orti ve care a n d lasti n g <7 2  h o urs ; 
 Ac ute iri n oteca n-ass o ciat e d diarr hea lasti n g < 7 da ys a n d c o ntr olle d wit h s u p p orti ve care;  
 G ra de ≥3 n a usea, v o miti n g, or c o nsti pati o n t hat is ma na gea bl e wit h s u p p orti ve care  a n d 
lasts < 7 2 h o urs; 
 G ra de 3 m uc ositis/st o matitis of < 7 2 h o urs d urati o n; 
 G ra de 3 fe ver or i nfecti o n;  
 Gra de ≥3 electr ol yte a b n or malit y t hat lasts < 7 2 h o urs, is n ot cli nicall y c o m plicate d, a n d 
res ol ves s p o nta ne o usl y or res p o n ds t o c o n ve nti o n al me dical i nter ve nti o ns; 
 Gra de ≥3 a m yl ase or li pase t hat is n ot ass ociate d wit h s y m pt o ms or cli nical 
ma nifestati o ns of pa ncreatitis;  or  
 As partate a mi n otra nsferase ( A S T) / A L T el e vati o n res ol vi n g t o eli gi bilit y criteria wit hi n 7 
da ys ; 
 
He mat ol o gi cal e v e nts:  
 C ycle Dela y :  a > 1 4 -da y dela y i n t he start of a s u bse q ue nt c ycle b eca use of ne utr o pe nia 
or t hr o m b oc yt o p e nia  i n t he a bse nce of b o n e marr o w disease pr o gressi o n s ee n o n 
cli nicall y i n dicat e d b o ne marr o w bi o ps y (if p erf or me d).  
N ote:  Patie nts w h o e x perie nce d os e -li miti n g ne utr o pe nia a n d/ or 
t hr o m b oc yt o pe ni a will ha ve t hese e ve nts re vi e we d b y t he s p o ns or t o disc uss 
attri b uti o n ( b o ne marr o w disease [ baseli ne a n d s u bse q ue nt, if perf or me d a n d 
cli nicall y i n dicat e d] vers us st u d y dr u gs).  Patie nts wit h b o ne marr o w disease 
pr o gress i o n will n ot be c o nsi dere d t o ha ve d os e-li miti n g he mat ol o gical t o xicities. 
 Gra de ≥3 t hr o m b oc yt o p e nia wit h cli nicall y si g nifi ca nt blee di n g ; or 
 Gra de ≥4 n e utr o pe nic fe ver . 
N ote:  ly m p h o pe nia is n ot c o nsi dere d a D L T u nless cli nicall y si g nifica nt.  
A g gre gate d ata will be re vie we d a n d ta ke n i nt o c o nsi derati o n f or det er mi ni n g t he R P 2 Ds.  
T he I 3 Y -M C -J P C S T o xicit y D o c u me ntati o n F or m m ust be c o m plete d a n d se nt t o Lill y f or e a c h 
p atie nt  d uri n g t he D L T peri o d i n or der f or ti mel y e val uati o n of D L Ts.   
 If a D L T is e x perie n ce d d uri n g t he D L T e val u ati o n peri o d,  t he I 3 Y-M C -J P C S T o xicit y 
D oc u me ntati o n F or m s h o ul d be c o m plete d a n d se nt t o Lill y wit hi n 3 da ys of bec o mi n g 
a ware of t he D L T.  
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
6 9  
 If n o D L T is e x perie nce d, t he f or m s h o ul d be c o m plete d a n d se nt 3 da ys aft er t he D L T 
e val uati o n peri o d has e n de d.  
4. 2.  
Scie ntific R ati o n ale f or St u d y Desi g n   
T he o verall rati o nale f or t he st u d y desi g n is descri be d i n t he I ntr o d ucti o n secti o n u n der St u d y 
Rati o nale ( Secti o n 2. 1 ) a n d i n Statistical C o nsi derati o ns ( Secti o n 9 ).  D ose selecti o n details ca n 
be f o u n d i n Secti o n 4. 3 .  
4. 3.  
J ustific ati o n f or D ose   
4. 3. 1.  
A be m acicli b   
A be macicli b has d e m o nstrate d efficac y wit h a t olera ble safet y pr ofile i n a d va nce d breast c a ncer 
at a m o n ot hera p y d os e of 2 0 0 m g BI D, a n d i n c o m bi nati o n wit h f ul vestra nt or ar o matas e 
i n hi bit ors at a d ose of 1 5 0 m g BI D ( Dic kler et al. 2 0 1 7; G oetz et al. 2 0 1 7; Sle d ge et al. 2 0 1 7 ; 
J o h nst o n et al. 2 0 1 9). Acr oss  all pi v otal re gistrati o n trials f or a be m acicli b i n a d ult patie nts wit h 
ca ncer, n o cli nicall y me a ni n gf ul effect of a ge, b o d y wei g ht, s e x, or race/et h nicit y o n t he P K  of 
a be maci cli b has bee n i de ntifie d. T heref ore, i n a d ults, a be macicli b is d ose d wit h o ut a dj ust me nt 
f or b o d y siz e. 
I n p e diatric p atie nts, the  e nz y me lar gel y res p o nsi ble f or t he cl eara nce of a b e macicli b  ( C Y P 3 A 4) 
reac h es mat urit y  after t he first year of life ( Bart eli n k et al. 2 0 0 6). Bet wee n t he a ge of 1 t o 1 2  
years, C Y P -me diate d m eta b olis m is lar gel y de p e n de nt o n li ver v ol u me, w hic h is better c orrelate d 
wit h b o d y s urface area ( B S A) rat her t ha n b o d y wei g ht ( Barteli n k et al. 2 0 0 6). As s uc h, i n 
pe diatrics, d oses will be scale d li nearl y acc or di n g t o t he patie nt’s  B S A ( m g/ m 2). U ntil a d diti o nal 
P K a n d safet y dat a bec o me a vaila ble f or t he dr u g c o m bi nati o n acr oss a wi de ra n ge of pe diatri c 
a ges a n d b o d y siz es, t he B S A a dj ust me nt will be a p plie d t o all pe diatric patie nts  < 1 8 years of 
a ge. F or partici p a nts a ge d 1 8 years a n d ol d er, bas e d o n t he k n o w n P K i n a d ults a n d lac k of 
re q uire d b o d y siz e a dj ust me nt, an e q ui vale nt  n o n -B S A -bas e d d os e will be use d  base d o n t he 
pla n ne d starti n g d ose a dj uste d f or a n ass u m e d a d ult B S A of 1. 7 3 m 2. 
F or  patie nts a ge d bet w ee n 6 m o nt hs a n d 1 year, t h e acti vit y of C Y P 3 A 4  is re d uce d b y 5 0 % 
c o m pare d t o t he t y pic al a d ult p o p ulati o n ( Bla ke et al. 2 0 0 5 ). Gi ve n t he  hi g h varia bilit y a n d wi de 
ra n ge of s afe a n d efficaci o us e x p os ures of a be macicli b i n t he a d ult p o p ulati o n, a n i ncrease i n 
e x p os ures of 2 -f ol d i n patie nts a ge d 6 m o nt hs t o 1 year is e x pecte d t o be well t olerate d b y t he 
pe diatric  patie nt p o p ulati o n. T he Incl u si o n C riteri a [ 1] a n d [ 2] i n St u d y J P C S Parts A a n d B f or 
b o d y w ei g ht (at least 1 0 k g) a n d B S A (at least 0. 5 m 2), a n d t he I n cl usi o n Criteria [3 ] f or t he 
disease c h aracteristics of patie nts e nr olle d i n Part C ( rela pse d/r efract or y n e ur o blast o ma) will 
m ost li kel y  e x cl u de patie nts w h o are y o u n ger t ha n 6 m o nt hs of a ge.   
P art A  
T he a be ma cicli b starti n g d ose of 7 0 m g/ m 2 BI D f or Part A  i n pe diatric p atie nts was selecte d 
base d o n 8 0 % of t h e B S A -a dj uste d a d ult d ose us e d f or a b e maci cli b c o m bi nati o n st u dies (t hat is, 
1 5 0  m g  BI D ÷ 1. 7 3  m ²× 0. 8 = 7 0 m g/ m ² BI D ).  Gi ve n  t he p ote ntial f or patie nts wit h lar ger B S A t o 
recei v e d oses i n e x cess of t he a p pr o ve d a d ult d ose, t he ma xi m u m d ose of a be macicli b will be 
ca p pe d at 1 5 0 m g BI D ( ma xi m u m a d ult  c o m bi nati o n d ose).  
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
7 0  
P art B  
Si nce Part B uses 1  less st u d y dr u g, it will li kel y b e m ore t olera ble t ha n t he tri plet c o m bi nati o n 
d ue t o fe wer e x pecte d a d verse e v e nts.  T heref ore, i n Part B , o ne d ose le vel hi g her t h a n t he M T D 
of a be ma cicli b ( n ot t o e xcee d 1 1 5 m g/ m2 BI D) i n Part A  will be use d as t he starti n g d ose i n 
c o m bi nati o n wit h te m oz ol o mi de 1 0 0 m g/ m 2/ da y o n Da ys 1 t hr o u g h 5 of a 2 1 -da y c ycl e  (see 
Secti o n 6. 1 ).  Starti n g at a hi g h er d ose le vel i n Part B ma y all o w t he M T D t o be esta blis he d wit h 
fe wer patie nts si nce fe wer d ose le vels ma y ha v e t o be teste d i n t he d o u blet escalati o n.  Gi ve n  t he 
p ote ntial f or patie nts wit h lar ger B S A t o recei ve d oses i n e x cess o f t he a p pr o ve d a d ult d ose, as 
wit h Part A, t he ma xi m u m d ose of a be macicli b will be ca p pe d at 1 5 0 m g BI D ( ma xi m u m a d ult 
c o m bi nati o n d ose).  
P art C  
I n Part C, t he M T D
A  of a be macicli b of 5 5 m g/ m 2 i n c o m bi nati o n wit h iri n oteca n a n d 
te m oz ol o mi de ( deter mi ne d i n Part A) will be use d i n c o m bi nati o n wit h di n ut u xi ma b  a n d G M-
C S F . If t his d ose le vel is n ot t olerated, a  l o wer d ose of 3 0 m g/ m2 will als o be e x pl ore d. T his 
3 0 m g/ m 2 d ose c orres p o n ds t o a n a d ult 5 0 m g d ose, a dj usti n g f or a t y pi cal a d ult  B S A of 1. 7 3 m 2. 
I n a d ult mali g na n cies , 5 0 m g a b e macicli b is t he l o west d ose wit h e xisti n g cli nical  efficac y data .    
Gi ve n t he a d diti o n of di n ut u xi ma b a n d G M -G S F t o t he Part A tri plet c o m bi nati o n, t he ma xi m u m 
d ose of a be m acicli b will be ca p p e d at 1 0 0 m g BI D  i n Part C t o a v oi d e xcessi ve e x p os ures i n t he 
lar gest patie nts. 
4. 3. 2.  
Te m o z ol o mi de   
I n Parts A a n d C  of t his st u d y, a te m oz ol o mi de d ose of 1 0 0 m g/ m 2/ da y will be use d o n Da ys 1 
t hr o u g h 5 of a 2 1 -d a y c ycle , w hic h has b ee n re p orte d t o be safe a n d t olera ble i n c o m bi nati o n 
st u dies i n pe diatric patie nts ( Case y et al. 2 0 0 9; Ba gatell et al. 2 0 1 1; M o d y et al. 2 0 1 7; Pal meri ni 
et al. 2 0 1 8).   
I n Part B, t he te m oz ol o mi de d ose ma y be es calat e d t o 1 50 m g/ m
2/ da y t o f urt her i ncrease 
te m oz ol o mi de e x p os ure, if eit her  
1.  t he M T D of a b e macicli b is n ot reac he d w he n d ose d at 1 1 5 m g/ m2 BI D i n P art B, or  
2.  a be maci cli b 1 1 5  m g/ m 2 is t he R P 2 D f or Part A.   
Te m oz ol o mi de 1 5 0 m g/ m 2/ da y has b ee n re p orte d as t olera ble i n ot her c o m bi nati o n st u dies 
( Ge oer ger et al. 2 0 0 5; K us h ner et al. 2 0 0 6; R u bie et al. 2 0 1 0; R u g gier o et al. 2 0 1 0; Wa g ner et al. 
2 0 1 0; H u m mel et al. 2 0 1 3; R u g gier o et al. 2 0 1 3; Di Gia n natale et al. 2 0 1 4; Sett y et al. 2 0 1 8 ), 
i ncl u di n g i n c o m bi nati o n wit h di n ut u xi ma b a n d te m oz ol o mi de ( M o d y  et al. 2 0 1 7).  
4. 3. 3.  
Iri n otec a n  
I n Parts A a n d C  of t his st u d y, iri n oteca n 5 0 m g/ m 2/ da y (i ntra ve n o us [I V]) will be a d mi nistere d 
o n Da ys 1 t hr o u g h 5 of  a 2 1-da y c ycl e, w hic h is cite d i n t he pe diatric secti o n of t he prescri bi n g 
i nf or mati o n (Iri n oteca n U S Pac ka ge I ns ert 2 0 2 0) a n d has bee n use d i n ot her pe diatri c trials 
( K us h ner et al. 2 0 0 6; Raci b ors ka et al. 2 0 1 3; D u B ois et al. 2 0 1 6), i ncl u di n g i n c o m bi nati o n wit h 
di n ut u xi ma b a n d te m oz ol o mi de ( M o d y et al. 2 0 1 7 ). 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
7 1  
4. 3. 4.  
Di n ut u xi m a b  a n d G M -C S F   
I n Part C, di n ut u xi ma b will be a d mi nistere d at a d ose of 1 7. 5  m g/ m 2/ da y ×  4  da ys of eac h c ycl e, 
as cite d i n t he pres cri bi n g i nf or m ati o n ( Di n ut u xi ma b  p ac ka ge insert , 2 0 1 5 ). T his d ose was 
pre vi o usl y a d mi nistere d t o pe diatric patie nts wit h  rela pse d/refract or y ne ur o blast o ma o n Da ys 2 
t hr o u g h 5  i n c o m bi nati o n wit h iri n oteca n (5 0 m g/ m 2/ da y o n Da ys 1 t hr o u gh 5 ), te m oz ol o mi de 
(1 0 0 m g/ m 2/ da y o n D a ys 1 t hr o u g h 5), a n d G M -C S F ( 2 5 0 μ g/ m 2 per d ose) s u bc uta ne o usl y o n 
D a ys 6– 1 2  i n St u d y A N B L 1 2 2 1 ( M o d y et al. 2 02 0 ). G M -C S F is a d de d t o di n ut u xi ma b t o 
a u g m e nt A D C C  base d o n t he A N B L 0 0 3 2 a n d A N B L 1 2 2 1 st u dies ( M o d y et al 2 0 2 0, Y u et al 
2 0 1 0). T his c o m bi nati o n  o f di n ut u xi ma b, G M -C S F , iri n oteca n, a n d te m oz ol o mi de, de m o nstrate d  
a ma na gea ble t o xicit y pr ofile a n d s u bsta ntial acti vit y wit h 2 2  of 5 3  patie nts e x hi biti n g o bjec ti ve 
res p o nses ( M o d y et al. 2 0 2 0) .  P atie nts i n Part C will recei ve t he s a me di n ut u xi ma b , G M -C S F , 
iri n oteca n, a n d te m oz ol o mi de d oses a n d a d mi nistrati o n sc he d ule as i n St u d y A N B L 1 2 2 1.   
Gi ve n  t hat di n ut ux i ma b is a m o n ocl o nal a nti b o d y, it is hi g hl y u nli kel y t hat it w o ul d affect t he 
cleara nce p at h wa ys of a b e macicli b, iri n oteca n, or te m oz ol o mi de, n or t hat t hese c o m bi nati o n 
dr u gs w o ul d affect t he cl eara n ce of di n ut u xi ma b. T heref ore, it is n ot e x pecte d t hat t he d oses of 
a n y of t he pla n ne d c o m bi nati o n st u d y dr u gs w o ul d nee d t o be altere d bas e d o n an a ntici pate d  P K 
i nteracti o n wit h di n ut u xi ma b . 
4. 4.  
E n d of St u d y  Defi niti o n   
T he e n d of t he st u d y is d efi ne d as t he d ate of last sc he d ule d pr o ce d ure s h o w n i n t he Sc he d ule of 
Acti vities  (S o A; Secti o n 1. 3 ) f or t he last partici pa nt i n t he trial. 
I n t he E U, st u d y c o m pleti o n is t he date of t he last visit or last sc he d ule d pr oce d ure s h o w n i n t he 
S o A  (Secti o n 1. 3 ) ass oci ate d wit h Part B.  
I n t he U S, st u d y c o m pleti o n is t he date of t he last visit or last sc he d ule d pr oce d ure s h o w n i n t he 
S o A ( Secti o n 1. 3 ) ass oci ate d wit h Part C.  
 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
7 2  
5.  
St u d y  P o p ul ati o n   
Pr os pecti ve a p pr o val of pr ot oc ol de viati o ns t o recr uit me nt a n d e nr oll me nt criteria, als o k n o w n as 
pr ot oc ol wai vers or e x e m pti o ns, is n ot per mitte d.  
5. 1.  
I ncl usi o n Criteri a  
Partici pa nt s are eli gi ble t o be i ncl u de d i n t he st u d y o nl y if all of t he f oll o wi n g criteria a p pl y:  
A ge  a n d Wei g ht  
1.  P arts A a n d B o nl y:   
a. Patie nts  m ust be  ≤1 8 years of a ge  at t he ti me of st u d y e nr oll me nt , a n d  
b.  B o d y wei g ht ≥1 0 k g a n d B S A ≥0. 5 m 2.  
 
P art C o nl y:   
a. Pati e nts m ust be < 2 1  years of a ge at t he ti me of st u d y e nr oll me nt.   
b. F or patie nts wit h  a starti n g a b e maci cli b d ose of 3 0 m g/ m 2  BI D, B S A m ust b e  ≥0. 3 
m 2  
 
All P arts : the M ostell er f or m ula s h o ul d be use d t o calc ulate B S A. 
 
2.  I n cl usi o n Criteri o n 2 has bee n delet e d. 
T y pe of  P artici p a nt a n d Dise ase C h ar acteristi cs  
3.  P arts A a n d B  o nl y : p atie nts wit h a n y rela pse d/refract or y m ali g n a nt s oli d t u m ors 
(e x cl u di n g l y m p h o ma), i ncl u di n g C N S t u m ors, t hat have  pr o gresse d o n sta n dar d 
t hera pies.  F or sites t hat are acti vel y e nr olli n g Parts B a n d C, patie nts wit h 
ne ur o blast o ma w h o are eli gi ble f or Part C will be e x cl u de d fr o m  Part B  u nl ess a p pr o ve d 
b y Lill y C R P/ C R S.  
P ar t C o nl y : patie nts wit h first rela pse/refract or y ne ur o blast o ma.  Refract or y is defi ne d 
as eit her less t ha n p artial res p o nse ( P R ) b y I N R C at t he c o ncl usi o n of at least 4 c ycl es of 
sta n dar d fr o nt-li ne i n d ucti o n c he m ot hera p y or pr o gressi ve diseas e  ( P D) d uri n g fr o nt-li ne 
t hera p y.  First rela pse is defi ne d as dise ase  rec urre nce f oll o wi n g c o m pleti o n of 
a g gressi ve m ulti -dr u g c h e m o t hera p y, s ur ger y, a ut ol o g o us ste m cell tra ns pl a nt a n d 
ra diati o n, wit h or wit h o ut  reti n oi ds.    
N O T E:  F or Part C, fr o nt-li ne c hem o t hera p y m ust ha ve  c o m prise d 2 or m ore a ge nts , 
i ncl u di n g a n al k yl ati n g a ge nt a n d a plati n u m -c o nt ai ni n g c o m p o u n d.  
 
F or P arts A, B , a n d  C:   Patie nts m ust ha ve at least o ne meas ura ble or e v al ua ble lesi o n 
as defi ne d b y R E CI S T v 1. 1  (Eise n ha uer et al. 2 0 0 9 ) or R A N O  f or C N S t u m ors (We n et 
al. 2 0 1 0 ).   
 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
7 3  
i. 
Meas ura ble is d efi ne d as a n o nl y m p h oi d s oft tiss ue mass ≥1 c m 
(l o n gest di me nsi o n) or l y m p h n o de ≥1. 5 c m (s h ort a xis)  o n a 
M RI or C T sca n  
ii. 
E val ua ble diseas e is defi ne d as  the prese n ce of at least o ne 
lesi o n, wit h n o lesi o n t hat ca n be acc uratel y meas ure d i n at least 
o ne di me nsi o n. S uc h lesi o ns ma y b e e val ua bl e b y n uclear 
me dici ne tec h ni q ues, i m m u n oc yt oc he mistr y t ec h ni q ues, t u m or 
mar kers or ot h er relia ble meas ures.  
iii. 
F or C N S t u m ors: Is olat e d le pt o me ni n geal disease i n 
rela pse d/r efract or y C N S t u m ors t hat is e val ua ble ma y b e eli gi ble 
f or i ncl usi o n after c o ns ultati o n wit h t he Lill y C R P/ C RS.  
F or  Part C:   A  t u m or (eit her m eas ura ble  or e val ua ble) t hat is eit her   
 MI B G -a vi d or  t hat de m o nstrate s i ncrease d F D G u pta ke o n P E T 
scan  (f or MI B G-n o na vi d t u m or) , or  
 via ble ne ur o blast o ma  c o nfir me d b y bi o ps y (s u b missi o n of 
pat h ol o g y re p ort is re q uir e d)   
Patie nts wit h i n v ol ve me nt of b o ne marr o w o nl y, wit h o ut a meas ura ble 
or e val ua ble l esi o n, are n ot eli gi ble.  
A N D  
Patie nts m ust ha ve ha d hist ol o gic verifi cati o n of m ali g na n c y at ori gi nal dia g n osis or 
rela pse, e x ce pt :  
a. patie nts wit h C N S ger m cell t u m ors or e x tra-cra ni al ger m -cell t u m ors a n d w h o 
ha ve ele v ati o ns of ser u m t u m or mar kers i ncl u di n g al p ha -fet o pr otei n or bet a-H C G , 
a n d 
b.  patie nts wit h i ntri nsic brai n ste m t u m ors  
 
I n t he j u d g me nt of t he i n vesti gat or, t h e patie nt is a n a p pr o pri ate ca n di date f or t he 
e x peri me ntal t hera p y c o m bi nati o n i n t he st u d y p art t hat is c urre ntl y e nr olli n g.   
 
Ne ur ol o gic deficits i n patie nts wit h C N S t u m ors m ust ha ve bee n sta bl e f or at least 7 
da y s pri or t o st u d y e nr oll me nt. 
 
4.  A La ns k y sc ore ≥5 0 f or patie nts < 1 6 years of a ge or a Kar n ofs k y sc ore ≥5 0 f or patie nts 
≥1 6 years of a ge  
 Patie nts w h o are u na bl e t o wal k beca use of paral ysis, b ut are u p i n a w heelc hair, 
will be c o nsi dere d a m b ulat or y f or t he p u r p ose of assessi n g t he perf or m a nce sc ore. 
 
5.  Patie nts m ust be a ble t o s wall o w  a n d/ or ha v e a gastric/ nas o gastric t u be. Refer t o 
S ecti o n 6. 1. 2  f or alter nati ve a d mi nistrati o n met h o ds . 
 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
7 4  
6.  Patie nts m ust ha ve disc o nti n ue d all pre vi o us treat me nts f or ca n cer or i n vesti gati o nal 
a ge nts as s h o w n bel o w a n d  m ust ha ve rec o v ere d fr o m t he ac ute effects t o Gra de ≤1 at 
t he ti me of e nr oll me nt, u nless dee me d cli nicall y i nsi g nifica nt b y t he  i n v esti gat or.  F or 
a ge nts wit h k n o w n A Es occ urri n g b e y o n d t he re q uire d wait peri o d o utli ne d i n t he ta ble, 
t his peri o d m ust be e xte n de d u ntil after t he ti me d uri n g w hi c h t he A E is k n o w n t o occ ur.  
C o ns ult wit h t he Lil l y C RP / C RS  f or t he a p pr o pri ate le n gt h of ti me pri or t o t he first d ose 
of st u d y tr eat me nt o n a d diti o nal t hera pies n ot me nti o ne d.  
Pre vi o us  Tre at me nt  
Le n gt h of Ti me Pri or t o First D ose of St u d y Tre at me nt  
C yt ot o xic a n d m yel os u p pressi ve 
c he m ot hera p y  
≥2 1 da ys after t he last d ose of c yt ot o xic or m yel os u p pressi ve 
c he m ot hera p y ( or ≥4 2 da ys if pri or nitr os o urea)  
He mat o p oietic gr o wt h fact ors  
≥1 4 da ys after t he last d ose of a l o n g -acti n g gr o wt h fact or ( e.g . 
pe gfil grasti m)  
≥7 da ys f or s h ort -acti n g gr o wt h fact or  
Cel l ular t hera p y 
≥4 2 da ys after t he c o m pleti o n of a n y t y pe of cell ular t hera p y ( e.g . 
m o difie d T cells, N K cells, de n dritic cells) a ge nt  
I nterle u ki ns, i nterfer o ns, a n d 
c yt o ki nes ( ot her t ha n 
he mat o p oietic gr o wt h fact ors)  
≥2 1 da ys after t he c o m pleti o n of i nterl e u ki ns, i nterfer o n, or c yt o ki nes , 
i ncl u di n g I L-2  
A nti b o d y t hera p y  
≥2 1 da ys after t he last i nf usi o n of a nti b o d y t hera p y , i ncl u di n g 
a nti -G D 2 m o n ocl o nal a nti b o d y  
N o n -m yel os u p pressi ve bi ol o gic 
a ge nt or reti n oi d ( P art C  o nl y)  
≥7 da ys  after last d ose  
Ra di ot hera p y  
≥1 4 da ys si nce s mall p ort ra diati o n t hera p y (i.e. l ocal palliati ve); ≥8 4 
da ys si nce lar ge -fiel d ra diati o n t hera p y (i.e. T BI , cra ni os pi nal , w h ole 
a b d o mi nal, t otal l u n g, ≥5 0 % or greater pel vic ra diati o n , ≥5 0 % marr o w 
s pace);  
≥4 2 da ys f or ot her s u bsta ntial b o ne marr o w ra diati o n or  1 3 1I-MI B G  
t hera p y. 
F or P art C o nl y:  N o mi ni m u m  i nter val bet wee n ra diati o n a n d st u d y 
e ntr y is re q uire d f or n o n -tar get lesi o ns. H o we ver, tar get lesi o ns m ust 
n ot ha ve recei ve d ra diati o n wit hi n 4 wee ks of st u d y e ntr y. Pre vi o usl y  
ra diate d lesi o ns ca n n ot be use d as tar get lesi o ns u nless t here is 
ra di o gra p hic e vi de nce of pr o gressi o n f oll o wi n g ra diati o n or a p ost-
ra diati o n bi o ps y c o nfir ms via ble ne ur o blast o ma. 
Ra di o p har mace utical t hera p y 
(e.g . ra di ola bele d a nti b o d y, 1 3 1I-
MI B G)  
≥4 2 da ys after ra di o p har mace utical t hera p y  
Ste m cell i nf usi o n wit h o ut T BI  
≥8 4 da ys si nce tra ns pla nt or st e m cell i nf usi o n 
C ortic oster oi ds  
≥1 4 da ys f or patie nts w h o ha ve recei ve d a c o urse of s yste mi c 
c ortic oster oi ds ( ≥5 da ys)  t o m o dif y i m m u ne A Es relate d t o pri or 
t hera p y.   
N ote:  P atie nts w h o are o n ster oi d i n halers f or ast h ma, c hr o ni c 
re place me nt f or e n d ocri ne dis or ders, or are o n a sta ble or decreasi n g 
d ose f or at least 7 da ys f or C N S lesi o ns  ma y still be eli gi ble  (c o ns ult 
Lill y C R P/ C R S)  
S ur ger y  
≥2 8 da ys after a maj or s ur gical pr oce d ure, la par osc o pic pr oce d ure, or 
si g nifica nt tra u matic i nj ur y.  S ur gical or ot her w o u n ds m ust be 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
7 5  
Pre vi o us  Tre at me nt  
Le n gt h of Ti me Pri or t o First D ose of St u d y Tre at me nt  
a d e q uatel y heale d pri or t o treat me nt.  
 Ce ntral li ne place me nt or s u bc uta ne o us p ort place me nt is n ot 
c o nsi dere d maj or s ur ger y  
 C o re bi o ps y, fi ne nee dle as pirate, a n d b o ne marr o w bi o ps y/ as pirate 
are n ot c o nsi dere d maj or s ur geries.  
A b bre viati o ns :  A E = a d verse e ve nt; C N S = ce ntral ner v o us s yste m; C R P/ C R S = cli nical researc h 
p h ysicia n/cli nical researc h sci e ntist; I N D = i n vesti gati o nal ne w dr u g; 1 3 1I-MI B G  = 1 3 1I-
metai o d o be nz yl g ua ni di ne ; N K = nat ural killer; T BI =t otal b o d y irra diati o n; X R T = p h ot o n ra diati o n 
t hera p y. 
 
7.  T he patie nt has a d e q uate he mat ol o gic a n d or ga n  f u ncti o n ≤2 wee k s (1 4  da ys) pri or t o 
first d ose of st u d y dr u g: 
S yste m  
L a b or at or y V al ue  
He m at ol o gic  
A N C  
P arts A a n d B:  1 0 0 0/ µ L  
P art C:  7 5 0/ µ L  
G -C S F ca n n ot be a d mi nistere d ≤1 wee k ( 7 da ys) pri or t o 
first d ose of st u d y dr u g.  P e gfil grasti m ca n n ot be 
a d mi nistere d ≤2 wee ks ( 1 4 da ys) pri or t o first d ose of 
st u d y dr u g. 
Platelets  
7 5, 0 0 0/ m m 3  
Platelet tra nsf usi o n t o meet t his e nr oll me nt  criteri o n is n ot 
all o we d wit hi n t he prece di n g 5 da ys of first d ose of st u d y 
dr u g.  
He m o gl o bi n  
8 g/ d L ( ≥8 0 g/ L)  
 
Tra nsf usi o ns t o i ncrease t he patie nt’s he m o gl o bi n le vel t o 
at least 8 g/ d L are per mitte d; h o we ver, st u d y treat me nt 
m ust n ot be gi n u ntil 7 da ys aft er t he tra nsf usi o n a n d C B C 
criteria f or eli gi bilit y are c o nfir me d ≤ 2 4 h o urs bef ore 
C 1 D 1  
He p atic  
T otal bilir u bi n  
1. 5 × U L N  
E xce pt patie nts wit h d oc u me nt e d  hist or y of Gil bert 
S y n dr o me w h o m ust ha ve a t otal bilir u bi n le vel of 
< 3. 0 × U L N  
A L T a n d A S T  
3 × U L N O R  
5. 0 × U L N if t he li ver has t u m or i n v ol ve me nt  
C o a g ul ati o n  

Pr ot hr o m bi n  Ti me  
P art C:  ≤1. 2 ×  U L N 
A b bre viati o ns:  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 S T  =  as partate 
a mi n otra nsferase; C 1 D 1 = C ycle 1 D a y 1; C B C = c o m plete bl o o d c o u nt; C R P/ C R S = cli ni cal researc h 
p h ysicia n/cli nical researc h sci e ntist;  G -C S F = gra n ul oc yte -c ol o n y  sti m ulati n g fact or; U L N =  u p per 
li mit of n or mal. 
 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
7 6  
 Creati ni ne cleara n ce or calc ulate d gl o mer ular filtr ati o n rate ( G F R)  
≥6 0  m L/ mi n/ m 2 
O R  
S er u m creati ni ne base d o n a ge/ ge n der as f oll o ws:  
A ge  
M a xi m u m ser u m cre ati ni ne ( m g/ d L)  
 
M ale  
Fe m ale  
1 -< 2 years  
0. 6  
0. 6  
2 -< 6 years  
0. 8  
0. 8  
6 t o < 1 0 years  
1. 0  
1. 0  
1 0 t o < 1 3 years  
1. 2  
1. 2  
1 3 t o < 1 6 years  
1. 5  
1. 4  
≥ 1 6 years  
1. 7  
1. 4  
T he t hres h ol d creati ni ne val ues i n t his ta ble were deri ve d fr o m t he Sc h wartz f or m ula (see Secti o n  1 0. 5 , 
A p pe n di x 5 ) f or esti mati n g G F R9 9 ( Sc h wartz a n d Ga ut hier 1 9 8 5) utilizi n g c hil d le n gt h a n d stat ure data 
p u blis he d b y t he Ce nters f or Disease C o ntr ol a n d Pre ve nti o n . 
 
2 8.  F or Part C o nl y:  n o d ys p ne a at r est a n d o x y ge n sat urati o n of ≥9 4 % o n r o o m air.  
2 9.  F or Part C o nl y:  A de q uate car diac f u ncti o n wit h a s h orte ni n g fracti o n of > 3 0 % or 
ejecti o n fracti o n ≥5 0 % o n car diac ec h o or gate d ra di o n ucle oti de st u d y.  
8.  Fe male p atie nts of c hil d b eari n g p ote ntial m ust ha v e a ne gati ve uri ne or ser u m pre g n a nc y 
test wit hi n 7 da ys pri or t o C ycle 1 Da y 1. 
9.  F e male p atie nts of re pr o d ucti ve p ote ntial m ust a gree t o use hi g hl y effecti ve 
c o ntrace pti ve preca uti o ns d uri n g t he trial.  F or a b e macicli b, fe m ales s h o ul d use 
c o ntrace pti o n f or  at least 3 wee ks f oll o wi n g t he last a be macicli b d ose.  F or ot her st u d y 
dr u gs, hi g hl y effecti ve c o ntrace pti ve preca uti o ns (a n d a v oi di n g s p er m d o nati o n) m ust be 
use d acc or di n g t o t heir la bel.  
1 0.  T he patie nt has a life e x pecta nc y of at least 8 w ee ks a n d a ble t o c o m plete at least 1 c ycle 
of treat me nt.  
1 1.  Patie nts/care gi vers are a ble a n d willi n g t o ma ke t h e msel ves a vaila bl e f or t h e d urati o n of 
t he st u d y a n d are willi n g t o f oll o w st u d y pr oce d ures, i ncl u di n g a d h ere nce t o t he P K 
sa m pli n g sc he d ul e. 
I nf or me d C o nse nt / Asse nt 
1 2.  T he i n vesti gat or, or a p ers o n desi g nat e d b y t he i n v esti gat or, will o btai n writte n i nf or me d 
c o nse nt/asse nt fr o m eac h st u d y partici p a nt or t he partici pa nt's le gall y acce pta ble 
re pres e ntati ve, pare nt(s), or le gal g uar di a n a n d t he participa nt’s asse nt, w he n a p plica ble, 
bef ore a n y st u d y -s pecific acti vit y is perf or me d u nl ess a wai ver of i nf or m e d 
c o nse nt/asse nt has bee n gra nte d b y a n I nstit uti o nal Re vie w B o ar d (I R B)/  I n de pe n de nt 
Et hics C o m mittee (I E C) .  T he i n vesti gat or will ret ai n t he ori gi n al c o p y of eac h 
parti ci pa nt's si g n e d c o nse nt/asse nt d oc u me nt.  
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
7 7  
 
5. 2.  
E xcl usi o n Criteri a   
Partici pa nts are e x cl u de d fr o m t he st u d y if a n y of t he f oll o wi n g criteria a p pl y:  
Me dic al C o n diti o ns  
1 3.  Ha ve ha d a n all o ge n eic b o ne marr o w or s oli d or ga n tra ns pla nt. 
1 4.  Ha ve recei v e d rece nt ( wit hi n 4 wee ks pri or t o C ycle 1 Da y 1 ) li ve vacci nati o n.  Seas o nal 
fl u a n d C O VI D v acci n es t hat d o n ot c o ntai n a li ve vir us are per mitte d.  
1 5.  Patie nts wit h ps yc hiatric ill ness/ s ocial sit uati o n t hat, i n t he o pi ni o n of t he 
i n vesti gat or, c o ul d ca use u nacce pta ble safet y ris ks or c o m pr o mise c o m plia nce 
wit h t he pr ot oc ol.  
1 6.  E x cl usi o n C riteri o n 1 6 has bee n del ete d . 
1 7.  Ha ve a k n o w n i nt olera bilit y or h y perse nsiti vit y  (s uc h as urticaria, aller gi c reacti o n 
i ncl u di n g a n a p h yl a xis, t o xic necr ol ysis, a n d Ste ve ns-J o h ns o n s y n dr o m e) t o a n y of t he 
st u d y treat me nts or its c o m p o ne nts rele va nt t o t he st u d y part t hat is c urre ntl y e nr olli n g or 
a k n o w n h y pers e nsiti vit y t o dacar bazi ne  
1 8.  Dia g n os e d a n d/ or tr eate d a d diti o nal mali g na nc y wit hi n 3 years pri or t o e nr oll me nt t hat, 
i n t he j u d g me nt of t he i n vesti gat or a n d Lill y, ma y affect t he i nter pretati o n of res ults, 
wit h t he e x ce pti o n of c urati vel y tr eate d basal cell carci n o ma of t he s ki n, s q ua m o us cell 
carci n o ma of t he s ki n, a n d/ or c urati vel y resecte d i n sit u cer vical a n d/ or breast ca ncers.  
1 9.  Are pre g na nt or breastf ee di n g.  
2 0.  T he patie nt has acti ve s yste mic i nfecti o ns (e.g . b acterial , f u n gal, or viral  
i nfecti o n re q uiri n g I V t hera p y). In di vi d uals wit h sta ble HI V , He patitis B , or C 
f or w h o m e x p os ure t o t he i n vesti gati o nal treat me nt is n ot e x pecte d t o e x acer bate 
t heir c urre nt disease ma y be c o nsi dere d  eli gi ble. Scree ni n g is n ot re q uire d f or 
e nr oll me nt.  
2 1.  T he patie nt has seri o us a n d/ or u nc o nt r olle d pree xisti n g me dical c o n diti o n(s) t hat, 
i n t he j u d g me nt of t he i n vesti gat or, w o ul d precl u d e partici pati o n i n t his st u d y 
(s uc h as i nterstitial l u n g disease, se vere d ys p n ea at rest or re q uiri n g o x y ge n 
t hera p y, hist or y of maj or s ur gical res ecti o n i n v ol vi n g t he st o mac h or s mall 
b o wel, or pree xisti n g Cr o h n’s disease or ul cerati ve c olitis or a pree xisti n g 
c hr o nic c o n diti o n res ulti n g i n cl i nicall y si g nifica nt diarr hea ). 
2 6.  Patie nts wit h a b o wel o bstr ucti o n will be e x cl u de d fr o m Part s A a n d C of t his 
st u d y. 
Pri or/ C o nc o mit a nt T her a p y  
2 2.  Patie nts treate d wit h dr u gs k n o w n t o be str o n g i n hi bit ors or i n d ucers of is oe nz y me 
c yt o c hr o me P 4 5 0 ( C Y P)3 A  or str o n g i n hi bit ors of uri di ne di p h os p hate -gl uc ur o n os yl 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
7 8  
tra nsferase 1 A 1 (U G T 1 A 1 ) if t he treat me nt ca n n ot be disc o nti n ue d or s witc he d t o a 
differe nt me di cati o n at least 5 half -li ves pri or t o st arti n g st u d y dr u g . 
2 3.  H a ve recei v e d a n y pri or C D K 4 &  6 i n hi bit or . 
3 0.  Part C  o nl y, ha ve recei ve d pri or s yste mic t h era p y f or rela ps e d /refract or y ne ur o blast o ma. 
3 1.  P atie nts wit h C N S disease are eli gi ble if s eiz ures a n d ot her ne ur ol o gical  s y m pt o ms ha ve 
bee n sta ble f or 7 da ys. H o we ver , p atie nts m ust n ot ha ve recei ve d e nz y me -i n d uci n g 
a ntic o n v ulsa nts , s uc h as p he n yt oi n, p he n o b ar bital, val pr oic aci d, or car ba m aze pi ne f or at 
least 7 da ys pri or t o starti n g st u d y dr u g. N o n -e nz y me-i n d uci n g a ntic o n v uls a nts, s uc h as 
ga b a pe nti n or le v etiraceta m , are acce pta ble.  
3 2.  Part C o nl y, ha ve recei ve d pri or a nti-G D 2 t hera p y d uri n g i n d ucti o n  p has e  
Pri or/ C o nc urre nt Cli nic al St u d y E x perie nce  
2 4.  A re c urre ntl y e nr olle d i n a n y ot h er cli nical st u d y i n v ol vi n g a n i n vesti gati o n al pr o d uct or 
n o n -a p pr o ve d us e of a dr u g or de vice ( ot her t ha n t he st u d y dr u g us e d i n t his st u d y ) or 
a n y ot h er t y pe of m e dical researc h j u d ge d n ot t o b e scie ntificall y or me di call y 
c o m pati ble wit h t his st u d y  
2 5.  Ha ve  partici pate d,  wit hi n t he last 3 0 da ys , i n a cli nical st u d y i n v ol vi n g a n i n vesti gati o nal 
pr o d uct.  If t he pre vi o us pr o d uct has a l o n g half -life, 5 half -li ves or 3 0 da ys,  w hic he ver 
is l o n ger, s h o ul d ha v e passe d.  E x ce pti o ns will be c o nsi dere d o n a cas e -b y -case basis b y 
t he Lill y C R P/ C R S. 
Ge netic Alter ati o ns  
2 7.   E x cl usi o n C riteri o n 2 7 has bee n del ete d.  
5. 3.  
Lifest yle C o nsi der ati o ns   
Patie nts s h o ul d refrai n fr o m c o ns u mi n g gra p efr uit, gra pefr uit j uice, a n d gra pefr uit -c o ntai ni n g 
pr o d ucts w hile o n st u d y d ue t o t he effect o n C Y P 3 A 4.   See  Secti o n 6. 5  f or a d diti o nal 
i nf or mati o n o n c o nc o mita nt me dicati o ns. 
5. 4.  
Scree n F ail ures   
Scree n fail ures are defi ne d as partici pa nt s w h o c o nse nt/asse nt t o partici pate i n t he cli nical st u d y 
b ut are n ot s u bse q ue ntl y e ntere d i n t he st u d y.  A mi ni mal set of scree n fail ure i nf or mati o n is 
re q uire d t o e ns ure tra ns p are nt r e p orti n g of scree n fail ure partici pa nt s t o meet t he C o ns oli date d 
Sta n dar ds of Re p orti n g Trials  p u blis hi n g re q uir e me nts a n d t o res p o n d t o q u eries fr o m re g ulat or y 
a ut h orities.  Mi ni mal i nf or mati o n i ncl u des de m o gra p h y, scree n fail ure det ails, eli gi bilit y criteri a, 
a n d a n y S A E . 
I n di vi d uals w h o d o n ot meet t he criteri a f or p arti ci pati o n i n t his st u d y (scree n fail ure) ma y b e 
rescree ne d.  I n di vi d uals ma y b e res cree ne d 1 ti me.   T he i nter val bet wee n rescree ni n g s h o ul d be 
≥2 wee ks.  Eac h ti me res cree ni n g is perf or me d, t h e i n di vi d ual a n d/ or t he i n di vi d ual’s le gall y 
acce pta ble re pres e ntati ve, pare nt(s), or le gal g uar dia n ( w he n a p plica ble) m ust si g n a ne w 
i nf or me d c o nse nt f or m (I C F) a n d ass e nt  (if a p plica ble) a n d will be assi g n e d a ne w i de ntificati o n 
n u m ber.  Re peati n g of la b orat or y tests d uri n g t he scree ni n g p eri o d or re peati n g scree ni n g tests t o 
c o m pl y wit h t he pr ot oc ol -desi g n ate d scree ni n g p eri o d d oes n ot c o nstit ute rescree ni n g.   Scree ni n g 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
7 9  
m ust occ ur wit h i n 2 8 da ys of C ycl e 1  D a y 1, b ut a 7 -da y wi n d o w be y o n d 2 8 da ys is acce pta ble 
wit h o ut bei n g c o nsi dere d as a pr ot oc ol de vi ati o n or scree n fail.  
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
8 0  
6.  
St u d y I nter ve nti o n   
St u d y i nter ve nti o n is defi ne d as a ny i n vesti gati o nal i nter ve nti o n(s), mar ket e d pr o d uct(s), 
place b o , or me di cal de vi ce (s) i nte n d e d t o be a d mi nistere d t o a st u d y p artici pa nt acc or di n g t o t he 
st u d y pr ot oc ol.  
6. 1.  
St u d y I nter ve nti o n(s) A d mi nistere d   
T he i n vesti gat or or his/ her desi g nee is res p o nsi ble f or t he f oll o wi n g:  
 e x plai ni n g t he c orrect us e of t he dr u gs a n d pla n ne d d urati o n of eac h i n di vi d ual’s 
treat me nt t o t he patie nt/st u d y site pers on nel/le gal r e prese nt ati ve  
 verif yi n g t hat i nstr ucti o ns are f oll o we d pr o perl y  
 mai ntai ni n g acc urate rec or ds of st u d y tr eat me nt dis pe nsi n g a n d c ollecti o n  
 rec or di n g all c o nc o mita nt me dicati o ns, i ncl u di n g pre me dicati o n, o n t he cas e re p ort 
f or m ( C R F) 
 at t he e n d o f t he st u d y, ret ur ni n g all u n use d me di cati o n t o Lill y, or its desi g nee, 
u nless Lill y a n d sites ha v e a gree d all u n use d me di cati o n is t o be destr o ye d b y t he site, 
as all o we d b y l ocal la w  
A be macicli b will be pr o vi de d b y t he s p o ns or as 2 5 -m g a n d 5 0 -m g ta blets f or oral a d mi nistrati o n.  
A d diti o nall y , in Part C, 2. 5 m g oral gra n ules ma y be use d. I n Parts A a n d B, the mi ni m u m d ose 
is 2 5 m g BI D d ue t o t he B S A re q uir e me nt of at least 0. 5 m 2. I n Part C, t he mi ni m u m d ose is 
 
or Secti o n 1 0. 8 , 
A p pe n di x 8).  
  
Refer t o t he A b e macicli b D osi n g C hart s i n Secti o n 1 0. 8  (A p pe n di x 8 ) f or t he d ose r o u n di n g r ules 
base d o n a patie nt’s B S A f or eac h d ose le vel a n d if usi n g gra n ules, t he n u m ber of gra n ules 
re q uire d f or eac h d ose.  
Partici pa nts  ta ki n g oral gra n ules s h o ul d f oll o w t he pr o vi de d i nstr ucti o ns f or t he dis pe nsi n g  
de vice a n d a d mi nistrati o n . 
U ntil P K sa m ples are c o m plete d o n C ycle 3 Da y  1, partici pa nts ma y o nl y s witc h a be maci cli b 
f or m ulati o ns (ta blets t o gra n ules or vice versa ) if n ecessar y f or  a d ose a dj ust me nt  or B S A 
c ha n ge. F oll o wi n g t h e last P K sa m ple, partici pa nts ma y s witc h f or m ulati o ns as necess ar y (f or 
reas o ns ot her t h a n d ose a dj ust me nt  or B S A c ha n ge ). Oral gra n ules a n d ta bl ets ca n ne v er be 
c o m bi ne d t o ma ke u p a si n gle d ose.  
If i nstr ucti o ns ha ve bee n pr o vi de d t o pre pare a b e macicli b i n f o o d/li q ui d, n o ot her me dicati o ns 
s h o ul d be a d de d t o t he f o o d/li q ui d  wit h a be macicli b.   
F or ea c h c ycle, t he act ual d ose a d mi nistere d f or all st u d y dr u gs m ust be wit hi n 1 0 % of t he 
pla n ne d d ose; a n y t otal c ycl e d ose e x cee di n g ± 1 0 % fr o m t he pla n ne d d os e f or t he c ycl e will 
res ult i n a pr ot oc ol de viati o n. Please c o ntact t he Lill y C R P/ C R S t o disc uss a n y q uesti o ns f or 
i n di vi d ual sit uati o ns.  
In v esti gati o nal dr u gs (i ncl u di n g a be m acicli b, di n ut u xi ma b , G M-C S F,  iri n oteca n, a n d 
te m oz ol o mi de) will be s u p plie d per l ocal la ws a n d re g ulati o n a n d c o u ntr y re q uire me nts . 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T
C CI
C CI

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
8 1  
A be macicli b d oses will b e a d mi nistere d at a p pr o xi matel y t he s a me ti mes o n eac h d a y.  Pleas e 
see Secti o n 1 0. 8 , A p pe n di x 8  (A be macicli b D osi n g C hart)  t o d eter mi ne if a c ha n ge i n B S A  
necessitates  a c ha n ge i n  a be macicli b  d osi n g . 
T he pla n ne d d urati o n of treat me nt is n ot fi x e d; partici pa nts will re mai n o n st u d y u ntil disease 
pr o gressi o n , u nacce pta bl e t o xicit y , or patie nt wit h dra wal (s ee Secti o n 7. 1 ).  C o nti n uati o n be y o n d 
C ycle 1 2 will be u p t o t he i n vesti gat or’s discreti o n a n d s h o ul d be disc uss e d wit h t he Lill y.  
T he f oll o wi n g tr eat me nts will be a d mi nistere d i n 2 1 -da y c ycl es.   Refer t o Secti o n s 1. 3. 1  a n d 
1. 3. 2  f or t he dail y sc he d ule.  
 A be m acicli b  BI D  orall y o n Da ys 1  t hr o u g h 2 1 acc or di n g t o  t he d osi n g ta bl es bel o w .  
D oses s h o ul d be se parate d b y at least 6 h o urs.   A be macicli b s h o ul d be s wall o we d w h ole  
(refer t o Secti o n 6. 1. 2  f or patie nts wit h s wall o wi n g diffi c ulties).  Partici pa nts  ta ki n g oral 
gra n ules s h o ul d f oll o w t he pr o vi de d i nstr ucti o ns f or t he dis pe nsi n g  d e vice a n d 
a d mi nistrati o n.  If a d ose is misse d , t he patie nt s h o ul d ta ke t he ne xt d ose at its sc he d ule d 
ti me. If a partici p a nt s pits o ut or v o mits a be macicli b  wit hi n 1 5 mi n utes of i n gesti o n, 
re peat t he d os e.  If v o miti n g occ urs a s ec o n d ti me, t he d ose s h o ul d n ot be re peate d. 
A be ma cicli b is a ut h orize d i n t he E U as defi ne d  b y t he E U cli nical trial re g ulati o n a n d is 
n ot use d acc or di n g t o E U a ut h orizati o n  i n t his st u d y. 
 T e m o z ol o mi de  o nce d ail y orall y o n Da ys 1  t hr o u g h 5 acc or di n g t o  t he d osi n g ta bles 
bel o w .  F or Part s A  a n d C , ta ke te m oz ol o mi de a p pr o xi matel y 1 h o ur pri or t o iri n oteca n .  
Te m oz ol o mi de ca n be ta ke n at t he sa me ti me as t he a be macicli b d ose.   T e m oz ol o mi de 
s h o ul d be ta ke n o n a n e m pt y st o mac h .  T e m oz ol o mi de s h o ul d be ta ke n acc or di n g t o l ocal 
sta n dar d of care (refer t o Secti o n 6. 1. 2  f or patie nts wit h s wall o wi n g diffic ulties). If a 
partici pa nt s pits o ut or v o mits te m oz ol o m i de ca ps ule(s) wit hi n 1 5 mi n utes of i n gesti o n, 
re peat t he d os e. If p artici pa nt v o mits te m oz ol o mi de  ca ps ule(s) a sec o n d ti me, t he d ose 
s h o ul d n ot be re peat e d. I n Part C, I V t e m oz ol o mi de ma y be all o we d if l ocall y s o urce d 
a n d a p pr o ve d b y t he Lill y C R P/ C R S. I V  t e m oz ol o mi de s h o ul d be a d mi nistere d o ver 
a p pr o xi matel y 9 0 mi n utes or per i nstit uti o nal sta n dar ds.  A mi ni m u m of 2 0 h o urs 
bet wee n te m oz ol o mi de d os es is rec o m me n de d.   
Te m oz ol o mi de  is a ut h orize d i n t he E U as defi ne d b y t he E U cli nical trial re g ulati o n a n d 
is n ot  use d acc or di n g t o E U a ut h orizati o n i n t his st u d y.  
 Iri n otec a n ( P arts A  a n d C  O nl y)  o nce dail y as I V i nf usi o n o n Da ys 1  t hr o u g h 5  
acc or di n g t o  t he d osi n g t a ble bel o w.  A  mi ni m u m of 2 0 h o urs bet wee n iri n oteca n d os es is 
rec o m me n de d. 
Iri n ot eca n is a ut h orize d i n t he E U as defi ne d b y t he E U cli nical trial re g ulati o n a n d is n ot 
use d acc or di n g t o E U a ut h orizati o n i n t his st u d y . 
 D in ut u xi m a b ( P a rt C O nl y) o nce dail y as a n I V i nf usi o n o ver 1 0 h o urs o n Da ys 2  
t hr o u g h 5 .  I nf usi o ns ma y be e xte nde d t o a ma xi m u m of 2 0  h o urs .  T he di n ut u xi ma b 
i nf usi o n s h o ul d f oll o w iri n oteca n. Hel d d oses of di n ut u xi ma b are n ot ma de u p.  See 
S ecti o n 6. 1. 1  f or detaile d a d mi nistrati o n g ui deli nes. 
Di n ut u xi ma b is  n ot  a ut h orize d i n t he E U . 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
8 2  
 G M -C S F ( P art C o nl y)  2 5 0 µ g/ m 2/ da y s u b Q o n Da ys 6 -1 2  ( ma y b e a d mi nistere d at 
h o me  per l ocal sta n d ar d of care). I V a d mi nistrati o n ( 2 h o ur d urati o n or per i nstit uti o nal 
sta n dar d) ma y b e a p pr o v e d b y Lill y C R P/ C R S.  Hel d d oses  of G M -C S F are n ot ma de u p.  
G M -C S F  is n ot  a ut h orize d i n t he E U . 
P ac k a gi n g a n d l a beli n g  
St u d y i nter ve nti o ns will be s u p plie d b y t he s p o ns or or its  desi g n ee  i n acc or da nce wit h c urre nt 
G o o d Ma n ufact uri n g Practice. St u d y i nter ve nti o ns will be la bele d as a p pr o priate f or c o u ntr y 
re q uire me nts. 
 
