Conditions: Synovial Sarcoma
Keywords: soft tissue sarcoma adolescents and young adults (AYAs) adolescent
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 23
Healthy volunteers: no

Brief summary:
This study is being conducted to test the safety and efficacy of ramucirumab in combination with other chemotherapy in the treatment of relapsed, recurrent, or refractory synovial sarcoma (SS) in children and young adults. This trial is part of the CAMPFIRE master protocol (NCT05999994) which is a platform to accelerate the development of new treatments for pediatric and young adult participants with cancer. Your participation in this trial could last 12 months or longer, depending on how you and your tumor respond.

Detailed description:

Arms:
arm 1: Participants received intravenous (IV) infusions of ramucirumab 9 milligrams per kilogram (mg/kg), gemcitabine 900 milligrams per meter square (mg/m2) on days 1, 8, and docetaxel 75 mg/m2 on day 8 of a 21-day cycle until disease progression or a criterion for discontinuation were met. arm 2: Participants received intravenous infusions of gemcitabine 900 mg/m2 on days 1, 8, and docetaxel 75 mg/m2 on day 8 of a 21-day cycle until disease progression or a criterion for discontinuation were met.

Interventions: intervention 1: Ramucirumab intervention 2: Gemcitabine intervention 3: Docetaxel
Intervention descriptions: intervention 1: Ramucirumab given IV intervention 2: Gemcitabine given IV intervention 3: Docetaxel given IV

Protocol document:
Prot_000.pdf: 
 
 
 
 
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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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
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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P a g e 3
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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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
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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
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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
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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
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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 
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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 
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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 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 
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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 
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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.
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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 )
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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 ).
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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. 
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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
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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 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
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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 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 , 
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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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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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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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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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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 
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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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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 .
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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, 
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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.
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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 ). 
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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.
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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

SAP_001.pdf: 
 
 
Statistical A nal ysis Pla n: J 1 S - M C-J V 0 2 ( v 3) 
 
 
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 9 -Ja n-2 0 2 2  
 


J 1 S -M C -J V 0 2 St ati sti c al A n al y si s Pl a n V 3
P a g e 1
L Y 3 0 0 9 8 0 6
1.
St ati sti c al A n al y si s Pl a n :
J 1 S -M C -J V 0 2 :  A R a n d o mi z e d, O p e n -L a b el P h a s e 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 d o c u m e nt i s c o nfi d e nti al a n d t h e i nf or m ati o n c o nt ai n e d 
wit hi n it m a y n ot b e r e pr o d u c e d or ot h er wi s e di s s e mi n at e d wit h o ut t h e a p pr o v al of Eli Lill y 
a n d C o m p a n y or it s s u b si di ari e s.  
N ot e t o R e g ul at or y A ut h oriti e s:
t hi s d o c u m e nt m a y c o nt ai n pr ot e ct e d p er s o n al d at a 
a n d/ or c o m m er ci all y c o nfi d e nti al i nf or m ati o n e x e m pt fr o m p u bli c di s cl o s ur e .  Eli Lill y a n d 
C o m p a n y r e q u e st s c o n s ult ati o n r e g ar di n g r el e a s e/r e d a cti o n pri or t o a n y p u bli c r el e a s e .  I n 
t h e U nit e d St at e s, t hi s d o c u m e nt i s s u bj e ct t o Fr e e d o m of I nf or m ati o n A ct ( F OI A) 
E x e m pti o n 4 a n d m a y n ot b e r e pr o d u c e d or ot h er wi s e di s s e mi n at e d wit h o ut t h e writt e n 
a p pr o v al of Eli Lill y a n d C o m p a n y or it s s u b si di ari e s.
R a m u cir u m a b ( L Y 3 0 0 9 8 0 6)
a n d 
S y n o vi al S ar c o m a
 
