A Randomized, Open-Label Phase 1/2 Study Evaluating Ramucirumab in Pediatric Patients and Young Adults With Relapsed, Recurrent, or Refractory Synovial Sarcoma
Phase: PHASE1
Conditions: Synovial Sarcoma
Sponsor: Eli Lilly and Company

 
 
 
 
Pr ot oc ol: J 1 S- M C-J V 0 2( g) 
 
 
A Ra n d o mize d, O pe n -La bel P hase 1/ 2 St u d y E val uati n g  Ra m ucir u ma b i n 
Pe diatric Patie nts a n d Y o u n g A d ults wit h  Rela pse d, Rec urre nt, or Refract or y 
S y n o vial Sarc o ma  
 
 
N C T 0 4 1 4 5 7 0 0  
 
 
A p pr o val Date: 1 3- Dec -2 0 2 1  

J 1 S -M C -J V 0 2( g) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 1
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
1. Pr ot o c ol A d d e n d u m J 1 S -M C -J V 0 2 ( g)
A R a n d o mi z e d , O p e n -L a b el P h a s e 1/ 2 St u d y  E v al u ati n g 
R a m u cir u m a b i n P e di atri c P ati e nt s a n d Y o u n g A d ult s wit h 
R el a p s e d, R e c urr e nt, or R efr a ct or y S y n o vi al S ar c o m a
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 pr ot o c ol a d d e n d u m 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 ed 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 r a m u cir u m a b ( L Y 3 0 0 9 8 0 6)], 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.  T hi s d o c u m e nt a n d 
it s a s s o ci at e d att a c h m e nts ar e s u bj e ct t o U nit e d St at e s 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. 
L Y 9 0 0 0 2 3 ( J A A A C A M P FI R E Pr ot o c ol); R a m u cir u m a b ( L Y 3 0 0 9 8 0 6)
T hi s a d d e n d u m i s t o b e p erf or m e d i n a d diti o n t o all pr o c e d ur e s r e q uir e d b y 
Pr ot o c ol J 1 S -M C -J A A A or a n y s u b s e q u e nt a m e n d m e nt s t o t h at pr ot o c ol.
Eli Lill y a n d C o m p a n y
I n di a n a p oli s, I n di a n a U S A 4 6 2 8 5
Pr ot o c ol A d d e n d u m J V 0 2 El e ctr o ni c all y Si g n e d a n d A p pr o v e d b y Lill y o n 7 D e c e m b er 2 0 1 8 
Pr ot o c ol A d d e n d u m A m e n d m e nt J V 0 2( a) El e ctr o ni c all y Si g n e d a n d A p pr o v e d b y Lill y o n 2 3 
J a n u ar y 2 0 1 9
Pr ot o c ol A d d e n d u m A m e n d m e nt J V 0 2( b ) El e ctr o ni c all y Si g n e d a n d A p pr o v e d b y Lill y o n 2 
A u g u st 2 0 1 9
Pr ot o c ol A d d e n d u m A m e n d m e nt J V 0 2( c) El e ctr o ni c all y Si g n e d a n d A p pr o v e d b y Lill y o n 2 6 
S e pt e m b er 2 0 1 9
Pr ot o c ol A d d e n d u m A m e n d m e nt J V 0 2( d) El e ctr o ni c all y Si g n e d a n d A p pr o v e d b y Lill y o n 1 7 
O ct o b er 2 0 1 9
Pr ot o c ol A d d e n d u m A m e n d m e nt J V 0 2( e ) El e ctr o ni c all y Si g n e d a n d A p pr o v e d b y Lill y o n 1 8 -
M a y -2 0 2 0
Pr ot o c ol A d d e n d u m A m e n d m e nt J V 0 2( f) El e ctr o ni c all y Si g n e d a n d A p pr o v e d b y Lill y o n 0 9- O ct -
2 0 2 0
Pr ot o c ol A d d e n d u m A m e n d m e nt J V 0 2( g ) El e ctr o ni c all y Si g n e d a n d A p pr o v e d b y Lill y o n d at e 
pr o vi d e d b el o w.
A p pr o v al D at e: 1 3- D e c- 2 0 2 1 G M T
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Fi nal
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P a g e 2
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
2. T a bl e of C o nt e nt s
Pr ot o c ol A d d e n d u m J 1 S -M C -J V 0 2 ( g)
A R a n d o mi z e d , O p e n -L a b el P h a s e 1/ 2 St u d y  E v al u ati n g 
R a m u cir u m a b i n P e di atri c P ati e nt s a n d Y o u n g A d ult s wit h 
R el a p s e d, R e c urr e nt, or R efr a ct or y  S yn o vi al S ar c o m a
S e cti o n
P a g e
1.
Pr ot oc ol  A d de n d u m J 1 S-M C -J V 0 2( g) A Ra n d omize d, O pe n -La bel 
P hase 1/ 2 St u d y  E val uati n g Ra m ucir u ma b i n Pe diatric Patie nts a n d 
Y o u n g A d ults wit h Rela pse d, Rec urre nt, or Refract or y S y n o vial 
Sarc o m a ..............................................................................................................................1
2.
Ta ble of C o nte nts ................................................................................................................2
3.
St u d y  J 1 S-M C -J V 0 2( g) A d de n d u m .....................................................................................8
3. 1.
S y n o psis .........................................................................................................................8
3. 2.
Sc he d ule of Act i vities ..................................................................................................1 0
3. 3.
I ntr o d ucti o n..................................................................................................................1 8
3. 3. 1.
St u d y  Rati onale ....................................................................................................1 8
3. 3. 2.
Bac k gr o u n d ..........................................................................................................1 9
3. 3. 2. 1.
S y n o vial Sarc o ma ...........................................................................................1 9
3. 3. 2. 2.
Ra m u ci r u ma b ................................................................................................. 1 9
3. 3. 2. 3.
G e m cita bi ne a n d D oceta xel ............................................................................2 0
3. 3. 3.
Be nefit/ Ris k Assess me nt ......................................................................................2 1
3. 4.
O bject i ves a n d E n d p oi nts .............................................................................................2 3
3. 5.
St u d y  Desi g n................................................................................................................2 3
3. 5. 1.
O verall Desi g n .....................................................................................................2 3
3. 5. 2.
N u m ber of Patie nts ...............................................................................................2 6
3. 5. 3.
E n d of St u d y  Defi niti on .......................................................................................2 6
3. 5. 4.
S ci e nt ific Rati o nale f or St u d y Desi g n...................................................................2 6
3. 5. 5.
J ustificati o n f or D ose ...........................................................................................2 7
3. 6.
St u d y  P o p ulat i on ..........................................................................................................2 9
3. 6. 1.
I ncl usio n  Crit eria ................................................................................................. 2 9
3. 6. 1. 1.
E xce pt i ons t o t he C A M P FI R E Master Pr ot oc ol I ncl usi o n 
Cri teria ...........................................................................................................3 0
3. 6. 2
E xcl usi o n Cri t eria ................................................................................................3 2
3. 6. 1. 2.
E xce pt i ons t o t he C A M P FI R E Master Pr ot oc ol 
E xcl usi o n Cri t eria ...........................................................................................3 4
3. 6. 3.
Lifest yle Restrict i on .............................................................................................3 4
3. 7.
Treat me nts ...................................................................................................................3 4
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L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
3. 7. 1.
Treat me nts A d mi nistere d .....................................................................................3 4
3. 7. 1. 1.
Pr e m e dicat i on ................................................................................................. 3 4
3. 7. 1. 1. 1.
Ra m u ci r u ma b ...........................................................................................3 4
3. 7. 1. 1. 2.
G e m cita bi ne..............................................................................................3 4
3. 7. 1. 1. 3.
D oceta xel ..................................................................................................3 4
3. 7. 1. 1. 4.  
G ra n ul oc yt e-C o l on y St i m ulati n g Fact ors ..................................................3 5
3. 7. 1. 2.
D osi n g Sc he d ule .............................................................................................3 5
3. 7. 1. 3.
D ose -Li mit i n g T o xicity Deter mi nati o n ...........................................................3 6
3. 7. 2.
Met h o d of Treat me nt Assi g n me nt
........................................................................3 9
3. 7. 3.
Bli n di n g ...............................................................................................................3 9
3. 7. 4.
D ose M o dificat i on ................................................................................................3 9
3. 7. 4. 1.
G ui deli nes f or He m at olo gi cal a n d N o n he mat olo gical  
D ose M o dificat i ons ........................................................................................4 0
3. 7. 4. 2.
Ra m u ci r u ma b D ose M o dificati ons A d verse E ve nts of 
S peci al I nterest ...............................................................................................4 6
3. 7. 5.
Treat me nt C o m plia nce .........................................................................................5 2
3. 7. 6.
C o nc o mita nt T hera p y ...........................................................................................5 2
3. 7. 6. 1.
S u p p orti ve Care ..............................................................................................5 2
3. 7. 6. 1. 1.
Tra nsf usi o ns .............................................................................................5 2
3. 7. 6. 1. 2.
Gr o wt h Fact ors .........................................................................................5 2
3. 7. 6. 1. 3.
A nt iemet ic A ge nts ....................................................................................5 2
3. 7. 6. 1. 4.
A nal gesic A ge nts ......................................................................................5 3
3. 7. 6. 1. 5.
A p pet ite Sti m ula nts ..................................................................................5 3
3. 7. 6. 1. 6.
Ot her S u p p orti ve Care A ge nts ..................................................................5 3
3. 7. 6. 1. 7.
S u p p orti ve Care b y  Ad verse E ve nt of S pecial 
I nterest:  Ra m ucir u ma b.............................................................................5 3
3. 7. 6. 1. 7. 1.
I nf usi on -Relate d Reacti o ns (I ncl u di n g 
H y perse nsi tivi t y R e a ctio ns) ................................................................. 5 3
3. 7. 6. 1. 7. 2.
H y perte nsi o n .......................................................................................5 4
3. 7. 6. 1. 7. 3.
Pr otei n uria ..........................................................................................5 4
3. 7. 6. 1. 7. 4.
T hr o m b oe m b o lic E ve nts .....................................................................5 4
3. 7. 6. 1. 7. 5.
Bl ee di n g/ He morr ha ge .........................................................................5 5
3. 7. 6. 1. 7. 6.
Gastr oi ntesti nal Perf orati o n ................................................................. 5 5
3. 7. 6. 1. 7. 7.
P os t erior Re versi ble E nce p hal o pat h y S y n dr o me ..................................5 5
3. 7. 6. 1. 7. 8.
C o n gest i ve Heart Fail ure.....................................................................5 6
3. 7. 6. 1. 7. 9.
Fist ul a F or mat i on ................................................................................5 6
3. 7. 6. 1. 7. 1 0.
S ur ger y  a n d I mpaire d W o u n d Heali n g ................................................5 6
3. 7. 6. 1. 7. 1 1.
Li ver Fail ure a n d Ot her Si g nifica nt Li ver I nj ur y ................................. 5 6
3. 8.
Di sc o nti n uatio n Cri t eri a ...............................................................................................5 6
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L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
3. 9.
St u d y  Assess me nts a n d Pr oce d ures ..............................................................................5 7
3. 9. 1.
Efficac y Assess me nts ...........................................................................................5 7
3. 9. 2.
A d verse E ve nts ....................................................................................................5 8
3. 9. 2. 1.
A d verse E ve nts of S pecial I nterest - Ra m ucir u ma b .........................................5 8
3. 9. 3.
S af et y ...................................................................................................................5 8
3. 9. 3. 1.
S af et y M o ni t ori n g...........................................................................................5 8
3. 9. 3. 1. 1.
S peci al He pat ic Safety Data C ollect i on .....................................................5 8
3. 9. 3. 1. 2.
M o ni t ori n g f or S pecific T o xicities-Gr o wt h Pl at e .......................................5 9
3. 9. 4.
P har mac o ki net ics ................................................................................................. 6 0
3. 9. 5.
P har mac o d y na mics ..............................................................................................6 0
3. 9. 5. 1.
I mm u n o ge nicit y Assess me nts .........................................................................6 0
3. 9. 6.
Bi o m ar kers ...........................................................................................................6 1
3. 9. 6. 1.
Tiss ue S a m ples f or Bi o m ar ker Researc h .........................................................6 1
3. 9. 6. 2.
Ot her Sa m ples f or Bi o mar ker Researc h ..........................................................6 1
3. 9. 7.
Heal t h Ec o n o mics................................................................................................6 1
3. 1 0.
Stat istical C o nsi derati o ns .............................................................................................6 2
3. 1 0. 1.
S a m ple Si ze Deter mi nat i on ..................................................................................6 2
3. 1 0. 2.
P o p ul at i ons f or A nal ysis ......................................................................................6 3
3. 1 0. 3.
Stati stical A nal ysis ...............................................................................................6 3
3. 1 0 . 3. 1.
Efficac y A nal ysis ...........................................................................................6 3
3. 1 0. 3. 2.
S af et y A nal ysis ...............................................................................................6 6
3. 1 0. 3. 3.
Ot her A nal ysis ................................................................................................6 6
3. 1 0. 3. 3 . 1.
P har mac o ki net ic/Im m u n o ge nicit y A nal yses ..............................................6 6
3. 1 0. 3. 3. 2.
Bi o m ar ker A nal yses ..................................................................................6 6
3. 1 0. 3. 4.
S u b gr o u p A nal ysis ..........................................................................................6 6
3. 1 0. 3. 5.
I nteri m A nal ysis .............................................................................................6 7
4.
Ref ere nces ........................................................................................................................6 8
J V 0 2 0 5 Pr ot oc ol A d de n da ( g). p df | V V- T M F- 4 2 9 2 2 1 7 | 1. 0
Fi nal
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J 1 S -M C -J V 0 2( g) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 5
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
Li st of T a bl e s
T a bl e
P a g e
Ta ble J V 0 2. 1.
Baseli ne Sc he d ule of Act i vities......................................................................1 0
Ta ble J V 0 2. 2.
O n -St u d y -Treat me nt Sc he d ul e of Act i vities...................................................1 2
Ta ble J V 0 2. 3.
P os t-St u d y -Treat me nt F oll o w -U p Sc he d ule of Act i vities ...............................1 5
Ta ble J V 0 2. 4.
C o nti n ue d Access Sc he d ule of Act i vities.......................................................1 7
Ta ble J V 0 2. 5.
R olli n g Si x R ules ( Ra m ucir u ma b at 9 m g/ k g) ................................................2 4
Ta ble J V 0 2. 6.
R olli n g Si x R ules ( Ra m ucir u ma b at 6 m g/ k g) ................................................2 5
Ta ble J V 0 2. 7.
J V 0 2 Treat me nt D osi n g Sc he d ule ( S y n o vial) .................................................3 5
Ta ble J V 0 2. 8.
D ose Re d ucti o ns f or Ra m ucir u ma b, G e mcita bi ne, a n d 
D oceta xel -Relate d T o xi cities .........................................................................4 0
Ta ble J V 0 2. 9.
Ge neral G ui deli nes f or St u d y  Treat me nt D ose M o dificat i on D ue t o 
T o xici ties Relate d t o Ra m ucir u ma b, Ge mcita bi ne, or D oceta xel ....................4 1
Ta ble J V 0 2. 1 0.
D osi n g Al g orit h m o n Da ys 1 a n d 8 f or Ge mcita bi ne, D oceta xel , a n d 
Ra m u ci r u ma b Base d o n A bs ol ute Ne utr o p hil C o u nt a n d Platelet C o u nt .........4 2
Ta ble J V 0 2. 1 1.
G ui deli nes f or D ose M o dificat i on D ue t o St u d y Dr u gs -Relate d 
N o n -H e m at olo gi c T o xicities ..........................................................................4 4
Ta ble J V 0 2. 1 2.
D ose -M o dificati o n G ui deli nes f or Ra m ucir u ma b f or A d verse E ve nts at 
Least P ossi bl y Relate d t o Ra m ucir u ma b, i ncl u di n g A d verse E ve nts of 
S peci al I nterest ..............................................................................................4 7
Ta ble J V 0 2. 1 3.
P F S E ve nt/ Ce ns ori n g Sc he me ........................................................................6 5
Ta ble J V 0 2. 1 4
Si m ulate d O perati n g C haracterist ics ..............................................................6 5
Ta ble J V 0 2. 1 5
I mpact of Heter o ge ne o us Effect -Si ze Bet wee n T u m ors ..................................6 6
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Li st of Fi g ur e s
Fi g ur e
P a g e
Fi g ure J V 0 2. 1.
Ill ustratio n of  St u d y J V 0 1 a n d St u d y J V 0 2 Desi g ns.......................................2 6
J V 0 2 0 5 Pr ot oc ol A d de n da ( g). p df | V V- T M F- 4 2 9 2 2 1 7 | 1. 0
Fi nal
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P a g e 7
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
Li st of Att a c h m e nt s
Att a c h m e nt
P a g e
At tac h me nt 1.
Pr ot oc ol  J V 0 2 A d de n d u m A b bre viati o ns a n d Defi niti ons ..............................7 3
At tac h me nt 2.
Pr ot oc ol  J V 0 2 A d de n d u m Cli nical La b orat or y T ests......................................7 7
At tac h me nt 3.
Pr ot oc ol  J V 0 2 A d de n d u m Sa m pli n g Sc he d ule f or Ge net ics/ 
Bi o m ar kers/I m m u n o ge nicit y/ P h ar mac o ki net ics .............................................8 0
At tac h me nt 4.
Pr ot oc ol  J V 0 2 A d de n d u m He patic Mo ni t ori n g Tests f or Treat me nt -
E mer ge nt A b n or malit y ..................................................................................8 4
At tac h me nt 5.
Pr ot oc ol  J V 0 2 Restricte d a n d Pr o hi bite d C o nc omit a nt T hera p y .....................8 5
At tac h me nt 6.
Pr ot oc ol  J V 0 2 List of C om m o n C Y P 3 A 4 I n hi bit ors a n d I n d ucers of 
D oceta xel ......................................................................................................8 7
At tac h me nt 7.
Pr ot oc ol  A d de n d u m A me n d me nt J 1 S-M C -J V 0 2(f) S u m mar y A 
Ra n d o mize d, O pe n- La bel  P hase 1/ 2 St u d y E val uati n g Ra m ucir u ma b i n 
P e di atric Patie nts a n d Y o u n g A d ult s wit h Rela pse d, Rec urre nt, or 
Refract or y  S y n o vial Sarc oma .........................................................................8 8
J V 0 2 0 5 Pr ot oc ol A d de n da ( g). p df | V V- T M F- 4 2 9 2 2 1 7 | 1. 0
Fi nal
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J 1 S -M C -J V 0 2( g) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 8
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
3. St u d y  J 1 S -M C -J V 0 2 ( g) A d d e n d u m
3. 1.
S y n o p si s
Pr ot oc ol Title:
A Ra n d o mize d , O pe n -La bel P h ase 1/ 2 St u d y  E val uati n g Ra m ucir u ma b i n Pe diatric Patie nts a n d 
Y o u n g A d ults wit h Rela pse d, Rec urre nt, or Refract or y S y n o vial Sarc o ma
R ati o n ale:
St u d y  J 1 S-M C -J V 0 2 (J V 0 2) is desi g ne d t o i n vesti gate t he efficac y of ra m ucir u ma b i n 
c o m bi nat i on wi t h ge mcita bi ne a n d d oceta xel f or t he treat me nt of pe diatric a n d y o u n g a d ult
patie nts wi t h s y n ovial sarc o ma ( S S ).
O bjecti ves a n d E n d p oi nts:
O bjecti ves
E n d p oi nts
Pri m ar y
T o e val uate t he efficac y of ra m ucir u ma b i n c o m bi nati o n 
wit h ge mcita bi ne a n d d oceta xel c o m pare d wit h 
ge mcita bi ne a n d d oceta xel i n pe diatric a n d y o u n g a d ult 
patie nts wit h S S .
P F S
Sec o n d ar y
T o e val uate t he safet y a n d t olera bilit y of ra m ucir u ma b i n 
c o m bi nati o n w it h ge mcita bi ne a n d d oceta xel c o m pare d 
wit h ge mcita bi ne a n d d oceta xel i n pe diatric a n d y o u n g 
a d ult patie nts wit h S S .
S A Es, A Es, safet y la b orat or y assess me nts, a n d vital 
si g ns
T o e val uate t he efficac y of ra m ucir u ma b i n c o m bi nati o n 
wit h ge mcita bi ne a n d d oceta xel c o m pare d wit h 
ge mcita bi ne a n d d oceta xel i n pe diatric a n d y o u n g a d ult 
patie nts wit h S S .
O R R, D o R, C R
T o c haracterize t he P K of ra m ucir u ma b w he n 
c o-a d mi nistere d wit h ge mcita bi ne a n d d oceta xel i n 
pe diatric a n d y o u n g a d ult patie nts wit h S S.
C ma x a n d C mi n
T o assess t he i m m u n o ge nicit y of ra m ucir u ma b w he n 
c o-a d mi nistere d wit h ge mcita bi ne a n d d oceta xel i n 
pe diatric a n d y o u n g a d ult patie nts wit h S S.
I nci de nce of i m m u n o ge nicit y
A b bre viati o ns:  A E = a d verse e ve nt; C ma x = ma xi m u m c o nce ntrati o n; C mi n = mi ni m u m c o nce ntrati o n; 
C R = c o m plete res p o nse; D o R = d ur ati o n of res p o nse; O R R = o verall res p o nse; P F S = pr o gressi o n -free s ur vi val; 
P K = p har mac o ki netics; S A E = seri o us a d verse e ve nt; S S = s y n o vial sarc o ma .
O ver all Desi g n:
St u d y  J V 0 2 is a ra n d o mize d, o pe n -la bel P h ase 1/ 2 st u d y  e val uati n g ra m ucir u ma b i n c om bi nat i on 
wi t h ge mcita bi ne a n d d oceta xel i n pe diatric a n d yo u n g a d ul t patie nts wi t h r ela pse d, rec urre nt, or 
refract or y S S .
J V 0 2 0 5 Pr ot oc ol A d de n da ( g). p df | V V- T M F- 4 2 9 2 2 1 7 | 1. 0
Fi nal
P P D

J 1 S -M C -J V 0 2( g) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 9
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
N u m ber of P atie nts:
A p pr o xi matel y  3 0 p atie nts will be e nr olle d.
T he st u d y  must e nr oll a mi ni m u m o f 5 pati e nts ≤1 7 years ol d wit h S S.
Tre at me nt Ar ms a n d D ur ati o n:
Treat me nt peri o d:  Patie nts will recei ve treat me nt u nt il e vi de nce of disease pr o gressi o n or ot her 
di sc o nti n uat i on cri t eria ha ve bee n f ulfille d.
F o ll ow- u p peri o d ( p ost disc o nt i n uati on):  a p pr o xi matel y 3 0 da ys.
D ose a n d Sc he d ule ( q 2 1 d a ys)
Ar m
R a m ucir u m a b
I V, D 1 a n d D 8
Ge mcit a bi ne
I V, D 1 a n d D 8
D ocet a xel
I V, D 8
N u m ber of C ycles
1
9 m g/ k g
9 0 0 m g/ m 2
7 5 m g/ m 2
Treat me nt will 
c o nti n ue u ntil a 
disc o nti n uati o n 
criteri o n is met.
2
N A
9 0 0 m g/ m 2
7 5 m g/ m 2
A b bre viati o ns:  D = da y; I V = i ntra ve n o us; q = e ver y; Q D = dail y.
J V 0 2 0 5 Pr ot oc ol A d de n da ( g). p df | V V- T M F- 4 2 9 2 2 1 7 | 1. 0
Fi nal
P P D

J 1 S -M C -J V 0 2( g) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 1 0
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
3. 2.
S c h e d ul e of A cti viti e s
T a bl e J V 0 2 . 1.
B a s eli n e S c h e d ul e of A cti viti e s
D a y Rel ati ve t o C 1 D 1
2 8
7
Pr oce d ure
I nstr ucti o ns
I nf or me d c o nse nt
X
I C F m ust be si g ne d bef ore a n y 
pr ot oc ol -s pecific pr oce d ures are perf or me d
I ncl usi o n/e xcl usi o n criteria
X
P h y sical e xa mi nati o n
X
I ncl u di n g hei g ht, wei g ht, a n d vital si g ns 
(te m perat ure, bl o o d press ure, a n d p ulse rate)
E C O G/ La ns k y/ Kar n ofs k y perf or ma nce 
stat us
X
Me dical hist or y
X
I ncl u di n g assess me nt of pree xisti n g 
c o n diti ons, hist o rical ill nesses, a n d ha bits
Pri o r a n d c urre nt a ntica ncer t hera p y
X
A E c ollecti o n
X
C T C A E, Versi o n 5. 0
C o nc o mita nt me dicati o n
X
Ra di ol o gic i ma gi n g of k n o w n / pri mar y 
lesi o ns a n d meas ure me nt of pal pa ble or 
visi ble lesi o ns
X

Preferre d m o dalities:
o
e xtre mit y/ hea d/ nec k: M RI
o
c hest/a b d o me n/ pel vis: C T

Perf or m acc or di n g t o R E CI S T 1. 1 
criteria. 

See Secti o n 3. 9. 1
Ra di ol o gic i ma gi n g f or e val uati o n of 
metastatic disease:   
c hest /a b d o me n/ pel vis 
X

Preferre d m o dalit y:
C T

Re q uire d o nl y if n ot perf or me d as part of 
pri mar y  lesi o n e val uati o n.

Perf or m acc or di n g t o R E CI S T 1. 1 
criteria. 

See Secti o n 3. 9. 1 .
Plai n a nter o p osteri or ra di o gra p h of a 
si n gle pr o xi mal ti bial gr o wt h plate
X
O nl y f or patie nts < 1 8 years of a ge.  See 
Secti o n 3. 9. 3. 1. 2
E C H O or M U G A
X
J V 0 2 0 5 Pr ot oc ol A d de n da ( g). p df | V V- T M F- 4 2 9 2 2 1 7 | 1. 0
Fi nal
P P D

J 1 S -M C -J V 0 2( g) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 1 1
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
E C G
X
L ocal testi n g.
He mat ol o g y
X
See Attac h me nt 2 f or desi g nati o n of l ocal or 
ce ntral testi n g.
C oa g ulati o n
X
See Attac h me nt 2 f or desi g nati o n of l ocal or 
ce ntral testi n g.
Cli nical c he mistr y
X
See Attac h me nt 2 f or desi g nati o n of l ocal or 
ce ntral testi n g.
Ur i nal ysis
X
See Attac h me nt 2 f or desi g nati o n of l ocal or 
ce ntral testi n g.
Pre g na nc y test
X
Ser u m or uri ne per i nstit uti o nal sta n dar d. 
A p plies o nl y t o fe males of c hil d beari n g 
p ote ntial.
See Attac h me nt 2 f or desi g nati o n of l ocal or 
ce ntral testi n g.
T S H a n d Free T 4
X
See Attac h me nt 2 f or desi g nati o n of l ocal or 
ce ntral testi n g.
Sa m ple c ollecti o n f or:
P har mac o ki netics
See Attac h me nt 3
I m m u n o ge nicit y
See Attac h me nt 3
Ge netics
See Attac h me nt 3
Bi o mar kers
See Attac h me nt 3
A b bre viati o ns:  A E = a d verse e ve nt; C 1 D 1 = C ycle 1 Da y 1; C T = c o m p ute d t o m o gra p h y; C T C A E = C o m m o n 
Ter mi n ol o g y Criteria f or A d verse E ve nts ( N CI 2 0 1 7 ); E C G = electr ocar di o gra m; E C H O = ec h ocar di o gra m; 
E C O G = Easter n C o o perati ve O nc ol o g y Gr o u p ( O ke n et al. 1 9 8 2); Fr ee T 4 = th y r oxi ne ; I C F = i nf or me d c o nse nt 
f or m; M RI
= ma g netic res o na nce i ma gi n g; M U G A = m ulti gate d ac q uisiti o n; R E CI S T 1. 1 = Res p o nse E val uati o n 
Criteria i n S oli d T u m ors, Versi o n 1. 1 ( Eise n ha uer et al. 2 0 0 9) ; T S H = t h yr oi d-sti m ulati n g h or m o ne.
J V 0 2 0 5 Pr ot oc ol A d de n da ( g). p df | V V- T M F- 4 2 9 2 2 1 7 | 1. 0
Fi nal
P P D

J 1 S -M C -J V 0 2( g) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 1 2
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
T a bl e J V 0 2 . 2.
O n -St u d y -Tr e at m e nt S c h e d ul e of A cti viti e s
F or C 1 D 1, e val uat i ons m u st be d o ne o n t he da y  of visit or wit hi n 7 da ys pri or.  F or all s u bse q ue nt visits, e val uat i ons m u st be d o ne o n 
t he da y of visit or wit hi n 3 da ys pri or. I n case of d ose i nterr u pti o n, t hese e val uati o ns will als o be d o ne at ma xi m u m fre q ue nc y e ver y 2 1 da ys.
Tre at me nt Peri o d 2 1- D a y C ycle
C ycle 1  
C ycle 2 - n
D a y wit hi n C ycle
1 
8 
1 
8
Pr oce d ure
I nstr ucti o ns
P h y sical e xa mi nati o n
X  
X  
X
Perf or m pri or t o a d mi nisteri n g st u d y dr u g(s).
Wei g ht
a n d hei g ht
X
X
Perf or m pri or t o a d mi nisteri n g st u d y dr u g(s).
Hei g ht t o be c ollecte d f or patie nts < 1 8 years of a ge o nl y.
Vital Si g ns
X  
X  
X  
X
Perf or m pri or t o a d mi nisteri n g st u d y dr u g(s).

I ncl u di n g te m perat ure, bl o o d press ure, a n d p ulse rate.
C o nc o mita nt 
me dicati o n
X  
X  
X  
X
A E c ollecti o n
X  
X  
X  
X
C T C A E, Versi o n 5. 0. T o be perf or me d bef ore treat me nt.
E C O G/ La ns k y/ 
Kar n ofs k y 
perf or ma nce stat us
X
X
Ra di ol o gic i ma gi n g
of k n o w n lesi o ns a n d 
c hest C T , a n d 
meas ure me nt of 
pal pa ble or visi ble
lesi o ns
Perf or m e ver y 9 w k ( ± 7 da ys)

Preferre d m o dalities:
o
e xtre mit y/ hea d/ nec k: M RI
o
c hest/a b d o me n/ pel vis: C T

Perf or m acc or di n g t o R E CI S T 1. 1 criteria, b y t he sa me met h o d use d at baseli ne, q 9 w k 
( ±7 da ys) starti n g fr o m C 1 D 1 u ntil d oc u me nte d disease pr o gressi o n per R E CI S T 1. 1 criteria, 
deat h, or st u d y c o m pleti o n, w hic he ver occ urs first.

After t hir d e val uati o n of sta ble disease or f oll o wi n g s ur gical resecti o n wit h clea n mar gi ns, 
o btai n e ver y 3 m o nt hs ( ± 1 4 da y s) t h ereafter. 

Perf or m as sc he d ule d, e ve n if st u d y trea t me nt is dela ye d or o mitte d.

L ocal testi n g .

See Secti o n 3. 9. 1
J V 0 2 0 5 Pr ot oc ol A d de n da ( g). p df | V V- T M F- 4 2 9 2 2 1 7 | 1. 0
Fi nal
P P D

J 1 S -M C -J V 0 2( g) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 1 3
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
Tre at me nt Peri o d 2 1- D a y C ycle
C ycle 1  
C ycle 2 - n
D a y wit hi n C ycle
1 
8 
1 
8
Pr oce d ure
I nstr ucti o ns
Plai n a nter o p osteri or 
ra di o gra p h of a si n gle 
pr o xi mal ti bial 
gr o wt h plate ( onl y  f or 
patie nts ra n d o mize d 
t o ra m ucir u ma b a n d 
wit h o pe n gr o wt h 
plate at baseli ne)
See I nstr ucti o ns
Perf or m e ver y 4 m o nt hs acc or di n g t o Secti o n 3. 9. 3. 1. 2 .
Patie nts m ust be f oll o we d f or d urati o n of st u d y or u ntil cl os ure of gr o wt h plate.
I n s o me ge o gra p hies, a n M RI of t he k nee m a y be a n alter nate o pti o n i nstea d of plai n ra di o gra p h .
E C G
Si n gle, at baseli ne.  Perf or m a d diti o nal e val uati o ns i n t he setti n g of car diac s y m pt o ms a n d/ or at t he 
discreti o n of t he i n vesti gat or.
L ocal testi n g.
He mat ol o g y
X  
X  
X  
X
F or C 1 D 1: ≤7 da ys pri or ; s u bse q ue nt c ollecti o ns: ≤3 da ys pri or t o a d mi nistrati o n of st u d y 
treat me nt, u nless m ore fre q ue nt assess me nt is cli nicall y i n dicate d.
See Attac h me nt 2 f or desi g nati o n of l ocal or ce ntral testi n g.
C oa g ulati o n
X
X
F or C 1 D 1: ≤7 da ys pri or ; s u bse q ue nt c ollecti o ns: ≤3 da ys pri or t o a d mi nistrati o n of st u d y 
treat me nt, u nless m ore fre q ue nt assess me nt is cli nicall y i n dicate d.
See Attac h me nt 2 f or desi g nati o n of l ocal or ce ntral testi n g.
Cli nical c he mistr y
X  
X  
X  
X
F or C 1 D 1: ≤7 da ys pri or ; s u bse q ue nt c ollecti o ns: ≤3 da ys pri or t o a d mi nistrati o n of st u d y 
treat me nt, u nless m ore fre q ue nt assess me nt is cli nicall y i n dicate d.
See Attac h me nt 2 f or desi g nati o n of l ocal or ce ntral testi n g.
Ur i nal ysis
X  
X  
X  
X
F or C 1 D 1: ≤7 da ys pri or ; s u bse q ue nt c ollecti o ns: ≤3 da ys pri or t o a d mi nistrati o n of st u d y 
treat me nt, u nless m ore fre q ue nt assess me nt is cli nicall y i n dicate d.
See Attac h me nt 2 f or desi g nati o n of l ocal or ce ntral testi n g.
Pre g na nc y test
See i nstr ucti o ns
Ser u m or uri ne per i nstit uti o nal sta n dar d.  A p plies o nl y t o fe males of c hil d beari n g p ote ntial.
Perf or m o n Da y 1 of eac h treat me nt c ycle (at least o nce e ver y 2 8 da ys) pri or t o a d mi nistrati o n of 
st u d y treat me nt.
See Attac h me nt 2 f or desi g nati o n of l ocal or ce ntral testi n g.
A d mi nister 
ra m ucir u ma b
(i n vesti gati o nal ar m)
X  
X  
X  
X
Pre me dicate acc or di n g t o Secti o n 3. 7. 1. 1 .  Patie nts m ust be cl osel y m o nit ore d f or a 1- h o ur 
o bser vati o n peri o d f oll o wi n g t he ra m ucir u ma b i nf usi o ns f or t he first 2 i nf usi o ns ( see Secti o n 
3. 7. 6. 1. 7. 1 ).
A d mi nister 
ge mcita bi ne
X  
X  
X  
X
Pre me dicate acc or di n g t o Secti o n 3. 7. 1. 1 .
J V 0 2 0 5 Pr ot oc ol A d de n da ( g). p df | V V- T M F- 4 2 9 2 2 1 7 | 1. 0
Fi nal
P P D

J 1 S -M C -J V 0 2( g) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 1 4
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
Tre at me nt Peri o d 2 1- D a y C ycle
C ycle 1  
C ycle 2 - n
D a y wit hi n C ycle
1 
8 
1 
8
Pr oce d ure
I nstr ucti o ns
A d mi nister d oceta xel
X
X
Pre me dicate acc or di n g t o Secti o n 3. 7. 1. 1 .
Sa m ple c ollecti o n 
f or:
P har mac o d y na mics
See Attac h me nt 3
P har mac o ki netics
See Attac h me nt 3
I m m u n o ge nicit y
See Attac h me nt 3
Ge netics
See Attac h me nt 3
Bi o mar kers
See Attac h me nt 3
A b bre viati o ns:  A E = a d verse e ve nt; C T = c o m p ute d t o m o gra p h y; C T C A E = C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts ( N CI 2 0 1 7 ); 
E C G = electr ocar di o gra m; E C O G = Easter n C o o perati ve O nc ol o g y Gr o u p ( O ke n et al. 1 9 8 2); I V = i ntra ve n o us; M RI = ma g netic res o na nce i ma gi n g; 
q = e ver y;  R E CI S T 1. 1 = Res p o nse E val uati o n Criteria i n S oli d T u m ors, Versi o n 1. 1 ( Eise n ha uer et al. 2 0 0 9); w k = wee k.
J V 0 2 0 5 Pr ot oc ol A d de n da ( g). p df | V V- T M F- 4 2 9 2 2 1 7 | 1. 0
Fi nal
P P D

J 1 S -M C -J V 0 2( g) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 1 5
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
T a bl e J V 0 2 . 3.
P o st -St u d y -Tr e at m e nt F oll o w -U p S c h e d ul e of A cti viti e s
S h ort -Ter m 
F oll o w -U p a
L o n g -Ter m 
F oll o w -U p
Visit
8 0 1 
8 0 2- 8 X X
Pr oce d ure
I nstr ucti o ns
P h y sical e xa mi nati o n
X
I ncl u di n g wei g ht, a n d vital si g ns (te m perat ure, 
bl o o d press ure, a n d p ulse rate)
I ncl u de hei g ht f or patie nts wit h o pe n gr o wt h plate. 
I n t he e ve nt of a b n or mal gr o wt h plate fi n di n gs, 
c o nti n ue t o o btai n hei g ht peri o dicall y at 
i n vesti gat or’s discreti o n.
C o nc o mita nt me dicati o n
X
A E c ollecti o n
X
C T C A E, Versi o n 5 . 0
E C O G/ La ns k y/ Kar n ofs k y 
perf or ma nce stat us
X
Ra di ol o gic i ma gi n g of k n o w n 
lesi o ns a n d c hest C T, a n d 
meas ure me nt of pal pa ble or 
visi ble lesi o ns
See i nstr ucti o ns

Preferre d m o dalities:
o
e xtre mit y/ hea d/ nec k:  M RI
o
c hest/a b d o me n/ pel vis:  C T

Per f orm q 9 w k ( ± 7 da ys) acc or di n g t o 
R E CI S T 1. 1 criteria or q 3 m o nt hs ( ± 1 4 da ys) 
after t hir d e val uati o n of sta ble disease or 
f oll o wi n g s ur gical resecti o n wit h clea n mar gi ns, 
b y t he sa me met h o d use d at baseli ne a n d 
t hr o u g h o ut t he st u d y, u ntil o ne of t he f oll o wi n g 
occ urs:
o
t he patie nt has d oc u me nte d disease 
pr o gressi o n
o
Patie nt has starte d ne w a nti -ca ncer t hera p y
o
t he st u d y’s pri mar y /fi nal a nal ysis of O S .