 
P art A:  Tri plet C o m bi n ati o n D osi n g  
D ose -Le v el 
C o h ort  
 
A be m acicli b  
Iri n otec a n 
Te m oz ol o mi de  
P atie nts  
D osi n g  
D osi n g  
D osi n g  
A -1  
3 -6  
5 5 m g/ m 2 BI D, 
P O  
5 0 m g/ m 2/ da y I V  
o n Da ys 1 -5 of a 2 1 -
da y c ycle  
1 0 0 m g/ m 2/ da y P O  
o n Da ys 1 -5 of a 2 1 -da y 
c ycle  
A 1 (st arti n g d ose)  
3 -6  
7 0 m g/ m 2 BI D, 
P O  
A 2  
3 -6  
9 0 m g/ m 2 BI D, 
P O  
A 3  
3 -6  
1 1 5 m g/ m 2 BI D, 
P O  
P art A D ose 
E x pa nsi o n  
6 -1 2 a 
M T D
A  
 
 
A b bre viati o ns:  BI D = t wice dail y; D L T = d ose -li miti n g t o xi cit y; I V = i ntra ve n o us; M T D
A  = P art A ma xi m u m 
t olerate d d ose; P O = orall y.  
a  E x pa nsi o n c o h orts will e nr oll 6 patie nts i nitiall y.  A d diti o nal patie nts ca n be e nr olle d if nec essar y t o c o nfir m 
safet y.  E xa m ples ma y i ncl u de testi n g a l o wer d ose i n 6 a d diti o nal patie nts if D L Ts are e x perie nce d b y at least 
2  of 6 patie nts i n t he i nitial e x pa nsi o n c o h ort or t o f urt her c o nfir m t olera bilit y of pr ol o n ge d treat me nt.  
P art B:  D o u blet C o m bi n ati o n D osi n g  
D ose -Le v el 
C o h ort  
 
A be m acicli b  
Te m oz ol o mi de  
P atie nts  
D osi n g  
D osi n g  
B -1  ( or 
bel o w) a 
3 -6  
D ose will be 
de -escalate d acc or di n g 
t o t he d ose le vels 
o utli ne d i n P art A, BI D, 
P O  
1 0 0 m g/ m 2/ da y P O  
o n Da ys 1 -5 of a 2 1 -d a y c ycle  
B 1 (st arti n g 
d ose) b  
3 -6  
O ne d ose le vel a b o ve 
M T D A , BI D, P O  
B 2 - B 4 a 
3 -6  
D ose will be escalate d 
acc or di n g t o t he d ose 
le vels o utli ne d i n 
P art  A  
B 5 c 
3 -6  
1 1 5 m g/ m 2 BI D, P O  
1 5 0 m g/ m 2/ da y P O  
o n Da ys 1 -5 of a 2 1 -d a y c ycle  
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
8 3  
D ose -Le v el 
C o h ort  
 
A be m acicli b  
Te m oz ol o mi de  
P atie nts  
D osi n g  
D osi n g  
P art B D ose 
E x pa nsi o n  
6 -1 2 d  
M T D
B  
te m oz ol o mi de R P 2 D  
( 1 0 0 m g/ m 2 or 1 5 0 m g/ m 2) 
A b bre viati o ns :  BI D = t wice dail y; I V = i ntra ve n o us; M T D = ma xi m u m t olerate d d ose; M T D A  = P art A ma xi m u m 
t olerate d d ose; M T D
B  = P art B  ma xi m u m t olerate d d ose ; P O = orall y; R P 2 D = rec o m me n de d P hase 2 d ose . 
a  D ose will be escalate d ( C o h orts B 1, B 2, B 3, B 4, B 5) or de-escalate d ( C o h orts B -1, B -2, B -3, B -4) f oll o wi n g d ose 
le vels as o utli ne d i n P art A as nee de d.  It is p ossi ble t hat n ot all d ose le vels will be e nr olle d.  
b  O ne d ose le vel hi g her t ha n t he M T D of a be macicli b i n P art A ( or 1 1 5 m g/ m 2 if t his was t he M T D
A ) will ser ve as 
t he starti n g d ose of a b e macicli b i n P art B. 
c  C o h ort B 5 will o nl y ta ke place if t he f oll o wi n g occ ur:  
 
1) T he M T D of a b e macicli b is n ot  reac he d w he n d ose d at 1 1 5 m g/ m2 BI D i n c o m bi nati o n wit h 1 0 0 m g/ m 2/ da y 
te m oz ol o mi de i n P art B; O R  
 
2) If a b e macicli b 1 1 5 m g/ m2 BI D is t he M T D
 f or P art A.  I n t his case, P art B will directl y start wit h C o h ort B 5 
usi n g a b e macicli b 1 1 5 m g/ m 2 BI D a n d te m oz ol o mi de 1 5 0 m g/ m 2/ da y.   
d  E x pa nsi o n c o h orts will e nr oll 6 patie nts i nitiall y .  A d diti o nal patie nts ca n be e nr olle d if nec essar y t o c o nfir m 
safet y.  E xa m ples ma y i ncl u de testi n g a l o wer d ose i n 6 a d diti o nal patie nts if D L Ts are e x perie nce d b y at least 
2  of 6 patie nts i n t he i nitial e x pa nsi o n c o h ort or t o f urt her c o nfir m t olera bilit y of  pr ol o n ge d treat me nt.  
P art C : C o m bi n ati o n D osi n g  
P art C D osi n g Sc he d ule  
 
D a y 1  
D a y 2  
D a y 3  
D a y 4  
D a y 5  
D a ys 6 -1 2  
D a ys 1 3 -2 1  
A be m acicli b P O  
5 5 m g/ m 2 BI D  x 2 1 da ys  a, b 
X  
X  
X  
X  
X  
X  
X  
Te m oz ol o mi de P O  
1 0 0 m g/ m 2/ da y x 5 da ys 
X  
X  
X  
X  
X  
 
 
Iri n otec a n I V 
5 0 m g/ m 2/ da y x 5 da ys 
X  
X  
X  
X  
X  
 
 
Di n ut u xi m a b  I V 
1 7. 5 m g/ m 2/ da y x 4 da ys 
 
X  
X  
X  
X  
 
 
G M -C S F  S u b Q  
2 5 0 µ g/ m 2/ da y x 7 da ys  
 
 
 
 
 
X  
 
A b bre viati o ns:  BI D = t wice dail y; G M -C S F = gra n ul oc yte -macr o p ha ge c ol o n y -sti m ulati n g fact or; 
I V =  i ntra ve n o us; P O = orall y; M T D
A  = P art A ma xi m u m t ol erate d d ose ; S u b Q = s u bc uta ne o us. 
a 
3 0 m g/ m 2 ma y be e val uate d d ue t o e xcessi ve t o xicities , if ne cessar y, as descri be d i n Secti o n 4. 1. 2 . 
b  A n i nter me diate d ose le vel (ie: bet wee n 5 5  m g/ m 2 a n d 3 0  m g/ m 2) ma y be e x pl ore d base d o n e mer gi n g data . 
6. 1. 1.  
D et aile d  A d mi nistr ati o n G ui deli nes (P art C O nl y)   
Si de effects s h o ul d be a ntici pate d wit h di n ut u xi ma b a d mi nistrati o n a n d ma y occ ur e v e n wit h use 
of pretreat me nt me dicati o ns. T he nee d t o sl o w, pa use , or e ve n dis c o nti n ue i nf usi o n s h o ul d be 
a ntici pate d a n d is n ot u ne x pecte d.  See Secti o n 6. 5. 3  f or g ui da nce f or s u p p orti ve ma na ge me nt of 
a ntici pate d di n ut u xi ma b -ass ociate d t o xicities.  
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
8 4  
D a ys 2 -5  
A d mi nister pre me dic ati o ns as o utli ne d in Secti o n s 6. 1. 4  a n d 6. 5. 3 . 
H o ur  0 :  A d mi nister a be macicli b a n d te m oz ol o mi de.  
H o ur 1:   A d mi nister iri n oteca n o ver 9 0 mi n utes a n d si m ulta ne o usl y be gi n n or mal sali ne 
b ol us of 1 0 -2 0 m L/ k g.  
H o ur  2. 5:   Be gi n di n ut u xi ma b i n f usi o n.  Start i nf usi o n rate at 0. 8 8 m g/ m2/ h o ur f or t he 
first 3 0 mi n utes. 
H o ur 3:   If starti n g rat e is t olerate d, i ncrease di n ut u xi ma b i nf usi o n rate t o 1. 7 5 
m g/ m 2/ h o ur.  If n ot t olerate d, see Secti o n 6. 5. 3  f or ma na ge me nt g ui deli nes 
N ote:  T he i nf usi o n s h o ul d be c o m plete d at H o ur 1 0 , b ut ma y be e xte n de d f or a ntici pate d 
t o xicities, s uc h as u nc o ntr olle d pai n, fe v er, h y p ote nsi o n, a n d tac h y p nea. T h e ma xi m u m 
i nf usi o n d urati o n is 2 0 h o urs; t he i nf usi o n M U S T be st o p pe d at 2 0 h o urs e ve n if t otal 
pla n ne d d ose has n ot c o m plete d.  T he i nf usi o n d urati o n a n d d ose deli vere d m ust be 
rec or de d. 
I m p ort a nt N ote: M o nit ori n g g ui deli nes s h o ul d be f oll o we d D U RI N G  di n ut u xi ma b i nf usi o n 
(see Secti o n 6. 1. 1. 1  i m mediatel y bel o w ). 
6. 1. 1. 1.  
M o nit ori n g  G ui deli nes  D u ri n g Di n ut u xi m a b  I nf usi o n ( D a ys 2-5)   
Vital si g ns s h o ul d be ass esse d e ver y1 5  mi n utes  f or t he first h o ur of i nf usi o n, t he n h o url y if 
sta ble.  M ore fre q ue nt assess me nt ma y b e re q uir e d base d o n t he patie nt’s cli nical c o n diti o n.  
Bet wee n di n ut u xi ma b i nf usi o ns, vital si g ns s h o ul d be meas ure d e ver y 4 h o urs  at a mi ni m u m . 
Strict meas ure me nt of i n t a ke a n d o ut p ut is re q uir e d o n Da ys 2-5.  
Dail y p h ysic al e x a m s, i ncl u di n g p u pillar y refle x es a n d e xtra oc ular m o ve m e nt e val uati o n, are 
re q uire d b ef ore eac h dail y i nf usi o n. 
Wei g h patie nts dail y t o assess fl ui d stat us.  Use di uretics wit h e xtre me ca uti o n.  
See Secti o n 6. 5. 3  f or g ui da nce f or s u p p orti ve ma na ge me nt of a ntici p ate d di n ut u xi ma b-ass ociate d 
t o xicities. 
6. 1. 2.  
P ati e nts wit h Diffic ult y S w all o wi n g After I niti ati n g Tre at me nt  
If a patie nt h as diffic ult y s wall o wi n g after i nitiati n g st u d y treat me nt, t he f oll o wi n g s h o ul d be 
c o nsi dere d.   I n all cas es, t he met h o d of a d mi nistrati o n s h o ul d be d oc u me nte d o n t he C R F. 
 F or a b e macicli b, t he M e dicati o n Alter nati ve A d mi nistrati o n G ui de  pr o vi des i nstr ucti o ns 
f or dis persi n g ta blets f or oral a d mi nistrati o n as well as dis persi n g ta blets/ gra n ules f or 
N G/ G -t u be a d mi nistrati o n. Patie nts u na ble t o s wallo w ta blets ma y als o switc h  t o oral 
gra n ules  ( Part C o nl y) (refer t o O ral G ra n ul e Dis pe nsi n g De vi ce a n d A d mi nistrati o n 
T rai ni n g V i de o a n d Oral Gra n ule s I F U).   
 F or te m oz ol o mi de, f oll o w sta n dar d of care f or alter nati ve a d mi nistrati o n ( Trissel et al. 
2 0 0 6; C C L G 2 0 1 6).    
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
8 5  
6. 1. 3.  
Criteri a t o Be gi n S u bse q ue nt C ycles of Tre at me nt   
T o be gi n d osi n g at eac h c ycle, t he f oll o wi n g criteria m ust be f ulfille d . If a patie nt has n ot met t he 
criteria t o s tart t he n e xt c ycl e, a n d t he t o xicit y d oes n ot warra nt an a be maci cli b  d ose h ol d per 
S ecti o n 6. 6. 1. 1  ( Parts A a n d B) or  Secti o n 6. 6. 1. 3  ( Part C), t he i n vesti gat or ma y use his/ her 
discreti o n t o h ol d a be ma cicli b  w hile waiti n g f or t he t o xicit y t o res ol v e. T h e d ose h ol d s h o ul d be 
rec or de d i n t he eC R F.  A c ycle ma y b e gi n 1 da y earl y  (i. e. Da y 2 1 ) if nee d e d for l o gistical 
reas o ns if all D a y 1 criteria are s atisfie d.  
 A bs ol ute ne utr o p hil c o u nt ≥7 5 0/ m m 3 
o  Parts A a n d B:  G -C S F is n ot per mitte d wit hi n t he past  4 8 h o urs  
o  Part C:  G -C S F is n ot per mitte d  
 Platelets ≥7 5, 0 0 0/ m m 3  (p latelet tra nsf usi o n is n ot per mitte d wit hi n t he past  7 2 h o urs)  
 T otal bilir u bi n ≤ 1. 5 ×  u p per li mit of n or mal ( U L N), e x ce pt patie nts wit h d oc u me nte d 
hist or y of Gil bert S y n dr o me w h o m ust ha ve a t otal bilir u bi n le vel of < 3. 0 × U L N  
 A S T  a n d A L T ≤3. 0 ×  U L N, or ≤5 ×  U L N if t h e tra nsa mi nase ele vati o n is d ue t o li ver  
metastases  
 F or parts A a n d B , patie nts m ust wei g h ≥1 0 k g a n d ha ve B S A ≥0. 5 m 2 
 F or part C, patie nt s wit h a starti n g a be macicli b d ose of 3 0 m g/ m 2  BI D, B S A m ust be ≥0. 3 
m 2 
 A n y n o n h e mat ol o gi c t o xicit y dee me d relate d t o st u d y treat me nt m ust be  N CI -C T C A E, 
v 5. 0 Gra de ≤1  or e q ui val e nt se verit y t o baseli ne u nless dee me d cli nicall y i nsi g nifica nt b y 
t he i n vesti gat or. 
6. 1. 4.  
Pre me dic ati o n   
Iri n ot eca n a n d te m oz ol o mi de s h o ul d be a d mi nistere d f oll o wi n g i nstit uti o nal -a p pr o ve d sta n dar d -
of -care pre me dicati o n g ui deli nes.  A d diti o nal pre me dicati o n a n d s u p p orti ve ma na ge me nt f or 
di n ut u xi ma b ca n be f o u n d i n Secti o n 6. 5. 3 . 
6. 1. 4. 1.  
N a use a   
A pr o p h yl actic tr eat me nt wit h a nti -e metics is rec o m me n de d bef ore eac h treat me nt wit h 
iri n oteca n a n d/ or t e m oz ol o mi de.  
6. 2.  
Pre p ar ati o n/ H a n dli n g/ St or a ge/ Acc o u nt a bilit y   
1.  T he i n vesti gat or or desi g nee m ust c o nfir m a p pr o priate st ora ge c o n diti o ns ha ve bee n 
mai ntai ne d d uri n g tra nsit f or all st u d y i nter ve nti o n recei v e d a n d a n y dis cre p a ncies are 
re p orte d a n d res ol ve d b ef ore use of t he st u d y i nter ve nti o n. 
2.  O nl y partici pa nts e nr olle d i n t he st u d y ma y recei v e st u d y i nter ve nti o n a n d o nl y 
a ut h orize d st u d y pers o n n el ma y s u p pl y , pre pare, or a d mi nis ter st u d y i nter ve nti o n.  All 
st u d y i nter ve nti o n m ust be st ore d i n a sec ure, e n vir o n me ntall y c o ntr olle d, a n d m o nit ore d 
( ma n ual or a ut o mat e d) area i n acc or da n ce wit h t he la bele d st ora ge c o n diti o ns wit h access 
li mite d t o t he i n vesti gat or a n d a ut h orize d st u d y p ers o n nel . 
3.  T he i n vesti gat or or a ut h orize d st u d y pers o n nel  is res p o nsi ble f or st u d y i nter ve nti o n 
acc o u nta bilit y, rec o nciliati o n, a n d rec or d m ai nte na nce ( i.e. recei pt, rec o n ciliati o n, a n d 
fi nal dis p ositi o n rec or ds). 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
8 6  
4.  F urt her g ui d a nce a n d i nf or mati o n f or t he f i nal dis p ositi o n of u n use d st u d y i nter ve nti o ns 
are pr o vi d e d i n t he P har mac y Ma n ual . 
5.  I n v esti gat ors s h o ul d c o ns ult t he st u d y dr u g i nf or m ati o n pr o vi de d i n t he la bel f or t he 
s pecific a d mi nistrati o n i nf or mati o n (i ncl u di n g war ni n gs, preca uti o ns, c o ntr ai n dicati o ns, 
a d verse reacti o ns, a n d d ose m o dificati o ns).  
6. 3.  
Me as ures t o Mi ni mize Bi as :  R a n d o miz ati o n a n d Bli n di n g   
T his is a n o pe n -la bel st u d y. 
6. 4.  
St u d y I nter ve nti o n C o m pli a nce   
St u d y  i nter ve nti o n will be a d mi nistere d u n der me dical s u per visi o n b y t h e i n vesti gat or or 
desi g nee. T he d os e of st u d y i nter ve nti o n a n d st u d y partici pa nt i de ntificati o n will be c o nf ir me d 
pri or t o t he ti me of d osi n g. T he d ate a n d ti me of eac h d ose a d mi nistere d wil l be rec or de d i n t he 
s o urce d oc u m e nts a n d will be pr o vi de d t o t he s p o ns or as re q u este d.  
W he n partici pa nts self -a d mi nister st u d y i nter ve nti o n(s) at h o me, c o m plia nce wit h st u d y  
i nter ve nti o n will be assesse d at Da y 1 (± 5 d a ys) of eac h C ycle st arti n g at C ycl e 2. C o m plia nce 
will be assesse d b y direct q uesti o ni n g, c o u nti n g ret ur ne d ta blets/ca ps ules, or  b y wei g h i n g 
ret ur ne d gra n ules. C o m plia nce ass ess me nts will be d oc u me nte d i n t he s o urce d oc u me nts a n d 
C R F. W he n assessi n g c o m plia nce of gra n ules, refer t o t he “ A be macicli b Oral Gra n ul es 
C o m plia nce F or m”. De vi ati o n(s) fr o m t he prescri b e d d osa ge re gi me n s h o ul d be rec or de d i n t he 
electr o nic case re p ort f or m ( eC R F) . 
A rec or d of t he q u a ntit y  of self-a d mi nistere d st u d y i nter ve nti o n(s) dis pe ns e d t o a n d ret ur n e d b y 
eac h p artici pa nt m ust be mai ntai ne d a n d rec o ncile d wit h st u d y i nter ve nti o n a n d c o m plia nce 
rec or ds. I nter ve nti o n start a n d st o p dates, i ncl u di n g dat es f or i nter ve nti o n dela ys an d/ or d ose 
re d ucti o ns, will als o be rec or de d i n t he C R F. 
T he patie nt m ust ta ke ≥7 5 % of t he pla n ne d d os es f or st u d y tr eat me nt i n a c ycl e t o be dee me d 
c o m plia nt u nless  d ose h ol ds are necessitate d b y A E .  As o utli ne d i n Secti o n 6. 6 , d ose 
s us pe nsi o ns or c ycle d ela ys ma y o cc ur a n d will n ot res ult i n a patie nt bei n g c o nsi dere d as 
n o nc o m plia nt.  A patie nt ma y b e c o nsi dere d n o nc o m plia nt if he/ s he is j u d ge d b y t he i n vesti gat or 
t o ha ve i nte nti o nall y or re peate dl y ta k e n ≥1 2 5 % of t he pla n ne d d oses of st u d y treat me nt i n a 
c ycle.  P ote ntial disc o nti n uati o n of a patie nt d ue t o st u d y dr u g n o nc o m plia nce will be disc usse d 
bet wee n t he i n v esti gat or a n d t he Lill y C R P / C R S bef ore a n y deter mi nati o n is ma de t o disc o nti n ue 
t he patie nt. 
6. 5.  
C o nc o mit a nt T her a p y   
Wit h t he e x ce pti o ns liste d i n t he secti o ns bel o w, n o ot her c he m ot hera p y, i n vesti gati o nal 
me dicati o ns, ot her a ntica n cer t hera p y, i m m u n ot hera p y, h or m o nal ca ncer t h era p y, her bal 
s u p ple me nts a n d/ or her bal dr u gs i nte n d e d t o treat ca ncer, ra diati o n, or s ur ger y f or ca ncer will be 
per mitte d w hile patie nts are o n st u d y treat me nt.  Palliati ve ra diati o n t hera p y will be per mitte d as 
detaile d i n Secti o n 6. 5. 1 . 
Beca use  of a p ote ntial i m pact o n a nti b o d y-de p e n d e nt cell ular c yt ot o xicit y, a n y tr eat me nt wit h 
i m m u n os u p pressi ve acti vit y a n d i m m u n o gl o b uli ns s h o ul d n ot be a d mi nistere d wit hi n 2 1  da ys  
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
8 7  
pri or t o  C ycle 1  a n d f or 1 wee k after fi n al di n ut u xi ma b i nf usi o n. H o we ver, t hese me dicati o ns  
ma y b e all o we d if me di call y nee de d t o treat ac ut e, p ote ntiall y life -t hr eate ni n g e v e nts. 
A n y me di cati o n or vacci ne (i ncl u di n g o v er -t h e-c o u nter or pres cri pti o n me dici nes, vita mi ns, 
a n d/ or her bal s u p ple me nts) t hat t he partici pa nt is recei vi n g at t he ti me of e nr oll me nt or recei ves 
d uri n g t he st u d y m ust be rec or de d al o n g wit h:  
 Reas o n f or use  
 Dates of a d mi nistrati o n i ncl u di n g start a n d e n d dates  
A be m acicli b  is e xte nsi vel y met a b olize d t hr o u g h o xi dati o n b y C Y P 3 A.  I n cli nical dr u g 
i nteracti o n st u dies, c oa d mi nistrati o n of clarit hr o m yci n, a str o n g C Y P 3 A i n hi bit or, i ncrease d 
e x p os ure (area u n der t h e c ur ve [ A U C] ) t o a be maci cli b b y 3. 4-f ol d ( St u d y I 3 Y-M C -J P B E) a n d 
c oa d mi nistrati o n of rifa m pi n, a str o n g C Y P 3 A i n d ucer, decrease d e x p os ure t o a be macicli b b y 
9 5 % ( St u d y I 3 Y -M C -J P B F).  T heref ore, gra pefr uit or gra pefr uit j uice , ca n na bis, ca n na bis 
pr o d ucts, a n d ot her s tr o n g i n hi bit ors of C Y P 3 A (s ee Secti o n 1 0. 6 , A p pe n di x 6 ) s h o ul d n ot be 
ta ke n d uri n g C ycle 1 .  Be y o n d C ycle 1 , gra pefr uit or gra pefr uit j uice, ca n na bis,  ca n na bis 
pr o d ucts,  as well as i n d u cers a n d str o n g or m o derate i n hi bit ors of C Y P 3 A s h o ul d be s u bstit ute d 
or a v oi de d if p ossi ble (see Secti o n 1 0. 6 , A p pe n di x 6 ).  T he i nf or mati o n i n A p pe n di x 6  is 
pr o vi de d f or g ui da n ce t o i n vesti gat ors a n d d o es n ot precl u de t he us e of t hes e me dicati o ns if 
cli nicall y i n dicat e d.  
All patie nts ma y recei ve s u p p orti ve t hera p y wit h de x a met has o ne, prefera bl y ≤7 da ys, if cli nicall y 
i n dicate d.  Patie nts re q uiri n g m ore t ha n 7 da ys of de x a met has o ne t hera p y will n ot i nc ur a 
pr ot oc ol de viati o n.  
A be macicli b c a n be c o a d mi nistere d wit h dr u gs t hat are s u bstrates of C Y P e nz y m es . 
A be macicli b a n d/ or its m aj or meta b olites i n hi bit t he effl u x tra ns p orters P -gl yc o pr ot ei n a n d 
breast c a ncer resista n ce pr otei n a n d re n al tra ns p ort ers or ga nic cati o n tra ns p orter 2, m ulti dr u g a n d 
t o xi n e xtr usi o n pr otei n ( M A T E) 1 a n d M A T E 2 -K at cli nicall y rele va nt c o nce ntrati o ns.  
T heref ore, s u bstrat es of t hese t ra ns p ort ers s uc h as metf or mi n a n d t h ose wit h a narr o w t hera p e utic 
i n de x s uc h as di g o xi n a n d d ofetili de s h o ul d be s u bstit ute d or a v oi de d if p ossi ble. 
T he acti ve met a b olite of iri n oteca n, S N -3 8, is met a b olize d via U G T 1 A 1.  Patie nts recei vi n g 
c o nc o mita nt ket o c o naz ole, a str o n g C Y P 3 A 4 a n d U G T 1 A 1 i n hi bit or, e x hi bite d i ncreas e d 
e x p os ures of iri n oteca n a n d S N -3 8  (Iri n oteca n U S Pac ka ge I ns ert 2 0 2 0).  T heref ore, str o n g 
i n hi bit ors of U G T 1 A 1 (e. g. ge mfi br ozil, ataza na vir, i n di na vir) s h o ul d n ot be ta ke n d uri n g 
C ycle  1.   Be y o n d C ycl e 1, str o n g i n hi bit ors of U G T 1 A 1 s h o ul d be s u bstit ute d or a v oi de d if 
p ossi ble.  
F or f urt her i nf or m ati o n re gar di n g c o n c o mita nt me dicati o ns wit h di n ut u xi ma b, G M -C S F, 
iri n oteca n, a n d te m oz ol o mi de refer t o t he g ui da nce i n eac h of t he pr o d u ct la bels. 
Li ve v acci n es are n ot per mitte d w hile o n treat me nt  a n d f or at least 3 m o nt hs after t he last d ose of 
a be maci cli b .  V acci n es t hat d o n ot c o ntai n a li ve vir us are per mitte d.   Li v e vacci nes f oll o wi n g 
treat me nt wit h ot her st u d y dr u gs s h o ul d be a d mi nistere d acc or di n g t o la bel.    
All c o nc o mita nt me dicati o n a d mi nistere d t o treat a n A E or S A E m ust be rec or de d u ntil 
res ol uti o n, or if e ve nts are n o l o n ger dr u g-relat e d, t he patie nt dies or is l ost t o f oll o w-u p, or a 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
8 8  
ne w treat me nt is i nitiate d.  W hile o n st u d y, pati e nts ma y be a d mi nistere d m e dicati o ns at t he 
discreti o n of t he i n vesti gat or t o treat A Es or as s u p p orti ve care (e .g . a nti-e metics, a nti bi otics) . 
T he Lill y C R P /C R S s h o ul d be c o ntacte d if t h ere are a n y q uesti o ns re gar di n g c o n c o mita nt or 
pri or t hera p y.  
6. 5. 1.  
P alli at i ve Me dici ne a n d S u p p orti ve C are  
All c o nc o mita nt me dicati o ns s h o ul d be rec or de d t hr o u g h o ut t he p atie nt’s p artici pati o n i n t he 
st u d y. 
P alli ati ve Me dici ne  
 Palliati ve ra diati o n t her a p y of ≤1 4 da ys is per mitte d after C ycl e 6  a n d after disc ussi o n 
wit h a n d a gree me nt of t h e Lill y C R P / C R S f or irra diati n g s mall areas of pai nf ul 
metastases t hat ca n n ot b e ma na ge d a d e q uatel y usi n g s yste mic or l ocal a nal gesics.  S uc h 
areas m ust n ot be a n i d e nt ifie d tar get lesi o n a n d m ust n ot c o nstit ute pr o gressi ve disease 
or meet R E CI S T criteria f or pr o gressi ve disease.  A be macicli b s h o ul d be s us pe n de d 
d uri n g t he p alliati ve ra di ot hera p y peri o d a n d u ntil c o m plete rec o ver y fr o m ac ute 
reacti o ns a n d p ot e ntial gastr oi ntesti nal  t o xicities.  A n y  s y m pt o matic deteri orati o n or 
cli nical disease pr o gressi o n re q uiri n g, i n t he o pi ni o n of t he i n vesti gat or, ot her f or ms of 
s pecific a nti-t u m or s yste mic t hera p y, will be ca us e f or disc o nti n uati o n of st u d y t hera p y. 
S u p p orti ve C are  
Patie nts s h o ul d recei ve f ull s u p p orti ve care.  
 T he use of a nti -di arr h eal ( i.e. l o pera mi de) me dicati o n is str o n gl y rec o m me n de d.  See  
Secti o n 6. 5. 2  f or details. 
 
In Parts A a n d B , the use of G -C S F is per mitte d f or all c ycles, i ncl u di n g C ycle 1, at t he 
discreti o n of t he i n vesti gat or base d o n A m erica n S ociet y of Cli nical O n c ol o g y ( A S C O ) 
( S mit h et al. 2 0 1 5) a n d E ur o pea n S ociet y f or Me dical O nc ol o g y ( Cra wf or d et al. 2 01 0 ) 
g ui deli nes . A d mi nistrati o n of G -C S F s h o ul d be c o nsi dere d al o n gsi de st u d y treat me nt f or 
t h ose patie nts at hi g h ris k of se vere ne utr o p e nia (e. g. pre vi o usl y tr eate d wit h 
c hem ot hera p y or ra di ati o n).   G -C S F is n ot all o we d i n Part C.  
 E r yt hr o p oieti n, t hr o mb o p oietic gr o wt h fact ors, pac ke d re d bl o o d cell tra nsf usi o ns, a n d 
ot her bl o o d pr o d ucts ma y be us e d acc or di n g t o A S C O g ui deli nes ( Rizz o et al. 2 0 0 8) at 
t he i n vesti gat or’s discreti o n. 
 Pr o p h yla ctic a nti bi otic treat me nt s h o ul d be c o nsiste nt wit h A S C O g ui deli nes 
(Le hr n bec her et al. 2 0 1 7 ). 
 P ne u m ocystis jir ovecii  p ne u m o nia ma y occ ur i n partici pa nts recei vi n g iri n oteca n a n d 
te m oz ol o mi de. P C P pr o p h yla xis is e nc o ura ge d. 
 Refer t o te m oz ol o mi de a n d iri n oteca n la bels f or rec o m me n dati o ns o n pr o p h ylactic 
s u p p orti ve care. 
6. 5. 2.  
S u p p orti ve M a n a ge me nt f or Di arr he a   
Diarr hea is a n  o verla p pi n g t o xicit y of a b e macicli b , iri n oteca n, a n d di n ut u xi ma b.  I t ma y b e 
diffic ult t o discer n t he differe n ce b et wee n ca uses of diarr hea .  I n v esti gat ors s h o ul d atte m pt t o 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
8 9  
deter mi ne t o w hic h st u d y dr u g t he diarr hea is li kel y attri b ute d  usi n g t he d escri pti o ns bel o w .  
Patie nts s h o ul d recei ve diarr hea  ma n a ge me nt i nstr ucti o ns a n d ma xi mal s u p p orti ve care .  
L o pera mi de is r ec o m me n de d . 
See Secti o n 6. 6. 1. 1  f or di arr hea -relate d d ose m o dificati o n s.  F or p atie nts i n Part C, see Secti o n  
6. 5. 3. 2  f or s u g geste d pre me dicati o n t o pre ve nt diarr hea. 
G ui d a nce f or di arr he a attri b ute d t o  iri n otec a n: 
Earl y diarr hea ( o ns et  d uri n g or s h ortl y after i nf usi o n) is us uall y tra nsie nt a n d i nfre q ue ntl y se vere.  
It ma y b e acc o m pa nie d b y c h oli ner gic s y m pt o ms of r hi nitis, i ncrease d s ali vati o n, mi osis, 
lacri mati o n, dia p h oresis, fl us hi n g, a n d i ntesti nal h y p er peristalsis t hat ca n ca use a b d o mi nal 
cra m pi n g.  Bra d ycar dia ma y o cc ur.  E arl y diarr hea a n d ot her c h oli ner gic s y m pt o ms ma y b e 
pre ve nte d a n d treate d.  C o nsi der pr o p h ylactic or t hera pe utic a d mi nistrati o n of atr o pi ne 
(acc or di n g t o la bel or i nstit uti o nal practice) u nless cli nicall y c o ntrai n dicat e d.  
Lat e diarr hea ( o nset  m or e t ha n 2 4 h o urs after a d mi nistrati o n ) ca n be life-t hreate ni n g si nc e it ma y 
be pr ol o n ge d , lea d t o d e h y drati o n, electr ol yte i m b ala nce, or se psis, a n d ca n be c o m plicate d b y 
c olitis, ulcerati o n, blee di n g, ile us, o bstr ucti o n, a n d i nfecti o n.  Cases of me gac ol o n a n d i ntesti nal 
perf orati o n ha ve bee n re p orte d.  Patie nts s h o ul d ha ve l o pera mi de a vaila bl e pri or t o first 
iri n oteca n i nf usi o n.  Be gi n l o pera mi de at t he first e pis o de of p o orl y f or me d , l o ose, or i ncrease d 
fre q ue n c y of  st o ol. M o nit or a n d re pl ace fl ui d a n d electr ol yt es.  Patie nts s h o ul d be f oll o we d 
cl osel y. 
Pr o p h yla ctic or c o n c o mita nt use of a nti bi otics, s uc h as cefi xi me , ca n be us e d at t he i n vesti gat or’s 
discreti o n  (Wa g n er et al. 2 0 0 8 ).   
Refer t o prescri bi n g i nf or mati o n f or a d diti o nal ma na ge me nt of diarr hea attri b ute d t o iri n oteca n.  
G ui d a nce f or di arr he a attri b ute d t o a be m aci cli b : 
Diarr hea wa s t he m ost fre q ue ntl y re p ort e d treat m e nt-e mer ge nt a d verse e v e nt ( T E A E ) wit h 
a be maci cli b i n a d ult P hase 3 re gistrati o n st u dies ( M O N A R C H 2 [ Sle d ge et al. 2 0 1 7]; 
M O N A R C H 3 [ G oetz et al. 2 0 1 7; J o h nst o n et al. 2 0 1 9 ]).  C har acteristics of a be macicli b diarr h ea 
fr o m t hese st u dies i ncl u d e: 
 Pre d o mi na ntl y of l o w se verit y ( Gra d e 1 or 2) wit h n o Gra de 4 or 5 diarr h ea o bser ve d.  
 In ci de nce was greatest d uri n g t he first m o nt h of a be macicli b treat me nt. 
 T he m e dia n ti me t o o nset of t he fir st diarr h ea e ve nt was 6 t o 8 da ys, a n d t he me dia n  
d urati o n of diarr hea f or Gra de  2 was 9  t o 1 1 da ys a n d Gra d e 3 was 6  t o 8  d a ys  
( A be maci cli b U S Pac ka ge I nsert 2 0 1 9 ). 
 G e nerall y ma n a gea ble wit h sta n dar d a nti -diarr heal a ge nts a n d d ose a dj ust me nt.  
Initiate s u p p orti ve m eas ures as earl y as p ossi ble.  S u p p orti ve meas ures i ncl u de:  
 A nti -diarr heal me dicati o n ( e. g. l o pera mi de) i nitiati o n at t he first si g n of l o ose st o ols.  
 Patie nt/care gi ver s h o ul d n otif y t he i n vesti gat or f or f urt her i nstr u cti o ns.  
 Patie nts s h o ul d be e nc o ura ge d t o dri n k s ufficie nt fl ui ds. 
 Site pers o n nel s h o ul d assess res p o nse wit hi n 2 4 h o urs.  
 M o dif y tr eat me nt  as o utli ne d i n Secti o n 6. 6  ( D ose M o dificati o n). 
 A dj ust d oses as o utli ne d i n Secti o n 6. 6. 1. 1 .   
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
9 0  
If se vere, me as ure  a bs ol ute  ne utr o p hil c o u nts , b o d y te m perat ur e , a n d m o nit or f or si g ns of 
bacterial i nf ecti o n .  If ass ociate d wit h fe v er or s e v er e ne utr o pe nia, b e gi n br oa d -s pectr u m 
a nti bi otics per i nstit uti o nal g ui deli nes . 
Patie nts wit h se vere diarr hea or a n y di arr h ea ass o ciate d wit h na usea or v o miti n g s h o ul d be 
caref ull y m o nit ore d a n d gi ve n I V h y drati o n a n d electr ol yt e re place me nt.   H os pitalizati o n s h o ul d 
be c o nsi dere d.   
6. 5. 3.  
S u p p orti ve  M a n a ge me nt  of A ntici p ate d Di n ut u xi m a b -Ass oci at e d T o xicities 
(P a rt C O nl y )  
Si de effects d uri n g  di n ut u xi ma b i nf usi o n s h o ul d be a ntici pate d a n d will fre q ue ntl y  occ ur e v e n 
wit h use of pretr eat me nt me dicati o ns. T he nee d t o sl o w, pa use , or disc o nti n ue i nf us i o n s h o ul d be 
a ntici pate d a n d is n ot u ne x pecte d.  Refer t o Secti o n 6. 6. 1. 3  f or d ose m o dificati o ns of 
di n ut u xi ma b . 
6. 5. 3. 1.  
H y p ote nsi o n  (W it h o ut E vi de nce of A ller gic R e acti o n)  
Severe Hy p o te nsi o n is defi ne d as : 
 S y m pt o matic d ecreas e i n  bl o o d press ure  a n d/ or  
 A ge 1 -1 2 years:  S B P < 7 0 m m H g  
 A ge > 1 2 years:  S B P < 8 0  m m H g  
 Eit her S B P or D B P decrease b y m ore t ha n 1 5 % fr o m baseli ne . 
If se vere, acc o m pa ni e d b y p o or p erf usi o n, e n d or ga n d ysf u ncti o n, or aci de mia , st o p i nf usi o n a n d 
i nitiate res uscitati o n eff orts. 
M o der ate Hy p ote nsi o n  is defi ne d as hy p ote nsi o n wit h n or m al  perf usi o n , a bse nce of  e n d or g a n 
dysf u ncti o n , a n d  wit h o ut aci de mi a  
F or m o derate h y p ote nsi o n:  
 Pa use di n ut u xi ma b i nf usi o n  
 Gi ve 2 0 m L/ k g n or m al sali ne b ol us  
 St o p or a dj ust narc otic a n d se dati n g H 1 bl oc ker i nf usi o ns  
 C o nsi der Tre n dele n b er g p ositi o n . 
F or m o derate h y p ote nsi o n t hat per sists des pite t he meas ures a b o ve:  
 Reassess perf usi o n a n d e n d or ga n f u ncti o n a n d i nitiate sta n dar d res uscitati o n eff orts 
 Re peat n or mal sali ne b ol us  
 C o nsi der al b u mi n i nf usi o n if al b u mi n le vel is < 3 g m/ d L 
 C o nsi der P R B C tra nsf usi o n if H g b is < 1 0 g m/ d L  
 C o nsi der  tra nsfer t o i nte nsi ve care u nit. 
If h y p ote nsi o n persists f oll o wi n g 2 fl ui d b ol uses, gi ve a d diti o nal b ol uses a n d i nitiate press ors.  
N ote t hat e pi ne p hri ne is preferre d o ver d o pa mi ne  base d o n its desire d vas o c o nstricti ve pr o perties.  
Res u m pti o n of di n ut u xi m a b i nf usi o n  after hy p ote nsi o n  
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
9 1  
F or h y p ote nsi o n t hat res ol ves pr o m ptl y a n d c o m pletel y wit h l i mite d res uscitati o n, di n ut u xi ma b 
ma y b e res u me d  at 5 0 % i nf usi o n rate . If > 2 0 h o urs ha ve ela ps e d si nce i nitiati o n of di n ut u xi ma b 
i nf usi o n, t he n d o n ot res u me t hat da y’s d ose . 
If sa me-d a y i nf usi o n is res u me d a n d if bl o o d press ures are sta ble f or 2 h o urs , t he i nf usi o n rate 
ma y b e i ncrease d t o t he  ma xi m u m rate f or re mai n der of t hat da y a n d s u bs e q ue nt da ys.  
If h y p ote nsi o n rec urs at a re d uce d s a me-d a y i nf usi o n rate, st o p t he i nf usi o n a n d re peat t he 
s u p p orti ve care meas ur es descri be d a b o ve .  D o n ot a d mi nister a n y a d diti o nal di n ut u xi ma b o n 
t hat da y.  T h e f oll o wi n g da y, e ns ure t h at t he patie nt is v ol u me re plete a n d be gi n i nf usi o n at 5 0 % 
rate.  
If bl o o d press ur e is sta ble f or 2 h o urs at a re d uce d rate, t he i nf usi o n ca n be i ncreas e d t o 
ma xi m u m  rate a n d, if t olerate d, s u bse q ue nt i nf usi o n da ys m a y be gi n at ma xi m u m  starti n g rate. 
If bl o o d press ur e o nl y  re mai ns sta ble at t he 5 0 % i nf usi o n rate, t he n all s u bse q ue nt i nf usi o ns 
s h o ul d be i nitiate d at t he 5 0 % i nf usi o n rate  wit h o ut atte m pts t o i ncrease . 
If > 6 0 m L/ k g fl ui d b ol uses were re q uir e d at ma xi mal di n ut u xi ma b rate, b ut t he 5 0 % i nf usi o n rate 
was t olerate d , t h e n all re mai ni n g da ys s h o ul d be a d mi nistere d at t he 5 0 % re d uce d i nf usi o n r ate 
wit h o ut atte m pts t o i ncrease . 
If press ors were re q uir e d b ut t he n were a ble t o be disc o nti n ue d a n d t he pati e nt’s bl o o d press ure 
re mai ne d sta ble f or ≥6 h o urs f oll o wi n g disc o ntin uati o n , t he ne xt da y’s di n ut u xi ma b i nf usi o n ma y 
res u me at 5 0 %. 
Patie nts w h o re q uire press or s u p p ort  f or ≥2 4 h o urs or m ore t ha n o nce m ust  per ma ne ntl y 
disc o nti n ue  all st u d y dr u gs .   
6. 5. 3. 2.  
D i arr he a M a n a ge me nt   
D ue t o iri n oteca n-i n d uce d diarr hea, c o nsi der usi n g cefi xi me ( 8 m g/ k g/ da y) or a n a vaila bl e 
e q ui vale nt of oral ce p h al os p ori n (i .e., cef p o d o xi me 1 0 m g/ k g/ da y di vi de d BI D; ma xi m u m d ose 
4 0 0 m g/ da y) starti n g 2 d a ys pri or t o first iri n oteca n d ose a n d c o nti n ue d u ntil 3 da ys after t he last 
iri n oteca n d ose p er c ycl e.  F or patie nts r ecei vi n g 5 da ys of iri n oteca n, t h e t otal c o urse of di arr h ea 
p re ve nti o n is 1 0 da ys.   
6. 5. 3. 3.  
Aller gic  Re a cti o n  d ue t o D in ut u xi m a b   
Pr o p hyl actic A n ti hist a mi ne 
 C o nsi der a d mi nistrati o n of a n a nti hista mi ne , s uc h as di p he n h y dra mi ne ( 0. 5 t o 1 m g/ k g; 
ma xi m u m d ose 5 0 m g) 2 0 mi n utes pri or t o di n ut u xi ma b a n d e ver y 4 t o 6 h o urs  as 
t olerate d d uri n g t he di n ut u xi ma b i nf usi o n.  
Mil d Aller gic Re acti o ns:  li mite d t o Gr a de 1 -2 r as h , fl us hi n g, urtic ari a , a n d / or dys p ne a  
S u g geste d  ma n a ge me nt of mil d aller gic reacti o ns i ncl u des  
 Decrease di n ut u xi ma b i nf usi o n rate t o 5 0 %  
 A d mi nister  a n H 1  bl oc ke r, s uc h as di p he n h y dra mi ne or cetirizi ne 
 A d mi nister H 2 bl oc ker  
 W he n  s y m pt o ms res ol ve, res u me ori gi nal i nf usi o n rate 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
9 2  
 If s y m pt o ms r ec ur, a gai n  decreas e i nf usi o n r ate t o 5 0 % 
 I nf usi o n M U S T be st o p pe d after 2 0 h o urs e v e n if f ull d ose has n ot bee n a d mi nistere d; 
d oc u me nt t otal a m o u nt of di n ut u xi ma b i nf use d.  
M o der ate t o Severe  Aller gic Re acti o ns:  i ncl u des a ny of t he f oll o wi n g: sy m pt o m atic 
br o nc h os p as m,  aller gy -rel ate d a n gi oe de m a, ge ner alize d e de m a, hy p ote nsi o n, or a n a p hyl a xis 
( Gr a de 3 or 4)  
S u g geste d ma n a ge me nt of m o derate t o se v ere aller gic reacti o ns i ncl u des  
 I m me diat el y st o p di n ut u xi ma b i nf usi o n  
 E val uate air wa y, breat hi n g, a n d circ ulati o n  
 F oll o w i nstit uti o nal g ui deli nes f or ra pi d res p o nse or critical care res p o nse t ea m 
 F or air wa y c o n cer ns:  
o  A d mi nister o x y ge n  a n d al b uter ol f or br o nc h os p as m  
o  A d mi nister I V di p he n h y dra mi ne  
o  A d mi nister e pi ne p hri ne (1: 1 0 0 0  I M rec o m me n de d) f or u p per air wa y i n v ol ve me nt  or 
if acc o m pa ni e d b y circ ulat or y c olla pse 
o  A d mi nister I V h y dr oc ortis o ne ( 1 -2 m g/ k g) f or a na p h yla xis wit h  car di o vasc ular 
c olla pse, if ≥2 d oses e pi n e p hri ne are re q uire d, or f or m o derate t o se v ere s y m pt o ms  
t hat rec ur u p o n di n ut u xi ma b  rec h alle n ge. 
 F or h y p ote nsi o n i n t he setti n g of aller gi c reacti o n  
o  Gi ve 2 0 m L/ k g n or m al sali ne b ol us   
o  St o p or a dj ust narc otics a n d se dati n g H 1 bl oc kers  
o  C o nsi der use of Tre n dele n b ur g  p ositi o n  
o  See pre vi o us secti o n f or h y p ote nsi o n ma na ge me nt . 
 F or mil d br o nc h os pas m or a n gi oe de ma  wit h o ut  i m pact o n  breat hi n g  a n d t hat  c o m pletel y 
res ol ves wit h o ut e pi ne p hri ne or  h y dr oc ortis o ne , di n ut u xi ma b i nf usi o n ma y res u me at 
5 0 % rate  
 F or h y p ote nsi o n t hat res ol ves f oll o wi n g fl ui d b ol us, di n ut u xi ma b i nf usi o n ma y res u me at 
5 0 % rate  o n t he s a me da y of t he reacti o n  
 If s y m pt o matic a n gi oe de ma or br o nc h os p as m  rec urs after di n ut u xi ma b  i nf usi o n res u mes, 
t he n disc o nti n ue i nf usi o n f or t hat da y  
 If s y m pt o ms r es ol ve d c o m pletel y o n t he da y di n ut u xi ma b was disc o nti n ue d, t he n r es u me 
t he f oll o wi n g da y  wit h h y dr oc ortis o ne 1 -2 m g/ k g I V  pre me di cati o n .  This r ec halle n ge 
s h o ul d be i n t he i nte nsi ve care u nit 
 If br o nc h os p as m or  a n gi oe de ma re q uires e pi n e p hri ne, per ma n e ntl y disc o nti n ue 
di n ut u xi ma b  
 F or br o n c h os pas m or a n gi oe de ma wit h  h y p ote nsi o n re q uiri n g v ol u me res us citati o n , refer 
t o h y p ote nsi o n g ui da nce i n S ecti o n 6. 5. 3. 1 . 
6. 5. 3. 4.  
C a pill ar y  Le a k S y n dr o me  (≥Gr a de 3)   
Ma na ge me nt of ca pillar y lea k s y n dr o me : 
 St o p  di n ut u xi ma b i nf usi o n  
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
9 3  
 A d mi nister o x y ge n a n d fl ui ds as a p pr o priate  
 Di uretics s h o ul d be use d wit h ca uti o n a n d h y p ote nsi o n s h o ul d be a v oide d  
 If s y m pt o ms persist o n t he sa me da y or rec ur o n s u bse q ue nt da ys wit hi n t he sa me c ycle, 
disc o nti n ue di n ut u xi ma b f or t hat c ycl e  
 O nl y res u me w he n ca pill ar y lea k s y m pt o ms are ≤Gra de 2  
 If res ol ves, res u me di n ut u xi ma b at 5 0 %  rate t he sa me da y a n d f or re mai ni n g d oses wit hi n 
t he sa me c ycl e. F or s u bse q ue nt c ycl es, t he di n ut u xi ma b ma y b e gi ve n at t h e f ull rate 
 If t hera p y-rel ate d ca pillar y le a k s y n dr o me re q uires press ors f or ≥2 4 h o urs or a n y d urati o n 
of mec ha nic al ve ntilati o n , t he patie nt m ust disc o nti n ue all st u d y dr u gs . 
6. 5. 3. 5.  
Re n al  I ns ufficie nc y  
 F or b or derli ne  h y p ote nsi o n, c o nsi der t he p ossi bilit y of re nal h y p o perf usi o n  a n d 
a d mi nister v ol u me as a p pr o priate  
 If creati ni ne is ≥2 ×  U L N a n d ele vati o n persists des pite o pti mize d fl ui d ma na ge me nt, h ol d 
di n ut u xi ma b i nf usi o n  
 M o dif y c o n c o mita nt me dicati o ns t hat ma y c o ntri b ute t o or be affect e d b y re nal 
i ns ufficie nc y 
 If uri ne o ut p ut n or malizes  a n d creati ni ne re tu r ns t o < 2×  U L N , t h e di n ut u xima b i nf usi o n 
ma y res u me at 5 0 %  rate.  If re n al fu ncti o n ret ur ns t o n or mal b y t he ne xt da y, di n ut u xi ma b 
i nf usi o n ma y res u me at t he f ull rate 
 If uri ne o ut p ut  has n ot n or malize d  a n d/ or creati ni ne re mai ns ≥2 ×  U L N b y D a y 7, n o 
f urt her di n ut u xi ma b s h o ul d be gi ve n i n t he c ycle.  If re n al f u ncti o n has n or malize d b y 
pla n ne d start date of ne xt c y cle, t he n retreat me nt is per mitte d.  
6. 5. 3. 6.  
H y p o n atre mi a ( ≥Gr a de 3; N a < 1 3 0 m E q/ L)   
 S witc h h y p ot o nic fl ui ds t o is ot o nic fl ui ds as c o m pat i bilities all o w 
 D o n ot a d m i nister oral free wat er 
 C orrect fl ui d l osses ca us e d b y di arr h ea  
 Use 3 % sali ne o nl y if:  
o  H y p o n atre mia le a ds t o seiz ure  
o  S o di u m  le vel decreas es  b y > 1 0 p oi nts i n  ≤6 h o urs  
o  S o di u m le vel < 1 1 7 m E q/ L  
 If Gra de 4 h y p o n atr e mia persists des pite o pti mal fl ui d ma na ge me nt, d o n ot a d mi nister 
di n ut u xi ma b d uri n g t he rest of t he c ycl e . M o nit or s o di u m le vels cl osel y i n t he s u bse q ue nt 
c ycle  
 If Gra de 4 h y p o n atre mia rec urs i n t he s u bse q ue nt c ycle des pite o pti mal fl ui d ma na ge me nt, 
per ma ne ntl y disc o nti n ue all st u d y dr u gs . 
6. 5. 3. 7.  
F e ver i n t he A bse nce of H y p ote nsi o n   
 A d mi nister a nti p yretics  
 If fe v er is persiste nt, adj ust fl ui ds t o acc o u nt f or i nse nsi ble l osses  
 O btai n bl o o d c ult ure a n d t he n ad mi nister e m piric a nti bi otics per  i nstit uti o nal p olic y. 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
9 4  
6. 5. 3. 8.  
T re at me nt -R el at e d P ai n   
 F or patie nts w h o e x pe rie nce pai n t hat is u n c o ntr olle d b y n arc otics , n o f urt h er 
di n ut u xi ma b s h o ul d be gi ve n  d uri n g a gi ve n c ycle  
 F or  rec urre nt u nc o ntr olle d pai n i n a s u bse q ue nt c ycle, disc o nti n ue all st u d y dr u gs  
 F or patie nts r e q uiri n g i ntra ve n o us narc otics f or ≥4 8 h o urs after c o m pleti o n of 
di n ut u xi ma b  i nf usi o n, ga ba pe nti n or si milar a ge nt s h o ul d be i nitiate d (if n ot alrea d y 
bei n g a d mi nistere d ) 
 If pai n re q uiri n g i ntra ve n o us narc otics f or ≥4 8 h o urs after c o m pleti o n of di n ut u xi ma b  
i nf usi o n rec urs i n a s u bs e q ue nt c ycle, disc o nti n u e all st u d y dr u gs .  
P ai n M a n a ge m e nt  
 N o n -o pi oi d a nal gesics (i .e., aceta mi n o p he n a n d i b u pr ofe n): bef ore eac h di n ut u xi ma b 
i nf usi o n a n d e ver y 4-6 h o urs as nee d e d f or p ai n a n d/ or fe ver  
 Ga ba pe nti n :  
o  1 0 m g/ k g/ da y 3 da ys bef ore di n ut u xi ma b i nf usi o n 
o  2 ×  1 0 m g/ k g/ da y 2 d a ys bef ore di n ut u xi ma b i nf usi o n 
o  3 ×  1 0 m g/ k g/ da y 1 d a y bef ore di n ut u xi ma b i nf usi o n; ca n be pa use d b et wee n c ycles 
or c o nti n u o us d uri n g c ycles  
o  Ta per d ose at disc o nti n uati o n of di n ut u xi ma b  
 M or p hi ne :  
o  0. 0 2 -0. 0 5 m g/ k g/ h o ur c o nti n u o us i nf usi o n p ri or t o di n ut u xi ma b i nf usi o n a n d  
o  0. 0 2 -0. 0 5 m g/ k g/ h o ur or as re q uire d f or a d e q uate pai n c o ntr ol d uri n g di n ut u xi ma b 
i nf usi o n a n d f or 2 h o urs after i nf usi o n is c o m plete 
o  Disc o nti n ue or re d u ce i nf usi o n rate (e. g. , 0. 0 1 m g/ k g/ h o ur) 2 h o urs aft er i nf usi o n 
eac h d a y, as t olerate d  
 If m or p hi ne is c o ntrai n di cate d, c o nsi der fe nt a n yl or h y dr o m or p h o ne p er i n vesti gat or 
discreti o n  
 Li d oc ai ne a n d/ or k eta mi ne ca n b e c o nsi dere d f or pai n t hat is n ot ma na gea ble usi n g t he 
a b o ve me dic ati o ns  
 Refer t o Secti o n 6. 1. 1  f or i nf usi o n rate a dj ust me nts of di n ut u xi ma b. 
6. 5. 3. 9.  
V is u al C h a n ges   
 D isc o nti n ue c urre nt c o urse of d i n ut u xi ma b f or patie nts w h o de vel o p dilate d p u pils wit h 
sl u g gis h li g ht refle x es 
 If pa pillar y a b n or malities re mai n sta ble or i m pr o ve bef ore t he ne xt c o urse, res u me 
di n ut u xi ma b at 5 0 % of pri or d ose  
 If t here is n o w orse ni n g of oc ular t o xicit y at t he re d uce d d ose, t h e n f ull d ose ma y  b e 
gi ve n i n s u bse q u e nt c o urses  
 If oc ular  t o xicit y w orse ns or rec urs after res u mi n g t he f ull d ose, per ma n e ntl y disc o nti n ue 
all st u d y dr u gs  
 Is olat e d cha n ges i n acc o m m o dati o n d o  n ot re q uire  d ose re d u cti o ns.  
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
9 5  
6. 5. 3. 1 0.  S er u m S ic k ness  
 I d e ntificati o n of ser u m sic k ness is i m p orta nt.  Si g ns a n d s y m pt o ms i ncl u de 
art hral gias/art hritis, s ple n o me gal y, l y m p ha de n o pat h y, gl o mer ul o ne p hritis i n t he prese n ce 
of persiste nt fe v ers, a n d c uta ne o us er u pti o ns  
 Ser u m sic k ness t y pic all y de vel o ps 1 t o 3 wee ks aft er a d mi nistrati o n of t he ca usati ve 
a ge nt b ut  ca n d e vel o p wit hi n 1 2 -3 6 h o urs i n  se nsitize d patie nts  
 Patie nts wit h Gra de 2 ser u m sic k ness  s h o ul d recei ve a nti hista mi nes  
 Patie nts wit h ≥ Gra de 3 s er u m sic k ness s h o ul d per ma ne ntl y disc o nti n ue all st u d y dr u gs .  
6. 5. 3. 1 1.  N e ur ot o xicit y   
 F or Gra de 3 s e ns or y or m ot or ne ur o pat h y, d isc o nti n ue di n ut u xi ma b f or t he re mai n der of 
t he c urre nt c ycle 
 If ne ur o pat h y  res ol ves b y start of ne xt c ycl e , re d u ce di n ut u xi ma b d ose  t o 5 0%  
 If ne ur o pat h y s y m pt o ms d o n ot res ol ve , or if t he y rec ur, t h e n per ma n e ntl y disc o nti n ue all 
st u d y dr u gs 
 Gra de 4 n e ur ot o xicit y  re q uires per ma n e nt di n ut u xi ma b disc o nti n uati o n.  
6. 6.  
D ose M o dific ati o n   
I n t he e ve nt of a c ycl e dela y d u e t o l o gistical r eas o ns ( e. g. d ue t o patie nt a v aila bilit y), t he patie nt 
s h o ul d c o nti n ue o n a be m acicli b  if t he patie nt has a de q uate dr u g s u p pl y.  If a patie nt’s treat me nt 
is i nterr u pte d as a res ult of n ot ha vi n g s ufficie nt dr u g s u p pl y, t he c ycle ma y be d ela ye d u p t o 7 
da ys (a n d n ot be c o nsi dere d a pr ot oc ol vi olati o n).  I n e x ce pti o nal circ u msta nces, a del a y > 7 da ys 
is per mitte d u p o n a gree m e nt bet wee n t h e i n vesti gat or a n d t he Lill y C R P/ C R S.  I n e x ce pti o nal 
cases, f or pla n ne d d ela ys (i ncl u di n g b ut n ot li mite d t o vacati o n or h oli da ys), a d diti o nal st u d y 
treat me nt ma y be dis pe ns e d u p o n c o ns ultati o n wit h Lill y C R P/ C R S . 
F or patie nts u n der g oi n g s ur ger y, refer t o t he f oll o wi n g g ui deli nes f or a be m acicli b d ose 
m o dificati o ns:  
 F or mi n or s ur geries a n d pr o ce d ures (e. g. a m b ulat or y), i n vesti gat ors s h o ul d treat as 
cli nicall y i n dicat e d a n d cl osel y m o nit or a n y si g ns of i nfecti o n or heali n g c o m plicati o ns.  
 F or maj or s ur geries, t he rec o m me n dati o n is t o s us pe n d d osi n g of a be macicli b f or at least 
7 da ys b ef ore a n d ma y b e res u me d as cli nicall y i n dicate d.  
 C o nsi der m o nit ori n g ne utr o p hils a n d platelets bef ore s ur ger y a n d bef ore res u mi n g 
a be maci cli b .  T he scars s h o ul d be ase ptic a n d t he heali n g pr ocess s h o ul d b e reas o n a ble 
bef ore res u mi n g a be m aci cli b.  
 D ose s us pe nsi o ns ≥2 1 da ys m ust be disc usse d wit h Lill y C R P/ C R S.  
P arts A a n d B:  
Patie nts ma y disc o nti n ue c he m ot hera p y w hile c o nti n ui n g a be macicli b m o n ot hera p y ( i.e. d u e t o 
mi n or c he m ot hera p y -ass ociate d t o xicities) u p o n disc ussi o n wit h t he Lill y C R P/ C R S.  I n t he 
e ve nt t hat a be ma cicli b m ust be disc o nti n ue d, patie nts ma y c o nti n ue t o r ecei ve  c he m ot hera p y.  
F or eac h st u d y dr u g, if f urt her d ose re d ucti o ns are re q uire d b e y o n d t he all o wa ble  d ose re d ucti o ns 
o utli ne d bel o w , t he dr u g s h o ul d be disc o nti n ue d. 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
9 6  
P art C:  
F or eac h st u d y dr u g , if f urt her d ose re d ucti o ns are re q uire d b e y o n d t he all o wa ble d ose re d ucti o ns 
o utli ne d bel o w , t he dr u g s h o ul d be disc o nti n ue d. If a n y st u d y dr u g m ust be d isc o nti n ue d, t he 
patie nt m ust disc o nti n ue  all pr ot oc ol t hera p y. Disc o nti n uati o n of c he m ot hera p y after  C ycl e 1 2 is 
per mitte d at t he i n vesti gat or’s discreti o n  wit h o ut ha vi n g t o disc o nti n ue a b e macicli b, 
di n ut u xi ma b, a n d G M -C S F  (refer t o Secti o n 4. 1 ).  F or d ose m o dificati o n g ui da nce s pecific t o 
Part C , see Secti o n  6. 6. 1. 3 .  F or d ose m o di ficati o ns of G M -C S F, refer t o Secti o n 6. 6. 1. 4 . 
 