 
 J 1 S-M C -J V 0 2: A R a n d o mi z e d, O p e n -L a b el P h a s e 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
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
St ati sti c al A n al y si s Pl a n V er si o n 1 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: 1 0 -D e c -
2 0 1 8
St ati sti c al A n al y si s Pl a n V er si o n 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: 1 3 -S e p -
2 0 2 1
St ati sti c al A n al y si s Pl a n V er si o n 3 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 9- J a n- 2 0 2 2 G M T
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 J 1 S-M C -J V 0 2 St ati sti c al A n al y si s Pl a n V 3
P a g e 2
L Y 3 0 0 9 8 0 6
2.
T a bl e of C o nt e nt s
S e cti o n
P a g e
1.
Stati stical A nal ysis Pla n:   
J 1 S-M C -J V 0 2:  A 
Ra n d o mize d, O pe n- La bel  P hase 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 .............................................................................................1
2.
Ta ble of C o nte nts ................................................................................................................2
3.
Re visi o n Hist or y .................................................................................................................7
4.
St u d y  O bjecti ves.................................................................................................................8
4. 1.
Pri mar y O bject i ve ..........................................................................................................8
4. 2.
Sec o n dar y  O bjecti ves.....................................................................................................8
4. 3.
E x pl or at or y  O bjecti ves...................................................................................................8
5.
St u d y Desi g n .......................................................................................................................9
5. 1.
St u d y  Desi g n..................................................................................................................9
5. 1. 1.
S u m mar y  of St u d y Desi g n......................................................................................9
5. 1. 2.
Deter mi nat i on of Sa m ple Size ..............................................................................1 0
5. 2.
Met h o d of Treat me nt Assi g n me nt
................................................................................1 1
6.
A Pri ori  St atistical Met h o ds ..............................................................................................1 3
6. 1.
Ge neral C o nsi derati o ns ................................................................................................1 3
6. 1. 1.
P o p ul at i ons f or A nal ysis ......................................................................................1 3
6. 1. 2.  
Ha n dli n g of Dr o p o uts a n d Missi n g Data ...............................................................1 4
6. 1. 3.
M ul tipl e C o m paris o ns/ M ult i plicity .......................................................................1 4
6. 2.
P ati e nt Dis p ositio n .......................................................................................................1 4
6. 3.
Pat ient  C haracteristics..................................................................................................1 5
6. 4.
Treat me nt C o m plia nce ................................................................................................. 1 5
6. 5.
C o nc o mita nt a n d P ost -Disc o nt i n uati on T hera p y ...........................................................1 5
6. 6.
Efficac y A nal yses ........................................................................................................1 5
6. 6. 1.
Pri mar y O utc o me a n d Met h o d ol o g y .....................................................................1 5
6. 6. 1. 1.
Pri mar y P F S E n d p o i nt Defi niti on a n d Ce ns ori n g R ules ..................................1 6
6. 6. 1. 2.
Ba yesia n Hierarc hical M o del f or Pri mar y Pr o gressi o n-
Free S ur vi val E n d p o i nt...................................................................................1 7
6. 6. 1. 3.
Pri or Distri b ut i ons f or C o ntr ol Pr o gressi o n -Free S ur vi val ...............................1 8
6. 6. 1. 4.
Retr os pecti ve ( Real W orl d) Data t o I nf or m C o ntr ol 
Pri ors ..............................................................................................................1 9
6. 6. 1. 5.
Pres pecifie d Hist orical C o ntr ol Matc hi n g Al g orit h m ......................................1 9
C CI
C CI
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 J 1 S-M C -J V 0 2 St ati sti c al A n al y si s Pl a n V 3
P a g e 3
L Y 3 0 0 9 8 0 6
6. 6. 1. 6.
Si m ulati o ns of Pri mar y Pr o gressi o n -Free S ur vi val 
E n d p oi nt .........................................................................................................2 1
6. 6. 1. 7.
Se nsit i vity A nal yses f or Pri mar y  Pr o gressio n -Free 
S ur vi val E n d p o i nt...........................................................................................2 4
6. 6. 1. 8.
E x pert Elicitat i on of C o ntr ol  Pr o gressio n -Free S ur vi val ..................................2 5
6. 6. 2.
Sec o n dar y  Efficac y A nal yses...............................................................................2 5
6. 7.
Bi oa nal y tic al a n d P har mac o ki netic/ P har mac o d y na mic Met h o ds ...................................2 6
6. 8.
S af et y A nal yses ............................................................................................................2 6
6. 8. 1.
E xte nt of E x p os ure ...............................................................................................2 6
6. 8. 2.  
A d verse E ve nts ....................................................................................................2 6
6. 8. 3.
Deat hs, Seri o us A d verse E ve nts, Ot her Si g nifica nt A d verse 
E ve nts ..................................................................................................................2 7
6. 8. 4.
Cli nical La b orat or y  E val uati on .............................................................................2 7
6. 8. 5.
Vi t al Sig ns a n d Ot her P h ysical Fi n di n gs ...............................................................2 7
6. 8. 6.
Electr ocar di o gra ms ..............................................................................................2 7
6. 9.
S u b gr o u p A nal yses .......................................................................................................2 7
6. 1 0.
Pr ot oc ol  Viol at i ons .......................................................................................................2 8
6. 1 1.
I nteri m A nal yses ..........................................................................................................2 8
6. 1 2.
A n n ual Re p ort A nal yses ...............................................................................................2 9
6. 1 3.
Cli nical Trial Re gistr y  A nal yses...................................................................................2 9
7.
Refere nces ........................................................................................................................3 1
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T a bl e of C o nt e nt s
T a bl e
P a g e
Ta ble 6. 1.
Pr o gressi o n - Free S ur vi val E ve nt/ Ce ns ori n g Sc he me......................................1 6
Ta ble 6. 2
V ari a bles f or Matc hi n g Real-W o rld Data ( Hi st oric al C o ntr ol) a n d 
Pr os pecti ve Pat ient s .......................................................................................2 1
Ta ble 6. 3.
Si m ulate d O perati n g C haracteri stics ..............................................................2 2
Ta ble 6. 4.
I mpact of Biase d Hist orical C o ntr ols o n T y pe I Err or ....................................2 3
Ta ble 6. 5.
I mpact of Heter o ge ne o us Effect -Si ze Bet wee n T u m ors ..................................2 3
Ta ble 6. 6.
I mpact o n I nteri m A nal ysis w he n N o R W data is I ncl u de d ............................2 4
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T a bl e of C o nt e nt s
Fi g ur e
P a g e
Fi g ure 5. 1.
J V A A st u d y desi g n..........................................................................................9
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T a bl e of C o nt e nt s
A p p e n di x
P a g e
A p pe n di x 1.
J A G S C o de f or Ba yesia n Hierarc hical M o del of Pri mar y P F S 
E n d p oi nt ........................................................................................................3 2
A p pe n di x 2.
Pri or Elici t atio n Pr ot oc ol ...............................................................................3 4
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3.
R e vi si o n Hi st or y
S A P Versi o n 1 was a p pr o ve d pri or t o fi rst patie nt visits for s t u dies 
 J 1 S-M C -
J V 0 2.
S A P Versi o n 2 was a p pr o ve d pri or t o t he i nteri m f utilit y a nal ysis. T he o verall c ha n ges a n d 
r atio al e for c ha n ges i nc or p orate d i n Versi o n 2 are as f oll o ws: Per c o m m u nicat i ons wit h t he F D A, 
a n a nal ysis pla n was de vel o pe d f or t he sce nari o w he n n o or li mite d real -w orl d e vi de nce is 
a vaila ble at i nteri m. Per c o m m u nicat i ons wit h t he F D A, a se nsit i vity a nal ysis usi n g t he 
c o mplete -case p o p ulat i on was a d de d. Real -w orl d e vi de nce ma y be e xcl u de d fr o m t he a nal ysis if 
b ot h m atc hi n g met h o ds are u ns uccessf ul i n i de nt if yi n g a rele va nt c o h ort of hist orical patie nts. 
S A P Versi o n 3 was a p pr o ve d pri or t o data base l oc k f or i nteri m f ut ility a nal ysis. A d de d 
“ Missi n g” fact or le vel t o t u mor size m atc hi n g varia ble. C ha n ge d le vels of li nes of t hera p y 
matc hi n g varia ble t o “ 1 st li ne”, “ 2 n d li ne a n d a b o ve”, a n d “ Missi n g .” E x pa n de d eli gi ble re gi me ns 
i n real-w orl d e vi de nce a nal ysis. S A P Versi o n 3 was a p pr o ve d pri or t o data base l oc k f or i nteri m 
a nal ysis.
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4.
St u d y  O bj e cti v e s
4. 1.
Pri m ar y  O bj e ctiv e
T he pri mar y o bject i ve of St u dies 
 J 1 S-M C -J V 0 2 ( St u d y J V 0 2) 
is t o e valuate efficac y o n t he basis of pr o gressi o n -free s ur vi val (P F S) per Res p o nse E val uati o n 
Cri teria i n S oli d T um o rs versi on 1. 1 ( R E CI S T v 1. 1) f or:


S y n o vial sarc oma ( S S) (St u d y  J V 0 2):  ra m ucir u ma b 9 m g/ k g o n Da ys 1 a n d 8 e ver y 3 
wee ks i n c o m bi nat i on wi t h ge mci ta bi ne ( 9 0 0 mg/ m 2 o n Da y s 1 a n d 8 of a 3-wee k c y cle) 
a n d d oceta xel ( 7 5 mg/ m 2 o n Da y  8 of a 3-wee k c ycle) vers us ge mcita bi ne/ d oceta xel 
alo ne
4. 2.
S e c o n d ar y O bj e cti v e s

S af et y a n d t olera bilit y ( serio us a d verse e ve nts [ S A Es ], a d verse e ve nts [ A Es ], safety 
la b orat or y assess me nts)

A d dit i onal efficac y meas ures ( o verall res p o nse rate [ O R R ], d urati o n o f res p o nse [D o R ], 
c o mplete res p o nse [ C R ])

P har mac o ki net ics ( P K) of  t he a b o ve ra mucir u ma b c o m bi nat i ons i n c hil dre n a n d yo u n g 
a d ults (m a xi m u m dr u g c o nce ntrati o n a n d mi ni m u m dr u g c o nce ntrati o n )

I mm u n o ge nicit y (inci de nce of i m m u n o ge nicit y)
4. 3.
E x pl or at o r y O bj e cti v e s

O verall s ur vi val ( O S)

D iffere nce i n pr o p orti o n of patie nts w h o bec ome eli gi ble f or s ur gical resect i on 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