See Secti o n 3. 9. 1
Plai n a nter o p osteri or 
ra di o gra p h of a si n gle 
pr o xi mal ti bial gr o wt h plate
f or patie nts ra n d o mize d t o 
ra m ucir u ma b wit h o pe n 
gr o wt h plates at baseli ne 
bei n g f oll o we d o n st u d y
X
X
( o nl y f or 
patie nts wit h 
a b n or mal 
gr o wt h plate 
fi n di n gs at 
V 8 0 1)
I n s o me ge o gra p hies, a n M RI of t he k nee m a y be a n 
alter nate o pti o n i nstea d of plai n ra di o gra p h .
L o n g -Ter m F oll o w -U p:
Fre q ue nc y of ra di o gra p hs i n L o n g -Ter m F oll o w -U p 
is per t he i n vesti gat or’s discreti o n acc or di n g t o 
Secti o n 3. 9. 3. 1. 2 .  C o nti n ue t o perf or m u ntil 
res ol uti o n of gr o wt h plate a b n or malities or gr o wt h 
plate cl os ure.
J V 0 2 0 5 Pr ot oc ol A d de n da ( g). p df | V V- T M F- 4 2 9 2 2 1 7 | 1. 0
Fi nal
P P D

J 1 S -M C -J V 0 2( g) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 1 6
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
S h ort -Ter m 
F oll o w -U p a
L o n g -Ter m 
F oll o w -U p
Visit
8 0 1 
8 0 2- 8 X X
Pr oce d ure
I nstr ucti o ns
C ollecti o n of s ur vi val 
i nf or mati o n
X
Perf or m q 3 m o nt hs ( ± 1 4 da ys).  If a n i n-pers o n 
visit is n ot p ossi ble, c o nfir m s ur vi val b y c o ntacti n g 
t he patie nt directl y via p h o ne u ntil deat h or st u d y 
c o m pleti o n .
C ollecti o n of 
p ostst u d y- treat me nt 
a ntica ncer t hera p y 
i nf or mati o n
X
X
Perf or m q 3 m o nt hs ( ± 1 4 da ys) f or t he first 2 years 
after disc o nti n uati o n fr o m st u d y treat me nt a n d 
q 6 m o nt hs ( ± 1 4 da ys) t hereafter, u ntil deat h or 
st u d y c o m pleti o n.
He mat ol o g y
X
See Attac h me nt 2 f or desi g nati o n of l ocal or ce ntral 
testi n g.
C oa g ulati o n
X
See Attac h me nt 2 f or desi g nati o n of l ocal or ce ntral 
testi n g.
Cli nical c he mistr y
X
See Attac h me nt 2 f or desi g nati o n of l ocal or ce ntral 
testi n g.
Ur i nal ysis
X
See Attac h me nt 2 f or desi g nati o n of l ocal or ce ntral 
testi n g.
T S H a n d Free T 4
X
See Attac h me nt 2 f or desi g nati o n of l ocal or ce ntral 
testi n g.
Sa m ple c ollecti o n f or:
P har mac o d y na mics
See Attac h me nt 3
P har mac o ki netics
See Attac h me nt 3
I m m u n o ge nicit y
See Attac h me nt 3
Ge netics
See Attac h me nt 3
Bi o mar kers
See Attac h me nt 3
A b bre viati o ns:  A E = a d verse e ve nt; C T = c o m p ute d t o m o gra p h y; C T C A E = C o m m o n Ter mi n ol o g y Criteria f or 
A d verse E ve nts ( N CI 2 0 1 7 ); E C O G = Easter n C o o perati ve O nc ol o g y Gr o u p ( O ke n et al. 1 9 8 2) ; Fr ee T 4 = 
th y r oxi n e ; M RI = ma g netic res o na nce i ma gi n g; O S = o verall s ur vi val; q = e ver y; R E CI S T 1. 1 = Res p o nse 
E val uati o n Criteria i n S oli d T u m ors, Versi o n 1. 1 ( Eise n ha uer et al. 2 0 0 9) ; T S H = t h yr oi d-sti m ulati n g h or m o ne.
a
S h ort -ter m f oll o w-u p be gi ns w h e 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.  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 i nf or me d c o nse 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.
J V 0 2 0 5 Pr ot oc ol A d de n da ( g). p df | V V- T M F- 4 2 9 2 2 1 7 | 1. 0
Fi nal
P P D

J 1 S -M C -J V 0 2( g) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 1 7
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
T a bl e J V 0 2 . 4.
C o nti n u e d A c c e s s S c h e d ul e of A cti viti e s
St u d y 
Tre at me nt
F oll o w -U p a
Visit
5 0 1- 5 X X
9 0 1
Pr oce d ure b
I nstr ucti o ns
A E c ollecti o n
X
X
C T C A E, Versi o n 5 . 0
P K, I G , a n d h y perse nsiti vit y  
la bs f or I R R e ve nts
(i ncl u di n g h y perse nsiti vit y 
reacti o ns)
I n t he e ve nt of a n I R R (i ncl u di n g h y perse nsiti vit y 
reacti o ns), bl o o d sa m ples will be c ollecte d as 
o utli ne d i n Secti o n 3. 7. 6. 1. 7. 1 a n d Attac h me nt 3 .
A d mi nister ra m ucir u ma b 
(i n vesti gati o nal ar m)
X
Pre me dicate acc or di n g t o Secti o n 3. 7. 1. 1 .  
A d mi nister ge mcita bi ne
X
Pre me dicate acc or di n g t o Secti o n 3. 7. 1. 1 .
A d mi nister d oceta xel
X
Pre me dicate acc or di n g t o Secti o n 3. 7. 1. 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 Ter mi n ol o g y Criteria f or A d verse E ve nts ( N CI 2 0 1 7) ; 
I G = i m m u n o ge nicit y; I R R = i nf usi o n-r elate d reacti o n; I V = i ntra ve n o us ; P K = p har mac o ki netics.
a
C o nti n ue d -access f oll o w-u p be gi ns w h e n t he patie nt a n d the 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 treat me nt i n t he c o nti n ue d -access peri o d a n d lasts a p pr o xi matel y 3 0 da ys.  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 i nf or me d c o nse 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.
b
Efficac y assess me nts will be d o ne at t he i n vesti gat or’s discreti o n base d o n t he sta n dar d of care.
J V 0 2 0 5 Pr ot oc ol A d de n da ( g). p df | V V- T M F- 4 2 9 2 2 1 7 | 1. 0
Fi nal
P P D

J 1 S -M C -J V 0 2( g) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 1 8
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
3. 3.
I ntr o d u cti o n
3. 3. 1.
St u d y R ati o n al e
A n gi o ge nesis is a bi o l ogic pr ocess t hat is i m p orta nt f or ca ncer gr o wt h a n d metastasis.  As a 
res ult, t he pat h wa ys t hat me diate a n gi o ge nesis are c o nsi dere d i m p orta nt tar gets i n ca ncer dr u g 
de vel o p m e nt.  Vasc ular e n d ot helial gr o wt h fact ors ( V E G Fs; i ncl u di n g V E G F- A, V E G F -B, 
V E G F -C, a n d V E G F -D) a n d pl a c e nt al gr o wt h fact or ha ve e mer ge d as ke y re g ulat ors of 
a n gi o ge nesis.  V E G F-A is disti nct wit hi n t he V E G F li ga n d fa mil y i n t hat it acts as a d o mi na nt 
e n d o t helial cell-s pecific mit o ge n d uri n g a n gi o ge nesis.  V E G F Rece pt or 2 is t he pri mar y me diat or 
of  pr oa n gio ge nic effects of V E G F -A a n d e x peri me ntal e vi de nce s u g gests t hat t he V E G F -
A/ V E G F Rece pt or 2 i nteracti o n pla ys a n i m p orta nt r ole i n t u m or a n gi o ge nesis.  T h eref ore, 
di sr u pti on of t he i nteracti o n bet wee n V E G F -A a n d V E G F Rece pt or 2 ma y ha ve t hera pe utic 
a p plicat i on i n t he treat me nt of ca ncer.
T u m or a n gi o ge nesis is a pri me pr ocess i n v ol ve d i n t u m or gr o wt h a n d re q uires t he i nteracti o n of 
vari o us cell fact ors, cell s, a n d tiss ues ( Ellis a n d Hic kli n 2 0 0 8).  Tar geti n g m ult i ple pr ocesses, 
s uc h as a n gi o ge nesis a n d cell c ycle c o ntr ol, is k n o w n t o effect i vel y treat ma n y ca ncers ( De Vit a 
et al. 1 9 7 5; Sa w yers 2 0 0 4; K ni g ht et al. 2 0 1 0; Car meleit a n d Jai n 2 0 1 1).
Si milar t o a d ul t t u mors, a n gi o ge nesis is u pre g ulate d i n pe diatric e m br y o n al t u mors m a ki n g it a n 
i m p orta nt pat h wa y.  V E G F a n d its d o w nstrea m sig nali n g pla y  a vit al r ole i n t u mor gr o wt h a n d 
metastasis i n c hil dre n. St u dies ha ve s h o w n hi g h le vels o f circ ulati n g V E G F le vels i n c hil dre n 
wi t h t u mors at baseli ne ( Bla n n et al . 2 0 0 1; H olzer et al . 2 0 0 1).
S of t tiss ue sarc omas ( S T S s) ha ve bee n s h o w n t o e x press V E G F a n d/ or V E G F R-2 t o var yi n g 
de grees. M ult i ple cli nical trials tar geti n g t he V E G F pat h wa y with m A b a ge nts or t y r osi ne ki nase 
i n hi bit ors ( T KIs) ha ve bee n c o n d ucte d i n patient s wit h S T Ss a n d de mo nstrate d acti vit y ( Ge or ge 
et al. 2 0 0 9; Ma ki et al. 2 0 0 9; Sleijfer et al. 2 0 0 9; F o x et al. 2 0 1 0; va n der Graaf et al. 2 0 1 2; 
Gl a de Be n der et al. 2 0 1 3; C his h o l m et al. 2 0 1 7). T he P A L A T T E st u d y , a ra n d o mize d, 
d o u bl e- bli n d, place b o -c o ntr olle d P hase 3 trial, i n vesti gati n g t he use of paz o pa ni b i n a d ult 
pati e nts wit h a d va nce d n o n-a dip o c y tic S T S, de mo nstrate d i m p r o ve d me dia n pr o gressio n -free 
s ur vi val ( P F S) i n t he T KI ar m ( va n der Graaf et al. 2 0 1 2).  T he B E R NI E trial, a pe diatric, o pe n -
la bel, ra n d omize d P hase 2 st u d y , i n vesti gate d t he a d diti on of be vaciz u ma b t o sta n dar d fr o nt -li ne 
c he m ot hera p y a n d mai nte na nce t her a p y vers us c he m ot hera p y a n d mai nte na nce alo ne f or pati e nts 
wi t h metastatic r ha b d o m y o sarc oma ( R M S) a n d n o n -r ha b d om y o sarci ma S T S ( N R S T S). W hile 
t he st u d y did n ot m e et its pri mar y e n d p oi nt of e ve nt-free s ur vi val ( E F S) acr oss all patient s wit h 
S T S, a s u bset a nal ysis i de nt ifie d a p ote ntiall y c om pelli n g be nefit i n t he N R S T S c o h ort wit h t he 
a d ditio n of  t he a nti-V E G F a ge nt.  F urt her m ore, t he safet y pr ofile o f t he a nt i-V E G F i n hi bit or i n 
c o m bi nat i on wi t h sta n dar d fr o nt-li ne c he m ot hera p y a n d mai nte na nce t hera p y i n pe diatric patie nts 
wi t h S T Ss was c o nsiste nt wit h t he k n o w n safety pr ofile i n a d ults a n d di d n ot e n ha nce t o xicit y i n 
t he ver y de nse c he mot h era p y pr ot o c ol ( C his h ol m et al. 2 0 17 ).
C o nsiste nt wit h t he cli nical data i m plicat i n g t he V E G F pat h wa y i n S T S, precli nical data i n S S 
pati e nt - deri ve d xe n o graft m o dels treate d wit h V E G F-tar gete d t hera p y, be vaciz u ma b or 
J V 0 2 0 5 Pr ot oc ol A d de n da ( g). p df | V V- T M F- 4 2 9 2 2 1 7 | 1. 0
Fi nal
P P D

J 1 S -M C -J V 0 2( g) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 1 9
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
paz o pa ni b, de m o nstrate d mar ke dl y s u p presse d t u m or gr o wt h a n d i n hi bit i on o f h ost a n gi o ge nesis.  
T he prese nce of V E G F le d t o S S t u m or pr oliferat i o n i n a n a ut ocri ne fas hi on a n d S S 1 8 -S S X, a 
tra nslo c ati o n s pecific f or S S, directs t he V E G F si g nal fr o m differe nt iati on t o cell gr o wt h 
i m plicati n g t he V E G F pat h wa y as a p ote ntial critical t hera pe utic tar get f or S S ( Wa ka mats u et al. 
2 0 1 4).   F urt her m ore, i n precli nical pat ie nt -deri ve d xe n o graft st u dies usi n g des m o plast ic s mall 
r o u n d cell t u m or (D S R C T ; St u di es C T G - 0 9 2 6 a n d C T G -1 4 5 8) a n d s y n o vial sarc oma (S S ;
St u di es C T G - 0 3 3 1 a n d C T G -1 1 7 3) m o dels, a m o use s urr o gate i n hi bit or tar geti n g V E G F 
Rece pt or 2 ( D C 1 0 1) ha d better t u m or e fficac y i n c o m bi nati on wi t h sta n dar d-of -care treat me nts 
( d o x or u bici n, d oceta xel/ ge mcita bi ne, or c yclo p h os p ha mi de) vers us sta n dar d of care al o ne .
T heref ore, St u dies J 1 S-M C -J V 0 1 (J V 0 1) a n d J V 0 2, are P hase 1/ 2 st u dies e val uat i n g 
r a mu ci r u ma b i n pe diatric pat ient s a n d yo u n g a d ul ts wit h r ela pse d, rec urre nt, or refract or y 
D S R C T (J V 0 1) or S S (J V 0 2) i n c om bi nat i on wi t h k n o w n c he mot h era p y bac k b o nes use d i n t hese 
setti n gs.  T u m or -s pecific c o ncl usi o ns re gar di n g i m pr o ve me nts i n e fficac y will be ma de f or eac h 
st u d y.  As a d di n g ra mucir u ma b ma y  si milarl y i m pr o ve o utc o mes for pati e nts wit h bot h di seases, 
t he statistical a nal ysis will als o i nc or p orate a f or mal mec ha nis m t o a da pti vel y b orr o w 
i nf or mat i on re gar di n g relat i ve be nefit o bser v e d acr oss b ot h st u dies.
T his a d de n d u m (J V 0 2) descri bes t he h y p ot hesis a n d details of t he S S i n vest i gati on. W he n 
r ele va nt t o t he disc ussi o n, refere nces t o t he D S R C T i n vesti gati o n (J V 0 1) will be i ncl u de d.
3. 3. 2.
B a c k gr o u n d
3. 3. 2. 1.
S y n o vi al S ar c o m a 
S S is t he m ost c o m m on n o n- r ha b d om y o sarc o ma S T S i n c hil dre n a n d a d olesce nts a n d ma kes u p 
1 0 % of all S T S s ( S o ole et al. 2 0 1 4).  S S is f ou n d i n b ot h pe diatrics a n d a d ults a n d is classifie d as 
a mali g na nt mese nc h y mal t u mor , c haracterize d b y l ocal i n vasi ve ness a n d a pr o pe nsit y t o 
metastasize ( Ferrari et al. 2 0 1 5). T hese t u m ors arise i n cl ose pr o xi mit y t o te n d o n s heat hs, j oi nt 
ca vit ies, a n d b ursae a n d ofte n metastasize t o t he l u n gs or l y m p h n o des ( Sta nelle et al. 2 0 1 3) . 
Trea t me nt strate gies ha ve bee n diffic ult t o i de ntif y d ue t o l o w i nci de nce a n d u n us ual cli nical 
be ha vi or t hat d oes n ot f o ll ow t y pi c al  patter ns of lo c al  rec urre nce, metastasis, or res p o nse t o 
treat me nt.  
F or b ot h a d ult a n d pe diatric pat ient s wit h S S, t he c urre nt sta n dar d a p pr oac h f or lo c al  disease is 
s ur gical resect i on; ra di at i on t hera p y  a n d/ or c he mot h era p y ma y be gi ve n bef ore or after s ur ger y.  
As a c he m ose nsit i ve mali g na nc y, S S t u m ors ha ve s h o w n res p o nse t o if osfa mi de -base d 
c he m ot hera p y (t ypicall y i n c o m bi nat i on wi t h d o x or u bici n, a n d ge nerall y with m ult i m o dal 
t hera p y).  H o we ver, t here is n o defi ne d sta n dar d treat me nt re gi me n i n t he rela pse d setti n g.  
Des pite i nit ial treat me nt, a p pr o xi matel y 2 5 % t o 4 0 % of pe diatric pat ient s wit h S S w h o i nitiall y 
prese nt wit h l ocal t u m ors de vel o p rec urre nt or refract or y  disease; i n t hese patient s t he 5-year 
o verall s ur vi val ( O S ) is just 3 0 % t o 4 2 % after rela psi n g ( Ferrari et al. 2 0 1 5 ; S o ole et al. 2 0 1 4).
3. 3. 2. 2.
R a m u cir u m a b
Ra m u ci r u ma b is a h u ma n rece pt or-tar gete d mo n ocl o n al a nti b o d y ( m A b) t hat s pecificall y bi n ds 
V E G F Rece pt or 2.  T he bi n di n g o f r a mucir u ma b t o V E G F Rece pt or 2 pre ve nts its i nteracti o n 
J V 0 2 0 5 Pr ot oc ol A d de n da ( g). p df | V V- T M F- 4 2 9 2 2 1 7 | 1. 0
Fi nal
P P D

J 1 S -M C -J V 0 2( g) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 2 0
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
wi t h acti vati n g li ga n ds ( V E G F-A, V E G F -C, a n d V E G F -D).  As a res ult, ra m ucir u ma b i n hi bits 
li ga n d-sti m ulate d acti vati o n of V E G F Rece pt or 2 a n d its d o w nstrea m si g nali n g c o m p o ne nts, 
i ncl u di n g p 4 4/ p 4 2 mit o ge n-acti vate d pr otei n ki nases.   T hi s ne utralizes li ga n d-i n d uce d 
pr oliferat i on a n d mi grati o n o f h u ma n e n d ot helial cells a n d ult i matel y i n hi bits t u mor gr o wt h a n d 
pr o pa gati o n.
Ra m u ci r u ma b has n ot bee n a p pr o ve d i n pe diatrics; h o we ver, is bei n g st u die d i n t he o n g oi n g 
I 4 T-M C -J V D A (J V D A) tria l.  I n a d ults, ra m u cir u ma b has i m pr o ve d o utc o mes, i ncl u di n g O S , i n 
m ult i ple i n dicati ons as b ot h a m o n ot hera p y  a n d c o m bi nati on wi t h ot her a ge nts.  Ra m ucir u ma b is 
a p pr o ve d as m o n ot hera p y or i n c o m bi natio n wi t h paclita xel i n t he U nite d States ( U S), t he 
E ur o pea n U ni o n ( E U), Ja pa n, a n d ot her c o u ntries f or t he treat me nt of a d ult patie nts wit h 
a d va nce d gastric ca ncer or gastr oes o p ha geal j u nct i o n ( G EJ) a de n ocarci n o ma wit h disease 
pr o gressi o n o n or after pri or plat i n u m a n d/ or flu or o p y rimi di ne c he m ot hera p y.  T he a p pr o val s 
were base d o n t he cli nical efficac y  a n d safety de m o nstrate d i n 2 gl o bal , ra n d o mize d, d o u ble-
bli n d , a n d place b o -c o ntr olle d P hase 3 st u dies, R E G A R D ( F uc hs et al. 2 0 1 4) a n d R AI N B O W 
( Wil ke et al. 2 0 1 4).
I n t he U S a n d t he E U, ra mu ci r u ma b i n c o m bi nati on wi t h FO L FI RI (i rin oteca n, 5 -fl u or o uracil, 
a n d f o li nic aci d) is a p pr o ve d f or t he treat me nt of metastatic c ol orectal ca ncer i n a d ult pati e nts 
wi t h disease pr o gressio n o n or after t hera p y  wit h be vaciz u ma b, o xali plati n, a n d a 
fl u or o p yrimi di ne ( R AI S E; Ta ber ner o et al. 2 0 1 5).
I n t he U S, ra m ucir u ma b i n c om bi nat i on wi t h d oceta xel is a p pr o ve d f or t he treat me nt of a d va nce d 
n o n- s mall c ell lu n g ca ncer ( N S C L C) i n a d ult pati e nts wit h disease pr o gressi o n o n or after 
pl at i n u m-base d c he m ot h era p y ( R E V E L; Gar o n et al. 2 0 1 4).  
3. 3. 2. 3.
G e m cit a bi n e a n d D o c et a x el
T he c o m bi nat i on of ge mcita bi ne a n d d oceta xel is a n effect i ve o pti o n f or pe diatric a n d y o u n g 
a d ult pati e nts wit h metastatic S T S a n d has bee n st u die d usi n g a di verse ra n ge of d oses a n d acr oss 
s u bty p es ( Ma ki et al. 2 0 0 7). F or patie nts wit h S S s pecificall y, A b o u har b et al. ( 2 0 1 4) descri be d 
t heir fi n di n gs of  acti vity i n a n i nst ituti o nal  r etr os pecti ve re vie w of 4 2 pe di atric a n d a d ult patie nts 
wi t h metastatic S S treate d wit h a ge mcita bi ne/ d oceta xel re gi me n f oll owi n g i ni tial tr e at me nt wit h 
d o x or u bi ci n a n d if osfa mi de.  Res p o nse rates were c o mplete res p o nse ( C R ) 2. 4 % ( 1/ 4 1), partial 
res p o nse (P R ) 7. 1 % ( 3/ 4 1) , a n d sta ble disease ( S D ) 3 3. 3 % ( 1 4/ 4 1 ), wit h a me dia n d uratio n of
res p o nse of  4 6 wee ks, 4 2 wee k s, a n d 1 6 wee ks, res pecti vel y.
T he c o m bi nat i on of ge mci ta bi ne a n d d oceta xel  wit h t he a nt i-V E G F pat h wa y i n hi bit or , 
be vaciz u ma b, has bee n e val uate d i n t wo pr os pecti ve S T S st u dies i ncl u di n g yo u n g a d ul ts, wit h 
c o mpelli n g o utc o mes . I n a P hase 2 st u d y in vest i gati n g t he c o m bi nati on i n 3 5 patie nts wit h 
metastati c or locall y rec urre nt S T S w h o recei ve d n o m ore t ha n o ne pri or li ne of c he m ot hera p y , 
t he o verall res p o nse rate was 4 9 % ( 1 7/ 3 5), i n w hic h 1 0 res p o n di n g pat ient s electe d t o st o p 
treat me nt t o u n der g o t u m or resecti o n ( Dic ks o n et al 2 0 1 5).  T hi s res p o nse rate was a n ota ble 
i m pr o ve me nt fr o m t he hist orical c o ntr ol rate of 1 6 % f or ge mcita bi ne a n d d oceta xel alo ne, 
descri be d b y Ma ki et al . ( 2 0 0 7). A P hase 1 b d ose -escalat i on st u d y e valu at e d t he c o m bi nat i on i n 
c he m ot hera p y-naï ve pat ient s wit h a d va nce d or rec urre nt S T S.  The 3 5 e val ua ble pati e nts ha d a n 
J V 0 2 0 5 Pr ot oc ol A d de n da ( g). p df | V V- T M F- 4 2 9 2 2 1 7 | 1. 0
Fi nal
P P D

J 1 S -M C -J V 0 2( g) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 2 1
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
o verall res p o nse rate of 3 1. 4 % a n d a disease c o ntr ol rate of 8 2. 8 % ( 5 C R, 6 P R , a n d 1 8 S D), f or 
w hic h t he me d ia n d urati o n of res p o nse was 6 m ont hs ( Versc hrae ge n et al 2 0 1 2).  Of t he t w o
pati e nts e nr olle d wit h S S, o ne ha d a P R a n d t he ot her S D .  T o get her, t hese data warra nt f urt her 
e x pl orat i on of ge mci ta bi ne a n d d oceta xel i n c o m bi nat i on wi t h ra m ucir u ma b i n patient s wit h 
r ela pse d, rec urre nt, or refract or y S S.
I nf usi on of ge mcita bi ne at a fi xe d -d ose rate refers t o i nf usi n g ge mcita bi ne at a c o nti n u o us rate 
e na bli n g t he mai nte na nce of t he ge mcita bi ne c o nce ntrati o n at a le vel t hat will o pti mize t he 
i nc or p orati o n of ge mcita bi ne tri p h os p hate, w hic h is t he acti ve ge mcita bi ne meta b o lite, i nt o 
de o x y rib o n ucleic aci d ( D N A) ( He nsle y et al. 2 0 0 8a).  St u dies ha ve s h o w n t hat ge mcita bi ne ma y 
ha ve greater acti vit y w he n gi ve n as a fi xe d -d ose rate i nf usi o n ( 1 0 m g/ m 2 / mi n) c o mpare d wi t h 
t he rec o m me n de d sc he d ule (a 3 0- mi n ute i nf usi o n) ( Te m per o et al. 2 0 0 3).
Fi xe d -d ose rate ge mcita bi ne ( 9 0 0 m g/ m 2 o ver 9 0 mi n utes [ fi xe d-d ose rate of 1 0 m g/ m 2 / mi n], 
Da ys 1 a n d 8, pl us d oceta xel 1 0 0 m g/ m 2 o n Da y  8) yiel de d hi g h o bject i ve res p o nse rates a m o n g 
pati e nts wit h a d va nce d lei om y o sar c o ma i n b ot h t he sec o n d -li ne a n d first-li ne setti n gs ( He nsle y et 
al. 2 0 0 8a, 2 0 0 8 b).  H o we ver, t o i ncrease t he t olera bility of  t his c he mot h era p y re gi me n a 
d oceta xel d ose of 7 5 m g/ m 2 has bee n selecte d f or t his st u d y .  S o me of t he t o xicit y see n i n 
pre vi o us c li nical e x perie nce (fati g ue, ast he nia, a n d fl ui d rete nti o n) was m ore t ypical  of t he 
d oceta xel c o u nter part, s u g gesti n g t hat t his d oceta xel d ose m o dificat i on c o ul d i m pr o ve t he 
t olera bilit y of t his re gi me n.  T his is c o nsiste nt wit h t he 7 5 -m g/ m 2 d oceta xel  d ose c h ose n i n 
rece nt P hase 3 Ge D Di S trial ( Se d d o n et al. 2 0 1 5).  T heref ore, t his P hase 1/ 2 tri al in vest i gates t he 
efficac y a nd safet y  of r a mucir u ma b i n c o m bi nati o n wit h ge mci ta bi ne ( 9 0 0 mg/ m 2 o ver 9 0 
mi n utes [fi xe d -d ose rate of 1 0 m g/ m 2 / mi n]) a n d d oceta xel ( 7 5 m g/ m 2 ) f or t he treat me nt of 
pe di atric patie nts a n d yo u n g a d ul ts wit h rela pse d, rec urre nt, or refract or y S S .
3. 3. 3.
B e n efit/ Ri s k A s s e s s m e nt
S S is t he m ost c o m m on n o nr ha b d o m y o sarc oma s oft tiss ue sarc o ma ( S T S) i n c hil dre n a n d 
a d olesce nts a n d ma kes u p 1 0 % of all S T Ss ( S o ol e et al. 2 0 1 4). C urre ntl y, t here is n o sta n dar d of 
care f or treati n g pe diatric a n d yo u n g a d ul t p atie nts wit h S S i n t he rela pse d setti n g, a n d t he 
o utc o m es are u nsat isfact or y, wit h 5-year s ur vi val rates as l o w as 3 0 % ( Ferrari et al. 2 0 1 2).  T h us, 
e ve n wit h treat me nts s uc h as ge mcita bi ne a n d d oceta xel, w hic h are n ot a p pr o ve d f or t he 
treat me nt of S S b ut are a m o n g t he a ge nts c urre ntl y use d t o treat t he disease, t here is st ill nee d f or 
f urt her i m pr o ve me nt of t his disease ( A b o u har b et al. 2 0 1 4). As S S t u mors dis pla y  r o b ust 
e x pressi o n of V E G F pat h wa y c o m p o ne nts, i ncl u di n g V E F G R -2, V E G F -A, - C, a n d - D, t here is 
t he p ote ntial for t hera pe uti c be nefit f or patie nts res ultin g fr o m V E G F R -2 i n hi bit i on wi t h 
r a mu ci r u m a b.  I mpr o ve d efficac y  wit h r a mu ci r u ma b i n c o m binat i on wi t h ge mcita bi ne a n d 
d oceta xel c he m ot hera p y is e x pecte d t o e n ha nce t hese effects wit hi n e v o l vi n g t u mors b y 
i m pe di n g t he V E G F pat h wa y’s mai nte na nce of vasc ular e n d ot helial cell s ur vi val a n d t he a bilit y 
t o dri ve a n gi o ge nesis.  C om pelli n g efficac y a n d acce pta ble safet y fi n di n gs ha ve als o bee n 
o bser ve d w he n t he relate d V E G F pat h wa y  in hi bit or be vaciz u ma b was a d de d t o a 
g e m cita bi ne/ d oceta xel bac k b o ne i n 2 pr os pecti ve S T S st u dies w hic h i ncl u de d yo u n g a d ul ts 
( Versc hrae ge n et al. 2 0 1 2; Dic ks o n et al. 2 0 1 5), an d i n a retr os pecti ve re vie w a n d a case series i n 
pe di atric a n d yo u n g a d ul t p atie nts wit h sarc o ma ( Hi n g ora ni et al. 2 0 1 2; K u o et al. 2 0 1 7).
J V 0 2 0 5 Pr ot oc ol A d de n da ( g). p df | V V- T M F- 4 2 9 2 2 1 7 | 1. 0
Fi nal
P P D

J 1 S -M C -J V 0 2( g) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 2 2
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
Gastr oi ntesti nal ( GI ) perf orati o n a n d se vere blee di n g i ncl u di n g GI he m orr ha ge are c o nsi dere d 
k e y  ris ks f or t he o verall be nefit /ris k assess me nt of ra m ucir u ma b i n t he treat me nt of patie nts. 
H o we ver, t he o verall re p orti n g rate of t hese e ve nts is l o w, a n d t hese ris ks are mit i gate d i n t he 
J V 0 2 pr ot oc ol t hr o u g h o n g oi n g s ur veilla nce, i de nt ificati on (a n d e xcl usi o n) of patie nts wit h hi g h 
blee di n g ris k, a n d d ose m o dificat i on or di sc o nti n uati o n of ra m ucir u ma b if a patie nt e x perie nces a 
GI perf orati o n/ he m orr ha ge . I n a d diti o n, t he c urre ntl y a vaila ble data fr o m st u d y J V D A i n dicate 
t hat t he pe di atric safety pr ofile o f r a mucir u ma b is c o nsiste nt wit h t hat o bser ve d i n a d ults, a n d t he 
maj orit y of  e ve nts are lo w gra de, m o ni t ora ble, a n d ma na gea ble.  T hese ris ks, al o n g wit h t he 
p ote nti al pe diatri c- s pecific c o ncer ns of oste oc h o n dr o pat h y of t he e pip h yseal  gr o wt h plate a n d 
effects o n re nal f u nct i on, w hic h are m o nit ore d i n t he st u d y , are c o nsidere d acce pta ble w he n 
w ei g h e d a gai nst s ur vi val be nefit s for pati e nts i n t his disease setti n g f or w hic h t here are n o ot her 
a p pr o ve d alter nati ves a n d a ver y s hort s ur vi val is e x pecte d.  C o m bi ni n g ra m ucir u ma b wit h 
g e m cita bi ne a n d d oceta xel c he mot h era pies— all wit h well-esta blis he d safet y pr ofiles — is 
a nt ici pate d t o offer i m pr o ve d t hera pe utic be nefit i n a n area of u n met me dical nee d a n d with a 
ma na gea ble safet y pr ofile t hat will be closel y  mo nit ore d t hr o u g h o ut t he st u d y .  T heref ore, t he 
be nefit /ris k assess me nt f or ra m ucir u ma b i n c o m bi nat i on wi t h ge mcita bi ne a n d d oceta xel is 
fa v ora ble a n d s u p p orts t he c o n d uct of t his trial.
J V 0 2 0 5 Pr ot oc ol A d de n da ( g). p df | V V- T M F- 4 2 9 2 2 1 7 | 1. 0
Fi nal
P P D

J 1 S -M C -J V 0 2( g) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 2 3
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
3. 4.
O bj e cti v e s a n d E n d p oi nt s
O bjecti ves
E n d p oi nts
Pri m ar y
T o e val uate t he efficac y of ra m ucir u ma b i n c o m bi nati o n 
wit h ge mcita bi ne a n d d oceta xel c o m pare d wit h 
ge mcita bi ne a n d d oceta xel i n pe diatric a n d y o u n g a d ult 
patie nts wit h S S .
P F S
Sec o n d ar y
T o e val uate t he safet y a n d t olera bilit y of ra m ucir u ma b i n 
c o m bi nat i on w it h ge mcita bi ne a n d d oceta xel c o m pare d 
wit h ge mcita bi ne a n d d oceta xel i n pe diatric a n d y o u n g 
a d ult patie nts wit h S S .
S A Es, A Es, safet y la b orat or y assess me nts, a n d vital 
si g ns
T o e val uate t he efficac y of ra m ucir u ma b i n c o m bi nati o n 
wit h ge mcita bi ne a n d d oceta xel c o m pare d wit h 
ge mcita bi ne a n d d oceta xel i n pe diatric a n d y o u n g a d ult 
patie nts wit h S S .

O R R

D o R

C R
T o c haracterize t he P K of ra m ucir u ma b w he n 
c o-a d mi nistere d wit h ge mcita bi ne a n d d oceta xel i n 
pe diatric a n d y o u n g a d ult patie nts wit h S S.
C ma x a n d C mi n
T o assess t he i m m u n o ge nicit y of ra m ucir u ma b w he n 
c o-a d mi nistere d wit h ge mcita bi ne a n d d oceta xel i n 
pe diatric a n d y o u n g a d ult patie nts wit h S S.
I nci de nce of i m m u n o ge nicit y
E x pl or at or y
T o e x pl ore a d diti o nal meas ures of t he efficac y of 
ra m ucir u ma b i n c o m bi nati o n wit h ge mcita bi ne a n d 
d oceta xel c o m pare d wit h ge mcita bi ne a n d d oceta xel i n 
pe diatric a n d y o u n g a d ult patie nts wit h S S .

O S

P F S 2

Differe nce i n pr o p orti o n of patie nts w h o bec o me 
eli gi ble f or s ur gical resecti o n of lesi o ns d ue t o 
d oc u me nte d t u m or res p o nse w hile o n st u d y t hera p y
T o e x pl ore t he ass ociati o ns bet wee n bi o mar kers, disease 
state, a n d cli nical o utc o mes
Bi o mar kers ma y be assesse d fr o m bl o o d a n d t u m or 
tiss ue sa m ples, u nless precl u de d b y l ocal re g ulati o ns
A b bre viati o ns:  A E = a d verse e ve nt; C ma x = ma xi m u m c o nce ntrati o n; C mi n = mi ni m u m c o nce ntrati o n; 
C R = c o m plete res p o nse; D o R = d urati o n of res p o nse; O R R = o verall res p o nse rate; O S = o verall s ur vi val; 
P F S = pr o gressi o n -free s ur vi val; S A E = seri o us a d verse eve nt ; S S = s y n o vial sarc o ma .
3. 5.
St u d y D e si g n
3. 5. 1.
O v er all D e si g n
St u d y  J V0 2 , c o m bi ne d wit h Pr ot oc ol  J 1 S-M C -J V A A ( herei nafter referre d t o as t he C A M P FI R E 
Master Pr ot oc ol ), is a P hase 1/ 2, ra n d o mize d i n vesti gati on i n pe diatric patient s a n d yo u n g a d ul ts 
di a g n ose d wit h r ela pse d, rec urre nt, or refract or y S S n ot a me n da ble t o s ur ger y e val uati n g 
r a mu ci r u ma b i n c o m bi nati on wi t h g e mcita bi ne a n d d oceta xel. Patie nts will be ra n d o mize d at a 
r atio of  2: 1 t o recei ve either e x peri me ntal or c o ntr ol  t hera p y res pecti vel y. 
T he pri mar y  e n d p oi nt of t he st u d y ( P F S) will be e valuate d via a Ba yesia n a nal ysis i nc or p orati n g 
i nf or mat i on re gar di n g hist orical c o ntr ol o utc o mes as well as effect -size o bser ve d o n St u d y  J V0 1 . 
T his desi g n all o ws f or a re d uce d pr o p orti o n of patie nts t o be ra n d omize d t o c o ntr ol t hera p y w hile 
J V 0 2 0 5 Pr ot oc ol A d de n da ( g). p df | V V- T M F- 4 2 9 2 2 1 7 | 1. 0
Fi nal
P P D

J 1 S -M C -J V 0 2( g) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 2 4
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
mai ntai ni n g p o wer i n li g ht of sa m ple -size li mitatio ns ass oci ate d wit h t he u n derl yi n g rarit y of  t he 
di sease.  Details o f t he Ba yesia n a nal ysis are pr o vi de d i n t he S A P , Secti o n 6 . 6. 1.  
T he st u d y  desi g n is ill ustrate d i n Fi g ure J V 0 2. 1 .
S afet y Le a d -i n Peri o d: T o assess e xcessi ve t o xicit y ass ociate d wit h t he e x peri me ntal 
r a mu ci r u ma b-base d c o m bi nati o n, a safet y lea d -i n p eri o d will be o bser ve d via t he r olli n g si x 
decisi o n fra me w or k of S k ol ni k et al. ( 2 0 0 8).  Base d o n t he first 2 t o 6 D L T -e val ua ble pat ient s
ra n d omize d t o th e ra mucir u ma b ar m at t he pla n ne d 9-m g/ k g d ose ( o n a D 1, D 8 e ver y 2 1 da y 
sc he d ule), t he r a mucir u ma b d ose will be de -escalate d t o 6 m g/ k g ( o n a D 1, D 8 e ver y 2 1 da y 
sc he d ule) f or St u d y  J V 0 2 s h o uld a n y of t he ‘ de-escalate’ crit eria (Ta ble J V 0 2. 5 ) be met , base d 
o n t he t otalit y of  t he data f or w hic h t he D L Ts are attri b uta ble t o ra m ucir u ma b e x p os ure.
Ot her wi se, e nr oll me nt will c o nti n ue as pla n ne d. If t he d ose is de-escalate d, St u d y J V 0 2 will be 
i m me diatel y ter mi nate d f or safety s h o uld a n y of t he criteria f or ter mi nat i n g t he st u d y be met d ue 
t o D L Ts o bser ve d at 6 m g/ k g (Ta ble J V 0 2. 6 ) base d o n t he t otalit y of t he data.   Ot her wise, 
e nr o ll me nt will c o nti n ue wi t h r a mucir u ma b d osi n g at 6 m g/ k g.
E nr oll me nt i n St u d y  J V 0 2 ma y 
be te m p oraril y  pa use d i n certai n circ u msta nces i n w hic h 6 r a m ucir u ma b pati e nts ha ve e nr o lle d at 
t he c urre nt d ose , b ut D L T data are pe n di n g i n m ore t ha n o ne patie nt (Ta ble J V 0 2. 5 a n d Ta ble 
J V 0 2.6 ).  Patie nts w h o c o mplete t he l ea d-i n peri o d will c o nti n ue u ntil o ne of t he disc o nti n uati on 
criteria is met.
See Secti o n 3. 7. 1. 3 f or deter mi nati o n of D L Ts.
T a bl e J V 0 2 .5.
R olli n g Si x R ul e s ( Ra m u cir u m a b at 9 m g/ k g )
N u m ber 
E nr olle d
N u m ber wit h 
D L T
N u m ber 
wit h o ut D L T
N u m ber 
Pe n di n g D L T 
D at a
S afet y Le a d -I n
R ules
2
0, 1
A n y
A n y
C o nti n ue Lea d -I n at 9 m g/ k g
2
2
0
0
De - Esc al ate t o 6 m g/ k g
3
0
0, 1, 2
3, 2, 1
C o nti n ue Lea d -I n at 9 m g/ k g
3
0
3
0
Lea d -I n Peri o d E n ds
3
1
A n y
A n y
C o nti n ue Lea d -I n at 9 m g/ k g
3
≥2
A n y
A n y
De - Esc al ate t o 6 m g/ k g
4
0
0, 1, 2, 3 
4, 3, 2, 1
C o nti n ue Lea d -I n at 9 m g/ k g
4
0
4
0
Lea d -I n Peri o d E n ds
4
1
A n y
A n y
C o nti n ue Lea d -I n at 9 m g/ k g
4
≥2
A n y
A n y
De - Esc al ate t o 6 m g/ k g
5
0
0, 1, 2, 3, 4 
5, 4, 3, 2, 1
C o nti n ue Lea d -I n at 9 m g/ k g
5
0
5
0
Lea d -I n Peri o d E n ds
5
1
A n y
A n y
C o nti n ue Lea d -I n at 9 m g/ k g
5
≥2
A n y
A n y
De - Esc al ate t o 6 m g/ k g
6
0
< 5
≥2
Pa use E nr oll me nt f or D L T Data
6
0
5, 6
1, 0
Lea d -I n Peri o d E n ds 
6
1
< 5
≥2
Pa use E nr oll me nt f or D L T Data
6
1
5
0
Lea d -I n Peri o d E n ds
6
≥2
A n y
A n y
De - Esc al ate t o 6 m g/ k g
A b bre viati o n:  D L T = d ose -li miti n g t o xicit y.
J V 0 2 0 5 Pr ot oc ol A d de n da ( g). p df | V V- T M F- 4 2 9 2 2 1 7 | 1. 0
Fi nal
P P D