P arts A a n d B: St arti n g D ose  a n d A dj ust me nts f or A be m acicli b -R el ate d T o xicities a  
D ose at 
E nr oll me nt  
First Re d ucti o n  
Sec o n d Re d ucti o n  
1 5 0 m g  
1 0 0  m g  
5 0  m g  
1 2 5 m g  
7 5  m g  
5 0  m g  
1 0 0 m g  
7 5 m g  
5 0  m g  
7 5 m g  
5 0 m g  
2 5 m g  
5 0 m g  
2 5 m g  
N ot per mitte d; m ust disc o nti n ue  
2 5 m g  
N ot per mitte d; m ust disc o nti n ue  
a R e d uce d d oses of a b e macicli b s h o ul d still be ta ke n t wice dail y.  
 
P art C: St arti n g D ose  a n d A dj ust me nts f or A be m acicli b -Rel ate d T o xicities a  
D ose at E nr oll me nt  
First Re d ucti o n  
Sec o n d Re d ucti o n  
1 0 0 m g  
7 5 m g  
5 0 m g  
7 5 m g  
5 0 m g  
2 5 m g  
5 0 m g  
2 5 m g  
1 7. 5 m g  
2 5 m g  
1 7. 5 m g  
1 0 m g  
2 2. 5 m g  
1 5 m g  
1 0 m g  
2 0 m g  
1 5 m g  
1 0 m g  
1 7. 5 m g  
1 2. 5 m g  
N ot per mitte d; m ust 
disc o nti n ue  
1 5 m g  
1 0 m g  
1 2. 5 m g  
N ot per mitte d; m ust 
disc o nti n ue  
1 0 m g  
a Re d uce d d oses of a b e macicli b s h o ul d still be ta ke n t wice dail y.   
 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
9 7  
D ose Le vels a n d A dj ust me nts f or Iri n otec a n -rel ate d T o xicities  
D ose at E nr oll me nt  
First Re d ucti o n  
Sec o n d Re d ucti o n  
5 0 m g/ m 2 
-2 5 %  
-5 0 %  
D ose Le vels a n d A dj ust me nts f or Te m oz ol o mi de -rel ate d T o xicities  
D ose at E nr oll me nt  
First Re d ucti o n  
Sec o n d Re d ucti o n  
1 5 0 m g/ m 2 
1 0 0 m g/ m 2 
7 5 m g/ m 2 
1 0 0 m g/ m 2 
7 5 m g/ m 2 
 
6. 6. 1.  
D ose  M o dific ati o n G ui d a nce d ue t o T o xicit y   
 T reat me nt will be s us pe n de d f or D L T a n d ma y be res u me d aft er res ol uti o n . T he  
a be maci cli b d ose m ust be re d uce d. If n o f urt her d ose re d ucti o ns are a v aila ble (refer t o 
Secti o n 6. 6 ), t he patie nt m ust disc o nti n ue a be macicli b.  F or t o xicities t hat are n ot d ose -
li miti n g, see Secti o n 6. 6. 1. 1 . 
 I n v esti gat ors will d oc u me nt w het her or n ot a n A E has a reas o na ble p ossibilit y of bei n g 
relate d t o eac h of t he st u d y dr u gs, ta ki n g i nt o acc o u nt t he disease, c o nc o mita nt treat me nts, 
or pat h ol o g ies, i n or d er t o i n di vi d uall y a dj ust st u d y dr u g d os es. 
 Treat me nt  ma y be s us pe n de d f or a m a xi m u m of 2 1 da ys t o all o w s uff icie nt ti me f or 
rec o ver y.  C ycle  del a y s > 2 1 da ys  d u e t o a n A E re q uire disc o nti n u ati o n of all st u d y 
treat me nts. 
 A n y  a d diti o nal q uesti o ns relate d t o d ose a dj ust me nts ma y be disc uss e d wit h t he Lill y 
C R P/ C R S.  
 F or Parts A a n d B o nl y . 
o  if t he A E  is, i n t he o pi ni o n of t he i n vesti gat or, m ore li kel y d u e t o 1 dr u g t ha n 
a n ot her, a dj ust me nt dr u g ca usi n g t h e t o xicit y s h o ul d be a dj uste d, a n d t he d os i n g 
a n d sc he d ule of t he ot her st u d y dr u gs ma y  b e mai ntai ne d.   
o  if t he r oles of eac h a ge nt are i m p ossi ble t o se parate, all i n v ol ve d t hera pies s h o ul d 
ha ve d ose a dj ust me nts a n d/ or s us pe nsi o ns. 
o  refer t o iri n oteca n a n d te m oz ol o mi de prescri bi n g i nf or mati o n f or a d diti o nal d ose 
m o dificati o n g ui deli nes.  
See Secti o n 6. 6. 1. 3  d ose m o dificati o n ta bles  f or g ui da nce s pecific t o Part C. 
6. 6. 1. 1.  
D ose M o dific ati o n G ui d a nce  d ue t o T o xicities C o nsi dere d t o be A ttri b ute d t o 
A be m acicli b   
A be macicli b h e m at ol o gi cal t o xicities ma y o v erla p wit h t h ose of  c he m ot hera p y.  T o ai d i n 
a p pr o priatel y attri b uti n g he mat ol o gic al t o xicities t o a be maci cli b, bel o w is a descri pti o n base d o n 
a d ult P hase 3 re gistrati o n st u dies ( M O N A R C H 2 [ Sle d ge et al. 2 0 1 7]; M O N A R C H 3 [ G oetz et al. 
2 0 1 7; J o h nst o n et al. 2 0 1 9 ]): 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
9 8  
 T he  T E A E of n e utr o pe ni a was t he m ost fre q ue nt he mat ol o gical t o xicit y re p orte d a n d was 
pre d o mi na ntl y of l o w -gra de se verit y  a n d n ot ass o ciate d wit h se vere i nfecti o n .  F e brile 
ne utr o pe nia was i nfre q u e nt .   
 N e utr o pe nia was o bser ve d earl y i n t he treat me nt c o urse, wit hi n t he first 2  m o nt hs, a n d 
mai ntai ne d o ver t he c o urse of treat me nt.  
 O n ce ntral la b orat or y a nal ysis, ne utr o p hil c o u nt decreas e fr o m t he b aseli ne visit was 
o bser ve d; mea n n e utr o p hil c o u nts ge nerall y re m ai ne d s ta ble at t he later visits a n d were 
re versi ble o n ce patie nts disc o nti n ue d fr o m treat me nt.   
 A ne mia a n d t hr o m b oc yt o pe nia were re p orte d b ut were less fre q u e nt t ha n n e utr o pe nia a n d 
m ostl y of l o w-gra de  se v erit y. 
See Secti o n 6. 6. 1. 3  d ose m o dificati o n ta bles f or g ui da nce s pecific t o Part C.  
Parts A a n d B: D os e m o dificati o n g ui da nce is o utli ne d bel o w f or he m at ol o gic t o xicities  
c o nsi dere d t o be  attri b ute d t o a be m aci cli b : 
T o xicit y T y pe  
T o xicit y Pr ofile a n d Se verit y  
A be m acicli b D ose 
S us pe nsi o n  
A be m acicli b D ose 
Re d ucti o n  
Ne utr o pe nia  
 
Gra d e 4 ( A N C < 5 0 0/ m m 3) 
I nitial i nci de nce 
D ose M U S T  be 
s us pe n de d u ntil A N C 
≥7 5 0/ m m 3  
 
D ose M A Y  be 
re d uce d at t he 
i n vesti gat or’s 
discreti o n  
C o nsi der a d diti o n of 
G -C S F at t he 
i n vesti gat or’s 
discreti o n acc or di n g 
t o A S C O/ E S M O 
g ui deli nes ( Cra wf or d 
et al. 2 0 1 0; S mit h et 
al. 2 0 1 5) 
If lasti n g > 7 da ys or ca usi n g 
c ycle dela y of > 1 4 da ys  
S us pe n d a be macicli b  
u ntil A N C ≥7 5 0/ m m 3 
D ose M U S T be 
re d uce d b y 1 d ose 
le vel. 
S u bse q ue nt i nci de nces  
S us pe n d a be macicli b 
u ntil A N C ≥7 5 0/ m m 3 
D ose M U S T be 
re d uce d b y 1 d ose 
le vel. 
T hr o m b oc yt o pe nia  
 
Gra d e 4 
( platelets < 2 5, 0 0 0/ m m
3) 
I nitial i nci de nce 
D ose M U S T be 
s us pe n de d u ntil 
platelets 
≥7 5, 0 0 0/ m m 3 
D ose M A Y be 
re d uce d at t he 
i n vesti gat or’s 
discreti o n.  
If lasti n g > 7 da ys or ca usi n g 
c ycle dela y of > 1 4 da ys  
D ose M U S T be 
s us pe n de d u ntil 
platelets 
≥7 5, 0 0 0/ m m 3 
D ose M U S T be 
re d uce d b y 1 d ose 
le vel. 
S u bse q ue nt i nci de nces  
D ose M U S T be 
s us pe n de d u ntil 
platelets 
≥7 5, 0 0 0/ m m
3 
D ose M U S T be 
re d uce d b y 1 d ose 
le vel. 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
9 9  
T o xicit y T y pe  
T o xicit y Pr ofile a n d Se verit y  
A be m acicli b D ose 
S us pe nsi o n  
A be m acicli b D ose 
Re d ucti o n  
F e brile ne utr o pe nia  
Gra d e 3  
D ose M U S T  be 
s us pe n de d u ntil 
t o xicit y res ol ves. 
D ose M A Y  be 
re d uce d b y 1 d ose 
le vel at t he 
i n vesti gat or’s 
discreti o n.  
Rec urre nt Gra de 3 a 
D ose M U S T  be 
s us pe n de d u ntil 
t o xicit y res ol ves. 
D ose M U S T  be 
re d uce d b y 1 d ose 
le vel. 
Gra d e 4  
D ose M U S T  be 
s us pe n de d u ntil 
t o xicit y res ol ves. 
D ose M U S T  be 
re d uce d b y 1 d ose 
le vel. 
A b bre viati o ns:  A N C = a bs ol ute ne utr o p hil c o u nt ; A S C O = A merica n S ociet y of Cli nical O nc ol o g y; C R P/ C R S = 
cli nical researc h p h ysicia n/cli nical researc h scie ntist; E S M O = E ur o pea n S ociet y f or Me dical O nc ol o g y; G -C S F  
= gra n ul oc yte -c ol o n y sti m ulati n g fact or. 
a Rec urre nt t o xicit y refers t o t he sa me e ve nt oc c urri n g wit hi n t he ne xt 8 wee ks (as meas ure d fr o m t he st o p date of 
t he prece di n g e ve nt).   
Parts A a n d B: T h e ta ble bel o w prese nts g ui da nce f or a be m acicli b d ose a dj ust me nts a n d 
s us pe nsi o ns d ue t o n o n he m at ol o gic t o xicit y c o nsi dere d t o be attri b ute d  t o a be m a cicli b. 
T o xicit y T y pe  
T o xicit y Pr ofile a n d 
Se verit y  
A be m acicli b D ose 
S us pe nsi o n  
A be m acicli b D ose 
Re d ucti o n  
N o n he mat ol o gic T o xicit y a 
(e xce pt diarr hea, 
A L T / A S T i ncrease d, a n d 
I L D/ p ne u m o nitis) 
P ersiste nt or rec urre nt  b 
Gra d e 2 t hat d oes n ot 
res ol ve wit h ma xi mal 
s u p p orti ve meas ures 
wit hi n 7 da ys t o baseli ne 
or Gra d e 1  u nless dee me d 
cli nicall y i nsi g nifica nt b y 
t he i n vesti gat or 
D ose M U S T  be 
s us pe n de d u ntil t o xicit y 
res ol ves t o eit her baseli ne 
or ≤Gra de 1.  
D ose M U S T  be re d u ce d 
b y 1 d ose le vel.  
Gra d e 3 or 4  
D ose M U S T  be 
s us pe n de d u ntil t o xicit y 
res ol ves t o eit her baseli ne 
or ≤Gra de 1.  
D ose M U S T  be re d uce d 
b y 1 d ose le vel.  
Diarr hea c 
Gra d e 2  t hat d oes n ot 
res ol ve wit hi n 2 4 h o urs t o 
≤Gra d e 1  
D ose M U S T  be 
s us pe n de d u ntil t o xicit y 
res ol ves t o ≤Gra de 1.  
D ose M A Y  be re d uce d b y 
1 d ose le vel.  
Gra d e 2 t hat persists or 
rec ursb after res u mi n g t he 
sa me d ose des pite 
ma xi mal s u p p orti ve 
meas ures  
D ose M U S T  be 
s us pe n de d u ntil t o xicit y 
res ol ves t o ≤Gra de 1.  
D ose M U S T  be re d uce d 
b y 1 d ose le vel.  
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 0 0  
T o xicit y T y pe  
T o xicit y Pr ofile a n d 
Se verit y  
A be m acicli b D ose 
S us pe nsi o n  
A be m acicli b D ose 
Re d ucti o n  
Gra d e 3 or 4  
D ose M U S T  be 
s us pe n de d u ntil t o xicit y 
res ol ves t o ≤Gra de 1.  
D ose M U S T  be re d uce d 
b y 1 d ose le vel.  
A n y gra d e t hat re q uires 
h os pitalizati o n  
D ose M U S T  be 
s us pe n de d u ntil t o xicit y 
res ol ves t o ≤Gra de 1.  
D ose M U S T  be re d uce d 
b y 1 d ose le vel.  
A L T / A S T I ncrease d 
P ersiste nt or rec urre ntb 
Gra d e 2 ( > 3. 0 -5. 0 × U L N), 
or Gra d e 3 ( > 5. 0 -
2 0. 0 × U L N) d 
D ose M U S T be 
s us pe n de d u ntil t o xicit y 
res ol ves t o baseli ne or 
Gra de 1.  
D ose M U S T be re d uce d 
b y 1 d ose le vel.  
Gra d e 4 ( > 2 0. 0 × U L N)  
A be macicli b treat me nt 
M U S T be disc o nti n ue d  
A be macicli b treat me nt 
M U S T be disc o nti n ue d  
A L T / A S T I ncrease d wit h 
i ncrease d t otal bilir u bi n, 
i n t he a bse nce of 
c h olestasis  
A L T/ A S T > 3. 0 × U L N  
wit h t otal bilir u bi n 
> 2 × U L N  
A be macicli b treat me nt 
M U S T be disc o nti n ue d.  
A be macicli b treat me nt 
M U S T be disc o nti n ue d.  
I L D / p ne u m o nitis 
Gra d e 2 t hat persists b or 
rec urs des pite ma xi mal 
s u p p orti ve meas ures a n d 
d oes n ot ret ur n t o baseli ne 
or Gra d e 1 wit hi n 7 da ys  
D ose M U S T be 
s us pe n de d u ntil t o xicit y 
res ol ves t o eit her baseli ne 
o r ≤Gra de 1.  
D ose M U S T  be re d uce d 
b y 1 d ose le vel.  
Gra d e 3 or 4  (se vere 
I L D/ p ne u m o nitis) 
A be macicli b treat me nt 
M U S T be disc o nti n ue d.  
A be macicli b treat me nt 
M U S T be disc o nti n ue d.  
A b bre viati o ns:  A L T = ala ni ne a mi n o tra nsferase; A S T = as partate a mi n otra nsferase ; I L D = i nterstitial l u n g disease; 
U L N = u p per li mit of n or mal . 
a A d diti o nal g ui da nce f or he p ati c a n d re nal m o nit ori n g is i n Se cti o n 8. 2. 1. 1  a n d Secti o n 8. 2. 1. 2 . 
b  Deter mi nati o n of persiste nt e ve nts will be at t he discreti o n of t he i n vesti gat or.  Rec urre nt t o xicit y refers t o t he 
sa me e ve nt o cc urri n g wit hi n t he ne xt 8 wee ks (as meas ure d fr o m t he st o p d ate of t he prece di n g e ve nt).  
c Diarr hea is a k n o w n o verla p pi n g t o xicit y of a be macicli b a n d iri n oteca n .  T his g ui da nce is f or diarr hea attri b ute d 
t o a b e macicli b.  Iri n oteca n has bee n re p orte d t o ca use ac ute/ c h oli ner gic diarr hea a n d late diarr hea ( > 2 4 h o urs 
p ost -i nf usi o n).  Refer t o t he la bel a n d i nstit uti o nal practice f or d ose m o dificati o ns f or diarr hea attri b ute d t o 
iri n oteca n.  See Secti o n 6. 5. 2  f or descri pti o ns of descri pti o ns of iri n oteca n-i n d uce d a n d a be macicli b-i n d uce d 
diarr hea a n d s u p p orti ve ma na ge me nt.  
d  Gra d e ≥3 A L T i ncrease d is a tri g ger f or a d diti o nal assess me nts a n d p ossi bl y he patic m o nit ori n g.  See 
Secti o n  8. 2. 1. 1  f or a d diti o nal g ui da nce f or he patic m o nit ori n g. 
6. 6. 1. 2.  
D ose  M o dific ati o n G ui d a nce d ue t o T o xicities C o nsi dere d t o be Attri b ute d t o 
Iri n otec a n  
F or i n di vi d uals recei vi n g iri n oteca n w h o e x perie n ce ele vate d bilir u bi n or i m paire d 
gl uc ur o ni d ati o n, t he f oll o wi n g g ui da n ce is s u g gest e d  f or all st u d y Parts : 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 0 1  
 Ele vate d bilir u bi n :  F or p atie nts wit h bilir u bi n ra n gi n g fr o m 1. 5 t o 3 ti mes t he U L N, a 
re d uce d d os e of iri n oteca n s h o ul d be c o nsi dere d.  F or patie nts wit h bilir u bi n be y o n d 
3  ti mes t he U L N, iri n oteca n s h o ul d n ot be use d.  
 I m paire d gl uc ur o ni d ati o n:  Patie nts k n o w n t o ha ve re d uce d U G T 1 A 1 acti vit y ( w het her 
pree xiste nt s u bsta nce -i n d uce d, diseas e-i n d uce d, d ue t o a n i n herite d dis or der [e. g. Gil bert 
s y n dr o me, Cri gler-N ajjar s y n dr o me], or i n d uce d b y trial t hera p y) ma y h a ve i ncreas e d ris k 
of he mat ol o gi cal t o xicit y a n d/ or diarr h ea. T h ese p artici pa nts s h o ul d be caref ull y 
m o nit ore d f or he mat ol o gic t o xicities  a n d diarr hea .  A re d uce d iri n oteca n starti n g d os e 
s h o ul d be c o nsi dere d f or patie nts w h o ha ve e x peri e nce d pri or he mat ol o gic t o xicit y or 
si g nifica nt diarr hea wit h pre vi o us treat me nt.  
 F or Gra de 4 t hera p y -relat e d diarr hea t hat de vel o ps des pite ma xi mal a nti-diarr hea 
me dicati o ns a n d pr o p h yl actic a nti bi otics, re d uce iri n oteca n b y 2 5 % (i .e., 3 7. 5 
m g/ m 2/ d ose) i n s u bse q ue nt c ycl es.   
See Secti o n 6. 6. 1. 3  d ose m o dificati o n ta bles f or g ui da nce s pecific t o Part C. 
6. 6. 1. 3.  
P a rt  C -S pecific D ose M o dific ati o ns   
 F or a n y t o xicit y attri b ute d t o a be macicli b  t hat is n ot liste d i n t he ta bles bel o w, refer t o 
ta bles i n Secti o n 6. 6. 1. 1  f or d ose m o dificati o ns of a be maci cli b. 
 F or a n y t o xicit y attri b ute d t o iri n oteca n t hat is n ot liste d i n t he ta ble s bel o w, refer t o 
Secti o n 6. 6. 1. 2  f or d ose m o dificati o ns of iri n oteca n. 
 All d ose re d ucti o ns s h o ul d be calc ul ate d fr o m t he starti n g d ose le vel.  
 
 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 0 2  
P art C  D ose M o dific ati o ns  for He m at ol o gic al T o xicities  
See Secti o n 6. 6. 1. 4  f or G M-C S F d ose m o dific ati o ns  
P atie nts k n o w n t o ha ve b o ne marr o w i n v ol ve me nt are n ot e val ua ble f or he mat ol o gical t o xicit y , a n d d ose 
m o dificati o n decisi o ns will be i n vesti gat or’s discreti o n.  
 
A be m acicli b  
Iri n otec a n 
Te m oz ol o mi de  
Di n ut u xi m a b  
Gr a de 4 
Ne utr o pe ni a  
1 st E ve nt  
H ol d u ntil A N C 
≥7 5 0/ m m
3, 
ma y re d uce d ose  
N o c ha n ge  
N o c ha n ge  
N o c ha n ge  
Lasti n g > 7 
da ys or c ycle 
dela y > 1 4 
da ys  
H ol d u ntil A N C 
≥7 5 0/ m m
3, 
m ust re d uce d ose  
Re d uce 2 5 %  
Re d uce 2 5 %  
Re d uce 2 5 %  
Rec urre nt 
Gra d e 4  
H ol d u ntil A N C 
≥7 5 0/ m m
3, 
m ust re d uce d ose  
Re d uce 2 5 %  
Re d uce 2 5 %  
Re d uce 2 5 %  
Rec urre nt 
c ycle dela y 
> 1 4 da ys 
des pite d ose 
re d ucti o na 
Disc o nti n ue all st u d y dr u gs  
Fe brile 
Ne utr o pe ni a  
Gra d e 3  
1 st E ve nt  
H ol d u ntil A N C 
≥7 5 0/ m m
3, 
ma y re d uce d ose  
N o c ha n ge  
N o c ha n ge  
N o c ha n ge  
Rec urre nt 
Gra d e 3  
H ol d u ntil A N C 
≥7 5 0/ m m
3, 
m ust re d uce d ose  
N o c ha n ge  
N o c ha n ge  
N o c ha n ge  
Gra d e 4  
H ol d u ntil A N C 
≥7 5 0/ m m
3, 
m ust re d uce d ose  
Re d uce 2 5 %  
Re d uce 2 5 %  
N o c ha n ge  
Rec urre nt 
Gra d e 4  
H ol d u ntil A N C 
≥7 5 0/ m m
3, 
f urt her re d uce d ose 
Re d uce 5 0 %  
Re d uce  5 0 %  
N o c ha n ge  
Gr a de 4 
T hr o m b oc yt o pe ni a  
1 st E ve nt  
H ol d u ntil platelets 
≥7 5, 0 0 0/ m m
3  
ma y re d uce d ose  
N o c ha n ge  
Re d uce 2 5 %  
N o c ha n ge  
Rec urs 
des pite d ose 
re d ucti o n 
Disc o nti n ue all st u d y dr u gs  
T hr o m b oc yt o pe ni a  
(A n y G ra d e) 
Ass oci ate d C ycle 
Del a y > 1 4 D a ys a  
1 st E ve nt  
H ol d u ntil platelets 
≥7 5, 0 0 0/ m m
3  
t he n re d uce d ose 
Re d uce 2 5 %  
Re d uce 2 5 %  
N o c ha n ge  
Rec urs 
des pite d ose 
re d ucti o n 
Disc o nti n ue all st u d y dr u gs  
A b bre viati o n: A N C = a bs ol ut e ne utr o p hil c o u nt .  
a 
Dela y of > 1 4 da ys i n dicates m ore t ha n  3 6 da ys fr o m Da y 1 of pre vi o us c ycle . 
 
 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 0 3  
P art C D ose M o dific ati o ns  f or Di arr he a 
 
A be m acicli b  
Iri n otec a n 
Te m oz ol o mi de  
Di n ut u xi m a b  
Gr a de 2  
D oes n ot R es ol ve t o 
≤Gr a de 1 W it hi n  
2 4 h o u rs 
1 st E ve nt  
H ol d u ntil 
≤Gra de 1,  
ma y  re d uce 
d ose  
H ol d u ntil 
≤Gra de 1,  
ma y  re d uce 
2 5 %  
N o c ha n ge  
N o c ha n ge  
P ersists or 
rec ursa des pite 
ma xi mal 
s u p p orti ve 
meas ures  
H ol d u ntil 
≤Gra de 1,  
t he n m ust  
re d uce d ose 
H ol d u ntil 
≤Gra de 1,  
ma y re d uce 
2 5 %  
N o c ha n ge  
N o c ha n ge  
Gr a de 3  Di arr he a  
 
H ol d u ntil 
≤Gra de 1,  
t he n re d uce 
d ose  
H ol d u ntil 
≤Gra de 1,  
ma y re d uce 
2 5 %  
N o c ha n ge  
N o c ha n ge  
Gr a de 4 Di arr he a  
1 st E ve nt  
H ol d u ntil 
≤Gra de 1,  
t he n re d uce 
d ose  
H ol d u ntil 
≤Gra de 1,  
re d uce 2 5 %  
N o c ha n ge  
N o c ha n ge  
Rec urs des pite 
a b e macicli b 
re d ucti o n 
H ol d u ntil 
≤Gra de 1,  
t he n re d uce 
d ose  
H ol d u ntil 
≤Gra de 1,  
re d uce 5 0 %  
N o c ha n ge  
N o c ha n ge  
Rec urs des pite 
a b e macicli b 
a n d  iri n oteca n 
re d ucti o n 
H ol d u ntil 
≤Gra de 1,  
t he n res u me 
re d uced  d ose  
H ol d u ntil 
≤Gra de 1,  
t he n res u me 
re d uced  
d ose  
N o c ha n ge  
Re d uce t o  
1 3. 1 3 m g/ m 2/ d ose 
Rec urs des pite 
ma xi m u m d ose 
re d ucti o ns 
Disc o nti n ue all st u d y dr u gs  
a Deter mi nati o n of persiste nt e ve nts will be at t he discreti o n of t he i n vesti gat or. Rec urre nt t o xicit y refers t o t he 
sa me e ve nt o cc urri n g wit hi n t he ne xt 8 wee ks (as meas ure d fr o m t he st o p date of t he prece di n g e ve nt).  
 
 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 0 4  
P art C D ose  M o dific ati o ns f or V o miti n g a n d  De h y dr ati o n  
 
 
A be m acicli b  
Iri n otec a n 
Te m oz ol o mi de  
Di n ut u xi m a b  
V o miti n g  
D es pite M a xi m u m 
S u p p orti ve C are  
P ersiste nt or 
rec urre nta 
Gra d e 2 t hat 
d oes n ot 
res ol ve wit hi n 7 
da ys t o baseli ne 
or Gra d e 1  
H ol d u ntil 
≤Gra de 1,  
t he n re d uce 
d ose  
N o c ha n ge  
N o c ha n ge  
N o c ha n ge  
Gra d e 3  
H ol d u ntil 
≤Gra de 1,  
t he n re d uce 
d ose  
N o c ha n ge  
N o c ha n ge  
N o c ha n ge  
Gra d e 4:  
1 st E ve nt  
H ol d u ntil 
≤Gra de 1,  
t he n re d uce 
d ose  
Re d uce 
2 5 %  
Re d uce 2 5 %  
N o c ha n ge  
Gra d e 4: 
Rec urs des pite 
s u p p orti ve care 
a n d  d ose 
re d ucti o ns 
Disc o nti n ue all st u d y dr u gs  
≥ Gr a de 3 
D e h y dr ati o n  
P ersisti n g > 3 D a ys  
N ot A ss oci ate d wit h 
V o miti n g or 
D i arr he a 
1 st E ve nt  
N o c ha n ge  
Re d uce 2 5 %  
Re d uce 2 5 %  
N o c ha n ge  
Rec urs des pite 
d ose re d ucti o ns 
Disc o nti n ue all st u d y dr u gs  
a Deter mi nati o n of persiste nt e ve nts will be at t he discreti o n of t he i n vesti gat or. Rec urre nt t o xicit y refers t o t he sa me 
e ve nt o cc urri n g wit hi n t he ne xt 8 wee ks (as meas ure d fr o m t he st o p date of t he prece di n g e ve nt).  
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 0 5  
P art C  D ose M o dific ati o ns f or He p at ot o xicit y  
 
 
A be m acicli b  
Iri n otec a n 
Te m oz ol o mi de  
Di n ut u xi m a b  
Ele v ate d Bilir u bi n  
1. 5 -3 x U L N  
N o c ha n ge  
H ol d u ntil 
≤Gra de 1 , 
m a y re d uce  
N o c ha n ge  
N o c ha n ge  
> 3 x U L N  
Disc o nti n ue all st u d y dr u gs  
 
Persiste nt or 
R ec urre nt a 
Gr a de 2  
A S T/ A L T Incre ase  
P ersiste nt or 
rec urre nt  
H ol d u ntil 
≤Gra de 1,  
t he n re d uce 
d ose  
N o c ha n ge  
N o c ha n ge  
N o c ha n ge  
Gr a de 3  
A S T or A L T 
Incre ase a 
≤7 da ys  
H ol d u ntil 
≤Gra de 1,  
t he n re d uce 
d ose  
N o c ha n ge  
N o c ha n ge  
N o c ha n ge  
P ersists > 7 
da ys  
H ol d u ntil 
≤Gra de 1,  
t he n re d uce 
d ose  
N o c ha n ge  
N o c ha n ge  
Re d uce t o  
1 3. 1 3 m g/ m 2/ d ose 
Rec urre nt 
des pite 
re d ucti o ns 
H ol d u ntil 
≤Gra de 1,  
t he n re d uce 
d ose  
N o c ha n ge  
N o c ha n ge  
Re d uce t o  
8. 7 5 m g/ m 2/ d ose 
Gr a de 4  
( > 2 0 x U L N  
A S T or A L T)  
A n y D ur ati o n b  
 
1 st E ve nt  
Disc o nti n ue all st u d y dr u gs   
A L T Incre ase  
(A n y G r a de)  
C a usi n g C ycle 
D el a y  
> 1 4 d a ys b , c 
1 st E ve nt  
M o dif y per  
Secti o n 6. 6. 1. 1  
N o c ha n ge  
N o c ha n ge  
Re d uce t o  
1 3. 1 3 m g/ m 2/ d ose 
Rec urs des pite 
di n ut u xi ma b 
d ose re d ucti o n  
Disc o nti n ue all st u d y dr u gs  
A b bre viati o ns: A L T = ala ni ne a mi n otra nsferase ; A S T = as partate a mi n otra nsferase ; U L N = u p per li mit of n or mal. 
a Deter mi nati o n of persiste nt e ve nts will be at t he discreti o n of t he i n vesti gat or. Rec urre nt t o xicit y refers t o t he 
sa me e ve nt o cc urri n g wit hi n t he ne xt 8 wee ks (as meas ure d fr o m t he st o p date of t he prece di n g e ve nt).  
b  Gra d e ≥3 A L T i ncrease d is a tri g ger f or a d diti o nal assess me nts a n d p ossi bl y he patic m o nit ori n g.  See 
Secti o n  8. 2. 1. 1  f or a d diti o nal g ui da nce f or he patic m o nit ori n g. 
c 
Dela y of > 1 4 da ys i n dicates m ore t ha n 3 5  da ys fr o m Da y 1 of pre vi o us c ycle . 
 
 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 0 6  
P art C  D ose M o dific ati o ns f or Miscell a ne o us T o xicit y  
 
 
A be m acicli b  
Iri n otec a n 
Te m oz ol o mi de  
Di n ut u xi m a b  
I L D  
or  
P ne u m o nitis  
P ersiste nt or 
rec urre nta 
Gra d e 2 des pite 
ma xi mal  
s u p p orti ve 
care b  
H ol d u ntil 
≤Gra de 1
 
t he n re d uce 
d ose  
H ol d u ntil 
≤Gra de 1
 
t he n re d uce 
d ose  
N o c ha n ge  
N o c ha n ge  
Gra d e 3 or 4  
Disc o nti n ue all st u d y dr u gs  
N o n he m at ol o gic 
T o xicit y n ot 
O t her wise 
D escri be d A b o ve  
Gra d e 2 
P ersiste nt or 
rec urre nta, b  
H ol d u ntil 
≤Gra de 1
 
t he n re d uce 
d ose  
N o c ha n ge  
N o c ha n ge  
N o c ha n ge  
Gra d e 3 or 4  
H ol d u ntil 
≤Gra de 1
 
t he n re d uce 
d ose  
H ol d u ntil 
≤Gra de  1
 
t he n re d uce 
d ose  
H ol d u ntil 
≤Gra de 1
 
t he n re d uce 
d ose  
N o c ha n ge  
A n y A E -A ss oci ate d  
C ycle D el a y of > 2 1 
D a ys c 
1 st E ve nt  
Disc o nti n ue all st u d y dr u gs  
A b bre viati o ns: A E = a d verse e ve nt; I L D = i nterstitial l u n g disease. 
a 
Deter mi nati o n of persiste nt e ve nts will be at t he discreti o n of t he i n vesti gat or. Rec urre nt t o xicit y refers t o t he 
sa me e ve nt o cc urri n g wit hi n t he ne xt 8 wee ks (as meas ure d fr o m t he st o p date of t he prece di n g e ve nt).  
b  D oes n ot res ol ve wit h ma xi mal s u p p orti ve meas ures wit hi n 7 da ys t o basel i ne or Gra de 1 u nless dee me d 
cli nicall y i nsi g nifica nt b y  t he i n vesti gat or. 
c 
Dela y of > 2 1 da ys i n dicates m ore t ha n 4 2 da ys fr o m Da y 1 of pre vi o us c ycle . E xce pti o nal circ u msta nces ma y be 
all o we d u p o n a p pr o val b y C R P/ C R S.  
6. 6. 1. 4.  
P a rt  C -S pecific D ose  M o dific ati o n G ui d a nce d ue t o T o xicit y Attri b ute d t o G M -
C S F   
W hite bl o o d cell ( W B C) c o u nt ele v ati o n  
 If t otal W B C c o u nt is > 5 0, 0 0 0/ u L, h ol d G M -C S F . 
 W he n W B C c o u nt ret ur ns t o < 2 0, 0 0 0/ u L, res u me G M -C S F at 5 0 % of d os e . 
 I n s u bs e q ue nt c ycl es, use f ull d ose of G M-C S F, b ut a dj ust d ose a gai n if t he W B C c o u nt 
> 5 0, 0 0 0/ u L.  
L oc alize d s ki n re acti o n  
 G M -C S F ca n b e c o nti n u e d w he n s ki n reacti o ns are l ocalize d a n d mil d . 
 R otati o n of i njecti o n si tes is rec o m me n de d. 
 Use of I V i nf usi o n, i ns ufl o n, or ot her s u bc uta ne o us i njecti o n p ort is n ot rec o m me n de d . 
 If ≥Gra d e 3 i njecti o n site reacti o n occ urs, per ma n e ntl y disc o nti n ue  G M -C S F .  
First -d ose re acti o n  
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 0 7  
A s y n dr o m e c haracteriz e d b y res pirat or y distress, h y p o xia, fl us hi n g, h y p ote nsi o n, s y nc o pe, 
a n d/ or tac h ycar dia h as bee n re p ort e d f oll o wi n g t h e a d mi nistrati o n of t he first d ose of G M -C S F 
wit h i n a c ycle. T his ge n erall y res ol ves wit h s y m pt o matic treat me nt a n d d o es n ot rec ur i n t he 
sa me c ycle.  
 If “first d ose reacti o n” occ urs, re d u ce t he ne xt G M -C S F d ose t o 5 0 % . 
 If a si milar reacti o n occ urs at t he 5 0 % d ose, p er m a ne ntl y disc o nti n ue G M -C S F .  
 If t he 5 0 % d o es n ot ca us e rec urre nt s y m pt o ms, es calate s u bse q u e nt d oses t o 1 0 0 %.  
o  If t here are rec urre nt se v ere s y m pt o ms, t he n all f ut ure d ose s will be re d u ce d t o 
5 0 %  wit h o ut a n y f urt her atte m pts t o escalate .  
o  If 5 0 % is t olerate d, t h at d ose s h o ul d be a d mi nistere d f or all s u bse q ue nt pr ot oc ol 
treat me nt f or t hat p atie nt. 
6. 7.  
I nter ve nti o n after t he E n d of t he St u d y   
T he e n d of st u d y defi niti o n is pr o vi de d i n Secti o n 4. 4 .  I n v esti gat ors will c o nti n ue t o f oll o w t he 
S o A (Secti o n 1. 3 ) u ntil n otifie d b y Lill y  t hat t he e n d of st u d y has o cc urre d. 
6. 7. 1.  
Tre at me nt after St u d y C o m pleti o n   
St u d y c o m pleti o n will occ ur f oll o wi n g t he fi nal a n al ysis of pri mar y a n d sec o n dar y o bjecti ves, as 
deter mi ne d b y Lill y.  I n v esti gat ors will c o nti n ue t o f oll o w t he S o A ( Secti o n 1. 3 ) f or all patie nts 
u ntil n otifie d b y Lill y t hat st u d y c o m pleti o n has occ urre d.  
6. 7. 1. 1.  
C o nti n ue d Access   
Partici pa nts w h o ar e still o n st u d y i nter ve nti o n at t he ti me of st u d y c o m pleti o n ma y c o nti n ue t o 
recei v e st u d y i nter ve nti o n if t he y are e x perie nci n g cli nical be nefit a n d n o u n d ue ris ks.  T he 
c o nti n ue d access peri o d will a p pl y t o t his st u d y o nl y if at least 1 partici pa nt is s till o n st u d y 
i nter ve nti o n w he n st u d y c o m pleti o n occ urs.  Lill y will n otif y i n v esti gat ors w he n t he c o nti n ue d 
access peri o d be gi ns.  Lill y ma y all o w patie nts t o e nr oll i n a “r oll o ver” pr ot oc ol t o pr o vi de l o n g -
ter m c o nti n ue d access f or patie nts e nr olle d i n this st u d y.  
Partici pa nts or t heir le gal re pres e ntati ves are n ot r e q uire d t o si g n a ne w I C F /asse nt ( as 
a p plica ble) b ef ore treat m e nt is pr o vi de d d uri n g t h e c o nti n ue d access p eri o d; t he i nitial I C F /asse nt 
(as a p plica bl e) f or t his st u d y i ncl u des c o nti n ue d access u n der t his pr ot oc ol.  
T he partici pa nt’s c o nti n ue d access t o st u d y i nter ve nti o n will e n d w he n a criteri o n f or 
disc o nti n uati o n is met ( Secti o n  7 ).  C o nti n ue d access f oll o w -u p will be gi n w he n  t he partici p a nt 
or le gal re prese nt ati ve, if a p plica ble,  a n d t h e i n vesti gat or a gree t o disc o nti n ue st u d y i nter ve nti o n 
a n d lasts a p pr o xi matel y 3 0 da ys.   F oll o w -u p pr o ce d ures will be perf or me d as s h o w n i n t he 
C o nti n ue d Access Sc he d ule of Acti vities  ( Secti o n 1. 3 ). 
D uri n g t h e c o nti n ue d access peri o d, all A Es a n d S A Es will be re p orte d o n  t he C R F.  Seri o us 
a d verse e ve nts will als o be re p ort e d t o Lill y Gl o b al Patie nt Safet y (see  Secti o n 8. 3 ).  I n t he e ve nt 
t hat a n S A E occ urs, Lill y ma y re q uest a d diti o nal i nf or mati o n (s uc h  as l oc al la b orat or y res ults, 
c o nc o mita nt me dicati o ns, a n d h os pitalizati o ns) i n or der t o e v al uate  t he re p orte d S A E.  
I n v esti gat ors will perf or m a n y ot her sta n dar d pr oce d ures a n d tests nee d e d t o treat a n d e v al uate 
patie nts; h o we v er, t he c h oice a n d ti mi n g of t h e tests will be at t he i n vesti gat or’s discreti o n.  Lill y 
will n ot r o uti nel y c ollect t he res ults of t hese ass ess me nts.  
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 0 8  
Partici pa nts w h o are i n s h ort -ter m f oll o w-u p w he n t he c o nti n ue d access peri o d be gi ns will 
c o nti n ue i n s h ort -ter m f oll o w-u p u ntil t he 3 0 -da y  s h ort-ter m f oll o w-u p visit is c o m plete d.  
I n all cases, n o f oll o w-u p pr oce d ures will be perf or me d f or a p artici pa nt w h o wit h dra ws 
i nf or me d c o nse nt/asse nt u nless he or s he has e x plicitl y pr o vi de d per missi o n a n d c o nse nt /asse nt. 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 0 9  
7.  
Disc o nti n u ati o n of St u d y I nter ve nti o n a n d P artici p a nt 
Disc o nti n u ati o n/ Wit h dr a w al   
7. 1.  
Disc o nti n u ati o n of St u d y I nter ve nti o n   
If a cli nic all y si g nifica nt fi n di n g is i de ntifie d after e nr oll me nt, t he i n vesti gat or or q ualifie d 
desi g nee will deter mi ne if t he partici pa nt ca n c o nti n ue i n t he st u d y a n d if a n y c h a n ge i n 
partici pa nt ma na ge me nt is nee de d.  A n y n e w cli n i call y rele va nt fi n di n g s h o ul d be re p orte d as a n 
A E.  
P ossi ble reas o ns lea di n g t o per ma ne nt disc o nti n uati o n of i n vesti gati o nal pr o d uct:  
 t he partici pa nt  or t he p artici pa nt’s  desi g n ee, f or e x a m ple, pare nts or l e gal g uar dia n,  
re q uests t o disc o nti n ue i n vesti gati o nal pr o d u ct.  
 p r o gressi ve dise ase 
 c ycle del a y > 2 1 da ys  d u e t o st u d y dr u g -relate d A Es, u nless a n e x ce pti o n has bee n gra nt e d 
u p o n c o ns ultati o n wit h t he Lill y C R P/ C R S f or a n e x ce pti o nal circ u msta nce  
 t he patie nt bec o mes pre g na nt d uri n g the st u d y  
 t he patie nt is si g nifica ntl y n o nc o m plia nt wit h st u d y pr oce d ures a n d/ or treat me nt 
 e nr oll me nt i n a n y ot h er cli nical trial i n v ol vi n g a n i n vesti gati o nal pr o d u ct or e nr oll me nt i n 
a n y ot h er t y pe of m e dical researc h j u d ge d n ot t o b e scie ntificall y or me d i call y c o m pati ble 
wit h t his st u d y  
 s p o ns or or i n vesti gat or d ecisi o n 
 the patie nt, f or a n y reas o n, re q uires tr eat me nt fr o m a n ot her t hera pe utic a ge nt t hat has 
bee n de m o nstrat e d t o be effecti ve f or tr eat me nt of t he st u d y i n dicati o n.  Disc o nti n uati o n 
fr o m a be ma cicli b will occ ur pri or t o i ntr o d ucti o n of t he ne w a ge nt 
 t he patie nt e x perie nces u nacce pta ble t o xicit y  
Partici pa nts  disc o nti n ui n g fr o m t he i n vesti gati o nal pr o d uct pre mat urel y f or a n y reas o n s h o ul d 
c o m plete A E  a n d ot her f oll o w -u p pr oce d ures per Secti o n  1. 3  (S o A ), Secti o n 8. 3  ( A d verse E ve nts 
a n d Seri o us A d vers e E ve nts), a n d Secti o n  8. 2  ( Safet y Ass ess me nts) of t he pr ot oc ol. 
7. 2.  
P artici p a nt Disc o nti n u ati o n/ Wit h dr a w al fr o m t he St u d y   
Partici pa nts  will be d isc o nti n ue d i n t he f oll o wi n g circ u msta nces:  
 e nr oll me nt i n a n y ot h er cli nical st u d y i n v ol vi n g a n i n vesti gati o nal pr o d u ct or 
e nr oll me nt i n a n y ot h er t y p e of me dical researc h j u d ge d n ot t o be 
scie ntificall y or me dic all y c o m p ati ble wit h t his st u d y 
 partici pati o n i n t he st u d y nee ds t o be st o p pe d f or me dical, safet y, re g ulat or y, 
or ot her reas o ns c o nsiste nt wit h a p plica ble la ws, re g ul ati o ns, a n d g o o d cli nical 
practice ( G C P)  
 partici pa nt  decisi o n  
o  t he partici pa nt or t he p atie nt’s desi g nee, f or e x a m ple, pare nts or le gal 
g uar dia n  re q uests t o be wit h dra w n fr o m t he st u d y 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 1 0  
Partici pa nts disc o nti n ui n g fr o m t he st u d y pre mat urel y f or a n y reas o n s h o ul d c o m plete A E  a n d 
ot her safet y f oll o w -u p per Secti o n  1. 3  (S o A ), Secti o n 8. 3  ( A d verse E v e nts a n d Seri o us A d verse 
E ve nts), a n d Secti o n  8. 2  ( Safet y Assess me nts) of t his pr ot oc ol. 
7. 3.  
L ost t o F oll o w  u p   
A  partici pa nt  will be c o nsi dere d l ost t o f oll o w -u p if he or s he re peate dl y fails t o ret ur n f or 
sc he d ule d visits a n d is u na ble t o be c o ntacte d b y t he st u d y site.  Site pers o n nel or desi g nee  are 
e x pecte d t o ma ke dili ge nt atte m pts t o c o ntact partici pa nts  w h o fail t o ret ur n f or a sc h e d ule d visit 
or were ot her wise u n a ble t o be f oll o we d u p b y t he site.  
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 1 1  
8.  
St u d y Assess me nts a n d Pr oce d ures   
 U nless ot her wise state d i n t he s u bsecti o ns bel o w, all sa m ples c ollecte d f or s pecifie d 
la b orat or y tests will be d estr o ye d wit hi n 6 0 da ys of recei pt of c o nfir m e d test res ults.  
Certai n sa m ples ma y be retai ne d f or a l o n ger peri o d, if necessar y, t o c o m pl y wit h 
a p plica ble la ws, re g ulati o ns, or la b orat or y certificati o n sta n dar ds.  
 St u d y pr oce d ures a n d t heir ti mi n g are s u m marize d i n t he S o A  ( Secti o n 1. 3 ). 
 I m me diat e safet y c o ncer ns s h o ul d be disc usse d wit h t he sp o ns or i m me diatel y u p o n 
occ urre nce or a w are ness t o deter mi ne if t he partici pa nt s h o ul d c o nti n ue or 
disc o nti n ue st u d y i nter ve nti o n. 
 A d here n ce t o t he st u d y d esi g n re q uire me nts, i ncl u di n g t h ose s pecifie d i n t he S o A  
( Secti o n 1. 3 ), is esse ntial a n d re q uir e d f or st u d y c o n d uct. 
 All scree ni n g e v al uati o ns m ust be c o m plete d a n d re vie we d t o c o nfir m t hat  p ote ntial 
partici pa nt s meet all eli gi bilit y criteria.  T h e i n vesti gat or will mai ntai n a scree ni n g l o g 
t o rec or d details of all partici pa nt s scree ne d a n d t o c o nfir m eli gi bilit y or rec or d 
reas o ns f or scree ni n g fail ure, as a p plica ble. 
 Pr oce d ures c o n d ucte d as part of t he partici pa nt’s r o uti ne cli nical ma na ge m e nt (e.g . 
bl o o d c o u nt)  a n d o btai ne d bef ore si g ni n g of t he I C F ma y be utilize d f or scree ni n g or 
baseli ne p ur p oses pr o vi de d t he pr oce d ures met t h e pr ot oc ol -s pecifie d criteria a n d 
were p erf or me d wit hi n t he ti me fra me defi ne d i n t he S o A  ( Secti o n 1. 3 ). 
 Re peat or u nsc h e d ule d sa m ples ma y be t a ke n f or safet y reas o ns f or t ec h nical iss ues 
wit h t he sa m ples.  
8. 1.  
Effic ac y Assess me nts   
T u m or assess me nts will be perf or me d f or eac h patie nt at t he ti mes s h o w n i n t he S o A 
( Secti o n 1. 3 ).   
Res p o nse E val uati o n Criteria i n S oli d T u m ors v 1. 1 ( Eise n ha uer et al. 2 0 0 9) a n d R A N O f or C N S 
t u m ors ( We n et al. 2 0 1 0) will be a p plie d as t he pri mar y criteri a i n Parts A a n d B, a n d  I N R C 
(Par k et al . 2 0 1 7)  i n Part C f or assess me nt of t u m or res p o nse a n d date of t u m or pr o gressi o n.  F or 
patie nts wit h e val ua ble disease o nl y, res p o ns e ass ess me nts s h o ul d be ma de acc or di n g t o R E CI S T 
v 1. 1. f or n o n -tar get disease o nl y .  
T he met h o d of t u m or ass ess me nt use d at b aseli ne m ust be use d c o nsiste ntl y t hr o u g h o ut t h e st u d y.  
L ocal t u m or i ma gi n g (i n vesti gat or assess me nt wit h site ra di ol o gical rea di n g) will be use d.   
C o m p ute d t o m o gra p h y ( C T) sca ns, i ncl u di n g s piral C T, are t he preferre d met h o ds of 
meas ure me nt ( C T s ca n t hic k ness rec o m me n d e d t o be ≤5 m m); h o we ver, ma g n etic res o n a n ce 
i ma gi n g is als o acce pta bl e i n certai n sit uati o ns, s u c h as w he n b o d y s ca ns are i n dicate d or if t h ere 
is a c o ncer n a b o ut ra di ati o n e x p os ure ass ociate d wit h C T, pri mar y C N S t u m ors, pri mar y b o ne 
t u m ors, or ot hers.  I ntra v e n o us c o ntrast is re q uir e d u nless medicall y c o ntrai n dicate d  or 
u na vaila ble d ue t o s h ort a ge  ( oral c o ntrast is o pti o nal). 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 1 2  
T he C T p orti o n of a P E T -C T ma y b e use d f or res p o nse assess me nt if t he site ca n d o c u me nt t hat 
t he C T is of i de ntical q ualit y t o a dia g n ostic C T.   
If i ma ges of b o n es are prese nt i n t he a b o ve s c he d ule d sca ns, b o nes s h o ul d b e assesse d f or gr oss 
b o ne a b n or malities.  
Refer t o t he S o A ( Secti o n 1. 3 ) for a d diti o nal details o n i ma gi n g.  
I n Part C  o nl y , h ist ol o gic e val uati o n f or b o n e  marr o w i n v ol ve me nt is re q uir e d  f or all patie nts at 
baseli ne .  F or patie nts wit h k n o w n b o ne marr o w i n v ol ve me nt, marr o w e val uati o n is als o re q uire d 
at t he e n d of C ycles 2, 4, a nd 6 a n d t he n after e ver y f o urt h c ycle t h ereafter . B o ne Marr o w 
e val uati o ns s h o ul d i ncl u de c yt ol o g y,  hist ol o g y, i m m u n o hist oc he mistr y, i m m u n oc yt ol o g y a n d 
R T -P C R as a vaila ble a n d per i nstit uti o nal sta n dar ds . F or patie nts wit h o ut marr o w i n v ol ve me nt, 
ree x a mi nati o n  s h o ul d occ ur f oll o wi n g C ycl e 6. N ote: If P D  is d oc u me nte d b y R E CI S T criteri a 
usi n g t u m or meas ur e me nts , or b y MI B G sca n, t he n a re peat b o ne marr o w e val uati o n  is n ot 
nee de d t o c o nfir m P D.  
I n Part C o nl y, p atie nts will u n der g o a  1 2 3 I-MI B G s ca n  f or t h e pres e nce or a bse nce of MI B G a vi d 
lesi o ns at t he start of t hera p y a n d acc or di n g t o t he S o A ( Secti o n 1. 3. 2 ). T h ose wit h MI B G a vi d 
lesi o ns will be e val ua ble f or MI B G res p o ns e .  F or all patie nts wit h MI B G -a vi d lesi o ns , i ncl u di n g 
t h ose wit h disease als o d etecta ble b y C T/ M RI , serial MI B G e val uati o ns ar e re q uire d p er t he 
S o A . P E T -C T  ma y re pla ce MI B G  o nl y f or p atie nts wit h o ut MI B G a vi d lesi o ns.  
I n Part C o nl y, res p o nse c o nfir mati o n is re q uire d base d o n a re peat assess me nt c o m plete d at least 
4 wee ks after i nitial res p o nse  f or patie nts wit h c o m plete res p o nse, partial r es p o nse, a n d mi n or 
res p o nse. 
See Secti o n 9. 4. 6  f or defi niti o ns of t he efficac y e n d p oi nts. 
8. 2.  
S afet y Assess me nts   
Pla n ne d ti me p oi nts f or all safet y assess me nts are pr o vi de d i n t he S o A  ( Secti o n 1. 3 ). 
Res ults fr o m a n y cli nical safet y la b orat or y test a n al yze d b y a ce ntr al la b orat or y (see 
Secti o n  1 0. 2 , A p pe n di x 2) will be pr o vi de d t o i n vesti gati ve sites b y Li ll y or its desi g nee. 
Refer t o Secti o n 8. 3  f or d etails o n t he rec or di n g of A Es. 
Lill y will peri o dicall y re vie w e v ol vi n g a g gre gate safet y data wit hi n t h e st u d y b y a p pr o priate 
met h o ds.  
 All e nr olle d patie nts will be c o nti n u o usl y m o nit ore d f or A Es.  D ose escal ati o n or t he o pe ni n g 
of ne w d osi n g/e x pa nsi o n c o h orts ca n o cc ur after pri or re vie w a n d disc ussi o n of safet y dat a 
bet wee n t he i n v esti gat or a n d Lill y.  T he d ecisi o n will be d oc u me nte d i n writi n g.  
 Safet y d ata of p atie nts e nr olle d i n t he e x pa nsi o n c o h orts will be re vie we d a n d disc usse d 
bet wee n t he i n v esti gat ors a n d Lill y after e v er y t hir d patie nt has c o m plete d t he D L T peri o d.  
8. 2. 1.  Cli nic al S afet y L a b or at or y Asse ss me nts  
 Lill y or its desi g n ee will pr o vi de t he i n vesti gat or wit h t he res ults of safet y la b orat or y tests 
a nal yze d  b y a ce ntral ve n d or, if a ce ntral ve n d or is use d f or t he cli nical trial.  
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 1 3  
 See Secti o n 1 0. 2 , A p pe n di x 2 f or t he list of cli nical la b orat or y tests t o be p erf or me d a n d 
t he S oA ( Secti o n 1. 3 ) f or t he ti mi n g a n d fre q ue n c y. 
 T he i n vesti gat or m ust re vie w t he la b orat or y res ults, d oc u me nt t his re vie w, a n d re p ort a n y 
cli nicall y rele va nt c ha n g es occ urri n g d uri n g t he st u d y as a n A E .  T h e la b orat or y re p orts 
m ust be retai ne d wit h s o urce d oc u m e nts u nless a S o urce D oc u m e nt A gree me nt or 
c o m para ble d o c u me nt cit es a n electr o nic l ocati o n t hat acc o m m o dates t h e e x pecte d 
rete nti o n d urati o n.  Cli nicall y si g nifica nt a b n or mal la b orat or y fi n di n gs are t h ose t hat are 
n ot ass ociate d wit h t he u n derl yi n g dise ase, u nless j u d ge d b y t he i n v esti gat or t o be m ore 
se vere t h a n e x pecte d f or t he partici pa nt's c o n diti o n. 
 All la b orat or y tests wit h val ues c o nsi dere d cli nicall y si g nifi ca ntl y a b n or mal d uri n g 
partici pati o n i n t he st u d y or u ntil V isit 8 0 1 after t he last d ose of st u d y i nter ve nti o n s h o ul d 
be re peate d u ntil t he val u es ret ur n t o n or mal or b aseli ne or are n o l o n ger c o nsi dere d 
cli nicall y si g nifica nt b y t he i n vesti gat or or me dical m o nit or.  
o  If s uc h val ues d o n ot ret ur n t o n or mal/ baseli ne wit hi n a peri o d of ti me j u d ge d 
reas o na bl e b y t he i n vesti gat or, t h e eti ol o g y s h o ul d be i de ntifie d, a n d t he s p o ns or 
n otifie d.  
o  All pr ot oc ol -re q uir e d la b orat or y assess me nts, as define d i n Secti o n 1 0. 2 , 
A p pe n di x 2, m ust be c o n d ucte d i n acc or da n ce wit h t he S o A ( Secti o n 1. 3 ), 
sta n dar d c ollecti o n re q uir e me nts, a n d la b orat or y ma n ual. 
o  If la b orat or y val ues fr o m n o n-pr ot oc ol s pecifi e d la b orat or y assess me nts 
perf or me d at a n i n vesti gat or -desi g nate d l ocal la b orat or y  re q uir e a c h a n ge i n 
partici pa nt ma na ge me nt or are c o nsi dere d cli nicall y si g nifica nt b y t he i n vesti gat or 
(e.g . S A E or A E or d ose m o dificati o n), t he n re p ort t he i nf or mati o n as a n A E. 
8. 2. 1. 1.  
He p atic S afet y M o nit ori n g   
I n t he ra n d o mize d P hase 3 st u dies ( M O N A R C H 2 a n d M O N A R C H 3), t here was a hi g her 
i nci de nce of i n crease d A L T a n d A S T, b ot h as T E A Es a n d o n ce ntral la b orat or y a nal ysis, i n t he  
a be maci cli b pl us e n d ocri ne t hera p y ar m s t ha n i n t he place b o pl us e n d o cri n e t hera p y ar ms.  T hese 
were pre d o mi na ntl y of Gra de 1 or Gra d e 2  se verit y, a n d a c o n c urre nt i ncrease i n bl o o d bilir u bi n 
was  i nfre q u e nt.  Ge n erall y, A L T a n d A S T i ncreas es were ma na gea ble b y d ose a dj ust me nt or 
d ose  s us pe nsi o n a n d res ol ve d u p o n disc o nti n uati o n of st u d y tr eat me nt.  Se veral patie nts ha d 
is olate d e pis o des of ele v ate d A L T a n d A S T t hat r es ol ve d wit h o ut d ose a dj ust me nt. 
Li ver testi n g ( Secti o n 1 0. 4 , A p pe n di x 4), i ncl u di n g A L T, A S T, al kali ne p h os p hatase , t otal 
bilir u bi n ( T B L ), direct bilir u bi n , ga m ma -gl uta m yl tra nsferase , a n d creati ne p h os p h o ki nase , 
s h o ul d be re peate d wit hi n 2 t o 4 da ys t o c o nfir m t he a b n or malit y a n d t o det er mi ne if it is 
i ncreasi n g or decreasi n g, if o ne or m ore of t hese c o n diti o ns occ ur: 
 