P F S 2

Bi o m ar kers
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5.
St u d y  D e si g n
5. 1.
St u d y D e si g n 
5. 1. 1.
S u m m ar y of St u d y D e si g n 
St u di es  
a n d J V 0 2 ar e ra n d om ize d, mul tice nter, P hase 2 st u dies i n pe diatric a n d yo u n g a d ul t 
pati e nts wit h r ela pse d, rec urre nt, or pr o gressi ve 
 a n d S S (St u d y  J V 0 2) t o 
e val uate t he efficac y ass o ciat e d wit h r a mucir u ma b i n c o m bi nat i on wi th c he m ot hera p y  vers us 
c he m ot hera p y alo n e.  T he pri mar y e n d p oi nt of eac h st u d y is P F S per R E CI S T v 1. 1, a nal yze d via 
a Ba yesia n hierarc hical m o d el  t hat all o ws ( 1) a da pti ve b orr o wi n g o n effect-size (l o g hazar d 
r atio) bet wee n St u dies 
 a n d J V 0 2 a n d ( 2) a u g me nt i n g wit h hist orical c o ntr ol data via t he use 
of  i nf or mati ve pri or distri b uti ons c o nstr ucte d fr o m real-w orl d ( R W) c o ntr ol o ut c o mes.  See 
Secti o n 6. 6. 1. 2 f or full  mat he mat ical detail re gar di n g t he Ba yesia n hierarc hical m o del 
s pecificati o n.  I n eac h st u d y, a t otal of  3 0 p atie nts will be ra n d o mize d at a ratio of  2: 1 t o recei ve 
r a mu ci r u ma b i n c o m bi nati on wi t h a t u mor -s pecific c he m ot hera p y bac k b o ne vers us 
c he m ot hera p y al o ne .  A sc he mat ic dia gra m of t he st u dies a n d t heir statistical/ti mi n g li n ka ges is 
pr o vi de d i n Fi g ure 5. 1 .
Fi g ur e 5 . 1.
J V A A st u d y d e si g n.
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 ns, a safet y lea d-i n p eri o d will be o bser ve d via t he r olli n g 6 
decisi o n fra me w or k of S k ol ni k et al. ( 2 0 0 8).  T he safet y lea d-i n decisi ons will be e val uate d 
i n di vi d uall y for eac h of St u d y
a n d St u d y  J V 0 2.  Base d o n t he first 2 t o 6 d ose -li miti n g 
t o xicit y (D L T ) e val ua ble pati e nts ra n d omize d t o t he ra mu ci r u ma b ar m at t he pl a n ne d d ose f or 
eac h st u d y (
 or 9 m g/ k g f or St u d y  J V 0 2), t he ra m ucir u ma b d ose will be 
de- escalate d (
 or 6 m g/ k g f or St u d y  J V 0 2) s h o uld a n y of t he r olli n g- 6
‘ de-escalate’ crit eria be met i n a gi ve n st u d y base d o n o bser ve d D L Ts relate d t o ra m ucir u ma b 
e x p os ure. Ot her wise, e nr oll me nt will c o nt i n ue as pla n ne d f or t he st u d y.  If t he d ose is de-
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escalate d, a st u d y ma y be ter mi nate d f or safet y s h o uld a n y  of t he crit eria for 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 t he l o w d ose .  Ot her wise, e nr o ll me nt will c o nti n ue wi t h 
r a mu ci r u ma b d osi n g at t he lo wer d ose as pla n ne d. E nr oll me nt i n a st u d y 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 ra m ucir u ma b patie 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 1 patie nt .  Patie nts w h o c o m p lete t he lea d-i n peri o d 
will c o nt i n ue u ntil o ne of t he disc o nti n uati on cri teria are met. 
I nteri m F utilit y A n al ysis :  
 
  Li ke wise f or St u d y J V 0 2, a n i nteri m f utility a nal ysis will be 
trig 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 
a n d 
J V 0 2 wit h a mi ni m u m of 8 e ve nts i n St u d y J V 0 2. At t he i nteri m futilit y l oo k f or St u d y J V 0 2, t he 
Ba yesia n 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 of treat me nt s u periori t y 
( P F S H R < 1 f or S S patie nts) 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.  Details of t he Ba yesia n m o del of P F S t o be a p plie d at t he 
i nteri m f utility a nal ysis are a vaila ble i n S ectio n 6. 1 1 . 
Pri m ar y A n al ysis :  If a gi ve n st u d y 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 nal 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 t otal e nr olle d patie nts (acr oss b ot h St u dies 
a n d J V 0 2, re gar dless o f w het her or n ot o ne 
sto p pe d earl y  for f ut ility) .  
 
 
  Li ke wise, t o c o ncl u de s uccess f or the i n vest i gati on i n St u d y  
J V 0 2, t he Ba yesia n a nal ysis m ust yiel d a mi ni m u m o f 9 9 % p osteri or pr o ba bilit y of tr e at me nt 
s u periori t y ( P F S H R < 1) f or t he S S p o p ulati on. 
5. 1. 2.
D et er mi n ati o n of S a m pl e Si z e
T ra diti onal o perati n g c haracterist ics ass ociate d wit h t he pr o pose d Ba yesia n desi g n were
e val uate d via trial si m ulat i on .  Trial si m ulat i ons were i m ple me nte d usi n g t he statist ical s oftware 
pac ka ge R .  Si m ulat i on res ults were i n de pe n de nt l y re plicate d.  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 S t u dies 
a n d J V 0 2, j oi nt sce nari os of tr ut h i n b ot h 
a n d S S m ust be c o nsi dere d w he n e val uat i n g o perati n g c haracteristics for eac h st u d y  
i n di vi d uall y.  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 bjecti ve:

T y pe I err or :  T y pe I err or here refers t o t he e ve nt t he 9 9 % s uccess criteri o n is reac he d 
f or a gi ve n t u mor w he n i n realit y t he u n derl yi n g P F S H R (i n t hat t u m or) is e q ual t o 1 .  
Gi ve n t he stri n ge nc y o f t he Ba yesia n s uccess criterio n  (i.e., 9 9 % p osteri or pr o ba bilit y of  
s u periori t y), false p ositives are u nli kel y  in S t u dies 
 a n d J V 0 2.  I n partic ular, u n der 
t he joi nt  n ull sce nario i n w hic h neit her 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 ype I err or rate f or eac h st u d y 
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i n di vi d uall y is a p pr o xi matel y . 0 0 3.  I mp orta ntl y, t he T y pe I err or rate re m ai 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 dies 
a n d J V 0 2 .   
 
 
 