J 1 S -M C -J V 0 2( g) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 2 5
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
T a bl e J V 0 2. 6.
R olli n g Si x R ul e s ( R a m u cir u m a b at 6 m g/ k g)
N u m ber 
E nr olle d
N u m ber wit h 
D L T
N u m ber 
w it h o ut D L T
N u m ber 
Pe n di n g D L T 
D at a
S afet y Le a d -I n
R ules
2
0, 1
A n y
A n y
C o nti n ue Lea d -I n at 6 m g/ k g
2
2
0
0
Ter mi n ate
3
0
0, 1, 2
3, 2, 1
C o nti n ue Lea d -I n at 6 m g/ k g
3
0
3
0
Lea d -I n Peri o d E n ds
3
1
A n y
A n y
C o nti n ue Lea d -I n at 6 m g/ k g
3
≥2
A n y
A n y
Ter mi n ate
4
0
0, 1, 2, 3 
4, 3, 2, 1
C o nti n ue Lea d -I n at 6 m g/ k g
4
0
4
0
Lea d -I n Peri o d E n ds
4
1
A n y
A n y
C o nti n ue Lea d -I n at 6 m g/ k g
4
≥2
A n y
A n y
Ter mi n ate
5
0
0, 1, 2, 3, 4 
5, 4, 3, 2, 1
C o nti n ue Lea d -I n at 6 m g/ k g 
5
0
5
0
Lea d -I n Peri o d E n ds
5
1
A n y
A n y
C o nti n ue Lea d -I n at 6 m g/ k g
5
≥2
A n y
A n y
Ter mi n ate
6
0
< 5
≥2
Pa use E nr oll me nt f or D L T Data
6
0
5, 6
1, 0
Lea d -I n Peri o d E n ds 
6
1
< 5
≥2
Pa use E nr oll me nt f or D L T Data
6
1
5
0
Lea d -I n Peri o d E n ds
6
≥2
A n y
A n y
Ter mi n ate
A b bre viati o n:  D L T = d ose -li miti n g t o xicit y.
I nteri m F utilit y A n al ysis: A n i nteri m f ut ility a nal ysis will be tri g gere d f or St u d y J V 0 2 w he n 
a p pr o xi matel y 2 4 t ot al P F S e ve nts ha ve bee n o bser ve d acr oss St u d y  J V0 1 a n d St u d y  J V 02 wi t h a 
mi ni m u m o f 8 e ve nts i n eac h st u d y. At  t he i nteri m f utility l oo k, t he Ba y esia n a nal ysis m ust 
pr o vi de a mi ni m u m of 6 0 % c o nfi de nce i n treat me nt s u peri orit y ( P FS hazar d rati o [ H R ] < 1 f or S S 
pati e nts) i n or der f or e nr oll me nt o n St u d y  J V 0 2 t o c o nti n ue. Ot her wise, e nr o ll me nt o n St u d y  
J V 0 2 will be st o p pe d. 
Pri m ar y A n al ysis:
If St u d y  J V 0 2 passes t he f utilit y  a nal ysis (a n d t h us c o nti n ues e nr oll me nt), 
t he pri mar y a na l ysis will be tri g gere d w he n P F S e ve nts ha ve occ urre d f or a p pr o xi matel y 8 0 % of 
t he e nr olle d pat ient s (acr oss b ot h St u d y  J V0 1 a n d St u d y  J V 02, re gar dl ess of w het her St u d y  J V 0 1
passe d its f ut ility l oo k). I n or der t o c o ncl u de s uccess f or t he i n vesti gati on i n S S, St u d y  J V 0 2
m ust carr y  a mi ni m u m of 9 9 % c o nfi de nce i n treat me nt s u peri ority ( P F S H R < 1 f or S S patie nts) 
e val uate d via t he Ba yesia n a nal ysis.
St u d y  c o mplet i on occ urs f o ll owi n g t he fi nal a nal ysis of P F S , as deter mi ne d b y Lill y.
J V 0 2 0 5 Pr ot oc ol A d de n da ( g). p df | V V- T M F- 4 2 9 2 2 1 7 | 1. 0
Fi nal
P P D

J 1 S -M C -J V 0 2( g) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 2 6
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
A b bre viati o ns:  n = a p pr o xi mate n u m ber of patie nts per gr o u p .
N ote: P F S t o be a nal yze d via Ba yesia n a nal ysis , w h ic h i ncl u des a da pti ve b orr o wi n g o n 
effect -size bet wee n J V 0 1 a n d J V 0 2 a n d a u g me ntati o n of c o ntr ol ar ms wit h hist orical 
data.
Fi g ur e J V 0 2. 1.
Ill u str ati o n of St u d y J V 0 1 a n d St u d y J V 0 2 D e si g n s
3. 5. 2.
N u m b er of P ati e nt s
A p pr o xi matel y  3 0 pat ient s older t ha n 1 2 m o nt hs a n d ≤2 9 years of a ge will be e nr olle d i n St u d y  
J V0 2 . T he st u d y  must e nr oll  a mi ni m u m of 5 patie nts ≤1 7 y ears o l d wit h S S .
P ati e nts will be allocate d bet wee n t he r a mucir u ma b a n d c o ntr ol ar m at a 2: 1 ratio.  
3. 5. 3.
E n d of St u d y D efi niti o n
E n d of t he st u d y  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 Sc he d ule of 
Act i vities ( Secti o n 3. 2 ) for t he l ast patie nt.
3. 5. 4.
S ci e ntifi c R ati o n al e f or St u d y D e si g n
T here i s c urre ntl y n o sta n dar d of care or a p pr o ve d a ge nts f or treati n g rela pse d or rec urre nt S S i n 
t he pe diatric setti n g.  S u periori t y of a n y o ne re gi me n has n ot bee n deter mi ne d f or S S, t h o u g h 
ma n y s yste mic treat me nt re gi me ns ha ve bee n trie d, li kel y c h ose n
i n part d ue t o patie nts’ past 
e x p os ure, t o xicit y pr ofiles, access t o a ge nts, a n d re gi o nal treat me nt prefere nces f or pretreate d 
sarc o mas.  O ne s uc h re gi me n t hat has de m o nstrate d s o me act i vity i n patie nts wit h rela pse d S S is 
g e m cita bi ne wit h d oceta xel ( A b o uhar b et al. 2 0 1 4).  
J V 0 2 0 5 Pr ot oc ol A d de n da ( g). p df | V V- T M F- 4 2 9 2 2 1 7 | 1. 0
Fi nal
P P D

J 1 S -M C -J V 0 2( g) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 2 7
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
Gi ve n S S i s a disease t hat stra d dles a d o lesce nce i nt o earl y a d ulth o o d, wi t h little t o n o e x pectatio n 
of  differe nce i n cli nical prese ntati o n or o utc o me, St u d y J V0 2 will i ncl u de c hil dre n, a d olesce nts, 
a n d yo u n g a d ul t p atie nts ≤2 9 y ears o f a ge t o e ns ure t he st u d y is feasi ble.  
3. 5. 5.
J u stifi c ati o n f or D o s e
A r a mu ci r u ma b d osi n g re gi me n of 9 m g/ k g i ntra ve n o usl y (I V) o n Da ys 1 a n d 8 e ver y  3 wee ks 
( Q 3 W) i n c om bi nati o n wit h ge mcita bi ne ( 9 0 0 m g/ m 2 I V o n Da ys 1 a n d 8 of a 3 -wee k c ycle) a n d 
d oceta xel ( 7 5 m g/ m 2 I V o n Da y  8 of a 3-wee k c y cle) will be e val uate d i n S S patie nts i n St u d y 
J V0 2 . 
Ra m u ci r u ma b d osi n g a n d sc he d ule are base d o n t he rec o m me n de d P hase 2 d ose ( R P 2 D) d ose 
deter mi ne d i n Part A of St u d y  J V D A i n c o nj u ncti o n wit h t he sc he d ule of t he 
g e m cita bi ne/ d oceta xel bac k b o ne bei n g use d. 
T o o pti mize t he d osi n g re gi me n s o u g ht t o treat pe diatric a n d y o u n g a d ult patie nts, t he R P 2 D i n 
J V D A was defi ne d as t he d ose ac hie vi n g t he stea d y -state mi ni m u m c o nce ntr atio n ( C mi n ) of  
≥5 0 μ g / mL i n a maj ority of  patient s, ass u mi n g a ma xi mall y t olerate d d ose was n ot reac he d . 
J ustificati o n f or t his tar get was base d o n t he o bser ve d ass ociati on bet wee n ra m ucir u ma b 
e x p os ure a n d a n i m pr o ve me nt i n O S a n d P F S i n P hase 3 st u dies , i n w hic h e x p os ure -res p o nse 
a nal ysis acr oss t he st u dies i n dicate d a n E C5 0 val ue of ~ 5 0 µ g/ m L. A mi ni m u m o f 5 0 µ g/ m L was 
t heref ore use d as t he tar gete d efficaci o us c o nce ntrati o n le vel f or select i on of t he R P 2 D i n J V D A. 
R es ults of t he d ose-fi n di n g c om p o ne n t of J V D A i de ntifie d t he R P 2 D f or pe diatric a n d y o u n g 
a d ult p atie nts as 1 2 m g/ k g w he n a d mi nistere d as m o n ot hera p y o n a n e ver y- 2-wee ks ( Q 2 W )
sc he d ule. T he safet y pr ofile of  t his re gi me n i n t he pe diatric p o p ulat i on was als o f ou n d t o be 
acce pta ble, a n d c o nsiste nt wit h r a mucir u ma b’s well -c haracterize d safety pr of ile i n t he a p pr o ve d
a d ult d osi n g re gi me ns of  8 m g/ k g Q 2 W a n d 1 0 m g / k g Q 3 W.  Of i nterest, t he 1 2-m g/ k g Q 2 W 
r a mu ci r u ma b d osi n g re gi me n has als o bee n s h o w n t o be well t olerate d i n a d ult st u dies w he n 
gi ve n as mo n ot hera p y  ( St u d y J V D B) a n d i n c o m bi nati on wi t h paclita xel ( St u d y J V C Z) i n 
pati e nts wit h gastric ca ncer.
T o verif y t he wei g ht - base d d osi n g a p pr oac h f or ra m ucir u ma b i n t he a ge ra n ge pr o p ose d f or 
St u d y  J V 02 , preli mi nar y p h ar m ac o ki netic ( P K ) data fr o m  J V D A was e val uate d (a ges: 3 t o 
2 1 years; b o d y  wei g ht: 1 1 t o 9 1 k g). A hi g her e x p os ure was ge nerall y o bser ve d i n pat ient s 
recei vi n g t he 1 2- m g/ k g d ose c o m pare d t o t h ose recei vi n g a n 8- m g/ k g d ose ( data o n file).  T he 
e x p os ures o bser ve d i n St u d y J V D A were si milar t o t h ose o bser ve d i n a d ult patie nts ( data o n 
file).  M ore o ver, wit hi n eac h d ose le vel, si milar ra m ucir u ma b e x p os ures were o bser ve d acr oss 
t he a ge a n d b o d y wei g ht ra n ges st u die d in J V D A ( data o n file), i n dicati n g t he b o d y wei g ht -base d 
d osi n g re gi me n is e x pecte d t o pr o d uce c o m para ble e x p os ure le vels f or patie nts wit hi n t he a ge 
ra n ge 3 t o 2 1 ye ars old.  P har mac o ki net ic data fr o m  a d ult p atie nts als o s u g geste d a si milar 
e x p os ure le vel f or patie nts fr om 2 1 t o 2 9 years f oll o wi n g t he sa me b o d y wei g ht -base d d osi n g 
re gi me n. Of n ote, P K data are n ot a vaila ble f or patie nts y o u n ger t ha n 3 years old.
S af et y data fr o m  t he n o n-ce ntral ner v o us s yste m (C N S ) ar m of J V D A ( Part A) i ncl u des data 
fr om 2 3 pati e nts.  T here were n o deat hs or life -t hreate ni n g e ve nts re p orte d d ue t o 
J V 0 2 0 5 Pr ot oc ol A d de n da ( g). p df | V V- T M F- 4 2 9 2 2 1 7 | 1. 0
Fi nal
P P D

J 1 S -M C -J V 0 2( g) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 2 8
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
treat me nt -e mer ge nt a d verse e ve nts ( T E A Es ) d uri n g t he st u d y.  O ne pat ient  e x perie nce d a 
d ose -li miti n g t o xicity ( D L T) at eac h d ose le vel.  T he e ve nt was Gra de 2 pr otei n uria, w hic h 
res ulte d i n t he pati e nt disc o nt i n ui n g treat me nt o n t heir res pecti ve d ose le vel.  N o ot her patie nts 
di sc o nti n ue d treat me nt d ue t o T E A Es.
Ni ne o ut of 2 3 patie nts e x perie nce d at least 1 seri o us a d verse e ve nt ( S A E) ( 3 9. 1 %), 2 ( 2 5. 0 %) at 
D ose Le vel 1 a n d 7 ( 4 6. 7 %) at D ose Le vel 2.  T he m ost fre q ue nt l y re p orte d S A Es were p yre xia 
( 3 patie nts) a n d d ys p nea a n d h y p o xia ( 2 patie nts eac h) , all re p orte d at D ose Le vel 2.  Ot her 
r ele va nt S A Es were p ul m o nar y he m orr ha ge , lu n g i nfect i on, a n d p ossi ble i nfect i on ( 1 patie nt 
eac h). T he S A Es re p orte d were Gra des 2 a n d 3, n o ne of w hic h re q uire d pat ient s t o disc o nti n ue 
fr om treat me nt.  M ost S A Es were c o nsiste nt wit h t he e x pecte d c o urses f or t he u n derl yi n g 
di seases a n d/ or f or patie nts o n ra m ucir u ma b treat me nt.
All patie nts e x perie nce d at l east 1 T E A E.  A hi g her i nci de nce of i n di vi d ual T E A Es was o bser ve d 
at D ose Le vel 2 c o m pare d wit h D ose Le vel 1 f or t he maj orit y of  e ve nts re p orte d; h o we ver, m ost 
of  t he T E A Es were l o w-gra de ( Gra de 1 or 2), wit h a si milar n u m ber of Gra de 3 e ve nts i n b ot h 
d ose l e vels.  O verall, t he most c o m m o n T E A Es occ urri n g i n > 4 0 % of  pat ient s were as partate 
a mi n otra nsferase ( A S T ) i ncrease d ( 1 3 patie nts), a ne mia a n d na usea ( 1 1 patie nts eac h), a n d 
v o mit i n g a n d hea dac he ( 1 0 patie nts eac h).  A t otal of 1 3 patie nts ( 5 6. 5 %) e x perie nce d Gra de 3 
T E A Es, 5 patie nts i n D ose Le vel 1 ( 6 2. 5 %) a n d 8 patie nts i n D ose Le vel 2 ( 5 3. 3 %).  T he m ost 
c o m m o n Gra de 3 T E A Es i ncl u de d l y m p h oc y te c o u nt decrease d a n d p y re xia a n d h y p o xia 
( 2 patie nts eac h).  
A d verse e ve nts of s pecial i nterest ( A E SIs ) t ypicall y  see n i n a d ult p atie nts treate d wit h 
r a mu ci r u ma b, i nclu di n g blee di n g/ he m orr ha ge , h y perte nsio n , a n d pr otei n uria, were als o o bser ve d 
i n pe diatri c a n d yo u n g a d ul t patie nts, a n d were pri maril y Gra de 1 or 2 e ve nts.
As t hese are rec o g nize d e ve nts occ urri n g with ra m ucir u ma b, t he J V 0 2 st u d y inc or p orates ris k 
mi ni mizat i on meas ures f or t hese A E SI s i ncl u di n g e xcl usi on of patie nts at hi g her ris k of t hese 
e ve nts, i.e., t h ose wit h u nc o ntr olle d h y perte nsi on, i ncrease d ris k f or blee di n g , or hi g h l e vels of 
uri ne p r otei n at baseli ne.  I n a d diti on, t hr o u g h o ut t he st u d y , t here is r o uti ne a n d fre q ue nt 
m o nit ori n g, wi t h g uideli nes f or s u p p orti ve care, d ose m o dificat i ons, a n d treat me nt 
di sc o nti n uati on t o assist i n t he ma na ge me nt of t hese e ve nts. 
D ue t o t he 3 -wee k c y cle o f t he ge mcita bi ne/ d oceta xel bac k b o ne, a Q 3 W re gi me n f or 
r a mu ci r u ma b was als o sel ecte d t o ease patie nt partici pat i on a n d a v o i d a d diti onal cli nical visits. 
Alt h o u g h t he Q 3 W re gi me n was n ot st u die d i n J V D A, res ults fr o m t he P K si m ulat i on i n dicate 
t hat ra mu ci r u ma b 9 mg/ k g o n Da y  1 a n d Da y 8 of a Q 3 W re gi me n s h o ul d ac hie ve a t otal 
e x p os ure si milar t o t he R P 2 D of 1 2 m g/ k g Q 2 W deter mi ne d i n J V D A ( data o n file). It is 
t heref ore e x pecte d t hat t he c h ose n ra m ucir u ma b re gi me n f or St u d y J V 0 2 of 9 m g/ k g o n Da ys 1 
a n d 8 will pr o vi de a c o m para ble safet y a n d efficac y pr ofile relat i ve t o t he 1 2 m g/ k g Q 2 W 
re gi me n.
T o mit i gate p ote ntial safety ris ks a n d e ns ure t he pr o p ose d re gi me n mai ntai ns a n acce pta ble 
safety pr ofile i n S S patie nts , a safety lea d-i n will be c o n d ucte d t o assess t he safet y a n d 
t olera bilit y of ra m ucir u ma b a d mi nistere d I V at  a d ose of 9 m g/ k g o n Da y s 1 a n d 8 Q 3 W i n 
J V 0 2 0 5 Pr ot oc ol A d de n da ( g). p df | V V- T M F- 4 2 9 2 2 1 7 | 1. 0
Fi nal
P P D

J 1 S -M C -J V 0 2( g) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 2 9
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
c o m bi nat i on wi t h ge mcita bi ne a n d d oceta xel, si nce t he selecte d ra m ucir u ma b d osi n g sc he d ule 
a n d c o m bi nat i on ha ve n ot bee n pre vi o usl y st u die d.  Base d u p o n t he re vie w of t he earl y  s af et y 
a nal ysis, st u d y mo dificati o ns m a y be warra nte d.
I n s u m mar y, t he d osi n g re gi me n of r a mu ci r u ma b 9 mg/ k g I V o n Da y s 1 a n d 8 Q 3 W i n 
c o m bi nat i on wi t h ge mcita bi ne ( 9 0 0 mg/ m 2 I V o n Da ys 1 a n d 8 of a 3 -wee k c y cle) a n d d oceta xe l 
( 7 5 mg/ m 2 I V o n Da y 8 of a 3-wee k c y cle) was selecte d f or t his st u d y  t o p ote ntiall y ma xi mize 
cli nical be nefit a n d is a ntici pate d t o pr o d uce a fa v ora ble be nefit -ris k pr ofile i n S S patient s.
3. 6.
St u d y P o p ul ati o n
3. 6. 1.
I n cl u si o n Crit eri a
P ati e nts are eli gi ble t o be incl u de d i n t he St u d y  J V0 2 o nl y if t he y  meet all of t he i ncl usi o n 
criteria i n Secti o n 6. 1 of t he C A M P FI R E M aster P r ot oc ol a n d t he f oll o wi n g criteria:
[ 14 ] P ati e nts must be 1 2 m o nt hs t o ≤2 9 y ears of a ge at t he ti me o f st u d y 
e nr o ll me nt.  
a)
I n t he E ur o pea n U ni on ( E U) c o u ntries partici pat i n g i n V ol unt ar y 
H ar m o nizat i on Pr oce d ure ( V H P, see Attac h me nt 1 ), patie nts must be 3 6 
m o nt hs t o ≤2 9 y ears of a ge a n d > 1 1 k g at t he ti me of st u d y e nr oll me nt. 
[ 1 5] P ati e nts wit h eit her r ela pse d, rec urre nt, or refract or y S S.
[1 6]
P ati e nts must :

ha ve meas ura ble disease b y R E CI S T 1. 1 .

ha ve recei ve d at least o ne pri or li ne of s yste mic treat me nt (i ncl u di n g 
ne o a dju va nt a n d a dj u va nt c he m ot hera p y ) t hat c o ntai ns if osfa mi de a n d/ or 
d o x or u bi ci n, or a n y a p pr o ve d t hera pies f or w hic h t he y are eli gi ble , u nless t he 
pati e nt is n ot a s uita ble ca n di date f or t he a p pr o ve d t hera p y. 

n ot be eli gi ble f or s ur gical resecti o n at ti m e of e nr oll me nt.
[1 7] P ati e nts must n ot ha ve recei ve d pri or e x p os ure t o ra m ucir u ma b.
[1 8 ] A de q uate car dia c fu n cti o n defi ne d as :

S h orte ni n g fracti o n of ≥2 7 % b y  ec h ocar dio gr a m , or

Eject i on fracti on of ≥5 0 % b y  gate d ra dio n ucli de st u d y .
[ 1 9] A de q uate bl o o d press ure ( B P) c o ntr ol defi ne d as:

P ati e nts ≥1 8 y ear s ol d: 
o
T he patie nt has c o ntr olle d h y perte nsi o n defi ne d as s yst olic 
B P ≤1 5 0 m m H g or diast olic B P ≤9 0 m m H g w here sta n dar d me dical 
ma na ge me nt is per mitte d.  Pl ease n ote t hat ≥2 serial B P rea di n gs 
s h o uld be o btai ne d a n d a vera ge d t o deter mi ne baseli ne B P.
J V 0 2 0 5 Pr ot oc ol A d de n da ( g). p df | V V- T M F- 4 2 9 2 2 1 7 | 1. 0
Fi nal
P P D

J 1 S -M C -J V 0 2( g) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 3 0
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6

P ati e nts < 1 8 years ol d:
o
A B P ≤ t he 9 5t h perce nt ile f or a ge, hei g ht, a n d ge n der meas ure d as 
descri be d i n N H B P E P W G o n Hi g h Bl o o d Press ure i n C hil dre n a n d 
A d o lesce nts ( 2 0 0 4), w here sta n dar d me dical ma na ge me nt is 
per mitte d . Pl ease n ote t hat ≥2 serial B P s s h o ul d be o btai ne d a n d 
a vera ge d t o deter mi ne baseli ne B P.
[ 2 0] T he patie nt has a n a de q uate c oa g ulat i on f unct i on as defi ne d b y I nter nat i onal N or malize d 
Rati o ≤1. 5 or pr ot hr o m bi n t i me ≤1. 5 × U L N, a n d partial t hr o m b o plast i n ti me ≤1. 5 × U L N if 
n ot recei vi n g a nt ic oa g ulat i on t hera p y .  F or patie nts recei vi n g a nt ic oa g ula nts, e xce pt i ons 
t o t hese c oa g ulati on para meters are all o we d if t he y are wit hi n t he i nte n de d or e x pecte d 
ra n ge for t hei r t hera pe utic use.  Patie nts must ha ve n o hi st or y of cli nicall y si g nifica nt
acti ve blee di n g ( defi ne d as wit hi n 1 4 da ys of first d ose of st u d y  dr u g) or a n y pat h o l ogi cal 
c o n ditio n t hat carries a hi g h ris k of blee di n g (f or e xa m ple, t u m or i n v o l vi n g major vessels ,
or k n o w n es o p ha geal varices).
3. 6. 1. 1.
E x c e pti o n s t o t h e C A M P FI R E M a st er Pr ot o c ol I n cl u si o n Crit eri a
F or St u d y  J V 0 2, t he bel o w incl usi o n cri t eria s h o ul d be use d i n place of t he 
C A M P FI R E Master Pr ot oc ol i ncl usi o n cri t eria of t he c orres p o n di n g n u m ber.
[ 5]
T he patie nt has a de q uate he mat ol o gic, or ga n, a n d c oa g ulat i on f uncti o n ≤1 
wee k ( 7 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
1 0 0 0/ µ L G -C S F per mitte d u p t o 4 8 h o urs pri or.
Patie nts wit h d oc u me nte d hist or y of be ni g n et h nic 
ne utr o pe nia or ot her c o n diti o ns c o ul d be c o nsi dere d wit h a 
l o wer A N C after disc ussi o n wit h a n d a p pr o val fr o m t he Lill y 
C R P/ C R S
Platelets
1 0 0, 0 0 0/ m m 3
Platelet tra nsf usi o n per mitte d u p t o 7 2 h o urs pri or.
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 after 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 wit hi n 2 4 hr of 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 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
2. 5 × 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
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 B C = c o m plete bl o o d c o u nt; 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.
J V 0 2 0 5 Pr ot oc ol A d de n da ( g). p df | V V- T M F- 4 2 9 2 2 1 7 | 1. 0
Fi nal
P P D

J 1 S -M C -J V 0 2( g) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 3 1
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
A de q uate re nal f u nct i on, defi ne d as:

Creati ni ne cleara nce or ra di osc o pe gl o mer ular f iltr atio n rate ( G F R) 
≥6 0 m L/ mi n/ m 2 (A p pe n di x 4 ) O R

S er u m  creati ni ne meeti n g t he f oll owi n g para meters: 
o
f or p atie nts ≥1 8 y ears of a ge ser u m creati ni ne ≤1. 5 × u p per li mit of 
n or m al ( U L N);
o
f or p atie nts < 1 8 years of a ge, ser u m creat i ni ne base d o n a ge/ ge n der 
as f oll ows:
A ge
M a xi m u m Ser u m
Cre ati ni ne ( m g/ d L)
Male
Fe male
1 t o < 2 y ears
0. 6
0. 6
2 t o < 6 y ears
0. 8
0. 8
6 t o < 1 0 y ears
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 t o < 1 8 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 f or 
esti mati n g gl o mer ular filtrati o n rate ( A p pe n di x 4 ).

Uri ne pr otei n meeti n g t he f o ll owi n g para meters:
o
F or pati e nts ≥1 8 y ears of a ge: < 2 + o n di pst ic k or r o uti ne uri nal ysis.  
If uri ne di pstic k or r o uti ne a nal ysis i n dicates pr otei n uria ≥2 +, t he n a 
2 4- h o ur uri ne m ust be c ollecte d a n d m ust de m o nstrate < 2 g of 
pr otei n i n 2 4 h o urs or t he uri ne pr otei n t o creati ni ne ( U P C) rati o 
fr om a ra n d o m uri ne sa m ple ca n be calc ulate d a n d m ust be < 1 t o 
all o w partici pat i on i n t he st u d y.
o
F or pati e nts < 1 8 years of a ge: ≤3 0 m g/ dl  uri ne a nal ysis or < 2 + o n 
di pst ic k. If uri ne di pstic k or r o uti ne a nal ysis i n dicates pr otei n uria
> 3 0 m g/ dl  or ≥2 +, t he n eit her a 2 4-h o ur uri ne ca n be c ollecte d a n d 
m ust de m o nstrate < 1 g of pr otei n i n 2 4 h o urs or t h e uri ne pr otei n t o 
creati ni ne ( U P C) rati o fr o m a ra n d o m uri ne sa m ple ca n be 
calc ulate d a n d m ust be < 1 t o all o w partici pati o n i n t he st u d y.
[ 7]
B ot h fe male a n d male pat ient s of c hil d beari n g p ote ntial m ust a gree t o use hi g hl y 
effect i ve c o ntrace pti ve preca uti o ns d uri n g t he trial a n d f or at least 3 m o nt hs 
f oll owi n g t he last d ose of ra m ucir u ma b a n d 6 m o nt hs f o ll owi n g t he l ast d ose of 
d oceta xel a n d ge mcita bi ne i n or der t o pre ve nt pre g na nc y.
J V 0 2 0 5 Pr ot oc ol A d de n da ( g). p df | V V- T M F- 4 2 9 2 2 1 7 | 1. 0
Fi nal
P P D

J 1 S -M C -J V 0 2( g) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 3 2
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
Fe males of c hil d -beari n g p ote ntial ( F O C B P) a n d males w h o are a bst i ne nt (if 
t his is c o mplete a bst i ne nce, as t heir preferre d a n d us ual lifestyle) or i n a sa me -
se x relat i ons hi p (as part of t heir preferre d a n d us ual lifestyle) m ust a gree t o 
eit her r e mai n a bst i ne nt or sta y i n a sa me-se x relat i o ns hi p with o ut se x ual 
r elat i ons hi ps wit h s o m e o ne of t he o p p osite se x. Peri o dic a bst i ne nce (e. g., 
cale n dar, o v ulat i on, s y m pt ot her mal, or p ost o v ul at i o n met h o ds), declarati on of 
a bsti ne nce j ust f or t he d urati o n of t he trial, a n d wit hdra wal are n ot acce pta ble 
met h o ds of c o ntrace pti o n.
Fe males: F O C B P parti ci pat i n g m u st test ne gati ve f or pre g na nc y prior t o 
i nitiati on of treat me nt as i n dicate d b y  a ne gati ve uri ne or ser u m pre g na nc y test 
at t he scree ni n g visit.  T w o f or ms of effect i ve c o ntrace pti o n, w here at least 
o ne f or m is hi g hl y effecti ve (less t ha n 1 % fail ure rate; i ncl u de s c o m bi nat i on 
or al  c o ntrace pti ves, i m pla nte d c o ntrace ptives , or i ntra uteri ne de vices) m ust be 
use d. Effect i ve c o ntrace pti o n (s uc h as male or fe male c o n d oms wit h 
s per mici de, dia p hra g ms wit h s per mic i de, or cer vi c al s p o n ges) ma y be use d as 
t he sec o n d t hera p y. Barrier pr otecti o n met h o ds wit h o ut c o nc o mit a nt use of a 
s per mici de are n ot a relia ble or acce pta ble met h o d. T h us, eac h barrier met h o d 
m ust i ncl u de use of a s per mici de (i.e., c o n d o m wit h s per mici de, di a p hra g m 
wi t h s per mici de, or female c o n d o m wit h s per mici de). It s h o ul d be n ote d t hat 
t he use of male a n d fe male c o n d o ms as a d o u ble barrier met h o d is n ot 
c o nsi dere d acce pta ble d ue t o t he hi g h fail ure rate w he n t hese met h o ds are 
c o m bi ne d.
Males:  Males, re gar dless of t heir fert ility stat us, with n o n pre g na nt F O C B P
part ners m ust a gree t o use c o n d o ms as well as o ne a d dit i onal hi g hl y effecti ve 
met h o d of c o ntrace pti o n ( less t ha n 1 % fail ure rate; i ncl u des c o m bi nat i on oral  
c o ntrace pti ves, i m pla nte d c o ntrace pti ves, or i ntra uteri ne de vices) i n or der t o 
pre ve nt pre g na nc y .
Barri er pr otectio n m et h o ds wit ho ut c o nc o mi ta nt use of a s per mici de are n ot a n 
effect i ve or acce pta ble met h o d of c o ntrace pti o n. T h us, eac h barrier met h o d m ust 
i ncl u de use of a s per mici de. It s h o ul d be n ote d, h o we ver, t hat t he use of male a n d 
fe male c o n d oms as a d o u ble barrier met h o d is n ot c o nsi dere d acce pta ble d ue t o t he 
hi g h fail ure rate w he n t hese barrier met h o ds are c o m bi ne d.  Males wit h pre g na nt 
part ners s h o ul d use c o n d o ms d uri n g i nte rc o urse f or t he d urati o n of t he st u d y for at 
least 3 mo nt hs after t he last d ose of st u d y  dr u g, or l o n ger , if a p pr o priate f or a n y st u d y 
dr u g acc or di n g t o t he la bel.
3. 6. 2
E x cl u si o n Crit eri a
P ati e nts will be e xcl u de d fr o m St u d y J V0 2 if t he y meet a n y of t he e xcl usi o n cri teria i n 
Secti o n 6. 2 of t he C A M P FI R E M aster P r ot oc ol or t he f o ll owi n g cri t eria:
[ 21] Are c urre nt l y ta ki n g a n y pr o hi bite d me dicati ons o utli ne d i n At tac h me nt 5.
[ 22] Bl ee di n g a n d t hr o m b osis:
J V 0 2 0 5 Pr ot oc ol A d de n da ( g). p df | V V- T M F- 4 2 9 2 2 1 7 | 1. 0
Fi nal
P P D

J 1 S -M C -J V 0 2( g) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 3 3
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6

P ati e nts wit h e vi de nce of acti ve blee di n g or a hist or y of si g nifica nt (≥Gra de 3) 
blee di n g e ve nt wit hi n 3 m o nt hs pri or t o e nr oll me nt are n ot eli gi ble .

P ati e nts wit h a blee di n g diat hesis or vasc ulit is are n ot eli gi ble.

P ati e nts wit h k n o w n or prior hist or y  in pri or 3 m o nt hs of es o p ha geal varices are n ot 
eli gi ble.

P ati e nts wit h a hist or y of dee p vei n t hr o m b osis re q uirin g me dical 
i nter ve nt i on (incl u di n g p ul m o nar y  e m b olis m) wit hi n 3 m o nt hs pri or t o st u d y  
e nr o ll me nt are n ot eli gi ble. 

P ati e nts wit h a hist or y of h e mo pt ysis or ot her si g ns of p ul m o nar y  he morr ha ge 
wi t hi n 3 mo n t hs prior t o st u d y  e nr oll me nt are n ot eli gi ble. 
[ 23] Car di ac:

P ati e nts wit h a hist or y of ce ntral ner v o us s yste m (C N S ) arterial/ ve n o us 
t hr o mb oe m b o lic e ve nts ( V T Es) i ncl u di n g tra nsie nt isc he mic attac k ( TI A) or 
cere br o vasc ular acci de nt ( C V A) wit hi n 6 m o nt hs pri or t o st u d y  e nr oll me nt are n ot 
eli gi ble.

P ati e nts wit h my o car dial i nfarct i on or u nsta ble a n gi na wit hi n t he pri or 6 m o nt hs .

P ati e nts wit h Ne w Y or k Heart Ass ociati on Gra de 2 or greater c o n gesti ve heart 
fail ure ( C H F).

P ati e nts wit h serio us a n d i na de q uatel y c o ntr olle d car diac arr h y t hmia .

P ati e nts wit h si g nifica nt vasc ular disease (e g, a ortic a ne ur ys m or hist or y  of a ortic 
di ssecti on) .

P ati e nts wit h cli nicall y si g nifica nt peri p heral vasc ular disease.
[ 24] P ati e nts w h o ha ve a hist or y of fist ula, gastr oint est i nal ( GI) ulcer or perf orati o n, or 
i ntr a-a b d o mi nal a bscess wit hi n 3 m o nt hs of st u d y  e nr oll me nt are n ot eli gi ble. 
[ 25] P ati e nts wit h a hist or y of h y perte nsi ve crisis or h y perte nsi ve e nce p hal o pat h y wit hi n 
6 m o nt hs of st u d y  e nr oll me nt are n ot eli gi ble.
[ 26] P ati e nts w h o ha ve n o n-heali n g w o u n d, u n heale d or i nc o m pletel y heale d fract ure, or a 
c o mp o u n d ( o pe n) b o ne fract ure at  t he ti me of e nr oll me nt are n ot eli gi ble.
[ 2 7] P ati e nts pre vi o usl y treate d a n d pr o gresse d o n c o m bi nat i on ge mci ta bi ne or d oceta xel.  
P ati e nts w h o recei ve d c o m bi nat i on as mai nte na nce t hera p y , wit ho ut pr o gressi o n, w o ul d be 
eli gi ble.
[2 8] P ati e nts wit h a k n o w n h y perse nsiti vity t o ra m ucir u ma b, g e m cita bi ne, d oceta xel , or a ge nts 
f or mulate d wi t h P ol ys or bate 8 0.
[2 9] He pati c i m pair me nt:

Se vere li ver cirr h osis C hil d -P u g h Class B ( or w orse) 

Ci rr h osis wit h a hist or y of he patic e nce p hal o pat h y 

Cli n icall y mea ni n gf ul ascites res ulti n g fr o m cirr h osis a n d re q uiri n g o n g oi n g treat me nt 
wi t h diuret ics a n d/ or parace ntesis

Hi st or y of he pat ore nal s y n dr o me.
J V 0 2 0 5 Pr ot oc ol A d de n da ( g). p df | V V- T M F- 4 2 9 2 2 1 7 | 1. 0
Fi nal
P P D

J 1 S -M C -J V 0 2( g) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 3 4
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
[ 30]
T he patie nt has a b o wel o bstr ucti o n, hist or y  or prese nce of i nfla m mat or y 
e nter o pat h y or e xte nsi ve i ntesti nal resecti on ( e g, he mic olect o m y or e xte nsi ve s mall 
i ntest i ne resecti o n with c hr o nic diarr hea), Cr o h n's disease, ulcerati ve c o litis, or 
c hr o nic diarr hea.
[ 31]
T he patie nt has s y m pt o mat ic i nterstitial p ne u mo nia or p ul m o n ar y fi br osis ( or 
c o nsiste nt fi n d i n gs of i nterstitial p ne u m o nia/ p ul m o n ar y fi br osis o n i ma gi n g).
[ 32] P ati e nts wit h C N S i n v ol ve me nt are i neli gi ble.
3. 6. 1. 2.
E x c e pti o n s t o t h e C A M P FI R E M a st er Pr ot o c ol E x cl u si o n Crit eri a
T here are n o e xce pti o ns t o t he C A M P FI R E Master Pr ot oc ol e xcl usi o n cri t eria. 
3. 6. 3.
Lif e st yl e R e stri cti o n
P ati e nts s h o uld r ef rai n fr o m c o ns u mi n g gra pefr 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 yt oc hr o me P 4 5 0 ( C Y P )3 A 4 a n d t he p ote ntial f or 
t o xicities relate d t o d oceta xel.
3. 7.
Tr e at m e nt s
3. 7. 1.
Tr e at m e nt s A d mi ni st er e d
A dela y  of a d ose d ue t o h oli da y, wee ke n d, ba d weat her, or ot her u nf oresee n circ u msta nces will 
be per mitte d f or a ma xi m u m o f ± 3 da ys a n d n ot c o u nte d as a pr ot oc ol de viat i on.  H o we ver, 
cli nical assess me nt ti me fra mes relat i ve t o dr u g a d mi nistrati o n, as s h o w n i n t he sc he d ule of 
acti vit ies, m ust be mai ntai ne d.
3. 7. 1. 1.
Pr e m e di c ati o n
All pre me dicati o n a d mi nistere d m ust be a de q uatel y d oc u me nte d i n t he electr o nic case re p ort 
f or m (e C R F).
3. 7. 1. 1. 1.
R a m u cir u m a b
P ati e nts s h o uld recei ve pre m e dicatio n wi t h dip he n h y dra mi ne or alter nati ve a nt i hista mi ne withi n 
3 0 t o 6 0 mi n utes pri or t o eac h i nf usi o n wi t h r a mucir u ma b.
3. 7. 1. 1. 2.
G e m cit a bi n e
Pr o p h ylactic a nt iemet ics s h o uld be r o uti nel y a d mi nistere d.  A d dit i onall y, pre me dicati o n f or 
g e m cita bi ne ma y be a d mi nistere d acc or di n g t o i nstit utio nal  g ui deli nes a n d/ or cli nical practice.  
All pre me dicati o n a d mi nistere d m ust be a de q uatel y d oc u me nte d i n t he e C R F.
Si tes s h o uld c o ns ul t t h e ma n ufact urer’s i nstr ucti o ns f or ge mcita bi ne f or c o m plete prescri bi n g 
i nf or mat i on (i ncl u di n g war ni n gs, preca u tio ns, c o ntrai n dicat i ons, a n d a d verse reacti o ns) a n d 
f oll ow i nst ituti o nal  pr oce d ures f or t he a d mi nistrati o n of ge mcita bi ne.
3. 7. 1. 1. 3.
D o c et a x el
Pr e m e dicat i on f or d oceta xel s h o uld be a d mi nistere d acc or di n g t o i nst itut i onal g ui deli nes a n d/ or 
cli nical practice a n d s h o ul d i ncl u de a c orticoster oi d pri or t o i nit iati on of eac h i nf usi on t o re d uce 
t he i nci de nce a n d se verit y of  fl ui d rete nti o n a n d h y perse nsiti vity react i ons ( H S Rs).  
J V 0 2 0 5 Pr ot oc ol A d de n da ( g). p df | V V- T M F- 4 2 9 2 2 1 7 | 1. 0
Fi nal
P P D