 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 1 4  
If a p artici p a nt wit h b aseli ne res ults of …  
de vel o ps t he f oll o wi n g ele v ati o ns:  
A L T or A S T < 1. 5 ×  U L N  
A L T or A S T ≥5 ×  U L N or  
A L T or A S T ≥3 ×  U L N c o nc urre nt wit h T B L 
≥2 ×  U L N  
A L T or A S T ≥1. 5 × U L N  
A L T or A S T ≥3 ×  bas eli ne or  
A L T or A S T ≥2 ×  bas eli ne or c o nc urre nt wit h 
T B L ≥2 ×  U L N  
A b bre viati o ns:  A L T = ala ni ne a mi n o tra nsferase; A S T = as partate a mi n otra nsferase ; T B L = t otal bilir u bi n; U L N = 
u p per li mit of n or mal.  
If t he a b n or m alit y persists or w orse ns, cli nical a n d la b orat or y m o nit ori n g a n d e val uati o n f or 
p ossi ble ca uses of a b n or mal li ver tests, s h o ul d be i nitiate d b y t he i n vesti gat or i n c o ns ultati o n 
wit h t he Lill y -desi g nate d me dical m o nit or.  At a mi ni m u m, t his e val uati o n s h o ul d i ncl u de 
p h ysical e x a mi nati o n a n d a t h or o u g h me dical hist or y, i ncl u di n g s y m pt o ms, rece nt ill nesses (f or 
e x am ple, heart fail ure, s yste mic i nfecti o n, h y p ote nsi o n, or seiz ures), hist or y of c o nc o mita nt 
me dicati o ns (i ncl u di n g o ver -t he-c o u nter, h er bal a n d dietar y s u p ple me nts, hist or y of alc o h ol 
dri n ki n g a n d ot her s u bsta nce a b use).   I n a d diti o n, t he e val uati o n s h o ul d i ncl u de a bl o o d test f or 
pr ot hr o m bi n ti me -i nter nati o nal n or malize d rati o; ser ol o gi cal tests f or vir al he patitis A, B, C, E, 
a ut oi m m u ne he patitis; a n d a n a b d o mi nal i ma gi n g st u d y (f or e x a m ple, ultras o u n d or C T sca n).  
Base d o n t h e patie nt’s hist or y a n d i nitial e val uati o n res ults, f urt her testi n g s h o ul d be c o nsi dere d, 
i n c o ns ultati o n wit h t he Lill y d esi g nate d me dical m o nit or, i ncl u di n g tests f or he patitis D vir us, 
c yt o me gal o vir us, E pstei n -Barr vir us, aceta mi n o p h e n le vels, aceta mi n o p he n pr otei n a d d ucts, 
ur i ne t o xic ol o g y s cree n, Wils o n’s disease, bl o o d alc o h ol le vels, uri nar y et h yl gl uc ur o ni de, a n d 
ser u m p h os p hati d ylet h a n ol.  Base d o n t he circ u msta nces a n d t he i n v esti gat or’s assess me nt of t he 
partici pa nt’s cli nical c o n diti o n, t he i n vesti gat or s h o ul d c o nsi der  referri n g t h e partici pa nt f or a 
he pat ol o gist or gastr oe nt er ol o gist c o ns ultati o n, m a g n etic res o n a nce c h ola n gi o pa ncreat o gra p h y, 
e n d osc o pic retr o gra d e c h ola n gi o pa n creat o gra p h y, car diac ec h o car di o gra m, a n d/ or a li ver bi o ps y.  
A d diti o n al He p atic S afet y C ollecti o n  
A d diti o nal safet y  data s h o ul d be c ollecte d via t he C R F if 1 or m ore of t he f oll o wi n g c o n diti o ns 
occ ur:  
I n p artici p a nts wit h b aseli ne A L T or A S T < 1. 5 U L N 
 Ele vati o n of ser u m A L T or A S T t o ≥5 × U L N o n 2 or m ore c o ns ec uti ve bl o o d tests  
 T he c o m bi nati o n of ele v ate d A L T or A S T ≥3 ×  U L N a n d ele vate d T B L  ≥2 ×  U L N  
I n p artici p a nts e nr olle d wit h b aseli ne A L T or A S T ≥1. 5 × U L N 
 E le vate d A L T or A S T  ≥3 ×  baseli ne o n 2 or m or e c o nsec uti ve tests  
 T he c o m bi nati o n of ele v ate d A L T or A S T ≥2 × baseli ne a n d ele v ate d T B L ≥2 × U L N  
I n all st u d y p artici p a nts 
 disc o nti n uati o n fr o m st u d y treat me nt d ue t o a h e p atic e ve nt or a b n or malit y of li ver tests  
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 1 5  
 occ urre nce of a h e patic e ve nt c o nsi dere d t o b e a n  S A E  
8. 2. 1. 2.  
G ui d a nce f or M o nit ori n g Re n al F u ncti o n   
A be macicli b has b ee n s h o w n t o i ncreas e ser u m creati ni ne d ue t o i n hi biti o n of re nal t u b ular 
tra ns p orters wit h o ut affecti n g gl o mer ular f u ncti o n (as meas ure d b y i o he x ol cleara nce) .  I ncreases 
i n ser u m creati ni ne occ urre d wit hi n t he first m o nt h  of a be macicli b treat me nt, re mai ne d sta ble 
t hr o u g h t he treat me nt peri o d, a n d were re v ersi ble u p o n treat me nt disc o nti n uati o n.  If 
deteri orati o n of re nal f u n cti o n is s us pecte d, ser u m creati ni ne s h o ul d n ot be t he o nl y meas ure me nt 
use d t o assess a patie nt’s re nal f u n cti o n.   
D ose  a dj ust me nts ( o missi o n, re d ucti o n, or disc o nti n uati o n) s h o ul d n ot be  s olel y bas e d o n 
i nter pretati o n of ser u m creati ni ne val ues beca us e t hese ma y n ot reflect r e nal f u ncti o n.  Ot her 
meas ures of re nal f u ncti o n s uc h as c ystati n C or calc ulate d  G F R s h o ul d be use d as a n alter nati ve 
t o creati ni ne as creati ni ne is n ot a n acc urate met h o d t o assess re nal f u n cti o n  i n t his sce nari o.  If 
deteri orati o n of re nal f u n cti o n is s us pecte d per t h e i n vesti gat or’s cli nical assess me nt, d ose 
a dj ust me nt s h o ul d f oll o w t he pr ot oc ol g ui d a nce f or n o n he mat ol o gi cal t o xicities. 
8. 2. 1. 3.  
G ui d a nce f or Ve n o us T hr o m b oe m b olic E ve nts   
I n t he ra n d o mize d P hase 3 st u dies i n breast ca n cer patie nts w h o recei ve d a b e macicli b i n 
c o m bi nati o n wit h e n d ocri ne t hera p y, t here was a greater n u m ber of p atie nts w h o e x perie nce d  
ve n o us t hr o m b oe m b olic e ve nts ( V T Es)  i n t he a be macicli b pl us e n d ocri ne t hera p y ar ms tha n i n 
t he place b o pl us e n d o cri ne t hera p y ar ms.  T he maj orit y of t he e ve nts were n o n -seri o us a n d were 
treate d wit h l o w-m olec ular -w ei g ht  h e pari n.  Ge nerall y, t hes e e v e nts di d n ot res ult i n 
disc o nti n uati o n of t he st u d y treat me nt.  At t his  ti me, t he mec h a nis m u n derl yi n g t he ass o ciati o n 
bet wee n a be ma cicli b a n d t he occ urre nce of  V T Es is n ot k n o w n.  F or s us pecte d or c o nfir me d 
V T E (e .g . dee p vei n t hr o m b osis or p ul m o nar y e m b olis m), treat me nt s h o ul d occ ur acc or di n g t o 
us ual cli nical practice.  
8. 2. 1. 4.  
G ui d a nce f or I nterstiti al L u n g Dise ase/ P ne u m o nitis   
I nterstitial l u n g diseas e/ p ne u m o nitis has bee n i de ntifie d as a n a d v erse dr u g reacti o n f or 
a be maci cli b.  T he maj orit y of e v e nts o bser ve d i n cli nical tr ials were Gra de 1 or Gra d e 2 wit h 
seri o us cases a n d fat al e v e nts re p orte d.  A d diti o nal i nf or mati o n is a vaila ble i n t he I B.  
As k y o ur patie nts t o re p ort a n y n e w or w orse ni n g p ul m o nar y s y m pt o ms s uc h as c o u g h, d ys p nea, 
fe ver, a n d i n vesti gate a n d treat as per yo ur l ocal cli nical practice , i n cl u di n g c ortic oster oi ds as 
a p pr o priate.  If i nterstitial l u n g disease/ p n e u m o nitis is s us pecte d, i n vesti gati o ns ma y i ncl u de 
i ma gi n g, s uc h as hi g h -res ol uti o n C T sca ns , br o nc h oal ve olar  la va ge, a n d bi o ps y as cli nicall y 
i n dicate d. 
Refer t o  Secti o n 6. 6  f or g ui da nce o n d ose a dj ust me nts of a be macicli b f or p atie nts wit h i nterstitial 
l u n g diseas e/ p ne u m o nitis.  Disc o nti n ue a be macicli b i n cases of se v ere i nterstitial l u n g 
disease/ p ne u m o nitis.  
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 1 6  
8. 3.  
A d verse E ve nts a n d Seri o us A d verse E ve nts   
I n v esti gat ors are res p o nsi ble f or m o nit ori n g t he s afet y of p artici pa nts w h o ha ve e ntere d t his 
st u d y a n d f or alerti n g Lill y or its desi g nee t o a n y e ve nt t hat see ms u n us ual, e ve n if t his e ve nt 
ma y b e c o nsi dere d a n u n a ntici pate d be nefit t o t he  partici pa nt . 
T he i n vesti gat or is res p o nsi ble f or t he a p pr o priate me dical c are of p artici pa nts  d uri n g t he st u d y.  
I n v esti gat ors m ust d oc u me nt t heir re vie w of eac h la b orat or y safet y re p ort. 
Defi niti o n of A E  
A n A E is a n y u nt o war d me dical occ urre n ce i n a partici pa nt a d mi nistere d a p har mace utical pr o d uct 
a n d w hic h d oes n ot necessaril y  h a ve a ca usal relati o ns hi p wit h t he st u d y i nt er ve nti o n. A n A E ca n 
t heref ore be a n y u nfa v o ura ble a n d u ni nte n d e d si g n (i ncl u di n g a n a b n or mal la b orat or y fi n di n g), 
s y m pt o m, or disease ( ne w or e x acer bate d) te m p orall y ass ociate d wit h t he use of a me dici n al 
(i n vesti gati o nal) pr o d uct, or i n vesti gati o nal c o m bi nati o n pr o d uct, w het her or n ot relate d t o t he 
me dici nal (i n vesti gati o nal) pr o d uct or i n vesti gati o nal c o m bi nati o n pr o d uct.  
E ve nts meeti n g t he A E defi niti o n   
 
A n y a b n or mal la b orat or y test res ults ( he mat ol o g y, cli nical c he mistr y, or uri nal ysis) or 
ot her safet y assess me nts, f or e x a m ple, E C G, ra di ol o gical sc a ns, a n d vital si g ns 
meas ure me nts, i ncl u di n g t h ose t hat w orse n fr o m baseli ne, c o nsi dere d cli nicall y 
si g nifica nt i n t he me dic al a n d scie ntific j u d g me nt of t he in vesti gat or, t hat is, n ot relate d t o 
pr o gressi o n of u n derl yi n g diseas e.   
 
E x acer bati o n of a c hr o ni c or i nter mitte nt pre -e xisti n g c o n diti o n i ncl u di n g eit her a n 
i ncreas e i n fre q u e nc y a n d/ or i nte nsit y of t he c o n diti o n.  
 
Ne w c o n diti o n detecte d or dia g n os e d afte r st u d y i nter ve nti o n a d mi nistrati o n e ve n t h o u g h 
it ma y ha v e bee n prese nt bef ore t h e start of t he st u d y.  
 
Si g ns, s y m pt o ms, or t he cli nical se q uelae of a s us pecte d dr u g -dr u g i nteracti o n.   
 
Me dicati o n err or, mis use, or a b use of I M P, i ncl u di n g si g ns, s y m pt o ms, or cli nical 
se q uelae. 
T he i n vesti gat or re m ai ns res p o nsi ble f or f oll o wi n g, t hr o u g h a n a p pr o priate healt h care o pti o n, 
A Es t hat are s eri o us or ot her wise me dicall y i m p ort a nt, c o nsi dere d relate d t o t he i n vesti gati o nal 
pr o d uct or t he st u d y, or t h at ca use d t he p artici pa nt  t o disc o nti n ue t he i n vesti gati o nal pr o d u ct 
bef ore c o m pleti n g t h e st u d y.  T he partici pa nt s h o ul d be f oll o we d u ntil t he e ve nt res ol ves, 
sta bilizes wit h a p pr o priate dia g n ostic e val uati o n, or is ot her wise e x plai ne d.  T he fre q u e nc y of 
f oll o w-u p e val uati o ns of t he A E is left t o t he discreti o n of t he i n vesti gat or.  
Lac k of dr u g effect is n ot a n A E i n cli nical st u dies, beca use t h e p ur p ose of t he cli nical st u d y is t o 
esta blis h treat me nt effect.  
After t he I C F is si g n e d (a n d asse nt, if a p plica ble), st u d y site pers o n nel will rec or d vi a C R F t he 
occ urre nce a n d nat ur e of eac h  p artici pa nt ’s pree xisti n g c o n diti o ns, i ncl u di n g cli nicall y 
si g nifica nt si g ns a n d s y m pt o ms of t he disease u n d er treat me nt i n t he st u d y.  I n a d diti o n, site 
pers o n nel will rec or d a n y c ha n ge i n t he c o n diti o n(s) a n d a n y ne w cli nicall y rele va nt c o n diti o ns 
as A Es.  I n vesti gat ors s h o ul d rec or d t heir assess m e nt of t he p ote ntial relat e d ness of eac h A E t o 
pr ot oc ol pr oce d ure  a n d i n vesti gati o nal pr o d u ct, via C R F.   
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 1 7  
T he i n vesti gat or will i nter pret a n d d o c u me nt w het her or n ot a n A E has a reas o na ble p ossi bilit y 
of bei n g relat e d t o st u d y treat me nt, st u d y d e vice, or a st u d y pr oce d ure, ta ki n g i nt o acc o u nt t he 
disease, c o n c o mita nt treat me nt , or pat h ol o g ies. 
A “reas o na ble p ossi bilit y” mea ns t hat t here is a ca use a n d effect relati o ns hi p bet wee n t he 
i n vesti gati o nal pr o d u ct, st u d y de vic e a n d/ or st u d y pr oce d ure a n d t he A E. 
T he i n vesti gat or a ns w ers yes/ n o w h e n ma ki n g t his assess me nt.  
Pla n ne d s ur geries a n d n o ns ur gic al i nter ve nti o ns s h o ul d n ot be re p orte d as A Es u nless t he 
u n derl yi n g me di cal c o n diti o n has w orse ne d d uri n g t he c o urse of t h e st u d y.  
If a partici pa nt ’s i n vesti gati o nal pr o d uct is disc o nti n ue d as a res ult of a n A E, st u d y site pers o n nel 
m ust re p ort t his t o Lill y or its desi g nee via C R F, clarif yi n g if p ossi ble t he circ u msta nces lea di n g 
t o a n y d os a ge m o dificati o ns, or disc o nti n uati o ns of treat me nt. 
Seri o us A d verse E ve nts  
A n S A E is a n y A E fr o m t his st u d y t hat res u lts i n o ne of t he f oll o wi n g o utc o mes: 
 deat h  
 i nitial or pr ol o n ge d i n patie nt h os pitalizati o n 
 a life-t hreate ni n g e x perie nce (t hat is, i m me diate ris k of d yi n g) 
 persiste nt or si g nifi ca nt disa bilit y/i nca pacit y  
 c o n ge nital a n o mal y/ birt h defect  
 i m p orta nt me dical e ve nts t hat ma y n ot be i m me diatel y life-t hreat e ni n g or res ult i n 
deat h or h os pitalizati o n b ut ma y je o par dize t he partici pa nt  or ma y re q uir e 
i nter ve nti o n t o pre ve nt o ne of t he ot her o ut c o mes liste d i n t he defi niti o n a b o ve.  
E x a 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 n c y r o o m or at h o me, bl o o d d yscrasias or 
c o n v ulsi o ns t hat d o n ot res ult i n i n patie nt h os pitalizati o n, or t he de vel o p me nt of 
dr u g d e pe n de nc y or dr u g a b use.  
All A Es occ urri n g after si g ni n g t he I C F are rec or de d i n t he C R F a n d assess e d f or seri o us criteria.  
T he S A E re p orti n g t o t he s p o ns or be gi ns  after t h e partici pa nt  has si g ne d t he I C F a n d has 
recei v e d i n vesti gati o nal pr o d uct.  H o we v er, if a n S A E occ urs after si g ni n g t he I C F, b ut pri or t o 
recei vi n g i n vesti gati o nal pr o d uct, t he S A E s h o ul d be re p ort e d t o t he s p o ns or as per S A E 
re p orti n g re q uir e me nts a n d ti meli nes (see Secti o n 8. 3. 1 ) if it is c o nsi dere d reas o na bl y p ossi bl y 
relate d t o st u d y pr oce d ure. 
St u d y site p ers o n nel m ust aler t Lill y or its desi g nee of a n y S A E wit hi n 2 4 h o urs of i n vesti gat or 
a ware ness of t he e ve nt vi a a s p o ns or -a p pr o ve d m et h o d.  If alerts are iss ue d via tele p h o ne, t he y 
are t o be i m me diatel y f oll o we d wit h official n otifi cati o n o n st u d y -s p ecific S A E f or ms.  T his 2 4 -
h o ur n otificati o n re q uir e me nt refers t o t he i nitial S A E i nf or mati o n a n d all f oll o w -u p S A E 
i nf or mati o n.  Partici pa nts wit h a seri o us he patic A E  s h o ul d ha ve a d diti o nal data c ollecte d usi n g 
t he C R F. 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 1 8  
Pre g n a nc y ( d uri n g mater nal or pater n al e x p os ure t o i n vesti gati o nal pr o d u ct) d oes n ot meet t he 
defi niti o n of a n A E.  H o we ver, t o f ulfill re g ulat or y re q uire me nts a n y pre g n a nc y s h o ul d be 
re p orte d f oll o wi n g t he S A E pr ocess t o c ollect dat a o n t he o utc o me f or b ot h m ot her a n d fet us. 
I n v esti gat ors are n ot o bli gat e d t o acti vel y see k A Es or S A Es i n s u bjects o nce t he y ha ve 
disc o nti n ue d a n d/ or c o m plete d t he st u d y (t he  parti ci pa nt  dis p ositi o n C R F has bee n c o m plet e d).  
H o we ver, if t he i n vesti gat or lear ns of a n y S A E, i ncl u di n g a d eat h, at a n y ti me after a s u bject has 
bee n disc har ge d fr o m t he st u d y, a n d h e/s he c o nsi d ers t he e v e nt reas o n a bl y p ossi bl y relate d t o t he 
st u d y treat me nt or st u d y partici pati o n, t he i n vesti gat or m ust pr o m ptl y n otif y Lill y. 
Seri o us a d verse e ve nts , i ncl u di n g deat h, ca us e d b y diseas e pr o gressi o n s h o ul d n ot be re p orte d 
u nless t he i n vesti gat or d ee ms t he m t o be p ossi bl y relate d t o st u d y treat me nt. 
S us pecte d U ne x pecte d Seri o us A d verse Re a cti o ns  
S us pecte d u ne x pecte d seri o us a d verse reacti o ns ( S U S A Rs) are seri o us e v e nts t hat are n ot liste d 
i n t he I B a n d t h at t he i n vesti gat or i d e ntifies as relate d t o i n vesti gati o nal pr o d uct or pr oce d ure.  
U nite d States 2 1 C F R 3 1 2. 3 2 a n d E ur o pea n U ni o n Cli nical Trial Directi ve 2 0 0 1/ 2 0/ E C a n d t he 
ass ociate d det aile d g ui da nces or nati o nal r e g ulat or y re q uire me nts i n partici pati n g c o u ntri es 
re q uire t he re p orti n g of S U S A Rs.  Lill y h as pr oce d ures t hat will be f oll o we d f or t he 
i de ntificati o n, rec or di n g, a n d e x pe dite d re p orti n g of S U S A Rs t hat are c o nsiste nt wit h gl o bal 
re g ulati o ns a n d t he ass o ciate d detaile d g ui da nces.  
8. 3. 1.  Ti me Peri o d a n d Fre q ue nc y f or C ollecti n g A E a n d S A E I nf or m ati o n   
Alt h o u g h all A Es after si g ni n g t he I C F are rec or de d b y t h e site i n t he C R F, S A E re p orti n g t o 
Lill y b e gi ns after t he pati e nt has si g n e d t he I C F a n d has recei ve d st u d y dr u g.  H o we ver, if a n 
S A E occ urs after si g ni n g t he I C F, b ut pri or  t o recei vi n g a be m acicli b , it nee ds t o be re p orte d 
O N L Y if it is c o nsi dere d reas o na bl y p ossi bl y relat e d t o st u d y pr oce d ures.  
Me dical occ urre n ces t hat be gi n b ef ore t he start of st u d y i nter ve nti o n b ut aft er o btai ni n g i nf or me d 
c o nse nt /asse nt will be rec or de d o n t he A E C R F.  
All S A Es will be rec or de d a n d re p ort e d t o t he s p o ns or or desi g nee i m me di atel y a n d u n der n o 
circ u msta nce s h o ul d t his e x cee d 2 4 h o urs.  T he i n vesti gat or will s u b mit a n y u p dat e d S A E data t o 
t he s p o ns or wit hi n 2 4 h o urs of it be i n g a vaila ble.  Seri o us a d verse e ve nt s, i ncl u di n g deat h, 
ca use d b y dise ase pr o gressi o n s h o ul d n ot be re p orte d u nless t he i n vesti gat or dee ms t he m t o be 
p ossi bl y relate d t o st u d y treat me nt.  
I n v esti gat ors are n ot o bli gat e d t o acti vel y see k A E or S A E after c o n cl usi o n of t he st u d y 
partici pati o n .  H o we v er, if t he i n vesti gat or l ear ns of a n y S A E, i ncl u di n g a deat h, at a n y ti me after 
a partici pa nt has b ee n dis c har ge d fr o m t he st u d y, a n d he/s he c o nsi ders t he e ve nt t o be reas o n a bl y 
relate d t o t he st u d y i nter ve nti o n or st u d y partici pati o n, t he i n vesti gat or m ust pr o m ptl y n otif y t he 
s p o ns or. 
Care will be ta ke n n ot t o i ntr o d uce bias w he n d etecti n g A Es a n d/ or S A Es.  O pe n -e n d e d a n d 
n o n -lea di n g ver bal q uesti o ni n g of t he p artici pa nt a n d/ or le gal g u ar dia n is t h e preferre d met h od t o 
i n q uire a b o ut A E occ urre nces . 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 1 9  
8. 3. 2.  F oll o w -u p of A Es a n d S A Es   
After t he i nitial A E/ S A E re p ort, t he i n vesti gat or is re q uire d t o pr o acti vel y f oll o w eac h partici pa nt 
at s u bse q ue nt visits/c o ntacts.  All S A Es  will be f oll o we d u ntil res ol uti o n, sta bilizati o n, t he e ve nt 
is ot her wise e x plai ne d, or t he partici pa nt is l ost t o f oll o w-u p (as defi ne d i n Secti o n  7. 3 ). 
8. 3. 3.  Re g ul at or y Re p orti n g Re q uire me nts f or S A Es   
 
Pr o m pt n otificati o n b y t he i n vesti gat or t o t he s p o ns or of a S A E is esse ntial s o t hat le gal 
o bli gati o ns a n d et hical res p o nsi bilities t o war ds t he safet y of partici pa nts a n d t he sa fet y 
of a st u d y i nter ve nti o n u n der cli nical i n vesti gati o n are met.  
 
T he s p o ns or has a l e gal r es p o nsi bilit y t o n otif y b ot h t he l ocal re g ulat or y a ut h orit y a n d 
ot her re g ulat or y a ge n cies a b o ut t he safet y of a st u d y i nter ve nti o n u n der cli nical 
i n vesti gati o n. T he  s p o ns or will e val uate t he re p orte d S A Es, i ncl u di n g c o nfir mati o n of 
relate d ness a n d assess me nt of e x pecte d ness. T he s p o ns or has pr ocesses f or safet y 
re p orts f or i de ntificati o n, rec or di n g, a n d e x pe dite d re p orti n g of S U S A Rs acc or di n g t o 
l ocal re g ulat or y re q uir e me nts. T he  s p o ns or will c o m pl y wit h c o u ntr y-s pecific re g ulat or y 
re q uire me nts r elati n g t o safet y re p orti n g t o t he re g ulat or y a ut h orit y, I R B/I E C, a n d 
i n vesti gat ors. 
 
 
 
A n i n vesti gat or w h o recei ves a n i n vesti gat or safet y re p ort descri bi n g a S A E or ot her 
s pecific safet y i nf or mati o n (e.g . s u m mar y or listi n g of S A Es) fr o m t he s p o ns or will 
re vie w a n d t h e n file it al o n g wit h t he I B a n d will n otif y t he I R B/I E C, if a p pr o priate 
acc or di n g t o l ocal re q uir e me nts.  
8. 3. 4.  
Pre g n a nc y   
 
Details of all pre g n a ncies a n d e x p os ure d uri n g breastfee di n g, fr o m t he ti me of treat me nt 
t hr o u g h 1 2 0 d a ys f oll o wi n g cessati o n of st u d y treat me nt, or 3 0 da ys f oll o wi n g cessati o n 
of st u d y tr eat me nt if t he partici pa nt i nitiates ne w a ntica ncer t hera p y.  
 
If a pre g na nc y is r e p orte d, t he i n vesti gat or s h o ul d i nf or m t he s p o ns or wit hi n 2 4 h o urs of 
lear ni n g of t he pre g na n c y a n d s h o ul d f oll o w t he pr oce d ures o utli ne d i n Secti o n 1 0. 3 , 
A p pe n di x 3 . 
 
A b n or mal pre g n a nc y o ut c o mes (e .g . s p o nta n e o us a b orti o n, fetal deat h, still birt h, 
c o n ge nital a n o malies, a n d ect o pic pre g n a nc y) are c o nsi dere d S A Es.  
 
A d diti o nal re q uire me nts f or pre g n a nc y testi n g d uri n g a n d after st u d y i nter ve nti o n are 
l ocate d i n Secti o n 1 0. 3 , A p pe n di x 3.  
 
T he i n vesti gat or is res p o ns i ble f or re vie w of me di cal hist or y, m e nstr ual hist or y, a n d 
rece nt s e x ual acti vit y t o decrease t he ris k f or i ncl usi o n of a fe male wit h a n earl y 
u n detecte d pre g na n c y . 
8. 3. 5.  
C ar di o v asc ul ar a n d De at h E ve nts   
N ot a p plica ble . 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 2 0  
8. 3. 6.  
C o m pl ai nt H a n dli n g   
Lill y c ollects pr o d u ct c o m plai nts o n i n vesti gati o nal pr o d ucts a n d dr u g d eli ver y s yste ms use d i n 
cli nical st u dies i n or der t o e ns ure t he s afet y of st u d y partici pa nts, m o nit or q ualit y, a n d facilitate 
pr ocess a n d pr o d uct i m pr o ve me nts.  
Partici pa nts will be i nstr ucte d t o c o ntact t he i n vesti gat or as s o o n as p ossi ble if he or s he has a 
c o m plai nt or pro ble m wit h t he i n vesti gati o nal pr o d uct s o t hat t he sit uati o n ca n be assess e d.  
8. 4.  Tre at me nt of O ver d ose   
Refer t o t he  I B a n d/ or Pr o d uct La bel f or a be macicli b  f or a vaila ble i nf or mati o n o n t he si g ns, 
s y m pt o ms, a n d treat me nt of o ver d ose. 
F or  di n ut u xi ma b, G M -C S F , iri n oteca n, a n d t e m oz ol o mi de, refer t o t he res pecti ve P r o d uct L a b el 
f or a vaila bl e i nf or mati o n o n t he si g ns, s y m pt o ms, a n d treat me nt of o v er d ose. 
8. 5.  
P h ar m ac o ki netics   
At t he visits a n d ti mes s pecifie d i n t he S o A  (Secti o n 1. 3 ), P K  sa m ples will be c ollecte d t o 
deter mi ne t he c o n ce ntr ati o ns of : 
 a be maci cli b  a n d its meta b olites M 2 a n d M 2 0   
 iri n oteca n a n d its meta b olite S N-3 8  
 te m oz ol o mi de 
T he P K of di n ut u xi ma b a n d G M -C S F will n ot be assesse d.  
T o e ns ure c o m pre he nsi v e P K sa m pli n g i n a pe di atric p o p ulati o n, Parts A a n d B are  desi g ne d t o 
e val uate at least 
 i ncl u di n g at least 
 
a n d at least 2
 If n o  patie nts 
 a n d e val u a ble i n 
t he a b o ve gr o u ps, t he n 
 will be e v al uate d. T h e n u m ber of patie nts 1 8 
years of a ge will be ca p p e d at  u ntil patie nt n u m bers i n t he a b o ve a ge gr o u ps are e nr olle d.  
A d diti o nall y, i n Part C, a t least 
 s h o ul d be i n t he a ge gr o u p 
 
of a ge , wit h at least 
 a n d at least 
 
 
A be macicli b d osi n g dates a n d ti mes are re q uire d t o be c ollecte d 3 da ys pri or t o t he P K sa m ples.  
T he date a n d e x act ti me of c ollecti o n of eac h P K  sa m ple m ust be rec or de d o n t he la b orat or y 
re q uisiti o n. Be y o n d t he first d ose, P K sa m ples ma y be ali g n e d t o c oi nci de wit h sta n dar d 
la b orat ories w h e n a p plica ble , wit h t he c ollecti o n dates/ti mes s pecifie d i n t he S o A ( Secti o n 1. 3. 3 ) 
t o be use d as a g ui de. 
F or patie nts r ecei vi n g c h e m ot hera p y i nf usi o ns , t h e P K sa m ples s h o ul d be dra w n fr o m a se parate 
li ne at a peri p heral a ccess site. 
A ma xi m u m of  5  sa m ples ma y be c ollecte d at a d diti o nal ti me p oi nts d uri n g t he st u d y if 
warra nte d a n d a gree d u p o n bet wee n b ot h t he i n vesti gat or a n d s p o ns or. I nstr ucti o ns f or t he 
c ollecti o n a n d ha n dli n g of bl o o d sa m ples will be pr o vi de d b y t he s p o ns or . T he act ual d ate a n d 
ti me (2 4 -h o ur cl oc k ti me ) of eac h sa m pli n g will be rec or de d.  
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 2 1  
T he P K sa m pli n g sc h e d ule is desi g ne d t o c o m pl y wit h bl o o d v ol u me li mitati o ns i n pe diatric 
patie nts.  If t he c ollecti o n of P K sa m ples will e x cee d ma xi m u m bl o o d dra w v ol u mes f or a n y 
patie nt, bl o o d sa m ples f or safet y will be pri oritize d o ver P K after disc ussi o n bet wee n t he s p o ns or 
a n d t he i n vesti gat or.  
Bi oa nal ytical s a m ples c ollecte d t o meas ure i n vesti gati o nal pr o d u ct c o nce ntr ati o n will be reta i ne d 
f or a ma xi m u m of 1 year f oll o wi n g last partici p a nt  visit f or t he st u d y.  D uri n g t his ti me, sa m ples 
re mai ni n g after t he bi oa n al yses m a y be use d f or e x pl orat or y a nal yses (s uc h as q ua ntificati o n of 
circ ulati n g meta b olites a n d/ or pr otei n bi n di n g w or k).  
8. 5. 1.  
P at i e nt Di ar y  
A diar y will be pr o vi de d t o patie nts /care gi vers i n or der t o hel p trac k date a n d ti me of eac h d os e 
d uri n g c ycles i n w hic h P K sa m ples are c ollecte d.  Patie nt diar y e val u ati o ns will occ ur t hr o u g h 
C ycle 3 Da y 1. T he di ar y is n ot i nte n de d f or c o m plia nce m o nit ori n g. Refer t o Secti o n 1. 3  f or 
a d diti o nal i nf or mati o n .  
8. 6.  P h ar m ac o d y n a mics   
P har mac o d y na mics will n ot be e val uate d i n t his st u d y.  
8. 7.  Ge netics   
8. 7. 1.  W h ole  Bl o o d a n d/ or S ali v a  S a m ple s f or P h ar m ac o ge netic Rese a rc h  
W h ole bl o o d a n d/ or sali va sa m ples will n ot be c ollecte d f or Parts A a n d B . O nl y w h ole bl o o d 
will be c ollecte d f or Part C  i n t his st u d y. Ge n etic researc h will n ot be perf or me d . 
8. 8.  Bi o m ar kers   
If a vaila bl e, partici pa nts’  s o matic alterati o ns ma y  be o btai ne d at bas eli ne as part of t heir me dical 
o nc ol o g y hist or y (s ee Secti o n 1. 3 ).  T his st u d y m a y  a nal yz e s o matic alterati o ns rele va nt t o st u d y 
i nter ve nti o n, mec ha nis m of acti o n, t he varia ble res p o nse t o st u d y dr u g(s), cell c ycle, a n d 
pat h wa ys ass oci ate d wit h ca ncer.  
See Secti o n 9. 4. 1 0  f or bi o mar ker a nal yses.  
8. 8. 1.  
Bi o m ar kers  f or P a rt C  
T his st u d y will a nal yze bi o mar kers rele va nt t o st u d y i nter ve nti o n, m ec ha nis m of acti o n, t he 
varia ble res p o nse t o st u d y dr u g(s) (i ncl u di n g e v al uati o n of A Es or differe n ces i n effi cac y), cell 
c ycle, i m m u ne f u ncti o n, or pat h wa ys ass o ciate d wit h n e ur o blast o ma. Sa m ples c ollecte d will 
e na ble e x a mi nati o n of t hese q uesti o ns t hr o u g h t he meas ure me nt of bi o m olec ules, i ncl u di n g 
D N A, R N A, pr otei ns, li pi ds, a n d ot her circ ul ati n g or cell ular ele me nts. Deri vati ves of sa m ples , 
f or e x a m ple, t u m or i ma ges, ca n als o b e use d t o i de ntif y bi o mar kers of p artici pa nt res p o nse or 
resista nce. E x ce pt f o r t he cases det aile d i n Secti o n  8. 8. 1. 1  (t u m or D N A se q ue nci ng wit h o ut 
patie nt -matc he d ger mli ne s u btracti o n) a n d Secti o n  8. 8. 1. 2  ([circ ulati n g t u m or D N A] ct D N A 
se q ue nci n g wit h o ut patie nt-matc he d ger mli ne s u btracti o n) , bi o mar ker a n al yses will n ot pr o d uce 
i nter preta ble res ults o n ger mli ne D N A a n d t heref ore will n ot lea d t o t he i de ntificati o n of ge n etic 
fi n di n gs. Bi o mar ker a nal ys es u si n g R N A as s u bstr ate will a v oi d t he i de ntificati o n of ge netic 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 2 2  
varia nts a n d will f oc us o n q ua ntif yi n g ge n e e x pressi o n a n d re p orti n g t u m or s o matic ge ne f usi o ns 
a n d ot her t u m or s o matic rearra n ge m e nts. Bi o mar ker a nal ysis res ults ma y o cc ur after t he cli nical 
st u d y re p ort (C S R ) is writte n a n d t heref ore a se parate bi o mar ker Data A nal ysis Pla n will be 
de vel o pe d.  
Sa m ples f or bi o mar ker researc h will be c ollecte d as s pecifie d i n t he S c he d ul e of A cti vities 
(Secti o n  1. 3 ), w here l ocal re g ul ati o ns all o w. It is p ossi ble t hat bi o mar ker data f or partici p a nts i n 
t he st u d y ha v e alr ea d y bee n ge nerate d fr o m sa m ples t hat were c ollecte d a n d a nal yze d pri or t o 
e nr olli n g i n t his  trial. T his ma y i ncl u de d ata ge n erate d fr o m ge n etic a nal ys es. If a v aila ble, t hese 
data ma y be re q ueste d fr o m me dical rec or ds f or use i n t he researc h d escri b e d i n Secti o ns 8. 8. 1. 1  
a n d 8. 8. 1. 2 , f or i nsta nce t o u n dersta n d t he r ole of vari o us c o-occ urri n g  alterati o ns  
Sa m ples ma y be us e d t o de vel o p relat e d res earc h met h o ds or t o vali date dia g n ostic t o ols or 
assa ys, b ut o nl y wit hi n t h e s pecific researc h s c o pe descri be d i n t his pr ot oc ol. T he sa m ples ma y 
be a nal yz e d as part of a m ulti -st u d y assess me nt of n o n-ge netic fact ors i n v ol ve d i n t he res p o nse 
t o st u d y i nter ve nti o n or st u d y i nter ve nti o ns of t his class, a n d/ or t o u n dersta n d st u d y diseas e or 
relate d c o n diti o ns, wit hi n t he sc o pe des cri be d i n t his pr ot oc ol. 
All sa m ples will be c o de d wit h t he partici pa nt n u m ber. T hese s a m ples a n d a n y d ata ge n erat e d 
ca n be li n ke d b ac k t o t he partici pa nt o nl y b y t h e st u d y site pers o n nel. Sa m ples will be retai ne d 
f or a ma xi m u m of 
 after t he last p artici pa nt visit f or t he st u d y, or f or a s h orter peri o d if 
l ocal re g ulati o ns a n d/ or E R Bs/I R Bs i m p ose s h ort er ti me li mits, at a facilit y selecte d b y t he 
S p o ns or or its desi g nee. T his rete nti o n peri o d e na bles use of ne w t ec h n ol o gies, res p o nse t o 
q uesti o ns fr o m re g ulat or y a ge ncies, a n d i n vesti gati o n of varia ble res p o nse t hat ma y n ot be 
o bser ve d u ntil later i n t he de vel o p me nt of st u d y treat me nt or after st u d y tr eat me nt bec o mes 
c o m merciall y a v aila ble. Tec h n ol o gies are  e x pecte d t o i m pr o ve d uri n g t he 
st ora ge p eri o d, 
a n d t heref ore, ca n n ot be s pecificall y na me d. Re gar dless of t he tec h n ol o g y utilize d, data 
ge n erat e d will be use d o nl y f or t h e s pecifi c bi o mar ker res earc h sc o pe d escri be d i n t his secti o n, 
a n d wit hi n t he li mits of t his pr ot oc ol. 
8. 8. 1. 1.  
Tiss ue  S a m ples f or Bi o m a r ker Rese arc h   
Tiss ue sa m ples f or bi o mar ker researc h will be c ollecte d f or t h e p ur p oses d escri be d i n 
Secti o n  8. 8. 1 . T he f oll o wi n g sa m ples f or bi o mar ker researc h will be c ollect e d acc or di n g t o t he 
sa m pli n g sc he d ul e i n t he S c he d ule of A cti vities (S ecti o n 1. 3 ), w here l ocal r e g ul ati o ns all o w. 
S u b missi o n of  t u m or sa m ple, arc hi val or fres h, o btai ne d pri or t o i nitiati o n of st u d y tr eat me nt, 
will be c ollecte d, w h e n  a vaila ble. T he m ost rece nt sa m ple is desire d. Rela pse or metastatic 
sa m ple w here a vaila bl e is preferre d. T h e t u m or sa m ples will prefera bl y b e i n t he f or m of a 
. If t his is n ot p ossi ble, a p pr o xi matel y 
 sli des of 
fres hl y pre p are d u nstai ne d 5-micr o n secti o ns ma y be pr o vi de d. D ue dili ge n ce s h o ul d be use d t o 
ma ke s ure t hat t u m or sa m ple, n ot a n or mal a djace nt or a t u m or mar gi n sa m ple, is pr o vi de d. 
Sa m ples ca n be se nt at a n y ti me d uri n g st u d y if n ot s u b mitte d at scree ni n g.  
Pat h ol o g y re p ort acc o m pa n yi n g t u m or tiss ue will be re q uest e d. Pat h ol o g y re p orts m ust be c o de d 
wit h t he partici pa nt n u m ber. Pers o nal i de ntifiers, i ncl u di n g t he partici pa nt’s na me a n d i nitials, 
m ust be re m o ve d fr o m t h e i nstit uti o nal pat h ol o g y re p ort pri or t o s u b missi o n. Arc hi val bl oc ks 
will be secti o ne d. S p o ns or has a ri g ht t o ret ai n a p orti o n of t he s u b mitte d tiss ue, a n d arc hi val 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T
C CI
C CI
C CI
C CI