 
T hi s 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 criteri o 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 the y o u n g a d ult/ pe diatric 
setti n g, St u di es 
 a n d J V 0 2 are 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 ype 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 om r a mucir u ma b -base d t hera p y  (i.e.,     =  
= . 3 3 ), t he 
Ba yesia n a nal ysis o f P F S yiel ds st atistical p o wer of a p pr o xi matel y 8 2 % t o c o nclu de 
s uccess f or eac h st u d y in di vi d uall y  ( n ot e, t he p o wer f or s uccess i n at le ast 1 st u d y is 
> 8 2 %) .  F or refere nce, a tr a dit i onal l og ra n k a nal ysis of  a n i n di vi d ual st u d y at 2 4 P F S 
e ve nts ( 8 0 % of 3 0 patie nts e nr olle d) at  = . 0 0 3 ( 1-si de d) w o ul d carr y a p pr o xi matel y 
4 3 % p o wer at   =
.3 3 .  N ot e , t his calc ulati on di d n ot i ncl u de a f ut ility a nal ysis s uc h as 
t hat pr o p ose d i n St u di es 
a n d J V 0 2, s o a fa irer 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 ˂ 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 nari os (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 2 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 Secti o n 6. 6. 1. 6 .
T he stri n ge nt pri mar y  s uccess crit eria for eac h t u m or, Pr (   < 1) > 9 9 % , was cali brate d t o 
e ns ure t hat meeti n g t he pri mar y e n d p o i 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 pat ient  be nefit (a d ditio nal P F S) f or t he pe di atric/ yo u n g a d ul t p o p ul atio n s
of  int erest .  Base d o n a lar ge si m ulat i on st u d y  (joi nt res ul ts of all sce narios c o nsi dere d i n Sect i on 
6. 6. 1. 6 ), w he n t he 9 9 % p osteri or pr o ba bilit y t hres h ol d is reac he d, 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 pti o n o f 3 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 mately 3 m o nt hs of a d di tio nal P F S i n t his 
p o p ul at i on wi t h hi g h u n met me dical nee d.
5. 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 pat ient ’s e nr oll me nt i nt o t he stu d y, a n eli gi bilit y c hec k m ust be 
c o n d ucte d bet wee n t he i n vest i gati onal site a n d t he Eli Lill y a n d C o m pa n y  (Lill y ) cli nical 
researc h pers o n nel t o c o nfir m t hat eac h patie nt me ets all e nr oll me nt criteria.  U p o n c o nfir mati o n 
of  eli gi bility,  t he site will re gister t he patie nt b y assig ni n g t he pati e nt a u niq ue st u d y  
i de ntificati 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.
A p pr o xi matel y  3 0 pat ient s f or eac h of St u di es 
a n d J V 0 2 wi ll be ra n d o mize d i n a 2: 1 rati o 
t o recei ve ra m ucir u ma b i n c om bi nati o n wit h t u m or -s pecific c he m ot hera p y vers us c he m ot hera p y 
alo ne, res pect i vel y.  Ra n d o mizat i on will be c o n d ucte d se paratel y bet wee n St u di es 
 a n d 
J V 0 2.
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F or S t u dies 
a n d J V 0 2, ra n d o mizat i on will be stratifie d acc or di n g t o sta gi n g at rela pse 
( metastatic vers us locall y a d va nce d).
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6.
A Pri ori St ati sti c al M et h o d s
6. 1.
G e n er al C o n si d er ati o n 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 .  T he 
i nter pretatio n of  t he st u d y res ults will be t he res p o nsi bility of  t he Lill y Cli nical Researc h 
P h ysicia n/ Cli nical Researc h Scie nt ist ( C R P/ C R S) a n d statisticia n.  T he C R P/ C R S a n d statisticia n 
will als o be res p o nsi ble f or t he a p pr o priate c o n d uct of  int er nal re vie ws f or b ot h t he fi nal st u d y 
re p ort a n d a n y st u d y-r elat e d material t o be a ut h orize d b y Lill y for p u blicat i on.
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 N L Y if it c ha n ges a pri nci pal feat ur e 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 ustificati o n f or ma ki n g t he c ha n ge will be descri be d 
i n t he cli nical st u d y re p ort.
U nless i n dic ate d bel o w, all a n al yses (i ncl u di n g all t a bles, fi g ures, a n d listi n gs) will be 
c o n d ucte d se p ar atel y f or St u dies 
a n d J V 0 2 .  A list of a nal yses will be ge nerate d f or 
eac h st u d y, wit h t u mor -s pecific m o dificati ons m a de t o t he ass ociate d a nal ysis s pecificat i ons t o 
acc o m m o date a n y differe nces i n re p orti n g (e. g. , bas eli ne/ de m o gra p hic i nf or mat i on).
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 bel o w.  F ull detail re gar di n g 
s pecificati o n of pri or di stri b uti ons f or pres pecifie d Ba yesia n a nal yses are pr o vi de d i n Secti on 
6. 6. 1. 2 .
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 int er vals ( CIs) will ha ve 2 -si de d c o vera ge e q ual t o 8 0 % .
6. 1. 1.
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 o mize 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 o mize 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 o mize d a n d n ot b y act ual 
treat me nt recei ve d.  T his a nal ysis s et 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 m ize d patie nts w h o recei ve d a n y q ua ntity of  st u d y 
treat me nt, re gar dless o f t heir eli gi bilit y for t he st u d y . T he safet y 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
a n d safety 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 baseli ne a n d at least 1 p ost baseli ne e v alua 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 bset of pat ient 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.
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6. 1. 2.
H a n dli n g of Dr o p o ut s a n d Mi s si n g D at a
Baseli ne will refer t o t he last n o n missi n g o bser vat i o n bef ore first a d mi nistrati o n of a n y treat me nt 
u nless state d ot her wise.  Missi n g data, e xce pt f or dates, will n ot be i m p ute d.  W he n dates a re 
use d i n calc ulat i ons, missi n g da ys will be re place d wit h 1 5 t h of  t he mo nt h a n d missi n g 
d a y / mo n t h wit h 0 1 J U L Y.  W here wi n d o ws are all o we d f or data c ollecti o n a n d t here is m ore 
t ha n 1 rea di n g i n a n y wi n d o w, a p pr o priate c o nsi derati o n will be gi ve n as t o w het her o nl y 1 val ue 
fr om t he wi n d o w s h o ul d be use d, a n d if s o h o w it s h o ul d be c h ose n.  T his c o ul d eit her be t he 
mea n ( ge o metric mea n) or t he val ue cl osest t o t he mi d -p oi nt of t he wi n d o w or t he val ue cl osest 
t o t he data c ollecti on ti me of a n ot her varia ble if t he a nal ysis i n v ol ves ti me-matc he d a nal yses.
Detaile d ce ns ori n g r ules f or e val uati o n o f t he pri mar y P F S e n d p oi nt are pr o vide d i n Ta ble 6. 1 .
I n a nal yses of t u m or res p o nse, patie nts w h o are i ne val ua ble f or t u mor res p o nse per R E CI S T v 1. 1 
will be i ncl u de d i n t he de n omi nat ors. 
6. 1. 3.
M ulti pl e C o m p ari s o n s/ M ulti pli cit y
T he pri mar y  (efficac y) e n d p o i nt ( P F S) is t o be e val uate d via t he pres pecifie d Ba yesia n 
hierarc hical a nal ysis .  T he Ba yesia n m o del a n d s uccess criteria d o n ot ma ke f or mal a dj ust me nts 
f or mul tiplici t y as St u di es 
a n d J V 0 2 are 2 se parate i n vesti gati ons ; t hus c o ntr ol  of t he 
fa mil y wise err or rate bet wee n b ot h t u m ors is n ot pla n ne d.  W hile b orr o wi n g bet wee n St u di es 
 a n d J V 0 2 is a c o m p o ne nt of t he a nal ysis, i n di vi d ual c o ncl usi ons will be dra w n f or S S a n d 
  T he s uccess criteri o n ma y be reac he d i n 1 , b ot h, or neit her of t he 2 t u mor t y p es .  
Differe nt esti mates of P F S a n d P F S H R ( wit h ass ociate d p osterior cre di ble sets) will be o btai ne d 
f or eac h t u mor. 
N o a dj ust me nt s for m ul tiplici t y are pla n ne d f or a n y sec o n dar y or e x plorat or y  e n d p oi nts. 
6. 2.
P ati e nt Di s p o siti o n
A detaile d descr i pti o n of pati e nt dis p ositio n will be pr o vi de d f or St u dies 
 a n d J V 0 2 
se paratel y.  It will incl u de a s u m mar y  of t he n u m ber a n d perce nta ge of scree ne d patie nts 
ra n d omize d i n t he st u dies , reas o ns f or disc o nti n uati on fr om st u d y tr e at me nt, a n d reas o ns f or 
d isc o nti n uat i on fr om t he st u d y.  Reas o n f or disc o nti n uati on fr o m b ot h st u d y  treat me nt a n d t he 
st u d y will be liste d b y t he pre deter mi ne d cate g ories.  F or treat me nt disc o nti n uati o n, t hese i ncl u de 
pr o gressi ve disease, A E, deat h, wit h dra wal b y  s u bject, p h ysician decisi o n, n o nc o m p lia nce with 
st u d y dr u g, pr ot oc ol de viati on, st u d y  ter mi nate d b y t he i nstituti o nal  re vie w b oar d/et hical re vie w 
b oar d ( I R B/ E R B)/s p o ns or, l ost t o f oll o w-u p; f or s t u d y disc o nti n uati on, t hese i ncl u de st u d y  
ter mi nate d b y s p o ns or, wit hdra wal b y s u bject, lost t o f o ll ow- u p, deat h.  If t he reas o n f or 
di sc o nti n uati on is A E or deat h, t he ass ociate d A E or ca use of deat h will be re p orte d.  T he 
di s p ositio n will  als o be liste d.  All patient s ra n d omize d i n t he st u d y will be i ncl u de d i n t he 
s u m maries a n d listi n gs.
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6. 3.
P ati e nt C h ar a ct eri sti c s
P ati e nt c haracterist ics will be s u m marize d a n d liste d f or all patient s ra n d omize d b y treat me nt, 
i ncl u di n g:

P ati e nt de mo gra p hics (i ncl u di n g a ge, se x, race a n d et h nicit y,  scree ni n g hei g ht a n d 
w ei g ht, a n d scree ni n g deri ve d b o d y  s urface area)