J 1 S -M C -J V 0 2( g) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 3 5
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
Rec o m me n de d c ortic oster oi ds i ncl u de de xa met has o ne starti n g t he da y  prior t o d oceta xel  a n d 
c o nti n ui n g f or 3 da ys or at t he discreti o n of t he i n vesti gat or.  Patie nts w h o de vel o p peri p heral 
e de ma as a side effect of d oceta xel ma y be treate d wit h di uret ics at t he discreti o n of t he 
i n vesti gat or.  A d diti o nal a ntiemet ic pre me dicati o n ma y be e m pl oy e d at t he discretio n of  t he 
i n vesti gat or.  All pre me dicati on a d mi nistere d m ust be a de q uatel y d oc u me nte d i n t he e C R F.
Si tes s h o uld c o ns ul t t h e ma n ufact urer’s i nstr ucti o ns f or d oceta xel f or c o m plete prescri bi n g 
i nf or mat i on (i ncl u di n g war ni n gs, preca uti o ns, c o ntrai n dicat i ons, a n d a d verse reacti o ns) a n d 
f oll ow i nst ituti o nal  pr oce d ures f or t he a d mi nistrati o n of d oceta xel.
3. 7. 1. 1. 4.
Gr a n ul o c yt e -C ol o n y Sti m ul ati n g F a ct or s
Gra n ul oc yte -c o l on y sti m ulati n g fact or (G- C S F ) use i s re q uire d i n all c ycles f or patie nts. T he G -
C S Fs s h o ul d be a d mi nistere d acc or di n g t o A merica n S ociet y of  Cli nical O n c olo g y  ( A S C O)
g ui deli nes ( S mit h et al . 2 0 0 6) a n d E ur o pea n S ociet y f or Me dical O nc o l og y  ( Cra wf or d et al. 
2 0 0 9) g ui deli nes .
Pr o p h y lactic use of G -C S F s h o ul d c o nsist of at l east 5 d a y s of G-C S F ( d ose per i nst ituti o nal  
sta n dar d) or a si n gle d ose of pe g - G-C S F ( d ose per i nst ituti o nal  sta n dar d) be gi n ni n g o n Da y  8 or 
9 per i ns tit utio nal  g ui deli nes. If G- C S F is gi ve n dail y, t he n c o nti n ue u nt il A N C ≥1 0 0 0/ µ L p ost 
na dir a n d disc o nt i n ue at least 2 4 h o urs pri or t o t he ne xt c y cle of t hera p y per st u d y.
3. 7. 1. 2.
D o si n g S c h e d ul e
T he f o ll owi n g treat m e nts will be a d mi nistere d i n t his st u d y e ver y 3-wee k ( 2 1 -d a y ) c ycle:
T a bl e J V 0 2. 7 .
J V 0 2 Tr e at m e nt D o si n g S c h e d ul e ( S y n o vi al)
St u d y Dr u g
Ar m
D ose
R o ute
Ti mi n g
Ra m ucir u ma b
1
9 m g/ k g b
I V
A p pr o xi matel y 6 0- mi n ute i nf usi o n o n Da y s 1 a n d 8 
of eac h 2 1 -da y  c ycle
Ge mcita bi ne a
1 a n d 2
9 0 0 m g/ m 2
I V
A p pr o xi matel y 9 0- mi n ute i nf usi o n o n Da y s 1 a n d 8 
of eac h 2 1 -da y  c ycle
D oceta xel
1 a n d 2
7 5 m g/ m 2
I V
A p pr o xi matel y 6 0- mi n ute i nf usi o n o n Da y 8 of eac h 
2 1- da y  c ycle
A b bre viati o n:  I V = i ntra ve n o us.
a
Patie nts m ust be cl osel y m o nit ore d f or a 1- h o ur o bser vati o n peri o d f oll o wi n g t he ra m ucir u ma b i nf usi o ns f or t he 
first 2 i nf usi o ns (see Secti o n 3. 7. 6. 1. 7. 1 ).
b
T he i nf usi o n ti me of ge mcita bi ne after its d ose re d ucti o n ma y be mai ntai ne d at 9 0 mi n utes or ma y be s h orte ne d 
t o kee p a rate of a p pr o xi matel y 1 0 m g/ m2/ mi n acc or di n g t o discreti o n of t he i n vesti gat or.  T he i nf usi o n start a n d 
st o p ti mes m ust be rec or de d.
c
D uri n g t he r olli n g -si x safet y lea d-i n, de-escalati o n of ra m ucir u ma b t o 6 m g/ k g ma y be necessar y per Ta ble 
J V0 2. 5 .
A c ycle is defi ne d as a n i nter val of 2 1 da ys.  
Ra m u ci r u mab s h o ul d be a d mi nistere d first, f oll owe d b y  ge mci ta bi ne, a n d t he n d oceta xel o n t he 
da ys w he n it is gi ve n.  F or t he first 2 ra m ucir u ma b i nf usi o ns, pati e nts must be cl osel y  mo ni t or e d 
f or a 1-h o ur o bser vat i on peri o d f ol l owi n g t he i nf usi o n bef ore recei vi n g ge m cita bi ne or d oceta xel 
(see Secti o n 3. 7. 6. 1. 7. 1 ).  T hereafter, ge mcita bi ne a n d d oceta xel ma y be gi ve n wit h o ut t he p ost-
r a mu ci r u ma b o bser vati on peri o d, u nless a n i nf usi o n-relate d reacti o n (I R R) has occ urre d.  T here
J V 0 2 0 5 Pr ot oc ol A d de n da ( g). p df | V V- T M F- 4 2 9 2 2 1 7 | 1. 0
Fi nal
P P D

J 1 S -M C -J V 0 2( g) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 3 6
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
are n o re q uire d wait i n g ti mes bet wee n t he a d mi nistrati o n of ge mcita bi ne a n d d oceta xel; 
h o we ver, a p pr o priate res pecti ve pre me dicati o ns are gi ve n f or eac h, as o utl i ne d Secti o n 3. 7. 1. 1 .  
After t he start of a c y cle, treat me nt s h o uld c o nti n ue o n sc he d ule if p ossi ble, b ut a varia nce of ± 3 
da ys m a y be all o we d t o ac c o m m o date h oli da ys, wee ke n ds, i ncle me nt weat her, or ot her 
j ustifia ble e ve nts.  If t he patie nt’s wei g ht fl uct uates b y m ore t ha n ± 1 0 % fr om t he weig ht use d t o 
calc ulate t he prior d ose, t he d ose of st u d y  dr u gs m ust be recalc ulate d.  St u d y  treat me nt ma y be 
m o di fie d acc or di n g t o Secti o n 3. 7. 4 .
If ra m ucir u ma b D a y- 1 d ose is dela ye d, a mi ni m u m of 1 wee k bet wee n ra m ucir u ma b 
a d mi nistrati o n is re q uire d. 
St u d y  dr u gs ca n o nl y be a d mi nistere d at t he i n vest i gati o nal site, at-h o me a d mi nistrati o n is n ot 
per mitte d i n t his st u d y . I n t he e ve nt of treat me nt dela ys of st u d y dr u gs t hat is greater t ha n 1 
treat me nt c ycle ( 2 1 d a y s), u nrelate d t o A Es b ut d ue t o u nf oreseea ble circ u msta nces (e. g., 
C O VI D -1 9 pa n de mic res ur ge nce) a n d i n t he pri nci pal i n vest i gat or’s discreti o n t he patie nt has 
e x perie nce d cli nical be nefit, a disc ussi o n wi t h Lill y C R P/ C R S s h o uld be d o ne bef ore res u mi n g 
st u d y dr u gs. I n a d ditio n, all  o n-tr e at me nt S o A as i n Ta ble J V0 2. 2 m u st res u me.
If a d ose de-escalati o n is dee me d a p pr o priate d uri n g t he safet y lea d -i n peri o d d ue t o 
D L Ts (Ta ble J V 0 2. 5 ), t he d ose of ra m ucir u ma b will de-escalate t o 6 mg/ k g.  N o c ha n ges t o t he 
pr oce d ures will be affecte d wit h t he e xce pti o n o f t he d ose of ra m ucir u ma b.
D uri n g t he c o urse of st u d y  treat me nt, patie nts ma y bec ome eli gi ble a n d u n der g o s ur gical 
resecti o n of t heir disease.  T hese patie nts ma y c o nti n ue t o recei ve st u d y treat me nt if dee me d 
be neficial i n c o ns ultati o n wit h t he Lill y C R P / C R S.  Treat me nt s h o ul d be he l d bef ore s ur ger y  a n d 
res u me at least 1 4 da ys p ost -s ur ger y w he n ac ute t o xicities of s ur ger y are rec o vere d per 
i n vesti gat or discreti on. Patie nts s h o ul d c o nt i n ue t o f oll ow st u d y  pr oce d ures o utli ne d i n t he 
pr ot oc ol  incl u di n g ra di o l ogi c e val uat i on.
Ra m u ci r u mab c o ntai ns 0. 1 m g of p ol ys or bate 8 0 i n eac h 1 ml o f me dici nal pr o d uct, w hic h is 
e q ui vale nt t o 0. 1 2 m g/ k g per d ose. Rarel y, patie nts ca n e x perie nce se vere aller gic reacti o ns t o 
p ol ys or bates.  Eac h ra m ucir u ma b 1 0 ml vial c o ntai ns 1 7 m g of s o di u m w hic h is le ss t ha n 1 m m ol 
s o diu m ( 2 3 m g), t hat i s, esse ntiall y ‘s o diu m  free.’  D oceta xel c o ntai ns a p pr o xi matel y 2 6 m g of 
p ol ys or bate 8 0 f or eac h 1 m g o f me d ici nal pr o d uct, w hic h res ults i n o ver 3 5 m g/ k g of 
p ol ys or bate 8 0 per d ose.  He pat o xicit y,  h y p ote nsio n , a n d h y perse nsitivit y are re p orte d as 
ass ociat e d wit h p ol ys or bate 8 0 use. T he p ote ntial f or t orsa des de p oi ntes i n h u ma ns d ue t o 
p ol ys or bate 8 0 is u n k n o w n.   
See g ui deli nes o n s u p p orti ve care ( Secti o n 3. 7. 6. 1 ) w hile a d mi nisteri n g st u d y treat me nt.  For a n y  
s pecific c o ncer ns n ot disc usse d i n t he g ui deli nes, i n vesti gat ors s h o ul d c o ns ult t he PI f or 
a d ditio nal  preca utio ns.
3. 7. 1. 3.
D o s e -Li miti n g T o xi cit y D et er mi n ati o n
A D L T is defi ne d as o ne of t he f oll owi n g A Es re p orte d d uri n g C ycle 1 of t he r olli n g si x safet y 
lea d-i n, if c o nsi dere d t o be defi nitel y, pr o ba bl y, or p ossi bl y relate d t o ra mu ci r u ma b b y t he 
J V 0 2 0 5 Pr ot oc ol A d de n da ( g). p df | V V- T M F- 4 2 9 2 2 1 7 | 1. 0
Fi nal
P P D

J 1 S -M C -J V 0 2( g) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 3 7
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
i n vesti gat or; a n d f ulfills a n y o ne of t he f oll o wi n g criteria usi n g t he Nati o nal Ca ncer I nst itute 
C o m m o n Ter mi n o l og y  Crit eri a for A d verse E ve nts ( N CI C T C A E ) Versi o n 5. 0:
1.  
H e patic bioc he mical tests will be c o nsi dere d D L Ts as f oll o ws:
P ati e nts wit h n or mal or near n or mal ala ni ne a mi n o tra nsferase (A L T ) or A S T at baseli ne 
( < 1. 5 x U L N):

A L T or A S T ≥8 × U L N o n 2 or m ore c o nsec uti ve tests (at least 2 da ys a part ) i n 
t he a bse nce of a clear ca use of he pat ic i nj ur y ot her t ha n t he st u d y dr u g. 

A L T or A S T ≥3 × U L N a n d T B L ≥2 × U L N o n 2 or m ore c o nsec ut i ve tests (at 
least 2 da ys a part ) i n t he abse nce of si g nifica nt c h olestasis a n d i n t he a bse nce of a 
clear ca use of he patic i nj ur y ot her t ha n t he st u d y dr u g. 
P ati e nts wit h ele vate d A L T or A S T at baseli ne ( ≥1. 5 x U L N):

A L T or A S T ≥5 × baseli ne o n 2 or m ore c o nsec uti ve tests (at least 2 da ys a part ) i n
t he a bse nce of a clear ca use of he pat ic i nj ur y ot her t ha n t he st u d y dr u g. 

A L T or A S T ≥3 × baseli ne a n d T B L ≥2 × U L N o n 2 or m ore c o nsec ut i ve tests (at 
least 2 da ys a part ) i n t he a bse nce of si g nifica nt c h olestasis a n d i n t he a bse nce of a 
clear ca use of he patic i nj ur y ot her t ha n t he st u d y dr u g. 
2.
A n y ot her n o n he mat ol o gi c t o xicit y Gra de ≥3 will be c o nsi dere d as D L T wit h t he 
f oll owi n g e xce pt i ons:
a)
Gra de 3 na usea, v o mit i n g diarr hea, a n d c o nst i pati on t hat ca n be c o ntr olle d 
wi t h treat me nt.  If persist i n g m o re t ha n 7 2 h o urs des pite ma xi mal s u p p orti ve 
i nter ve nt i on , c o nsider e d a D L T .
b)
As y m pt o mat ic tra nsie nt Gra de 3 electr ol yte dist ur ba nce t hat ca n be c o ntr olle d 
wi t h or al s u bstituti o n t hera p y  or b y I V i nf usio n s, a n d d oes n ot re q uire 
h os pi talizatio n 
c)
Gra de 3 fati g ue.
d)
Gra de 3 fever or Gra de 4 fe ver < 4 8 h o urs .
e)
Gra de 3 i nfect i on
N ote: Aller gic re acti o ns are N O T c o nsi dere d a D L T, eve n if necessit ati n g 
disc o nti n u ati o n of a st u dy dr u g.
3.
T he f o ll owi n g he mat ol o gi c t o xicities will be c o nsi dere d a D L T:
a)
Gra de 4 a ne mia , persiste nt des pite ma xi mal s u p p orti ve i nter ve nt i on
b)
Pl at elet c o u nt < 2 0, 0 0 0/ m m3 o n 2 se parate da ys, or re q uiri n g a platelet tra nsf usi o n o n 
2 se parate da y s, wit hi n a 7- d a y  p erio d
c)
Pl at elet c o u nt < 5 0, 0 0 0/ m m3 if ass ociate d wit h me di call y rele va nt blee di n g
d)
A bs ol ute ne utr o p hil c o u nt ( A N C ) < 5 0 0/ m m 3 f or > 7 da ys
o
N ote: Fe br ile ne utr o pe ni a will o nl y be c o nsi dere d a D L T if t he A N C < 5 0 0/ m m 3
f or > 7 da ys.
J V 0 2 0 5 Pr ot oc ol A d de n da ( g). p df | V V- T M F- 4 2 9 2 2 1 7 | 1. 0
Fi nal
P P D

J 1 S -M C -J V 0 2( g) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 3 8
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
e)
M yel os u p pressi o n  t hat ca uses a dela y of > 1 4 da y s i n i nitiati n g C ycle 2
f)
Ot her he mat ol o gical D L Ts :
• A n y arterial t hr o m b oe m b olic e ve nt (A T E; i ncl u di n g cere br o vasc ular 
isc he mia, peri p heral, or visceral arterial isc he mia)
• A n y ≥Gra de 3 V T E
• A n y t hr o m b otic e ve nt re q uiri n g s yste mic a nti-c oa g ulat i on
• A n y ≥Gra de 3 he m orr ha ge
4.
H y perte nsi o n: 
a)
P ati e nts ≥1 8 y ear s ol d: Gra de 3 or 4 as defi ne d i n t he C T C A E v 5. 0
b)
P ati e nts < 1 8 years ol d: 
o
A n y Gra de 4 h y perte nsi o n
o
A B P > 2 5 m m H g a b o ve t he 9 5t h perce nt ile f or a ge, hei g ht, a n d ge n der c o nfir me d 
b y re peate d meas ure me nt is d ose -li miti n g.
o
I n patie nts w h o be gi n a n d are c o mplia nt o n a nti h y perte nsi ve t hera p y, a 
B P > 1 0 m m H g , b ut ≤2 5 m m H g a b o ve t he 9 5t h perce nt ile f or a ge, heig ht, a n d 
ge n der ( N H B P E P W G o n Hi g h Bl o o d Press ure i n C hil dre n a n d A d o lesce nts, 
2 0 0 4) f or > 1 4 da y s, des pite a p pr o priate ma na ge me nt wit h a nt i h y perte nsi ve 
t hera p y is d ose-li miti n g.
5.
Pr otei n uria: 
a)
P ati e nts ≥1 8 y ear s ol d: 2 4- h o ur uri ne pr otei n of 2 t o 3 g/ 2 4 h o urs c o nfir me d wit h a 
sec o n d meas ure me nt wit hi n 7 2 h o urs; or ≥3 g/ 2 4 h o n first assess me nt.
b)
P ati e nts < 1 8 years ol d: uri ne pr otei n/creat i ni ne ( P/ C) rati o of > 1 a n d < 1. 9 , calc ulate d 
fr om a ra n d o m uri ne c o llecti on a n d c o nfir me d wit h a sec o n d meas ure me nt wit hi n 
7 2 h o urs; or a U P C rati o > 1. 9 o n first assess me nt .
6.
A n y GI perf orati o n e ve nt 
7.
Gra de ≥2 p os t erior re versi ble e nce p hal o pat h y s y n dr o me ( P R E S)
8 .
Gra de 5 t o xicit y (t hat is, deat h) if c o nsi dere d relate d t o st u d y tr e at me nt
9.
A n y ot her si g nifica nt t o xicit y dee me d b y  t he pri mar y in vesti gat or a n d Lill y  cli nical 
researc h pers o n nel t o be d ose -li miti n g, f or e xa m ple:
a) A n y t o xicit y t h at is p ossi bl y relate d t o st u d y treat me nt  t hat re q uires t he wit hdra wal  of 
t he patie nt fr o m t he st u d y d uri n g o bser vati o n peri od
b) A dela y of > 1 4 da ys d ue t o persiste nt Gra de ≥2 treat me nt -relate d t o xicities i n C ycle 1 
wi t h t he e xce ptio n of  fat i g ue
Ot her p ote ntiall y re versi ble ris k fact ors f or t h e A E s h o ul d be i de ntifie d a n d a d dresse d as 
a p pr o priate.  P ote ntial D L Ts t hat are reas o na bl y a ntici pate d A Es f or c o nc o mita nt me dicat i on 
s h o uld be re vie we d b y t he treati n g i n vest i gat or a n d Lill y cli nical researc h p h ysicia n (C R P )
J V 0 2 0 5 Pr ot oc ol A d de n da ( g). p df | V V- T M F- 4 2 9 2 2 1 7 | 1. 0
Fi nal
P P D

J 1 S -M C -J V 0 2( g) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 3 9
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
bef ore fi nal deter mi nat i on as a D L T.  Re vie w a n d disc ussi o n ma y i ncl u de a d diti onal 
parti ci pat i n g i n vesti gat ors.  S uc h re vie w ma y deter mi ne t hat c o nf o u n di n g fact ors re n der t he case 
t o be n ot e val ua ble f or t he p ur p oses of d ose selecti o n.
A D L T -e val ua ble patie nt is c o nsi dere d t o be o ne w h o ei t her c o mplete d 1 c y cl e of treat me nt or 
di sc o nti n ue d fr om t he treat me nt d ue t o a D L T.  A D L T - n o n-e val ua ble patie nt is c o nsi dere d o ne 
w h o e x perie nce d disease pr o gressi o n, was n o nc o m plia nt, disc o nt i n ue d f or reas o ns ot her t ha n 
A Es wit hi n t he first c y cle o f treat me nt, or did n ot c o m plete t he safet y  mo ni t ori n g f or t he D L T 
Assess me nt Peri o d f or a n y  reas o n ot her t ha n a D L T a n d will be c o nsi dere d n o n- e val ua ble f or 
D L T assess me nt.  A d dit i onal pat ient s ma y be i ncl u de d i n t he safet y lea d-i n t o re place a n y patient  
dee m e d n o n-e val ua ble.
3. 7. 2.
M et h o d of Tr e at m e nt A s si g n m e nt
P ati e nts w h o meet all crit eria for e nr oll me nt will be ra n d o ml y assi g ne d t o recei ve st u d y
treat me nt .  Bef ore eac h patient ’s e nr oll me nt i nt o t he st u d y, a n eli gi bility c hec k m ust be 
c o n d ucte d bet wee n t he i nvest i gati onal site a n d t he Lill y cli nical researc h pers o n nel t o c o nfir m 
t hat eac h patie nt meets all e nr oll me nt criteria.  U p o n c o nfir mat i on of eli gi bilit y,  t he site will 
r e gister t he patie nt b y assi g ni n g t he patie nt a u niq ue st u d y  ide ntificat i on n u m ber via t he 
I nteracti ve We b -Res p o nse S yste m (I W R S), w hic h is accessi ble 2 4 h o urs a da y .  St u d y dr u g will 
be all ocate d t o patie nts usi n g t he I W R S.
P ati e nts w h o meet all crit eria for e nr oll me nt will b e ra n d o ml y assi g ne d t o recei ve ge mcita bi ne 
a n d d oceta xel wi t h or wit h o ut ra m ucir u ma b.
A p pr o xi matel y  3 0 pat ient s will be ra n d omize d i n a 2: 1 rati o (ra m ucir u ma b ar m vers us c o ntr ol 
res pecti vel y).  
Ra n d o mizati o n will be stratifie d b y sta gi n g at rela pse ( metastatic disease vers us l ocall y 
a d va nce d).
3. 7. 3.
Bli n di n g
T his is a n o pe n -la bel st u d y.
3. 7. 4.
D o s e M o difi c ati o n
D ose a dj ust me nt s (s us pe nsi ons , re d uctio ns , or disc o nti n uat i ons ) will be ma de base d o n t he 
cli nical assess me nt of he mat ol o gic a n d n o n he mat ol o gic t o xicit ies ( defi ne d as a n A E p ossi bl y 
r elate d t o st u d y tr e at me nt per i n vest i gat or j u d g me nt).  T he C T C A E v 5. 0 will be use d t o assess 
A Es.  Treat me nt ma y  be s us pe n de d f or a ma xi m u m o f 2 8 da ys t o all o w a patie nt s ufficie nt ti me 
f or rec o ver y fr o m st u d y treat me nt-relate d t o xicity.   Ot her p ote ntiall y re versi ble ris k fact ors f or 
t he A E s h o uld b e i de nt ifie d a n d a d dresse d as a p pr o priate.  If a patie nt d oes n ot rec o ver fr o m t he 
t o xicit y wit hi n 2 8 da ys fr om t he ti me of last treat me nt, t he patie nt s h o ul d be c o nsi dere d f or 
p er m a ne nt disc o nt i n uati on fr o m st u d y treat me nt.  I n e xce pti onal circ u msta nces, a dela y > 2 8 da ys 
is per mitte d u p o n a gree me nt bet wee n t he i n vesti gat or a n d t he Lill y C R P/Cli nical Researc h 
S ci e nt ist (C R S ).
J V 0 2 0 5 Pr ot oc ol A d de n da ( g). p df | V V- T M F- 4 2 9 2 2 1 7 | 1. 0
Fi nal
P P D

J 1 S -M C -J V 0 2( g) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 4 0
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
I n ge neral, d ose a dj ust me nt s of  o ne st u d y dr u g (ra m ucir u ma b, g e m cita bi ne, or d oceta xel) d ue t o 
t o xicit y g ui da nce o utli ne d i n Secti o n 3. 7. 4. 1 will n ot necessitate s us pe nsi ons, re d ucti o ns or 
di sc o nti n uati ons of  t he ot her u nrelate d st u d y dr u g(s).  H o we ver, cl ose c o nsi derati o n m ust be 
ma de b y t he i n vest i gat or t o a d mi nister all st u d y treat me nts per t he sc he d ule o utli ne d i n 
Secti o n 3. 7. 1 .
A n y pat ient  w h o re q uires a d ose re d ucti o n f or dr u g-relate d t o xicity will c o nt i n ue t o recei ve t he 
re d uce d d ose f or t he re mai n der of t he st u d y wi t h t he e xce pti on s s pecifie d i n Ta ble J V 0 2. 1 0 . F or 
r a mu ci r u ma b, ge mci ta bi ne, or d oceta xel , a n y patient  w h o has ha d 2 d ose re d ucti o ns i n t he sa me 
age nt a n d w h o e x perie nces a t o xicit y t hat w o uld ca use a t hi r d d ose re d uctio n m ust be 
di sc o nti n ue d fr om t hat st u d y tr e at me nt. If all st u d y a ge nts are hel d be y on d t he d urati o n of o ne 
c ycle, w he n rei nit iate d dee m t hat Da y 1 of t he s u bse q ue nt c ycle.
Ta ble J V0 2. 8 prese nts t he d ose re d ucti o n f or ra m ucir u ma b, ge mcita bi ne, a n d d oceta xel.  D ose 
a djust m e nts re q uir e d for h e m at olo gi c a n d n o n he mat olo gi c t o xicit y d ue t o ra mu ci r u ma b, 
g e m cita bi ne, or d oceta xel are prese nte d i n Ta ble J V0 2. 1 0 a n d Ta ble J V 0 2. 1 1 , res pecti vel y.  
T a bl e J V 0 2 . 8.
D o s e R e d u cti o n s f or R a m u cir u m a b, G e m cit a bi n e, a n d 
D o c et a x el -R el at e d T o xi citi e s
St u d y Dr u g
St arti n g D ose
D ose Re d ucti o n
First
Sec o n d
Ra m ucir u ma b
9 m g/ k g
7 m g/ k g
5 m g/ k g 
if de-esc al ate d
6 m g/ k g 
5 m g/ k g 
4 m g/ k g
Ge mcita bi ne a
9 0 0 m g/ m 2
6 7 5 m g/ m 2
5 0 0 m g/ m 2
D oceta xel
7 5 m g/ m 2
6 0 m g/ m 2
4 5 m g/ m 2
a
T he i nf usi o n ti me of ge mcita bi ne after its d ose re d ucti o n ma y be mai ntai ne d at 9 0 mi n utes or ma y be s h orte ne d 
t o kee p a rate of a p pr o xi matel y 1 0 m g/ m2/ mi n acc or di n g t o discreti o n of t he i n vesti gat or.  T he i nf usi o n start a n d 
st o p ti mes m ust be rec or ded.
3. 7. 4. 1.
G ui d eli n e s f or H e m at ol o gi c al a n d N o n h e m at ol o gi c al D o s e M o difi c ati o n s
I n ge neral, ra m ucir u ma b t hera p y d oes n ot nee d t o be altere d f or eit her ge mcita bi ne- or 
d oceta xel -relate d t o xicit y.  Si milarl y, ge mci ta bi ne or d oceta xel d o n ot nee d t o be altere d f or 
r a mu ci r u ma b-relate d t o xicit y.  I n vesti gat ors will i nter pret a n d d oc 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 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 
di sease, c o nc o mit a nt treat me nts, or pat h ol o gies, i n or der t o i n di vi d uall y a dj ust st u d y dr u g d oses.  
I n t he case of t o xicity f or w hic h t he relati ve r oles of eac h a ge nt are i m p ossi ble t o se parate, it is 
e x pecte d t hat o missi o ns a n d/ or d ose re d ucti o ns of all i n v o l ve d a ge nts w o uld res ul t.  I n cases i n 
w hic h A Es, i n t he o pi ni o n o f t he i n vest i gat or, are m ore li kel y d ue t o 1 dr u g t ha n a n ot her, 
a djust m e nt of 1 of t he c he m ot hera p y a ge nts a n d n ot t he ot her is per missi ble.  Ge neral g ui deli nes 
f or st u d y treat me nt d ose mo dificat i ons d ue t o t o xicit ies are prese nte d i n Ta ble J V 0 2.9 . D o se 
a djust m e nt g uideli nes f or s pecific he mat ol o gi c a n d n o n he mat ol o gic t o xicit y d ue t o ra m ucir u ma b, 
g e m cita bi ne, a n d/ or d oceta xel are prese nte d i n Ta ble J V0 2. 1 0 a n d Ta ble J V 0 2. 1 1 , res pecti vel y. 
J V 0 2 0 5 Pr ot oc ol A d de n da ( g). p df | V V- T M F- 4 2 9 2 2 1 7 | 1. 0
Fi nal
P P D

J 1 S -M C -J V 0 2( g) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 4 1
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
See Secti o n 3. 7. 4. 2 a n d Ta ble J V 0 2. 1 2 f or a d dit i on al re q uire me nts a n d d ose a dj ust me nt  
g ui deli nes relate d t o p ote ntial I R Rs a n d a d verse e ve nts of s pecial i nterest ( A E SIs ) t hat ma y occ ur 
d uri n g or f o ll owi n g ra m ucir u ma b a d mi nistrati o n.
T a bl e J V 0 2. 9 .
G e n er al G ui d eli n e s f or St u d y Tr e at m e nt D o s e M o difi c ati o n D u e t o 
T o xi cit i e s R el at e d t o R a m u cir u m a b, G e m cit a bi n e , or D o c et a x el
Re acti o n Gr a de
Re q uire d D ose M o dific ati o n
Gra de 1
N o d ose m o dificati o n is re q uire d.
Gra de 2
Persiste nt or rec urre nt Gra de 2 n ot res ol vi n g wit h ma xi mal s u p p orti ve meas ures: at t he 
i n vesti gat or’s discreti o n, t he patie nt ma y c o nti n ue t o recei ve st u d y dr u g per pr ot oc ol, 
pr o vi de d t hat t he e ve nt d oes n ot p ose a seri o us healt h ris k or is easil y treate d.
Gra de 3 
F or a Gra de 3 t o xicit y n ot a de q uatel y c o ntr olle d wit h a p pr o priate s u p p orti ve care a n d 
assesse d as relate d t o st u d y dr u g , t he d ose m ust be wit h hel d u ntil t o xicit y is ≤Gra de 1 or has 
ret ur ne d t o pretreat me nt baseli ne; t he n treat me nt ma y res u me at a re d uce d d ose le vel. A n 
e xce pti o n t o t his w o ul d be is olate d la b -o nl y  i n creases i n G G T or A L P. If t o xicit y rec urs after 
t hera p y res u mes des pite u p t o t w o d ose re d ucti o ns , t he n treat me nt s h o ul d be disc o nti n ue d.

First occ urre nce:   Dela y a ge nt u ntil res ol ve d t o Gra de s 0-1.
o
If res ol ve d t o Gra des 0-1, re d uce d ose.
o
If N O T res ol ve d t o Gra des 0- 1 wit hi n a reas o na ble ti mefra me (i.e. wit hi n 
2 8 da ys) , disc o nti n ue a ge nt at i n vesti gat or’s discreti o n.

Sec o n d occ urre nce:  Dela y a ge nt u ntil res ol ve d t o Gra de s 0- 1.
o
If res ol ve d t o Gra des 0-1, re d uce d ose.
o
If N O T res ol ve d t o Gra des 0-1 wit hi n a reas o na ble ti mefra me ( i.e. wit hi n 
2 8 da ys) , disc o nti n ue age nt.
Gra de 4
Per ma ne nt disc o nti n uati o n s h o ul d be c o nsi dere d f or a n y patie nt e x perie nci n g Gra de 4 t o xicit y 
assesse d as relate d t o st u d y dr u g.  A n e xce pti o n t o t his w o ul d be is olate d la b -o nl y  i n creases i n 
G G T or A L P.  H o we ver, if res u m pti o n of d osi n g is dee me d a p pr o priate b y t he i n vesti gat or, 
treat me nt ma y res u me o nl y after c o ns ultati o n wit h t he Lill y C R P/ C R S, wit h t he d ose re d uce d.  
If Gra de 4 t o xicit y rec urs after t hera p y res u mes, st u d y dr u g will be disc o nti n ue d.
E xce pti o ns are Gra de 4 fe ver or Gra de 4 la b orat or y a b n or malit y, i n w hic h case:

First occ urre nce:   Dela y a ge nt u ntil res ol ve d t o Gra de s 0-1.
o
If res ol ve d t o Gra des 0-1, ma y res u me a ge nt at ori gi nal d ose at t he discreti o n of 
t he i n vesti gat or.
o
If N O T res ol ve d t o Gra des 0-1 wit hi n a reas o na ble ti mefr a me (i.e. wit hi n 
2 8 da ys) , disc o nti n ue a ge nt at i n vesti gat or’s discreti o n.

Sec o n d occ urre nce:  Dela y a ge nt u ntil res ol ve d t o Gra de s 0- 1.
o
If res ol ve d t o Gra des 0-1, re d uce d ose.
o
If N O T res ol ve d t o Gra des 0-1 wit hi n a reas o na ble ti mefra me (i.e. wit hi n 
2 8 da y s), disc o nti n ue a ge nt at i n vesti gat or’s discreti o n.
A b bre viati o ns: A L P = al kali ne p h os p hatase; C R P = cli nical researc h p h ysicia n ; C R S = cli nical researc h scie ntist; 
G G T = ga m ma -gl uta m yl tra nsferase .
N ote: If a patie nt d oes n ot rec o ver fr o m t he t o xicit y wit hi n 2 8 da ys fr o m t he ti me of last treat me nt, t he patie nt 
s h o ul d be c o nsi dere d f or per ma ne nt disc o nti n uati o n fr o m st u d y treat me nt.  I n e xce pti o nal circ u msta nces, a 
dela y > 2 8 da y s is per mitte d u p o n a gree me nt bet wee n t he i n vesti gat or a n d t he Lill y C R P/ C R S.
J V 0 2 0 5 Pr ot oc ol A d de n da ( g). p df | V V- T M F- 4 2 9 2 2 1 7 | 1. 0
Fi nal
P P D

J 1 S -M C -J V 0 2( g) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 4 2
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
T a bl e J V 0 2 .1 0 .
D o si n g Al g orit h m o n D a y s 1 a n d 8 f or G e m cit a bi n e, D o c et a x el, a n d R a m u cir u m a b B a s e d o n A b s ol ut e 
N e utr o p hil C o u nt a n d Pl at el et C o u nt
T o xicit y
D a y 1 a
D a y 8 b
G e m
R a m ucir u m a b c
G e m
D oc
R a m ucir u m a b c
N O T E S 
A bs ol ute Ne utr o p hil C o u nt (cells/ μ L)
≥1 0 0 0
A d mi nister
A d mi nister  
A d mi nister  
A d mi nister  
A d mi nister
5 0 0 t o < 1 0 0 0
O mit
A d mi nister
Dela y u ntil A N C
≥1 0 0 0 o n l y if 
Ge m n ot 
a d mi nistere d o n 
Da y  1 d ue t o 
A N C . Ot her wise, 
re d uce at 
i n vesti gat or 
discreti o n d
Dela y u ntil A N C 
≥1 0 0 0 o nl y  if 
Ge m n ot 
a d mi nistere d o n 
Da y  1 d ue t o 
A N C. Ot her wise, 
re d uce at 
i n vesti gat or 
discreti o n d
A d mi nister
Da y  8 d ose re d ucti o n of ge mcita bi ne or d oceta xel 
beca use of Da y 8 bl o o d c o u nt para meters d oes 
n ot nee d t o be c o nti n ue d o n Da y 1 of t he 
s u bse q ue nt c ycle if res ol ve d.
< 5 0 0
Dela y a n d re d uce 
at i n vesti gat or 
discreti o n d
Dela y at 
i n vesti gat or 
discret i on
O mit a n d re d uce 
at s u bse q ue nt 
c ycles at 
i n vesti gat or 
discreti o n d
Dela y a n d re d uce 
at s u bse q ue nt 
c ycles at 
i n vesti gat or 
discreti o n d. See 
n otes f or f urt her 
i nstr ucti on.
Dela y at 
i n vesti gat or 
discreti o n
Ge mcit a bi ne
I n case of rec urre nce re d uce d ose of ge mcita bi ne 
t o t he ne xt d ose le vel f or s u bse q ue nt c ycles.
D ocet a xel
At Da y  8 wit h h ol d d ose u ntil A N C≥1 0 0 0 or o mit 
if t he treat me nt is dela ye d > 7 da ys.
Gra de 4 
ne utr o pe nia 
lasti n g > 7 da y s
or
≥Gra de 3 
ne utr o pe nic 
fe ver/i nfecti o n
Dela y a n d re d uce d
Dela y 
O mit a n d re d uce d
at s u bse q ue nt 
c ycles
Dela y a n d re d uce d
at s u bse q ue nt 
c ycles. See n otes 
f or f urt her 
i nstr ucti on.
Dela y 
D ocet a xel
At Da y  8 wit h h ol d d ose u ntil A N C ≥1 0 0 0 a n d 
re d uce ( o mit if t he treat me nt is dela ye d > 7 da ys). 
Pl atelet C o u nt (cells/ μ L)
5 0 , 0 0 0 t o 
< 1 0 0, 0 0 0
O mit
A d mi nister
Re d uce at 
i n vesti gat or 
discreti o n d
Re d uce at 
i n vesti gat or 
discreti o n d
A d mi nister
Da y  8 d ose re d ucti o n of ge mcita bi ne or d oceta xel 
beca use of Da y 8 bl o o d c o u nt para meters d oes 
n ot nee d t o be c o nti n ue d o n Da y 1 of t he 
s u bse q ue nt c ycle if res ol ve d.
< 5 0 , 0 0 0
Dela y a n d re d uce d
Dela y at 
i n vesti gat or 
discreti o n
O mit a n d re d uce d
at s u bse q ue nt 
c ycles
O mit a n d re d uce d
at s u bse q ue nt 
c ycles
Dela y at 
i n vesti gat or 
discreti o n 
O mit ge mcita bi ne or d oceta xel at Da y 8 a n d t he n 
re d uce ge mcita bi ne t o t he ne xt a p pr o priate d ose 
le vel f or s u bse q ue nt c ycles.
J V 0 2 0 5 Pr ot oc ol A d de n da ( g). p df | V V- T M F- 4 2 9 2 2 1 7 | 1. 0
Fi nal
P P D

J 1 S -M C -J V 0 2( g) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 4 3
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
N ote:  F or ot her he mat ol o gic t o xicities n ot s pecifie d please refer t o Ta ble J V 0 2.9 .
a
Da y  1 tr eat me nt m a y  be dela ye d f or u p t o 1 4 da ys t o all o w a patie nt s ufficie nt ti me f or rec o ver y fr o m st u d y dr u g-relate d t o xicit y or n o n-st u d y-dr u g -relate d 
e ve nts at t he i n vesti gat or’s discreti o n (e g, a n a ut o m o bile acci de nt).  I n e xce pti o nal cases, l o n ger dela ys ma y be all o we d after disc ussi o n wit h t he Lill y 
C R P/ C R S.
b
Da y  8 tr eat me nt ma y be dela ye d f or u p t o 7 da ys t o all o w a patie nt s ufficie nt ti me f or rec o ver y fr o m st u d y dr u g-relate d t o xicit y or n o n-st u d y-dr u g -relate d 
e ve nts at t he i n vesti gat or’s discreti o n ( e g, a n a ut o m o bile acci de nt).  If Da y 8 treat me nt is dela ye d > 7 da ys, Da y 8 s h o ul d be o mitte d i n or der t o mai ntai n t he 
2 1- da y  c ycle a n d treat me nt s h o ul d be res u me d wit h pla n ne d Da y 1 tr eat me nt of t he ne xt c ycle.  A mi ni m u m of 7 da ys’ i nter val bet wee n a n y ra m ucir u ma b 
d ose m ust be mai ntai ne d.
c
I n vesti gati o nal ar m. 
d
Re d ucti o n d ose per Ta ble J V0 2. 8
J V 0 2 0 5 Pr ot oc ol A d de n da ( g). p df | V V- T M F- 4 2 9 2 2 1 7 | 1. 0
Fi nal
P P D