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 2 3  
bl oc ks ma y b e ret ur n e d t o t he st u d y site, u p o n re q uest. Tiss ue bl oc ks fr o m bi o psies c ollecte d at 
baseli ne  or diseas e pr o gressi o n ma y b e ret ur n e d t o sites if t here is a vaila bl e tiss ue left o ver, u p o n 
re q uest. 
T u m or D N A a n al ysis ( w h ole e x o me or pa nel D N A se q ue nci n g) m a y be perf or me d wit h patie nt -
matc he d ger mli ne D N A s u btracti o n. Ger mli ne D N A f or eac h p atie nt will ori gi na te fr o m D N A 
e xtracte d fr o m w h ole bl o o d as descri be d i n Secti o n  8. 8. 1. 3 . Re vie w of ger mli ne D N A 
se q ue nci n g res ults ma y b e c o n d ucte d, b ut o nl y f or data q ualit y c o ntr ol p ur p oses. At n o p oi nt i n 
t his pr ocess will ger mli ne D N A varia nts be a n al yzed a n d i nter prete d b y t h e researc h p ers o n nel. 
As s uc h, t u m or D N A a n al ysis wit h ger mli ne D N A s u btracti o n will n ot pr o d uce i nter preta ble 
res ults o n ger mli ne D N A, is n ot c o nsi dere d ge neti c researc h, a n d t heref ore, will n ot lea d t o t he 
i de ntificati o n of ge netic i nci de ntal fi n di n gs. Ge netic i nci de ntal fi n di n gs are variati o ns prese nt i n 
ger mli ne D N A t hat are disc o vere d u ni nte nti o nall y.  
T u m or D N A a n al ysis ( w h ole e x o me or pa n el D N A se q ue nci n g) m a y be perf or me d wit h o ut 
ger mli ne D N A s u btr acti o n. W he n a nal yze d t his w a y, it ma y b e c o nsi dere d ge n etic res earc h a n d 
t he i de ntificati o n of ge netic i nci de ntal fi n di n gs is p ossi ble. H o we ver, t h e met h o ds use d i n t his 
st u d y f or bi o mar ker a nal ys es are n ot cli nicall y v ali date d t o detect ger mli ne varia nts, a n d 
t heref ore, n o cli nical c o n cl usi o ns ca n be deri ve d fr o m t he m. As s uc h, n o ge netic fi n di n gs will be 
re p orte d t o t he p atie nts partici pati n g i n bi o mar k er researc h, s u bject t o l ocal re g ulati o ns. 
T u m or R N A se q ue nci n g a nal ys es q ua ntitate tiss ue m R N A e x pressi o n le vels, re p ort ge ne f usi o ns, 
s plice varia nts, a n d ot her s o matic rearra n ge me nts a n d d o n ot detect ger mli ne varia nts. T heref ore, 
t hese a nal yses are n ot c o nsi dere d ge n etic res earc h, a n d n o ge netic fi n di n gs will be i de ntifie d.  
8. 8. 1. 2.  
Pl as m a S a m ples f or Bi o m a r ker Rese arc h   
Plas ma sa m ples f or bi o mar ker researc h will be c ollecte d fr o m p artici pa nts as s pecifie d i n t he  
S c he d ule of A cti vities (Secti o n  1. 3 ), w here l ocal r e g ul ati o ns all o w. 
Plas ma sa m ples ma y als o be use d f or ct D N A a nal ys es. ct D N A a n al ysi s ma y be p erf or me d wit h 
patie nt -matc he d ger mli ne D N A s u btracti o n. Ger mli ne D N A f or eac h p atie nt will ori gi nate fr o m 
D N A e xtracte d fr o m w h ole bl o o d as descri be d i n Secti o n 8. 8. 1. 3 . Re vie w of ger mli ne D N A 
se q ue nci n g res ults ma y b e c o n d ucte d, b ut o nl y f or data q ualit y c o ntr ol  p ur p oses. At n o p oi nt i n 
t his pr ocess will ger mli ne D N A varia nts be a n al yze d a n d i nter prete d b y th e researc h p ers o n nel. 
As s uc h, ct D N A a nal ysis wit h ger mli ne D N A s u btracti o n will n ot  pr o d uce i nter preta bl e res ults 
o n ger mli ne D N A, is n ot c o nsi dere d ge netic researc h, a n d t heref ore,  will n ot lea d t o t he 
i de ntificati o n of ge netic i nci de ntal fi n di n gs. 
ct D NA a n al ysis ma y b e perf or me d wit h o ut ger mli ne D N A s u btracti o n. I n t his case, it ma y be 
c o nsi dere d ge netic researc h , a n d t he i de ntificati o n of ge netic i nci de nt al fi n di n gs is p ossi ble. 
Re gar dless of w h et her p artici pa nt -matc he d ger mli ne D N A s u btracti o n is use d  or n ot d uri n g t he 
ct D N A a n al ysis, t he met h o ds use d i n t his st u d y f or bi o mar ker a nal yses are n ot cli nicall y 
vali date d t o detect ger mli ne varia nts, a n d t h eref ore, n o cli nical c o ncl usi o ns ca n be d eri ve d fr o m 
t he m. As s uc h, n o ge neti cs fi n di n gs will be re p orte d t o t he patie nts partici p ati n g i n bi o mar ker 
researc h, s u bject t o l ocal re g ulati o ns. 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 2 4  
8. 8. 1. 3.  
W h ole  Bl o o d S a m ples  f or Bi o m a r ker Rese arc h  
A w h ole -bl o o d sa m ple f or bi o mar ker researc h will be c ollecte d fr o m all partici pa nts as s pecifie d 
i n t he Sc he d ule of A cti vit ies (Secti o n 1. 3 ), w here l ocal re g ulati o ns all o w. T his sa m ple ma y b e 
use d f or t he e xtracti o n of D N A t hat all o ws patie nt -matc he d ger mli ne D N A s u btracti o n d u ri n g 
t u m or D N A a nal ysis fr o m tiss ue ( Secti o n 8. 8. 1. 1 ) a n d ct D N A ( Secti o n 8. 8. 1. 2 ). 
8. 9.  Me dic al Res o urce Utiliz ati o n a n d He alt h Ec o n o mics   
Healt h ec o n o mics a n d me dical res o urce utilizati o n para meters will n ot be e val uate d i n t his st u d y.  
8. 1 0.  
Pr o d uct Acce pt a bilit y a n d P al at a bilit y  Assess me nts   
T he patie nt a n d/ or care gi ver will be as ke d t o pr o vi de res p o nses t o q uesti o ns desi g ne d t o assess 
t he acce pta bilit y a n d p alata bilit y of t he ta blet s wall o we d w h ole, disperse d i n f o o d or li q ui d, or 
dis perse d a n d a d mi nistere d t hr o u g h a nas o gastric or gastr ost o m y t u be ( K ozare wicz 2 0 1 4 ).  If t he 
patie nt is usi n g a be m acicli b oral gra n ules, t he pati e nt a n d/ or care gi ver will be as ke d t o pr o vi de 
res p o nses t o q uesti o ns desi g ne d to ass ess t he acce pta bilit y a n d palata bilit y of t he oral gra n ules 
s wall o we d w h ole, pla ce d i n f o o d or li q ui d, or dis perse d a n d a d mi nistere d t hr o u g h a nas o gastri c 
or gastr ost o m y t u be.  T h e q uesti o n naire f or ta blet or oral gra n ul e acce pta bilit y will assess t he  
s u bject’s a bilit y t o s wall o w t he dr u g pr o d uct as d esi g ne d.  T he q uesti o n naire f or acce pta bilit y 
a n d palata bilit y of t he ta blet or oral gra n ul es dis perse d i n f o o d or li q ui d will assess t he s u bject’s 
e x perie nce relati n g t o t he taste, a p peara n ce, s mell, m o ut hfeel, a n d aftertaste of t he dis persi o n a n d 
ease of pre pari n g a n d ta ki n g t he dis persi o n.  T h e q uesti o n naire f or acce pta bilit y of t h e ta blet or 
oral gra n ules dis perse d a n d a d mi nistere d t hr o u g h a nas o gastric or gastr ost o m y t u be will assess 
t he ease of pre p arati o n a n d a d mi nistrati o n of t he dis persi o n.  T he a p pr o priate q uesti o n naire will 
be a d mi nistere d at t he ti me of d osi n g or wit hi n a p pr o xi matel y 3 0 mi n utes after d osi n g at C ycle 1 
Da y 1, C ycle 1 Da y 1 5, a n d C ycle 2 Da y 1.  If a p atie nt c ha n ges t he m et h o d of a be macicli b 
a d mi nistrati o n or f or m ulati o n  (ta blets t o gra n ules or vice versa) at a n y p oi nt d uri n g t he trial, t he 
a p pr o priate q u esti o n naire c orres p o n di n g t o t he ne w a d mi nistrati o n met h o d or f or m ulati o n s h o ul d 
be c o m plete d at t he n e xt cli nic visit f oll o wi n g t he met h o d c ha n ge.  T h e q uesti o n naire will be 
c o m plete d b y care gi vers ( pr o x y) f or patie nts a ge d ≤5 years.  F or patie nts ≥6 years ol d t o < 1 2 
years ol d, b ot h patie nt a n d care gi ver will c o m plete t he q uesti o n nair es.  F or patie nts ≥1 2 years ol d, 
t he q uesti o n naire will be self -c o m plete d.  
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 2 5  
9.  
St atistic al C o nsi der ati o ns   
9. 1.  
St atistic al H y p ot heses   
P arts A a n d B  
Parts A a n d B of St u d y J P C S is desi g ne d t o e val u ate  
 t he P K, safet y, a n d t olera bilit y of a be macicli b i n c o m bi nati o n wit h iri n oteca n a n d 
te m oz ol o mi de (Part A ) a n d a be maci cli b i n c o m bi nati o n wit h te m oz ol o mi de (Part B ) 
i n pe diatric patie nts wit h rela pse d/r efract or y s oli d t u m ors t hat ha ve pr o gresse d o n  
sta n dar d treat me nt, 
 t he R P 2 D , a n d  
 preli mi nar y efficac y .  
Lill y h y p ot h esiz e s t hat a be macicli b i n c o m bi nati o n wit h te m oz ol o mi de a n d iri n oteca n ( Part A ), 
a be maci cli b i n c o m bi nati o n wit h te m oz ol o mi de ( Part B ) will be  s ufficie ntl y t olera ble wit h 
e vi de nce of cli nical a cti vit y t o s u p p ort f urt her de v el o p me nt.  
P art C  
Lill y h y p ot h esiz es t hat a be macicli b i n c o m bi nati o n wit h di n ut u xi ma b, G M -C S F, iri n oteca n, a n d 
te m oz ol o mi de ( Part C) will be s ufficie ntl y t olera bl e a n d ha v e s ufficie nt a nti-t u m or acti vit y. T h e 
dr u g c o m bi nati o n  will be assesse d b y e v al uati n g t he P K, safet y, a n d t olera bilit y of t h e dr u g 
c o m bi nati o n i n pe diatric a n d y o u n g a d ult  patie nts wit h rela pse d/refract or y ne ur o blast o ma.   
At t he sa me ti me, t he a nti -t u m or acti vit y is assess e d usi n g Si m o n’s o pti mal t w o-sta ge desi g n 
( Si m o n 1 9 8 9) , w here the n ull h y p ot hesis is t hat t he  o bjecti ve res p o nse rate ( O R R) 
 
 a n d 
t he alter nati ve h y p ot hesis is t hat t he O R R 
   
9. 2.  
S a m ple  Size Deter mi n ati o n   
A p pr o xi matel y 3 0  t o 1 1 7  patie nts will be e nr olle d i n t his P hase 1 b/ 2 st u d y, wit h 2 4  t o 6 0  i n Parts 
A a n d B  a n d 6 t o 5 7 i n Part C . T he sa m ple siz e f or Parts A a n d B is pri maril y  d eter mi ne d b y 
D L Ts ( u p t o 6 e val ua bl e patie nts at a d ose le vel  bef ore esta blis hi n g t he M T D) , w hile t he sa m ple 
siz e f or Part C de pe n ds o n b ot h D L Ts  a n d res p o ns es. T he ma xi m u m  sa m ple siz e of 5 7 i n Part C 
is deter mi ne d b y c o nsi deri n g d ose fi n di n g a n d e ns uri n g t hat 
 patie nts are treate d o n t he R P 2 D . 
T he sa m ple siz e of  
is deter mi ne d usi n g Si m o n’s o pti mal t w o -sta ge d esi g n wit h a p o wer of 
8 0 % a n d a o n e -si de d t y p e I err or rate of 0. 0 2 5 , gi ve n a n ull O R R of  
 a gai nst a n alter nati ve 
O R R of 
 ass u me d at t he R P2 D .   
9. 3.  
P o p ul ati o ns f or A n al yses   
F or p ur p os es of a n al ysis, t he f oll o wi n g p o p ulati o ns are defi ne d:  
P o p ul ati o n  
Descri pti o n  
E ntere d  
All partici pa nts w h o si g n i nf or me d c o nse nt/asse nt  (if a p plica ble) 
Treate d P atie nts  
(safet y p o p ulati o n) 
P atie nts w h o ha ve bee n assi g ne d t o st u d y treat me nt a n d ha ve recei ve d at least 1 
d ose of a n y st u d y treat me nt.  
Scree n Fail ures  
P atie nts or le gal g uar dia n (if a p plica ble) w h o ha ve si g ne d i nf or me d 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T
C CI
C CI
C CI
C CI
C CI
C CI

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 2 6  
c o nse nt/asse nt, d o n ot meet eli gi bilit y criteria or d ue t o A Es, p h ysicia n’s 
decisi o n, etc. a n d are n ot e nr olle d.  
Patie nts w h o wit h dra w fr o m t he st u d y bef ore recei vi n g st u d y dr u g(s) will be re place d a n d will  
n ot be i ncl u de d i n t he safet y or effi cac y assess me nts.  Safet y a nal yses will b e c o n d ucte d o n all  
patie nts w h o ha ve bee n e x p ose d t o st u d y dr u g, re gar dless of w h et her t he y are dee m e d e val u a ble  
f or ot her ass ess me nts.  I n Parts A, B, a n d Sta ge 1 of Part C, an y patie nt w h o is disc o nti n ue d fr o m 
t he st u d y bef ore c o m pleti n g 1 c ycle will be dee me d D L T n o n -e v al ua ble f or assess me nt of t he 
c o m bi nati o n  u nless  t he patie nt e x perie nces a D L T pri or t o wit h dra wal.  If a patie nt is 
n o nc o m plia nt d uri n g C ycle 1  or recei ves < 7 5 %  of d oses  d ue t o reas o ns ot her t ha n dr u g -relate d 
t o xicit y, he or s h e will be c o nsi dere d D L T n o n -e v al ua ble f or assess me nt of t he c o m bi nati o n a n d 
ma y  b e re pla ce d.  D L T n o n -e val ua ble p atie nts ma y be re place d t o e ns ure t hat e n o u g h patie nts 
c o m plete 1 c ycle u nless  accr ual t o t hat c o h ort has st o p pe d  d ue t o a D L T.  
9. 4.  
St atistic al A n al yses   
9. 4. 1.  
Ge ner al St atistic al C o nsi der ati o ns   
Statistical a nal ysis of t his st u d y will be t he res p o nsi bilit y of Lill y or its desi g nee .  T he a nal yses 
f or t his st u d y will be des cri pti ve, e x ce pt f or p ossi ble e x pl orat or y a nal ysis as dee me d a p pr o priat e.  
Data a n al ys es will be pr o vi de d b y st u d y part, d ose gr o u p, a n d f or all st u d y patie nts c o m bi ne d 
w he re v er a p pr o priate.  F or c o nti n u o us varia bles, s u m mar y statistics will i ncl u de n u m ber of 
patie nts, mea n, me dia n, sta n dar d de viati o n, mi ni m u m, a n d ma xi m u m.  Cate g orical vari a bles will 
be s u m mariz e d usi n g n u m ber of patie nts, fre q ue n c y, a n d perce nta ges.  Missi n g data will n ot be 
i m p ute d, e x ce pt f or missi n g dat e of birt h f or a nal ysis p ur p ose.  If birt h year a n d m o nt h is 
a vaila ble a n d d ate is n ot a vaila ble or missi n g, d ate will be i m p ute d t o t he 1 5t h of t hat m o nt h.  
Refer t o t he statistical a n al ysis pla n f or t his  st u d y f or f urt her detail. 
T he i nter pret ati o n of t he st u d y res ults will be t he res p o nsi bilit y of t h e i n vesti gat or wit h t he Lill y 
C R P/ C R S, p har mac o ki neticist, a n d statisticia n.  T he Lill y C R P/ C R S a n d statisticia n will als o be 
res p o nsi ble f or t he a p pr o priate c o n d uct of a n i nter nal re vie w f or b ot h t he fi nal st u d y re p ort a n d 
a n y st u d y-relate d m aterial t o be a ut h orize d b y Lill y f or p u blicati o n. 
A n y c ha n ge t o t he d ata a nal ysis met h o ds descri be d i n t he pr ot oc ol will re q uire a n a me n d m e nt 
O N L Y if it c ha n ges a pri nci pal feat ure of t he pr ot oc ol.  A n y ot h er c h a n ge t o t he data a n al ysis 
met h o ds descri be d i n t he pr ot oc ol, a n d t he j ustificati o n f or ma ki n g t he c ha n ge, will be descri b e d 
i n t he C S R .  A d diti o nal e x pl orat or y a nal yses of t he data will be co n d u cte d as dee me d 
a p pr o priate.  
9. 4. 2.  
A n al ysis P o p ul ati o n   
All e ntere d patie nts will be us e d i n s u m marizi n g patie nt dis p ositi o n.  All treate d patie nts (safet y 
p o p ulati o n) will be use d i n a nal yzi n g patie nt c haracteristics  a n d safet y a n d efficac y dat a.  
9. 4. 3.  
P a rtici p a nt  Dis p ositi o n   
A detaile d descri pti o n of partici pa nt dis p ositi o n will be pr o vi de d .  It will i ncl u de a s u m mar y of 
t he n u m ber a n d perce nta ge of patie nts e nteri n g t h e st u d y, tr eate d, reas o ns f or disc o nti n uati o n 
fr o m st u d y tr eat me nt, a n d reas o ns f or disc o nti n uati o n fr o m st u d y.  Reas o ns of disc o nti n uati o n 
fr o m st u d y tr eat me nt a n d st u d y will  be liste d .  
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 2 7  
All cli nicall y rele va nt pr ot oc ol de viati o ns will be liste d b y pre -deter mi ne d cate g ories ( e.g . 
i ncl usi o n/e x cl usi o n criteria, n o n-c o m plia nce wit h pr ot oc ol pr oce d ures, dr u g d osa ge/i nter ve nti o n, 
use of e x cl u de d treat me nts, i nf or me d c o nse nt/asse nt pr ocess, c o nti n ui n g aft er meeti n g 
wit h dra wal criteria, or ot her).  
9. 4. 4.  
P ati e nt  C h ar acteristics   
Patie nt c haracteristics will i ncl u de a s u m mar y of t he f oll o wi n g:  
 Patie nt de m o gra p hics  
 Baseli ne dise ase c haracteristics  
 Pri or disease -relate d t hera pies 
 C o nc o mita nt me d icati o ns 
Ot her patie nt c h aracteristics will be s u m marize d as dee me d a p pr o priate.  
9. 4. 5.  
S afet y A n al yses   
All patie nts w h o ha ve recei ve d at least 1 d ose of a n y st u d y treat me nt will be e va l uat e d f or safet y 
a n d t o xicit y.  
Safet y a nal yses will i ncl u de s u m maries of t he f oll o wi n g:  
 A d verse e ve nts , i ncl u di n g se v erit y a n d p ossi ble relati o ns hi p t o st u d y dr u g 
 D ose a dj ust me nts  
 Vital si g ns  
 D ose -li miti n g t o xicities  
 La b orat or y v al ues  
9. 4. 6.  
Effic ac y A n al yses   
T he st u d y w as n ot desi g n e d t o ma ke a n efficac y assess me nt  i n Parts A a n d B, 
 
 T h e f oll o wi n g efficac y 
meas ures  will be liste d a n d s u m mari z e d w here a p pr o priate.  
9. 4. 6. 1.  
P a rts A a n d B  Effic ac y A n al yses   
Parts A a n d B will  n ot ha ve  a f or m al effi cac y assess me nt. T he f oll o wi n g efficac y meas ures are 
i m p orta nt sec o n dar y e n d p oi nts meas ure d  usi n g R E CI S T v 1. 1  or  R A N O  criteria. 
O bjecti ve R es p o nse R ate ( O R R) :  T h e O R R  is t he perce nta ge of patie nts wit h a best res p o nse 
of c o m plete res p o nse [ C R] or partial res p o nse [ P R]   
D ur ati o n of Res p o nse ( D o R):  T he D o R is defi n e d o nl y f or res p o n d ers ( p atie nts wit h a C R or 
P R) .  It is meas ur e d fr o m t he date of first e vi de nce of a C R or P R t o t he date of o bjecti ve 
pr o gressi o n or t he d ate of deat h d ue t o a n y ca use, w hic he ver is earlier.  
Dise ase C o ntr ol R ate  ( D C R):  T he D C R is t he perce nt a ge of patie nts wit h a best res p o nse of 
C R, P R, or sta ble disease ( S D).  
Cli nic al Be nefit R ate ( C B R) :  T he C B R is t he perce nta ge of patie nts wit h a best res p o nse of C R 
or P R, or S D  f or at least 6 m o nt hs. 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T
C CI

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 2 8  
Pr o g ressi o n -free s ur vi v al ( P F S):  Pr o gressi o n -free s ur vi val is meas ure d  as t he ti me fr o m first 
d ose of a n y st u d y dr u g t o pr o gressi ve dise ase or deat h, w hic he v er occ urs first .  T he P F S rate will 
be calc ul ate d at a p pr o pri ate ti me i nter vals  (e.g . at 3 a n d 6 m o nt hs ).  
9. 4. 6. 2.  
P a rt  C  Effic ac y A n al yses   
I n Part C, the pri mar y efficac y me as ure is i n vesti gat or-assess e d t u m or res p o nse as defi ne d b y 
I N R C. T he pri mar y e n d p oi nt O R R  will be base d o n t he 2 0 1 7  I N R C (Par k  et al. 2 0 1 7 ) as 
descri be d i n Secti o n  9. 4. 6. 2. 1 . T he pri mar y a n al ysis of O R R will occ ur 6 c ycl es after last patie nt 
has e ntere d treat me nt, i n o r der t o e ns ure a d e q uate res p o nse a n d d ura bilit y of res p o nse data is 
a vaila ble at t he ti me of a nal ysis. T he p oi nt esti mate of O R R wit h a t w o -si de e x act 9 5 % 
c o nfi de nce i nter val will be pr o vi de d , a n d o n e-si d e d e x act p-val ue will be re p orte d.   
9. 4. 6. 2. 1.   2 0 1 7 I N R C   
F or Part C, efficac y will be e val uat e d  usi n g t he 2 0 1 7  I N R C (Par k  et al. 2 0 1 7 ).  
A res p o n der is defi ne d as a n y p atie nt w h o e x hi bits a C R , P R , or M R . 
T he res p o nse criteri a i nte grate t he res p o nse of all lesi o ns usi n g  C T/ M RI  a n d/ or  MI B G / F D G-P E T  
lesi o ns, a n d assess me nt of b o ne marr o w diseas e.  
Pri m ar y t u m o r  (s oft tiss ue) res p o nse is as f oll o ws: 
 C o m plete Res p o nse ( C R):  
o  < 1 0 m m resi d ual s oft tiss ue at pri mar y site A N D   
o  c o m plete res ol uti o n of MI B G -a vi d t u m ors or F D G-P E T u p ta ke (f or MI B G-
n o na vi d  t u m ors) at pri mar y site 
 Partial Res p o nse ( P R) :  
o  ≥3 0 % decrease i n l o n gest dia meter of pri mar y site  A N D  
o  MI B G -a vi d t u m ors or F D G -P E T u pta ke (f or MI B G -n o n a vi d t u m ors) at pri mar y 
site is sta ble, i m pr o ve d, or res ol ve d 
 Sta ble Disease ( S D) : N eit her P R n or P D at t he pri mar y site  
 Pr o gressi ve Diseas e ( P D) :  
o  > 2 0 % i ncrease i n l o n gest dia meter tak i n g as refere nce t he s mallest s u m w hile o n 
st u d y, i ncl u di n g b aseli ne s u m if t hat is t he s mallest, A N D  
o  mi ni m u m a bs ol ute i ncrease of 5 m m i n l o n gest di me nsi o n  
o  N ote:  a lesi o n t hat d oes n ot meet P D meas ure me nt criteria b ut has fl u ct uati n g 
MI B G a vi dit y will n ot be c o nsi dere d P D  
 
 
S oft tiss ue a n d b o ne met ast atic dise ase t u mo r res p o nse  is as f oll o ws: 
 C o m plete Res p o nse ( C R):  C o m plete res ol uti o n of all disease sites  defi ne d  as: 
o  n o n pri mar y tar get a n d n o ntar get lesi o ns < 1 0 m m A N D  
o  l y m p h n o des i de ntifie d as tar get lesi o ns decreas e t o a s h ort a xis < 1 0 m m A N D 
o  MI B G -a vi d  u p dat e or F D G -P E T u pta ke (f or MI B G-n o na vi d t u m ors)  of 
n o n pri mar y lesi o ns res ol ves c o m pletel y  
 Partial Res p o nse ( P R):    ≥3 0 % decrease i n s u m of dia meters a of n o n pri mar y tar get lesi o ns 
c o m pare d wit h bas eli ne A N D all of  t he f oll o wi n g: 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 2 9  
o  N o ntar get lesi o ns ma y be sta ble or  s maller i n size A N D 
o  ≥5 0 % re d ucti o n i n MI B G a bs ol ute b o ne sc ore ( relati ve MI B G b o ne sc ore ≥0. 1 t o 
≤0. 5) or ≥5 0 % re d u cti o n i n n u m ber of F D G -P E T -a vi d b o ne lesi o ns b , c A N D  
o  N o ne w lesi o ns  
 Pr o gressi ve Diseas e ( P D) : A n y of t h e f oll o wi n g:  
o  A n y n e w s oft tiss ue lesi o n detecte d b y C T/ M RI t hat is als o MI B G a vi d or F D G -
P E T a vi d  
o  A n y n e w s oft tiss ue lesi o n see n o n a nat o mic i ma gi n g t hat is  bi o psie d a n d 
c o nfir me d t o be n e ur o blast o ma or  ga n gli o ne ur o blast o ma  
o  A n y n e w b o ne site t hat is MI B G -a vi d  
o  A ne w b o ne site t hat is F D G -P E T a vi d (f or MI B G -n o na vi d  t u m ors) A N D has 
C T/ M RI fi n di n gs c o nsiste nt wit h t u m or O R  has bee n c o nfir me d hist ol o gicall y t o 
be ne ur o blast o ma or  ga n gli o ne ur o blast o ma  
o  > 2 0 % i ncrease i n l o n gest dia meter ta ki n g as refere nce t he  s mallest s u m o n st u d y 
(t his i nclu des t he baseli n e s u m if t hat  is t he s mallest o n st u d y) A N D mi ni m u m 
a bs ol ute i ncrease of  5 m m i n s u m of dia meters of tar get s oft tiss ue lesi o ns  
o  Relati ve MI B G s c ore ≥ 1. 2 c 
 Sta ble disease ( S D) : N eit her P R  n or  P D  of n o n pri mar y l esi o ns  
 
a S u m of dia meters is defi ne d as t he s u m of t he s h ort a xis of discrete l y m p h  n o des (ie, cer vic al, a xillar y n o des) 
a d de d t o t he s u m of t he l o n gest dia meters of  n o n – l y m p h n o d e s oft tiss ue metastases. Mass es of c o n gl o merate 
n o n discrete  l y m p h n o des will be meas ure d usi n g l o n gest dia meter.  
b F or patie nts wit h s oft tiss ue metastatic disease, res ol uti o n of MI B G a n d/ or F D G -P E T u pta ke at t he s oft tiss ue 
sites is n ot re q uire d; all size re d ucti o n criteria m ust be f ulfill e d.   
c  MI B G sc ori n g of b o ne lesi o ns  will c o nsist  of 9 sect ors (cra ni o-facial, cer vical a n d t h oraci c s pi ne, 
ri bs/ster n u m/cla vicles/sca p ula, l u m bar a n d sacral s pi ne, pel vis, u p per ar ms, l o wer ar ms a n d ha n ds, fe m urs, a n d 
l o wer le gs a n d feet). Eac h sect or will be sc ore d fr o m 0 -3 (0 = n o site s; 1 = 1 site; 2 = m ore t ha n 1 site; 3 = massi ve 
i n v ol ve me nt [ > 5 0 % of se g me nt]) usi n g t he C urie sc ori n g met h o d ( ma xi m u m a bs ol ute sc ore of 2 7). T he sc ore of 
eac h sect or will be c ollecte d i n t he C R F. Relati ve MI B G sc ore is t he a bs ol ute sc ore f or b o ne lesi o ns at ti me of 
res p o nse assess me nt  di vi de d b y t he a bs ol ute sc ore f or b o ne lesi o ns at baseli ne bef ore  t hera pe utic i nter ve nti o ns. 
T he sa me sc ori n g met h o d (e g, C urie) m ust be use d at all  ass ess me nt ti me p oi nts. MI B G si n gle -p h ot o n e missi o n 
c o m p ute d t o m o gra p h y ( S P E C T) or MI B G-S P E C T/ C T ma y be us e d f or sc ori n g p ur p oses, b ut t he sa me  i ma gi n g 
met h o d ol o g y s h o ul d be use d f or all e val uati o ns.   
 
B o ne m arr o w res p o nse  is deter mi ne d b y c yt ol o g y (rec o m me n d e d t o be acc o m pa nie d b y 
i m m u n oc yt ol o g y)/ hist ol o g y (acc o m p a nie d b y i m m u n o hist oc he mistr y [ B urc hill et al. 2 0 1 7 ]). Use 
t he b o ne marr o w sa m ple wit h t he hi g hest perce nt a ge of t u m or i nfiltrati o n t o assess res p o nse. 
Gra di n g is as f oll o ws:  
 C o m plete Marr o w Res p o nse:   N o t u m or i nfiltrati o n o n reassess me nt, i n de pe n de nt of 
baseli ne t u m or i n v ol ve me nt  
 Pr o gressi ve Marr o w Disease:   eit her  
o  b o ne marr o w wit h o ut t u m or i nfiltrati o n t hat bec o mes  > 5 % t u m or i nfiltrati o n o n 
reassess me nt, or  
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 3 0  
o  b o ne marr o w wit h t u m or i nfiltrati o n t hat i ncreases b y > 2 ti mes a n d h as > 2 0 % 
t u m or i nfiltrati o n o n reassess me nt  
 Mi ni mal Disease ( M D) : a n y of t he f oll o wi n g: 
o  ≤5 % t u m or i nfiltrati o n at baseli ne a n d re mai ns > 0 t o ≤5 %  t u m or i nfiltrati o n o n 
reassess me nt, or  
o  n o t u m or i nfiltrati o n at baseli ne a n d  ≤5 % t u m or i nfiltrati o n o n reassess me nt, or  
o  > 2 0 % t u m or i nfiltrati o n at baseli ne a n d  > 0 t o ≤5 % t u m or i nfiltrati o n o n 
reassess me nt 
 Sta ble Marr o w Dise ase :  Persiste nce of > 5 % t u m or i nfiltrati o n o n reassess me nt t hat d oes 
n ot meet t he criteria f or C R, M D,  or P D . 
 
O ver all res p o nse  is as f oll o ws: 
 C o m plete Res p o nse ( C R ): All c o m p o ne nts meet criteria f or C R  
 Partial Res p o nse ( P R):   
o  P R i n ≥1 c o m p o ne nt  A N D  
o  A L L ot h er c o m p o ne nts are eit her C R, M D  ( b o ne marr o w o nl y), P R (s oft tiss ue or 
b o ne), or NI  (site n ot i n v ol ve d at st u d y e ntr y re mai n u ni n v ol ve d)  A N D  
o  N o c o m p o ne nt wit h P D  
 Mi n or Res p o nse ( MR ):  
o  P R or C R i n ≥1  c o m p o ne nt A N D 
o  S D i n ≥1 c o m p o ne nt  A N D  
o  N o c o m p o ne nt  wit h P D  
 Sta ble disease ( S D) :  
o   S D i n ≥1 c o m p o ne nt  A N D  
o   N o better t ha n S D  or NI (site n ot i n v ol ve d at st u d y e ntr y a n d re mai ns 
u ni n v ol ve d)  A N D  
o  N o c o m p o ne nt wit h P D  
 Pr o gressi ve Diseas e ( P D):   A n y c o m p o n e nt wit h P D  
 
T he o verall res p o nse bas e d o n t he c o m bi ne d e v al uati o ns is s u m marize d i n t he ta ble bel o w. T he 
best res p o nse o bser ve d at a n y ti me p oi nt f or eac h i n di vi d ual patie nt will be c o nsi dere d t hat 
patie nt’s best o vera ll res p o nse o n t his st u d y. 
Pri m ar y 
t u m or 
S oft tiss ue or b o ne 
met ast atic dise ase  
B o ne m arr o w 
met ast atic dise ase  
O ver all 
res p o nse  
C R  
C R  
C R  
C R  
C R f or o ne cate g or y a n d C R or NI f or re mai ni n g cate g ories  
C R  
C R  
C R  
M D  
P R  
C R  
P R  
C R  
P R  
C R  
P R  
M D  
P R  
C R  
P R  
NI  
P R  
C R  
NI  
M D  
P R  
P R  
C R  
C R  
P R  
P R  
C R  
NI  
P R  
P R  
C R  
M D  
P R  
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 3 1  
Pri m ar y 
t u m or 
S oft tiss ue or b o ne 
met ast atic dise ase  
B o ne m arr o w 
met ast atic dise ase  
O ver all 
res p o nse  
P R  
P R  
C R  
P R  
P R  
P R  
NI  
P R  
P R  
P R  
M D  
P R  
P R  
NI  
C R  
P R  
P R  
NI  
NI  
P R  
P R  
NI  
M D  
P R  
NI  
C R  
M D  
P R  
NI  
P R  
C R  
P R  
NI  
P R  
M D  
P R  
C R  
C R  
S D  
M R  
C R  
P R  
S D  
M R  
C R  
S D  
C R  
M R  
C R  
S D  
M D  
M R  
C R  
S D  
S D  
M R  
C R  
S D  
NI  
M R  
C R  
NI  
S D  
M R  
P R  
C R  
S D  
M R  
P R  
P R  
S D  
M R  
P R  
S D  
C R  
M R  
P R  
S D  
M D  
M R  
P R  
S D  
S D  
M R  
P R  
S D  
NI  
M R  
P R  
NI  
S D  
M R  
S D  
C R  
C R  
M R  
S D  
C R  
M D  
M R  
S D  
C R  
S D  
M R  
S D  
C R  
NI  
M R  
S D  
P R  
C R  
M R  
S D  
P R  
M D  
M R  
S D  
P R  
S D  
M R  
S D  
P R  
NI  
M R  
S D  
S D  
C R  
M R  
S D  
NI  
C R  
M R  
NI  
C R  
S D  
M R  
NI  
P R  
S D  
M R  
NI  
S D  
C R  
M R  
S D  
S D  
M D  
S D  
NI  
S D  
M D  
S D  
S D  
NI  
M D  
S D  
NI  
NI  
M D  
S D  
S D  
S D  
S D  
S D  
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 3 2  
Pri m ar y 
t u m or 
S oft tiss ue or b o ne 
met ast atic dise ase  
B o ne m arr o w 
met ast atic dise ase  
O ver all 
res p o nse  
S D  
NI  
S D  
S D  
NI  
S D  
S D  
S D  
NI  
S D  
NI  
S D  
NI  
NI  
S D  
S D  
P D i n a n y si n gle cate g or y  
P D  
Res p o nse t hat is n ot e val ua ble f or a n y si n gle cate g or y t hat ha d 
meas ura ble or e val ua ble t u m or at baseli ne a n d n o P D f or a n y 
cate g or y 
N ot 
e v al u a ble  
Res p o nse e val uati o n n ot d o ne f or o ne or m ore cate g or y  
N ot d o ne  
A b bre viati o ns: C R = c o m plete res p o nse; M D = mi ni mal dise ase; M R  = mi n or res p o nse; NI = n ot i n v ol ve d  (site n ot 
i n v ol ve d at baseli ne  a n d re mai ns n ot i n v ol ve d); P D = pr o gressi ve disease; P R = partial res p o nse; S D = sta ble 
disease.  
9. 4. 7.  
P h ar m a c o ki netic/ P h ar m a c o d y n a mic A n al yses   
All patie nts w h o ha ve recei ve d at least  1  d ose of st u d y treat me nt a n d at least 1  p ost baseli ne 
e val ua ble P K sa m ple will be i ncl u de d i n t he P K a nal ysis p o p ulati o n.  
A be macicli b, iri n oteca n, a n d te m oz ol o mi de  c o nce ntrati o ns will be s u m marize d b y a nal y te usi n g  
descri pti ve statistics.  A d diti o nal a na l yses utilizi n g t he p o p ulati o n P K a p pr oac h ma y als o be 
c o n d ucte d if dee me d a p pr o priate.  Relati o ns hi ps bet wee n  e x p os ure a n d meas ures of efficac y a n d 
safet y ma y be e x pl ore d. 
9. 4. 8.  
S u b gr o u p A n al yses   
S u b gr o u p a n al ys es f or P K, effic ac y, a n d safet y will be perf or me d b y met h o d of a d mi nistrati o n 
( w h ole a d mi nistrati o n a n d alter nati ve a d mi nistrati o n) of st u d y dr u g w he n a p plica ble . 
9. 4. 9.  
Pr o d uct Acce pt a bilit y a n d P al at a bilit y   
Res p o nses fr o m t he dr u g pr o d uct  acce pta bilit y a n d palata bilit y q uesti o n nair es  f or ta blet a n d oral 
gra n ules  s wall o w e d w h ol e, dis perse d i n f o o d or li q ui d, or dis perse d a n d a d mi nistere d t hr o u g h a 
nas o gastric or gastr ost o m y t u be  will be s u m marize d cate g oricall y (fre q ue nc y a n d p erce nta ge) b y 
a ge gr o u p, f or eac h visit se parat el y a n d i n a g gre gate.  I n a d diti o n, ge ner al tre n ds  i n acce pta bilit y 
a n d palata bilit y fr o m C ycle 1 Da y 1 ( baseli ne), C ycl e 1 Da y 1 5, a n d C ycl e 2 Da y 1  will be 
a nal yze d.  
9. 4. 1 0.  
Bi o m ar ker A n al yses   
S o matic alterati o ns  relate d t o treat me nt, treat me nt mec ha nis m, a n d/ or ca ncer ma y  b e c ollecte d 
a n d re p ort e d.  I n a d diti o n, t he relati o ns hi p bet wee n s o matic alterati o ns a n d cli nical o utc o me ma y  
be assesse d.  
9. 5.  
I nteri m A n al yses  
D ata will be re vi e we d o n a c o h ort -b y -c o h ort basis d uri n g t he st u d y, u ntil t he M T Ds ( n ot t o 
e x cee d 1 1 5 m g/ m 2 BI D)  are det er mi ne d  f or Part s A  a n d B  or 
  T he p ur p ose of 
t hese re vie ws is t o e val uate t he safet y d ata at eac h d ose le vel a n d det er mi ne if a D L T has b ee n 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T
C CI

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 3 3  
o bser ve d t hat w o ul d s u g gest t he M T D f or eac h c o h ort has bee n met or e x cee d e d  i n t he d ose 
fi n di n g p orti o n .  T he i n v esti gat ors a n d Lill y st u d y tea m  will ma ke t he deter mi nati o n re gar di n g 
d ose escal ati o n base d u p o n t he re vie w of t he safet y a n d t olera bilit y d ata as descri be d i n t his 
pr ot oc ol.  
D uri n g t h e d ose -e x pa nsi o n  p orti o n of eac h st u d y part, i nteri m a nal yses ma y be c o n d ucte d t o 
re vie w a v aila ble safet y, P K, a n d effic ac y d ata.  
 
D M C will c o n d uct t he first 
i nteri m a nal ysis a p pr o xi matel y 2  m o nt h s ( or earli er if dee me d a p pr o priate) after Sta ge 1’s last 
patie nt  be gi ns C ycl e 1 . If a n y of t he f oll o wi n g st o p pi n g r ules are  met or a si g nifica nt s afet y 
si g nal is i de ntifie d, t he D M C ma y rec o m me n d ter mi nati o n of e nr oll me nt, a n d/ or ter mi nati o n of 
st u d y treatme nt.  
 R ule A: st o p f or t o xicit y if 
of t he D L T -e val u a ble patie nts e x perie nce D L T . 
 R ule B: st o p f or i nt olera bilit y if 
 p atie nts disc o nti n ue d ue t o a treat me nt-relate d 
A E bef ore c o m pleti n g  c ycles. 
 R ule C: st o p f or  i ns ufficie nt e vi de nce of a nti-t u m or acti vit y if 
 of t he 
 patie nts 
are res p o n ders (i.e., ha v e o bjecti ve t u m or res p o ns e, i ncl u di n g a best o verall res p o nse 
of c o m plete res p o nse [ C R] , partial res p o nse [ P R] or mi n or res p o nse [ M R] per I N R C) . 
If 5 5 m g/ m 2 is declare d t he M T D, b ut  eit her R ule A or B  is tri g gere d d uri n g  c o h ort e x pa nsi o n, 
t he D M C ma y rec o m me n d t hat s u bse q ue nt patie nts be treate d at 3 0 m g/ m 2. See Secti o n 4. 1. 2 . 
T he D M C will meet a n d re vie w t he o v erall safet y a n d effi cac y d ata a p pr o xi matel y e ver y 6 
m o nt hs t hereafter w hile patie nts re mai n i n t he st u d y. At t he rec o m me n d ati o n of t he D M C, t he 
fre q ue n c y of safet y i nteri m a nal ys es ma y be m o difie d. See  Secti o n 1 0. 1. 4  f or f urt her details.  
Ot her i nteri m a nal ysis m a y b e  a d d e d as dee me d a p pr o priate b y t he s p o ns or.  
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T
C CI
C CI
C CI
C CI
C CI
C CI

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 3 4  
1 0.  
S u p p orti n g D oc u me nt ati o n a n d O per ati o n al C o nsi der ati o ns   
1 0. 1.  
A p pe n di x 1 :  Re g ul at or y, Et hic al, a n d St u d y O versi g ht 
C o nsi der ati o ns   
1 0. 1. 1.  
Re g ul at or y a n d Et hic al C o nsi der ati o ns   
 T his st u d y will be c o n d u cte d i n acc or da n ce wit h t he pr ot oc ol a n d wit h t he f oll o wi n g:  
o  C o nse ns us et hical pri nci ples deri ve d fr o m i nter nati o nal g ui deli nes i ncl u di n g t he 
Declarati o n of Helsi n ki a n d C o u ncil f or I nter nati o nal Or ga nizati o ns of Me dical 
Scie nces I nter nati o nal Et hical G ui deli nes  
o  A p plica ble I nter nati o nal C o u ncil f or Har m o nisati o n (I C H) G C P G ui deli nes 
o  A p plica ble la ws a n d re g ulati o ns  
 T he pr ot oc ol, pr ot oc ol a me n d me nts, I C F, I B, a n d ot her rele va nt d oc u me nts (e .g . 
a d vertise me nts) m ust be s u b mitte d t o a n I R B/I E C b y t he i n vesti gat or a n d re vie we d a n d 
a p pr o ve d b y t he I R B/I E C bef ore t he st u d y is i nitiate d.  
 A n y a me n d me nts t o t he pr ot oc ol will re q uire I R B/I E C a p pr o val bef ore i m ple me ntati o n of 
c ha n ges ma d e t o t he st u d y des i g n, e x ce pt f or c ha n ges n ecess ar y t o eli mi nat e a n 
i m me diate hazar d t o st u d y partici pa nts. 
 Pr ot oc ols a n d a n y s u bsta ntial a me n d me nts t o t he pr ot oc ol will re q uire healt h a ut h orit y 
a p pr o val pri or t o i nitiati o n e x ce pt f or c ha n ges necessar y t o eli mi nate a n i m me d iate 
hazar d t o st u d y partici pa nts . 
 T he i n vesti gat or will be res p o nsi ble f or t he f oll o wi n g:  
o  Pr o vi di n g writte n s u m maries of t he stat us of t he st u d y t o t he I R B/I E C a n n uall y or 
m ore fre q u e ntl y i n acc or da nce wit h t he re q uire m e nts, p olicies, a n d pr oce d ures 
esta blis he d b y t h e I R B/I E C  
o  N otif yi n g t he I R B/I E C of S A Es or ot her si g nifica nt safet y fi n di n gs as re q uire d b y 
I R B/I E C pr oce d ures 
o  Pr o vi di n g o versi g ht of st u d y c o n d u ct f or p artici pa nts u n der t heir res p o nsi bilit y  
a n d a d here nce t o re q uir e me nts of 2 1 C F R, I C H g ui deli nes, t he I R B/I E C, 
E ur o pea n re g ulati o n 5 3 6/ 2 0 1 4 f or cli nical st u dies (if a p plica ble), a n d all ot her 
a p plica ble l ocal re g ulati o ns  
o  Re p orti n g t o t he s p o ns or or desi g nee si g nifica nt iss ues relate d t o partici pa nt 
safet y, partici p a nt ri g hts, or data i nte grit y. 
After rea di n g t he pr ot o c ol, eac h pri nci p al i n vesti gat or will si g n t he pr ot oc ol si g nat ure p a ge a n d 
se n d a c o p y of t h e si g n e d pa ge t o a Lill y re prese nt ati ve. 
T he C S R c o or di nati n g i n vesti gat or will si g n t he fi nal C S R f or t his st u d y, i n dicati n g a gree me nt 
that, t o t he best of his or her k n o wle d ge, t he re p ort acc uratel y descri bes t he c o n d uct a n d res ults 
of t he st u d y.  
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 3 5  
1 0. 1. 2.  
I nf or me d C o nse nt Pr ocess  
 
T he i n vesti gat or or his/ her re prese nt ati ve will e x plai n t he nat ure of t h e st u d y, i ncl u di n g 
t he ris ks a n d be nefits, t o t he partici pa nt or his/ her le gall y a ut h orize d re pres e ntati ve a n d 
a ns wer all q uesti o ns re gar di n g t he st u d y.  
 
Partici pa nts m ust be i nf or me d t hat t heir partici p ati o n is v ol u ntar y .  Partici p a nts or t heir 
le gall y a ut h orize d re pres e ntati ve ( defi ne d as t he p artici pa nt’s pare nt, g uar dia n, or le gal 
re pres e ntati ve) will be re q uire d t o si g n a stat e me nt of i nf or me d c o nse nt t hat meets t he 
re q uire me nts of 2 1 C F R 5 0, l ocal re g ulati o ns, I C H g ui deli nes, Healt h I ns ura nce 
P orta bilit y a n d Acc o u nta bilit y Act re q uir e me nts, w here a p plica ble, a n d t he I R B/I E C or 
st u d y ce nt er. 
 
T he me dical r ec or d m ust i ncl u de a state me nt t hat l e gall y a ut h orize d re prese ntati ve 
( pare nt/ g uar dia n) c o nse nt a n d c hil d/a dolesce nt ass e nt (if dee m e d a p pr o priat e b y l o cal 
et hics re vie w) was o btai n e d bef ore t he partici pa nt was e nr olle d i n t he st u d y a n d t he date 
t he writte n c o nse nt w as o btai ne d.  T he me dical rec or d s h o ul d als o descri be h o w t he 
cli nical i n vesti gat or d eter mi ne d t h at t he pers o n si g ni n g t he I C F was t he p artici pa nt’s 
le gall y a ut h orize d re pres e ntati ve ( pare nt/ g uar dia n).  T he a ut h orize d pers o n o btai ni n g 
t he i nf or me d c o nse nt m ust als o si g n t he I C F. 
 
Partici pa nts a n d, w he n a p plica ble, t heir le gall y a ut h orize d re prese nt ati v e 
( pare nt/ g uar dia n) m ust b e re-c o nse nte d t o t he m ost c urre nt versi o n of t he I C F(s) d uri n g 
t heir partici pati o n i n t he st u d y. 
 
Mi n or partici pa nts m ust be re -c o nse nte d if t h e y reac h t he a ge of maj orit y d uri n g t he 
c o urse of t he st u d y, i n or der t o c o nti n ue parti ci pati n g.  
 
A c o p y of t he I C F(s) m ust be pr o vi de d t o t he partici pa nt, t he partici pa nt’s l e gall y 
a ut h orize d re pres e ntati ve, or t he partici pa nt’s p are nt/ g uar dia n w he n a p plica ble.  
Partici pa nts w h o are rescree ne d a n d/ or t heir le gall y a ut h orize d re pres e ntati ve ar e re q uir e d t o si g n 
a ne w I C F a n d ass e nt, if a p plica ble . 
1 0. 1. 3.  
D at a Pr otecti o n   
 Partici pa nts will be assi g ne d a u ni q ue i de ntifier b y t he s p o ns or t o pr ot ect t he partici pa nt’s 
pers o nal dat a. A n y partici pa nt i nf or mati o n, s uc h as rec or ds, datasets or tiss ue sa m ples 
t hat are tr a nsferre d t o t he s p o ns or will c o ntai n t he i de ntifier o nl y. Partici pa nt na mes or 
a n y i nf or mati o n w hic h w o ul d ma ke t he partici pa nt i de ntifia ble will n ot be tra nsferre d.  
 T h e partici pa nt m ust be i nf or me d t hat t he partici pa nt’s pers o nal st u d y -relat e d data will be 
use d b y t h e s p o ns or i n acc or da nce wit h l ocal dat a pr otecti o n la w. T he l e vel of discl os ure 
m ust als o be e x plai ne d t o t he partici pa nt w h o will be re q uir e d t o gi v e c o nse nt f or t heir 
data t o be use d as d escri b e d i n t he i nf or me d c o ns e nt. T his is d o ne b y t he site pers o n nel 
t hr o u g h t he i nf or me d c o nse nt pr ocess. 
 T he partici pa nt m ust be i nf or me d t hr o u g h t he i nf or me d c o nse nt b y t he site pers o n nel t hat 
t heir me dical rec or ds ma y be e x a mi ne d b y Cli nical Q ualit y Ass ura nce a u dit ors or ot her 
a ut h orize d pers o n nel a p p oi nte d b y t he s p o ns or, b y a p pr o priate I R B/I E C me m bers, a n d b y 
i ns pect ors fr o m re g ulat or y a ut h orities. 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 3 6  
 T he s p o ns or has pr o cesses i n place t o e ns ure i nf or mati o n sec urit y, d ata  i nte grit y, a n d d ata 
pr otecti o n. T hese pr ocess es a d dress ma n a ge me nt of data tra nsfer, a n d pre v e nti o n a n d 
ma na ge me nt of u n a ut h oriz e d access, discl os ure, disse mi nati o n, alterati o n or l oss of 
i nf or mati o n or pers o nal d ata. T hese pr ocess es i ncl u de a p pr o pri ate co nti n ge nc y pl a n(s) f or 
a p pr o priate a n d ti mel y res p o nse i n t he e ve nt of a d ata sec urit y breac h.  
 T he tra nsf er of p ers o nal data is s u bject t o a p pr o priate safe g u ar ds t hr o u g h c o ntract ual 
a gree m e nts a n d pr ocesses. T he s p o ns or’s pr ocesses are c o m plia nt wit h l ocal  pri vac y la ws 
a n d rele v a nt le gislati o ns i ncl u di n g t he Ge neral Data Pr otecti o n Re g ul ati o n ( G D P R).  
1 0. 1. 4.  
C o m mittee Str uct ure   
I n Part C, after t he s afet y lea d-i n, interi m a nal yses f or saf et y a n d efficac y will be c o n d ucte d  
u n der t he g ui da nce of a n i n de pe n de nt D M C. T he D M C will c o nsist of at least 3 me m bers, 
i ncl u di n g a c hair, a p h ysi cia n, a n d a statisticia n. T he D M C will c o m m u nicate a n y 
rec o m me n dati o ns bas e d o n i nteri m a nal ysis t o t he S p o nsor. F urt her details o n t he me m bers, 
acti vities, a n d res p o nsi bilities of t he D M C ca n be f o u n d i n t he D M C c harter . 
 
1 0. 1. 5.  
Disse mi n ati o n of Cli nic al St u d y D at a   
Re p orts  
O n c o m pleti o n of t he res earc h, a re p ort or s u m mar y s h all be s u b mitte d t o re g ul at or y b o dies 
acc or di n g t o l ocal la w.  T he s p o ns or will discl ose a s u m mar y of st u d y i nf or mati o n, i ncl u di n g 
ta b ular st u d y res ults, o n p u blicl y a v aila ble we bsit es w here re q uir e d b y l ocal la w or re g ulati o n. 
D at a  
T he s p o ns or pr o vi des access t o all i n di vi d ual partici pa nt data c ollecte d d uri n g t he trial, after 
a n o n y mizati o n, e x ce pt  f or p har mac o ki netic a n d ge netic data.  
Data are a v aila ble t o re q uest 6 m o nt hs after t he i n dicati o n st u die d has bee n a p pr o ve d i n t he U S 
a n d E U a n d after pri mar y p u blicati o n acce pt a nce, w hic he ver is lat er. N o e x pirati o n date of dat a 
re q uests is c urre ntl y s et o nce data are m a de a v aila ble. 
Access is pr o vi de d after a pr o p osal has b ee n a p pr o ve d b y a n i n de pe n d e nt r e vie w c o m mittee 
i de ntifie d f or t his p ur p os e a n d aft er recei pt of a si g ne d d ata-s h ari n g a gree me nt. 
Data a n d d o c u me nts, i ncl u di n g t he st u d y pr ot oc ol, statistical a nal ysis pla n, cli nical st u d y re p ort, 
a n d bla n k or a n n otat e d case re p ort f or ms, will be pr o vi de d i n a sec ure dat a -s hari n g e n vir o n me nt 
f or u p t o 2 years per pr o p osal. 
F or details o n s u b mitti n g a re q uest, see t he i nstr ucti o ns pr o vi de d at w w w. vi vli. or g.  
1 0. 1. 6.  
D at a Q u alit y Ass ur a nce   
T o e ns ure acc urate, c o m plete, a n d relia bl e data, Lill y or its re prese ntati ve will d o t he f oll o wi n g:  
 pr o vi de i nstr ucti o nal material t o t he st u d y sites, as a p pr o priate  
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 3 7  
 pr o vi de s p o ns or start -u p trai ni n g t o i nstr uct t he i n vesti gat ors a n d st u d y c o or di nat ors.  
T his trai ni n g will gi v e  i nstr ucti o n o n t he pr ot oc ol, t he c o m pleti o n of t he C R Fs, a n d st u d y 
pr oce d ures.  
 ma ke peri o dic visits t o t he st u d y site  
 be a vaila ble f or c o ns ultati o n a n d sta y i n c o nt act wit h t he st u d y site p ers o n nel b y mail, 
tele p h o ne, a n d/ or fa x 
 re vie w a n d v erif y d ata re porte d t o detect p ote ntial err ors . 
I n a d diti o n, Lill y or its re prese ntati ve will peri o dicall y c h ec k a sa m ple of t h e partici pa nt dat a 
rec or de d a gai nst s o urce d oc u me nts at t he st u d y sit e.  T he st u d y ma y be a u dite d b y Lill y or its 
re pres e ntati ve a n d/ or re g ulat or y a ge nci es at a n y ti me.  I n v esti gat ors will be gi ve n n otice bef ore 
a n a u dit occ urs.  
T he i n vesti gat or will kee p rec or ds of all ori gi n al s o urce d ata.  T his mi g ht i ncl u de la b orat or y tests, 
me dical rec or ds, a n d cli nical n otes.  If re q ueste d, the i n vesti gat or will pr o vi de Lill y , a p plica ble 
re g ulat or y a ge ncies, a n d a p plica ble et hical re vie w b oar ds ( E R Bs) wit h direct access t o ori gi n al 
s o urce d oc u m e nts. 
D at a C a pt ure S yste m  
T he i n vesti gat or is res p o nsi ble f or e ns uri n g t he acc urac y, c o m plete ness, le gi bilit y, a n d ti meli ness 
of t he data re p orte d t o t h e s p o ns or.  
A n electr o nic data ca pt ure ( E D C) s yste m will be use d i n t his st u d y f or t he c ollecti o n of C R F data.  
T he i n vesti gat or mai ntai ns a se parate s o urce f or t he data e nt ere d b y t he i n vesti gat or or desi g nee 
i nt o t he s p o ns or-pr o vi de d E D C s yste m.  T he i n vesti gat or is res p o nsi ble f or t he i de ntificati o n of 
a n y d ata t o be c o nsi dere d s o urce a n d f or t he c o nfir mati o n t hat data re p orte d are acc urate a n d 
c o m plete b y si g ni n g t he C R F.  
A d diti o nall y, cli nical o ut c o me a ssess me nt ( C O A) data (e.g . s cales, self-re p orte d diar y dat a, 
rati n g s cales, taste a n d palata bilit y q uesti o n naire) will be c ollecte d b y t he partici pa nt/a ut h orize d 
st u d y pers o n n el, via a pa per s o urce d oc u me nt a n d will be tra nscri be d b y t h e a ut h orize d st u d y 
p ers o n nel site i nt o t he E D C s yste m/ via direct dat a ca pt ur e d i n t he E D C s yste m a n d will ser ve as 
t he s o urce d o c u me ntati o n. 
Data c ollecte d via t he s p o ns or -pr o vi de d dat a  ca pt ure s yste m(s) will be st or e d at t hir d -part y  
or ga niz ati o ns .  T he i n vesti gat or will ha ve  c o nti n u o us access t o t he data d uri n g t he st u d y a n d u ntil 
dec o m missi o ni n g of t he data ca pt ur e s yste m(s).  Pri or t o dec o m missi o ni n g, t he i n vesti gat or will 
recei v e a n arc hi val c o p y of perti ne nt data f or rete nti o n. 
Data ma na ge d b y a ce ntr al ve n d or, s uc h as la b orat or y test d ata, will be st ore d electr o ni call y i n 
t he ce ntral v e n d or’s d ata base s yste m a n d res ults will be pr o vi de d t o t he i n vesti gat or f or re vie w 
a n d rete nti o n.   Dat a will s u bse q ue ntl y b e tra nsferre d fr o m t he ce ntral ve n d or t o t he Lill y data 
ware h o us e.  
Data fr o m c o m plai nt f or ms s u b mitte d t o Lill y will be e nc o de d a n d st ore d i n t he gl o bal pr o d u ct 
c o m plai nt ma na ge me nt s yste m.  
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 3 8  
1 0. 1. 7.  
S o urce D oc u me nts   
 
S o urce d oc u me nts pr o vi d e e vi de nce f or  t h e e xiste nce of t he p artici pa nt a n d s u bsta ntiate 
t he i nte grit y of t h e data c ollecte d.  S o urce d o c u me nts are file d at t he i n v esti gat or’s site.  
 