Baseli ne disease c haracterist ics (i ncl u di n g disease sta gi n g at baseli ne a n d i nitial 
di a g n osis, perf or m a nce stat us at  baseli ne, ti me-t o-rela pse after fr o nt-li ne t hera p y f or 
a d va nce d disease, n u m ber of pri or li nes of s yste mic t hera p y  for a d v a nce d disease, prior 
r a diot h era p y, prior s ur ger y  a n d ass ociate d o utc o me )
6. 4.
Tr e at m e nt C o m pli a n c e
All i ntra ve n o us (I V) stu d y dr u gs will be a d mi nistere d o nl y at t he i n vest i gati onal sites b y t he 
a ut h orize d st u d y site pers o n nel.  As a res ult, treat me nt c o mplia nce is e ns ure d f or I V dr u gs.  All 
st u d y dr u gs i n St u d y  J V 0 2 are t o be a d mi nistere d i ntra ve n o usl y; t hus s u m mar y  of treat me nt 
c o mplia nce will  not be a p plica ble i n St u d y  J V 0 2.
6. 5.
C o n c o mit a nt a n d P o st -Di s c o nti n u ati o n T h er a p y
Pri or a n d c o nc o mita nt m e dicat i ons a n d t hera pies (e. g., tra nsf usi ons) will be liste d a n d 
s u m marize d b y tr e at me nt ar m f or t he safety p o p ul atio n i n eac h st u d y .
T he n u m bers a n d perce nta ges of patie nts recei vi n g p ost disc o nt i n uati on a nt ica ncer t hera pies will 
be pr o vi de d b y  t yp e of  t her a p y (s ur ger y, r a diot h era p y, or s yste mic t hera p y), a n d b y dr u g class 
a n d/ or na me, o verall a n d b y li ne of t hera p y.
6. 6.
Effi c a c y A n al y s e s
6. 6. 1.
Pri m ar y O ut c o m e a n d M et h o d ol o g y
T he pri mar y  efficac y e nd p oi nt, P F S , will be a nal yze d via a j o i nt hierarc hical Ba yesia n m o del
(see Secti o n 6. 6. 1. 1 ).  W hile i n di vi d ual i nfere nces/c o ncl usi o ns will be ma de f or eac h St u d y  
a n d St u d y J V 0 2, a si n gle joi nt  Ba yesia n hierarc hic al mo d el  will be fit t o t he P F S data fr o m b ot h 
St u d y   
an d St u d y  J V 02 as descri be d bel o w .  T he Ba yesia n a nal ysis i n v o l ves ( 1) a u g me nti n g 
t he c o ntr ol ar ms wit h matc he d (t u m or -s pecific) hist orical R W data vi a a p o wer prior a p pr oac h 
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a n d ( 2) a da pti ve b orr o wi n g of P F S effect -size (lo g H R f or treat me nt vers us c o ntr ol) bet wee n 
St u d y  
 a n d St u d y J V 0 2 via a ra n d om- effects s pecificat i on wi t hi n t he Ba yesia n hierarc h y. 
W hile P F S fr o m St u di es 
 a n d J V 0 2 will be m o dele d withi n t he sa me Ba yesia n hierarc hical 
m o d el f or t he pri mar y a nal ysis, t he mo d el  is c o nstr ucte d s uc h t hat res pecti ve s uccess criteria ca n 
a n d will be e val uate d se paratel y (a n d li ke wise esti mates of H R wit h ass ociate d cre di ble i nter vals 
will differ bet wee n St u dies 
 a n d J V 0 2).  O ne, b ot h, or neit her of St u di es 
 a n d J V 0 2 
ma y meet t he criteri o n f or s uccess o n t he basis of P F S .  T he pri mar y  s uccess criteria at t he 
pri mar y  a nal ysis (t o occ ur w he n a p pr o xi matel y 8 0 % of patie nts e nr olle d o n St u di es 
 a n d 
J V 0 2 ha ve ha d d oc u me nte d PF S e ve nts) are:


F or St u d y  J V 0 2, t he Ba yesia n mo d el  must yiel d p osteri or Pr (    < 1 |    ) > 9 9 %
i n or der t o call s uccess i n S S