J 1 S -M C -J V 0 2( g) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 4 4
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
T a bl e J V 0 2 .1 1 .
G ui d eli n e s f or D o s e M o difi c ati o n D u e t o St u d y Dr u g s -R el at e d N o n -H e m at ol o gi c T o xi citi e s
T o xicit y
D a y 1 a
D a y 8 b
N O T E S
G e m
R a m ucir u m a b c
G e m
D oc
R a m ucir u m a b c
Gr a de 1 t o 2 t ot al bilir u bi n 
A d mi nister
A d mi nister  
A d mi nister
O mit
A d mi nister
E xce pti o n:
Patie nts wit h 
Gil bert’s S y n dr o me ma y ha ve a 
t otal bilir u bi n < 3 m g/ d L bef ore 
re q uiri n g a d ose re d ucti o n i n 
vi n orel bi ne .
Refer t o Secti o n 3. 9. 3. 1. 1 a n d 
Attac h me nt 4 f or he patic safet y 
m o nit ori n g.
A S T a n d/ or A L T > 1. 5 x U L N c o nc o mit a nt 
wit h A L P > 2. 5 x U L N
A d mi nister
A d mi nister  
A d mi nister
Disc o nti n ue
A d mi nister
Gr a de ≥3 t ot al bilir u bi n 
Dela y a n d 
re d uce
I n vesti gat or 
Discreti o n
Re d uce or 
o mit at 
i n vesti gat or 
discreti o n d
Disc o nti n ue
I n vesti gat or 
Discreti o n
Re d uce d ge mcita bi ne a n d 
disc o nti n ue d oceta xel f or all 
s u bse q ue nt c ycles. 
Per ma ne ntl y disc o nti n ue 
ge mcita bi ne a n d d oceta xel i n 
case of se vere he patic t o xicit y.
Refer t o Secti o n 3. 9. 3. 1. 1 a n d 
Attac h me nt 4 f or he patic safet y 
m o nit ori n g.
Gr a de ≥3 A S T or A L T ele v ati o ns
Gr a de 2 ne ur ol o gic t o xicit y
A d mi nister
A d mi nister  
A d mi nister
Re d uce
A d mi nister
Gr a de 3 ne ur ol o gic t o xicit y
A d mi nister
A d mi nister  
A d mi nister
Disc o nti n ue
A d mi nister
C yst oi d m ac ul ar e de m a ( C M E)
A d mi nister
A d mi nister  
A d mi nister
Disc o nti n ue
A d mi nister
If visi o n bec o mes i m paire d, 
see k pr o m pt o p ht hal m ol o g y 
e val uati o n t o l o o k f or C M E
Se vere p ul m o n ar y t o xicit y
Disc o nti n ue
I n vesti gat or 
Discreti o n
Disc o nti n ue
I n vesti gat or 
Discreti o n
I n vesti gat or 
Discreti o n
I ncl u di n g u ne x plai ne d ne w or 
w orse ni n g d ys p nea.
He m ol ytic Ure mic S y n dr o me or se vere re n al 
i m p air me nt
Disc o nti n ue
I n vesti gat or 
Discreti o n
Disc o nti n ue
Disc o nti n ue
I n vesti gat or 
Discreti o n
C a pill ar y Le a k S y n dr o me
Disc o nti n ue
I n vesti gat or 
Discreti o n
Disc o nti n ue
Disc o nti n ue
I n vesti gat or 
Discreti o n
J V 0 2 0 5 Pr ot oc ol A d de n da ( g). p df | V V- T M F- 4 2 9 2 2 1 7 | 1. 0
Fi nal
P P D

J 1 S -M C -J V 0 2( g) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 4 5
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
T o xicit y
D a y 1 a
D a y 8 b
N O T E S
G e m
R a m ucir u m a b c
G e m
D oc
R a m ucir u m a b c
P osteri or re versi ble e nce p h al o p at h y 
s y n dr o me
Disc o nti n ue
Disc o nti n ue  
Disc o nti n ue
Disc o nti n ue  
Disc o nti n ue
A b bre viati o ns:  A L P = al kali ne p h os p hatase; A L T = ala ni ne a mi n otra nsferase; A S T = as partate a mi n otra nsferase ; C R P = cli nical researc h p h ysicia n ; 
C R S = cli nical researc h scie ntist; D oc = d oceta xel; Ge m = ge mcita bi ne.
a
Da y  1 tr eat me nt m a y  be dela ye d f or u p t o 1 4 da ys t o all o w a patie nt s ufficie nt ti me f or rec o ver y fr o m st u d y dr u g-relate d t o xicit y or n o n -st u d y-dr u g -relate d 
e ve nts at t he i n vesti gat or’s discreti o n ( e g, a n a ut o m o bile acci de nt).  I n e xce pti o nal cases, l o n ger dela ys ma y be all o we d after disc ussi o n wit h t he Lill y 
C R P/ C R S.
b
Da y  8 tr eat me nt ma y be dela ye d f or u p t o 7 da ys t o all o w a patie nt s ufficie nt ti me f or rec o ver y fr o m st u d y dr u g-relate d t o xicit y or n o n-st u d y-dr u g -relate d 
e ve nts at t he i n vesti gat or’s discreti o n ( e g, a n a ut o m o bile acci de nt).  If Da y 8 treat me nt is dela ye d > 7 da ys, Da y 8 s h o ul d be o mitte d i n or der t o mai ntai n t he 
2 1- da y  c ycle a n d treat me nt s h o ul d be res u me d wit h pla n ne d Da y 1 treat me nt of t he ne xt c ycle.  A mi ni m u m of 7 da ys’ i nter val bet wee n a n y ra m ucir u ma b 
d ose m ust be mai ntai ne d.
c
I n vesti gati o nal ar m. 
d
Re d ucti o n d ose per Ta ble J V0 2. 8
J V 0 2 0 5 Pr ot oc ol A d de n da ( g). p df | V V- T M F- 4 2 9 2 2 1 7 | 1. 0
Fi nal
P P D

J 1 S -M C -J V 0 2( g) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 4 6
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
3. 7. 4. 2.
R a m u cir u m a b D o s e M o difi c ati o n s A d v er s e E v e nt s of S p e ci al I nt er e st
T he ra m ucir u ma b d ose ma y nee d t o be m o difie d if t he patie nt e x perie nces a n A E, i ncl u di n g a n 
A E SI ( Secti o n 3. 9. 2. 1 ).  D o ses ma y be dela ye d t o all o w ti me f or t he patie nt t o rec o ver fr om t he 
e ve nt.  Certai n A Es re q uire i m me diate a n d per ma ne nt disc o nt i n uati on of st u d y  treat me nt (see 
Ta ble J V 0 2. 1 2 ).  If a d mi nistrati o n of ra m ucir u ma b is dela ye d f or m ore t ha n 6 wee ks ( 2 c ycles) 
after Da y 1 of t h e most rece nt treat me nt c y cle, t he patie nt s h o uld be di sc o nti n ue d fr o m 
r a mu ci r u ma b treat me nt , u nless a lo n ger s us pe nsi o n has s peci ficall y bee n dee me d a p pr o priate f or 
a gi ve n patie nt i n disc ussi o n wit h t he Lill y C R P/ C R S .  A n y pat ient  w h o re q uires a d ose 
re d uctio n will c o nt i n ue t o recei ve a re d uce d d ose u ntil disc o nti n uati o n fr om r a mucir u ma b or 
di sc o nti n uati on fr om t he st u d y.  A n y p atie nts re q uiri n g d ose re d ucti o n t o less t ha n 5 m g/ k g ( 4 
m g/ k g f or patie nts treate d o n d ose de -escalat i on) of ra m ucir u ma b will ha ve ra m ucir u ma b 
di sc o nti n ue d.  S uc h patie nts ma y  c o nti n ue with ge mcita bi ne a n d/ or d oceta xel as per pr ot oc ol .
Ta ble J V0 2. 8 prese nts t he ra m ucir u ma b d ose re d ucti o ns.
Ta ble J V 0 2. 1 2 prese nts t he criteria f or d ose m o dificati o ns a n d d ose disc o nt i n uati ons a p plica ble 
if t he patient  e x perie nces a ra m ucir u ma b A E SI or ot her A Es at least p ossi bl y relate d t o 
r a mu ci r u ma b.  
J V 0 2 0 5 Pr ot oc ol A d de n da ( g). p df | V V- T M F- 4 2 9 2 2 1 7 | 1. 0
Fi nal
P P D

J 1 S -M C -J V 0 2( g) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 4 7
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
T a bl e J V 0 2 .1 2 .
D o s e -M o difi c ati o n G ui d eli n e s f or R a m u cir u m a b f or A d v er s e E v e nt s at L e a st P o s si bl y R el at e d t o 
R a m u cir u m a b, i n cl u di n g A d v er s e E v e nt s of S p e ci al I nt er e st
A d verse E ve nt
N O T E: All s pecific a dverse eve nts liste d are 
defi ne d as A E SIs i n Secti o n 3. 7. 6. 1. 7 .
C T C A E 
Gr a de
D ose -M o dific ati o n G ui deli nes
N O T E S: 
D ose re d ucti o ns t o occ ur as defi ne d i n T a ble J V 0 2. 8
Tre ati n g p hysici a ns c a n m o dify or disc o nti n ue r a m ucir u m a b m ore 
c o nserv atively t h a n i n t he g ui d a nce bel o w.
1.
I nf usi o n-rel ate d re acti o n (i ncl u di n g 
h y perse nsiti vit y re acti o ns)
1.a.
I nf usi o n-relate d reacti o n
2
I nterr u pt a n d re d uce t he i nf usi o n rate b y 5 0 % f or t he d urati o n of t he i nf usi o n a n d 
f or all f ut ure i nf usi o ns.
Pri o r t o all f ut ure i nf usi o ns of ra m ucir u ma b, pre me dicate wit h:

a n i ntra ve n o us hista mi ne H 1 a nta g o nist, s uc h as di p he n h y dra mi ne 
h y dr oc hl ori de

de xa met has o ne or e q ui vale nt

aceta mi n o p he n/ paraceta m ol
1. b.
I nf usi o n-relate d reacti o n
3- 4
I m me diatel y a n d per ma ne ntl y disc o nti n ue ra m ucir u ma b
2.
H y perte nsi o n f or p atie nts ≥1 8 ye ars ol d:
2.a.
H y perte nsi o n ( n o n -life-t hreate ni n g a n d ass ociate d 
wit h s y m pt o ms)
N O T E:  H y perte nsi o n s h o ul d be m o nit ore d pri or t o 
eac h ra m ucir u ma b i nf usi o n.
3

Dela y ra m ucir u ma b u ntil t he h y perte nsi o n is c o ntr olle d wit h me dicati o n a n d 
is res ol ve d t o Gra des 0- 2.
o
If c o ntr olle d wit h me dicati o n a n d res ol ve d t o Gra des 0-2, t he n ma y 
res u me ra m ucir u ma b at c urre nt d ose.

If N O T c o ntr olle d wit h me dicati o n a n d n ot res ol ve d t o Gra des 0-2 wit hi n a 
reas o na ble ti mefra me (e. g. 2 8 da ys), disc o nti n ue ra m ucir u ma b at 
i n vesti gat or’s discreti o n.
2. b.
U n c o ntr olle d h y perte nsi o n, h y perte nsi ve crisis, or 
h y perte nsi ve e nce p hal o pat h y
4
I m me diatel y a n d per ma ne ntl y disc o nti n ue ra m ucir u ma b.
J V 0 2 0 5 Pr ot oc ol A d de n da ( g). p df | V V- T M F- 4 2 9 2 2 1 7 | 1. 0
Fi nal
P P D

J 1 S -M C -J V 0 2( g) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 4 8
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
A d verse E ve nt
N O T E: All s pecific a dverse eve nts liste d are 
defi ne d as A E SIs i n Secti o n 3. 7. 6. 1. 7 .
C T C A E 
Gr a de
D ose -M o dific ati o n G ui deli nes
N O T E S: 
D ose re d ucti o ns t o occ ur as defi ne d i n T a ble J V 0 2. 8
Tre ati n g p hysici a ns c a n m o dify or disc o nti n ue r a m ucir u m a b m ore 
c o nserv atively t h a n i n t he g ui d a nce bel o w.
3
H y perte nsi o n f or p atie nts < 1 8 ye ars ol d:

B P U L N i n c hil dre n : ≤9 5t h perce ntile f or a ge, hei g ht, a n d ge n der meas ure d 
as descri be d i n N H B P E P W G o n Hi g h Bl o o d Press ure i n C hil dre n a n d 
A d olesce nts (2 0 0 4 ). 

Baseli ne B P is t he a vera ge of t he serial B P s o btai ne d at least 5 mi n a part o n 
t he sa me e xtre mit y, i n t he sa me p ositi o n wit h a n a p pr o priate size d c uff.

Ele vati o n i n eit her s yst olic or diast olic B P is vali d f or d ose m o dificati o ns

Ele vate d B P s h o ul d be re -e val uate d o n t he sa me da y f or c o nfir mati o n. If 
ele vate d, B P m o nit ori n g s h o ul d occ ur at least t wice wee kl y u ntil B P ≤U L N
H y perte nsi o n s h o ul d be ma na ge d wit h a p pr o priate a nti -h y perte nsi ve a ge nt(s) as 
cli nicall y i n dicate d. Hi g hl y rec o m me n de d t o c o ns ult pe diatric car di ol o g y or 
ne p hr ol o g y f or e val uati o n a n d ma na ge me nt of h y perte nsi o n i n t he pe diatric 
p o p ulati o n
3. a.
B P: ≤1 0 m m H g a b o ve U L N f or a ge 

A d mi nister ra m ucir u ma b at t he c urre nt d ose.

Rec hec k B P wit hi n 3 da ys
o
If B P ≤U L N, t he n c o nti n ue o n c urre nt ra m ucir u ma b d ose
o
If > U L N, start a nti-h y perte nsi ve t hera p y a n d c o nti n ue o n c urre nt 
ra m ucir u ma b d ose

if B P ≤U L N wit hi n 1 4 da ys, c o nti n ue o n a nti -h y perte nsi ve t hera p y 
a n d c urre nt ra m ucir u ma b d ose
If B P > U L N after 1 4 da ys o n a nti-h y perte nsi ve t hera p y ; see li ne 3.c.
3. b.
B P: > 1 0 m m H g t o 2 5 m m H g a b o ve U L N f or a ge or 
> 3 5 m m H g a b o ve baseli ne

Start a nti -h y perte nsi ve t hera p y a n d c o nti n ue o n c urre nt ra m ucir u ma b d ose

if B P ≤U L N wit hi n 1 4 da ys, c o nti n ue o n a nti -h y perte nsi ve t hera p y 
a n d c urre nt ra m ucir u ma b d ose
If B P > U L N after 1 4 da ys o n a nti-h y perte nsi ve t hera p y ; see li ne 3.c.
3.c.
B P: > 2 5 m m H g a b o ve U L N

H ol d ra m ucir u ma b a n d start or c o nti n ue a nti-h y perte nsi ve t hera p y

if B P ≤U L N wit hi n 1 4 da ys, c o nti n ue o n a nti -h y perte nsi ve t hera p y 
a n d res u me ra m ucir u ma b at a re d uce d d ose
If B P > U L N after 1 4 da ys o n a nti-h y perte nsi ve t hera p y i m me diatel y a n d 
per ma ne ntl y disc o nti n ue ra m ucir u ma b
J V 0 2 0 5 Pr ot oc ol A d de n da ( g). p df | V V- T M F- 4 2 9 2 2 1 7 | 1. 0
Fi nal
P P D

J 1 S -M C -J V 0 2( g) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 4 9
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
A d verse E ve nt
N O T E: All s pecific a dverse eve nts liste d are 
defi ne d as A E SIs i n Secti o n 3. 7. 6. 1. 7 .
C T C A E 
Gr a de
D ose -M o dific ati o n G ui deli nes
N O T E S: 
D ose re d ucti o ns t o occ ur as defi ne d i n T a ble J V 0 2. 8
Tre ati n g p hysici a ns c a n m o dify or disc o nti n ue r a m ucir u m a b m ore 
c o nserv atively t h a n i n t he g ui d a nce bel o w.
3. d.
H y perte nsi o n , h y perte nsi ve crisis, or h y perte nsi ve 
e nce p hal o pat h y
4
I m me diatel y a n d per ma ne ntl y disc o nti n ue ra m ucir u ma b
4.
Pr otei n uri a f or p atie nts ≥1 8 ye ars ol d:
4.a.
Pr otei n uria = 2 + ( di pstic k or r o uti ne uri nal ysis) a

A d mi nister ra m ucir u ma b at t he c urre nt d ose if cli nicall y i n dicate d.

O btai n 2 4 -h o ur uri ne pr otei n res ults wit hi n 3 da ys pri or t o t he ne xt 
ra m ucir u ma b d ose.
o
If uri ne pr otei n is < 2 g/ 2 4 hr, a d mi nister ra m ucir u ma b at t he patie nt's 
c urre nt d ose.
o
If uri ne pr otei n is 2 g/ 2 4 h r, m o dif y t he ra m ucir u ma b d ose base d o n 
2 4- h o ur c ollecti o n.  See Pr otei n uri a 2 g/ 2 4 h ( 2 4 -h o ur uri ne 
c ollecti o n), li ne 4 . c a n d 4. d .
4. b.
Pr otei n uria > 2 + ( di pstic k or r o uti ne uri nal ysis) a

O mit ra m ucir u ma b a n d o btai n 2 4 -h o ur uri ne pr otei n res ults wit hi n 3 da ys 
pri or t o t he ne xt ra m ucir u ma b d ose .

Dela y ra m ucir u ma b u ntil uri ne pr otei n ret ur ns t o < 2 g/ 2 4 hr 
o
If uri ne pr otei n is < 2 g/ 2 4 hr, n o f urt her d ose dela y or d ose re d ucti o n is 
re q uire d.
o
If uri ne pr otei n re mai ns 2 g/ 2 4 h r; see li ne 4 . c a n d 4. d .
4.c.
Pr otei n uria 2 g/ 2 4 h r ( 2 4-h o ur uri ne c ollecti o n) a

First or sec o n d occ urre nce :  dela y ra m ucir u ma b u ntil uri ne pr otei n ret ur ns 
t o < 2 g/ 2 4 hr.
o
If uri ne pr otei n ret ur ns t o < 2 g/ 2 4 hr, re d uce ra m ucir u ma b d ose.
o
If uri ne pr otei n re mai ns 2 g/ 2 4 hr a n d is n ot res ol ve d wit hi n a 
reas o na ble ti mefra me, disc o nti n ue ra m ucir u ma b at i n vesti gat or’s 
discreti o n.

T hir d occ urre nce :  disc o nti n ue ra m ucir u ma b.
4. d.
Pr otei n uria > 3 g/ 2 4 h r or i n t he setti n g of ne p hr otic 
s yn dr o me a
I m me diatel y a n d per ma ne ntl y disc o nti n ue ra m ucir u ma b.
5. 
Pr otei n uri a f or p atie nts < 1 8 ye ars ol d:
5.a.
Pr otei n uria trace ( di pstic k or r o uti ne uri nal ysis)a
H ol d ra m ucir u ma b a n d o btai n a ra n d o m uri ne sa m ple t o calc ulate t he U P C rati o. 
See li nes 5 . b.t o 5 . d.
J V 0 2 0 5 Pr ot oc ol A d de n da ( g). p df | V V- T M F- 4 2 9 2 2 1 7 | 1. 0
Fi nal
P P D

J 1 S -M C -J V 0 2( g) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 5 0
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
A d verse E ve nt
N O T E: All s pecific a dverse eve nts liste d are 
defi ne d as A E SIs i n Secti o n 3. 7. 6. 1. 7 .
C T C A E 
Gr a de
D ose -M o dific ati o n G ui deli nes
N O T E S: 
D ose re d ucti o ns t o occ ur as defi ne d i n T a ble J V 0 2. 8
Tre ati n g p hysici a ns c a n m o dify or disc o nti n ue r a m ucir u m a b m ore 
c o nserv atively t h a n i n t he g ui d a nce bel o w.
5. b.
U P C rati o < 1a
A d mi nister ra m ucir u ma b at patie nt’s c urre nt d ose as sc he d ule d.
5.c.
U P C rati o 1 -1. 9 a

H ol d ra m ucir u ma b a n d re peat a sec o n d meas ure me nt wit hi n 7 2 h o urs of t he 
ne xt sc he d ule d d ose . 
o
If U P C rati o ret ur ns t o < 1, a d mi nister ra m ucir u ma b at c urre nt d ose
o
If U P C rati o re mai ns 1-1. 9, o mit ra m ucir u ma b u ntil U P C rati o ret ur ns t o 
< 1 

If U P C rati o ret ur ns t o < 1 wit hi n 1 4 da ys, res u me ra m ucir u ma b 
wit h d ose re d ucti o n
If U P C rati o re mai ns ≥1 f or 1 4 da ys or m ore, i m me diatel y a n d per ma ne ntl y 
disc o nti n ue ra m ucir u ma b 
5. d.
U P C rati o > 1. 9 a
I m me diatel y a n d per ma ne ntl y disc o nti n ue ra m ucir u ma b.
6.
Arteri al t hr o m b oe m b olic e ve nts, ve n o us 
t hr o m b oe m b olic e ve nts
3 or 4
I m me diatel y a n d per ma ne ntl y disc o nti n ue ra m ucir u ma b.
7.
Blee di n g/ He m orr h a ge
Blee di n g/ He m orr ha ge
2
C o nti n ue wit h treat me nt u nless i n vesti gat or c o nsi dere d relate d.  See 
Ta ble J V 0 2.9 .
Blee di n g/ He m orr ha ge
3 or 4
I m me diatel y a n d per ma ne ntl y disc o nti n ue ra m ucir u ma b.
8.
G astr oi ntesti n al perf or ati o n
I m me diatel y a n d per ma ne ntl y disc o nti n ue ra m ucir u ma b.
9.
Re versi ble p osteri or le u k oe nce p h al o p at h y 
s y n dr o me
I m me diatel y a n d per ma ne ntl y disc o nti n ue ra m ucir u ma b.
1 0.
C o n gesti ve he art f ail ure
C o n gesti ve heart fail ure
2
C o nti n ue wit h treat me nt u nless i n vesti gat or c o nsi dere d relate d.  See 
Ta ble J V 0 2.9 .
C o n gesti ve heart fail ure
3 or 4
I m me diatel y a n d per ma ne ntl y disc o nti n ue ra m ucir u ma b.
1 1.
Fist ul a f or m ati o n
I m me diatel y a n d per ma ne ntl y disc o nti n ue ra m ucir u ma b.
1 2.
I m p aire d w o u n d he ali n g
1 2.a.
Pri o r t o pla n ne d s ur ger y
Wit h h ol d ra m ucir u ma b.
1 2. b
After s ur ger y
Res u me ra m ucir u ma b base d o n cli nical j u d g me nt.
1 2.c.
W o u n d -heali n g c o m plicati o ns de vel o pe d d uri n g 
st u d y treat me nt
Dela y ra m ucir u ma b d osi n g u ntil t he w o u n d is f ull y heale d.
J V 0 2 0 5 Pr ot oc ol A d de n da ( g). p df | V V- T M F- 4 2 9 2 2 1 7 | 1. 0
Fi nal
P P D

J 1 S -M C -J V 0 2( g) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 5 1
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
A d verse E ve nt
N O T E: All s pecific a dverse eve nts liste d are 
defi ne d as A E SIs i n Secti o n 3. 7. 6. 1. 7 .
C T C A E 
Gr a de
D ose -M o dific ati o n G ui deli nes
N O T E S: 
D ose re d ucti o ns t o occ ur as defi ne d i n T a ble J V 0 2. 8
Tre ati n g p hysici a ns c a n m o dify or disc o nti n ue r a m ucir u m a b m ore 
c o nserv atively t h a n i n t he g ui d a nce bel o w.
1 3 .
H y p ot h yr oi dis m
2- 4
T hera p y  wit h ra m ucir u ma b ca n be c o nti n ue d w hile treat me nt f or t he t h yr oi d 
dis or der is i nstit ute d.
1 4.
He p atic e nce p h al o p at h y a n d/ or he p at ore n al 
s y n dr o me res ulti n g fr o m li ver cirr h osis
I m me diatel y a n d per ma ne ntl y disc o nti n ue ra m ucir u ma b,
D ose -M o dific ati o n G ui deli nes f or R a m ucir u m a b f or A d verse E ve nts at le ast P ossi bl y Rel ate d t o R a m ucir u m a b, i ncl u di n g A d verse E ve nts
of S peci al 
I nterest (c o ncl u de d)
A b bre viati o ns:  A E SI = a d verse e ve nt of s pecial i nterest; C T C A E = C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts; N CI = Nati o nal Ca ncer I nstit ute ; 
U P C = ur i ne pr otei n t o creati ni ne.
a
Perf or m uri nal ysis wit hi n 3 da ys pri or t o eac h i nf usi o n of ra m ucir u ma b.  If 2 4 -h o ur uri ne c ollecti o n or U P C rati o ( < 1 8 years of a ge) is also perf or me d, t he 
res ults of t hese c ollecti o n s s ho ul d be use d f or cli nical decisi o n -ma ki n g.
J V 0 2 0 5 Pr ot oc ol A d de n da ( g). p df | V V- T M F- 4 2 9 2 2 1 7 | 1. 0
Fi nal
P P D

J 1 S -M C -J V 0 2( g) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 5 2
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
3. 7. 5.
Tr e at m e nt C o m pli a n c e
N o a d di tio n al  r e q uire me nts.  Refer t o t he C A M P FI R E Master Pr ot oc ol f or treat me nt c o m plia nce. 
3. 7. 6.
C o n c o mit a nt T h er a p y
D oceta xel is a C Y P 3 A 4 s u bstrate.  I n vitr o st u dies ha ve s h o w n t hat t he meta b o lis m of d oceta xel 
ma y be m o difie d b y t he c o nc o mit a nt a d mi nistrati o n of c o m p o u n ds t hat i n d uce, i n hi bit, or are 
meta b o lize d b y C Y P 3 A 4.  A v o i d c o nc urre nt use of d oceta xel with i n hi bit ors a n d i n d ucers of 
C Y P 3 A 4.  Refer t o Attac h me nt 6 f or a list of c o m m on C Y P 3 A 4 i n d ucers a n d i n hi bit ors.  Use of 
a dr u g t hat is liste d i n At tac h me nt 6 w he n t here is n o a p pr o priate cli nical s u bst itute f or t hat dr u g 
will n ot be c o nsi dere d a pr ot oc ol vi o lati on.  Cl ose m o ni t ori n g f or t o xicit y a n d a d oceta xel d ose 
re d uctio n c o ul d be c o nsi dere d i f s yste mic a d mi nistrati o n of a p ote nt C Y P 3 A 4 i n hi bit or ca n n ot be 
a v o i de d.
A list of restricte d a n d e xcl u de d c o nc omit a nt t hera pies a n d e xce pt i ons is pr o vi de d i n 
At tac h me nt 5.  All pre me dicati on, s u p p orti ve care, a n d c o nc o mita nt me dicat i on m u st be re p orte d 
o n t he C R F at eac h visit.
3. 7. 6. 1.
S u p p orti v e C ar e
P ati e nts s h o uld recei ve f ull s u p p orti ve care t o ma xi mize q ualit y of  life.  Patie nts will recei ve 
s u p p ortive care as j u d ge d b y t he treati n g p h ysicia n.  If it is u nclear w het her a t hera p y  s h o uld be 
re gar de d as s u p p orti ve care, 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.  Use of a n y 
s u p p orti ve care s h o ul d be rec or de d o n t he e C R F.  I n vesti gat ors s h o uld c o ns ul t t he PI f or 
a d ditio nal  preca utio ns.  S pecific A Es ha ve bee n i de ntifie d base d o n past data f or s pecial 
m o nit ori n g a n d, w he n necessar y, s u p p orti ve care.  F or ra m ucir u ma b, t hese are referre d t o as 
A E SI s.
3. 7. 6. 1. 1.
Tr a n sf u si o n s
Tra nsf usi o ns of re d bl o o d cells, platelets, or ot her bl o o d pr o d ucts are per mitte d at t he 
i n vesti gat or’s discreti on.
3. 7. 6. 1. 2.
Gr o wt h F a ct or s
See Secti o n 3. 7. 1. 1. 4 f or re q uire d use of G-C S F. 
T he as -nee de d use of er yt hr oi d- sti m ulati n g fact ors (e g, er yt hr o p oiet i n) is per mitte d at t he 
di scretio n of  t he i n vesti gat or base d o n A S C O g ui deli nes ( Ri zz o et al. 2 0 0 4 ) (Attac h me nt 5 ).
3. 7. 6. 1. 3.
A nti e m eti c A g e nt s
Pr o p h ylactic a nt iemet ics s h o uld be r o uti nel y a d mi nistere d per i nst ituti o nal  sta n dar d f or 
g e m cita bi ne.  T he use of a nt iemet ic a ge nts is per mitte d at t he discreti on of t he i n vest i gat or f or 
r a mu ci r u ma b a n d d oceta xel.  Acce pta ble a ntiemet ic a ge nts i ncl u de 5- h y dr o x y tr ypta mi ne 3 ( 5-
H T 3) rece pt or a nta g o nists (e g, o n da nsetr o n), d o pa mi ne rece pt or a nta g o nists (e g, 
met oc l opra mi de), c ortic oster oi ds ( e g, de xa met has o ne), a n d ot hers.
J V 0 2 0 5 Pr ot oc ol A d de n da ( g). p df | V V- T M F- 4 2 9 2 2 1 7 | 1. 0
Fi nal
P P D

J 1 S -M C -J V 0 2( g) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 5 3
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
3. 7. 6. 1. 4.
A n al g e si c A g e nt s
T he use of a nal gesic a ge nts is per mitte d at t he discreti o n of t he i n vest i gat or.  O piate a n d 
n o n o pi ate a nal gesic a ge nts are per mitte d (i ncl u di n g aceta mi n o p he n/ paraceta m o l); h o we ver, use 
of  n o nster oi dal a nt i-i nfla m mat or y dr u gs (N S AI Ds ) a n d/ or as piri n is restricte d ( Attac h me nt 5 ).
3. 7. 6. 1. 5.
A p p etit e Sti m ul a nt s
T he use of a p pet ite sti m ula nts is per mitte d at t he discreti o n of t he i n vest i gat or.  E xa m ples 
i ncl u de me gestr ol acetate, dr o na bi n ol, a n d ot hers.
3. 7. 6. 1. 6.
Ot h er S u p p orti v e C ar e A g e nt s
T he use of be nz o diaze pi nes, a nt i de pressa nts, la xati ves, a n d ot her a ge nts t hat ma y be hel pf ul i n 
c o ntr olli n g disease-relate d s y m pt o ms are als o per mitte d a n d e nc o ura ge d, e xce pt as pr o hi bite d i n 
At tac h me nt 5.
3. 7. 6. 1. 7.
S u p p orti v e C ar e b y A d v er s e E v e nt of S p e ci al I nt er e st: R a m u cir u m a b
Refer t o Ta ble J V 0 2. 1 2 f or A E SI d ose m o dificati on g ui deli nes. 
3. 7. 6. 1. 7. 1.
I nf u si o n-R el at e d R e a cti o n s (I n cl u di n g H y p er s e n siti vit y R e a cti o n s)
A d mi nistrati o n of  mo n o cl o nal a nt i b o dies s uc h as ra m ucir u ma b ca n res ult i n H S Rs, i ncl u di n g 
i m me diate reacti o ns li ke a na p h ylactic reacti ons or I R Rs a n d dela ye d react i ons s uc h as t h ose 
i n v ol vi n g t he muc oc uta ne o us s y st e m. I n t he e ve nt of a n I R R, e ver y eff ort s h o ul d be ma de t o 
c ollect bl o o d sa m ples will be c o llecte d f or P K a n d i m m u n o ge nicit y a nal ysis f or ra mucir u ma b, at 
t he f o ll owi n g ti me p oi nts:  
(i)
as close as p ossi ble t o t he o nset of t he I R R, 
(ii)
at t he res ol ut i on of t he I R R, a n d 
(iii)
3 0 da y s fol l owi n g t he I R R.
I n a d diti on, i n t he case of ge neralize d urticaria or a na p h yla xis, bl o o d a n d uri ne sa m ples s h o ul d 
be c o llecte d as descri be d i n At tac h me nt 3 h y p erse nsit i vity la bs): 
(i)
After t he pati e nt has bee n sta bilize d, o btai n a sa m ple wit hi n 1 -2 h o urs of t he e ve nt ;
h o we ver, sa m ples ma y  be o btai ne d as late as 1 2 h o urs after t he e ve nt as a nal yt es ca n 
r e mai n altere d f or a n e xte n de d peri o d of ti me. Rec or d t he ti me at w hic h t he sa m ple 
wa s c ollecte d.
(ii)
O btai n a f o ll ow -u p sa m ple 3 0 da y s f oll owi n g t he I R R or at t he ne xt re g ularl y 
sc he d ule d visit f oll owi n g t he I R R , w hic he ver is later.
I nf usi on- r elate d reactio ns ma y  occ ur d uri n g or f oll o wi n g ra m ucir u ma b a d mi nistrati o n.  Patie nts 
s h o uld be cl osel y m o ni t or e d for si g ns a n d s y m pt o ms i n dicat i ve of a n I R R fr o m t he i nitiati on of 
t he i nf usi o n i n a n area w here res uscitat i on e q ui p me nt a n d ot her a ge nts (s uc h as e pi ne p hr i ne a n d 
c ortic oster oids) are rea dil y  a vaila ble.
Si g ns a n d s y m pt o m s us uall y d e v elo p d uri n g or s h ortl y  after i nf usio n  a n d ge nerall y res ol ve 
wi t hi n 2 4 h o urs.  S y m pt o ms of I R Rs i ncl u de ri g ors/tre m ors, bac k pai n/s pas ms, c hest pai n a n d/ or 
tig ht ness, c hills, fl us hi n g, d y s p nea, w heezi n g, h y p o xia, a n d parest hesia.  I n se vere cases, 
s y m pt o ms i ncl u de br o nc h os pas m, s u pra ve ntric ular tac h ycar dia, a n d h y p ote nsi o n.
J V 0 2 0 5 Pr ot oc ol A d de n da ( g). p df | V V- T M F- 4 2 9 2 2 1 7 | 1. 0
Fi nal
P P D

J 1 S -M C -J V 0 2( g) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 5 4
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
Ta ble J V 0 2. 1 2 prese nts ra m ucir u ma b d ose m o dificati o n f or patie nts w h o e x perie nce a n I R R 
ass ociat e d wit h r a mucir u ma b.
P ati e nts must be cl os el y  mo ni t or e d for a 1 -h o ur o bser vat i on peri o d f oll o wi n g t he r a mucir u ma b 
i nf usi ons f or t he first 2 i nf usi ons.  If t he patie nt s h o ws n o e vi de nce of a n I R R wit h t he first 2 
i nf usi ons of eac h st u d y  dr u g, n o o bser vati on peri o d is re q ui r e d for s u bse q ue nt i nf usi o ns.  I n t he 
e ve nt a n I R R occ urs t hereafter, t he 1 -h o ur o bser v ati o n s h o ul d be rei nst itute d.
F or t he first 2 ra m ucir u ma b i nf usi o ns, m eas ure B P a n d p ulse at t he f oll o wi n g ti me 
p oi nts: (i) wi t hi n 1 5 mi n utes pri or t o t he i nf usi on, (ii) after c o m plet i on of t he i nf usi o n, a n d 
(iii) at t he e n d of t he 1 -h o ur p ost -i nf usi on o bser vati o n peri o d.  F or all  s u bse q ue nt i nf usi ons of 
r a mu ci r u ma b, meas ure B P a n d p ulse pri or t o t he i nf usi on.  Meas ure ot her vital si g ns as cli nicall y 
i n dicate d.
S u p p orti ve care s h o ul d be e m pl o ye d i n acc or da nce wit h t he s y m pt o ms or si gns. Parti ci pa nts 
s h o uld be treate d a p pr o priatel y  b y t he i n vestigat or. If a si g nifica nt H S R occ urs ( Gra des 3 or 4), 
di sc o nti n ue ra m ucir u ma b p er ma ne nt l y.
3. 7. 6. 1. 7. 2.
H y p ert e n si o n
A n i ncrease d i nci de nce of se vere h y perte nsi o n ( C T C A E Gra de 3) has bee n re p orte d i n patie nts 
recei vi n g ra m ucir u mab c o m pare d wit h place b o.  I n m ost cases, h y perte nsi o n was c o ntr olle d 
usi n g sta n dar d a nt i h y perte nsi ve treat me nt.  Pree xisti n g h y perte nsi on s h o ul d be c o ntr olle d bef ore 
starti n g ra m ucir u ma b treat me nt.
M o ni t ori n g of B P is re q uire d d uri n g part ici pati on o n trial , a n d m ust occ ur pri or t o, ra m ucir u ma b 
t hera p y t o e ns ure a p pr o priate d osi n g a n d a d mi nistrati o n.  E ver y atte mpt s h o ul d be m a de t o 
c o ntr ol B P pri or t o starti n g treat me nt wit h ra m ucir u ma b a n d t hr o u g h o ut t he st u d y t o s yst olic 
< 1 4 0 m m H g a n d diast olic < 9 0 m m H g for p ati e nt s > 1 8 y ears-ol d, a n d < u p per li mit of n or mal 
(U L N ) f or patie nts u n der 1 8 years of a ge .  R o uti ne cli nical a n d la b orat or y mo ni t ori n g is re q uire d 
i n patie nts w h o a gai n de vel o p h y perte nsi on or e x peri e nce a deteri orati o n i n pre vi o us 
h y perte nsi o n.
3. 7. 6. 1. 7. 3.
Pr ot e i n uri a
Pr otei n uria is a n a d verse effect f or all t hera pies tar geti n g t he V E G F/ V E G F R 2 pat h wa y, 
i ncl u di n g ra m ucir u ma b.  I n ra m ucir u ma b cli nical trials, t he maj ority of  e ve nts were Gra de 1 or 2.  
M o ni t ori n g f or t he de vel o p me nt or w orse ni n g of pr otei n uria d uri ng ra m uci r u ma b t hera p y is 
re q uire d.  Disc o nti n ue ra mucir u ma b if t he pat ient  e x perie nces pr otei n uria > 3 g/ 2 4 h o urs f or 
pati e nts > 1 8 years ol d, U P C rati o > 1. 9 f or patie nts u n der 1 8 y ears of a ge, or ne p hr otic s y n dr o me.
3. 7. 6. 1. 7. 4.
T hr o m b o e m b oli c E v e nt s
3. 7. 6. 1. 7. 4. 1.
Art eri al T hr o m b o e m b oli c E v e nt s
S eri o us, s o m et i mes fatal A T Es, i ncl u di n g m y ocar dial i nfarct i on, car di ac arrest, C V A , a n d 
cere bral isc he mia, ha ve bee n re p orte d i n cli nical trials.
3. 7. 6. 1. 7. 4. 2.
V e n o u s T hr o m b o e m b oli c E v e nt s
Ve n o us t hr o m b oe m b o lic e ve nts are ass ociate d wit h ca ncer; h o we ver, t he i nci de nce o f V T Es 
li kel y v aries de pe n di n g o n t he t ype of ca ncer, sta ge, a n d i nte nsit y of i ma gi n g.  A d dit i onall y , 
J V 0 2 0 5 Pr ot oc ol A d de n da ( g). p df | V V- T M F- 4 2 9 2 2 1 7 | 1. 0
Fi nal
P P D