Data re p orte d o n t he C R F or e ntere d i n t he e C R F t hat are tr a nscri be d fr o m s o urce 
d oc u me nts m ust be c o nsiste nt wi t h t he s o urce d oc u me nts or t he discre p a ncies m ust be 
e x plai ne d.  T he i n vesti gat or ma y n ee d t o r e q uest pre vi o us me dical r ec or ds or tra nsfer 
rec or ds, d e pe n di n g o n t h e st u d y.  Als o, c urre nt m e dical rec or ds m ust be a v aila ble.  
1 0. 1. 8.  
St u d y a n d Site Cl os ure   
1 0. 1. 8. 1.  Disc o nti n u ati o n of t he St u d y   
T he st u d y will be disc o nti n ue d if Lill y or its desi g nee  j u d ges it necessar y f or medical, safet y, 
re g ulat or y, or ot her reas o ns c o nsiste nt wit h a p plica ble la ws, re g ulati o ns, a n d G C P . 
1 0. 1. 8. 2.  Disc o nti n u ati o n of St u d y Sites   
St u d y site p artici pati o n ma y b e disc o nti n ue d  if Lill y or its desi g n ee , the i n vesti gat or, or t he E R B 
of t he st u d y site  j u d ges it necessar y f or me dical, s afet y, re g ulat or y, or ot her reas o ns c o nsiste nt 
wit h a p plica ble la ws, re g ulati o ns, a n d G C P.  
1 0. 1. 9.  
P u blic ati o n P olic y   
I n acc or da n ce wit h Lill y’s p u blicati o n p olic y, t he res ults of t his st u d y will be s u b mitte d f or 
p u blicati o n b y a p eer -re vie we d j o ur nal if t he res ults are dee me d t o be of si g nifica nt me dical 
i m p orta nce. 
 
 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 3 9  
1 0. 2.  
A p pe n di x 2 :  Cli nic al L a b or at or y Tests   
 
T he tests detaile d bel o w  will be perf or me d as i n dicate d i n t he ta ble s b el o w . Tests t o be 
perf or me d f or st u d y Parts A a n d B are prese nt e d i n o ne  ta ble, an d t he t ests t o be 
perf or me d i n Part C i n a sec o n d, se parate ta bl e.  
 
If t here is a n a b n or mal la b orat or y val ue or a b n or m al val ue f or a n y ot her dia g n ostic or 
scree ni n g test ( e.g . bl o o d press ure i ncreas e d, ne utr o p hils decreas e d) , t his s h o ul d be 
e ntere d i nt o t he C R F.  D o n ot e nter t he test a b n or malit y, e nter t h e dia g n osis or 
cate g orical ter m.  
 
Pr ot oc ol -s pecific re q uire me nts f or i ncl usi o n or e x cl usi o n of partici pa nts are detaile d i n 
Secti o n  5  of t he pr ot oc ol.  
 
A d diti o nal tests ma y be p erf or me d at a n y ti me d uri n g t he st u d y as d eter mi ne d necessar y 
b y t he i n vesti gat or or re q uire d b y l o cal r e g ulati o ns.  
 
L ocal la b orat or ies m ust be q uali fie d i n acc or da n ce wit h a p plica ble l ocal r e g ulati o ns. 
I n v esti gat ors m ust d oc u me nt t heir re vie w of t he l a b orat or y safet y res ults. 
 
 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 4 0  
Cli nic al L a b or at or y Tests  f or P arts A  a n d B  
He m at ol o g y:  l ocal or i n vesti gat or-desi g nate d la b orat or y  
He m o gl o bi n  
L y m p h oc ytes  
He mat ocrit  
M o n oc ytes  
Er yt hr oc yte c o u nt  
E osi n o p hils  
Le u k oc ytes  
Bas o p hils  
Ne utr o p hils, se g me nte d a n d ba n de d  
Platelets  
Cli nic al C he mistr y:  l ocal or i n vesti gat or-desi g nate d la b orat or y  
Ser u m C o nce ntr ati o ns of:  
S o di u m  
Al kali ne p h os p hatase  
P otassi u m  
Creati ni ne  
C hl ori de  
Calci u m  
Bicar b o nate  
Gl uc ose  
T otal bilir u bi n  
Al b u mi n  
Direct bilir u bi n  
T otal Pr otei n  
Ala ni ne a mi n otra nsferase  
Bl o o d urea nitr o ge n  ( B U N) or bl o o d urea 
As partate a mi n otra nsferase  
B eta -H C G *  
C S F C o nce ntr ati o ns of:  
B eta -H C G *  
C ystati n C  
Al p ha -fet o pr otei n*  
 
Al p ha -fet o pr otei n * 
Pre g n a nc y Test (f or fe male p atie nts of c hil d beari n g p ote nti al):  l ocal or i n vesti gat or-desi g nate d la b orat or y  
Ser u m pre g na nc y test  
Uri ne pre g na nc y test  
 
 
 
 
C S F c yt ol o g y *  
*If a p plica ble f or patie nts w h o ma y ha ve  p ositi ve t u m or mar kers or c yt ol o g y (d o ne if cli ni call y i n dicate d a n d 
feasi ble at baseli ne ) f or t u m or res p o nse.  See Secti o n 1. 3  f or m ore details. 
 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T
C CI
C CI
C CI
C CI

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 4 1  
Cli nic al L a b or at or y Tests f or P art C  
He m at ol o g y:  l ocal or i n vesti gat or-desi g nate d la b orat or y  
He m o gl o bi n  
L y m p h oc ytes  
Le u k oc ytes  
Platelets  
Ne utr o p hils, a bs ol ute ne utr o p hil c o u nt  
 
Cli nic al C he mistr y:  l ocal or i n vesti gat or-desi g nate d la b orat or y  
Ser u m C o nce ntr ati o ns of:  
S o di u m  
Al kali ne p h os p hatase  
P otassi u m  
Creati ni ne  
C hl ori de  
Calci u m  
Bicar b o nate  
Gl uc ose  
T otal bilir u bi n  
Al b u mi n  
Direct bilir u bi n  
T otal Pr otei n  
Ala ni ne a mi n otra nsferase  
Bl o o d urea nitr o ge n  ( B U N) or bl o o d urea 
As partate a mi n otra nsferase  
C ystati n C a 
P h os p h or us  
Ma g nesi u m  
A b bre vi ate d C he mistr y P a nel (electr ol ytes a n d creati ni ne): l ocal or i n vesti gat or-desi g nat e d la b orat or y  
Ser u m C o nce ntr ati o ns of:  
S o di u m  
Bicar b o nate  
P otassi u m  
Creati ni ne  
C hl ori de  
 
Pre g n a nc y Test (f or fe male p atie nts of c hil d beari n g p ote nti al):  l ocal or i n vesti gat or-desi g nate d la b orat or y  
Ser u m pre g na nc y  test 
Uri ne pre g na nc y test  
 
 
 
 
 
Pr ot hr o m bi n ti me  
a C ystati n C is o pti o nal . 
 
 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T
C CI
C CI
C CI
C CI

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 4 2  
1 0. 3.  
A p pe n di x 3 :  C o ntr ace pti ve G ui d a nce a n d C ollecti o n of Pre g n a nc y 
I nf or m ati o n  
Defi niti o ns:  
W o m a n of C hil d be ari n g P ote nti al ( W O C B P)  
A w o ma n is c o nsi dere d fertile f oll o wi n g m e narc h e a n d u ntil bec o mi n g p ost -me n o pa usal u nless 
per ma ne ntl y sterile (see bel o w).  
If fertilit y is u nclear (e.g . a me n orr hea i n a d oles ce nts or at hletes) a n d a me nstr ual c ycle ca n n ot be 
c o nfir me d bef ore first d ose of st u d y i nter ve nti o n, a d diti o nal e val uati o n s h o ul d be c o nsi dere d . 
W o me n i n t he f oll o wi n g cate g ories are n ot c o nsi dere d  W O C B P : 
1.  Pre me narc hal  
2.  F e male wit h 1 of t he f oll o wi n g:  
 
D oc u me nte d h ysterect o m y  
 
D oc u me nte d bilateral sal pi n gect o m y  
 
D oc u me nte d bilateral o o p h orect o m y  
 
F or i n di vi d uals wit h per ma ne nt i nfertilit y d ue t o a n alter nat e me dical ca us e ot her t ha n t he 
a b o ve (e.g . M ulleria n  a ge nesis, a n dr o ge n i nse nsiti vit y), i n vesti gat or discreti o n s h o ul d be 
a p plie d t o deter mi ni n g st u d y e ntr y. 
 
N ote:  D oc u me ntati o n ca n c o me fr o m t he site pers o n nel’s :  re vie w of t he partici pa nt’s 
me d ical rec or ds, me dic al e x a mi nati o n, or me dical hist or y i nter vie w. 
 
 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 4 3  
C o ntr ace pti o n G ui d a nce:  
C O N T R A C E P TI V E S a  A L L O W E D D U RI N G T H E S T U D Y I N C L U D E:  
Hi g hl y Effecti ve M et h o ds b  T h at H a ve L o w User De pe n de nc y  
 
I m pla nta ble pr o gest o ge n-o nl y h or m o ne c o ntrace pti o n ass oci ate d wit h i n hi biti o n of o v ulati o n c 
 
I ntra uteri ne de vice 
 
I ntra uteri ne h or m o ne-releasi n g s yste mc 
 
Bilateral t u bal occl usi o n  
 
Vasect o mize d part ner  
 
( V asect o mize d p art ner is a hi g hly effective c o ntr ace ptive met h o d pr ovi de d t h at t he p art ner is t he s ole sex u al 
p art ner of t he w o m a n of c hil d be ari n g p ote nti al a n d t he a bse nce of s per m h as bee n c o nfir me d.  If n ot, a n 
a d diti o n al hi g hly effective met h o d of c o ntr ace pti o n s h o ul d be use d.  S per m at o ge nesis cycle is a p pr oxi m ately 
9 0 d ays.)  
Hi g hl y Effecti ve M et h o ds b  T h at Are User De pe n de nt  
 
C o m bi ne d (estr 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 c 
o  
oral  
o  
i ntra va gi nal 
o  
tra ns der mal 
o  
i nj ecta ble 
 
Pr o gest o ge n -o nl y h or m o ne c o ntrace pti o n ass ociate d wit h i n hi biti o n of o v ulati o n c 
o  
oral  
o  
i nj ecta ble 
 
Se x ual a bsti ne nce  
( Sex u al a bsti ne n ce is c o nsi dere d a hi g hly effective met h o d o nly if defi ne d as refr ai ni n g fr o m heter osex u al 
i nterc o urse d uri n g t he e ntire peri o d of risk ass oci ate d wit h t he st u dy i nterve nti o n.  T he reli a bility of sex u al 
a bsti ne nce nee ds t o be ev al u ate d i n rel ati o n t o t he d ur ati o n of t he st u dy a n d t he preferre d a n d us u al lifestyle of 
t he p artici p a nt.) 
a) C o ntrace pti ve use b y me n or w o me n s h o ul d be c o nsiste nt wit h l ocal re g ulati o ns re gar di n g t he use of 
c o ntrace pti ve  met h o ds f or t h ose partici pati n g i n cli nical st u dies.  
b)  Fail ure rate of < 1 % per year w he n use d c o nsiste ntl y a n d c orrectl y.  T y pical use fail ure rates differ fr o m t h ose 
w he n use d c o nsiste ntl y a n d c orrectl y.  
c) Male c o n d o ms m ust b e use d i n a d diti o n t o h or m o nal c o ntra ce pti o n.  If l ocall y re q uire d, i n acc or da nce wit h 
Cli nical Trial Facilitati o n Gr o u p ( C T F G) g ui deli nes, acce pt a ble c o ntrace pti ve met h o ds are li mite d t o t h ose 
w hic h i n hi bit o v ulati o n as t he pri mar y m o de of acti o n.  
N ote:  P eri o dic a bsti ne nce (cal e n d ar, s y m pt ot her mal, p ost -o v ulati o n met h o ds), wit h dra wal (c oit us i nterr u pt us), 
s per mici des o nl y, a n d lactati o nal a me n orr h oea met h o d ( L A M) are n ot acce pta ble met h o ds of c o ntrace pti o n f or 
t his st u d y.  Male c o n d o m a n d fe male c o n d o m s h o ul d n ot be use d t o get her ( d ue t o ris k of fail ure wit h fricti o n)  
 
 
 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 4 4  
C ollecti o n of Pre g n a nc y I nf or m ati o n  
M ale p artici p a nts wi t h p art ners w h o bec o me pre g n a nt 
 
T he i n vesti gat or will atte m pt t o c ollect pre g na nc y i nf or mati o n o n a n y male partici pa nt’s 
fe male part ner w h o b ec o mes pre g na nt w hile t he male partici pa nt is i n t his st u d y.  T his 
a p plies o nl y t o male p artici pa nts w h o recei ve a be macicli b . 
 
After o btai ni n g t he n ecessar y si g n e d i nf or me d c o nse nt fr o m t he pre g n a nt fe male part ner 
directl y, t h e i n vesti gat or will rec or d pre g na nc y i nf or mati o n o n t he a p pr o pri ate f or m a n d 
s u b mit it t o t he s p o ns or wit hi n 2 4 h o urs of lear ni n g of t he part ner’s pre g n a nc y.   T he fe male 
part ner will als o be f oll o we d t o deter mi ne t he o ut c o me of t he pre g na n c y.   I nf or mati o n o n t he 
stat us of t he m ot her a n d c hil d will be f or war de d t o t he s p o ns or.  Ge nerall y, t he f oll o w -u p 
will be n o l o n ger t h a n 6 t o 8  wee ks f oll o wi n g t he esti mate d deli ver y date.  A n y ter mi nati o n 
of t he pre g n a nc y will be re p orte d re gar dless of fetal stat us ( prese n ce or a bs e nce of 
a n o malies) or i n dicati o n f or t he pr oce d ure.  
Fe m ale P a rtici p a nts w h o bec o me pre g n a nt  
 T he i n vesti gat or will c ollect pre g n a nc y i nf or m ati o n o n a n y fe male p artici pa nt w h o bec o mes 
pre g na nt w hile partici pati n g i n t his st u d y.  I nf or m ati o n will be rec or de d o n t he a p pr o priat e 
f or m a n d s u b mitte d t o t he s p o ns or wit hi n 2 4 h o urs of lear ni n g of a partici p a nt's pre g na n c y.   
 T he partici pa nt will be f oll o we d t o deter mi ne t he o utc o me of t he pre g na nc y.  T he 
i n vesti gat or will c ollect f oll o w-u p i nf or mati o n o n t he partici pa nt a n d t he ne o nate a n d t he 
i nf or mati o n will be f or war de d t o t he s p o ns or.  Ge nerall y, f oll o w -u p will n ot be re q uire d f or 
l o n ger t h a n 6 t o 8 wee ks be y o n d t h e esti mate d deli ver y d ate.  A n y ter mi nati o n of pre g na n c y 
will be re p orte d, re gar dless of fetal stat us ( prese nce or a bse n ce of a n o malies) or i n dicati o n 
f or t he pr oce d ure. 
 W hile pre g na n c y itself is n ot c o nsi dere d t o be a n A E or S A E, a n y pre g na n c y c o m plicati o n 
or electi v e ter mi nati o n of a pre g na n c y will be re p orte d as a n A E or S A E.  A s p o nta ne o us 
a b orti o n is al wa ys c o nsi d ere d t o be a n S A E a n d will be re p orte d as s uc h.  A n y p ost -st u d y 
pre g na nc y relat e d S A E c o nsi dere d reas o na bl y relate d t o t he st u d y i nter ve nti o n b y t he 
i n vesti gat or will be re p orte d t o t he s p o ns or as descri be d i n Secti o n 8. 3. 2 .  W hile t he 
i n vesti gat or is n ot o bli gate d t o acti vel y see k t his i nf or mati o n in f or mer st u d y partici pa nts, he 
or s he ma y lear n of a n S A E t hr o u g h s p o nt a ne o us re p orti n g.  
 A n y fe male p artici pa nt w h o bec o mes pre g na nt w hile partici pati n g i n t he st u d y will 
disc o nti n ue st u d y i nter ve nti o n a n d be wit h dra w n fr o m t he st u d y . 
 
 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 4 5  
1 0. 4.  A p pe n di x 4 :  Li ver  S afet y :  S u g geste d Acti o ns a n d F oll o w -u p 
Assess me nts   
Selecte d tests ma y be o bt ai ne d i n t he e ve nt of a treat me nt -e mer ge nt he patic a b n or malit y a n d ma y 
be re q uir e d i n f oll o w -u p wit h partici pa nts  i n c o ns ultati o n wit h t he Lill y C R P/ C R S  or Lill y’s 
desi g nee .  La bs will be assesse d b y l o cal or i n vesti gat or -desi g nate d la b orat or y.  
 
He m at ol o g y  
Cli nic al C he mistr y  
He m o gl o bi n  
T otal bilir u bi n  
He mat ocrit  
Direct bilir u bi n  
Er yt hr oc ytes ( R B Cs - re d bl o o d cells) 
Al kali ne p h os p hatase ( A L P)  
Le u k oc ytes ( W B Cs - w hite bl o o d cells)  
Ala ni ne a mi n otra nsferase ( A L T)  
Differe ntial:  
As partate a mi n otra nsferase ( A S T)  
    Ne utr o p hils, se g me nte d  
Ga m ma -gl uta m yl tra nsferase ( G G T)  
    L y m p h oc ytes  
Creati ne ki nase ( C K) 
    M o n oc ytes  
Ot her C he mistr y  
    B as o p hils  
Aceta mi n o p he n  
    E osi n o p hils  
Aceta mi n o p he n pr otei n a d d ucts  
Platelets  
Al kali ne p h os p hatase is oe nz y mes  
Cell m or p h ol o g y ( R B C a n d W B C)  
Cer ul o plas mi n  
C o a g ul ati o n  
C o p per  
Et h yl alc o h ol ( Et O H)  
Pr ot hr o m bi n ti me, I N R ( P T-I N R) 
Ha pt o gl o bi n  
Ser ol o g y  
I m m u n o gl o b uli n I g A ( q ua ntit ati ve) 
 
He p atitis A vir us ( H A V) testi n g:  
I m m u n o gl o b uli n I g G ( q ua ntit ati ve) 
    H A V t otal a nti b o d y  
I m m u n o gl o b uli n I g M ( q ua ntit ati ve) 
    H A V I g M a nti b o d y  
P h os p hati d ylet ha n ol ( P Et h)  
He p atis B vir us ( H B V) testi n g:  
Uri ne C he mistr y  
    He p atitis B s urface a nti ge n ( H Bs A g)  
Dr u g scree n  
    He p atitis B s urface a nti b o d y (a nti -H Bs)  
Et h yl gl uc ur o ni de ( Et G)  
    He p atitis B c ore t otal a nti b o d y (a nti -H B c)  
Ot her Ser ol o g y  
    He p atitis B c ore I g M a nti b o d y  
A nti -n uclear a nti b o d y ( A N A)  
    He p atitis B c ore I g G a nti b o d y  
A nti -s m o ot h m uscle a nti b o d y ( A S M A) a  
    H B V D N A  c  
A nti -acti n a nti b o d y b  
He p atis C vir us ( H C V) testi n g:  
E pstei n -Barr vir us ( E B V) testi n g:  
    H C V a nti b o d y  
    E B V a nti b o d y  
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 4 6  
    H C V R N A  c  
    E B V D N A  c 
He p atitis D vir us ( H D V) testi n g:  
C yt o me gal o vir us ( C M V) testi n g:  
    H D V a nti b o d y  
    C M V a nti b o d y  
He p atitis E vir us ( H E V) testi n g:  
    C M V D N A  c 
    H E V I g G a nti b o d y  
Her pes si m ple x vir us ( H S V) testi n g:  
    H E V I g M a nti b o d y  
    H S V ( T y pe 1 a n d 2) a nti b o d y  
    H E V R N A c  
    H S V ( T y pe 1 a n d 2) D N A  c 
Micr o bi ol o g y
 
Li ver ki d ne y micr os o mal t y pe 1 ( L K M -1) a nti b o d y  
C ult ure:  
 
    Bl o o d  
 
    Uri ne  
 
a N ot re q uire d if a nti -acti n a nti b o d y is teste d.  
b N ot re q uire d if a nti-s m o ot h m uscle a nti b o d y ( A S M A) is test e d. 
c Refle x/c o nfir mati o n de p e n de nt o n re g ulat or y re q uire me nts, testi n g a vaila bilit y, or b ot h.  
 
 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 4 7  
1 0. 5.  
A p pe n di x 5 :  Cre ati ni ne Cle ar a nce F or m ul a  
N ote:  T his f or m ula is t o be use d f or calc ulati n g creati ni ne cleara n ce ( Cr Cl) fr o m l oc al 
l a b or at or y res ults o nl y. 
Patie nts ≥1 8 years ol d  
C oc kcr oft -G a ult pre dicti o n of Cr Cl fr o m ser u m creati ni ne ( 1 9 7 6)  
F or ser u m creati ni ne c o n ce ntrati o n i n m g / d L: 
Cr Cl =  
( m L/ mi n) 
(1 4 0 –  a ge a )  (wt )  0. 8 5 (if fe male), or   1. 0 (if male) 
7 2   ser u m cre ati ni ne (m g/ d L ) 
 
F or ser u m creati ni ne c o n ce ntrati o n i n µ m ol/ L:  
Cr Cl =  
( m L/ mi n) 
 (1 4 0 –  a ge a )  (wt )  0. 8 5 (if fe male), or   1. 0 (if male) 
0. 8 1   ser u m cre ati ni ne (m ol/ L ) 
a A ge i n years, wei g ht ( wt) i n kil o gra ms.  
S o urce:  C oc kcr oft a n d G a ult 1 9 7 6.  
 
-O R - 
P atie nts < 1 8 years ol d.  
 
All Fe males a n d Pre -a d ol esce nt Males:  
C cr ( m L/ mi n/ 1. 7 3 m2) = 0. 5 5 x Hei g ht (c m)/ Scr ( m g/ d L) 
A d olesce nt Males:  
C cr ( m L/ mi n/ 1. 7 3 m2) = 0. 7 0 x Hei g ht (c m)/ Scr ( m g/ d L) 
 
N ote:  C cr = creati ni ne cl eara n ce a n d S cr = ser u m creati ni ne   
 
S o urce s:  Sc h wartz et al. 1 9 7 6; Sc h wartz a n d Ga ut hier 1 9 8 5. 
 
 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 4 8  
1 0. 6.  
A p pe n di x  6 :  I n d ucers a n d Str o n g I n hi bit ors of C Y P 3 A 4   
N ote : T he i nf or mati o n i n t his ta ble is pr o vi de d f or g ui da nce t o i n vesti gat ors. T his list is n ot 
i nte n de d t o be e x ha usti ve, b ut wit h a vaila ble i nf or mati o n c o nti n uall y e v ol vi n g, t he stat us of 
e ver y rele va nt dr u g ca n n ot be g u ara ntee d.  Please c o ns ult wit h t he me dical m o nit or i n case of a n y 
d o u bt a b o ut a p ote ntial dr u g -dr u g i nteracti o n.  
Str o n g I n d ucers of C Y P 3 A 4  
S peci al St at us  
A mi n o gl utet hi mi de  
A pal uta mi de  
Car ba maze pi ne  ( dail y d ose e xcee di n g 6 0 0 m g)  
E nzal uta mi de  
Ver y li mite d use. P ossi bl y a vaila ble i n E g y pt, Lit h ua nia  
 
 
F os p he n yt oi n (see als o p he n yt oi n)  
I v osi de ni b 
L u macaft or  
Mit ota ne  
P he n o bar bital  
 
P he n yt oi n  
 
Rifa b uti n  
Rifa m pici n (rifa m pi n)  
Rifa p e nti ne  
 
 
 
St J o h n’s w ort  
S u p ple me nt or f o o d/ dri n k  
 
M o der ate I n d ucers of C Y P 3 A 4  
 
B ose nta n  
C ar ba maze pi ne ( dail y d ose 6 0 0 m g or l o wer)  
Ce n o ba mate  
Da brafe ni b  
Da ns he n ( S alvi a milti orr hiz a ) 
Efa vire nz  
Ela g oli x  
E nc orafe ni b  
Etra viri ne  
Ge nistei n  
L o pi na vir (al o ne)  
L orlati ni b  
M o dafi nil  
Nafcilli n (i ntra ve n o us)  
P e nt o bar bital  
Pri mi d o ne  
S ot orasi b  
T hi ori dazi ne  
T ociliz u ma b (atliz u ma b)  
 
 
 
 
S u p ple me nt or f o o d/ dri n k  
 
 
P r o ba ble m o derate i n d ucer base d o n o bser ve d a ut oi n d ucti o n 
 
S u p ple me nt or f o o d/ dri n k  
 
 
 
Ver y li mite d use ; A vaila ble i n U S 
Ver y li mite d use 
 
 
Ver y li mite d use; a vaila ble i n U S; i m p orta ble i nt o U K  
N o n -tra diti o nal mec ha nis m: re verses t he I L-6 me diate d 
s u p pressi o n of C Y P 3 A acti vit y i n patie nts wit h r he u mat oi d 
art hritis  
 
 
Str o n g I n hi bit ors of C Y P 3 A 4  
 
Ataza na vir a n d c o bicistat  
B oce pre vir  
Ceriti ni b  
 
 
 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 4 9  
Clarit hr o m yci n  
C o bicistat (see ataza na vir a n d c o bicistat)  
C o ni va pta n  
Da n o pre vir a n d rit o na vir  
El vite gra vir a n d rit o na vir  
F osa m pre na vir a n d rit o na vir  
Gra p efr uit j uice  
I delalisi b 
I n di na vir a n d rit o na vir  
 
 
 
 
 
 
S u p ple me nt or f o o d/ dri n k  
 
 
Itrac o naz ole 
 
J osa m yci n 
Ket o c o naz ole  
O utsi de U S  
Ver y li mite d use  
L o nafar ni b  
L o pi na vir a n d rit o na vir  
Mife prist o ne  
Nefaz o d o ne  
Nelfi na vir  
N ir matrel vir a n d rit o na vir 
P osac o naz ole  
Ri b ocicli b  
Rit o na vir  
Sa q ui na vir a n d rit o na vir  
T elit hr o m yci n  
Ti pra na vir a n d rit o na vir 
T ucati ni b  
Vie kira x  ( parita pre vir a n d rit o na vir a n d 
o m bitas vir a n d/ or dasa b u vir)  
V oric o naz ole  
 
 
Ver y li mite d use; C us hi n g’s disease i n U S  
Ver y li mite d use; A vaila ble i n U S  
 
 
 
 
 
 
 
 
 
O utsi de of U S  
 
 
 
 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 5 0  
1 0. 7.  
A p pe n di x 7: Pr o visi o ns f or C h a n ges i n St u d y C o n d uct D uri n g 
E xce pti o n al Circ u mst a nces   
I m ple me nt ati o n of t his a p pe n di x 
T he c ha n ges t o pr oce d ures descri be d i n t his a p p e n di x are te m p orar y meas ures i nte n de d t o be 
use d o nl y d uri n g s p ecific ti me peri o ds as direct e d b y t he s p o ns or i n p art ners hi p wit h t he 
i n vesti gat or. 
E xce pti o n al circ u mst a nces  
E x ce pti o nal circ u msta nces are rare e v e nts  t hat ma y ca use disr u pti o ns t o t he c o n d uct of t he st u d y. 
E x a m ples i ncl u de pa n de mics or nat ural disasters.  T hese disr u pti o ns ma y li mit t he a bilit y of t h e 
i n vesti gat ors, partici pa nts, or b ot h t o atte n d o n-site visits or t o c o n d uct pla n ne d st u d y pr oce d ures. 
I m ple me nti n g c h a n ges u n der e xce pti o n al circ u mst a nces  
I n a n e x ce pti o nal circ u msta nce, after recei vi n g t h e s p o ns or’s writte n a p pr o val, sites ma y 
i m ple me nt c ha n ges if per mitte d b y l ocal r e g ulati o ns.  
Et hical Re vie w B o ar ds ( E R Bs), re g ul at or y b o dies a n d a n y ot h er rele va nt l ocal a ut h orities, as 
re q uire d, will be n otifie d as earl y as p ossi ble t o c o m m u nicate i m ple me ntati o n of c ha n ges i n 
st u d y c o n d u ct d ue t o e x ce pti o nal circ u msta nces.  T o pr otect t he safet y of st u d y partici p a nts, 
ur ge nt c ha n ges ma y be i m ple me nte d be f ore s uc h c o m m u nicati o ns are ma de, b ut all c ha n ges will 
be re p ort e d as s o o n as p ossi ble f oll o wi n g i m ple me ntati o n.  If a p pr o val of E R Bs, re g ulat or y 
b o dies, or b ot h is re q uire d per l ocal r e g ulati o ns, c o nfir mati o n of t his a p pr o val will be retai ne d i n 
t he st u dy rec or ds.  
I n t he e ve nt writte n a p pr o val is gra nte d b y t he s p o ns or f or c h a n ges i n st u d y c o n d u ct, a d diti o nal 
writte n g ui da n ce, if n ee d e d, will be pr o vi de d b y t he s p o ns or.  
I n e x ce pti o nal circ u msta nces, t he fle xi bilit y meas ures o utli ne d i n t he S o A ( Secti o n 1. 3 ) a n d t his 
a p pe n di x  ma y be c o nsi dere d f or t he f oll o wi n g visits  after c o ns ultati o n wit h a n d pri or a p pr o val b y 
t he s p o ns or: 
 P art A:  Visits  8 a n d 1 5 of C ycl es 1 a n d 2 , s h ort-t er m f oll o w-u p  
 P art B:  All visits i n C ycles 1 a n d 2, a n d Da y 1 of c ycles wit h i ma gi n g pr oce d ures , s h ort-
ter m f oll o w-u p  
1 0. 7. 1.  
I nf or me d C o nse nt  
A d diti o nal c o nse nt/asse nt fr o m t he partici pa nt will be o btai ne d, as re q uire d b y E R B’s a n d l ocal 
re g ulati o ns.  Asse nt will als o be o btai ne d t o t he sa me para met ers, wit h c o ns e nt f or partici p a nts 
reac hi n g t he l e gal a ge f or c o nse nt d uri n g t he trial f or c o nti n ue d partici pati o n, f or:  
 partici pati o n i n re m ote visits, as defi ne d bel o w i n Secti o n 1 0. 7. 2. 1 , 
 alter nate d eli ver y of st u d y i nter ve nti o n a n d a ncillar y s u p plies, a n d   
 pr o visi o n of t heir pers o n al or me dical i nf or m ati o n re q uire d pri or t o i m ple me ntati o n of 
t hese acti vities. 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 5 1  
1 0. 7. 2.  
C h a n ges i n St u d y C o n d uct   
C ha n ges i n st u d y c o n d u ct n ot descri be d i n t his a p pe n di x , or n ot c o nsiste nt wit h a p plica ble l ocal 
re g ulati o ns, are n ot all o we d. 
T he f oll o wi n g c ha n ges i n h o w st u d y c o n d u ct will be perf or me d (e. g. virt ual vs at t he 
i n vesti gati ve site) will n ot be c o nsi dere d pr ot oc ol de viati o ns.  E ver y eff ort s h o ul d be ma de f or 
t he partici pa nt t o ret ur n t o o n-site visits as s o o n as reas o na bl y p ossi ble, w hile e ns uri n g t he safet y 
of t he partici pa nt a n d i n vesti gati o nal site staff.  
1 0. 7. 2. 1.  Re m ote Visits   
I n s o urce d o c u me nts a n d t he C R F, t he st u d y site s h o ul d ca pt ure t he met h o d, wit h a s pecific 
e x pla nati o n f or a n y data missi n g beca us e of misse d i n -pers o n site visits.   Re m ote visits will 
i ncl u de a c o m bi nati o n of tele me dici ne a n d m o bile healt hcare  as a p pr o priate, acc or di n g t o t he 
i n vesti gat or’s discreti o n a n d writte n a p pr o val b y t he s p o ns or. 
A ssess me nts ma y b e c o m plete d b y a c o m bi nati o n of vi de o c o nfere n ce (t ele me dici ne) a n d m a y  
als o i ncl u de m o bile  healt hcare  f or t he f oll o wi n g visits: 
 P art A:   Visits 8 a n d 1 5 of C ycl es 1 a n d 2 , s h ort-t er m f oll o w-u p  
 P art B:  All visits i n C ycles 1 a n d 2, a n d Da y 1 of c ycles wit h i ma gi n g pr oce d ures , s h ort-
ter m f oll o w-u p . 
A p plica ble a ssess me nts i ncl u de p h ysical e xa m a n d wei g ht, vital si g ns, 
 
 perf or ma nce stat us, q uesti o n naires, re vie w of patie nt diar y, i ma gi n g (see hea di n g 
bel o w), P K (see hea di n g bel o w), A E c ollecti o n a n d gra di n g, a n d c o n c o mita nt me dicati o n 
rec or din g.  Ot h er ass ess me nts (s uc h as a p plica ble bl o o d dra ws a n d pre g n a nc y tests) ma y be 
c o m plete d re m otel y acc or di n g t o l ocal re g ulati o ns b y a m o bile  h ealt hcare s er vice or at a l ocal 
cli nic wit h o ut vi de o c o nfere nce at t he i n vesti gat or’s discreti o n.   If t here is a c o ncer n d uri n g t he 
re m ote visit, t he partici pa nt s h o ul d ha ve a n o n-site f oll o w-u p visit as s o o n as p ossi ble.  
Tele me dici ne:  Tec h n ol o g y -assiste d virt ual visits, i ncl u di n g vi de o, t o c o m plete a p pr o pri ate 
st u d y assess me nts are acce pta ble.  
M o bile  he alt hc are:   H ealt hcare visits ma y b e perf or me d at l ocati o ns ot her t ha n t he st u d y site 
(f or e x a m ple, partici pa nt’s h o me) w he n p artici pa nts ca n n ot tra vel t o t he site d ue t o a n 
e x ce pti o nal circ u msta nce .  S uc h visits will be perf or me d b y a m o bile healt h care pr o vi der trai ne d 
o n t he st u d y.  
L oc al I m a gi n g:   I n e x ce pti o nal circ u msta nces, i ma gi n g pr oce d ures re q uire d d uri n g scree ni n g, 
o n -st u d y tr eat me nt, or f oll o w u p ma y b e perf or me d l ocall y at a n alter nate l ocati o n t ha n t he st u d y 
site or desi g n ate d facilit y.  I ma gi n g facilit y, i ma ge ac q uisiti o n pr ot oc ol, a n d i ma gi n g m o dalit y  
s h o ul d be c o nsiste nt f or all visits f or a gi ve n patie nt.  A differe nt facilit y ma y be utilize d after 
recei vi n g a p pr o val fr o m t he s p o ns or.  T he sa m e i ma ge ac q uisiti o n pr ot oc ol a n d i ma gi n g 
m o dali t y m ust re mai n t he sa me acr oss facilities.  
Re gar dless of t he t y pe of re m ote visits i m ple me nte d, t he pr ot oc ol re q uire m e nts f or re p orti n g of 
a d verse e ve nts ( A Es), seri o us a d verse e ve nts ( S A Es), a n d pr o d uct c o m plai nts as o utli ne d i n 
Pr ot oc ol J P C S re mai n u nc ha n ge d.  F urt her m ore, e ver y eff ort s h o ul d be ma de t o e na ble 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T
C CI

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 5 2  
partici pa nts t o ret ur n t o o n -site visits as s o o n as reas o na bl y p ossi ble, w hile e ns uri n g t h e safet y of 
b ot h t he partici pa nts a n d t he site staff.  
P h ar m a c o ki netics  
If i n e x ce pti o nal circ u msta nces a p atie nt is u na ble t o be o n -site f or te m oz ol o mi de or iri n oteca n 
P K sa m pli n g, o nl y a be m acicli b P K sa m ples s h o ul d be c ollecte d re m otel y a n d t he 
te m oz ol o mi de/iri n oteca n sa m ples s h o ul d be rec or de d as n ot c ollecte d o n t h e re q uisiti o n f or m b y 
t he n urse. 
1 0. 7. 2. 2.  St u d y I nt er ve nti o n a n d A ncill ar y S u p plies (I ncl u di n g P artici p a nt Di aries)   
W he n a  partici pa nt is u na ble t o g o t o t he site t o recei ve st u d y s u p plies d uri n g n or mal o n -site 
visits, t he site s h o ul d w or k wit h t he s p o ns or t o deter mi ne a p pr o priate acti o ns.  T hese acti o ns 
ma y i ncl u d e:   
 as ki n g t he p artici pa nt or desi g nee t o g o t o t he site a n d recei ve st u d y s u p plies fr o m site 
staff wit h o ut c o m pleti o n of a f ull st u d y visit,  
 arra n gi n g d eli ver y of st u d y s u p plies, a n d  
 w or ki n g wit h t he s p o ns or t o deter mi ne h o w st u d y i nter ve nti o n t hat is t y picall y 
a d mi nistere d o n site will be a d mi nistere d t o t he partici pa nt; f or e x a m ple, d uri n g a 
m o bile healt hcare visit.  
T hese re q uire me nts m ust be met bef ore acti o n is ta k e n:  
 Alter nate deli ver y of a b e macicli b a n d te m oz ol o mi de  s h o ul d be perf or me d i n a 
ma n ner t hat d oes n ot c o m pr o mise pr o d uct i nte grit y.   T he e xisti n g pr ot oc ol 
re q uire me nts f or pr o d uct acc o u nta bilit y re mai n u n c ha n ge d, i ncl u di n g verifi cati o n of 
partici pa nt’s r ece i pt of st u d y s u p plies. 
 W he n deli veri n g s u p plies t o a l ocati o n ot her t ha n t he st u d y site (f or e x a m ple, 
partici pa nt’s h o me), t h e i n vesti gat or, s p o ns or, or b ot h s h o ul d e ns ure o versi g ht of t he 
s hi p pi n g pr ocess t o e ns ur e acc o u nta bilit y a n d pr o d uct q ualit y (t hat is, st ora ge 
c o n diti o ns mai ntai ne d a n d i ntact pac ka gi n g u p o n recei pt).  
 I nstr u cti o ns ma y b e pr o vi de d t o t he partici pa nt or desi g nee o n t he fi n al dis p ositi o n of 
a n y u n us e d or c o m plet e d st u d y s u p plies . 
I n a d diti o n, if st u d y i nter ve nti o n will be a d mi nistere d to t he partici p a nt d uri n g a m o bile 
healt hcare visit or at a n alter nate l ocati o n, t his a d diti o nal re q uire me nt m ust be met:  
O nl y a ut h orize d pers o n n el ma y s u p pl y  st u d y i nter ve nti o n. See Secti o n 6. 2 . 
1 0. 7. 2. 3.  Scree ni n g Peri o d G ui d a nce   
If t he scree ni n g peri o d lasts f or m ore t ha n 3 5 da ys d ue t o e xce pti o nal circ u msta nces , the 
partici pa nt m ust be disc o nti n ue d beca use of scree ni n g i nterr u pti o n d ue t o a n e x ce pti o nal 
circ u msta nce.   T his is d oc u me nte d as a s cree n fail i n t he C R F.   T his scree n fail  d ue t o a n 
e x ce pti o nal circ u msta nce  is all o we d i n a d diti o n t o t he mai n pr ot oc ol scree n fail.  T he p artici p a nt 
ca n rec o nse nt a n d b e res cree ne d as a n e w partici p a nt wit h a ne w partici pa nt n u m ber.  
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 5 3  
A n y s cree ni n g pr oce d ures t hat fall o utsi de of t he re q uire d wi n d o ws per t he J P C S Pr ot oc ol 
Sc he d ule of Scree ni n g A cti vities ( Pr ot oc ol Secti o n 1. 3 ) m ust be re peate d. 
1 0. 7. 3.  
D oc u me nt ati o n   
1 0. 7. 3. 1.  D oc u me nt ati o n of C h a n ges i n St u d y C o n d uct   
C ha n ges t o st u d y c o n d u ct will be d oc u me nte d:  
 Sites will i de ntif y a n d d o c u me nt t he details of h o w partici pa nts, visit t y pes, a n d 
c o n d ucte d acti vities were affecte d b y e x ce pti o nal  circ u msta nces. 
Dis pe nsi n g/s hi p me nt rec or ds of st u d y i nter ve nti o n a n d rele va nt c o m m u nicati o ns, 
i ncl u di n g dele gati o n, s h o ul d be file d wit h site st u d y rec or ds. 
 S o urce d oc u me nts ge n erate d at a l ocati o n ot her t h a n t he st u d y site s h o ul d b e part of 
t he i n vesti gat or’s s o urce d oc u me ntati o n a n d s h o ul d be tra nsferre d t o t he sit e i n a 
sec ure a n d ti mel y m a n ner. 
 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 5 4  
1 0. 8.  
A p pe n di x 8: A be m acicli b D osi n g C h art s  
 
P arts A a n d B:  
 
B S A R a n ges ( m 2) f or e a c h D ose Le vel  
D ose ( BI D)  
5 5 m g/ m 2 
7 0 m g/ m 2 
9 0 m g/ m 2 
1 1 5 m g/ m 2 
2 5 m g  
0 . 5 0-0. 6 8  
0. 5 0 -0. 5 3  
 
 
5 0 m g  
0. 6 9 -1. 1 3  
0. 5 4 -0. 8 9  
0. 5 0 -0. 6 9  
0. 5 0 -0. 5 4  
7 5 m g  
1. 1 4 -1. 5 9  
0. 9 0 -1. 2 4  
0. 7 0 -0. 9 7  
0. 5 5 -0. 7 6  
1 0 0 m g  
1. 6 0 -2. 0 4  
1. 2 5 -1. 6 0  
0. 9 8 -1. 2 4  
0. 7 7 -0. 9 7  
1 2 5 m g  
2. 0 5 -2. 4 9  
1. 6 1 -1. 9 6  
1. 2 5 -1. 5 2  
0. 9 8 -1. 1 9  
1 5 0 m g  
2. 5 0 +  
1. 9 7 +  
1. 5 3 +  
1. 2 0 +  
A b bre viati o ns: BI D = t wice dail y; B S A = b o d y s urface area . 
 
 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 5 5  
P art C:  
 
B S A R a n ges ( m 2) f or e a c h D ose Le vel 
D ose ( BI D)  
3 0 m g/ m 2  
5 5 m g/ m 2  
1 0 m g  
0. 3 0 -0. 3 7 a 
0. 2 0  
1 2. 5 m g  
0. 3 8 -0. 4 5  
0. 2 1 -0. 2 4  
1 5 m g  
0. 4 6 -0. 5 4  
0. 2 5 -0. 2 9  
1 7. 5 m g  
0. 5 5 -0. 6 2  
0. 3 0 -0. 3 4  
2 0 m g  
0. 6 3 -0. 7 0  
0. 3 5 -0. 3 8  
2 2. 5 m g  
0. 7 1 -0. 7 9  
0. 3 9 -0. 4 3  
2 5 m g  
0. 8 0 -1. 2 4  
0. 4 4 -0. 6 8  
5 0 m g  
1. 2 5 -2. 0 8  
0. 6 9 -1. 1 3  
7 5 m g  
2 .0 9 -2. 9 1  
1. 1 4 -1. 5 9  
1 0 0 m g  
2. 9 2 +  
1. 6 0 +  
A b bre viati o ns: BI D = t wice dail y; B S A = b o d y s urface area.  
a At t he 3 0 m g/ m 2 d ose, patie nts m ust b e ≥0. 3 m 2 as a s maller B S A w o ul d re q uire a d os e t hat e xcee d s t heir 
calc ulate d d ose b y > 1 0 % .  
 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 5 6  
A be m acicli b Or al Gr a n ules D osi n g C h art  
D ose ( m g)  
De vice Setti n g  
# Ti mes t o Dis pe nse  
# Gr a n ules per d ose  
1 0  
4  
1  
4  
1 2. 5  
5  
1  
5  
1 5  
6  
1  
6  
1 7. 5  
7  
1  
7  
2 0  
8  
1  
8  
2 2. 5  
9  
1  
9  
2 5  
1 0  
1  
1 0  
5 0  
2 0  
1  
2 0  
7 5  
1 5  
2  
3 0  
1 0 0  
2 0  
2  
4 0  
 
 
 
 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 5 7  
1 0. 9.  
A p pe n di x 9 : C o u ntr y -S pecific Re q uire me nts   
T he c o u ntr y -s p ecific a d d e n du m  prese nte d i n t his a p pe n di x m ust be perf or me d i n a d diti o n  t o all 
pr oce d ures re q uir e d b y t he c urre nt versi o n of Pr ot oc o l JP C S  w here a p plica ble.  T he c o ns oli dati o n 
of t his c o u ntr y-s pecifi c a d de n du m  i n t he J P C S pr ot oc ol  a p pe n di x is t o facilitate tra nsiti o n of t his 
trial t o t he Cli nical Trial I nf or mati o n S yste m  ( C TI S) u n der t he ne w cli nical trial re g ulati o n i n t he 
E U . 
1 0. 9. 1.  
A d de n d u m 2. 3  ( C o u ntr y-S pecific C o nte nt f or t he E ur o pe a n U ni o n )  
T his a d de n d u m a d dress es t he a d diti o nal re q uire m e nts f or St u d y J P CS  sites i n t he E U. T he 
p ur p ose of t his a d de n d u m is t o i nc or p orate fee d b ac k fr o m t he c o m pete nt a ut h orities wit hi n t he 
E U . 
T he f oll o wi n g t a ble descri bes t he c ha n ges bei n g ma de t o Pr ot oc ol J P C S f or partici pa nts i n t he 
E U . 
M ai n Pr ot oc ol Secti o n # a n d N a me  
Descri pti o n of C h a n ge  
1. 3 . Sc he d ule of A cti vities  
A d de d te xt i n dicati n g t he i n vesti gat ors will 
pr o vi de a ge -a p pr o priate e x pla nati o ns 
5. 1 . I n cl usi o n Criteria 
I n cl usi o n criteri o n 5 was m o difie d t o s pecif y 
“i ntact ca ps ules ”  
6. 1 St u d y I nter v e nti o n(s) A d mi nistere d  
Re m o ve d t he all o wa nce of ot her pres e ntati o ns 
of te m oz ol o mi de  
6. 1. 2. Patie nts wit h Diffic ult y S wall o wi n g 
After I n itiati n g Treat me nt 
Re m o ve d b ullet f or te m o z ol o mi de  
1 0. 1. 5. Disse mi nati o n of Cli nical St u d y Data  
A d de d q ualif yi n g te xt t o “re p orts” c o nte nt  
1 0. 2. 1. Bl o o d V ol u mes  
A d de d bl o o d v ol u me det ails f or Parts A a n d B  
Pr ot oc ol  R e visi o ns  
F or J P C S  Pr ot oc ol A d de n d u m, a d diti o ns ha ve bee n i de ntifie d b y t he us e of u n dersc ore  a n d 
deleti o ns ha ve bee n i de ntifie d b y stri ket hr o u g h. 
Pr ot oc ol Secti o n 1. 3 Sc he d ule of Acti vities  
I n v esti gat ors will pr o vi de a ge-a p pr o pri ate e x pla nati o ns t o all c hil dre n pri or t o a n y assess me nt or 
pr oce d ure. I n vesti gat ors s h o ul d assess a n d m o nit or p h ysic al pai n a n d distress at eac h visit.  
Pr ot oc ol Secti o n 5. 1 I ncl usi o n Criteri a  
[ 5] Patie nts m ust be a ble t o s wall o w  i ntact ca ps ules. 
 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 5 8  
Pr ot oc ol Secti o n 6. 1 St u d y I nter ve nti o n(s) A d mi nistere d  
…  
Te m o z ol o mi de  o nce d ail y orall y o n Da ys 1 t hr o u g h 5 at t he d os e s pecifi e d i n t he d osi n g 
ta bles bel o w.  F or Part A, ta ke te m oz ol o mi de a p pr o xi matel y 1 h o ur pri or t o iri n oteca n 
i nf usi o n.  Te m oz ol o mi de ca n be ta ke n at t he sa m e ti me as t he first abe macicli b d ose.  
Te m oz ol o mi de s h o ul d be ta ke n o n a n e m pt y st o mac h .  Te m oz ol o mi de s h o ul d be ta ke n b y 
oral a d mi nistrati o n  acc or di n g t o  la bel sta n dar d of care (refer t o Secti o n 6. 1. 1. f or patie nts will 
s wall o wi n g diffic ulties).  Ot her pres e ntati o ns (e. g. I V)  of te m oz ol o mi de ma y be all o we d 
u p o n disc ussi o n wit h t he Lill y C R P/ C R S.  T he met h o d of a d mi nistrati o n s h o ul d be 
d oc u me nte d o n t he C R F . 
…  
 
Pr ot oc ol Secti o n 6. 1. 2 . P ati e nts wit h Diffic ult y S w all o wi n g After I niti ati n g Tre at me nt 
If a patie nt h as diffic ult y s wall o wi n g after i nitiati n g st u d y treat me nt, t he f oll o wi n g s h o ul d be 
c o nsi dere d.  I n all cas es, t he met h o d of a d mi nistrati o n s h o ul d be d oc u me nte d o n t he C R F.  
 F or a b e macicli b , refer t o t he Me dicati o n Alter n ati ve A d mi nistrati o n g ui de.   
 F or te m oz ol o mi de, f ol l o w sta n dar d of care f or alter nati ve a d mi nistrati o n ( Trissel et al. 
2 0 0 6; C C L G 2 0 1 6).  
 
Pr ot oc ol Secti o n 1 0. 1. 5  Disse mi n ati o n of Cli nic al St u d y D at a  
Disse mi nati o n of st u d y d ata will be perf or me d acc or di n g t o all a p plica ble Lill y a n d i nter nati o nal 
p olicies.  
Re p orts  
O n c o m pleti o n of t he res earc h, re gar dless of w h et her t he trial is ter mi nate d pre mat urel y or t h ere 
are u nfa v o ura bl e res ults,  a re p ort or s u m mar y s hall be s u b mitte d t o re g ulat or y b o dies a n d et hics 
c o m mittees  acc or di n g t o l ocal la w wit hi n 6 m o nt hs . I n a d diti o n , T the s p o ns or will discl ose a 
s u m mar y of st u d y i nf or mati o n, i ncl u di n g ta b ular st u d y res ults, o n p u blicl y a vaila ble we bsites 
w here re q uire d b y l o cal l a w or re g ulati o n wit hi n 6 m o nt hs . 
Pr ot oc ol Secti o n 1 0 .2 .1 . Bl o o d V ol u mes 
T he hi g h est v ol u me of bl o o d pla n ne d t o be dra w n fr o m patie nts f or p har mac o ki netics ( P K) a n d 
safet y la bs i n o ne da y is 
 
 A d diti o nall y, t he hi g hest v ol u me of bl o o d pla n ne d t o be dra w n fr o m 
p atie nts f or P K a n d safet y la bs i n
 
T h eref ore, 
t hese v ol u mes are l ess t ha n t he ma xi m u m li mits calc ulate d usi n g t he safe wei g ht -b ase d li mit 
f or m ula f or a 1 0 k g patie nt, w hic h is t he s mallest patie nt all o we d t o e nr oll o n t his st u d y. 
 