N o te t hat if St u di es 
 or J V 0 2 st o p earl y f or f utility (at t he f utility i nteri m a nal ysis) 
t hat st u d y ca n n ot clai m s uccess at f ut ure a nal yses.
T o c orres p o n d wit h t he 9 9 % s u peri orit y crit erio n, 9 8 % e q ual -taile d p osterior cre di ble i nter vals 
will be pr o vi de d alo n g wi t h esti mates ( p osteri or me dia ns) of  P F S H R (treat me nt vers us c o ntr ol) 
i n eac h t u mor (i .e., se paratel y f or St u di es 
 a n d J V 0 2).  Pl ots of  esti mate d ( Wei b ull) s ur vi val 
c ur ves will be pr o vi de d f or eac h st u d y se paratel y.  Esti mates of la n d mar k P F S a t mo nt hs 3, 6, 9, 
a n d 1 2 ( alo n g wi t h 8 0 % e q ual-taile d p osterior cre di ble i nter vals) will be pr o vi de d. 
6. 6. 1. 1.
Pri m ar y P F S E n d p oi nt D efi niti o n a n d C e n s ori n g R ul e s
Pr o gressi o n -free s ur vi val ( P F S) is defi ne d as t he ti me fr om ra n d omizat i on u nt il t he first 
i n vesti gat or-deter mi ne d o bject i ve pr o gressi o n as defi ne d b y R E CI S T v 1. 1, 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 asse ss 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 Ta ble 6. 1 ).
T a bl e 6 . 1.
P r o gr e s si o n- Fr e e S u r vi v al 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
I n vesti gat or assesse d t u m or pr o gressi o n or 
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 ra di ol o gical assess me nt 
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 gical 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 ra di ol o gical 
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 
ran d o mizati o n b,c
Ce ns ore d
Date of ra n d o mizati o n
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Ne w a ntica ncer treat me nt starte d a n d n o 
t u m or pr o gressi o n or deat h wit hi n 1 4 da ys
Ce ns ore d
Date of a de q uate ra di ol o gical assess me nt 
bef ore (start of ne w t hera p y + 1 4 da ys) or date 
of ra n d o mizati o n ( w hic he ver is later)
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 ra di ol o gical t u m or 
assess me nt or ra n d o mizati o n ( whi c he ver is 
later)b,c
Ce ns ore d
Date of last a de q uate ra di ol o gical assess me nt 
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; S D = sta ble disease.
a
S y m pt o ma tic deteri orati o n (i.e., s y m pt o matic pr o gressi o n t hat is n ot ra di ol o gicall y c o nfir me d) will n ot be 
c o nsi dere d as t u m or pr o gressi o n.
b
A de q uate ra di ol o gical t u m or assess me nt 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
Ra di ol o gic i ma gi n g f or t u m or assess me nt will be perf or me d e ver y 6 wee ks ( ± 7 da ys) after ra n d o mizati o n 
(re gar dless of treat me nt dela ys) d uri n g t he St u d y Treat me nt Peri o d, u ntil disease pr o gressi o n O R st u d y 
c o m pleti o n or 1 4 m o nt hs after ra n d o mizati o n, w h ic hever occ urs first.  Refer t o f o ot n ote b f or a n y patie nt w h ose 
disease has n ot pr o gresse d b y 1 4 m o nt hs after ra n d o mizati o n.  A n y patie nt w h ose disease has n ot pr o gresse d b y 
1 4 m o nt hs after ra n d o mizati o n will be e val uate d f or res p o nse e ver y 1 2 wee ks ( ± 7 da ys) fr o m 1 4 m o nt hs after 
ra n d o mizati o n, u ntil disease pr o gressi o n O R st u d y c o m pleti o n O R 3 years after ra n d o mizati o n, w hic he ver occ urs 
first; t he n as per sta n dar d cli nical practice after t hat.  
6. 6. 1. 2.
B a y e si a n Hi er ar c hi c al M o d el f or Pri m ar y P r o gr e s si o n- Fr e e S ur vi v al
E n d p oi nt 
Let  a n d   de n ote t he o bser ve d P F S e ve nt/ce ns ori n g ti me a n d e ve nt i n dicat or (i.e.,   = 1 if 
P F S e ve nt a n d   = 0 if ce ns ore d), res pecti vel y, f or eac h pr os pecti ve patient  .  Let  () = 1, 2
i n dicate t he t u m or c o h ort t o w hic h patie nt  bel o n gs.  We c o nsi der a para metric (i n t his case 
Wei b ull) s ur vi val m o del t o yiel d a p pr o priate bala nce of fle xi bilit y/ sta bility gi ve n s mall sa m ple 
sizes.  Eac h patie nt  t hus c o ntri b utes t he f o ll owi n g t o t he j oi nt  li keli h o o d:
 (, | ) = e x p {−( | )} ⋅ℎ(| )  ,
w here ℎ(| ) de n otes t he Wei b ull hazar d:
ℎ(| ) =
e x p   () ⋅  () ⋅ () ⋅ () ⋅  () a n d  (| ) de n otes t he c orres p o n di n g c u m ulati ve hazar d:
 (| ) = e x p   () ⋅  () ⋅ () ⋅  () .
I n t he a b o ve n otati o n, we n ote t hat     = e x p (  ) a n d        = e x p (  ).  T he q ua ntities 
  ,   ,   , a n d   are t he us ual s ha pe a n d rate para meters c haracterizi n g t he Wei b ull fa mil y o f 
li keli h o o d distri b uti ons (s u bscri pts i n dicat i n g t u m or c o h ort).
T he m ec ha nis m wit h w hic h we facilitate t he a da pti ve b orr o wi n g bet wee n t u m ors c o m prises 
esse nt iall y a ra n d om- effects met a-a nal ysis of t he l o g H Rs :
  ,  ~  (,   ),
wi t h  ~ ( 0, 1) a n d  ~ ( 0, 1) . 
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T he pri or di stri b utio n f or t he bet wee n -t u mor sta n da r d de viati o n  is a n i m p orta nt dri ver of t he 
de gree o f b orr o wi n g bet wee n t u m ors.  T his pri or distri b ut i on ma i ntai ns c o nser vati vis m re gar di n g 
varia bilit y (of  r a mu ci r u ma b P F S effect size) bet wee n t u m ors base d o n hist orical data acr oss t he 
r a mu ci r u ma b pr o gram .  A Ba yesia n ra n d o m- effects met a-a nal ysis o f t he lo g P F S H R o bser ve d i n 
all c o m p lete d ra n d o mize d p hase 3 trials of r a mu cir u m a b was c o n d ucte d .  N ote t hat t hese st u dies 
t o get her c o m prise a ver y heter o ge ne o us p o ol of t u m or t ypes rel at i ve t o St u dies 
a n d J V 0 2 
( 2 s u bt y pes of s oft-tiss ue sarc oma) .  T he res ult i n g p osteri or me dia n of t he sta n dar d de viati o n 
para m eter ( g o ver ni n g varia bilit y bet wee n tr ue l o g P F S H R s) was e q ual t o a p pr o xi matel y . 2, 
w hic h is s u bsta nt iall y bel o w t he me dia n a n d u p per li mit of t he ( 0, 1) pri or c h ose n here .  
I mp orta ntl y, w e n ote t hat ( u n der t he pr o p ose d pri or f or ) e ve n i n t he e ve nt of ver y str o n g 
heter o ge neit y i n tr ue effect size (     = 1 a n d 
or vi ce versa) t he T y pe I err or f or 
t he pri mar y decisio n  r ule i n t he ne gat i ve t u m or is still c o ntr olle d bel o w 2 % ( 1-side d) (see Ta ble 
6. 5 .). 
T he h y per pri or distri b ut i on f or t he acr oss-t u mor m ea n para meter  has bee n set t o a N or mal 
di stri b uti on wi t h mea n e q ual t o zer o a n d sta n dar d de viati on e q ual t o 1, re prese nt i n g a s o me w hat 
c o nser vati ve pri or ( yet q uite diff use o n t he l o g H R scale).
6. 6. 1. 3.
Pri or Di stri b uti o n s f or C o ntr ol P r o gr e s si o n-F r e e S ur vi v al
T o c o m plete t he a b o ve Ba yesia n hierarc h y , w e must s pecif y t he pri or distri b uti o ns f or 
para m eters g o ver ni n g t he Wei b ull s ur vi val c ur ves f or patie nts recei vi n g t he c o ntr ol re gi me ns, 
na mel y t he para m eters   ,   ,   , a n d   .  T he pri or distri b uti o ns f or t hese para meters will be 
deri ve d fr o m R W P F S data o btai ne d fr o m pati e nts wit h 
 a n d S S treate d wit h 
c he m ot hera p y i n t he rela pse d setti n g, matc he d t o t he pr os pecti ve pat ient s e nr olli n g o n t he 
r a mu ci r u ma b ar ms of St u d ies
 a n d J V 0 2.  As c o ntr ol o utc o me s must be all o we d t o differ 
bet wee n t he 2 t u mors, t he matc hi n g al g orit h m a n d s u bse q ue nt pri or s pecificat i on will be 
perf or m e d se paratel y wit hi n eac h t u m or. 
At  t he pri mar y a nal ysis, a t otal of 2 0 hist orical R W patient s per t u m or will be matc he d t o t he 
c orr es p o n di n g 2 0 pr os pecti ve pat ient s (e nr olle d o n t he ra m ucir u ma b ar m) acc or di n g t o t he 