J 1 S -M C -J V 0 2( g) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 5 5
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
V T Es ha ve bee n ass ociate d wit h s o me a nt ian gi o ge nic t hera p y , alt ho u g h t he i nci de nce vari es 
de pe n di n g o n t he t y pe of t hera p y , use of c o nc o mita nt c he mot h era p y a ge nts, a n d s pecific disease 
state.  T he V T Es ha ve bee n re p orte d fr o m cli nical st u dies i n vest i gati n g ra m ucir u ma b, 
parti c ularl y i n t he c o nte xt of metastatic disease or i n re gi o ns a djace nt t o i m pla nte d ve n o us access 
de vices.
3. 7. 6. 1. 7. 5.
Bl e e di n g/ H e m orr h a g e
Ra m u ci r u ma b is a n a ntian gi o ge nic t hera p y  a nd has t he p ote ntial t o i ncrease t he ris k of se vere 
blee di n g.  Se vere GI he m orr ha ges, i ncl u di n g fatal e ve nts, ha ve bee n re p orte d i n pat ient s wit h 
gastri c- G EJ ca ncer treate d wit h ra m ucir u ma b i n c o m bi nat i on wi t h paclit a x el.
S eri o us he m orr ha gic A Es ha ve bee n re p orte d fr o m cli nical st u dies i n vest i gati n g ra m ucir u ma b.  
H e m orr ha gic c o m plicat i ons are ass ociate d wit h s o me mali g na ncies ( ie, variceal blee di n g fr o m 
p ortal  h y perte nsi on i n he pat ocell ular carci n o ma, l ower GI he m orr ha ge fr o m  bo w el  metastases i n 
o vari a n carci n o ma), alt h o u g h t he rate of t hese c o m plicat i ons varies c o nsi dera bl y.  As detaile d i n 
t he ra mucir u ma b I n vesti gat or’s Br oc h ure (I B), t he i nci de nces of he m orr ha gic e ve nts t o date, 
sig nifica nt bac k gr o u n d i nci de nce of  blee di n g i n s o me mali g na ncies, a n d use of c o nc o mita nt 
a nt i platelet t hera p y in s ome of t he re p orte d cases precl u de a n y defi nit i ve ass ociati o n bet wee n 
blee di n g a n d ra m ucir u ma b, alt h o u g h o n g oi n g s ur veilla nce a n d i de ntificat i on (a n d e xcl usi o n) of 
pati e nts w ith hi g h blee di n g ris k re mai n esse nt ial a n d are detaile d i n t he i ncl usi on/e xcl usi o n 
criteria.
3. 7. 6. 1. 7. 6.
G a str oi nt e sti n al P erf or ati o n
A n i nfre q ue nt i nci de nce of GI perf orati o ns has bee n ass ociate d wit h s ome a nt ian gi o ge nic 
t hera pe utic a ge nts, most s pecificall y i n t he c o nte xt of c olorectal  ca ncer (treate d wit h c om bi nat i on 
re gi me ns, i ncl u di n g a nti-V E G F a nt i b o dies a n d c ytot o xi c c he mot h era p y) a n d i n a d va nce d o varia n 
ca ncer.  T hese e ve nts ma y be ass ociate d wit h e xte nsi ve a b d o mi nal/ perit o neal disease b ur de n.  
Gastr oi ntesti na l p erf or ati o n has bee n re p orte d fr o m cli nical st u dies i n vest i gati n g ra m ucir u ma b.  
T he i nci de nces of t hese e ve nts t o date a n d prese nce of si g nifica nt c o m or bi dit ies a n d ris k fact ors 
precl u de a n y  defi nitive ass ociati o n wit h ra m ucir u ma b, al t ho u g h o n g oi n g s ur ve illa nce re mai ns 
esse nt ial.  M ore i nf or mati o n a b o ut GI perf orati o n ma y be f o u n d i n t he I B.
3. 7. 6. 1. 7. 7.
P o st eri or R e v er si bl e E n c e p h al o p at h y S y n dr o m e
P os t erior re versi ble e nce p hal o pat h y s y n dr o me is a n ac ute ne ur ol o gical dis or der c haracterize d b y 
vari o us ne ur ol o gical si g n s a n d s y m pt o ms i n c o nj u ncti on wi t h disti ncti ve ne ur oi ma gi n g fi n di n gs 
reflecti n g vas o ge nic e de ma, ofte n i n ass ociati on wit h ele vate d B P (Bart y ns ki a n d B oar d ma n 
2 0 0 7; Bart y ns ki 2 0 0 8a; F u gate a n d Ra bi nstei n 2 0 1 5; Fisc her a n d Sc h m utz har d 2 0 1 7). B ot h 
cli nical a n d i ma gi n g feat ures are us uall y re versi ble ( Hi nc he y et al. 1 9 9 6; Lee et al. 2 0 0 8; F u gate 
a n d Ra bi nstei n 2 0 1 5). 
Cases of P R E S, i ncl u di n g fatal cases, ha ve bee n rarel y re p orte d i n pat ient s recei vi n g 
r a mu ci r u ma b. Posteri or re versi ble e nce p hal o pat h y  s yn dr o me s y m pt o ms ma y incl u de seiz ure, 
hea dac he, na usea/ v o mit i n g, bli n d ness, or altere d c o nsci o us ness, wit h or wit h o ut ass ociate d 
h y perte nsi o n. 
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Fi nal
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J 1 S -M C -J V 0 2( g) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 5 6
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
P os t erior re versi ble e nce p hal o pat h y s y n dr ome s h o uld be i de nt ifie d a n d treate d pr o m ptl y i n or der 
t o mi ni mize p ote ntial for p er m a ne nt ne ur olo gi cal da ma ge.  A dia g n osis of P R E S ca n be 
c o nfir me d b y brai n i ma gi n g (e. g., ma g net ic res o na nce i ma gi n g [ M RI]). Treat me nt e nc o m passes 
caref ul c o ntr ol of B P, wit h dra wal o f p ote nti all y ca usati ve me dicat i on, a n d a d mi nistrati o n of 
a nt ic on v u lsa nt a ge nts t o t h ose e x perie nci n g seiz ures ( St ott et al. 2 0 0 5). 
P er m a ne nt l y disc o nti n ue ra m ucir u ma b i n patient s w h o e x perie nce P R E S.
3. 7. 6. 1. 7. 8.
C o n g e sti v e H e art F ail ur e
A n i ncrease d ris k of C H F has bee n ass ociate d wit h s o me a ntia n gi o ge nic t hera pe utic a ge nts, 
parti cularl y i n pat ient s wit h metastatic breast ca ncer pre vi o usl y treate d wit h a nt hrac ycli nes.  A 
s mall n u m ber of C H F e ve nts (i ncl u di n g fatal) were als o re p orte d i n patient s w h o ha d recei ve d 
r a mu ci r u ma b after prior treat m e nt wit h a nt hrac ycli nes i n t he P hase 2 a nd P hase 3 st u dies.
P ati e nts wit h ris k fact ors s h o uld be cl osel y m o nit ore d f or si g ns a n d s y m pt o ms of C H F.
Ca uti o n s h o ul d be e xercise d w he n treati n g patie nts wit h cli nicall y  si g nifica nt car dio vasc ular 
di sease, s uc h as pree xisti n g c or o nar y arter y disease or CH F.  Ra m ucir u ma b s h o ul d be 
di sc o nti n ue d i n t he e ve nt of a n y Gra de 3 or 4 e ve nts c o nsiste nt wit h C H F.
3. 7. 6. 1. 7. 9.
Fi st ul a F or m ati o n
Beca use fist ula f or mat i on has bee n ass ociate d wit h a ntia n gi o ge nic a ge nts, patie nts ma y be at 
i ncrease d ris k f or t he de vel o p me nt of fist ula w he n treate d wit h ra m ucir u ma b.  S o me fist ulas ca n 
be res o l ve d wit h s ur gical pr oce d ures; h o we ver, fist ulas ca n be fatal.  T he i m pact o n t he q uality of  
life of ha vi n g a fist ula varies acc or di n g t o t he l ocati o n a n d e xte nt of t he fist ula ( C he n a n d Clec k 
2 0 0 9).
3. 7. 6. 1. 7. 1 0.
S ur g er y a n d I m p air e d W o u n d H e ali n g
Beca use ra m ucir u ma b is a n a nt ian gi o ge nic t hera p y, it ma y ha ve t he p ote ntial t o a d versel y affect 
w o u n d heali n g.  Ra m ucir u ma b di d n ot i m pair w o u n d heali n g i n a st u d y  c o n d ucte d i n a ni mals; 
h o we ver, t he i m pact of ra m ucir u ma b o n seri o us or n o n heali n g w o u n ds has n ot bee n e val uate d i n 
h u ma ns.
3. 7. 6. 1. 7. 1 1.
Li v er F ail ur e a n d Ot h er Si g nifi c a nt Li v er I nj ur y
Li ver fail ure or ot her si g nifica nt li ver i nj ur y e ve nts, s uc h as he patic e nce p hal o pat h y, ha ve bee n 
o bser ve d i n patie nts recei vi n g ra m u ci r u ma b.  Patie nts wit h 1) cirr h osis at a le v el of C hil d-P u g h 
Cl ass B ( or w orse) or 2) cirr h osis (a n y de gree) a n d a hist or y of he pat ic e nce p hal o pat h y or 
cli nicall y mea ni n gf ul ascites res ult i n g fr om cirr h osis s h o uld n ot be e nr olle d i n cli nical trials wit h 
r a mu ci r u ma b.  “ Cli nicall y mea ni n gf ul ascites” is defi ne d as ascites res ulti n g fr om cirr h osis a n d 
re q uirin g o n g o i n g treat me nt wit h di uretics a n d/ or parace ntesis.
3. 8.
Di s c o nti n u ati o n Crit eri a

Relate d t o I n vest i gat or/ P h ysicia n decisi ons
o
t he i n vest i gat or/ p h ysicia n deci des t hat t he patie nt s h o ul d be disc o nti n ue d fr o m t he 
st u d y or st u d y dr u g(s).
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P P D

J 1 S -M C -J V 0 2( g) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 5 7
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
o
if t he patient , for a n y  reas o n, re q uires treat me nt wit h a n ot her t hera pe utic a ge nt 
t hat has bee n de m o nstrate d t o be effect i ve f or treat me nt of S S , disc o nti n uatio n 
fr om t he st ud y  dr u g(s) occ urs pri or t o i ntr o d ucti o n of t he ot her a ge nt.

Relate d t o pati e nt, pare nt, or le gal g uar dia n
o
t he patie nt or t he patie nt’s desi g nee (f or e xa m ple, pare nts or le gal g uar dia n) 
re q uests t o be disc o nti n ue d fr om t he st u d y or st u d y dr u g.

Relate d t o S p o ns or
o
Lill y st o ps t he st u d y  or st o ps t he patie nt’s partici pati o n i n t he st u d y for m e dical, 
safety,  r e 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 ons, a n d 
G C P.

T he patie nt bec o me s pre g na nt d uri n g t he st u d y.

T he patie nt has ra di o gra p h ic pr o gressi ve disease or si g nifica nt s y m pt o matic disease 
deteri or ati o n c haracterize d as pr o gressi o n of disease, i n t he o pi ni o n of i n vest i gat or, i n t he 
a bse nce of ra di o gra p hic e vi de nce of P D. I n t he e ve nt a patie nt is disc o nti n ue d fr om 
treat me nt d ue t o s ym pt o m atic deterior ati o n, e ver y  effort s h o ul d be m a de t o d oc u me nt 
di sease pr o gressio n, u nless i t is n ot me dicall y a p pr o priate.

T he patie nt e x perie nces u nacce pta ble t o xicit y (for e xa m ple, a persiste nt m o derate t o xicit y 
t hat is i nt olera ble t o t he patie nt).

T h e patie nt is n o nc om p lia nt wit h st u d y pr oce d ures a n d/ or treat me nt.  

T he patie nt has ha d ma xi m u m d ose re d ucti o ns of ra m ucir u ma b, ge mcita bi ne or d oceta xel 
all o we d per pr ot oc ol a n d e x perie nces a n A E t hat w o ul d ca use a n a d dit i on al  d ose 
re d uctio n.

T he patie nt is e nr olle d i n a n y ot her cli nical st u d y i n v ol vi n g a n i n vesti gati onal pr o d uct or 
a n y ot her t ype of me dical researc h j u d ge d n ot t o be scie nt ificall y or me dicall y c om pat i ble 
wi t h t his st u d y.
F or a d di tio nal  tr e at me nt disc o nti n uati on cri t eria see Secti o n 3. 7. 4 . 
3. 9.
St u d y A s s e s s m e nt s a n d Pr o c e d ur e s
Secti o n 3. 2 pr o vi des t he Sc he d ule of Act i vities for t hi s st u d y.
At tac h me nt 2 pr o vi des a list of t he la b orat or y tests t hat will be perf or me d f or t his st u d y.
At tac h me nt 3 pr o vi des t he sc he d ule f or c ollect i on of sa m ples i n t his st u d y .
3. 9. 1.
Effi c a c y A s s e s s m e nt s
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 Sc he d ule of 
Act i vities ( Secti o n 3. 2 ).
Ma g net ic res o na nce i ma gi n g ( M RI) sca ns are t he preferre d met h o ds of meas ure me nt f or 
e xtre mit y,  hea d, or nec k; c o m p ute d t o m o gra p h y ( C T ) is preferre d f or c hest, a b d o me n, or pel vis.
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J 1 S -M C -J V 0 2( g) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 5 8
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
S pi r al C T s ( C T sca n t hic k ness rec o m me n de d t o be 5 m m) are als o acce pta ble i n certai n 
sit u atio ns .  I ntra ve n o us a n d oral c o ntrast is re q uire d w he n a b d o mi nal a n d pel vic C Ts are 
o btai ne d u nless m e dicall y c o ntrai n dicate d ; n o oral c o ntrast is re q uire d w he n j ust c hest C Ts are 
bei n g o btai ne d .
T he C T p orti o n of a p ositr o n e missi o n t o m o gra p h y ( P E T) -C T sca n ma y be use d as a met h o d of 
res p o nse assess me nt if t he site ca n d oc u me nt t hat t he C T is of i de ntical dia g n ostic q uality t o a 
di a g n ostic C T ( wit h I V a n d oral c o ntrast, as a p pro pri at e). A P E T sca n al o ne or as part of a 
P E T -C T ma y be perf or m e d for a d di tio n al  a nal yses b ut ca n n ot be use d t o assess res p o nse 
acc or di n g t o R E CI S T 1. 1 ( Eise n ha uer et al. 2 0 0 9) .
T he m et h o d of t u mor assess me nt use d at baseli ne m ust be use d c o nsiste ntl y t h r o u g h o ut t he 
st u d y.  Ra diol o gi c sca n of t he t h ora x is re q uire d.
See Secti o n 3. 1 0. 3. 1 f or defi niti ons of t he efficac y  e n d p oi nts.
3. 9. 2.
A d v er s e E v e nt s
Refer t o t he C A M P FI R E Master Pr ot oc ol f or A d verse E ve nt i nf or mat i on.
3. 9. 2. 1.
A d v er s e E v e nt s of S p e ci al I nt er e st - R a m u cir u m a b
Secti o n 3. 7. 6. 1. 3 descri bes s u p p orti ve care meas ures f or eac h ra m ucir u ma b A E SI.  Ta ble
J V0 2 . 1 2 prese nts t he d ose -m o dificat i on g ui deli nes f or ra m ucir u ma b A E SIs.  C o ntact t he Lill y 
C R P if q uesti o ns arise c o ncer ni n g A E SIs.
A n y treat me nt -r elate d I R Rs are defi ne d acc or di n g t o t he C T C A E Versi o n 5. 0 defi nit i on ( Ge ner al 
Dis or ders a n d A d mi nistr ati o n- Site C o n diti o ns ).  S y m pt o ms occ urri n g d uri n g or f oll o wi n g 
i nf usi on of i n vest i gati onal t hera p y ma y als o be defi ne d acc or di n g t o A E cate g ories s uc h as 
aller gic reacti o n, a na p h yla xis, or c yt o ki ne release s y n dr o me ( I m m u ne Syste m Dis or ders).  I n t he 
setti n g of s y m pt o ms occ urri n g d uri n g or f oll owi n g i nf usi o n o f i n vesti gati onal t hera p y , 
i n vesti gat ors are e nc o ura ge d t o use t he A E t er m “i nf usio n -relate d reacti o n” a n d a n y a d ditio n al 
t er ms (i ncl u di n g t h ose n ot liste d here) t hat best describe t he e ve nt.
3. 9. 3.
S af et y
3. 9. 3. 1.
S af et y M o nit ori n g
T he Lill y C R P will  mo ni t or s afet y data t hr o u g h o ut t he c o urse of t he st u d y .  
T he st u d y  will b e mo ni t or e d for e xcessi ve t o xi cit y e x perie nce d be yo n d t he D L T assess me nt 
p eri o d.  If e xcessi ve t o xicit y is o bser ve d, t he st ud y ma y be a me n de d, or treat me nt wit h t he 
c o m bi nat i on halte d t o a d dress t he safet y c o ncer n, as a p pr o priate.
3. 9. 3. 1. 1.
S p e ci al H e p ati c S af et y D at a C oll e cti o n
If, f oll owi n g t he i nit iati o n of cl ose he patic m onit ori n g as per master pr ot oc ol S ect i on 9. 4. 2 , o ne 
or m ore of t he f oll o wi n g c o n dit i ons are met, a d dit i o nal he patic data s h o ul d be c ollecte d as per 
At tac h me nt 4.

P ati e nts e nr olle d wit h n or mal or near n or mal A L T or A S T ( <1. 5 × U L N):
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J 1 S -M C -J V 0 2( g) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 5 9
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
o
ele vat i on of ser u m  AL T or A S T ≥8 × U L N ; or
o
ele vate d A L T or A S T ≥5 × U L N a n d t otal bilir u bi n ≥2 × U L N .

P ati e nts e nr olle d wit h ele vate d A L T or A S T (≥1. 5 × U L N):
o
A L T or A S T ≥4 × baseli ne ; or
o
A L T or A S T ≥3 × baseli ne a n d t otal bil ir u bi n ≥2 × U L N .

di sc o nti n uati on fr om st u d y treat me nt d ue t o a he patic e ve nt or a n a b n or malit y of  
li ver tests.

occ urre nce of a he pat ic e ve nt c o nsi dere d t o be a n S A E.
3. 9. 3. 1. 2.
M o nit ori n g f or S p e cifi c T o xi citi e s -Gr o wt h Pl at e
I n a d diti on t o m o ni t ori n g hei g ht o n trial, pat ient s ra n d omize d t o t he ra m ucir u ma b ar m a n d < 1 8 
years o f a ge will ha ve a plai n a nter o p osterior ( A P ) r a dio gra p h of a si n gle pr o xi mal t i bial gr o wt h 
pl ate o btai ne d prior t o t he first d ose of pr ot oc ol t hera p y . 

If patient s ra n d o mize d t o t he ra m ucir u ma b ar m are f o u n d t o ha ve a cl ose d t i bial gr o wt h 
pl ate, n o f urt her ra di o gra p hs will be re q uire d. 

If patient s ra n d o mize d t o t he ra m ucir u ma b ar m are f o u n d t o ha ve a n o pe n ti bial gr o wt h 
pl ate, t he n re peat plai n A P ra di o gra p hs of t he sa me l ocat i on e ver y 4 m o nt hs a n d at s h ort -
t er m fol l ow- u p, or u ntil t he gr o wt h plate has cl ose d .
I n s o me ge o gra p hies, a n M RI of t he k nee ma y be a n alter nate o pti o n i nstea d of a plai n A P 
r a dio gra p h .
P ati e nts wit h e vi de nce of gr o wt h plate t hic ke ni n g or ot her c ha n ges s h o ul d ha ve a k nee M RI 
perf or m e d t o f urt her assess t he de gree of p h yseal pat h ol o g y a n d u n der g o m ore fre q ue nt x-r a y 
f oll ow u p at l east e ver y 3 m o nt hs or as cli nicall y i n dicate d. M RI s h o ul d be perf or me d wit h o ut 
c o ntrast. 
P ati e nts wit h k nee M RI c ha n ges s h o ul d be ma na ge d i n a n i n di vi d ualize d ma n ner. Deci sio ns 
re gar di n g c o nti n uati on of ra m ucir u ma b s h o ul d be ma de after disc ussi o n wi t h t he Lill y C R P, 
ta ki n g i nt o acc o u nt t he prese nce of a n y s y m pt o ms refera ble t o t he k nee as well as t he patie nt’s 
res p o nse t o ra m ucir u ma b. C o ns ultati o n wit h a n ort h o pe dic s ur ge o n ma y als o be i n dicate d. Pl a ns 
f or fol l ow- u p i ma gi n g will als o be ma de o n a n i n di vi d ualize d basis, ta ki n g i nt o acc o u nt t he 
prese nce of s y m pt o ms at t he k nee or ot her j o i nts as well as t he decisi o n t o c o nti n ue ra m ucir u ma b 
or n ot.

M o ni t ori n g i n t he F oll o w-u p peri o d f or pati e nts wit h o pe n ti bial gr o wt h plate o n st u d y
a n d ra n d o mize d t o t he ra m ucir u ma b ar m: 
o
S h ort ter m  foll o w - u p: All patient s wit h a n o pe n gr o wt h plate w hile o n st u d y 
s h o uld re peat pl ai n A P ra dio gra p h a n d o btai n a hei g ht meas ure me nt. 
o
I n s o me ge o gra p hies, a n M RI of t he k nee ma y be a n alter nate o pti o n i nstea d of a 
pl ai n A P ra dio gra p h.
o
L o n g -t er m fol l ow- u p: O nl y  for p ati e nts wit h a n a b n or mal gr o wt h plate fi n di n g at 
s h ort-t er m fol l ow- u p, c o nti n ue t o perf or m plai n A P ra di ol ogi c e val uat i ons a n d 
o btai n hei g ht meas ure me nts u ntil res o l uti on o f gr o wt h plate a b n or malit ies or 
J V 0 2 0 5 Pr ot oc ol A d de n da ( g). p df | V V- T M F- 4 2 9 2 2 1 7 | 1. 0
Fi nal
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J 1 S -M C -J V 0 2( g) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 6 0
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
gr o wt h plate cl os ure, w hic he ver occ urs first .  Fre q ue nc y of b ot h t he ra di o gra p hs 
a n d hei g ht meas ure me nts are per t he i n vesti gat or’s discret i on / patie nt c o n ve nie nce 
d uri n g l o n g -t er m fol l ow- u p.
o
I n s o me ge o gra p hies, a n M RI of t he k nee ma y be a n alter nate o pti o n i nstea d of a 
pl ai n A P ra dio gr a p h.
3. 9. 4.
P h ar m a c o ki n eti c s
Bl o o d sa m ples will be c ollecte d fr o m st u d y  patient s o n t he ra m u ci r u ma b ar m t o assess 
r a mu ci r u ma b c o nce ntratio ns i n ser u m  as s pecifie d i n At tac h me nt 3.  I nstr ucti o ns a n d s u p plies f or 
t he c ollect i on, ha n dli n g, a n d s hi p pi n g of sa m ples will be pr o vi de d b y Lill y or t he ce ntral 
la b orat or y.
F or all patie nts ( w het her i n t he ra m ucir u ma b ar m or t he c o ntr ol ar m), in t he e ve nt of a n I R R, 
e ver y atte mpt s h o ul d be ma de t o c ollect bl o o d sa m ples f or a nti -r a mucir u ma b a nti b o d y  a n d ser u m 
r a mu ci r u ma b c o nce ntratio n deter mi nat i on at t h ose gi ve n ti me p o i nts, as descri be d i n At tac h me nt 
3 .  Refer t o Attac h me nt 3 f or t he ti mi n g of bl o o d sa m ple c ollecti on d uri n g t he c o nti n ue d-access 
p eri o d.
S er u m  c o nce ntratio ns of  r a mucir u ma b will be a nal yze d at a la b orat or y  desi g nate d b y t he s p o ns or 
usi n g a vali date d met h o d.  
Bi oa nal y tic al sa m ples c ollecte d t o meas ure ra mu cir u m a b c o nce ntrati o n will be retai ne d f or a 
ma xi m u m of  1 ye ar fol l owi n g t he l ast patie nt visit for t he st u d y .
3. 9. 5.
P h ar m a c o d y n a mi c s
See Secti o n 3. 9. 6 , Bi o mar kers.
3. 9. 5. 1.
I m m u n o g e ni cit y A s s e s s m e nt s
Bl o o d sa m pl es f or i m m u n o ge nicit y testi n g will be c ollecte d o n all pat ient s t o deter mi ne a nti b o d y 
pr o d ucti o n a gai nst ra m ucir u ma b at s pecifie d ti me p oi nt s a n d i n t he e ve nt of a n I R R (Attac h me nt 
3 ).  Refer t o Attac h me nt 3 f or t he ti mi n g of i m m u n o ge nicity testi n g d uri n g t he c o nti n ue d-access 
p eri o d.
I mm u n o ge nicit y will  be assesse d b y a vali date d assa y desi g ne d t o detect a nti-dr u g a nti b o dies i n 
t he prese nce o f r a mucir u ma b.  A nt i b o dies ma y be f urt her c haracterize d a n d/ or e val uate d f or t heir 
a bilit y t o ne utralize t he acti vity of  r a mucir u ma b.
T o i nter pret t he res ults of i m m u n o ge nicit y i n t he ra m ucir u ma b ar m, t he c o nce ntratio n of  
r a mu ci r u ma b i n t he blo o d will als o be m eas ure d at t he sa me ti me p oi nts (Attac h me nt 3 ).
S a m ples ma y  be st ore d f or a ma xi m u m of 1 5 ye ars fol l owi n g l ast patie nt visit for t he tri al at a 
facility selecte d b y Lill y t o e nable f urt her a nal ysis of i m m u ne res p o nses t o ra m ucir u ma b.  T he 
d urati o n all o ws Lill y t o res p o n d t o re g ulat or y  re q uests relate d t o ra m ucir u ma b.
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J 1 S -M C -J V 0 2( g) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 6 1
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
3. 9. 6.
Bi o m ar k er s
Bi o m ar ker researc h will a d dress q uesti o ns as descri be d i n Sect i ons 9. 7 a n d 9. 8 of t he 
C A M P FI R E Master P r ot oc ol.  T his st u d y  will a nal yze bio m ar kers rele va nt t o ra mucir u ma b, 
mec ha nis m o f actio n of  r a mucir u ma b, t he varia ble res p o nse t o st u d y  dr u g(s), i m m u ne f u ncti on, 
a n gi o ge nesis, a n d pat h wa ys ass ociate d wit h S S .  
S a m ples f or bi o m ar ker researc h will be c o llecte d as s pecifie d i n At tac h me nt 3, w here l ocal 
re g ulat i ons all o w. C ollecti o n o f sa m ples f or bi omar ker researc h will be o pti o nal.
3. 9. 6. 1.
Ti s s u e S a m pl e s f or Bi o m ar k er R e s e ar c h
Tiss ue sa m ples f or bi o mar ker researc h will be c ollecte d f or t he p ur p oses descri be d i n 
Secti o n 3. 9. 6 .  T he f oll owi n g sa m ples f or bi o m ar ker researc h will be c ollecte d acc or di n g t o t he 
sa m pli n g sc he d ule i n Attac h me nt 3 , w here l ocal re g ulati ons all o w.
C ollect i on of t he f o ll owi n g t u m or tiss ue sa m ple(s) is o pti o nal f or all patie nts partici pat i n g i n t his 
st u d y:

a n arc hi ve d t u m or sa m ple

a t u mor ti ss ue sa m ple fr om a ne wl y o btai ne d bio ps y  s peci me n ma y be re q ueste d at a later 
ti me p oi nt (e g, aft er a str o n g res p o nse or disease pr o gress i on). S uc h a d dit i onal bi o psies 
are o ptio nal  a n d s h o uld be perf or m e d o nl y if cli nicall y feasi ble. If t hese a d diti onal 
sa m ples are re q ueste d, t he y will be use d t o f urt her i n vesti gate bi omar kers t hat ma y 
e x plai n treat me nt res p o nse a n d resista nce mec ha nis ms.   If a bi o ps y is s u b mitte d, d ue 
dili ge nce s h o ul d be use d t o e ns ure t hat t u m or s peci me ns ( n ot a n or mal a djace nt or a 
t u mor m ar gi n sa m ple) are pr o vi de d a n d t hat t he t u m or sa m ple c o ntai ns t u m or cells pri or 
t o s hi p me nt t o t he ce ntral la b orat or y.  See t he La b orat or y Ma n ual f or details re gar di n g 
sa m ple c ollecti on a n d ha n dli n g.   
3. 9. 6. 2.
Ot h er S a m pl e s f or Bi o m ar k er R e s e ar c h
T he f o ll owi n g sa m ples f or bi o mar ker researc h will be c ollecte d acc or di n g t o t he sa m pli n g 
sc he d ule i n At tac h me nt 3, w here l ocal re g ulati o ns all o w:

w h o le bl o o d f or p har mac o ge n o mic researc h (as descri be d i n Sect i on 9. 7 of  
C A M P FI R E M aster P r ot oc ol) 

ser u m

pl as ma
A ma xi m u m of 4 sa m ples ma y be c ollecte d at a d diti o nal st u d y ti me p oi nts, if warra nte d a n d 
a gree d u p o n b y t he i n vesti gat or a n d Lill y.
3. 9. 7.
H e alt h E c o n o mi c s
Heal t h ec o n o mics a n d me dical res o urce utilizati on para meters will n ot be e val uate d i n t his st u d y .
J V 0 2 0 5 Pr ot oc ol A d de n da ( g). p df | V V- T M F- 4 2 9 2 2 1 7 | 1. 0
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J 1 S -M C -J V 0 2( g) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 6 2
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
3. 1 0. St ati sti c al C o n si d er ati o n s
3. 1 0. 1. S a m pl e Si z e D et er mi n ati o n
Tra di tio nal o perati n g c haracterist ics ass ociate d wit h t he pr o p ose d Ba yesia n desi g n (S A P ,
Secti o n 6. 6. 1 ) were e val uate d via trial si m ulati on. N ote t hat d ue t o t he a da pti ve b orr o wi n g o n 
P F S effect -size bet wee n J V 0 2 a n d J V 0 1, joi nt  sce narios of  tr ut h i n b ot h S S a n d D S R C T m ust be 
c o nsi dere d w he n e val uat i n g o perati n g c haracteristics f or J V 0 2 (a n d li ke wise f or J V 0 1). U n der 
t he pr o p ose d a nal ysis fra me w or k, t he sa m ple size is c o nsi dere d a de q uate t o s u p p ort t he pri mar y 
o bj ect i ve:

T y pe I err or:
Re p orte d T y pe I err ors are o ne -side d. T y pe I Err or here refers t o t he 
e ve nt t he 9 9 % s uccess criteri o n f or St u d y  J V 0 2 is met w he n , i n reality,     = 1 . Gi ve n 
t he strin ge nc y  of t he Ba yesia n s uccess criteri o n (i. e., 9 9 % pr o ba bilit y of s u peri orit y 
t hres h ol d), false p ositi ves are u nli kel y f or St u d y  J V 0 2. I n partic ular, w he n neither t u m or 
c o h ort tr ul y be nefits fr o m r a mucir u ma b -base d t hera p y  (i. e.,     =        = 1 ), t he 
T y pe I err or rate f or St u d y  J V 0 2 is a p pr oxi matel y . 0 0 3.  I m p orta ntl y, t he T y pe I err or rate 
r e mai ns lo w e ve n u n der sce nari os of str o n g heter o ge neit y i n effect-size bet wee n St u d y  
J V 0 1 a n d St u d y J V 0 2. I n partic ular, if     = 1 , b ut        = . 5 , t he pr o ba bility o f 
T y pe I err or f or St u d y J V 0 2 is still less t ha n 2 %. T his is d ue t o b ot h t he a da pti ve nat ure 
of  t he hierarc hical b orr o wi n g a n d t he stri n ge nt pri mar y s uccess crit erio n.  

P o wer: Gi ve n t he lar ge ma g nit u de of P F S be nefit tar gete d i n t he y o u n g a d ult/ pe diatric 
setti n g, J V0 2 is u nli kel y t o miss tr ul y sta n dar d of  care-c ha n gi n g i m pr o ve me nts d ue t o 
T y pe II err or. U n der t he tar get sce nari o i n w hic h b ot h t u m ors be nefit s u bsta nt iall y fr o m 
r a mu ci r u ma b-base d t hera p y  o n t he basis of P F S 
(ie,     =        = . 3 3 ), t he Ba yesia n a nal ysis of  P F S yiel ds statistical p o wer of 
a p pr o xi matel y 8 2 % t o c o nclu de s uccess i n S S. F or refere nce, a tra dit i onal l og- ra n k 
a nal ysis of S S at 2 4 P F S e ve nts (i n de pe n de nt l y fr o m D S R C T) at  = . 0 0 3 ( 1-si de d) 
carries a p pr o xi matel y 4 3 % p o wer at     = . 3 3 ( n ote this calc ulat i on di d n ot i ncl u de a 
f utility a nal ysis s uc h as t hat pr o p ose d i n J V 0 2 , s o a fairer assess me nt of p o wer u n der t he 
tra ditio n al  a p pr oac h w o uld act uall y be l o wer t ha n 4 3 %).

Si m ulati o n res ults o ver a d dit i onal j o i nt n ull/alter nati ve a n d c o ntr ol sce narios (i ncl u di n g 
sce nari os of str o n g heter o ge neit y i n effect-size bet wee n t he t w o a d de n da a n d mis matc h of 
hist ori cal/ pr os pecti ve c o ntr ols) are ta b ulate d a n d re vie we d i n t he S A P , Secti o n 6. 6. 1 .
Tri al si m ulat i ons were i m ple me nte d usi n g t he statistical s o ftwar e pac ka ge R. Si m ulat i on res ults 
were i n de pe n de nt l y re plicate d.
T he stri n ge nt pri mar y s uccess criteri o n, Pr (    < 1) > 9 9 % , was cali brate d t o e ns ure t hat 
meet i n g t he pri mar y e n d p oi nt s h o uld i m pl y  bot h  statistical si g nifica nce a n d lar ge esti mate d 
ma g nit u de of  patient  be nefit (3 m o nt hs a d ditio nal P F S) f or t he pe diatric/ y o u n g a d ul t p o p ulatio n 
of  int erest. T he i nter pretati o n of t he stri n ge nt s uccess criteri o n is t hat t he p osteri or pr o ba bilit y of  
t he H R bei n g less t ha n 1 is greater t ha n 9 9 %, gi ve n t he o bser ve d data fr o m  J V 0 2, o bser ve d data 
fr om J V 0 1 i nc or p orate d via d y na mic b orr o wi n g, a n d pri or distri b ut i ons.  Base d o n a lar ge 
si m ulati on st u d y  (S A P , Secti o n 6. 6. 1 ), w he n t he 9 9 % p osteri or pr o ba bility t hres h ol d is reac he d, 
J V 0 2 0 5 Pr ot oc ol A d de n da ( g). p df | V V- T M F- 4 2 9 2 2 1 7 | 1. 0
Fi nal
P P D

J 1 S -M C -J V 0 2( g) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 6 3
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
t he ass ociate d esti mate of t he P F S H R (    ) is n o lar ger t ha n a p pr o xi matel y . 5 1. U n der a n 
e xa m ple ass u m pt i on of t hree m o nt hs f or c o ntr ol me dia n P F S (a n d a f urt her ass u m pt i on of 
e x p o ne nt iall y distri b ute d P F S), t he mi ni mal effect size of     = . 5 1 w o ul d c orres p o n d t o 
a p pr o xi matel y 3 mo n ths of a d dit i on al  P F S i n t his p o p ulat i on wi t h hi g h u n met me dical nee d.
3. 1 0. 2. P o p ul ati o n s f or A n al y si s
T he f o ll owi n g a nal ysis sets will be defi ne d f or t his st u d y :
I nte nti o n-t o-tre at (I T T) a n al ysis set: will i ncl u de all ra n d omize d pat ient s. S h o ul d t he 
r a mu ci r u ma b d ose be de -escalate d d uri n g t he safet y lea d-i n peri o d, all ra n d omize d patie nts will 
still be i ncl u de d i n t he I T T a nal ysis set re gar dless of assi g ne d d ose.  T he I T T a nal ysis o f efficac y 
data will c o nsi der all ocat i on of pat ient s t o treat me nt gr o u ps as ra n d omize d a n d n ot b y  act ual 
treat me nt recei ve d.  T his a nal ysis set will be use d f or all baseli ne a n d efficac y  assess me nts.
S afet y a n al ysis set:   will i ncl u de all ra n d o mize d patie nts w h o recei ve d a n y q ua nt ity of  st u d y 
treat me nt, re gar dless o f t heir eli gi bilit y f or t he st u d y.  T he safety e val uat i on will be perf or me d 
base d o n t he first d ose of st u d y  treat me nt a patie nt act uall y recei ve d, re gar dless of t he ar m t o 
w hic h he or s he was ra n d o mize d.  T he safet y a nal ysis set will be use d f or all d osi n g/e x p os ure, 
safety,  a n d res o urce utilizat i on a nal yses.
P h ar m ac o ki netic a n al ysis set:   will i ncl u de all ra n d omize d pat ient s w h o recei ve d at least 1 f ull 
d ose of st u d y  treat me nt a n d ha ve at least 1 p ost baseli ne e val ua ble P K sa m ple.
Bi o m ar ker a n al ysis set:   will i ncl u de t he s u bs et of patient s fr o m t he I T T a nal ysis set fr o m 
w h o m a vali d assa y r es ult has bee n o btai ne d.
3. 1 0. 3. St ati sti c al A n al y si s
Stati stical a nal ysis of t his st u d y will be t he res p o nsi bilit y of Lill y or i ts desig nee.
F or Ba yesia n a nal yses, p osteri or me dia ns a n d 8 0 % (e q ual -taile d) Ba yesia n cre di ble i nter vals will 
be pr o vi de d f or rele va nt q ua ntit ies u nless ot her wise state d. F ull detail re gar di n g s pecificat i on of 
pri or di stri b uti ons will be o utli ne d i n t he S A P. 
All fre q ue ntist tests of treat me nt effect will be c o n d ucte d at a 1- si de d al p ha le vel of . 1, u nless 
ot her wi se state d, a n d all c o nfi de nce i nter vals ( CIs) will be c o m p ute d wit h ( 2 -side d) c o vera ge 
e q ual t o 8 0 %.
A n y c ha n ge t o t he data 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 me nt 
o nl y  if it c ha n ges a pri ncip al  feat ure of t he pr ot oc ol.  A n y ot her c ha n ge t o t he data a nal ysis 
met h o ds descri be d i n t he pr ot oc ol, a n d t he j ust ificati o n f or ma ki n g t he c ha n ge, will be descri be d 
i n t he S A P a n d t he cli nical st u d y re p ort.  A d ditio n al  e x plor at or y  a nal yses of t he data will be 
c o n d ucte d as dee me d a p pr o priate.
3. 1 0. 3. 1. Effi c a c y A n al y si s
T his sect i on disc usses statist ical a nal yses of pri mar y a n d sec o n dar y efficac y e nd p oi nts. 
E x pl or at or y  efficac y a nal yses will be disc usse d i n t he S A P.
J V 0 2 0 5 Pr ot oc ol A d de n da ( g). p df | V V- T M F- 4 2 9 2 2 1 7 | 1. 0
Fi nal
P P D

J 1 S -M C -J V 0 2( g) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 6 4
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
Pr o gressi o n -free s ur vi v al is defi ne d as t he ti me fr o m ra n d omizat i on u ntil t he first occ urre nce of 
d oc u m e nte d disease pr o gressio n per R E CI S T v 1. 1 criteria or deat h fr o m a n y ca use i n t he 
a bse nce of pr o gressi ve disease.  Patie nts k n o w n t o be ali ve a n d wit h o ut disease pr o gressi o n will 
be ce ns ore d at t he ti me of t he last a de q uate t u m or assess me nt (a detaile d P F S e ve nt/ce ns ori n g 
sc he me is pr o vi de d i n t he Ta ble J V 0 2. 1 3 ).  
Pr o gressi o n -free s ur vi val will be c o m pare d bet wee n treat me nt ar ms usi n g t he Ba yesia n 
hierarc hical Wei b ull m o del o utli ne d i n t he S A P , Secti o n 6. 6. 1 , wit h ass ociate d s uccess/f ut ility 
crit eria base d o n t he p osteri or distri b uti on of t he H R     . 
T he Ba yesia n m o del i n v o l ves t w o mec ha nis ms o f statistical b orr o wi n g t o b o ost p o wer i n li g ht of 
li mite d sa m ple size via ac k n o wle d ge me nt of rele va nt data e x o ge n o us t o t he J V 0 2 e nr olle d 
p o p ul at i on. Fi rst, a Ba yesia n a u g me nte d c o ntr ol ( B A C) a p pr oac h will i nc or p orate hist orical P F S 
o utc o m es fr o m pr o pe nsit y-matc he d real w orl d hist orical c o ntr ol patie nts. T he hist orical c o ntr ol 
data will be d o w n -wei g hte d usi n g a fi xe d p o wer pri or (I bra hi m et al. 2 0 1 5).
T he B A C a p pr oac h 
re d uces t he re q uire d pr o p orti o n of patie nts ra n d o mize d t o t he pr os pecti ve c o ntr ol ar m i n J V 0 2. 
Sec o n d, t he Ba y esia n mo d el  incl u des a m ec ha nis m f or d y na mic b orr o wi n g o n effect -size (lo g 
P F S H R ) bet wee n t he t w o a d de n da, J V 0 2 a n d J V 0 1. T h is is acc om p lis he d via a si m ple 
ra n d om- effects met a-a nal yt ic fra me w or k wit hi n t he Ba yesia n mo d el . T he d y na mic b orr o wi n g o n 
effect -size b o osts p o wer s u bsta nt iall y u n der ke y sce narios i n w hic h b ot h t u m ors ( b ot h J V 0 1 a n d 
J V 0 2 p o p ulati ons) tr ul y be nefit fr o m t he a d ditio n of ra m ucir u ma b t o sta n dar d c he m ot hera p y ,
w hile mai ntai ni n g acce pta ble c o ntr ol of T y pe I err or i n sce nari os of str o n g heter o ge neit y i n 
effect -size (see Ta ble J V 0 2. 1 4 a n d Ta ble J V 0 2. 1 5 ). 
J V 0 2 0 5 Pr ot oc ol A d de n da ( g). p df | V V- T M F- 4 2 9 2 2 1 7 | 1. 0
Fi nal
P P D