 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T
C CI
C CI

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 5 9  
Bl o o d Dr a w V ol u m e s P er Vi sit ( m L) –  P art A  
B aseli ne a 
C ycle 1 D a y 1  
C ycle 1 D a y 8  
C ycle 1 D a y 1 5  
C ycle 2 D a y 1  
 
 
 
 
 
C ycle 2 D a y 2  
C ycle 2 D a y 8  
C ycle 2 D a y 1 5  
C ycle 3 D a y 1  
C ycle 3 D a y 8  
4  
3  
 
 
 
C ycle 3 D a y 1 5  
C ycle 4 a n d 
o n w ar d D a y 1  
C ycle 4 a n d 
o n w ar d D a y 8  
C ycle 4 a n d 
o n w ar d D a y 1 5  
Visit 8 0 1  
 
 
 
 
 
Re n al M o nit ori n g  
He p atic 
M o nit ori n g  
T u m or M ar kers a 
 
 
 
 
 
a If a p plica ble, s o me patie nts ma y ha ve a d diti o nal bl o o d dra ws f or t u m or mar kers (al p ha-fet o pr otei n a n d beta -
H C G) . 
b 
 
 
 
 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 6 0  
Bl o o d Dr a w V ol u m e s P er Vi sit ( m L) –  P art B  
B aseli ne a 
C ycle 1 D a y 1  
C ycle 1 D a y 8  
C ycle 1 D a y 1 5  
C ycle 2 D a y 1  
 
 
 
 
 
C ycle 2 D a y 2  
C ycle 2 D a y 8  
C ycle 2 D a y 1 5  
C ycle 3 D a y 1  
C ycle 3 D a y 8  
 
 
 
 
 
C ycle 3 D a y 1 5  
C ycle 4 a n d 
o n w ar d D a y 1  
C ycle 4 a n d 
o n w ar d D a y 8  
C ycle 4 a n d 
o n w ar d D a y 1 5  
Visit 8 0 1  
 
 
 
 
 
Re n al M o nit ori n g  
He p atic 
M o nit ori n g  
T u m or M ar kers a 
 
 
 
 
 
a If a p plica ble, s o me patie nts ma y ha ve a d diti o nal bl o o d dra ws f or t u m or mar kers ( al p ha-fet o pr otei n a n d beta -
H C G) . 
b 
 
 
 
 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 6 1  
 
1 0. 1 0.  
A p pe n di x 1 0 :  A b bre vi ati o ns  a n d Defi niti o ns  
T er m  
D efi niti o n  
a b u s e  
Use of a st u d y i nter ve nti o n f or recreati o nal p ur p oses or t o mai ntai n a n a d dicti o n or 
de p e n de nce  
A D C C  
a nti b o d y de p e n de nt cell ular c yt ot o xicit y  
A E  
a d verse e ve nt:  A n y u nt o war d me dical occ urre nce i n a patie nt or cli nical i n vesti gati o n 
s u bj ect a d mi nistere d a p har ma ce utical pr o d uct t hat d oes n ot necessaril y ha ve a ca usal 
relati o ns hi p wit h t his treat me nt.  A n a d verse e ve nt ca n t heref ore be a n y u nfa v ora ble a n d 
u ni nte n de d si g n (i ncl u di n g a n a b n or mal la b orat or y fi n di n g), s y m pt o m, or disease 
te m p orall y ass ociate d wit h t he use of a me dici nal (i n vesti gati o nal) pr o d uct, w het her or 
n ot relate d t o t he m e dici nal (i n vesti gati o nal) pr o d uct.  
A L T  
ala ni ne a mi n otra nsferase  
A S C O  
A merica n S ociet y of Cli nical O nc ol o g y  
A S T  
as partate a mi n otra nsferase  
a ut h ori z e d I M P  
A p plic a ble t o t he E U o nly : a me dici nal pr o d uct a ut h orize d i n acc or da nce wit h 
Re g ulati o n ( E C) N o 7 2 6/ 2 0 0 4 or i n a n y Me m ber State c o ncer ne d i n acc or da nce wit h 
Directi ve 2 0 0 1/ 8 3/ E C, irres pecti ve of c ha n ges t o t he la belli n g of t he me dici nal pr o d uct, 
w hic h is use d as a n i n vesti gati o nal me dici nal pr o d uct  
A U C  
area u n der t he c ur ve  
BI D  
t wice dail y 
B S A  
b o d y  s urface area 
C B C  
c o m plete bl o o d c o u nt  
C B R  
cli nical be nefit rate  
C D K  
c ycli n-de p e n de nt ki nase  
C D K 4  
c ycli n-de p e n de nt ki nase 4  
C D K 6  
c ycli n-de p e n de nt ki nase 6  
C N S  
ce ntral ner v o us s yste m  
C O A  
cli nical o utc o me assess me nt  
c o m pl ai nt  
A c o m plai nt is a n y writte n, el ectr o nic, or oral c o m m u nicati o n t hat alle ges deficie ncies 
relate d t o t he i de ntit y, q ualit y, p urit y, d ura bilit y, relia bilit y, safet y or effecti ve ness, or 
perf or ma nce of a dr u g or dr u g deli ver y s yste m.  
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 6 2  
c o m pli a n c e  
A d here nce t o all st u d y -relate d, go o d cli nical practice ( G C P), a n d a p plica ble re g ulat or y 
re q uire me nts. 
C R  
c o m plete res p o nse  
Cr Cl  
creati ni ne cleara nce  
C R F  
case re p ort f or m  
C R P / C R S 
cli nical researc h p h ysicia n /cli nical researc h scie ntist:  I n di vi d ual res p o nsi ble f or t he 
me dical c o n d uct of t he st u d y.  Res p o nsi bilities of t he C R P / C R S ma y be perf or me d b y a 
p h ysicia n,  cli nical researc h sci e ntist, gl o bal safet y p h ysicia n or ot her me dical officer.  
C S F  
cere br os pi nal fl ui d  
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  
ct D N A  
circ ulati n g t u m or D N A  
C T C A E  
C o m m o n T er mi n ol o g y Criteri a f or A d verse E ve nts  
C Y P  
c yt oc hr o me P 4 5 0  
D B P  
diast olic bl o o d press ure  
D C R  
disease c o ntr ol rate  
D L T  
d ose -li miti n g t o xicit y 
D o R  
d urati o n of res p o nse  
E D C  
electr o nic data ca pt ure  
e nr oll  
T he act of assi g ni n g a partici p a nt t o a treat me nt.  P artici pa nts w h o are e nr olle d i n t he 
st u d y are t h ose w h o ha ve bee n assi g ne d t o a treat me nt.  
e nt er  
P artici pa nts e ntere d i nt o a st u d y are t h ose w h o si g n t he i nf or me d c o nse nt  f or m directl y 
or t hr o u g h t heir le gall y acce pta ble re prese ntati ves.  
E R B  
et hical re vie w b oar d  
F D G  
fl u or o de o x y gl uc ose 
G C P  
g o o d cli nical practice  
G -C S F  
gra n ul oc yte -c ol o n y sti m ulati n g fact or  
G D 2  
disial o ga n gli osi de bel o n gi n g t o b -series ga n gli osi de 
G D P R  
E U Ge neral Data Pr otecti o n Re g ulati o n  
G F R  
gl o mer ular filtrati o n rate  
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 6 3  
G M -C S F  
gra n ul oc yte macr o p ha ge c ol o n y  sti m ulati n g fact or 
H 1  
H 1  hista mi ne  rece pt or 
H & E  
he mat o x yli n -e osi n stai n  
H C G  
h u ma n c h ori o nic g o na d otr o pi n  
H E R 2 - 
h u ma n e pi der mal gr o wt h fact or rece pt or 2 ne gati ve 
H g b  
he m o gl o bi n  
H R +  
h or m o ne rece pt or -p ositi ve  
H V A  
h o m o va nillic aci d  
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 
I nter nati o nal C o u ncil f or Har m o nisati o n 
I E C 
I n de p e n de nt Et hics C o m mitte e 
I H C 
i m m u n o hist oc he mistr y 
I L D 
i nterstitial l u n g disease 
I M 
i ntra m usc ular 
I M P 
I n vesti gati o nal Me dici nal Pr o d uct (see als o “i n vesti gati o nal pr o d uct”) 
A me dici nal pr o d uct w hic h is bei n g teste d or use d as a refere nce, i ncl u di n g as a place b o, 
i n a cli nical trial. 
I nf or m e d c o n s e nt 
A pr ocess b y w hic h a partici pa nt v ol u ntaril y c o nfir ms his or her willi n g ness t o 
partici pate i n a partic ular st u d y, after ha vi n g bee n i nf or me d of all as pects of t he st u d y 
t hat are rele va nt t o t he partici pa nt’s decisi o n t o partici pate.  I nf or me d c o nse nt is 
d oc u me nte d b y mea ns of a writte n, si g ne d a n d date d i nf or me d c o nse nt f or m . 
I N R C 
I nter nati o nal Ne ur o blast o ma Res p o nse Criteria 
i nt eri m a n al y si s 
A n i nteri m a nal ysis is a n a nal ysis of cli nical st u d y data, se p arate d i nt o treat me nt gr o u ps, 
t hat is c o n d ucte d bef ore t he fi nal re p orti n g data b ase is creat e d/l oc ke d.  
i n v e sti g ati o n al 
pr o d u ct  
A p har mace utical f or m of a n acti ve i n gre die nt or place b o bei n g teste d or use d as a 
refere nce i n a cli nical trial, i ncl u di n g pr o d ucts alrea d y o n t he mar ket w he n use d or 
asse m ble d (f o r m ulate d or pac ka ge d) i n a wa y differe nt fr o m t he a ut h orize d f or m, or 
mar kete d pr o d ucts use d f or a n u na ut h orize d i n dicati o n, or mar kete d pr o d ucts use d t o 
gai n f urt her i nf or mati o n a b o ut t he a ut h orize d f or m.  
I R B 
I nstit uti o nal Re vie w B oar d 
I V 
Intra ve n o us  
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 6 4  
M A T E  
m ulti dr u g a n d t o xi n e xtr usi o n pr otei n  
m e di c ati o n err or  
Err ors i n t he prescri bi n g, dis p e nsi n g, or a d mi nistrati o n of a st u d y i nter ve nti o n, 
re gar dless of w het her or n ot t he me dicati o n is a d mi nistere d t o t he partici pa nt or t he err or 
lea ds t o a n A E. Me dicati o n err or ge nerall y i n v ol ve a fail ure t o u p h ol d o ne or m ore of t he 
fi ve “ri g hts” of me dicati o n us e: t he ri g ht partici pa nt, t he ri g ht dr u g, t he ri g ht d ose, ri g ht 
r o ute, at t he ri g ht ti me. 
I n a d diti o n t o t he c ore fi ve ri g hts, t he f oll o wi n g ma y als o represe nt me dicati o n err ors:  
• d ose o missi o n ass ociate d wit h a n A E or a pr o d uct c o m plai nt 
• dis pe nsi n g or use of e x pire d me dicati o n 
• use of me dicati o n past t he re c o m me n de d i n-use date  
• dis pe nsi n g or use of a n i m pr o perl y st ore d me dicati o n 
• use of a n a d ulterate d d osa ge f or m or a d mi nistrati o n tec h ni q ue i nc o nsiste nt wit h t he 
me dicati o n's la beli n g (f or e xa m ple, S u m mar y of Pr o d uct C haracteristics, I B, l ocal 
la bel, pr ot oc ol), or 
• s hare d use of cartri d ges, prefille d pe ns, or b ot h. 
MI B G  
metai o d o be nz yl g ua ni di ne  
mi s u s e  
Use of a st u d y i nter ve nti o n f or self -treat me nt t hat eit her is i nc o nsiste nt wit h t he 
prescri be d d osi n g re gi me n, i n dicati o n, or b ot h, or is o btai ne d wit h o ut a prescri pti o n  
m R N A  
messe n ger R N A  
M T D  
ma xi m u m t olerate d d ose  
M T D
A  
P art A ma xi m u m t olerate d d ose  
N CI  
Nati o nal Ca ncer I nstit ute  
NI M P  
N o n -i n vesti gati o nal Me dici nal Pr o d uct. 
A me dici nal pr o d uct use d f or t he nee ds of a cli nical trial as descri be d i n t he pr ot oc ol, b ut 
n ot as a n i n vesti gati o nal me di ci nal pr o d uct. E xa m ples i ncl u de resc ue me dicati o n, 
challe n ge a ge nts, a ge nts t o assess e n d p oi nts i n t he cli nical tri al, or bac k gr o u n d 
treat me nt. 
 
 
O R R  
o bj ecti ve res p o nse rate  
P D  
pr o gressi ve disease  
P E T  
p ositr o n e missi o n t o m o gra p h y  
P F S  
pr o gressi o n -free s ur vi val 
P K  
p har mac o ki netic (s) 
P O  
orall y  
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T
C CI

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 6 5  
P R  
partial res p o nse  
P R B C  
p ac ke d  re d bl o o d cell 
P R O/ e P R O  
patie nt -re p orte d o utc o mes/ele ctr o nic patie nt-re p orte d o utc o mes 
Q D  
dail y  
R A N O  
Res p o nse Assess me nt i n Ne ur o -O nc ol o g y  
R B  
reti n o blast o ma 
R E CI S T  
Res p o nse Criteria i n S oli d T u m ors  
R P 2 D  
rec o m me n de d p hase 2 d ose 
S A E  
seri o us a d verse e ve nt 
S B P  
s yst olic bl o o d press ure 
s cr e e n  
T he act of deter mi ni n g if a n i n di vi d ual meets mi ni m u m re q uire me nts t o bec o me part of 
a p o ol of p ote ntial ca n di dates f or partici pati o n i n a cli nical st u d y.  
S D  
sta ble disease 
S o A  
Sc he d ule of Acti vities  
S U S A R  
s us pecte d u ne x pecte d seri o us a d verse reacti o n  
Refers t o a n a d verse e ve nt t hat occ urs i n a cli nical trial parti ci pa nt, w hic h is assesse d b y 
t he s p o ns or a n d or st u d y i n vesti gat or as bei n g u ne x pecte d, seri o us a n d as ha vi n g a 
reas o na ble p ossi bilit y of a ca usal relati o ns hi p wit h t he st u d y i nter ve nti o n. 
T B L  
t otal bilir u bi n 
T E A E  
Treat me nt -e mer ge nt a d verse e ve nt:  A n u nt o war d me dical o cc urre nce t hat e mer ges 
d uri n g a defi ne d treat me nt peri o d, ha vi n g bee n a bse nt pretreat me nt, or w orse ns relati ve 
t o t he pretreat me nt state, a n d d oes n ot necessaril y ha ve t o ha ve a ca usal relati o ns hi p 
wit h t his treat me nt.  
U G T 1 A 1  
uri di ne di p h os p hate -gl uc ur o n os yl tra nsferase 1 A 1  
U L N  
u p per li mit of n or mal  
V G P R  
ver y g o o d partial res p o nse  
V M A  
va nill yl ma n delic aci d  
V T E  
ve n o us t hr o m b oe m b olic e ve nt  
W B C  
w hite bl o o d cell  
W O C B P  
w o ma n / w o me n of c hil d beari n g p ote ntial  
 
 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 6 6  
1 0. 1 1.  
A p pe n di x 1 1 :  Pr ot oc ol A me n d me nt Hist or y   
T he Pr ot oc ol A me n d me nt S u m mar y of C ha n ges T a ble f or t he c urre nt a me n d me nt is l ocate d 
directl y b ef ore t he Ta bl e of C o nte nts ( T O C).  
A me n d me nt (e): 1 1-J ul -2 0 2 2   
T his a me n d me nt is c o nsi dere d t o be s u bsta ntial. 
T he a me n d me nt is c o nsi dere d t o be s u bsta ntial beca use it is li kel y t o ha ve a si g nifica nt i m pact o n 
t he  
● safet y or t he ri g hts of t h e st u d y partici p a nts, a n d  
● t he q ualit y or s afet y of a n y i n vesti gati o nal me dici nal pr o d uct use d i n t he st u d y.  
O ver all  R ati o n ale f or t he A me n d me nt:  
T he pri mar y reas o n f or a me n di n g t he J P C S pr ot oc ol is t o a d d st u d y Part C . Part C will e val uate 
a be maci cli b i n c o m bi nati o n wit h di n ut u xi ma b, gra n ul oc yte m acr o p ha ge c ol o n y -sti m ulati n g 
fact or (G M -C S F ; sar gra m osti m ), iri n oteca n, a n d te m oz ol o mi de i n pe diatric patie nts wit h 
rela pse d/r efract or y n e ur o blast o ma .  
Secti o n # a n d N a me  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
1. 1 . S y n o psis; 1. 2 . Sc he ma; 1. 3. 2 . 
Sc he d ule of Acti vities f or P art C; 4. 1 . 
O verall Desi g n; 4. 1. 1. D ose Escalati o n 
Met h o d f or P arts A a n d B; 4. 1. 2. T w o -
sta ge Desi g n f or P art C; 6. 1. St u d y 
I nter ve nti o n(s) A d mi nistere d; 6. 5. 
C o nc o mita nt T hera p y; 8. 1 . Efficac y 
Assess me nts; 8. 8. 1. Bi o mar kers f or 
P art C; 8. 8. 1. 1. Tiss ue Sa m ples f or 
Bi o mar ker Researc h; 8. 8. 1. 2. Plas ma 
Sa m ples f or Bi o mar ker Researc h; 
8. 8. 1. 3. W h ole Bl o o d Sa m ples f or 
Bi o mar ker Researc h; 9. 1 . Statistical 
H y p ot heses; 9. 3 . P o p ulati o ns f or 
A nal ysis; 9. 4. 6 . Efficac y A nal yses; 
9. 4. 6. 2. P art C Efficac y A nal yses; 
1 0. 2. A p pe n di x 2 : Cli nical La b orat or y 
T ests  
A d diti o n of P art C t o St u d y D esi g n  
See O verall Rati o nale f or 
A me n d me nt  
1. 1 . S y n o psis; 3 . O bj ecti ves a n d 
E n d p oi nts  
U p date d  o bj ecti ves f or P art C ; s pecifie d 
a b e macicli b f or acce pta bilit y/ palata bilit y 
o bj ecti ve a n d e n d p oi nt; re m o ve d plas ma 
fr o m P K e n d p oi nt 
U p date d f or P art C ; 
clarificati o ns  
1. 1 . S y n o psis; 4. 1 . O verall Desi g n; 9. 2 . 
Sa m ple Size Deter mi nati o n  
U p date d t otal n u m ber of patie nts t o be 
e nr olle d  
U p date d f or P art C  
1. 3. 1. Sc he d ule of Acti vities f or P arts 
A a n d B  
A d de d pre g na nc y test t o list of la b orat or y 
assess me nts at scree ni n g t hat d o n ot ha ve t o 
be perf or me d at t he cli nical tri al site  
Fle xi bilit y f or patie nts  
1. 3. 1. Sc he d ule of Acti vities f or P arts 
F or a nat o mic ra di ol o gic i ma gi n g, e dite d 
te xt re gar di n g perf or ma nce of i ma gi n g as 
Clarificati o n  
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 6 7  
Secti o n # a n d N a me  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
A a n d B  
part of r o uti ne cli nical care  
1. 3. 1. Sc he d ule of Acti vities f or P arts 
A a n d B; 8. 1 0. Pr o d uct Acce pta bilit y 
a n d P alata bilit y Assess me nts  
A d de d clarificati o ns f or w he n 
q uesti o n naires are nee de d  
Clarificati o n  
1. 3. 1. S c he d ule of Acti vities f or P arts 
A a n d B  
A d de d a ge s pecificati o ns f or 
La ns k y/ Kar n ofs k y perf or ma nce stat us  
Clarificati o n  
1. 3. 1.  Sc he d ule of Acti vities f or P arts 
A a n d  B  
A d de d li ne f or partici pa nt ret ur ns st u d y 
dr u gs  
Clarificati o n f or 
c o m plia nce assess me nt  
1. 3. 1.  Sc he d ule of Acti vities f or P arts 
A a n d  B  
Re m o ve d E C G a n d C ystati n C fr o m 
p osttreat me nt f oll o w -u p pr oce d ures  
N ot necessar y  
1. 3. 1. Sc he d ule of Acti vities f or P arts 
A a n d B  
A d de d o pti o n f or la b orat or y a n d pre g na nc y 
tests t o be c ollecte d l ocall y f or all patie nts 
at a n y ti me i n t he st u d y; re m o ve d n otes 
re q uiri n g patie nt t o g o t o l ocal la b orat or y 
cl ose t o patie nt’s h o me if n ot perf or me d at 
t he i n vesti gati ve site 
Fle xi bilit y f or patie nts  
1. 3. 3. P har mac o ki netic Sa m pli n g a n d 
St u d y Dr u g D osi n g Sc he d ule  
Ref or matte d ta ble; a d de d details f or P art C  
Clarificati o n; u p date f or 
P art C  
2. 1 . St u d y Rati o nale; 2. 2 . B ac k gr o u n d; 
2. 2. 4 . Di n ut u xi ma b; 2. 2. 5 . G M -C S F  
U p date d t o i ncl u de c o nte nt f or P art C  
U p date f or P art C  
2. 2. 1 . T e m oz ol o mi de; 2. 2. 2 . 
Iri n oteca n; 4. 3. 2. T e m oz ol o mi de; 
4. 3. 3 . Iri n oteca n 
M o ve d te m oz ol o mi de a n d iri n oteca n 
c o nte nt t o s u bsecti o ns u n der D ose 
J ustificati o n 
M o ve d t o i m pr o ve 
rea da bilit y 
2. 2. 6 . Precli nical a n d Cli nical 
Rati o nale  
Secti o n n u m ber c ha n ge d a n d u p date d 
fi g ure ca pti o n f or A 6 7 3 E wi n g’s sarc o ma 
C D X m o del i n mice  
Clarificati o n  
2. 3 . B e nefit/ Ris k Assess me nt  
A d de d c o nte nt f or P art C  
U p date f or P art C  
4. 1. 1 . D ose Escalati o n Desi g n f or P arts 
A a n d B  
M o difie d D L T -e val ua ble defi niti o n; 
Re m o ve d M T D defi niti o n fr o m secti o n  
U p date f or P art C / 
rea dabilit y  
4. 1. 1 . D ose Escalati o n Desi g n f or P arts 
A a n d B  
Re w or de d details of i ntra patie nt d ose 
escalati o n n ot bei n g per mitte d  
Clarificati o n  
4. 1. 1 . D ose Escalati o n Desi g n f or P arts 
A a n d B; 4. 1. 3 . D ose -Li miti n g 
T o xicit y Deter mi nati o n a n d M a xi m u m 
T olerate d D ose Defi niti o n  
M o ve d state me nt of e nr oll me nt bei n g 
s us pe n de d i n t he e ve nt of Gra de 5 A E t o 
Secti o n 4. 1. 3; M o ve d state me nt D L T 
declarati o n i n t he e ve nt of si g nifica nt 
t o xicities 
Clarificati o n / re a da bilit y 
4. 1. 2 . T w o -sta ge Desi g n f or Part C 
A d de d details of  desi g n f or P art C  
U p date f or P art C  
4. 1. 3. D ose -Li miti n g T o xicit y 
Deter mi nati o n a n d Ma xi m u m 
T olerate d D ose Defi niti o n  
Re vise d state me nt t hat i n vesti gat ors a n d 
Lill y C R P/ C R S ca n declare a D L T i f 
patie nt e x perie nces d ose -li miti n g t o xicit y; 
A d de d state me nt t hat if a patie nt recei ves 
< 7 5 % of a n y pla n ne d C ycle 1 st u d y dr u g 
d oses d ue t o dr u g -relate d t o xi cit y, t he 
t o xicit y will be declare d a D L T 
Re w or de d f or clarit y; 
a d de d t o br oa de n D L T 
defi niti o n  
4. 1. 3. D ose -Li miti n g T o xicit y 
A d de d state me nt t hat all Gra d e ≥3 
Re w or de d f or clarit y  
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 6 8  
Secti o n # a n d N a me  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
Deter mi nati o n a n d Ma xi m u m 
T olerate d D ose Defi niti o n  
n o n he mat ol o gical A Es o utsi de of liste d 
e xce pti o ns will be c o nsi dere d a D L T  
4. 1. 3. D ose -Li miti n g T o xicit y 
Deter mi nati o n  a n d Ma xi m u m 
T olerate d D ose Defi niti o n  
C ha n ge d “s u bse q ue nt c o urse” t o 
“s u bse q ue nt c ycle” u n der he mat ol o gical 
e ve nts  
Clarificati o n  
4. 1. 3. D ose -Li miti n g T o xicit y 
Deter mi nati o n a n d Ma xi m u m 
T olerate d D ose Defi niti o n  
Re w or de d ac ute iri n oteca n -ass ociate d 
diarr hea defi niti o n  
Clarificati o n  
4. 1. 3. D ose -Li miti n g T o xicit y 
Deter mi nati o n a n d Ma xi m u m 
T olerate d D ose Defi niti o n  
A d de d “ C ycle Dela y” t o first 
He mat ol o gical e ve nts b ullet  
Clarificati o n  
4. 1. 3. D ose -Li miti n g T o xicit y 
Deter mi nati o n a n d Ma xi m u m 
T olerate d D ose Defi niti o n  
U p date d la n g ua ge re gar di n g t he T o xicit y 
D oc u me ntati o n F or m  
O perati o nal  
4. 3. 1 . A be macicli b  
Re vise d a be macicli b d ose j ustificati o n  
I m pr o ve d rea da bilit y; 
U p date f or P art C  
4. 3. 2. T e m oz ol o mi de; 4. 3. 3. 
Iri n oteca n; 4. 3. 4. Di n ut u xi ma b a n d 
G M -C S F  
A d de d secti o n s 
A d de d t o pr o vi de 
j ustificati o n f or d oses i n 
res pecti ve st u d y parts 
4. 4. E n d of St u d y Defi niti o n  
A d de d te xt descri bi n g st u d y c o m pleti o n i n 
t he E U a n d U S f or P arts B a n d C, 
res pecti vel y 
U p date f or P art C  
5. 1 . I ncl usi o n Criteria 
A d de d P art -s pecific re q uire me nts i n 
Criteria 1  a n d 3  
U p date f or P art C  
5. 1. I ncl usi o n Criteria  
Re m o ve d I ncl usi o n 2  
C o m bi ne d a ge/ wei g ht 
re q uire me nts i n I ncl usi o n 
Criteri o n 1  
5. 1 . I ncl usi o n Criteria 
I ncl usi o n 6: M o difie d ta ble of pre vi o us 
treat me nts a n d a d de d clarificati o ns  
U p date f or P art C  
5. 1 . I ncl usi o n Criteria 
I ncl usi o n 7: A d de d s pecificati o ns f or P arts 
A, B, a n d C w here a p plica ble  
U p date f or P art C  
5. 1 . I ncl usi o n Criteria 
I ncl usi o n 9: U p date d c o ntrace pti ve 
re q uire me nts 
U p date wit h m ost rece nt 
a be macicli b g ui da nce  
5. 1 . I ncl usi o n Criteria 
A d de d I ncl usi o n 2 8 a n d 2 9  
U p date f or P art C  
5. 2 . E xcl usi o n Criteria  
E xcl usi o n 1 4: s pecifie d t hat C O VI D 
vacci nes t hat d o n ot c o ntai n a li ve vir us are 
per mitte d  
Clarificati o n  
5. 2 . E xcl usi o n Criteria  
Re m o ve d E xcl usi o n 1 6  
Al i g n me nt wit h safet y 
g ui da nce  
5. 2 . E xcl usi o n Criteria  
E xcl usi o n 2 1: Re m o ve d “se vere re nal 
i m pair me nt” 
Re d u n da nt wit h I ncl usi o n 7  
5. 2 . E xcl usi o n Criteria  
A d de d E xcl usi o n 2 6, 3 0, 3 1  
U p date f or P art C  
5. 2 . E xcl usi o n Criteria  
Re m o ve d E xcl usi o n 2 7  
S p o ns or strate g y decisi o n 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 6 9  
Secti o n # a n d N a me  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
6. 1. St u d y I nter ve nti o n(s) 
A d mi nistere d  
A d de d d osi n g i nstr ucti o n s pecificati o ns f or 
P arts A, B, C as a p plica ble  
U p date f or P art C  
6. 1. St u d y I nter ve nti o n(s) 
A d mi nistere d  
A d de d clarificati o n f or partici pa nts ta ki n g 
oral gra n ules s h o ul d f oll o w pr o vi de d 
i nstr ucti o ns 
Clarificati o n  
6. 1. 1 . Detaile d A d mi nistrati o n 
G ui deli nes ( P art C O nl y); 6. 1. 1. 1 . 
M o nit ori n g G ui deli nes D uri n g 
Di n ut u xi ma b I nf usi o n ( Da ys 2 -5)  
A d de d Secti o ns  
U p date f or P art C  
6. 1. 2. P atie nts wit h Diffic ult y 
S wall o wi n g After I nitiati n g Treat me nt 
A d de d details f or oral gra n ule 
a d mi nistrati o n/ dis persi o n  
U p date f or P art C  
6. 1. 3. Criteria t o Be gi n S u bse q ue nt 
C ycles of Treat me nt  
E dite d first b ullet t o clarif y G -C S F use i n 
P arts A a n d B ; s pecifie d G -C S F is n ot 
per mitte d i n P art C ; clarifie d “a n y 
n o n he mat ol o gic t o xicit y dee me d relate d t o 
st u d y treat me nt” 
U p date  f or P art C; 
clarificati o n  
6. 1. 4. Pre me dicati o n; 6. 1. 4. 1. Na usea; 
Secti o n 6. 5. 2 . S u p p orti ve Ma na ge me nt 
f or Diarr hea 
M o ve d te xt fr o m 6. 1. 4 t o 6. 1. 4. 1; M o ve d 
te xt re gar di n g v o miti n g ass ociate d wit h 
diarr hea t o Secti o n 6. 5. 2  
Clarificati o n / rea da bilit y  
6. 2. 
Pre p arati o n/ Ha n dli n g/ St ora ge/ Acc o u nt
a bilit y 
Re m o ve d refere nce t o P har ma c y Ma n ual  
O perati o nal  
6. 4. St u d y I nter ve nti o n C o m plia nce  
Re place d c o m plia nce te xt wit h c o nte nt 
a d dressi n g st u d y i nter ve nti o n 
a d mi nistrati o n a n d c o m plia nc e assess me nt  
M o difie d f or ti mi n g  
6. 4. St u d y I nter ve nti o n C o m plia nce  
A d de d te xt f or oral gra n ules  
U p date f or P art C  
6. 4. St u d y I nter ve nti o n C o m plia nce  
A d de d “ u nless d ose h ol ds are necessitate d 
b y A E.” t o state me nt re gar di n g perce nta ge 
of d oses nee de d f or c o m plia nc e  
Clarificati o n  
6. 5 . C o nc o mita nt T hera p y  
Delete d “ Seas o nal fl u” vacci nes, a n d ma de 
it ge neral “ Vacci nes” 
Clarificati o n  
6. 5. 1. P alliati ve Me dici ne a n d 
S u p p orti ve Care  
A d de d te xt i n sec o n d b ullet i n S u p p orti ve 
Care s u bsecti o n clarif yi n g t hat G -C S F use 
is per mitte d i n P arts A a n d B; h o we ver, G-
C S F is n ot per mitte d i n P art C  
U p date f or P art C  
6. 5. 1. P alliati ve Me dici ne a n d 
S u p p orti ve Care  
A d de d b ullet re gar di n g ris k of P C P i n 
partici pa nts rec ei vi n g iri n otec a n a n d 
te m oz ol o mi de, a n d t hat P C P pr o p h yla xis is 
e nc o ura ge d  
Ali g n me nt  wit h c urre nt 
safet y 
6. 5. 2. S u p p orti ve Ma na ge me nt f or 
Diarr hea  
S pecifie d t hat l o pera mi de s h o ul d be rea dil y 
a vaila ble t o be gi n treat me nt of late diarr hea 
pri or t o first iri n oteca n i nf usi o n 
Clarificati o n  
6. 5. 3. S u p p orti ve Ma na ge me nt of 
A ntici pate d Di n ut u xi ma b -Ass ociate d 
T o xicities ( P art C O nl y)  
A d de d secti o n a n d s u bse q ue nt s u bsecti o ns 
6. 5. 3. 1 t hr o u g h 6. 5. 3. 1 1  
U p date f or P art C  
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 7 0  
Secti o n # a n d N a me  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
6. 6. D ose M o dificati o n  
C ha n ge d “st u d y treat m e nt” t o 
“a b e macicli b” ; M o difie d title a n d ta ble 
val ues i n “ Starti n g D ose a n d A dj ust me nts 
f or A be macicli b-Relate d T o xicities”. 
C ha n ge d d osi n g u nits fr o m m g/ m 2 t o m g; 
a d de d la n g ua ge a n d s u bsecti o ns f or P art C  
Clarificati o ns; u p date f or 
P art C  
6. 6. 1. D ose M o dificati o n G ui d a nce 
d ue t o T o xicit y  
U p date d secti o n t o ali g n wit h D L T 
g ui da nce a n d pr o vi de a d diti o nal 
clarificati o ns / better rea da bilit y  
Ali g n me nt wit h D L T 
g ui da nce / clarificati o ns  
6. 6. 1. 1. D ose M o dificati o n G ui da nce 
d ue t o T o xicities C o nsi dere d t o be  
Attri b ute d t o A be macicli b  
Delete d all b ut t he first se nte nce of f o ot n ote 
“a” bel o w t he d ose m o dificati o n g ui da nce 
ta ble f or he mat ol o gic t o xicities c o nsi dere d 
t o be attri b ute d t o a be macicli b 
Delete d beca use Gra d e 3 
he mat ol o gical t o xicit y is 
n ot liste d i n t his ta ble 
e xce pt fe brile ne utr o pe nia  
6. 6. 1. 2. D ose M o dificati o n G ui da nce 
d ue t o T o xicities C o nsi dere d t o be 
Attri b ute d t o Iri n oteca n  
U p date d secti o n t o ali g n wit h safet y 
g ui da nce a n d pr o vi de a d diti o nal 
clarificati o ns  
Clarificati o n / u p date wit h 
iri n oteca n safet y 
i nf or mati o n 
6. 6. 1. 3. P art C -S pecific D ose 
M o dificati o ns ; 6. 6. 1. 4. D ose 
M o dificati o n G ui da nce d ue t o T o xicit y 
Attri b ute d t o G M -C S F  
A d de d secti o ns  
U p date f or P art C  
7. 1. Disc o nti n uati o n of St u d y 
I nter ve nti o n 
Delete d p orti o n of fi nal b ullet p oi nt “ … or a 
D L T at t he l o west d ose le vel u n der 
i n vesti gati o n.” 
D ue t o ne w o pti o ns t o d ose 
re d uce base d o n stre n gt h 
( m g) rat her t hat d ose le vel 
( m g/ m2) 
7. 2. 1. Disc o nti n uati o n of I na d verte ntl y 
E nr olle d P atie nts  
Re m o ve d secti o n  
O perati o nal  
8. 2. 1. 2. G ui da nce f or M o nit ori n g 
Re nal F u ncti o n  
E dite d w or di n g re gar di n g meas ures of re nal 
f u ncti o n 
F or clarit y  
8. 4. Treat me nt of O ver d ose  
A d de d o ver d ose te xt f or i nter ve nti o ns ot her 
t ha n a be macicli b 
U p date f or P art C / 
clarificati o n  
8. 5. P har mac o ki netics  
A d de d details f or P art  C  
U p date f or P art C  
8. 5. 1. P atie nt Diar y  
A d de d state me nt t hat t he patie nt diar y is 
n ot i nte n de d f or c o m plia nce m o nit ori n g  
Clarificati o n  
8. 7. 1. W h ole Bl o o d a n d/ or Sali va 
Sa m ples f or P har mac o ge netic 
Researc h  
A d de d te xt clarif yi n g t hat w h ole bl o o d 
a n d/ or sali va sa m ples will n ot be c ollecte d 
i n P arts A a n d B, b ut t hat w h ole bl o o d b ut 
n ot sali va will be c ollecte d i n P art C. Als o 
a d de d te xt stati n g t hat ge netic researc h 
w o ul d n ot be perf or me d  
U p date f or P art C  
8. 1 0 . Pr o d uct Acce pta bilit y a n d 
P alata bilit y Asse ss me nts 
M o ve d te xt fr o m u n der Secti o n 8. 1 t o ne w 
Secti o n 8. 1 0; a d de d te xt f or acce pta bilit y 
a n d palata bilit y of a be macicli b oral 
gra n ules  
Clarificati o n; u p date f or 
P art C  
9. 3 . P o p ulati o ns f or A nal ysis  
Delete d se nte nce at e n d of secti o n 
re gar di n g re place me nt of patie nts t o e ns ure 
a d e q uate P K 
Re m o ve re d u n da nc y  
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 7 1  
Secti o n # a n d N a me  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
9. 4. 6. 1. P arts A a n d B Efficac y 
A nal yses  
S pecifie d t hat P arts A a n d B will n ot ha ve a 
f or mal efficac y assess me nt 
Clarificati o n  
9. 4. 6 .2. 1.  2 0 1 7  I N R C 
A d de d descri pti o n of I N R C res p o nse 
gra di n g  a n d s u m marizati o n us e d i n P art  C  
U p date f or P art C  
9. 4. 7 . P har mac o ki netic / 
P har mac o d y na mic A nal yses  
Clarifie d t hat a be macicli b, iri n oteca n, a n d 
te m oz ol o mi de c o nce ntrati o ns will be 
s u m marize d b y a nal yte 
Clarificati o n  
9. 4. 8 . S u b gr o u p A nal yses 
A d de d “ w he n  a p plica ble” at t he e n d of t he 
se nte nce. 
Clarificati o n  
9. 4. 9 . Pr o d uct Acce pta bilit y a n d 
P alata bilit y  
A d de d “ oral gra n ules” t o first se nte nce.  
U p date f or P art C  
9. 5. I nteri m A nal yses  
A d de d te xt t o clarif y i nteri m a nal yses a n d 
M T D i n P arts A a n d B a n d c o nfir mi n g 
safet y i n P art C; a d de d details of D M C i n 
P art C  
U p date f or P art C  
1 0. 1. 1. Re g ulat or y a n d Et hical 
C o nsi derati o ns  
A d de d fi nal b ullet: “ Re p orti n g si g nifica nt 
iss ues relate d t o partici pa nt safet y, 
partici pa nt ri g hts, or data i nte grit y”  
P er ne w E M A  g ui da nce 
relate d t o E U C T R 
5 3 6/ 2 0 1 4  
1 0. 1. 4. C o m mittee Str uct ure  
A d de d details of D M C f or P art C  
U p date f or P art C  
1 0. 6. A p pe n di x 6: I n d ucers a n d Str o n g 
I n hi bit ors of C Y P 3 A 
E dite d ta ble of i n d ucers a n d str o n g 
i n hi bit ors of C Y P 3 A 
U p date f or c urre nt 
a be macicli b g ui da nce  
1 0. 7. A p pe n di x 7: Pr o visi o ns f or 
C ha n ges i n St u d y C o n d uct D uri n g 
E xce pti o nal Circ u msta nces  
A d de d s h ort -ter m f oll o w-u p t o t he P art  A 
a n d P art B b ullet s 
I n dicates t he visits f or 
w hic h fle xi bilit y w o ul d 
a p pl y 
1 0. 8. A p pe n di x 8: A be macicl i b D osi n g 
C harts  
U p date d ta ble f or P arts A a n d B, a d de d 
ta ble f or P art C 
U p date d r o u n di n g f or 
c o nsiste nc y; u p date f or P art 
C  
T hr o u g h o ut t he pr ot oc ol  
Mi n or f or matti n g a n d e dit orial c ha n ges  
Mi n or, t heref ore n ot 
detaile d  
 
A me n d me nt d : 0 4 M arc h 2 0 2 1  
T his a me n d me nt is c o nsi dere d t o be n o n s u bsta ntial base d o n t he criteria set f ort h i n Article 1 0(a) 
of Directi ve 2 0 0 1/ 2 0/ E C of t he E ur o pea n Parlia me nt a n d t he C o u ncil of t he E ur o pea n U ni o n 
beca use it neit her si g nifica ntl y i m pacts t he safet y or p h ysic al/ me ntal i n te grit y of partici pa nts n or 
t he scie ntific val ue of t he st u d y. 
O ver all R ati o n ale f or t he A me n d me nt  
T he p ur p ose of t his a me n d me nt is t o i nc or p orate re g ul at or y a ge n c y fee d bac k a n d ma ke mi n or 
clarificati o ns f or c o nsiste nc y wit hi n t he d oc u me nt.  
Secti o n # a n d N a me  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
1. 3 Sc he d ule of 
Acti vities; A p pe n di x 2: 
S pecifie d l u m bar p u nct ur e at baseli ne 
s h o ul d be perf or m e d if cli nicall y i n dicate d 
Re g ulat or y a ge n c y 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 7 2  
Secti o n # a n d N a me  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
Cli nical La b orat or y Tests  
a n d feasi ble  
fee d bac k 
1. 3 Sc he d ule of A cti vities  Re m o ve d bla n k f o ot n ote  
E dit orial  
5. 1 I n cl usi o n Criteria  
S pecifie d c o ntr ace pti ve g ui da nce f or st u d y 
dr u gs m ust f oll o w la bel, re m o ve d 
t y p o gra p hical err or 
Re g ulat or y a ge n c y 
fee d bac k, e dit orial 
c orrecti o n  
8. 3 A d verse E v e nts a n d 
Seri o us A d verse E v e nts  
Clarifie d t hat S A E state me nt a p plies t o 
st u d y treat me nt  
Clarificati o n  
1 0. 7. 2. 1 Re m ote Visits  
A d de d s h ort -ter m f oll o w-u p t o list of visits 
all o wi n g re m ote visits t o matc h te xt i n 
Secti o n 1. 3  
C o nsiste nc y wit h S o A  
 
 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 7 3  
A me n d me nt c : 1 5 J a n u ar y 2 0 2 1  
T his a me n d me nt is c o nsi dere d t o be s u bsta ntial base d o n t he criteri a set f ort h i n Article 1 0(a) of 
Directi ve 2 0 0 1/ 2 0/ E C of t he E ur o pea n Parlia me nt a n d t he C o u ncil of t he E ur o pea n U ni o n.  
O ver all R ati o n ale f or t he A me n d me nt:  
T he p ur p ose of t his a me n d me nt is t o pr o vi de a d diti o nal o perati o nal fle xi bilit y f or sites a n d 
partici pa nts.  
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 7 4  
Secti o n # a n d N a me  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
1. 1. S y n o psis; 1. 3. Sc he d ule of 
Acti vities; 3. O bjecti ves a n d 
E n d p oi nts; 8. 1. Efficac y 
Assess me nts; 9. 4. 6. Efficac y 
A nal yses  
A d de d R A N O criteria f or C N S 
t u m ors t o sec o n dar y o bjecti ve; 
u p date d i ma gi n g g ui da nce a n d 
a nal ysis la n g ua ge t hr o u g h o ut 
d oc u me nt  
R A N O a d de d t o pr o vi de m ore acc urate 
res p o nse assess me nt of C N S t u m ors 
1. 3. Sc he d ule of Acti vities; 
A p pe n di x 7: Pr o visi o ns f or 
C ha n ges i n St u d y C o n d uct 
D uri n g E xce pti o nal 
Circ u msta nces  
A d de d a p pe n di x a n d g ui da nce 
f or e xce pti o nal circ u msta nces 
a n d eli gi bilit y f or re m ote visits  
Sit e a n d patie nt fle xi bilit y  
1. 3 Sc he d ule of Acti vities; 8. 8. 
Bi o mar kers; 9. 4. 1 0. Bi o mar ker 
A nal yses  
A d de d la n g ua ge f or p ote ntial 
a nal yses if a vaila ble  
A d diti o n of a nal ysis  
1. 3. Sc he d ule of Acti vities  
A d de d/ m o difie d c ollecti o n ti me 
a n d visit wi n d o ws f or p h ysical 
e xa m a n d wei g ht,  
 
 vital si g ns, 
La ns k y/ Kar n ofs k y perf or ma nce 
stat us, patie nt diar y re vie w, a n d 
la b assess me nts 
Sit e a n d patie nt fle xi bilit y; ali g n me nt 
wit h re q uire d o n -site visits 
1. 3. Sc he d ule of Acti vities  
A d de d l u m bar p u nct ure t o 
sc he d ule f or a p plica ble patie nts 
Ali g n me nt wit h p ote ntial a nal ysis f or 
a p plica ble patie nts  
1. 3. Sc he d ule of Acti vities  
Clarifie d t hat s h ort -ter m f oll o w-
u p lasts f or 3 0 da ys fr o m t he 
last a d mi nistrati o n of st u d y 
dr u gs  
Clarificati o n  
2. 2. 1. T e m oz ol o mi de  
Clarifie d te m oz ol o mi de d oses 
i n Part A a n d Part B of st u d y 
Clarificati o n  
2. 3. 1. Be nefit/ Ris k Assess me nt 
of C O VI D -1 9  
A d de d la n g ua ge descri bi n g 
be nefit/ris k assess me nt of trial 
acti vities d uri n g t he C O VI D -1 9 
pa n de mic  
Pr o vi de d rati o nale f or c o n d ucti n g st u d y 
d uri n g C O VI D -1 9 pa n de mic  
4. 1. 2. D ose -Li miti n g T o xicit y 
Deter mi nati o n a n d Ma xi m u m 
T olerate d D o se Defi niti o n 
M o difie d he mat ol o gical e ve nts; 
a d de d g ui da nce f or c o m pleti o n 
of T o xicit y D oc u me ntati o n 
F or m  
M o difie d t o pr o vi de m ore clarit y f or 
he mat ol o gical e ve nts a n d t o all o w G -
C S F; g ui da nce a d de d t o pr o vi de clarit y 
t o i n vesti gat ors 
5. 1. I ncl usi o n Crite ria 
A d de d la n g ua ge o utli ni n g 
re q uire me nts f or e val ua ble 
lesi o ns, C N S t u m ors, a n d 
hist ol o gical verificati o n of 
mali g na nc y  
Pr o vi de d clarit y t o e ns ure patie nt 
p o p ulati o n is acc uratel y e nr olle d  
5. 2. E xcl usi o n Criteria  
A d de d s pecificati o n of s o matic 
or ger mli ne R B m utati o n t o 
criteri o n 2 7 
Clarificati o n  
6. 1. St u d y I nter ve nti o n(s) 
A d de d ne w a p pe n di x a n d 
G ui da nce a d de d f or deter mi ni n g if a 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T
C CI

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 7 5  
Secti o n # a n d N a me  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
A d mi nistere d; A p pe n di x 8: 
A be macicli b D osi n g C hart  
g ui da nce i n 6. 1; a d de d g ui da nce 
f or misse d or v o mite d d oses of 
a be macicli b a n d te m oz ol o mi de  
c ha n ge i n B S A necessitates a c ha n ge i n 
a be macicli b d osi n g; a d de d i nstr ucti o ns 
i n case of misse d or v o mite d d ose 
6. 1. 2. Criteria t o Be gi n 
S u bse q ue nt C ycles of 
Treat me nt  
Re m o ve d he m o gl o bi n ≥8 g/ d L  
C orrecti o n  
6. 2. 
Pre parati o n/ Ha n dli n g/ St ora ge/
Acc o u nta bilit y  
M o difie d re q uire me nt f or 
st ora ge c o n diti o n c o nfir mati o n; 
a d de d s u p pl y, pre parati o n, a n d 
a d mi nistrati o n fle xi bilit y f or 
a ut h orize d st u d y pers o n nel  
A d mi nistrati ve  
6. 5. C o nc o mita nt T hera p y  
Clarifie d t hat li ve vacci nes 
f oll o wi n g treat me nt wit h ot her 
st u d y dr u gs s h o ul d be 
a d mi nistere d acc or di n g t o la bel  
Clarificati o n  
6. 5. 1. Palliati ve Me dici ne a n d 
S u p p orti ve Care  
U p date d g ui da nce f or G -C S F  
All o wa nce of G -C S F i n or der t o 
i ncrease s u p p orti ve care meas ures 
6. 5. 2. S u p p o rti ve Ma na ge me nt 
f or Diarr hea 
C ha n ge d “after eac h l o ose 
st o ol” t o “at t he first si g n of 
l o ose st o ols” 
Re vise d g ui da nce t o ali g n wit h 
I n vesti gat or’s Br oc h ure 
6. 6. 1. 1. D ose M o dificati o n 
G ui da nce d ue t o T o xicities 
C o nsi dere d t o be Attri b ute d t o 
A be macicli b  
U p date d a be macicli b d ose 
m o dificati o n i nstr ucti o ns  
U p date d t o ali g n wit h I n vesti gat or’s 
Br oc h ure a n d t o ma ke d ose a dj ust me nts 
f or he mat ol o gical t o xicit y 
7. 3. L ost t o F oll o w u p  
A d de d “ or desi g nee” t o f oll o w 
u p i nstr ucti o ns  
A d mi nistrati ve  
8. St u d y Assess me nts a n d 
Pr oce d ures  
Re m o ve d “ Pr ot oc ol wai vers or 
e xe m pti o ns are n ot all o we d”  
A d mi nistrati ve  
8. 2. 1. Cli nical Safet y 
La b orat or y Assess me nts  
Re vise d la b orat or y re p ort a n d 
s o urce d oc u me nt la n g ua ge 
A d mi nistrati ve  
1 0. 1. 1. Re g ulat or y a n d Et hical 
C o nsi derati o ns  
Clarificati o n o n i n vesti gat or 
o versi g ht  
A d mi nistrati ve  
1 0. 1. 5. Data Q ualit y Ass ura nce  Re vise d C O A data c ollecti o n 
re q uire me nts 
A d mi nistrati ve  
A p pe n di x 2: Cli nical 
La b orat or y T ests  
A d de d la n g ua ge s pecif yi n g 
l ocal la b orat or y m ust meet 
q ualificati o ns acc or di n g t o l ocal 
re g ulati o ns; c ha n ge d “eac h 
la b orat or y safet y re p ort” t o “t he 
la b orat or y safet y res ults”; 
a d de d beta -H C G, al p ha -
fet o pr otei n, a n d C S F c yt ol o g y 
testi n g f or a p plica ble patie nts 
A d mi nistrati ve; beta -H C G, al p ha -
fet o pr otei n, a n d C S F c yt ol o g y a dde d t o 
assess t u m or res p o nse f or a p plica ble 
patie nts  
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 7 6  
Secti o n # a n d N a me  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
A p pe n di x 4: Li ver Safet y: 
S u g geste d Acti o ns a n d F oll o w -
u p Assess me nts  
U p date d ta ble of tests  
U p date d t o ali g n wit h safet y g ui da nce  
T hr o u g h o ut  
Mi n or e dit orial a n d f or matti n g 
c ha n ges 
Mi n or, t heref ore n ot detaile d  
 
 
 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 7 7  
A me n d me nt b : 0 8 J ul y 2 0 2 0  
T his a me n d me nt is c o nsi dere d t o be n o n s u bsta ntial base d o n t he criteria set f ort h i n Article 1 0(a) 
of Directi ve 2 0 0 1/ 2 0/ E C of t he E ur o pea n Parlia me nt a n d t he C o u ncil of t he E ur o pea n U ni o n 
beca use it neit her si g nif ica ntl y i m pacts t he safet y or p h ysic al/ me ntal i nte grit y of partici pa nts n or 
t he scie ntific val ue of t he st u d y. 
O ver all R ati o n ale f or t he A me n d me nt:  
T his a me n d me nt i nc or p orates c h a n ges acc or di n g t o re g ulat or y a ge nc y fee d bac k i n a d diti o n t o 
e dits ma de t o pr o vi de i m pr o ve d clarit y f or sites.  
Secti o n # a n d N a me  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
Title Pa ge  
A d de d re g ulat or y a ge n c y i de ntifier 
n u m bers  
Per re g ulat or y a ge nc y 
fee d bac k 
Secti o n 1. 3 Sc he d ule of 
Acti vities  
Re m o ve d vital si g ns e val uati o n o n C ycle 
5 -n Da y 1 5  
E dit orial err or, Da y 1 5 
e val uati o n di d n ot ali g n 
wit h i nstr ucti o nal te xt  
Secti o n 1. 3 Sc he d ule of 
Acti vities  
U p date t o p h ysical e xa m details  
Per re g ulat or y a ge nc y 
fee d bac k 
Secti o n 1. 3 Sc he d ule of 
Acti vities  
U p date t o ra di ol o gic i ma gi n g n otes  
Per re g ulat or y a ge nc y 
fee d bac k 
Secti o n 2. 3 Be nefit/ Ris k 
Assess me nt  
C orrecti o n t o f oc us t he b e nefit o n t he 
pri mar y o bjecti ve  
Per re g ulat or y a ge nc y 
fee d bac k 
Secti o n 4. 3 J ustificati o n 
f or D ose 
A d de d C Y P 3 A mat urati o n o n a be maci cli b 
P K e x p os ure bac k gr o u n d  
Per re g ulat or y a ge nc y 
fee d bac k 
Secti o n 6. 1 St u d y 
I nter ve nti o ns 
A d de d dr u g s o urci n g i nf or mati o n  
Per re g ulat or y a ge nc y 
fee d bac k 
Secti o n 8. 1 Efficac y 
Assess me nts  
A d de d details o n assessi n g f or gr oss b o ne 
a b n or malities  
Per re g ulat or y a ge nc y 
fee d bac k 
Secti o n 8. 2. 1. 2  
U p date t o re n al f u ncti o n m o nit ori n g 
g ui da n ce  
C o nsiste nc y wit h 
I n v esti gat or’s Br oc h ure 
Secti o n 1 0. 1. 3 Data 
Pr otecti o n  
A d de d clarificati o n t hat s p o ns or will verif y 
t hat partici pa nts ha ve c o nse nte d, i n writi n g, 
t o direct access t o t heir me dical rec or ds f or 
trial-relate d m o nit ori n g, a u dit, I R B/ E R B 
re vie w, a n d re g ulat or y i ns pecti o n 
Per re g ulat or y a ge nc y 
fee d bac k 
Secti o n 1 0. 1. 4. 
Disse mi nati o n of Cli nical 
St u d y Data  
A d de d la n g ua ge re gar di n g t he s u b missi o n 
of a re p ort or s u m mar y of researc h t o 
re g ulat or y b o dies 
Per re g ulat or y a ge nc y 
fee d bac k 
Secti o n 1 0. 1. 8 
P u blicati o n P olic y  
A d de d descri pti o n of p u blicati o n p olic y  
Per re g ulat or y a ge nc y 
fee d bac k 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 7 8  
Secti o n # a n d N a me  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
T hr o u g h o ut  
Mi n or e dit orial a n d f or m atti n g c h a n ges  
Mi n or, t heref ore n ot 
detaile d  
 
 
 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 7 9  
A me n d me nt a : 1 7 A pril 2 0 2 0 
T his a me n d me nt is c o nsi dere d t o be s u bsta ntial base d o n t he criteri a set f ort h i n Article 1 0(a) of 
Directi ve 2 0 0 1/ 2 0/ E C of t he E ur o pea n Parlia me nt a n d t he C o u ncil of t he E ur o pea n U ni o n.  
O ver all R ati o n ale f or t he A me n d me nt:  
T his a me n d me nt i nc or p orates c h a n g es acc or di n g t o re g ulat or y a ge nc y fee d bac k i n a d diti o n t o 
e dits ma de t o pr o vi de i m pr o ve d clarit y f or sites.  
Secti o n # a n d N a me  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
Secti o n 1. 1. S y n o psis 
(I nter ve nti o n Gr o u ps a n d 
D urati o n), Secti o n 1. 2. 
Sc he ma, Secti o n 6. 1 . 
St u d y I nter v e nti o n(s) 
A d mi nistere d  
U p date d c o h ort la bels a n d descri pti o ns  
A d de d clarit y t o d osi n g 
c o h orts  
Secti o n 1. 3. Sc he d ule of 
Acti vities, A p pe n di x 2:  
Cli nical La b orat or y Tests  
 