pres pecifie d al g orit h m pr o vi de d bel o w.  A si m ple p o wer pri or a p pr oac h (I bra hi m et al. 2 0 1 5) 
will be a d o pte d t o f or mall y i nc or p orate t he matc he d R W hist orical c o ntr ol s u bje cts i nt o t he 
Ba yesia n a nal ysis o f pr os pecti ve P F S i n a ma n ner t hat a p pr o priatel y  d o w n wei g hts t he i nfl ue nce 
of  t he hist orical d at a.  Precisel y as a b o ve (for t he pr os pecti ve data) , let    a n d     de n ote t he 
o bser ve d P F S e ve nt/ce ns ori n g t i me a n d e ve nt f or eac h hist orical patie nt .  Let    () = 1, 2
i n dicate t he t u m or c o h ort t o w hic h hist orical c o ntr ol patie nt  bel o n gs.  Eac h hist orical patie nt t hus c o ntri b utes t he f o ll owi n g t o t he re wei g hte d j o i nt li keli h o o d:
 (, | ) =  e x p −     ⋅ℎ        ,
w here ℎ(| ) de n otes t he Wei b ull hazar d:
ℎ(| ) =
  () ⋅ () ⋅  () a n d  (| ) de n otes t he c orres p o n di n g c u m ulati ve hazar d:
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 (| ) =   () ⋅  () .
N ote t hat here t he para meters   ,   ,   , a n d   are e xactl y t h ose w hic h a p pear i n t he j o i nt 
li keli h o o d f or t he pr os pecti ve data a b o ve, s o t hat t he re wei g hte d li keli h o o d f or t he hist orical data 
(t o get her wit h t he h y per pri ors disc usse d i n t he f oll o wi n g para gra p h) f u ncti ons as a n i nf or mat i ve 
pri o r for t h ose q ua ntit ies.  I mp orta ntl y, t he p o wer para meter   will be set t o a pres pecifie d val ue 
of  . 5 t o s u bsta ntiall y d o w n wei g ht t he i nfl ue nce of t he hist orical c o ntr ol data relat i ve t o t he 
pr os pecti ve c o ntr ol data, c orres p o n di n g t o a pri or effecti ve sa m ple size i n eac h t u m or of 
a p pr o xi matel y 1 0 e ve nts (a n d fe wer if a n u m ber of t he matc he d hist orical patie nts were ce ns ore d 
f or P F S).
Fi nall y , we s pecif y h y per priors f or   ,   ,   , a n d   .  F or   a n d   , we ass u me i n de pe n de nt 
tr u ncate d n or mal pri ors,      (1, 1 ) ⋅   > 0  ( w hic h ce nters t he c ur ves wea kl y at t he m ore 
parsi m o ni o us e x p o ne nt ial s ur vi val m o del), a n d f or   a n d   , we ass u me diff use/ n o ni nf or mat i ve 
i n de pe n de nt ga m ma pri ors,      ( . 1, . 1).
If a de q uate real-w orl d o ut c o m es are n ot a vaila ble at i nteri m (see Secti o n 6. 1 1 ), t he f utility 
a nal ysis will use t he Ba yesia n hierarc hical m o del i n Secti o n 6. 6. 1. 2 usi n g o nl y pr os pecti ve 
pati e nts a n d t he n o ni nf or mat i ve h y per pri ors f or   ,   ,   , a n d   descri be d i n t he pre vi o us 
para gra p h. 
6. 6. 1. 4.
R etr o s p e cti v e ( R e al W orl d) D at a t o I nf or m C o ntr ol Pri or s
T he pri or di stri b utio ns f or P F S o n t he c o ntr ol ar ms i n St u d y
 a n d St u d y  J V 0 2 will be 
c o nstr ucte d (as descri be d a b o ve) fr o m P F S o utc o mes f or patie nts wit h rela pse d 
 or S S 
treate d wit h c he m ot hera p y or paz o pa ni b i n t he R W setti n g.  T hese data will be o btai ne d fr o m 
c hart re vie ws c o n d ucte d at i nst ituti o ns i ncl u di n g U S sites .  Eli gi ble patie nts will ha ve bee n 
i nitiall y dia g n ose d wit h  
or S S bef ore a ge 4 0 years.  T hi s a ge li mit is hi g her t ha n t he 
eli gi bilit y crit erio n f or St u dies 
a n d J V 0 2 , as pat h olo g y  a n d o utc o mes are n ot e x pecte d t o 
var y  base d o n a ge i n t hese diseases; t heref ore, t he a ge ra n ge was e x pa n de d t o facilitate i m pr o ve d 
matc hi n g o n ot her i m p orta nt pr o g n ostic fact ors.  Eli gi ble patie nts m ust ha ve pr o gresse d o n at 
least 1 c o urse of c he m ot hera p y f or rela pse d, rec urre nt , or p r ogressi ve disease i n or der t o esti mate 
P F S f or at least 1 li ne of t hera p y.  V ari a bles t o be e xtracte d i ncl u de patie nt a n d baseli ne/ disease 
c haracterist ics, as well as treat me nts (s ur ger y, ra di ot hera p y, c he mot h era p y) a n d o utc o mes si nce 
i nitial  
 or S S dia g n osis.  Pr o gressi o n dates will be base d pri maril y o n p h ysicia n n otes a n d 
will n ot re q uire re -i nter pretatio n of  r a diol o gi c sca ns.  T he tar get sa m ple size is 1 0 0 c harts eac h 
f or 
a n d S S at  t he ti me of t he fi nal a nal ysis. 
6. 6. 1. 5.
Pr e s p e cifi e d Hi st ori c al C o ntr ol M at c hi n g Al g orit h m
A pr o pe nsit y- base d matc hi n g alg ori t h m will  be ut ilize d t o matc h eac h of t he 2 0 pr os pecti ve 
r a mu ci r u ma b patient s wit h a hist orical c o ntr ol patie nt (c o n d ucte d se paratel y withi n eac h t u m or) .  
T he i n de pe n de nt ( baseli ne/ de m o gra p hic) v ari a bles t o be use d f or p ur p oses of matc hi n g are 
pr o vi de d i n Ta ble 6. 2 .  Hist orical patie nts wit h c hart re vie ws c o ntai n i n g m ult i ple eli gi ble li nes of 
t hera p y will be use d as disti nct o bser vati ons f or matc hi n g, wi t h P F S calc ulate d fr o m t he r ele va nt 
li ne of t hera p y. T he de pe n de nt varia ble is t he bi nar y c o h ort i n dict o r ( pr os pecti vel y ra n d omize d 
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r a mu ci r u ma b s u bject vers us hist orical c o ntr ol s u bject).  T he pr o pe nsit y sc ore mo d el s 
(c o nstr ucte d se paratel y f or St u d y 
 a n d St u d y J V 0 2) will be de vel o pe d usi n g ma i n-effects 
l ogist ic re gressi on (e. g., PR O C L O GI S TI C i n S AS ).
A nearest -nei g h b or pr o pe nsit y- s c or e matc hi n g alg ori t h m will  be i m ple me nte d o n t he l o gi t of 
pr o pe nsit y sc ore a gai nst a cali per of wi dt h e q ual t o 0. 2 of t he p o ole d sta n dar d de viat i on of t he 
l ogi t of t he pr o pe nsit y sc ores.  Matc hi n g wit h re pl ace me nt will be use d s o t hat a u ni q ue c o h ort of 
matc he d hist orical patie nts is o btai ne d re gar dless of a n y ar bitrar y  or deri n g of t he pr os pecti ve 
patie nts .  I n t he case of tie d pr o pe nsit ies, all tie d nearest nei g h b ors will be i nc or p orate d i nt o t he 
p o wer pri or, wit h t he p o wer para meter f or eac h c orres p o n di n g li keli h o o d ter m si m pl y a dj uste d 
d o w n war d fr o m t he origi nal   = . 5 t o t he q ua ntity . 5 /  w here   is t he n u m ber of tie d 
matc hes o btai ne d f or pr os pecti ve pat ient  .
If f or a n y reas o n (e. g., s mall sa m ple size) t he m o del-base d calc ulati o n of pr o pe nsit ies is n ot 
feasi ble, t he metric-base d Ma hala n o bis nearest -nei g h b or ( wit h re place me nt) a p pr oac h will be 
use d f or m atc hi n g. If Ma hala n o bis
matc hi n g is als o n ot feasi ble (e. g. sa m ple c o varia nce matri x 
ca n n ot be esti mate d or i n verte d), real-w orl d o utc o mes will be o mit te d fr o m t he a nal ysis. 
T he pr o pe nsit y m o d el  a n d matc hi n g al g orit h m will be e xec ute d at b ot h the i nteri m f ut ility 
a nal ysis a n d t he fi nal a nal ysis of P F S. T he pr o pe nsit y m o del will be u p date d at t he fi nal a nal ysis 
base d o n t he f ull p o p ulat i on of pr os pecti vel y ra n d o mize d (ra m ucir u ma b) patie nts a n d hist orical 
c o ntr ol p atie nts. T he s u bset of patie nts w h o were i ncl u de d i n t he i nteri m a nal ysis ma y t heref ore 
be matc he d t o differe nt hist orical c o ntr ol patie nts at t he fi nal a nal ysis t ha n at t he i nteri m a nal ysis.
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T a bl e 6. 2
V ari a bl e s f or M at c hi n g R e al - Worl d D at a ( Hi st ori c al C o ntr ol) a n d 
Pr o s p e cti v e P ati e nt s
V ari a ble N a me
Descri pti o n
C ate g ories/ U nits
Le vels f or M atc hi n g
A ge
Patie nt a ge o n C 1 D 1 of li ne of 
s yste mic t hera p y f or a d va nce d 
disease i n t he 
rela pse d/rec urre nt/ pr o gressi ve 
setti n g. 
Y ears