J 1 S -M C -J V 0 2( g) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 6 5
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
F ull mat he mat ical detail (i ncl u di n g pri or s pecificati on) re gar di n g t he Ba y esia n mo d el  for P F S is 
ela b orate d i n t he S A P al o n g wit h c o m p uter c o de i n t he J A G S la n g ua ge ( Pl u m mer et al. 2 0 1 7) 
use d f or i m ple me nt i n g Mar k o v C hai n M o nte Carl o ( M C M C) si m ulati on fr om t he a p pr o xi mate 
p osteri or distri b ut i on . 
T o c orres p o n d wit h t he 9 9 % s u peri orit y t hres h ol d f or s uccess, a 9 8 % (e q ual-taile d) Ba yesia n 
cre di ble i nter val will be pr o vi de d t o acc o m pa n y t he me dia n of t he p osteri or distri b ut i on of t he 
H R     . I n a d diti o n, P F S c ur ves, me dia n P F S, a n d P F S rates at vari o us ti me p o i nts will be 
esti mate d via c orres p o n di n g p osteri or s u m maries a n d re p orte d alo n g wi t h ass ociate d 80 % 
Ba yesia n cre di ble i nter vals w here a p pr o priate.  Per se nsit i vity, t hese q ua nt ities will als o be 
esti mated usi n g t he tra dit i onal met h o d of Ka pla n- Meier ( Ka pla n a n d Meier 1 9 5 8).  A d dit i onal 
details are a vaila ble i n S A P Secti o n 6. 6.
T a bl e J V 0 2 .1 3 .
P F S E v e nt/ C e n s ori n g S c h e m e
Sit u ati o n a
E ve nt/ Ce ns or
D ate of E ve nt or Ce ns or
T u m o r pr o gressio n o r deat h
E ve nt
Earliest date of P D or deat h
N o t u m or pr o gressi o n a n d n o deat h
Ce ns ore d
Date of last a de q uate t u m or assess me nt, per 
R E CI S T 1. 1 criteria, or date of ra n d o mizati o n 
( w hic he ver is later)b
U nless
N o baseli ne ra di ol o gic t u m or assess me nt 
a vaila ble
Ce ns ore d
Date of ra n d o mizati o n
N o a de q uate p ost baseli ne t u m or assess me nt 
a vaila ble a n d deat h re p orte d after 2 sca n 
i nter vals f oll o wi n g ra n d o mizati o nb,c
Ce ns ore d
Date of ra n d o mizati o n
T u m o r pr o gressi o n or deat h d oc u me nte d
i m me diatel y after 2 o r m ore sca n i nter vals 
f oll o wi n g last a de q uate t u m or assess me nt 
or  ra n d o mizati o n ( w hic he ver is later)b,c
Ce ns ore d
Date of last a de q uate t u m or assess me nt, per 
R E CI S T 1. 1 criteria, or date of ra n d o mizati o n 
( w hic he ver is later)b 
A b bre viati o ns:  C R = c o m plete res p o nse; P D = pr o gr essi ve disease; P F S = pr o gressi o n -free s ur vi val; P R = partial 
res p o nse; R E CI S T 1. 1 = Res p o nse E val uati o n Criteria i n S oli d T u m ors, Versi o n 1. 1; S D = sta ble disease.
a
S y m pt o matic deteri orati o n ( i e, s ym pt o matic pr o gressi o n t hat is n ot c o nfir me d per R E CI S T 1. 1 criteria) will n ot 
be c o nsi dere d as t u m or pr o gressi o n.
b
A de q uate t u m or assess me nt per R E CI S T 1. 1 criteria refers t o a n assess me nt wit h o ne of t he f oll o wi n g res p o nses:  
C R, P R, S D, or P D.
c
Refer t o t he statistical a nal ysis pla n f or t he defi niti o n of 2 sca n i nter vals, i ncl u di n g a n y a dj ust me nt f or sca n 
wi n d o w .
T a bl e J V 0 2. 1 4
Si m ul at e d O p er ati n g C h ar a ct eri sti c s
Tr ue H az ar d R ati o
Pr( P ass I nteri m)
Pr( P ass Fi n al)
S S
D S R C T
S S
D S R C T
S S
D S R C T
1. 0 0
1. 0 0
0. 4 4
0. 4 4
0. 0 0 3
0. 0 0 3
0. 5 0
0. 5 0
0. 9 6
0. 9 6
0. 3 7
0. 3 7
0. 3 3
0. 3 3
0. 9 9
0. 9 9
0. 8 2
0. 8 2
J V 0 2 0 5 Pr ot oc ol A d de n da ( g). p df | V V- T M F- 4 2 9 2 2 1 7 | 1. 0
Fi nal
P P D

J 1 S -M C -J V 0 2( g) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 6 6
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
T a bl e J V 0 2. 1 5
I m p a ct of H et er o g e n e o u s Eff e ct-Si z e B et w e e n T u m or s
Tr ue H az ar d R ati o
Pr( P ass I nteri m)
Pr( P ass Fi n al)
S S
D S R C T
S S
D S R C T
S S
D S R C T
1
0. 8 0
0. 5 0
0. 6 1
0. 0 0 8
0. 0 1 8
1
0. 5 0
0. 6 0
0. 8 8
0. 0 1 5
0. 1 6 4
O ver all res p o nse r ate is defi ne d as t he n u m ber of patie nts w h o ac hie ve a best o verall res p o nse 
of  C R or P R di vi de d b y t he t otal n u m ber of patie nts ra n d omize d t o t he c orres p o n di n g treat me nt 
ar m (I T T p o p ulat i on).  C o nfir mati o n o f P R or C R is re q uire d. T he O R R, wit h 8 0 % CI base d o n 
t he met h o d of Cl o p per a n d Pears o n ( 1 9 3 4), will be s u m marize d f or eac h treat me nt ar m a n d 
c o mpare d bet wee n treat me nt ar ms usi n g Fis her’s e xact test at 1 -si de d le vel  = . 1 .
D ur ati o n of res p o nse is defi ne d as t he ti me fr om t he date t hat meas ure me nt crit eria f or C R or 
P R ( w hic he ver is first rec or de d) are first met u nt il t he first date t hat disease is rec urre nt or 
d oc u m e nte d disease pr o gressio n is o bser ve d, per R E CI S T 1. 1 criteria, or t he date of deat h fr o m 
a n y ca use i n t he a bse nce of d oc u me nte d disease pr o g ressi o n or rec urre nce.
3. 1 0. 3. 2. S af et y A n al y si s
All patie nts w h o recei ve at least 1 d ose of a n y st u d y t hera p y will be e val uate d f or safet y a n d 
t o xicit y.
Refer t o t he C A M P FI R E Master Pr ot oc ol Secti o n 1 0. 3. 1 f or a d ditio nal safet y a nal ysis.
3. 1 0. 3. 3. Ot h er A n al y si s
3. 1 0. 3. 3. 1. P h ar m a c o ki n eti c /I m m u n o g e ni cit y A n al y s e s
S er u m  c o nce ntratio ns of  st u d y dr u g (ra mu ci r u ma b) prior t o i nf usi o n (tr o u g h c o nce ntrati o n) a n d 
at t he e n d of t he i nf usi o n (a p pr o xi matel y pea k c o nce ntrati o n) will be s u m marize d usi n g 
descri pt i ve statistics.  A d diti onal a nal ysis ut ilizi 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 ra m ucir u ma b e x p os ure a n d meas ures 
of  efficac y a n d safety will be e x pl ore d.  Details will be descri be d i n t he S A P.
I mm u n o ge nicit y i nci de nce will be ta b ulate d, a n d c orrelati o n of i m m u n o ge nicit y t o ra mucir u ma b 
dr u g l e vel, acti vit y, a n d safet y will  be assesse d as a p pr o priate.
3. 1 0. 3. 3. 2. Bi o m ar k er A n al y s e s
Bi o m ar kers rele va nt t o ra m ucir u ma b, mec ha nis m of acti o n of ra m ucir u ma b, t he varia ble 
res p o nse t o st u d y dr u g(s), i m m u ne f u ncti on, a n gi o ge nesis, a n d pat h wa ys ass ociate d wit h ca ncer 
will be a nal yze d f or ass ociat i on wi t h disease state a n d cli nical o utc o mes.   
3. 1 0. 3. 4. S u b gr o u p A n al y si s
A pres pecifie d list of s u b gr o u ps will be i de nt ifie d i n t he S A P a n d will i ncl u de (at a mi ni m u m) a 
c o mparis o n bet wee n a d ults a n d pe diatrics wit h res pect t o certai n safet y a n d efficac y meas ures.  
T he treat me nt effect wit hi n eac h s u b gr o u p w ill be s u m marize d.  Ot her s u b gr o u p a nal yses n ot 
s pecifie d i n t he S A P ma y be perf or me d as dee me d a p pr o priate.  T hese s u b gr o u ps will be base d 
o n i m p orta nt c haracterist ics, f or e xa m ple, pr o g n ostic si g nifica nce.
J V 0 2 0 5 Pr ot oc ol A d de n da ( g). p df | V V- T M F- 4 2 9 2 2 1 7 | 1. 0
Fi nal
P P D

J 1 S -M C -J V 0 2( g) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 6 7
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
3. 1 0. 3. 5. I nt eri m A n al y si s
Data will be re vie we d o n a n o n g oi n g basis d uri n g t he safet y lea d-i n peri o d t o i nf or m t he 
r olli n g-si x decisi on r ules.
A n i nteri m f ut ility a nal ysis will be tri g gere d w he n a p pr o xi matel y 2 4 t otal P F S e ve nts ha ve bee n 
o bser ve d acr oss St u d y  J V 0 1 a n d St u d y J V 0 2 wit h a mi ni m u m of 8 e ve nts i n eac h st u d y. At  t he 
i nteri m f utilit y l oo k, t he Ba yesia n of P F S a nal ysis m ust pr o vi de a mi ni m u m of 6 0 % p osteri or 
pr o ba bilit y o f s u periori t y ( P F S H R < 1 f or S S patie nts) i n or der f or e nr oll me nt o n St u d y J V 02 t o 
c o nti n ue. Ot her wise, e nr o ll me nt o n St u d y J V 02 will be st o p pe d.
I n or der t o mi ni mize t he o perati o nal a n d statistical bias t hat res ult fr o m perf or mi n g a n i nteri m 
a nal ysis, t he i nteri m a nal yses f or t his st u d y will be c o n d ucte d u n der t he a us pices of a n 
I n de pe n de nt Data M o nit ori n g C om mittee (I D M C).  T he p ur p os e of t he I D M C is t o a d vise Lill y 
re gar di n g t he c o nti n ui n g safety of  st u d y participa nts a n d t he c o nti n ui n g vali dit y a n d scie nt ific 
merit of t he trial.  Details of t he I D M C are pr o vi de d i n t he I D M C c harter.
J V 0 2 0 5 Pr ot oc ol A d de n da ( g). p df | V V- T M F- 4 2 9 2 2 1 7 | 1. 0
Fi nal
P P D

J 1 S -M C -J V 0 2( g) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 6 8
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
4. R ef er e n c e s
A b o u har b S, War ne ke C, Ra vi V, L u d wi g J A, Lazar
AJ F, Patel S, Be nja mi n R S, Ara uj o D M.
2 0 1 4 S y n o vial sarc o ma: E val uat i on of res p o nse t o treat me nt wit h ge mci ta bi ne a n d d oceta xel. J 
Cli n O nc ol . 2 0 1 4; 3 2: 1 5 _s u p pl, 1 0 5 6 4- 1 0 5 6 4.
Bart y ns ki W S, B oar d ma n J F. Dist i nct i ma gi n g patter ns a n d lesi on distri b u tio n i n p osteri or 
re versi ble e nce p hal o pat h y s y n dr ome. A m J Ne ur or a di ol . 2 0 0 7; 2 8( 7): 1 3 2 0- 1 3 2 7.
Bart y ns ki W S. P osteri or re versi ble e nce p hal o pat h y s y n dr o me, part 2: c o ntr o versies s urr o u n di n g 
pat h o p h ysi o l og y  of vas o ge nic e de ma. A m J Ne ur or a di ol . 2 0 0 8; 2 9( 6): 1 0 4 3 -1 0 4 9.
Bl a n n A D, Li J L, Li C, K u mar S. I ncrease d ser u m V E G F i n 1 3 c hil dre n wit h Wil ms' t u m o ur 
falls after s ur ger y b ut risi n g le vels pre dict p o or pr o g n osis. C a ncer Lett . 2 0 0 1; 1 7 3( 2): 1 8 3-1 8 6.
Car m eliet P, Jai n R K. M olec ular mec ha nis ms a n d cli n ical a p plicati ons of a n gi o ge nesis. N at ure . 
2 0 1 1; 4 7 3( 7 3 4 7): 2 9 8 - 3 0 7.
C he n H X, Clec k J N. A d verse effects of a nt ica ncer a ge nts t hat tar get t he V E G F pat h wa y. N at Rev 
Cli n O nc ol . 2 0 0 9; 6( 8): 4 6 5- 4 7 7.
C his h o l m J C, Mer ks J H M, Casa n o va M, Bis o g n o G 4 Or bac h D, Ge ntet J C, 
T h o massi n -Defac helles A S, C hasta g ner P, L o wis S, R o n g he M, Mc H u g h K, va n Rij n R R, 
Hilt o n M, Bac hir J, F ürst -Rec kte n wal d S, Ge oer ger B, O berli n O; E ur o pea n pae diatric S oft 
tiss ue sarc oma St u d y Gr o u p ( E p S S G) a n d t he E ur o pea n I n n o vati ve T hera pies f or C hil dre n 
wi t h Ca ncer (I T C C) C o ns orti u m. O pe n-la bel, mul tice ntre, ra n d o mise d, P hase II st u d y of t he 
E p S S G a n d t he I T C C e val uat i n g t he a d diti on of be vaciz u ma b t o c he m ot hera p y i n c hil d h o o d 
a n d a d o lesce nt patie nts wit h metastatic s oft tiss ue sarc o ma (t he B E R NI E stu d y). E ur J C a ncer . 
2 0 1 7; 8 3: 1 7 7 - 1 8 4.
Cl o p per CJ, Pears o n E S. T he Use of C o nfi de nce or Fi d ucial Li mits Ill ustrate d i n t he Case of t he 
Bi n o mial. Bi o metrik a . 1 9 3 4; 2 6( 4): 4 0 4-4 1 3.
De Vi ta V T, Y o u n g R C, Ca nell os G P. C o m bi nati on vers us si n gle a ge nt c he m ot hera p y : a re vie w 
of  t he basis f or selecti on of dr u g treat me nt of ca ncer. C a ncer . 1 9 7 5; 3 5( 1): 9 8-1 1 0.
Di c ks o n M A, D' A da m o D R, Ke o ha n M L, D' A n gel o S P, Car vajal R D, G o u n der M M, Ma ki R G, 
Qi n L X, Lef k o witz R A, Mc Ke n n o n O R, Hirst C M, Sc h wartz G K, Ta p W D.  P hase II Trial o f 
G e m cita bi ne a n d D oceta xel wit h Be vaciz u ma b i n S oft Tiss ue Sarc oma. S arc o m a . 
2 0 1 5; 2 0 1 5: 5 3 2 4 7 8.
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 y t her S, M o o ne y M, R u bi nstei n L, S ha n kar L, D o d d L, Ka pla n R, Lac om be D, Ver weij J. 
Ne w res p o nse e val uat i on cri teria i n s oli d t u m o urs: re vise d R E CI S T g ui deli ne ( versi on 1. 1). 
E ur J C a ncer . 2 0 0 9; 4 5( 2): 2 2 8- 2 4 7.
Ellis L M, Hic kli n DJ. V E G F- tar gete d t hera p y: mec ha nis ms of a nt i-t u mo ur acti vit y. N at Rev 
C a ncer . 2 0 0 8; 8( 8): 5 7 9- 5 9 1.
Ferrari  A, De Sal v o G L, Dall’I g na P, Meazza C, De Le o nar dis F, Ma nzitti C, de I oris M A, 
Casa n o va M, Carli M, Bis o g n o G. Sal va ge rates a n d pr o g n ostic fact ors after rela pse i n 
c hil dre n a n d a d o lesce nts wit h init iall y localize d s y n o vial  s ar c o ma. E ur J C a ncer . 
2 0 1 2; 4 8( 1 8): 3 4 4 8 – 3 4 5 5.
J V 0 2 0 5 Pr ot oc ol A d de n da ( g). p df | V V- T M F- 4 2 9 2 2 1 7 | 1. 0
Fi nal
P P D

J 1 S -M C -J V 0 2( g) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 6 9
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
Ferrari  A, De Sal v o G L, Bre n na n B, va n N oesel M M, De Pa oli A, Casa n o va M, Fra nc otte N, 
Kelse y  A, Ala g gio R, O berli n O, Carli M, Be n -Ar us h M, Ber ger o n C, Mer ks J H, Je n ne y M, 
Ste ve ns M C, Bis o g n o G, Or bac h D. S y n o vial sarc o ma i n c hil d re n a n d a d olesce nts: t he 
E ur o pea n Pe diatric S oft Tiss ue Sarc o ma St u d y  Gr o u p pr os pecti ve trial ( E p S S G N R S T S 2 0 0 5). 
A n n O nc ol . 2 0 1 5; 2 6( 3): 5 6 7-5 7 2.
Fisc her M, Sc h m utz har d E. P osteri or re versi ble e nce p hal o pat h y  s y n dr o me. J Ne ur ol.
2 0 1 7; 2 6 4( 8): 1 6 0 8 - 1 6 1 6.
F o x E, A p lenc R, Ba gatell R, C h u k M K, D o m bi E, G o o ds pee d W, G o o d wi n A, Kr o m ple ws ki M, 
Ja ya pra kas h N, Mar otti M, Br o w n K H, We nric h B, A da ms o n P C, Wi de ma n n B C, Balis F M. A 
P hase 1 trial a n d p har mac o ki net ic st u d y of ce dira ni b, a n orall y bi oa vaila ble pa n– vasc ular 
e nd ot helial gr o wt h fact or rece pt or i n hi bit or, i n c hil dre n a n d a d olesce nts wit h refract or y  s oli d 
t u mors. J Cli n O nc ol. 2 0 1 0; 2 8( 3 5): 5 1 7 4-5 1 8 1.
F uc hs C S, T o mase k J, Y o n g CJ, D u mitr u F, Passalac q ua R, G os wa mi C, Safra n H, d os 
Sa nt os L V, A prile G, Ferr y D R, Melic har B, Te hfe M, T o p uz o v E, Zalc ber g J R, C ha u I, 
Ca m p bell W, Si va na n da n C, Pi kiel J, K os hiji M, Hs u Y, Lie pa A M, Ga o L, Sc h wartz J D, 
Ta ber ner o J; R E G A R D Trial I n vesti gat ors. Ra m ucir u ma b m o n ot hera p y  for pre vi o usl y treate d 
a d va nce d gastric or gastr o -oes o p ha ge al ju n cti o n a de n ocarci n o m a ( R E G A R D): a n 
i nter nat i onal, ra n d o mise d, m ult ice nter, place b o-c o ntr olle d, P hase 3 tri al. L a ncet . 
2 0 1 4; 3 8 3( 9 9 1 1): 3 1 - 3 9.
F u gate J E, Ra bi nstei n A A. P osteri or re versi ble e nce p hal o pat h y s y n dr o me: cli nical a n d 
r a diol o gical  ma nifestatio n s, pat h o p h ysiol o g y, a n d o utsta n di n g q uest i ons. L a ncet Ne ur ol . 
2 0 1 5; 1 4( 9): 9 1 4 - 9 2 5.
Gar o n E B, Ci ulea n u T E, Arri eta O, Pra b has h K, S yri g os K N, G o ksel T, Par k K, G or b u n o va V, 
K o wal ysz y n R D, Pi kiel J, Cz yze wicz G, Orl o v S V, Le wa ns ki C R, T h o mas M, Bi d o li P, 
Da k hil S, Ga ns S, Ki m J H, Gri g oresc u A, Karase va N, Rec k M, Ca p p uzz o F, Ale xa n dris E, 
Sas he g yi A, Y uras o v S, Pér ol M. Ra m ucir u ma b pl us d oceta xel vers us place b o pl us d oceta xel 
f or sec o n d-li ne treat me nt of sta ge I V n o n-s mall-c ell lu n g ca ncer after disease pr o gressi o n o n 
pl at i n u m-base d t hera p y  ( R E V E L): a mul tice ntre, d o u ble-bli n d, ra n d o mise d P hase 3 tri al. 
L a ncet . 2 0 1 4; 3 8 4( 9 9 4 4): 6 6 5-6 7 3.
Ge or ge S, Merria m P, Ma ki R G, Va n de n A b beele A D, Ya p J T, A k h urst T, Har m o n D C, 
B h uc har G, O’ Mara M M, D’ A da m o D R, M or ga n J, Sc h warz G K, Wa g ner AJ, B utr y ns ki J E, 
D e m etri G D, Ke o ha n M L. M ultice nter P hase II trial of  s u nitini b i n t he treat m e nt of 
n o n gastr oi ntesti nal str o mal t u m or sarc o mas. J Cli n O nc ol. 2 0 0 9; 2 7( 1 9): 3 1 5 4- 3 1 6 0.
Gl a de Be n der J L, Lee A, Rei d J M, Bar uc hel S, R o berts T, V oss S D, W u B, A her n C H, 
I n gle A M, Harris P, Wei gel BJ, Bla ne y S M. P hase I p har mac o ki net ic a n d p har mac o d y na mic 
st u d y of paz o pa ni b i n c hil dre n wit h s oft tiss ue sarc o ma a n d ot her refract or y s oli d t u m ors: a 
C hil dre n’s O nc o l og y  Gr o u p P hase I c o ns orti u m re p ort. J Cli n O nc ol. 2 0 1 3; 3 1( 2 4): 3 0 3 4-3 0 4 3.
He nsle y M L, Blessi n g J A, De geest K, A b ulafia O,
R ose P G, H o mesle y H D. Fi xe d -d ose rate 
g e m cita bi ne pl us d oceta xel as sec o n d-li ne t hera p y f or metastatic uteri ne lei om y os arc o ma: a 
G y nec o l ogi c O n c olo g y  Gr o u p P hase II st u d y. Gy nec ol O nc ol . 2 0 0 8a; 1 0 9( 3): 3 2 3-3 2 8.
J V 0 2 0 5 Pr ot oc ol A d de n da ( g). p df | V V- T M F- 4 2 9 2 2 1 7 | 1. 0
Fi nal
P P D

J 1 S -M C -J V 0 2( g) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 7 0
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
He nsle y  M L, Blessi n g J A, Ma n nel R, R ose P G. Fi xe d - d ose rate ge mcita bi ne pl us d oceta xel as 
first-li ne t hera p y f or metastatic uteri ne lei om y os arc o ma: a G y nec olo gi c O nc olo g y  Gr o u p 
P hase II trial. Gy nec ol O nc ol . 2 0 0 8 b; 1 0 9( 3): 3 2 9-3 3 4.
Hi nc he y J, C ha ves C, A p pi g na ni B, Bree n J, Pa o L, Wa n g A, Pessi n M S, La m y C, Mas J L, 
Ca pla n L R. A re versi ble p osteri or le u k oe nce p hal o pat h y  s y n dr o me. N E n gl J Me d . 
1 9 9 6; 3 3 4( 8): 4 9 4 - 5 0 0.
Hi n g ora ni P, Es h u n F, W hite -C o lli ns A, Wata na be M. Ge mcita bi ne, d oceta xel, a n d be vaciz u ma b 
i n rela pse d a n d refract or y pe diatric sarc o mas. J Pe diatr He m at ol O nc ol . 2 0 1 2; 3 4( 7): 5 2 4- 5 2 7.
H ol zer G, O ber mair A, K osc hat M, Pre yer O, K otz R, Trie b K. C o nce ntratio n of  vasc ular 
e n d ot helial gr o wt h fact or ( V E G F) i n t he ser u m of patie nts wit h mali g na nt b o ne t u m ors. Me d 
Pe di atr O nc ol . 2 0 0 1; 3 6( 6): 6 0 1- 6 0 4.
I bra hi m J G, et al. T he p o wer pri or: t he or y a n d a p plicati ons. St at Me d . 2 0 1 5; 3 4( 2 8): 3 7 2 4- 3 7 4 9.
Ka pla n E L, Meier P. N o n para metric esti mat i on of i nc o m p lete o bser vati ons. J A mer St at Ass oc . 
1 9 5 8; 5 3: 4 5 7 - 4 8 1.
K ni g ht Z A, Li n H, S h o kat K M. Tar geti n g t he ca ncer ki n o m e t hr o u g h p ol y p har mac ol o g y. 
N at Rev C a ncer . 2 0 1 0; 1 0( 2): 1 3 0-1 3 7.
K u o C, Ke nt P M, L o ga n A D, Ta m ul o nis K B, Dalt o n K L, Bat us M, Fer na n dez K, Mcfall
R E. 
D oceta xel, be vaciz u ma b, a n d ge mcita bi ne f or ver y hi g h ris k sarc o mas i n a d olesce nts a n d 
y o u n g a d ul ts: A si ngle -ce nter e x perie nce. Pe di atr Bl o o d C a ncer . 2 0 1 7; 6 4( 4):e 2 6 2 6 5.
Lee V H, Wij dic ks E F, Ma n n o E M, Ra bi nstei n A A. Cli nical s pectr u m of re versi ble p osteri or 
le u k oe nce p hal o pat h y s yn dr o m e. Arc h Ne ur ol . 2 0 0 8; 6 5( 2): 2 0 5- 2 1 0.
Ma ki  R G, Wat he n J K, Patel S R, Prie bat D A, O k u n o S H, Sa m uels B, Fa n ucc hi M, Har m o n D C, 
Sc h uetze S M, Rei n ke D, T hall P F, Be nja mi n R S, Ba ker L H, He nsle y M L. Ra n d o mize d P h ase
II st u d y of ge mcita bi ne a n d d oceta xel c o mpare d wi t h ge mcita bi ne alo n e i n pat ient s with 
metastati c s oft tiss ue sarc o mas: res ults of Sarc o ma Allia nce f or Researc h T hr o u g h 
C olla b orati o n St u d y  0 0 2. J Cli n O nc ol. 2 0 0 7; 2 5( 1 9): 2 7 5 5- 2 7 6 3.
Ma ki  R G, D’ A da mo D R, Ke o ha n M L, Sa ulle M, Sc h uetze S M, U n de via S D, Li vi n gst o n M B, 
C o o ne y  M M, He nsle y M L, Mit a M M, Ta ki m ot o C H, Kraft A S, Elias A D, Br oc kstei n B, 
Bl ac hère N E, E d gar M A, Sc h wartz L H, Qi n L -X, A nt o nesc u C R, Sc h wartz G K. P hase II st u d y  
of  s orafe ni b i n patient s wit h metastatic or rec urre nt sarc o mas. J Cli n O nc ol. 
2 0 0 9; 2 7( 1 9): 3 1 3 3 - 3 1 4 0.
[ N C C N] Nati o nal C o m pre he nsi ve Ca ncer Net w or k. N C C N g ui deli nes. 2 0 1 5. A vaila ble at: 
ht t p:// w w w. ncc n. or g/ pr ofessi onals/ p h ysicia n _ gls/f _ g ui deli nes.as p. Accesse d Oct o ber 2 7, 
2 0 1 5.
[ N CI] Nati o nal Ca ncer I nstit ute. Ca ncer T hera p y E val uati on Pr o gra m , C o m mo n  Ter mi n ol og y  
Cri teria f or A d verse E ve nts, Versi o n 5. 0, D C T D, N CI, NI H, D H H S. 2 0 1 7. P u blis he d 2 7 
N o ve m ber 2 0 1 7.
[ N H B P E P W G] Nati o nal Hi g h Bl o o d Press ure E d ucati o n Pr o gra m W or ki n g Gr o u p o n Hi g h 
Bl o o d Press ure i n C hil dre n a n d A d olesce nts. T he f o urt h re p ort o n t he dia g n osis, e val uat i on, 
a n d treat me nt of hi g h bl o o d press ure i n c hil dre n a n d a d olesce nts. Pe di atrics . 2 0 0 4; 1 1 4(s u p pl 2 
4t h Re p ort): 5 5 5 -5 7 6.
J V 0 2 0 5 Pr ot oc ol A d de n da ( g). p df | V V- T M F- 4 2 9 2 2 1 7 | 1. 0
Fi nal
P P D

J 1 S -M C -J V 0 2( g) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 7 1
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
O ke n M M, Creec h R H , T or m e y D C, H ort o n J , Da vis T E, Mc Fa d de n E T, Car b o ne P P. T o xi cit y 
a n d res p o nse criteria of t he Easter n C o o perati ve O nc o l og y  Gr o u p. A m J Cli n O nc ol . 
1 9 8 2; 5: 6 4 9 - 6 5 5.
Pl u m mer M. J A G S Versi o n 4. 3. 0 user ma n ual. 2 0 1 7.
Ri zz o J D, Br o u wers M, H urle y P, S eide nfel d J, Arcas o y  M O, S pi va k J L, Be n nett C L, B o hli us J, 
E va nc h u k D, G o o de MJ, Ja k u b o ws ki A A, Re ga n D H, S o merfiel d M R; A meri ca n S ociet y of  
Cli nical O nc o l og y; A merica n S ociet y of  He mat olo g y . A merica n S ociety of  Cli nical 
O nc o l og y / A merica n S ociet y of  He mat olo g y  cli nical practice g uideli ne u p date o n t he use of 
e p oeti n a n d dar be p oeti n i n a d ult pat ient s wit h ca ncer. J Cli n O nc ol. 2 0 10; 2 8( 3 3): 4 9 9 6 -5 0 1 0. 
Sa w y ers C. Tar gete d ca ncer t hera p y. N at ure . 2 0 0 4; 4 3 2( 7 0 1 5): 2 9 4- 2 9 7.
Se d d o n B, Sc urr M, J o nes R L, W o o d Z, Pr o pert- Le wis C, Fis her C, Fla na ga n A, S u n kersi n g J, 
A' Her n R, W hela n J, J u ds o n I. A P hase II trial t o assess t he acti vit y of ge mc ita bi ne a n d 
d oceta xel as first li ne c he m ot hera p y treat me nt i n patie nts wit h u nresecta ble lei o m y os ar c o m a.
Cli n S arc o m a Res . 2 0 1 5; 5: 1 3.
S k ol ni k J M 1, Barrett J S, Ja y ara ma n B, Patel D, A da ms o n P C. S h orte ni n g t he ti meli ne o f 
pe di atric P hase I trials: t he r olli n g si x desi g n. J Cli n O nc ol. 2 0 0 8; 2 6( 2): 1 9 0- 1 9 5.
Sl eijfer S, Ra y-C o q uar d I, Pa pai Z, Le Ces ne A, Sc urr M, Sc h öffs ki P, C olli n F, Pa n dite L, 
Marrea u d S, De Bra u wer A, v o n Gla b be ke M, Ver weij J, Bla y J -Y. Paz o pa ni b, a m ul tiki nase 
a n gi o ge nesis i n hi bit or, i n patie nts wit h rela pse d or refract or y a d va nce d s oft tiss ue sarc oma: a 
P hase II st u d y  fr o m t he E ur o pea n Or ga nisati o n f or Researc h a n d Treat me nt of Ca ncer– S of t 
Tiss ue a n d B o ne Sarc o ma Gr o u p ( E O R T C St u d y  6 2 0 4 3). J Cli n O nc ol. 2 0 0 9; 2 7( 1 9): 3 1 25-
3 1 3 2.
S m ith TJ, K hatc heressia n J, L y ma n G H, Ozer H, Ar mita ge J O, Bal d ucci L, Be n nett C L, 
Ca nt or S B, Cra wf or d J, Cr oss SJ, De metri G, Desc h C E, Pizz o P A, Sc hiffer C A, Sc h wartz ber g 
L, S o m erfiel d M R, S o ml o G, Wa de J C, Wa de J L, Wi n n RJ, W oz nia k AJ, W olff A C. 2 0 0 6 
u p date of rec o m me n dat i ons f or t he use of w hite bl o o d cell gr o wt h fact ors: a n e vi de nce-base d 
cli nical practice g ui deli ne. J Cli n O nc ol. 2 0 0 6; 2 4( 1 9): 3 1 8 7- 3 2 0 5.
S o ol e F, Ma u pai n C, Defac helles A S, Ta q ue S, Mi nar d- C o li n V, Ber ger o n C, De R yc ke Y, 
Or bac h D. S y n o vial sarc o ma rela pses i n c hil dre n a n d a d o lesce nts: pr o g n ostic fact ors, 
treat me nt, a n d o utc o me. Pe di atr Bl o o d C a ncer . 2 0 1 4; 6 1( 8): 1 3 8 7- 1 3 9 3.
Sta nelle EJ, C hrist is on- La ga y  E R, Heale y J H, Si n ger S, Me yers P A, La Q ua glia M P. Pe diatric 
a n d a d o lesce nt s y n ovial sarc o ma: m ult i variate a nal ysis of pr o g n osti c fact ors a n d s ur vi val 
o utc o m es. A n n S ur g O nc ol . 2 0 1 3; 2 0( 1): 7 3- 7 9.
St ott V L, H urrell M A, A n ders o n TJ. Re versi ble p osteri or le u k oe nce p hal o pat h y s y n dr o me: a 
mis n o mer re vie we d. I nt Me d J. 2 0 0 5; 3 5( 2): 8 3-9 0.
Ta ber ner o J, Y os hi n o T, C o h n A L, O ber ma n n o va R, B o d o k y  G, Garcia- Car b o ner o R, 
Ci ulea n u T E, P ort n o y  D C, Va n C utse m E, Gr ot he y A, Pra us o vá J, Garcia- Alf o ns o P, 
Y a m a z a ki K, Cli n ga n P R, L o nar di S, Ki m T W, Si m ms L, C ha n g S C, Nasr o ula h F; R AI S E 
St u d y  I n vesti gat ors. Ra mucir u ma b vers us place b o i n c o m bi nat i on wi t h sec o n d-li ne F O L FI RI 
i n patie nts wit h metastatic c ol orectal carci n oma t hat pr o gresse d d uri n g or after first -li ne 
J V 0 2 0 5 Pr ot oc ol A d de n da ( g). p df | V V- T M F- 4 2 9 2 2 1 7 | 1. 0
Fi nal
P P D

J 1 S -M C -J V 0 2( g) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 7 2
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
t hera p y wit h be vaciz u ma b, o xali plat i n, a n d a fl u or o p yrimi di ne ( R AI S E): a ra n d o mise d, 
d o u bl e- bli n d, m ult ice ntre, P hase 3 st u d y . L a ncet O nc ol . 2 0 1 5; 1 6( 5): 4 9 9-5 0 8.
Taji ma Y, Is o nis hi K, Kas hi wa ba T, Tas hir o K. T w o si milar cases o f e nce p hal o pat h y, p ossi bl y a 
re versi ble p osteri or le u k oe nce p hal o pat h y s yn dr o me: serial fi n di n gs of ma g net ic res o na nce 
i ma gi n g, SP E C T a n d a n gi o gra p h y. I nter n Me d. 1 9 9 9; 3 8( 1): 5 4- 5 8.
T e m per o M, Pl u n kett W, R ui z Va n Ha pere n V, Hai ns w ort h J, H oc hster H, Le nzi R, 
A b br uzzese J. Ra n d omize d P hase II c o mparis o n of d ose -i nte nse ge mcita bi ne: t hirt y- mi n ute 
i nf usi on a n d fi xe d d ose rate i nf usi o n i n patient s wit h pa ncreatic a de n ocarci n oma. J Cli n O nc ol. 
2 0 0 3; 2 1( 1 8): 3 4 0 2 - 3 4 0 8.
va n der Graaf W T A, Bla y  J-Y, C ha wla S P, Ki m D -W, B ui -N g u ye n B, Casali P G, Sc h ö ffs ki P, 
A g lietta M, Sta d d o n A P, Be p p u Y, Le Ces ne A, Gel der bl om H, J u ds o n I R, Ara ki N, O uali M, 
Marrea u d S, H o d ge R, De wji M R, C oe ns C, De metri G D, Fletc her C D, Dei T os A P, 
H o he n ber ger P. Paz o pa ni b f or metastatic s o ft-tiss ue sarc o ma ( P A L E T T E): a ra n d o mise d, 
d o u bl e- bli n d, place b o -c o ntr olle d P hase 3 trial. L a ncet . 2 0 1 2; 3 7 9( 9 8 2 9): 1 8 7 9-1 8 8 6.
Versc hrae ge n C F, Arias -P uli d o H, Lee SJ, M o v va S, Cerilli L A, E ber har dt S, Sc h mit B, Q ui n n 
R, M uller C Y, Ra bi n o witz I, P ur d y  M, S n y der D, B oc kla ge T.  P hase I B st u d y of t he 
c o m bi nat i on of d oceta xel, ge mcita bi ne, a n d be vaciz u ma b i n pat ient s wit h a d va nce d or
rec urre nt s oft tiss ue sarc oma: t he A xtell re gi me n.  A n n O nc ol . 2 0 1 2; 2 3( 3): 7 8 5-7 9 0.
Wa ka mats u T, Na ka N, Sasa ga wa S, Ta na ka T, Ta ke na ka S, Ara ki N, Ue da T, Nis hiza wa Y, 
Y os hi ka wa H, It o h K. Deflect i on of vasc ular e n d ot helial gr o wt h fact or acti o n b y S S 1 8 -S S X 
a n d c o m p osite vasc ular e n d ot helial gr o wt h fact or - a n d c he m o ki ne ( C- X-C m otif ) recept or 4 -
tar gete d t hera p y in s y n ovial sarc o ma. C a ncer Sci. 2 0 1 4; 1 0 5( 9): 1 1 2 4 - 3 4.
Wil ke H, M ur o K, Va n C utse m E, O h S C, B o d o k y G, S hi ma da Y, Hir o na ka S, S u gi m ot o N, 
Li pat o v O, Ki m  T Y, C u n ni n g ha m D, R o u gier P, K o mats u Y, Aja ni J, E mi g M, Carlesi R, 
Ferr y  D, C han dra wa nsa K, Sc h wartz J D, O hts u A; R AI N B O W St u d y  Gr o u p. Ra mu ci r u ma b 
pl us paclita xel vers us place b o pl us paclita xel i n patie nts wit h pre vi o usl y treate d a d va nce d 
gastri c or gastr o -oes o p ha geal j u nct i on a de n ocarci n o ma ( R AI N B O W): a d o u ble -bli n d, 
ra n d omise d P h ase 3 tri al. L a ncet O nc ol . 2 0 1 4; 1 5( 1 1): 1 2 2 4- 1 2 3 5.
J V 0 2 0 5 Pr ot oc ol A d de n da ( g). p df | V V- T M F- 4 2 9 2 2 1 7 | 1. 0
Fi nal
P P D

J 1 S -M C -J V 0 2( g) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 7 3
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
At t a c h m e nt 1.
Pr ot o c ol J V 0 2 A d d e n d u m A b br e vi ati o n s 
a n d D efi niti o n s
T he List of a b bre viat i ons a n d defi nit i ons f ou n d i n t he St u d y J V 0 2 A d de n d u m are i ncl u de d 
bel o w.
T er m
D efi niti o n
5- H T 3
5 h y dr o x y tr ypta mi ne 3
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 
patie nt a d mi nistere d a p har mace utical pr o d uct a n d 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 h et her or n ot relate d t o t he me dici nal (i n vesti gati o nal) pr o d uct.
A E SI
a d verse e ve nt of s pecial i nterest
A L P
al kali ne p h os p hatase
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 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 T E
arterial t hr o m b oe m b olic e ve nt
B P
bl o o d press ure
C H F
c o n gesti ve heart fail ure
CI
c o nfi de nce i nter val
C m a x
ma xi m u m c o nce ntrati o n
C mi n
mi ni m u m c o nce ntrati o n
C N S
ce ntral ner v o us s yste m
C O G
C hil dre n’s O nc ol o g y Gr o u p
c oll e cti o n d at a b a s e
A c o m p uter data base w here cli nical st u d y data are e ntere d a n d vali date d.
C R
c o m plete res p o nse
C R F
case re p ort f or m
J V 0 2 0 5 Pr ot oc ol A d de n da ( g). p df | V V- T M F- 4 2 9 2 2 1 7 | 1. 0
Fi nal
P P D