Per re g ulat or y fee d b ac k 
Secti o n 1. 3. Sc he d ule of 
Acti vities  
S plit vital si g ns fr o m p h ysical e xa m r o w; 
pr o vi de d a d diti o nal c ollecti o n g ui da nce  
Create d ne w r o w a n d 
detaile d i nstr ucti o ns f or 
clarit y 
Secti o n 1. 3. Sc he d ule of 
Acti vities  
A d de d visit wi n d o ws t o p h y sical e x a ms, 
La ns k y/ K ar n ofs k y p erf or ma nce stat us, 
pre g na nc y t ests, a n d la b assess me nts  
Wi n d o ws a d de d t o 
pr o vi de fle xi bilit y  
Secti o n 1. 3. Sc he d ule of 
Acti vities  
Re vise d n otes f or a d v erse e ve nt 
c ollecti o n/ C T C A E gra di n g i n t he 
C o nti n ue d Access Peri o d  
Clarifi cati o n of w he n 
vital si g ns a n d la b orat or y 
tests s h o ul d be 
perf or me d  
Secti o n 1. 3. Sc he d ule of 
Acti vities  
A d de d ti me p oi nt t o c ollect q uesti o n naire if 
met h o d of a be macicli b a d mi nistrati o n is 
c ha n ge d at a n y p oi nt d uri n g t he trial  
A d diti o nal ti me p oi nt f or 
m ore  r o b ust data set 
Secti o n 1. 3. Sc he d ule of 
Acti vities  
Re vise d n otes f or diar y c o m pleti o n  
Clarificati o n t hat 
care gi v ers ca n c o m plete 
t he diar y if nee de d 
Secti o n 1. 3. Sc he d ule of 
Acti vities  
A me n de d i nstr ucti o ns f or he mat ol o g y, 
cli nical c he mistr y, c ystati n C, a n d ser u m or 
uri ne pre g n a nc y test  
Clarificati o n o n ti mi n g of 
sa m ples 
Secti o n 2. 2. Bac k gr o u n d  
A d de d a se nte nce a b o ut t he 5 -year 
p ostrela pse s ur vi val r ate f or pe diatric s oli d 
t u m ors t o e m p hasize u n met nee d f or t his 
st u d y 
Clarificati o n  
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T
C CI

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 8 0  
Secti o n # a n d N a me  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
Secti o n 2. 2. 1. 
Te m oz ol o mi de  
A me n de d a t u m or t y pe tar gete d b y 
te m oz ol o mi de i n pe diatric patie nts  
C orrecti o n a n d 
clarificati o n  
Secti o n 2. 2. 4. Precli nical 
a n d Cli nical Rati o nale  
A d de d clarificati o n of cli nicall y rele va nt 
ra n ge f or a be m acicli b 
Per re g ulat or y fee d b ac k  
Secti o n  2. 3. Be nefit/ Ris k 
Assess me nt  
A d de d la n g ua ge clarif yi n g a d diti o nal 
p ote ntial be nefit of c o m bi nati o n tar gete d 
t hera pies 
Clarificati o n  
Secti o n 4. 1. 1. D ose 
Escalati o n Met h o d  
Re vise d D L T -e v al ua ble descri pti o n  
Descri pti o n re vise d f or 
c o nsiste nc y  
Secti o n 4. 1. 1. D ose 
Escalati o n Met h o d  
A d de d details of safet y re vie ws wit hi n 
d ose escal ati o n a n d e x pa nsi o n c o h orts i n 
t he e ve nt of Gra de 5 A Es.  Als o a d de d 
c o nsi derati o ns f or starti n g Part B at a d os e 
of 5 5 m g/ m 2. 
Per re g ulat or y fee d b ac k  
Secti o n 4. 1. 1. D ose 
Escal ati o n Met h o d  
A d de d state me nt r e gar di n g e nr oll me nt 
s us pe nsi o n i n t he e ve nt of a n y Gra de 5 
a d verse e ve nt  
Per re g ulat or y fee d b ac k  
Secti o n 4. 1. 2. 
D ose -Li miti n g T o xicit y 
Deter mi nati o n  
Re m o val of cli nicall y n o nsi g nifica nt, 
treata ble, or re v ersi ble la b orat or y 
a bn or malities; re m o val of electr ol yte 
a b n or malities res p o nsi ve t o 
s u p ple me ntati o n wit hi n 7 da ys; r e vise d 
Gra de 3 diarr hea e v e nt; re vise d electr ol yte 
a b n or malities e ve nt; a d d e d clarifi cati o n f or 
Gra de ≥3 a m yl ase or li pase e ve nt; re m o v e d 
platelet c o u nt; a d de d Gra de ≥3 
t hr o m b oc yt o pe ni a wit h cli nicall y 
si g nifica nt blee di n g; a d de d Gra d e ≥4 
ne utr o pe nic fe ver  
Per re g ulat or y fee d b ac k  
Secti o n 4. 3. J ustificati o n 
f or D ose 
Pr o vi de d a d diti o nal j ustificati o n f or d ose 
le vels i n Part B of st u d y 
Per re g ulat or y fee d b ac k  
Secti o n 5. 1. I n cl usi o n 
Criteria  
M o difie d I ncl usi o n Criteri o n 3 t o s pecif y 
t hat t he criteri o n a p plies t o t he st u d y part 
c urre ntl y e nr olli n g  
M o difie d f or clarit y  
Secti o n 5. 1. I n cl usi o n 
Criteria  
A d de d resi d ual p eri p heral se ns or y 
ne ur o pat h y as a n e x ce pti o n t o I ncl usi o n 
Criteri o n 6  
Clarificati o n of eli gi ble 
p o p ulati o n  
Secti o n 5. 2. E x cl usi o n 
Criteria  
Re m o ve d refere n ce t o r a n d o mizati o n a n d 
re place d wit h C ycl e 1 Da y 1 fr o m 
E x cl usi o n Criteri o n 1 4  
Clarificati o n  
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 8 1  
Secti o n # a n d N a me  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
Secti o n 5. 2. E x cl usi o n 
Criteria  
A d de d E x cl usi o n Criteri o n 2 6 relate d t o 
b o wel o bstr ucti o n  
Per re g ulat or y fee d b ac k  
Secti o n 5. 2. E x cl usi o n 
Criteria  
A d de d “ or str o n g i n hi bit ors of U G T 1 A 1 ” 
t o E x cl usi o n Criteri o n 2 2 
Per re g ulat or y fee d b ac k  
Secti o n 5. 2. E x cl usi o n 
Criteria  
Re m o val of “( 4 m o nt hs f or st u dies 
co n d ucte d i n J a pa n)” fr o m E x cl usi o n 
Criteri o n 2 5  
Clarificati o n of eli gi ble 
p o p ulati o n  
Secti o n 5. 2. E x cl usi o n 
Criteria  
A d de d E x cl usi o n Criteri o n 2 7  
E x cl u de patie nts wit h 
k n o w n reti n o blast o ma 
m utati o n  
Secti o n 6. 1. St u d y 
I nter ve nti o n(s) 
A d mi nistere d  
A d de d st ate me nt directi n g rea der t o a n 
a be maci cli b d osi n g c h art base d o n patie nt’s 
B S A le vel  
St u d y t o ol pr o vi des 
assi g ne d d os e  
Secti o n 6. 1. St u d y 
I nter ve nti o n(s) 
A d mi nistere d  
Re m o ve d state me nts re gar di n g s o urci n g of 
st u d y dr u gs 
S o urci n g c o vere d i n 
ot her d oc u me nts  o utsi de 
pr ot oc ol  
Secti o n 6. 1. 1. Patie nts 
wit h Diffic ult y 
S wall o wi n g Aft er 
I nitiati n g Treat me nt 
A d de d ne w s ecti o n t o pr o vi de g ui da nce f or 
patie nts ha vi n g diffic ult y wit h s wall o wi n g  
Per re g ulat or y fee d b ac k  
Secti o n 6. 1. 2. Criteria t o 
Be gi n S u bse q ue nt C ycle s 
of Treat me nt  
A d de d criteri o n relate d t o wei g ht a n d B S A  
E ns ures patie nts are still 
wit hi n size re q uire d i n 
eli gi bilit y criteria  
Secti o n 6. 5. C o nc o mita nt 
T hera p y  
Re vise d ca n na bis a n d ca n na bis pr o d uct use 
la n g u a ge; la n g ua ge re gar di n g C Y P e nz y me 
s u bstrates a n d de x a met has o ne t hera p y 
a d de d  
Clarificati o n of 
acce pta ble c o n c o mita nt 
t hera p y 
Secti o n 6. 5. C o nc o mita nt 
T hera p y  
A d de d ca uti o nar y la n g ua ge re gar di n g use 
of str o n g i n hi bit ors of U G T 1 A 1  
Per re g ulat or y fee d b ac k  
Secti o n 6. 6. 1. 2. D ose 
M o dificati o n G ui da nce 
d ue t o T o xicities 
C o nsi dere d t o be 
Attri b ute d t o Iri n oteca n  
D ose m o dificati o n g ui da nce f or iri n oteca n 
a d de d  
Per re g ulat or y fee d b ac k  
Secti o n 8. 1. 1. Pr o d uct 
Acce pt a bilit y a n d 
Palata bilit y Assess me nts  
A d de d la n g ua ge if patie nt c ha n ges met h o d 
of a be ma cicli b a d mi nistrati o n at a n y p oi nt 
d uri n g t he tri al  
A d diti o nal ti me p oi nt f or 
m ore r o b ust data set  
Secti o n 8. 2. Safet y 
Assess me nts  
Pr o vi de d a d diti o nal details re gar di n g 
m o nit ori n g a n d re vie w of safet y data  
Per re g ulat or y fee d b ac k  
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 8 2  
Secti o n # a n d N a me  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
Secti o n 8. 5. 1. Patie nt 
Diar y  
A d de d refere nce t o care gi ver  
Clarificati o n  
A p pe n di x 2:  Cli nical 
La b orat or y T ests  
Re m o ve d refere n ce t o r ec o ncili n g l ocal a n d 
ce ntral la bs a n d 
 
 
Clarificati o n a n d 
re g ulat or y fee d bac k, 
res pecti vel y 
A p pe n di x 6:  I n d ucers 
a n d Str o n g I n hi bit ors of 
C Y P 3 A  
A d de d f o ot n ote a a n d u p date d M o derate 
I n d u cers of C Y P 3 A 
Clarificati o n a n d re m o val 
of ite m fr o m list t o ali g n 
wit h m ost rece nt 
g ui da nce  
T hr o u g h o ut  
Mi n or e dit orial a n d f or m atti n g c h a n ges  
Mi n or, t heref ore n ot 
s u m marize d 
 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T
C CI

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 8 3  
1 1.  
Refere nces   
A be macicli b [ U S pac ka ge i nsert]. I n dia na p olis, I N: Eli Lill y a n d C o m pa n y; 2 0 1 9 . 
Ba gat ell R, L o n d o n W B, Wa g ner L M, V oss S D, Ste wart C F, M aris J M, Kretsc h mar C, C o h n S L. 
P hase II st u d y of iri n oteca n a n d te m oz ol o mi de i n c hil dre n wit h rela ps e d or refract or y 
ne ur o blast o ma: a C hil dre n’s O nc ol o g y Gr o u p st u d y. J Cli n O nc ol. 2 0 1 1; 2 9 ( 2): 2 0 8-2 1 3.  
Ba gat ell R, N orris R, I n gle A M, A hre n C, V oss S, F o x E, Little A R, Wei gel BJ, A da ms o n P C, 
Bla ne y S. P hase I trial of te msir oli m us i n c o m bi nati o n wit h iri n oteca n a n d te m oz ol o mi de i n 
c hil dre n, a d oles ce nts a n d y o u n g a d ults wit h rel a pse d or refract or y s oli d t u m ors: a C hil dre n’s 
O nc ol o g y Gr o u p St u d y. Pe di atr Bl o o d C a ncer. 2 0 1 4; 6 1 ( 5): 8 3 3-8 3 9.  
Bart eli n k I H, Ra de ma k er C M, Sc h o b be n A F, va n de n A n ker J N. G ui deli nes o n pae diatric d osi n g 
o n t he basis of de vel o p m e ntal p h ysi ol o g y a n d p h ar mac o ki netic c o nsi d erati o ns. Cli n 
P h ar m ac oki net . 2 0 0 6; 4 5( 1 1): 1 0 7 7-9 7. htt ps:// d oi. or g/ 1 0. 2 1 6 5/ 0 0 0 0 3 0 8 8 -2 0 0 6 4 5 1 1 0 -0 0 0 0 3  
Bla ke MJ, Castr o L, Lee der J S, Kear ns G L. O nt o ge n y of dr u g meta b olizi n g e nz y mes i n t he 
ne o nate. Se mi n Fet al Ne o n at al Me d . 2 0 0 5; 1 0( 2): 1 2 3-1 3 8.  
htt ps:// d oi. or g/ 1 0. 1 0 1 6/j.si n y. 2 0 0 4. 1 1. 0 0 1  
B urc hill S A, Beis ke  K, S hi ma da H, et al. Rec o m m e n dati o ns f or t he sta n d ar dizati o n of b o ne 
marr o w diseas e assess me nt a n d re p orti n g i n c hil dr e n wit h ne ur o blast o ma o n be half of t he 
I nter nati o nal N e ur o blast o ma Res p o nse Criteria B o ne Marr o w W or ki n g Gr o u p . C a ncer. 
2 0 1 7; 1 2 3( 7): 1 0 9 5 -1 1 0 5. htt ps:// d oi. or g/ 1 0. 1 0 0 2/c ncr. 3 0 3 8 0  
Case y D A, We xler L H, Merc ha nt M S, C h o u AJ, Mer ola P R, Price A P, Me yers P A. Iri n oteca n 
a n d te m oz ol o mi de f or E wi n g sarc o ma: t he Me m orial Sl oa n -Ketteri n g e x perie nce. P e di atr 
Bl o o d C a nce r. 2 0 0 9; 5 3( 6): 1 0 2 9 -1 0 3 4.  
Cas h T, A g uilera D, M ac y M, H off ma n L, D orris K, Mc Crac k e n C, Ha n berr y B, Cast elli n o R, 
Mac D o nal d T, Wet m ore C. P hase 1 st u d y of a b e m acicli b i n c hil dre n wit h r ec urre nt a n d 
refract or y s oli d t u m ors i ncl u di n g mali g na nt br ai n t u m ors [abstract]. I n: A A C R -N CI -E O R T C 
I nter nati o nal C o nfere nce o n M olec ular Tar gets a n d Ca ncer T h era p e utics; 2 6 -3 0 Oct o ber 2 0 1 9 ; 
B ost o n, M A ; 2 0 1 9. A bstract nr C 0 0 2. 
[ C C L G] C hil dre n’s Ca ncer a n d Le u kae mia Gr o u p . Ca ncer Dr u gs Fact sheet.  2 0 1 6. A vaila ble at: 
htt ps:// w w w.ccl g. or g. u k/ write/ Me dia U pl oa ds/ P u blicati o ns/ Dr u g % 2 0 Facts h eets % 2 0( P D Fs)/ Dr
u g _ Facts h eet _ Te m oz ol o mi de _ We b. p df.  
Cefal o G, Massi mi n o M, R u g gier o A, Bar o ne G, Ri d ola V, S preafic o F, P ote pa n P, A bate M E, 
Mascari n M, G arrè M L, Peril o n g o G, Ma d o n E, C ol osi m o C, R iccar di R. T e m oz ol o mi de is a n 
acti ve a ge nt i n c hil dre n wit h rec urre nt me d ull o blast o ma/ pri miti ve ne ur oect o der mal t u m or: a n 
Italia n m ulti-i nstit uti o nal p hase II tri al. Ne ur o O nc ol. 2 0 1 4; 1 6( 5): 7 4 8 -7 5 3.  
Cesc hel S, Cas ott o V, Valsecc hi M G, Ta mar o P, Ja n k o vic M, Ha n a u G, F ossati F, Pill o n M, 
R o n delli R, Sa n dri A, Sil vestri D, Ha u pt R, C utti ni M. S ur vi val after rel a ps e i n c hil dre n wit h 
s oli d t u m ors: a f oll o w-u p st u d y fr o m t he It alia n off -t hera p y re gistr y. Pe di atr Bl o o d C a ncer. 
2 0 0 6; 4 7( 5): 5 6 0 -5 6 6.  
C oc kcr oft D W, Ga ult M H. Pre dicti o n of creati ni ne cleara nce fr o m s er u m creati ni ne. Ne p hr o n . 
1 9 7 6; 1 6( 1): 3 1 -4 1.  
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 8 4  
C o he n KJ, P ollac k I F, Z h o u T, B u xt o n A, H ol mes EJ, B ur ger P C, Brat DJ, R ose n bl u m M K, 
Ha milt o n R L, La ve y R S,  Hei de ma n R L. Te m oz ol o mi de i n t he treat me nt of hi g h -gra de gli o mas 
i n c hil dre n: a re p ort fr o m t he C hil dre n’s O nc ol o g y Gr o u p. Ne ur o O nc ol. 2 0 1 1; 1 3 ( 3): 3 1 7-3 2 3.  
C o o k Sa n gar M L, Ge n o v esi L A, Na ka m ot o M W, Da vis MJ, K n o bla u g h S E, Ji P, Millar A, 
Wai n wri g ht BJ, Ol s o n J M. I n hi biti o n of C D K 4/ 6 b y pal b o cicli b si g nifica ntl y e xte n ds s ur vi val 
i n me d ull o blast o ma patie nt-deri ve d x e n o graft m o use m o dels. Cli n C a ncer Res. 
2 0 1 7; 2 3( 1 9): 5 8 0 2 -5 8 1 3.  
Cra wf or d J, Caserta C, R oila F ; E S M O G ui deli nes W or ki n g Gr o u p. He mat o p oietic gr o wt h 
fact ors: E S M O C li nical P ractice G ui deli nes f or t he a p plicati o ns. A n n O nc ol. 2 0 1 0; 2 1(s u p pl 
5): 2 4 8 -2 5 1.  
Da nt o nell o T M, I nt -Vee n C, Wi n kler P, Le us c h n er I, Sc h uc k A, Sc h mi dt B F, L o c h b ue hler H, 
Kirsc h S, Hall me n E, Veit -Frie dri c h I, Bielac k S S, Ni g gli F, Kaza n o ws ka B, La d e nstei n R, 
Wie be T, Kli n ge biel T, Tre u ner J, K osciel nia k E. I nitial patie nt c haracteristic s ca n pre dict 
patter n a n d ris k of rela ps e i n l ocalize d r ha b d o m y osarc o ma. J Cli n O nc ol. 2 0 0 8; 2 6( 3): 4 0 6 -4 1 3.  
De Si o L, Mila n o G M, C astella n o A, J e n k ner A, Fi da ni P, D o mi nici C, D o nfra ncesc o A. 
Te m oz ol o mi de i n resista nt or rela pse d p e diatric s oli d t u m ors  [ p u blis he d c orrecti o n a p p ears i n 
Pe di atr Bl o o d C a ncer . 2 0 0 6; 4 7( 5): 6 4 7-6 4 8] . Pe di atr Bl o o d C a ncer. 2 0 0 6; 4 7( 1): 3 0 -3 6.  
Di Gia n natale A, Dias -G astellier N, De v os A, Mc  H u g h K, B o u b a ker A, C o ur b o n F, Versc h u ur 
A, D ucass o ul S, Male kza de h K, Casa n o va M, A m or os o L, C h ast a g ner P, Z waa n C M, M u nzer 
C, Aerts I, La n d ma n -Par ker J, Riccar di R, Le Del e y M C, Ge oer ger B, R u bie H. P hase II st u d y 
of te m oz ol o mi de i n c o m bi nati o n wit h t o p oteca n ( T O T E M) i n rela ps e d or refract or y 
ne ur o blast o ma: a E ur o pea n I n n o vati ve T h era pies f or C hil d re n wit h Ca ncer-SI O P -E ur o pea n 
Ne ur o blast o ma st u d y. E ur J C a ncer. 2 0 1 4; 5 0( 1): 1 7 0 -1 7 7.  
Dic kler M N, T ola n e y S M, R u g o H S, C ortés J, Diéras V, Patt D, Wil ders H, H u dis C A, 
O’ S ha u g h ness y J, Za m or a E, Yar dl e y D A, Fre nzel M, K o uste nis A, Bas el ga J. M O N A R C H 1, 
a p hase II st u d y of a b e macicli b, a C D K 4 a n d C D K 6 i n hi bit or, as a si n gle a ge nt, i n patie nts 
wit h refract or y H R +/ H E R 2 - metastatic breast ca n cer. Cli n C a ncer Res.  2 0 1 7; 2 3( 1 7): 5 2 1 8 -
5 2 2 4.  
Di n ut u xi ma b  [ pac ka ge i nsert]. Sil ver S pri n g, M D : U nite d T hera pe utics  C or p.; 2 0 1 5 . 
D o wless M, L o wer y C D, S hac klef or d T, Re ns c hler M, Ste p he ns J, Flac k R, Bl osser W, G u pta S, 
Ste wart J, We bster Y, De m pse y J, Va n W ye A B, E bert P, I v erse n P, Olse n J B, G o n g X, 
B uc ha n a n S, H o u g ht o n P, Sta ncat o L. A be macicli b is acti ve i n precli nical m o de ls of E wi n g 
sarc o ma via m ulti pr o n ge d re g ulati o n of cell c ycle, D N A met h yl ati o n, a n d i nterfer o n pat h wa y 
si g nali n g. Cli n C a ncer Res. 2 0 1 8; 2 4( 2 3): 6 0 2 8 -6 0 3 9.  
D u B ois S G, Marac helia n A, F o x E, K u d g us R A, Rei d J M, Gr os he n S, Mal var J, Ba gatell R, 
Wa g ner L, Maris J M, Ha w ki ns R, C o urtier J, Lai H, G o o darzia n F, S hi ma da H, Czar nec ki S, 
Tsa o -Wei D, Matt ha y K K, M osse Y P. P hase I st u d y of t he a ur ora A ki nas e i n hi bit or aliserti b 
i n c o m bi nati o n wit h iri n oteca n a n d t e m oz ol o mi de f or patie nts wit h rela ps e d or refract or y 
ne ur o blast o ma : a N A N T (N e w A p pr oac h es t o N e ur o blast o ma T hera p y) trial. J Cli n O nc ol. 
2 0 1 6; 3 4 ( 1 2): 1 3 6 8-1 3 7 5.  
Eise n ha uer E A, T herasse P, B o gaerts J, Sc h wartz L H, Sar ge nt D, F or d R, Da nce y J, Ar b uc k S, 
G w yt h er S, M o o ne y M, R u bi nstei n L, S ha n k ar L, D o d d L, Ka pla n R, Lac o m be D, Ver weij J. 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 8 5  
Ne w res p o nse e v al uati o n criteria i n s oli d t u m ors: re vise d R E CI S T g ui deli ne ( ver si o n 1. 1). E ur 
J C a ncer. 2 0 0 9; 4 5( 2): 2 2 8 -2 4 7.  
Ge oer ger B, B o ur dea ut F, D u B ois S G, Fisc h er M, Geller JI, G ottar d o N G, Mara belle A, Pears o n 
A DJ, M o da k S, Cas h T, R o bi ns o n G W, M otta M, Mata n o A, B h a nsali S G, D o bs o n J R, 
Paras ura ma n S, C hi S N. A p hase I st u d y of  t he C D K 4/ 6 i n hi bit or ri b ocicli b ( L E E 0 1 1) i n 
pe diatric patie nts wit h mali g na nt r h a b d oi d t u m ors, ne ur o blast o ma, a n d ot h er s oli d t u m ors. Cli n 
C a ncer Res. 2 0 1 7; 2 3 ( 1 0): 2 4 3 3-2 4 4 1.  
Ge oer ger B, Vass al G, D oz F, O’ Q ui gle y J, Wartelle M, Wats o n AJ, Ra q ui n Ma, Fra p p az D, 
C hasta g n er P, Ge ntet J C, R u bie H, C o ua net D, Ge offra y A, Djafari L, Mar gis o n G P, Pei n F. 
D ose fi n di n g a n d O 6 -al k yl g ua ni ne -D N A al k yltra nsferas e st u d y of cis plati n c o m bi ne d wit h 
te m oz ol o mi de i n pae diatric s oli d mali g na ncies. Br J C a ncer. 2 0 0 5; 9 3( 5): 5 2 9 -5 3 7.  
G oetz M P, T oi M, Ca m p o ne M, S o h n J, Pal uc h -S hi m o n S, H u o ber J, Par k I H, Tré d a n O, C he n 
S C, Ma ns o L, Free d m a n O C, Gar nica J aliffe G, F orrester T, Fre nzel M, Barri ga S, S mit h I C, 
B o ura y o u N, Di Le o A. M O N A R C H 3: a be maci cli b as i nitial t hera p y f or a d va n ce d breast 
ca ncer. J Cli n O nc ol. 2 0 1 7; 3 5( 3 2): 3 6 3 8 -3 6 4 6.  
G o n g X, Lit c hfiel d L M, We bster Y, C hi o L C, W o n g S S, Ste wart T R, D o wl ess M, Ze n g Y, 
T orres R, B o e h n ke K, M ur C, Mar u gá n C, Ba g uer o C, Y u C, Bra y S M, W ul ur I H, Bi C, C h u 
S, Qia n H R, I v erse n P W, Merz o u g F F, Ye X S, Rei n har d C, De Di os A, D u J, Cal d well C W, 
Lal le n a MJ, Bec k ma n n R P, B uc ha n a n S G. Ge n o mic a berrati o ns t hat acti vat e D-t y pe c ycli ns 
are ass o ciate d wit h e n h a nce d se nsiti vit y t o t he C D K 4 a n d C D K 6 i n hi bit or a be maci cli b. 
C a ncer Cell. 2 0 1 7; 3 2( 6): 7 6 1 -7 7 6.  
G uerra -G arc ía P, Mars hall L V, C oc kle J V, Ra mac ha n dra n P V, Sara n F H, J o nes C, Carceller F. 
C halle n gi n g t he i n discri mi nate use of te m oz ol o mi de i n pe diatric hi g h -gra d e gli o mas: A re vie w 
of past, c urre nt, a n d e m er gi n g t hera pies. Pe di atr  Bl o o d C a ncer . 2 0 2 0; 6 7( 1):e 2 8 0 1 1. 
Ha s hiz u me R, Z ha n g A, M ueller S, Pra d os M D, L ulla R R, G ol d ma n S, Saratsis A M, Mazar A P, 
Ste g h A H, C he n g S Y, H or bi ns ki C, Haas -K o ga n D A, Sar kari a J N, Wal d ma n T, J a mes C D. 
I n hi biti o n of D N A d a ma ge re pair b y t he C D K 4/ 6 i n hi bit or pal b ocicli b dela ys irra diate d 
i ntracra ni al at y pi cal terat oi d r ha b d oi d t u m or a n d gli o blast o ma x e n o graft re gr o wt h. Ne ur o 
O nc ol. 2 0 1 6 ; 1 8( 1 1): 1 5 1 9-1 5 2 8.  
H o u g ht o n PJ, Ste wart C F, C hes hire PJ, Ric h m o n d L B, Kirstei n M N, P o q uette C A, Ta n M, 
Frie d ma n H S, Bre nt T P. A ntit u m or acti vit y of te m oz ol o mi de c o m bi ne d wit h iri n oteca n is 
partl y i n de p e n de nt of O 6 -met h yl g ua ni n e -D N A met h yltra nsferase a n d mis matc h re pair 
p he n ot y p es i n x e n o graft m o dels. Cli n C a ncer Res. 2 0 0 0; 6( 1 0): 4 1 1 0 -4 1 1 8.  
H u m mel T R, W a g ner L, A hre n C, F o ula di M, Rei d J M, Mc G o ver n R M, A mes M M, G il berts o n 
RJ, H ort o n T, I n gl e A M, W ei gel B, Bla ne y S M. A pe diatric p has e 1 trial of v ori n ostat a n d 
te m oz ol o mi de i n rela pse d or refract or y pri mar y brai n or s pi nal c or d t u m ors: a C hil dre n’s 
O nc ol o g y Gr o u p p has e 1 c o ns orti u m st u d y. Pe di atr Bl o o d C a ncer . 2 0 1 3;6 0( 9): 1 4 5 2 -1 4 5 7.  
Iri n ot eca n [ U S pac k a ge i nsert]. Ne w Y or k, N Y: Pfizer I nj ecta bles; 2 0 2 0 . 
J o h nst o n S, Marti n M, Di Le o A, I m S A, A wa d a A, F orrester T, Fre nzel M, Har de b ec k M C, C o x 
J, Barri ga S, T oi M, I wat a H, G oetz M P. M O N A R C H 3 fi nal P F S: a ra n d o mize d st u d y of 
a be maci cli b as i nitial t hera p y f or a d va nce d breast ca ncer. N PJ Bre ast C a ncer. 2 0 1 9; 5: 5.  
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 8 6  
K ozare wicz P. Re g ulat or y pers pecti ves o n acce pta bilit y testi n g of d osa ge f or ms i n c hil dr e n. I nt J 
P h ar m. 2 0 1 4 ; 4 6 9( 2): 2 4 5-2 4 8.  
K ur uc u N, Sari N, Il ha n I E. Iri n oteca n a n d te m oz ol o mi de treat me nt f or rela pse d E wi n g s arc o m a: 
a si n gle -ce nt er e x perie nce a n d re vi e w of t he literat ure. Pe di atr He m at ol O n c ol. 2 0 1 5; 3 2( 1): 5 0 -
5 9.  
K us h ner B H, Kra mer K, M o da k S, C he u n g N K. Iri n oteca n pl us te m oz ol o mi de f or rel a pse d or 
refract or y n e ur o blast o ma. J Cli n O nc ol. 2 0 0 6; 2 4( 3 3): 5 2 7 1 -5 2 7 6.  
La d e nstei n R, P ötsc h ger U, Valtea u -C o u a net D, et al.; I nterle u ki n 2 wit h a nti -G D 2 a nti b o d y 
c h 1 4. 1 8/ C H O ( di n ut u xi ma b beta) i n patie nts wit h hi g h -ris k n e ur o blast o ma ( H R-
N B L 1/ SI O P E N): a m ulti ce ntre, ra n d o mise d, p has e 3 trial. L a ncet O nc ol . 2 0 1 8; 1 9( 1 2): 1 6 1 7-
1 6 2 9. htt ps:// d oi. or g / 1 0. 1 0 1 6/ S 1 4 7 0-2 0 4 5( 1 8) 3 0 5 7 8 -3  
La d e nstei n R L, P oetsc h ger U, V altea u -C o ua n et D, et al.; Ra n d o mizati o n of d ose -re d u ce d 
s u bc uta ne o us i nterle u ki n-2 (scI L 2) i n mai nte na nce i m m u n ot hera p y (I T) wit h a nti -G D 2 
a nti b o d y di n ut u xi ma b beta ( D B) l o n g -ter m i nf usi o n ( L TI) i n fr o nt– li ne hi g h-ris k 
ne ur o blast o ma patie nts: Earl y res ults fr o m t he H R -N B L 1/ SI O P E N trial. J Cli n O nc ol.  
2 0 1 9; 3 7 (1 5 ):1 0 0 1 3 -1 0 0 1 3 . htt ps:// d oi. or g/ 1 0. 1 0 1 6/ S 1 4 7 0 -2 0 4 5( 1 8) 3 0 5 7 8 -3  
La u L , L o n d o n  W B  ( 2 0 1 2). Rec urre nt n e ur o blast o ma . Hir o y u ki  S hi ma da ( E d.) . 
htt p:// w w w.i ntec h o pe n.c o m/ b o o ks/ ne ur o blast o ma -prese nt -a n d-f ut ure/rec urre nt-ne ur o bl ast o ma  
Le Te uff G, Casta ne d a -H ere dia A, D uf o ur C, J as pa n T, Cal m o n R, De v os A, Mc H u g h K, 
Le bl o n d P, Fra p p az D, Aerts I, Z waa n C M, D ucass o u S, C hasta g ner P, V ersc h u ur A, 
C orra di ni N, Casa n o va M, R u bie H, Riccar di R, Le Dele y M C, Vassal G, Ge oer ger B; 
E ur o pea n c o ns orti u m I n n o vati ve T hera pies f or C hil dre n wit h Ca ncer (I T C C).  P hase II st u d y 
of te m oz ol o mi de a n d t o p oteca n ( T O T E M) i n c hil dre n wit h rela ps e d or refract or y e xtracra nial 
a n d ce ntr al ner v o us s yste m t u m ors i ncl u di n g me d ull o blast o ma wit h p ost h oc Ba yesia n 
a nal ysis: A E ur o pea n I T C C st u d y. P e di atr Bl o o d C a ncer.  2 0 2 0; 6 7( 1):e 2 8 0 3 2.  
Lear y S E, W oz nia k A W, Bill u ps C A, W u J, Mc P hers o n V, Neel M D, Ra o B N, Da w N C. 
S ur v i val of pe diatric pati e nts after rela pse d ost e osarc o ma: t he St. J u de C hil dre n’s Researc h 
H os pital e x perie nce. C a n cer. 2 0 1 3; 1 1 9( 1 4): 2 6 4 5 -2 6 5 3.  
Le hr n bec her T, R o bi ns o n P, Fis her B, Ale x a n der S, A m ma n n R A, Bea u c h er ni n M, Carlesse F, 
Gr oll A H, Ha usler G M, Sa nt ola ya M, Stei n bac h WJ, Casta g n ola E, Da vis B L, D u p uis L L, 
Ga ur A H, Tissi n g WJ E, Za o utis T, P hilli ps R, S u n g L. G ui d eli ne f or t he m a na ge me nt of fe v er 
a n d ne utr o pe nia i n c hil dre n wit h ca ncer a n d h e mat o p oietic ste m -cell tra ns pl a ntati o n reci pie nts: 
2 0 1 7 u p date . J Cli n O nc ol. 2 0 1 7; 3 5( 1 8): 2 0 8 2 -2 0 9 4.  
Li u K X, Nara nj o A, Z ha n g F F, et al.; Pr os pecti ve eval uati o n of ra diati o n d ose escal ati o n i n 
p atie nts w it h h i g h-ris k n e ur o blast o ma a n d g r oss resi d ual d isease aft er sur ger y: A re p ort fr o m 
t he C hil dre n's O n c ol o g y Gr o u p A N B L 0 5 3 2 St u d y. J Cli n O nc ol . 2 0 2 0; 3 8( 2 4): 2 7 4 1-2 7 5 2. 
htt ps:// d oi. or g/ 1 0. 1 2 0 0/J C O. 1 9. 0 3 3 1 6.  
L o n d o n W B, Castel V, M o nclair T, A m br os P F, Pears o n A DJ, C o h n S L, Bert h ol d F, 
Na ka ga wara A, La d e nstei n R L, Ie h ara T, M att ha y K K . Cli nical a n d bi ol o gi cal feat ures 
pre dicti ve of s ur vi v al aft er rel a pse of ne ur o blast o ma: A re p ort fr o m t he i nter nati o nal 
ne ur o blast o ma ris k gr o u p pr oject. J Cli n O nc ol . 2 0 1 1; 2 9( 2 4): 3 2 8 6-3 2 9 2.  
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 8 7  
M o d y R, Nara nj o A, V a n R y n C, Y u A L, L o n d o n W B, S h ul ki n B L, Parisi  M T, Ser vaes S E, 
Diccia n ni M B, S o n del P M, Be n der J G, Maris J M, Par k J R, Ba gat ell R. Iri n oteca n -
te m oz ol o mi de wit h refract or y or rel a pse d ne ur o blast o ma ( C O G A N B L 1 2 2 1): a n o pe n-la bel, 
ra n d o mize d, p hase 2 trial. L a ncet O nc ol. 2 0 1 7; 1 8( 7): 9 4 6 -9 5 7.  
M o d y R, Y u A L, N ara nj o A, et al. Iri n oteca n, te m oz ol o mi de, a n d d i n ut u xi ma b w it h G M-C S F i n 
chil dre n w it h refract or y or rela pse d n e ur o blast o m a: A re p ort fr o m t he C hil dre n's O nc ol o g y 
Gr o u p. J Cli n O nc ol . 2 0 2 0; 3 8( 1 9): 2 1 6 0-2 1 6 9. htt p /d oi /1 0. 1 2 0 0/J C O. 2 0. 0 0 2 0 3  
M o le naar JJ, K oster J, E b us M E, va n Sl uis P, Wester h o ut E M, de Preter K, Gisselss o n D, Øra I, 
S pele ma n F, Car o n H N, Verstee g R. C o p y n u m ber defects of G 1 -Cell c ycl e ge nes i n 
ne ur o blast o ma are fre q ue nt a n d c orrelate wit h hi g h e x pressi o n of E 2 F tar get ge nes a n d a p o or 
pr o g n osis. G e nes C hr o m os o mes C a ncer.  2 0 1 2; 5 1( 1): 1 0 -1 9.  
[ N CI] Nati o nal Ca ncer I nstit ute. Ca ncer i n C hil dre n a n d A d oles ce nts. 2 0 1 8. A vaila ble at: 
htt ps:// w w w.ca ncer. g o v/t y p es/c hil d h o o d -ca n cers/c hil d -a d olesce nt -ca ncers-fact-s heet. 
Access e d A pril 1 9, 2 0 1 9.  
Orte ga S, Mal u m bres M, Bar baci d M. C ycli n D -de pe n de nt ki nases, I N K 4 i n hi bit ors a n d ca ncer. 
Bi oc hi m Bi o p hys Act a. 2 0 0 2 ;1 6 0 2( 1): 7 3 -8 7.  
Pal meri ni E, J o nes R L, S et ola E, Picci P, Marc hesi E, L u ksc h R, Gri g n a ni G, Cesari M, L o n g hi 
A, A bate M E, Pai oli A, Sz ucs Z, D’a m br osi o L, Sc otla n di K, Fa gi oli F, As aftei S, Ferrari S. 
Iri n ot eca n a n d te m oz ol o mi de i n rec urre nt E wi n g sarc o ma: a n a nal ysis i n 5 1 a d ult an d pe diatric 
patie nts. Act a O nc ol. 2 0 1 8; 5 7( 7): 9 5 8 -9 3 4.  
Par k J R, Ba gat ell R, C o h n S L, et al. Re visi o ns t o t he I nter n ati o nal Ne ur o bl ast o ma Res p o nse 
Criteria: A co nse ns us state me nt fr o m t he n ati o nal ca ncer instit ute cli nical trials p la n ni n g 
m eeti n g. J Cli n O nc ol. 2 0 1 7; 3 5( 2 2): 2 5 8 0-2 5 8 7. htt ps:// d oi. or g/ 1 0. 1 2 0 0/J C O. 2 0 1 6. 7 2. 0 1 7 7  
Pat nai k A, R ose n L S, T ola ne y S M, T olc her A W, G ol d ma n J W, Ga n hi L, P a pa d o p o ul os K P, 
Beera m M, Rasc o D W, Hilt o n J F, Nasir A, Bec k ma n n R P, Sc ha de A E, F ulf or d A D, N g u ye n 
T S, Marti nez R, K ula nt hai vel P, Li L Q, Fre nzel M, Cr o nier D M, C ha n E M, Fla hert y K T, We n 
P Y , S ha pir o GI. Efficac y a n d safet y of a be macicli b, a n i n hi bit or of C D K 4 a n d C D K 6, f or 
patie nts wit h breast ca n cer, n o n -s mall cell l u n g ca ncer, a n d ot h er s oli d t u m ors. C a ncer Disc ov. 
2 0 1 6; 6 ( 7): 7 4 0-7 5 3.  
Raci b ors ka A, Bils ka K, Dra b k o K, C ha ber R, P o g orzala M,  W yr o be k E, P olcz y ńs ka K, 
R o g o ws ka E, R o dri g u ez -Gali n d o C, W oz nia k W. Vi ncristi ne, iri n oteca n, a n d te m oz ol o mi de i n 
patie nts wit h rela pse d a n d refract or y E wi n g s arc o ma. Pe di atr Bl o o d C a ncer. 
2 0 1 3; 6 0( 1 0): 1 6 2 1 -1 6 2 5.  
Ra der  J, R ussell M R, Hart L S, Na k aza wa M S, Belcastr o L T, Marti nez D, Li Y, Car pe nter E L, 
Atti ye h E F, Dis ki n SJ, Ki m S, Paras ura ma n S, Ca p o ni gr o G, Sc h n e p p R W, W o o d A C, Pa wel 
B, C ole K A, Maris J M. D ual C D K 4/ C D K 6 i n hi biti o n i n d uces cell -c ycle arrest a n d se n esce n ce 
i n ne ur o blast o ma. Cli n C a ncer Res. 2 0 1 3; 1 9 ( 2 2): 6 1 7 3-6 1 8 2.  
Ra u b TJ, Wis hart G N, K ula nt hai vel P, Stat o n B A, Aja mie R T, Sa wa da G A, Gel bert L M, 
S ha n n o n H E, Sa nce hz -M arti nez C, De Di os A. Br ai n e x p os ure of t w o selecti ve d ual C D K 4 
a n d C D K 6 i n hi bit ors a n d t he a ntit u m or acti vit y of C D K 4 a n d C D K 6 i n h i biti o n i n c o m bi nati o n 
wit h te m oz ol o mi de i n a n i ntracra ni al gli o blast o ma x e n o graft. Dr u g Met a b Dis p os. 
2 0 1 5; 4 3 ( 9): 1 3 6 0-1 3 7 1.  
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 8 8  
R i ha ni A, Va n des o m pele J, S pele ma n F, Va n Maer ke n T. I n hi biti o n of C D K 4/ 6 as a n o vel 
t hera pe utic o pti o n f or ne ur o blast o ma. C a ncer C ell I nt. 2 0 1 5; 1 5: 7 6.  
Rizz o J D, S o merfiel d M R, Ha gert y K L, Sei de nfiel d J, B o hli us J, Be n nett C L, Cella D F, 
Dj ul be g o vic B, G o o d e MJ, J a k u b o ws ki A A, Raric k M U, Re ga n D H, Lic hti n A E ; A merica n 
S ociet y of Cli nical O n c ol o g y ; A merica n S ociet y of He mat ol o g y. Use of e p oeti n a n d 
dar be p oeti n i n patie nts wit h ca ncer: 2 0 0 7 A m erica n S ociet y of Cli nical O n c ol o g y/ A meric a n 
S ociet y of He mat ol o g y cli nical practice g ui d eli ne u p date  [ p u blis he d c orrecti o n a p pears i n J 
Cli n O nc ol. 2 0 0 8; 2 6( 7): 1 1 9 2 ]. J Cli n O nc ol . 2 0 0 8; 2 6( 1): 1 3 2-1 4 9.  
R u bie H, Ge oer ger B, Fra p paz D, Sc h mitt A, Le bl o n d P, N dia ye A, Aerts I, Le Dele y M C, 
Ge ntet J C, Paci A, C hasta g n er P, Dias N, Dj afari L, Pas q uet M, C hat el ut E, La n d m a n -Par ker J, 
C orra di ni N, Vassal G. P hase I st u d y  of t o p oteca n i n c o m bi nati o n wit h te m oz ol o mi de 
( T O T E M) i n r ela pse d or refract or y p ae diatric s oli d t u m o urs. E ur J C a ncer. 2 0 1 0; 4 6( 1 5): 2 7 6 3 -
2 7 7 0.  
R u g gier o A, Rizz o D, Atti nà G, Lazzaresc hi I, Mastra n gel o S, Ma urizi P, Mi gli orati R, Bert oli ni 
P, Past ore M, C o l osi m o C, Riccar di R. P hase I st u d y of te m oz ol o mi de c o m bi ne d wit h oral 
et o p osi de i n c hil dre n wit h rec urre nt or pr o gressi v e me d ull o blast o ma. E ur J C a ncer. 
2 0 1 0; 4 6( 1 6): 2 9 4 3 -2 9 4 9.  
R u g gier o A, Rizz o D, Atti nà G, Lazzaresc hi I, Ma urizi P, Ri d ola V, Mastra n gel o S, Mi gli orati R, 
Bert oli ni P, C ol osi m o C, Riccar di R. P hase I st u d y of te m oz ol o mi de c o m bi ne d wit h oral 
et o p osi de i n c hil dre n wit h mali g na nt glial t u m ors. J Ne ur o o nc ol. 2 0 1 3; 1 1 3 ( 3): 5 1 3-5 1 8.  
Saa b  R , Bills J L, Mic eli A P, A n ders o n C M, K h o ur y J D, Fr y D W, Na vi d F, H o u g ht o n PJ, S ka pe k 
S X. P har mac ol o gic i n hi biti o n of c ycli n -d e pe n d e nt ki nase 4/ 6 acti vit y arrests pr oliferati o n i n 
m y o blasts a n d r h a b d o m y osarc o ma -d eri ve d cells. M ol C a ncer T her.  2 0 0 6 ; 5( 5): 1 2 9 9-1 3 0 8.  
Sc h wartz GJ, Ha yc o c k G B, E del ma n n C M Jr, S pi tzer A. A si m ple esti mate of gl o mer ular 
filtrati o n rate i n c hil dre n deri ve d fr o m b o d y le n gt h a n d plas ma creati ni ne. P e d iatrics. 
1 9 7 6; 5 8( 2): 2 5 9 -2 6 3.  
Sc h wartz GJ, Ga ut h ier B. A si m ple esti mate of gl o mer ular filtrati o n rate i n a d olesce nt b o ys. J 
Pe di atr. 1 9 8 5; 1 0 6( 3): 5 2 2 -5 2 6.  
Sett y Ba, Sta ne k J R, Mascare n h as L, Miller A, Ba gat ell R, O kc u F, Nic h olls L, L ys ec ki D, 
G u pta A A. Vi ncristi ne, iri n oteca n, a n d te m oz ol o mi de i n c hil dre n a n d a d ol esce nts wit h 
rela pse d r ha b d o my osarc o ma. Pe di atr Bl o o d C a ncer. 2 0 1 8; 6 5( 1).  
S herr CJ. Ca ncer cell c ycles. Scie nce. 1 9 9 6 ; 2 7 4( 5 2 9 3): 1 6 7 2-1 6 7 7.  
Si m o n R. O pti mal t w o -sta ge desi g ns f or p h ase II cli nical trials. C o ntr ol Cli n Tri als. 
1 9 8 9; 1 0( 1): 1 -1 0. htt ps:// d oi. or g/ 1 0. 1 0 1 6/ 0 1 9 7 -2 4 5 6( 8 9) 9 0 0 1 5 -9  
Sle d ge G W Jr, T oi M , Ne ve n P, S o h n J, I n o u e K, Pi v ot X, B ur dae v a O, O k era M, Mas u d a N, 
Ka uf ma n P A, K o h H, Grisc h ke E M, Fre nzel M, Li n Y, Barri ga S, S mit h I C, B o ura y o u N, 
Ll o m bart -C ussa c A. M O N A R C H 2: a be macicli b i n c o m bi nati o n wit h f ul vestra nt i n w o me n 
wi t h H R +/ H E R 2- a d va nce d breast ca ncer w h o h a d pr o gresse d w hile recei vi n g e n d o cri ne 
t hera p y. J Cli n O nc ol. 2 0 1 7; 3 5( 2 5): 2 8 7 5 -2 8 8 4.  
S mit h TJ, B o hl ke K, L y ma n G H, Cars o n K R, Cra wf or d J, Cr oss SJ, G ol d ber g J M, 
K hatc heressia n J L, Lei g hl N B, Per ki ns C L, S o ml o G, Wa de J L, W oz nia k AJ, A mirta ge J O ; 
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 8 9  
A merica n S ociet y of Cli nical O nc ol o g y . Rec o m me n dati o ns f or t he use of W B C gr o wt h 
fact ors: A merica n S ociet y of Cli nical O n c ol o g y Cli nical Practice G ui deli ne u p date. J Cli n 
O nc ol. 2 0 1 5; 3 3( 2 8): 3 1 9 9 -3 2 1 2.  
Sta hl M, Ra nft A, Pa ul u sse n M, B ölli n g T, Viet h V, Bielac k S, G örtitz I, Bra u n-M u nzi n ger G, 
Har des J, J ür ge ns H, Dir kse n U. Ris k of rec urre n ce a n d s ur vi v al after rela pse i n patie nts wit h 
E wi n g sarc o ma. P e di atr Bl o o d C a ncer. 2 0 1 1; 5 7( 4): 5 4 9 -5 5 3.  
St ur m D, Pfister S M, J o nes D T W. Pe d iatric gli o m as: c urre nt c o nce pts of di a g n osis, bi ol o g y, a n d 
cli nical ma na ge me nt. J Cli n O nc ol. 2 0 1 7; 3 5 ( 2 1): 2 3 7 0-2 3 7 7.  
Te m oz ol o mi de [ U S pac ka ge i nsert]. W hite h o use Stati o n, NJ: Merc k & C o., I n c.; 2 0 1 7 . 
T ola ne y S M, Sa he bja m S, R h u n E L, et al. A p hase II st u d y of a be m acicli b i n patie nts wit h brai n 
metastases sec o n d ar y t o h or m o ne rece pt or -p ositi v e breast ca ncer. Cli n C a ncer Res. 
2 0 2 0; 2 6( 2 0): 5 3 1 0 -5 3 1 9. htt ps:// d oi. or g/ 1 0. 1 1 5 8/ 1 0 7 8 -0 4 3 2.ccr -2 0 -1 7 6 4  
T orres -G uz m á n R, Calsi na B, H er m os o A, Ba q uer o C, Al varez B, A m at J, Mc N ult y A M, G o n g 
X, B oe h n k e K, D u J, de Di os A, Bec k ma n n R P, B uc ha n a n S, Lalle na MJ. Precli nical 
c haracteriz ati o n of a b e macicli b i n h or m o ne rece pt or p ositi ve breast c a ncer. O nc ot ar get. 
2 0 1 7; 8( 4 1): 6 9 4 9 3 -6 9 5 0 7.  
Trissel L A, Z ha n g Y, K o o ntz S E. Te m oz ol o mi de sta bilit y i n e xte m p ora ne o usl y c o m p o u n de d 
oral s us pe nsi o ns. I nt J P h ar m C o m p d. 2 0 0 6; 1 0( 5): 3 9 6 -3 9 9.  
T wist CJ, Sc h mi dt M L, Nara nj o A, et al.; Mai ntai ni n g o utsta n di n g o utc o m es u si n g res p o nse- a n d 
b i ol o g y-b as e d thera p y f or inter me diate -ris k n e ur o blast o ma: a re p ort fr o m t he C hil dre n's 
O nc ol o g y Gr o u p St u d y A N B L 0 5 3 1. J Cli n O nc ol . 2 0 1 9; 3 7( 3 4): 3 2 4 3-3 2 5 5. 
htt ps:// d oi. or g/ 1 0. 1 2 0 0/J C O. 1 9. 0 0 9 1 9  
Wa g ner L M, Cre ws K R, Iac o n o L C, H o u g ht o n PJ, F uller C E, Mc Car ville M B, G ol ds b y R E, 
Al britt o n K, Ste wart C F, Sa nta na V M. P hase I tri al of te m oz ol o mi de a n d pr otracte d iri n oteca n 
i n pe diatric patie nts wit h refract or y s oli d t u m ors. Cli n C a ncer Res. 2 0 0 4; 1 0 ( 3): 8 4 0-8 4 8.  
Wa g ner L M, Cre ws K R, Ste wart C F, R o dri g uez -Gali n d o C, Mc Nall -K na p p R Y, Al britt o n K, 
Pa p p o A S, F ur ma n W L. Re d uci n g iri n oteca n -ass o ciate d diarr hea i n c hil dr e n. Pe di atr Bl o o d 
C a ncer . 2 0 0 8; 5 0( 2): 2 0 1-2 0 7.  
Wa g ner L M, P ere ntesis J P, Rei d J M, A mes M M, Saf gre n S L, Nels o n M D Jr., I n gle A M, Bla ne y 
S M, A da ms o n P C. P hase I tri al of t w o sc he d ul es of vi ncristi ne, oral iri n oteca n, a n d 
te m oz ol o mi de ( V OI T) f or c hil dre n wit h rel a pse d or refract or y s oli d t u m ors: a C hil dre n’s 
O nc ol o g y Gr o u p p has e I c o ns orti u m st u d y. Pe di atr Bl o o d C a ncer. 2 0 1 0; 5 4( 4): 5 3 8 -5 4 5.  
Wa g ner L M, Villa bla nca J G, Ste w art C F, Cre ws K R, Gr os he n S, Re y n ol ds C P, Par k J R, Maris 
J M, Ha w ki ns R A, Dal dr u p-Li n k H E, J ac ks o n H A, Matt ha y K K. P hase I tri al of oral iri n oteca n 
a n d te m oz ol o mi de f or c hil dre n wit h rela pse d hi g h -ris k ne ur o blast o ma: A n e w a p pr oac h t o 
ne ur o blast o ma t hera p y c o ns orti u m st u d y. J Cli n O ncol . 2 0 0 9; 2 7( 8):1 2 9 0 -1 2 9 6.  
We n P Y, Mac d o nal d D R, Rear d o n D A, Cl o u g hes y T F, S ore nse n A G, Gal a nis E, De Gr o ot J, 
Wic k W, Gil bert M R, Lass ma n A B, Tsie n C, Mi k kelse n T, W o n g E T, C ha m berlai n M C, 
St u p p R, La m b or n K R, V o gel ba u m M A, va n d e n Be nt MJ, C ha n g S M. U p date d res p o ns e 
assess me nt criteri a f or hi g h -gra de gli o mas: Res p o nse Assess me nt i n Ne ur o -O nc ol o g y 
W or ki n g Gr o u p. J Cli n O nc ol. 2 0 1 0; 2 8( 1 1): 1 9 6 3 -1 9 7 2.  
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P C S(f) 
 
L Y 2 8 3 5 2 1 9  
1 9 0  
Y u A L , Gil ma n A L , Oz ka y n a k M F et al. A nti -G D 2 a nti b o d y wit h G M -C S F, i nterle u ki n -2, a n d 
is otreti n oi n f or ne ur o blast o ma. N E n gl J Me d . 2 0 1 0;3 6 3 :1 3 2 4 – 1 3 3 4.  
htt ps:// d oi. or g/ 1 0. 1 0 5 6/ N EJ M oa 0 9 1 1 1 2 3  
Z h o u MJ, D oral M Y, D u B ois S G, et al. Differe nt o utc o mes f or rela pse d vers us refract or y 
ne ur o blast o ma aft er t hera p y wit h ( 1 3 1)I -metai o d o be nz yl g ua ni di ne (( 1 3 1)I -MI B G). E ur J 
C a ncer . 2 0 1 5; 5 1( 1 6): 2 4 6 5-2 4 7 2. htt ps:// d oi. or g/ 1 0. 1 0 1 6/j.ejca. 2 0 1 5. 0 7. 0 2 3  
Z h u K, Li u L, Z h a n g J, Wa n g Y, Lia n H, Fa n G, Jia n Z, Z h a n g C Y, C he n X, Z h o u G. Mi R -2 9 b 
s u p presses t he pr olif erati o n a n d mi grati o n of oste osarc o ma cells b y t ar geti n g C D K 6. Pr otei n 
Cell. 2 0 1 6; 7( 6): 4 3 4 -4 4 4.  
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T

Si g nat ure Pa ge f or V V- C LI N- 0 9 5 0 0 5 v 1. 0
Si g nat ure Pa ge f or V V- C LI N- 0 9 5 0 0 5 v 1. 0
A p pr o val
1 8-J ul- 2 0 2 3 1 3: 4 5: 0 0 G M T + 0 0 0 0
A p pr o val
1 8-J ul- 2 0 2 3 1 4: 1 7: 5 4 G M T + 0 0 0 0
A p pr o ve d o n 1 8 J ul 2 0 2 3 G M T
P P D
P P D