J 1 S -M C -J V 0 2( g) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 7 4
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
C R P
cli nical researc h p h ysicia n:  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 ma y be perf or me d b y a p h ysicia n, cli nical researc h 
scie ntist, gl o bal safet y p h ysicia n, or ot her me dical officer.
C R S
Cli nical Researc h Scie ntist
C T
c o m p ute d t o m o gra p h y
C T C A E
C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts
C V A
cere br o vasc ular acci de nt
C Y P
c yt oc hr o me P 4 5 0
D L T
d ose -li miti n g t o xicit y
D S R C T
des m o plastic s mall r o u n d cell t u m or
E C G
electr ocar di o gra m
E C O G
Easter n C o o perati ve O nc ol o g y Gr o u p
e C R F
electr o nic case re p ort f or m
e n d of st u d y
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 Sc he d ule of Acti vities 
( Secti o n 3. 5. 3 ) f or t he last patie nt.
e nr oll
T he act of assi g ni n g a patie nt t o a treat me nt.  Patie 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
Patie 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
E U
E ur o pea n U ni o n
F O C B P
fe males of c hil d beari n g p ote ntial
G- C S F
gra n ul oc yte -c ol o n y sti m ulati n g fact or
G E J
gastr oes o p ha geal j u ncti o n
GI
gastr oi ntesti nal
G G T
ga m ma -gl uta m yl tra nsferase
H R
hazar d rati o
H S R
h y perse nsiti vit y reacti o n
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
J V 0 2 0 5 Pr ot oc ol A d de n da ( g). p df | V V- T M F- 4 2 9 2 2 1 7 | 1. 0
Fi nal
P P D

J 1 S -M C -J V 0 2( g) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 7 5
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
i nt eri m a n al y si s
A n a nal ysis of cli nical st u d y data c o n d ucte d bef ore t he fi nal re p orti n g data base is 
create d/l oc ke d.
I R B
i nstit uti o nal re vie w b oar d
I R R
i nf usi o n-relate d reacti o n
I T T
i nte nti o n-t o-treat:  T he pri nci ple t hat asserts t hat t he effect of a treat me nt p olic y ca n be 
best assesse d b y e val uati n g o n t he basis of t he i nt e n ti o n t o treat a patie nt (i e, t he 
pla n ne d treat me nt re gi me n) rat her t ha n t he act ual treat me nt gi ve n.  It has t he 
c o nse q ue nce t hat patie nts all ocate d t o a treat me nt gr o u p s h o ul d be f oll o we d u p, 
assesse d, a n d a nal yze d as me m bers of t hat gr o u p irres pecti ve o f t heir c o m plia nce t o t he 
pla n ne d c o urse of treat me nt.
I W R S
i nteracti ve We b -res p o nse s yste m
L L T
Me d D R A L o wer Le vel Ter m
m A b
m o n ocl o nal a nti b o d y
M e d D R A
Me dical Dicti o nar y f or Re g ulat or y Acti vities
M RI
ma g netic res o na nce i ma gi n g
N CI C T C A E
Nati o nal Ca ncer I nstit ute C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts
N S AI D
n o nster oi dal a nti -i nfla m mat or y dr u g
N S C L C
n o n- s mall cell l u n g ca ncer
O S
o verall s ur vi val
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 R
partial res p o nse
P R E S
p osteri or re versi ble e nce p hal o pat h y s y n dr o me
P T
Me d D R A Preferre d Ter m
Q 2 W
e ver y t w o wee ks
Q 3 W
e ver y t hree wee ks
r a n d o mi z e
T he pr ocess of assi g ni n g patie nts t o a n e x peri me ntal gr o u p o n a ra n d o m basis.
R E CI S T
Res p o nse E val uati o n Criteria i n S oli d T u m ors
J V 0 2 0 5 Pr ot oc ol A d de n da ( g). p df | V V- T M F- 4 2 9 2 2 1 7 | 1. 0
Fi nal
P P D

J 1 S -M C -J V 0 2( g) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 7 6
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
r e p orti n g d at a b a s e
A p oi nt -i n-ti me c o p y of t he c ollecti o n data base.  T he fi nal re p orti n g data base is use d t o 
pr o d uce t he a nal yses a n d o ut p ut re p orts f or i nteri m or fi nal a nal yses of data.
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 A P
statistical a nal ysis pla n
S O C
Me d D R A S yste m Or ga n Class
S S
s yn o vial sarc o ma
st u d y c o m pl eti o n
Occ urs f oll o wi n g t he fi nal a nal ysis of pr o gressi o n -free s ur vi val, as deter mi ne d b y Lill y.
TI A
tra nsie nt isc he mic attac k
U L N
u p per li mit of n or mal
U P C
uri ne pr otei n t o creati ni ne
V E G F
vasc ular e n d ot helial gr o wt h fact or
V H P
V ol u ntar y Har m o nizati o n Pr oce d ure ( partici pati n g c o u ntries i ncl u de: Bel gi u m, 
Ger ma n y P EI, Ital y, Net herla n ds, a n d S pai n)
V T E
ve n o us t hr o m b oe m b olic e ve nt
J V 0 2 0 5 Pr ot oc ol A d de n da ( g). p df | V V- T M F- 4 2 9 2 2 1 7 | 1. 0
Fi nal
P P D

J 1 S -M C -J V 0 2( g) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 7 7
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
At t a c h m e nt 2.
Pr ot o c ol J V 0 2 A d d e n d u m Cli ni c al 
L a b or at or y  T e st s
Cli nic al L a b or at or y Tests
He m at ol o g y – la b orat or ya
L oc al
Ce ntr al
Le u k oc ytes ( W B C)
x
Ne utr o p hils b
x
L y m p h oc y t es
x
M o n oc ytes
x
E osi n o p hils
x
Bas o p hils
x
Er y t hr oc ytes ( R B C)
x
He m o gl o bi n ( H G B)
x
He mat ocrit ( H C T)
x
Mea n c or p usc ular v ol u me ( M C V)
x
Mea n c or p usc ular he m o gl o bi n c o nce ntrati o n ( M C H C)
x
Platelets ( P L T)
x
M a n u al Differe nti al
– la b orat or y
L oc al : x
Ce ntr al
C o a g ul ati o n - la b orat or y
L oc al
Ce ntr al
Acti vate d partial t hr o m b o plasti n ti me (a P T T) or Partial 
t hr o m b o plasti n ti me ( P T T)
x
I nter nati o nal n or malize d rati o (I N R) or Pr ot hr o m bi n ti me ( P T)
x
J V 0 2 0 5 Pr ot oc ol A d de n da ( g). p df | V V- T M F- 4 2 9 2 2 1 7 | 1. 0
Fi nal
P P D

J 1 S -M C -J V 0 2( g) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 7 8
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
Cli nic al C he mistr y – la b orat or y
L oc al
Ce ntr al
Ser u m C o nce ntr ati o ns of:
Ala ni ne a mi n otra nsferase ( A L T)
x
Al b u mi n
x
Al kali ne p h os p hatase
x
As partate a mi n otra nsferase ( A S T)
x
Bilir u bi n, direct
x
Bilir u bi n, t otal
x
Bl o o d urea nitr o ge n ( B U N) or bl o o d urea
x
Calci u m
x
Creati ni ne
x
Gl uc ose n o nfasti n g
x
Ma g nesi u m
x
P h os p hate
x
P otassi u m
x
Pr otei n
x
S o di u m
x
Uri n al ysis – la b orat or y
L oc al
Ce ntr al
Bl o o d
x
Gl uc ose
x
Ket o nes
x
p H
x
Pr otei n
x
S pecific gra vit y
x
Ur i ne le u k oc yte esterase
x
Pre g n a nc y Test (f or fe male patie nts of c hil d beari n g p ote ntial) -
la b orat or y
L oc al
Ce ntr al
Ser u m / uri ne pr e g na nc y test
x
T S H a n d F ree T 4 – la b orat or y
L oc al:   x
Ce ntr al
H y perse nsiti vit y Tests – la b orat or y
L oc al
Ce ntr al
Tr y ptase c
x
Ur i ne N- met h y l hista mi ne
x
C o m ple me nts

C 3a

C 5a
x
C y t o ki ne Pa nel

I L- 6

I L- 1 β

I L- 1 0
x
J V 0 2 0 5 Pr ot oc ol A d de n da ( g). p df | V V- T M F- 4 2 9 2 2 1 7 | 1. 0
Fi nal
P P D

J 1 S -M C -J V 0 2( g) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 7 9
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
A b bre viati o ns:  C R F = case re p ort f or m; E G F R = e pi der mal gr o wt h fact or rece pt or; Fr ee T 4 = th y r oxi n e ; I L = 
i nterle u ki n; K -r as = Kirste n rat sarc o ma; R B C = re d bl o o d cells; T S H = t h yr oi d-sti m ulati n g h or m o ne; W B C = 
w h ite bl o o d cells.
a
Treat me nt a n d e nr oll me nt decisi o ns will be base d o n l ocal la b orat or y res ults.
b
Ne utr o p hils re p orte d b y a ut o mate d differe ntial he mat ol o g y i nstr u me nts i ncl u de b ot h se g me nte d a n d ba n d 
f or ms. W he n a ma n ual differe ntial is nee de d t o re p ort t he ne utr o p hils, t he se g me nte d a n d ba n d f or ms s h o ul d be 
a d de d t o get her a n d rec or de d o n t he C R F, u nless t he C R F s pecificall y pr o vi des a n e ntr y fiel d f or ba n ds.
c
If a tr y ptase sa m ple is o btai ne d m ore t ha n 2 h o urs after t he e ve nt (i.e. wit hi n 2-1 2 h o urs) or is n ot o btai ne d beca use m ore t ha n 
1 2 h o urs ha ve la pse d si nce t he e ve nt, o btai n uri ne f or N- met h yl hista mi ne ( N M H) testi n g. N ote t hat f or tr y ptase ser u m 
sa m ples o btai ne d wit hi n 2-1 2 h o urs of t he e ve nt, uri ne N M H testi n g is perf or me d i n a d diti o n t o tr y ptase testi n g. C ollect t he 
first v oi d uri ne f oll o wi n g t he e ve nt. O btai n a f oll o w -u p uri ne f or N M H testi n g at t he ne xt re g ularl y sc he d ule d vis it or after 
4 wee ks, w hic he ver is later.
J V 0 2 0 5 Pr ot oc ol A d de n da ( g). p df | V V- T M F- 4 2 9 2 2 1 7 | 1. 0
Fi nal
P P D

J 1 S -M C -J V 0 2( g) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 8 0
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
At t a c h m e nt 3.
Pr ot o c ol A d d e n d u m J V 0 2 S a m pli n g 
S c h e d ul e f or G e n eti c s/ 
Bi o m ar k er s/I m m u n o g e ni cit y / P h ar m a c o ki n eti c s
P har mac o ki net ic sa m ples will be c ollecte d f or ra m ucir u ma b i n patient s i n t he ra m ucir u ma b ar m.  
Im m u n o ge nicit y (I G) sa mples will  be c ollecte d f or pati e nts i n b ot h t he r a mu ci r u ma b a n d c o ntr ol 
ar ms.  Pre d ose sa m ples s h o ul d be ta ke n as cl ose as p ossi ble t o t he start of first i nf usi o n, t hat is 
r a mu ci r u ma b i nf usio n , b ut ca n be dra w n u p t o 1 h o ur ( 6 0 mi n utes) pri or t o start of i nf usi on, a n d 
e xact cloc k rea di n gs s h o ul d be rec or de d.  P ost d ose ( p ost e n d of i nf usi on) sa m ples f or P K s h o ul d 
be dra w n, prefera bl y wit hi n 1 5 mi n utes after t he e n d of t he ra m ucir u ma b i nf usi o n, a n d a n e xact 
cloc k rea di n g f or t he sa m ple dra w s h o ul d be rec or de d.
Preferre d ti me wi n d o ws f or eac h P K/I G sa m ple c ollect i on are als o pr o vi de d i n t he ta bles i n t his 
secti on.  W hile best eff orts s h o ul d be ma de t o dra w t he bl o o d sa m ple f or P K/I G wit hi n t he ti me 
wi n d o w pr o vi de d, it is m ore i m p orta nt t o e ns ure t he pre d ose sa m ple is act uall y c ollecte d bef ore 
t he start of ra m ucir u ma b i nf usi o n a n d p ost -d ose sa m ples ( p ost e n d of i nf usi o n sa m ples) are 
c ollecte d after i nf usi o n is act uall y c om p lete d.  It is als o e q uall y i m p orta nt t o rec or d t he act ual 
date a n d ti me of bl o o d c ollecti o n f or t he P K/I G sa m ple o n t he Re q uisit i on F or m  after dra wi n g 
t he sa mple ( ie, d o n ot rec or d pla n ne d ti me of c o llecti o n).  Sa m ple c ollecti on f or p ost -i nf usi on 
P K/I G m ust be fr o m  t he o p p osite ar m t o t hat use d f or st u d y dr u g i nf usio n .  If t he dr u g was 
a d mi nistere d via a ce ntral ve n o us cat heter, t he sa m ple c o llecti on s h o ul d be fr o m a differe nt site.
I n a d diti on, if a pat ient  i n either t he ra m ucir u ma b or c o ntr ol  ar m e x perie nces a n I R R, bl o o d 
sa m ples s h o ul d be dra w n f or b ot h P K a n d I G.  Sa m ples will be ta ke n at t he f o ll owi n g ti me 
p oi nts:  ( 1) as s o o n as p ossi ble after t he o nset of t he I R R, ( 2) at t he res ol ut i on of t he I R R, a n d ( 3) 
3 0 da y s after t he I R R.
J V 0 2 0 5 Pr ot oc ol A d de n da ( g). p df | V V- T M F- 4 2 9 2 2 1 7 | 1. 0
Fi nal
P P D

J 1 S -M C -J V 0 1 (f) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 8 1
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
S a m pli n g S c h e d ul e f or G e n eti c s/ Bi o m ar k er s/I m m u n o g e ni cit y/ P h ar m a c o ki n eti c s
Pr oce d ure
S a m ple Ti me
C ycle 1
C ycle 
2
C ycle 5  
C ycle 9
C ycle 
1 3
S h ort -Ter m
F oll o w -U p
D a y 1  
D a y 8  
D a y 1  
D a y 1  
D a y 8  
D a y 1  
D a y 1
Wee k 
0
Wee k 
1
Wee k 
3
Wee k 
1 2
Wee k 
1 3
Wee k 
2 4
Wee k 
3 6
P har mac o ki netics a
(f or ra m ucir u ma b 
ar m o nl y)
Pri o r t o ra m ucir u ma b 
i nf usi o nb,c
X  
X  
X  
X
X  
X
A n y  ti me d uri n g t he s h ort-ter m 
f oll o w-u p visit
Wit hi n 0. 5 h o urs after 
t he e n d of t he 
ra m ucir u ma b i nf usi o n
a n d pri or t o 
ge mcita bi ne i nf usi o n c
X 
I m m u n o ge nicit ya
Pri o r t o c he m ot hera p y
i nf usi o nb,c
X
X
X
A n y  ti me d uri n g t he s hort -ter m 
f oll o w-u p visit
T u m o r tiss ued,e
Pri o r t o c he m ot hera p y
i nf usi o nb
X
Ser u m f or 
bi o mar kers d (f or 
b ot h treat me nt 
ar ms).
Pri o r t o c he m ot hera p y
i nf usi o nb
X
X
Plas ma f or 
bi o mar kers d (f or 
b ot h treat me nt 
ar ms).
Pri o r t o c he m ot hera p y
i nf usi o nb
X
X
A n y  ti me d uri n g t he s h ort-ter m 
f oll o w-u p visit
J V 0 2 0 5 Pr ot oc ol A d de n da ( g). p df | V V- T M F- 4 2 9 2 2 1 7 | 1. 0
Fi nal
P P D

J 1 S -M C -J V 0 1 (f) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 8 2
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
W h ole bl o o d
d (f or 
b ot h treat me nt 
ar ms).
Pri o r t o c he m ot hera p y
i nf usi o nb
X f
A b bre viati o ns:  C 5 D 8 = C ycle 5 Da y 8; e C R F = electr o nic case re p ort f or m; hr = h o ur; I G = i m m u n o gl o b uli n; I R R = i nf usi o n-relate d reacti o n; 
P K = p har mac o ki netic .
N ote:  F or t h ose patie nts o n t he ra m ucir u ma b ar m, ra m ucir u ma b i nf usi o n is gi ve n o n Da ys 1 a n d 8 e ver y 3 wee ks.  T he i nf usi o n d urati o n is 1 hr.  Eac h c ycle is a 
2 1- da y  c ycle.
a
I n th e  e ve nt of a n I R R (i ncl u di n g h y perse nsiti vit y reacti o ns), a d diti o nal bl o o d sa m ples will be c ollecte d fr o m all patie nts, w het her i n t he ra m ucir u ma b ar m or 
t he c o ntr ol ar m, f or b ot h P K a n d I G a nal ysis at t he f oll o wi n g ti me p oi nts:  (i) as cl ose as p ossi ble t o t he o nset of t he I R R, (ii) at t he res ol uti o n of t he I R R, a n d 
(iii) 3 0 da ys f oll o wi n g t he I R R (see ta ble bel o w).
b
C y cle 1 Da y 1 sa m ples ca n be c ollecte d wit hi n 7 da ys pri or t o ra m ucir u ma b i nf usi o n; C ycle 1 Da y 8 a n d C ycle 2 t o C ycle 1 3 Da y 1 sa m ples ca n be c ollecte d 
wit hi n 3 da ys pri or t o ra m ucir u ma b i nf usi o n.
B ut pre d ose sa m ples s h o ul d be prefera bl y c ollecte d wit hi n 1 h o ur pri or t o start of ra m ucir u ma b i nf usi o n if 
p ossi ble.  Ser u m a n d plas ma bi o mar kers c ollecte d at C 5 D 8 ca n be c ollecte d at a n y ti m e d ur i n g t he sc he d ule d visit. 
c
W hile best eff orts s h o ul d be ma de t o dra w t he bl o o d sa m ple f or P K/I G wit hi n t he ti me wi n d o ws pr o vi de d a b o ve, it is m ore i m p or ta nt t o e ns ure t he pre d ose 
sa m ple is act uall y c ollecte d bef ore t he start of first i nf usi o n a n d p ost d ose sa m ples are c ollecte d after t he i nf usi o n is act uall y c o m plete d.  It is als o e q uall y 
i m p orta nt t o rec or d A C T U A L date a n d ti me of bl o o d c ollecti o n f or t he P K/I G sa m ple o n t he Re q uisiti o n F or m A F T E R dra wi n g t he sa m ple a n d t o acc uratel y 
rec or d t he A C T U A L i nf usi o n start a n d e n d dates a n d ti mes o n t he e C R F t o be a ble t o use t he data f or a nal yses.  Sa m ple c ollecti o n f or p ost -i nf usi o n P K/I G 
m ust be fr o m t he o p p osite ar m t o t hat use d f or st u d y dr u g i nf usi o n.  If t he dr u g was a d mi nistere d via a ce ntral ve n o us cat het er, t he sa m ple c ollecti o n s h o ul d be 
fr o m a differe nt site. 
d
C ollecti o n of t u m or tiss ue a n d bi o mar kers (ser u m, plas ma, w h ole bl o o d) is o pti o nal.  Pre vi o usl y arc hi ve d f or mali n-fi xe d paraffi n-e m be d de d t u m or tiss ue 
o btai ne d fr o m t he pri mar y t u m or or metastat ic site s h o ul d be pr o vi de d as a wh ole bl oc k or u nstai ne d sli des.
e
O pti o nal c ollecti o n of a n a d diti o nal bi o ps y s peci me n after treat me nt start ma y be re q ueste d.
f
A pretreat me nt bl o o d sa m ple is preferre d; h o we ver, t he w h ole bl o o d sa m ple f or ge netic a nal ysis (as descri be d i n Secti o n 9. 7 of t he mai n pr ot oc ol) ma y be 
c ollecte d at a later ti me p oi nt if necessar y.
I nf u si o n-R el at e d R e a cti o n (I n cl u di n g H y p er s e n siti vit y R e a cti o n s) I m m u n o g e ni cit y/ P h ar m a c o ki n eti c s S a m pli n g f or A L L 
P ati e nt s a
Pr oce d ure
S a m ple Ti me
O nset of t he I R R
O nce 
He m o d y n a mic all y 
St a bl e b
R es ol uti o n of t he I R R
3 0 d a ys f oll o wi n g t he I R R
P K
X
X
X
I m m u n o ge nicit y
X
X
X
H y perse nsiti vit y testi n g 
X
X c
J V 0 2 0 5 Pr ot oc ol A d de n da ( g). p df | V V- T M F- 4 2 9 2 2 1 7 | 1. 0
Fi nal
P P D

J 1 S -M C -J V 0 1 (f) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 8 3
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
A b bre viati o ns: I R R = i nf usi o n -relate d reacti o ns; P K = p har mac o ki netics
a
I n t he e ve nt of a n I R R (i ncl u di n g h y perse nsiti vit y reacti o ns), a d diti o nal bl o o d sa m ples will be c ollecte d fr o m all patie nts, w het her i n t he ra m ucir u ma b ar m or 
t he c o ntr ol ar m, f or b ot h P K a n d I G a nal ysis at t he f oll o wi n g ti me p oi nts:  (i) as cl ose as p ossi ble t o t he o nset of t he I R R, (ii) at t he res ol uti o n of t he I R R, a n d 
(iii) 3 0 da ys f oll o wi n g t he I R R.
b
After t he patie nt has bee n sta bilize d o btai n a sa m ple wit hi n 1 -2 h o urs of t he e ve nt ; h o we ver, sa m ples ma y be o btai ne d as late as 1 2 h o urs after t he e ve nt as 
a nal ytes ca n remai n altere d f or a n e xte n de d peri o d of ti me. Rec or d t he ti me at w hic h t he sa m ple was c ollecte d .
c
O btai n a f oll o w -u p sa m ple at t he 3 0 -da y f oll o w-u p or at t he ne xt re g ularl y sc he d ule d visit f oll o wi n g t he I R R, w hic he ver is later.
J V 0 2 0 5 Pr ot oc ol A d de n da ( g). p df | V V- T M F- 4 2 9 2 2 1 7 | 1. 0
Fi nal
P P D

J 1 S -M C -J V 0 2( g) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 8 4
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
At t a c h m e nt 4.
Pr ot o c ol J V 0 2 A d d e n d u m H e p ati c 
M o nit ori n g T e st s f or Tr e at m e nt -E m er g e nt A b n or m alit y
S el ecte d tests ma y be o btai 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 uire d i n f o ll o w-u p wi t h p atie nts i n c o ns ultat i o n wit h t he Lill y C R P .
He p atic M o nit ori n g Tests
He p atic He m at ol o g y a
H a pt o gl o bi n a
He m o gl o bi n ( H G B)
He mat ocrit ( H C T)
He p atic C o a g ul ati o n a
Er y t hr oc ytes ( R B C)
Pr ot hr o m bi n ti me ( P T)
Le u k oc ytes ( W B C)
Pr ot hr o m bi n ti me, I N R
Ne utr o p hils b
L y m p h oc y t es
He p atic Ser ol o gies a,c
M o n oc ytes
He patitis A a nti b o d y, t otal
E osi n o p hils
He patitis A a nti b o d y, I g M
Bas o p hils
He patitis B s urface a nti ge n
Platelets ( P L T)
He patitis B s urface a nti b o d y
He patitis B C ore a nti b o d y
He p atic C he mistr y a
He patitis C a nti b o d y
T otal bilir u bi n
He patitis E a nti b o d y, I g G
Direct bilir u bi n
He patitis E a nti b o d y, I g M
Al kali ne p h os p hatase
Ala ni ne a mi n otra nsferase ( A L T)
Rec o m me n de d A ut oi m m u ne Ser ol o g y
As partate a mi n otra nsferase ( A S T)
A nti- n uclear a nti b o d y a
Ga m ma -gl uta m yl tra nsferase ( G G T)
A nti- s m o ot h m uscle a nti b o d ya
Creati ne p h os p h o ki nase ( C P K) 
A nti- acti n a nti b o d ya
A b bre viati o ns:  C R F = case re p ort f or m; I g G = i m m u n o gl o b uli n G; I g M = i m m u n o gl o b uli n M; I N R = i nter nati o nal 
n or malize d rati o; R B C = re d bl o o d cells; W B C = w hite bl o o d cells.
a
Assa y e d b y l ocal la b orat or y.
b
Ne utr o p hils re p orte d b y a ut o mate d differe ntial he mat ol o g y i nstr u me nts i ncl u de b ot h se g me nte d a n d ba n d 
f or ms. W he ne ver a ma n ual differe ntial is nee de d t o re p ort t he ne utr o p hils, t he se g me nte d a n d ba n d f or ms s h o ul d 
be a d de d t o get her a n d rec or de d o n t he C R F, u nless t he C R F s pecificall y pr o vi des a n e ntr y fi el d f or ba n ds.
c
Refle x/c o nfir mati o n de pe n de nt o n re g ulat or y re q uire me nts a n d/ or testi n g a vaila bilit y.
J V 0 2 0 5 Pr ot oc ol A d de n da ( g). p df | V V- T M F- 4 2 9 2 2 1 7 | 1. 0
Fi nal
P P D

J 1 S -M C -J V 0 2( g) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 8 5
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
At t a c h m e nt 5.
Pr ot o c ol J V 0 2 R e stri ct e d a n d Pr o hi bit e d 
C o n c o mit a nt T h er a p y
T he ta ble bel o w descri bes me dicat i ons, treat me nts, a n d dr u g classes res tricte d or pr o hi bite d, wit h 
e xce pti o ns a n d c o n dit i ons f or use d uri n g t he st u d y treat me nt perio d ( t here are n o pr o hi bite d 
t hera pies d uri n g t he f o ll ow- u p peri o d).  Patie nts w h o , i n t he assess me nt b y t he i n vesti gat or, 
re q uire t he use of a n y of t he pr o hi bite d treat me nts f or cli nical ma na ge me nt s h o ul d be re m o ve d 
fr om t he trial.  P atie nts ma y recei ve ot her s u p p orti ve t hera p y or vacci nati ons t hat t he i n vest i gat or 
dee ms t o be me dicall y necessar y .
J V 0 2 0 5 Pr ot oc ol A d de n da ( g). p df | V V- T M F- 4 2 9 2 2 1 7 | 1. 0
Fi nal
P P D

J 1 S -M C -J V 0 2( g) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 8 6
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
T her a p y
All o we d 
As 
Nee de d
All o we d f or 
C hr o nic Use
E xce pti o ns or C o n diti o ns f or Use
A nti- platelet t hera p y
a n d N S AI D S
Yes
Yes, wit h 
restricti o ns
C hr o nic use of as piri n u p t o 3 2 5 m g/ da y is per mitte d. C hr o nic 
use of N S AI Ds is n ot per mitte d. H o we ver, i n certai n me dical 
sit uati ons, N S AI Ds ma y be t he best treat me nt o pti o n (e g, f or 
pai n ma na ge me nt) a n d are t heref ore per mitte d as nee de d. 
I n crease d ris k of blee di n g s h o ul d be c o nsi dere d b y t he treati n g 
p h y sicia n a n d t he patie nt.
A ntic oa g ulati o n 
t hera p y
N o
Yes, wit h 
restricti o ns
At e nr oll me nt, patie nts o n f ull -d ose a ntic oa g ulati o n m ust be o n 
a sta ble d ose ( mi ni m u m d urati o n 1 4 da ys) of oral a ntic oa g ula nt 
or  l o w m olec ular wei g ht he pari n or si milar a ge nt.  If o n 
warfari n, t he patie nt m ust ha ve a n I N R ≤3 a n d n o acti ve blee di n g 
or  pat h ol o gical c o n diti o n prese nt t hat carries a hi g h ris k of 
blee di n g ( e g, t u m or i n v ol vi n g maj or vessels or k n o w n varices).
A nti- ca ncer 
bi ol o gical t hera p y
N o  
N o
C he m ot hera p y
N o  
N o
C Y P 3 A 4 str o n g 
i n hi bit ors/i n d ucers
N o  
N o
See list i n Attac h me nt 6 .
Er y t hr oi d gr o wt h 
fact ors
Yes
N o
F oll o w l ocal g ui deli nes.
E x peri me ntal 
me dici nes or 
i n vesti gati o nal 
a ge nts
N o  
N o
Ot her t ha n ra m ucir u ma b, ge nta mici n, d oceta xel
Gl uc oc ortic oi ds
Yes
Yes, wit h
restricti o ns
S y ste mic gl uc oc ortic oi ds are per mitte d t o m o d ulate s y m pt o ms 
fr o m a n e ve nt of cli nical i nterest of s us pecte d i m m u n ol o gic 
eti ol o g y.  Use i n patie nts wit h c o ntrast aller gies is acce pta ble. A 
te m p orar y c o urse of c ortic oster oi ds will be all o we d for  ot her 
i n dicati o ns, at t he discreti o n of t he pri nci pal i n vesti gat or (e g, 
c hr o nic o bstr ucti ve p ul m o nar y disease, ra diati o n, na usea, etc).  
T he use of p h ysi ol o gic d oses of c ortic oster oi ds ma y be 
a p pr o ve d after c o ns ultati o n wit h t he S p o ns or.
N ote:  I n hale d ster oi ds are all o we d f or ma na ge me nt of ast h ma.
I m m u n ot hera p y 
N o  
N o
Ot her t ha n i n hale d ster oi ds a n d vacci nati o ns.
Li ve vacci nes
N o
N / A
Pr o hi bite d as c o nc o mita nt t hera p y d uri n g t he st u d y a n d f or at 
least 3 m o nt hs after last d ose of st u d y dr u g.
Ra diati o n t hera p y
N o  
N o
L ocalize d ra diati o n t hera p y t o a s y m pt o matic, s olitar y lesi o n or 
t o t he brai n ma y be all o we d after c o ns ultati o n wit h t he S p o ns or. 
N ote:  Ge mcita bi ne m ust n ot be a d mi nistere d f or at least 7 da ys 
bef ore or after ra diati o n treat me nt. 
A b bre viati o ns:  B C R P = breast ca ncer -resista nce pr otei n; I N R = i nter nati o nal n or malize d rati o; 
N S AI D = n o nster oi dal a nti -i nfla m mat or y dr u gs.
J V 0 2 0 5 Pr ot oc ol A d de n da ( g). p df | V V- T M F- 4 2 9 2 2 1 7 | 1. 0
Fi nal
P P D

J 1 S -M C -J V 0 2( g) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 8 7
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
At t a c h m e nt 6.
Pr ot o c ol J V 0 2 Li st of C o m m o n C Y P 3 A 4 
I n hi bit or s a n d I n d u c er s of D o c et a x el
T he ta ble bel o w descri bes t he dr u g class a n d ass ociate d me dicat i ons t hat will be restricte d d uri n g 
t he st u d y treat me nt perio d.  Pati e nts w h o, i n t he assess me nt b y t he i n vestigat or, re q ui re t he use of 
a n y of t he pr o hi bite d treat me nts f or cli nical ma na ge me nt s h o ul d disc o nt i n ue d oceta xel (see 
Secti o n 3. 7. 6 ).  T hi s is n ot a n all-i ncl usi ve list a n d d ue dili ge nce s h o ul d be f oll owe d. 
C Y P 3 A 4 I n d ucers
Str o n g C Y P 3 A 4 I n hi bit ors
M o der ate C Y P 3 A 4 I n hi bit ors
A mi n o gl utet hi mi de
Clarit hr o m yci n 
A mi o dar o ne
B ose nta n
C hl ora m p he nic ol
A m pre na vir
Car ba maze pi ne
C o bi cistat 
A pre pita nt a
Efa vire nz (i n li ver o nl y)
C o ni va pta n
Ataza na vir
F os p he n yt oi n 
Cre m o p h or E L
Ci meti di ne
Nafcilli n
C y cl os p ori ne
Ci pr ofl o xaci n
Ne vira pi ne
Dela vir di ne
Cl otri maz ole
O xcar baze pi ne
Dicl ofe nac
Dar u na vir
Pe nt o bar bital
Diltiaze m
Dar u na vir a n d rit o na vir
P he n o bar bital
El vite gra vir a n d rit o na vir
Desi pra mi ne
P he n yt oi n
E n o xaci n
D o x yc ycli ne
Pri mi d o ne
F osa m pre na vir
Dr o ne dar o ne
Rifa b uti n
Gra pefr uit j uice
Efa vire nz
Rifa m pi n
I n di na vir
Er y t hr o m yci n
Rifa pe nti ne
I n di na vir a n d rit o na vir
F K 1 7 0 6
St J o h n's w ort
Itrac o naz ole
Fl uc o naz ole 
Ket oc o naz ole
Fl u v o xa mi ne
L o pi na vir a n d rit o na vir
Hal o peri d ol
Mi befra dil
I mati ni b
Mic o naz ole
Metr o ni daz ole
Nefaz o d o ne
N orfl o xaci n
Nelfi na vir
Pr otease i n hi bit ors
Nicar di pi ne
Q ui ni di ne
P osac o naz ole 
Sc hisa n dra s p he na nt hera e xtract
Q ui ni di ne
Sertrali ne
Rit o na vir 
Tetrac ycli ne
Sa q ui na vir 
T ofis o pa m
Telit hr o m y ci n
Vera pa mil
T he o p h ylli ne
Tr olea n d o m yci n
V oric o naz ole
a
A pre pita nt is all o we d w he n gi ve n acc or di n g t o l ocal practice a n d i nstit uti o nal g ui deli nes a n d if n o alter nati ve 
a ntie metic is rec o m me n de d.
J V 0 2 0 5 Pr ot oc ol A d de n da ( g). p df | V V- T M F- 4 2 9 2 2 1 7 | 1. 0
Fi nal
P P D

J 1 S -M C -J V 0 2( g) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 8 8
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 6
At t a c h m e nt 7.
Pr ot o c ol A d d e n d u m A m e n d m e nt J 1 S -M C -
J V 0 2( g) S u m m ar y  A R a n d o mi z e d, O p e n -L a b el P h a s e 1/ 2 
St u d y  E v al u ati n g R a m u cir u m a b i n P e di atri c P ati e nt s a n d 
Y o u n g A d ult s wit h R el a p s e d, R e c urr e nt, or R efr a ct or y  
S y n o vi al S ar c o m a
D O C U M E N T HI S T O R Y
D oc u me nt
D ate
A me n d me nt f
9- Oct - 2 0 2 0
A me n d me nt e
1 8 -Ma y - 2 0 2 0
A me n d me nt d
1 7 -Oct - 2 0 1 9
A me n d me nt c
2 6 -Se p - 2 0 1 9
A me n d me nt b
2- A u g - 2 0 1 9
A me n d me nt a
2 3 -Ja n-2 0 1 9
Ori gi nal Pr ot oc ol
7- Dec - 2 0 1 8
A me n d me nt g
T his a me n d me nt is c o nsi dere d t o be n o ns u bsta nt ial.
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 is bei n g u p date d t o ali g n uri nal ysis c ollecti on i n t he sc he d ule of act i vities wi t h 
m o nit ori n g ta ble i n later secti o ns. Ot her c ha n ges a n d clarificat i ons were ma de base d o n rece nt 
fee d bac k fr om sit es.
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. 2 Sc he d ule of Act i vities; 3. 9. 3. 1. 2 
M o ni t ori n g f or S pecial T o xicities: 
Gr o wt h Pl at e
A d de d te xt t o clarif y 
“Pl ai n a nter o p osterior 
r a dio gra p h of a si n gle 
pr o xi mal t i bial gr o wt h 
pl at e” are for parti ci pa nts 
ra n d omize d t o t he 
r a mu ci r u ma b treat me nt 
ar m o nl y.
U p date base d o n s ite a n d 
re g ulat or y fee d bac k. 
3. 2 Sc he d ule of Act i vities
A d de d te xt t o clarif y 
ti mi n g of ra di ol ogi c 
i ma gi n g be gi ns at C 1 D 1.
Mi n or cl arificat i on.
J V 0 2 0 5 Pr ot oc ol A d de n da ( g). p df | V V- T M F- 4 2 9 2 2 1 7 | 1. 0
Fi nal
P P D

J 1 S -M C -J V 0 2( g) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 8 9
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 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. 2 Sc he d ule of Act i vities; 3. 9. 3. 1. 2 
M o ni t ori n g f or S pecial T o xicities: 
Gr o wt h Pl at e
A d de d te xt t o all o w a n 
alter nate o ptio n of  M RI of 
t he k nee i n s o me 
ge o gra p hi es for gr o wt h -
pl at e mo ni t ori n g i nstea d of 
pl ai n A P ra dio gra p h.
Re g ulat or y  re q uire me nt.
3. 2 Sc he d ule of Act i vities
A d de d Da y 8 Uri nal ysis 
t hr o u g h o ut t he treat me nt 
p eri o d.
Ali g n wit h m o nit ori n g 
ta ble i n pr ot oc ol. 
3. 7. 1. 2 D osi n g Sc he d ule
A d de d te xt t o i n dicate a 
mi ni m u m o f 1 wee k be 
o bser ve d bet wee n 
r a mu ci r u ma b 
a d mi nistrati o n if t he 
r a mu ci r u ma b d ose is 
d el a ye d. 
Si te clarificati on.
3. 7. 1. 2 D osi n g Sc he d ule
A d de d i nf or mat i on rel ate d 
t o treat me nt dela ys d ue t o 
u nf oreseea ble 
circ u msta nces.
A d de d t o a d dress i nsta nces 
of  e xce ptio n al  
circ u msta nces. 
3. 7. 4. 1 G ui deli nes f or He mat ol o gical 
a n d N o n he mat ol o gical D ose 
M o dificat i ons
A d de d “f o ot n ote d” i n
Ta ble J V 0 2 . 1 0 a n d Ta ble 
J V 0 2. 1 1 t o clarif y t hat 
Ta ble J V 0 2. 8 s h o u l d be 
use d f or d ose re d ucti o ns .
Si te clarificati on.
3. 7. 4. 1 G ui deli nes f or He mat ol o gical 
a n d N o n he mat ol o gical D ose 
M o dificat i ons
S plit cell i n Ta ble J V 0 2. 1 1
f or Gra de ≥3 t otal 
bilir u bi n a n d Gra de ≥3 
A S T or A L T ele vat i ons
Mi n or cl arificat i on.
At tac h me nt 3 Pr ot oc ol A d de n d u m 
J V 02 S a m pli n g Sc he d ule f or 
Ge net ics/ Bio m ar kers/ 
I mm u n o ge nicit y/  P har mac o ki netics
Cl arifie d “ser u m for 
bi o mar kers,” “ plas ma f or 
bi o mar kers,” a n d “ w h o le 
bl o o d” are t o be c ollecte d 
f or b ot h ar ms a n d are 
o pti o nal .
Si te clarificati on.
J V 0 2 0 5 Pr ot oc ol A d de n da ( g). p df | V V- T M F- 4 2 9 2 2 1 7 | 1. 0
Fi nal
P P D

J 1 S -M C -J V 0 2( g) Cli ni c al Pr ot o c ol A d d e n d u m
P a g e 9 0
L Y 9 0 0 0 2 3; L Y 3 0 0 9 8 0 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
T hr o u g h o ut
Mi n or e di t orial a n d 
d oc u m e nt for m atti n g 
re visi ons
T hese are mi n or c ha n ges; 
t heref ore, t he y ha ve n ot 
bee n s u m marize d.
J V 0 2 0 5 Pr ot oc ol A d de n da ( g). p df | V V- T M F- 4 2 9 2 2 1 7 | 1. 0
Fi nal
P P D

L e o  D o c u m e n t  I D  =  c 6 4 e d b 3 d - 8 e 4 1 - 4 d 1 c - 8 5 1 c - 9 2 8 6 1 9 9 f 9 e 1 e
A p p r o v e r :  
A p p r o v a l  D a t e  &  T i m e :  1 3 - D e c - 2 0 2 1  1 7 : 0 7 : 1 7  G M T
S i g n a t u r e  m e a n i n g :  A p p r o v e d
A p p r o v e r :  
A p p r o v a l  D a t e  &  T i m e :  1 3 - D e c - 2 0 2 1  1 7 : 5 6 : 5 7  G M T
S i g n a t u r e  m e a n i n g :  A p p r o v e d
J V 0 2 0 5 Pr ot oc ol A d de n da ( g). p df | V V- T M F- 4 2 9 2 2 1 7 | 1. 0
Fi nal
P P D
P P D
P P D