< 1 8

≥1 8

Missi n g
Li ne of T hera p y
Li ne of s yste mic t hera p y f or 
a d va nce d disease
Inte ger

1 n d li ne

2 r d li ne a n d 
a b o ve 

Missi n g
Ti me- t o-Rela pse
Ti me bet wee n t he last date of 
a d mi nistrati o n of i nitial c o urse of 
t hera p y (s yste mic, ra di ot hera p y, 
s ur ger y) a n d date of dia g n osis f or 
rela pse d/rec urre nt disease.  If 
disease pr o gresse d d uri n g t he i nitial 
treat me nt, ti me-t o-rela pse is 0 
( m o nt hs).
Y ears
S S:

< 2 y ears

≥2 y ears

Missi n g
Metastatic Disease at 
Rela pse
I n dict or of t he prese nce of 
metastases as of C 1 D 1 of li ne of 
s yste mic t hera p y f or a d va nce d 
disease i n t he 
rela pse d/rec urre nt/ pr o gressi ve 
setti n g.
Y ears

Yes

N o

Missi n g
I nitial T u m or Size   
Size of t u m or at i nitial dia g n osis of 
S S or 
C m
S S:

< 5 c m

≥5 c m

Missi n g
A b bre viati o ns:  C 1 D 1 = C ycle 1 Da y 1; C m = ce nti meter; 
; S S = 
sy n o vial sarc o ma.
6. 6. 1. 6.
Si m ul ati o n s of Pri m ar y P r o gr e s si o n- Fr e e S ur vi v al E n d p oi nt 
Tra di tio nal o perati n g c haracterist ics (e. g., T y pe I a n d T y pe II err or rates) f or t he pr o p ose d 
Ba yesia n a nal ysis ha ve bee n e val uate d via trial si m ulat i on .  F or si m plicit y, i n all sce nari os, P F S 
o utc o m es were si m ulate d fr o m e x p o ne ntial distri b uti o ns ( n oti n g t hat t he act ual Ba yesia n m o del 
f or t he P F S anal ysis all o ws n o nc o nsta nt hazar d).  T hr o u g h o ut, a fi xe d hist orical c o ntr ol pri or (t he 
sa me f or eac h t u m or) f or t he rate a n d s ha pe para meters of t he c o ntr ol Wei b ull c ur ves was 
c o nstr ucte d wit h pri or effect i ve sa m ple size of a p pr o xi matel y 1 0 e ve nts t o mi mic t he realit y of  
t he a b o ve pri or c o nstr ucti o n al g orit h m.  T o e m be d realist ic c o ntr ol ass u m pti ons, t he mar gi nal 
pri or f or t he rate para meter was set t o a Ga m ma ( 1 0, 4 2. 7 8) base d o n a di git ize d Ka pla n-Meier 
c ur ve f or P F S o utc o mes i n pat ient s wit h S S w h o receive d ge mcita bi ne i n c o m bi nat i on wi t h 
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d oceta xel i n t he rela pse d setti n g ( A b o u har b et al. 2 0 1 4) .  T he me dia n o f t his prior is . 2 2 6 .  
E xce pt f or t he sce nari os i n Ta ble 6. 3 (i n w hic h t he i m pact of biase d hist orical c o ntr ols is 
e x plicit l y st u die d), t he pr os pecti ve P F S data o n c o ntr ol was si m ulate d fr o m t he e x p o ne ntial 
di stri b uti on wi t h hazar d e q ual t o . 2 2 6.  T he mar gi nal pri or f or t he s ha pe para meter was set t o a 
U nif or m  (. 5, 1. 5), s o t hat its ce nter was c o nsiste nt wit h t he e x p o ne ntial ass u m pti o n fr om w hic h 
t he patie nt data were si m ulate d. 
Ta ble 6. 3 pr o vi des t he si m ulate d pr o ba bilit ies of passi n g t he i nteri m f utility cri t erio n (c o nti n ui n g 
e nr o ll me nt) a n d passi n g fi nal ( pri mar y) s uccess criteri o n f or eac h of 7 sce nari os i n w hic h t he 
u n der l yi n g H R is t he sa me i n b ot h t u m ors.  N ote t hat t o pass t he fi nal s uccess criteri o n, t he 
i nteri m crit erio n m ust al s o be passe d ( ot her wise t he fi nal a nal ysis w o ul d ne ver ha ve bee n 
c o n d ucte d) s o t he last 2 c o l um ns act uall y pr o vi de t he pr o ba bilit y of passi n g b ot h t he i nteri m a n d 
fi nal criteria.  We see t hat u n der t he j oi nt n ull ( Sce nari o 1), t he stri n ge nt s uccess criteri o n ( 9 9 % 
Ba yesia n pr o ba bilit y of s u peri orit y)  yiel ds ver y str o n g c o ntr ol of T ype I err or .  I n dee d, w he n 
neit her t u mor be nefits 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, t he 
pr o ba bilit y o f passi n g t he pri mar y  s uccess crit erio n is a b o ut . 0 0 3 i n eac h t u m or .  Fr o m  Sce nari o 
7, we see t hat w he n b ot h t u m ors be nefit n ota bl y fr o m t he a d dit i on of ra m ucir u ma b ( H R =. 3 3 i n 
b ot h t u m ors), u n der t he pr o p ose d Ba yesia n desi g n, t he p o wer f or eac h t u m or i n di vi d uall y is 
8 2 %. 
T a bl e 6. 3.
Si m ul at e d O p er ati n g C h ar a ct eri sti c s
Sce n ari o 
N u m ber
Tr ue H az ar d R ati o
Pr( P ass I nteri m)
Pr( P ass Fi n al)
S S
S S
S S
1
1. 0 0
0. 4 4
0. 0 0 3
2
0. 8 0
0. 6 7
0. 0 3
3
0. 7 0
0. 7 9
0. 0 7
4
0. 6 0
0. 8 9
0. 1 8
5
0. 5 0
0. 9 6
0. 3 7
6
0. 4 0
0. 9 9
0. 6 4
7
0. 3 3
0. 9 9
0. 8 2
A b bre viati o ns:  
; Pr =pr o ba bilit y ; S S = sy n o vial sarc o ma.
A d dit i onal si m ulati o n w or k was perf or me d t o e val uate o perati n g c haracteristics of t he desi g n 
u n der sce nari os of p ote ntial pri or/ data c o nflict .  I n Ta ble 6. 4 , we e val uate t he i m pact of 
p ote nti all y biase d hist oric al c o ntr ol o utc o mes o n T y pe I err or rates i n t he pr os pecti ve st u d y .  B y 
‘ biase d’, we me a n t hat t he hist orical c o ntr ol data lea d t o pri ors t hat are l ocate d a wa y  fr o m t he 
tr ue para meters g o ver ni n g P F S o utc o mes f or t he pr os pecti ve c o ntr ol s u bjects.  I n Sce nari os 8- 1 1 , 
t he priors f or c o ntr ol  P F S hazar d were ce ntere d at a val ue of . 2 2 6 i n eac h t u mor wi t h varia bility 
c orres p o n di n g t o a p pr o xi matel y 1 0 e ve nts.  H o we ver, i n eac h S ce nario 8- 1 1, t he tr ue hazar d o n 
c o ntr ol was set t o s o me val ue s m aller t ha n . 2 2 6 (i n b ot h t u m ors si m ulta ne o usl y) w hic h, of  
c o urse, has t he i m pact of i nflat i n g T ype I err or .  Fr o m Sce nari o 1 1, we see t hat e ve n u n der 
s u bsta ntial pri or/ data c o nflict (i.e. , w he n t he pr os pecti ve vers us hist orical c o ntr ols differ b y a H R
of  . 6 5 i n b ot h t u mors), t he T y pe I err or rate re mai ns s mall ( < 2 %).  T hi s is t he res ult of ( 1) a ver y 
stri n ge nt s uccess criteri o n a n d ( 2) pri or effecti ve sa m ple size of o nl y  1 0 e ve nts per t u mor s o t hat 
t he pr os pecti ve data are n ot o ver w hel me d b y t he pri ors. 
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T a bl e 6. 4.
I m p a ct of Bi a s e d Hi st ori c al C o ntr ol s o n T y p e I Err or
Sce n ari o 
N u m ber
Tr ue C T R L H az ar d
H R ( Pr os p. vs. Hist. C T R L)
Pr( P ass Fi n al)
S S
S S
S S
8
. 2 1 4 7
0. 9 5
0. 0 0 6
9
. 1 9 2 1
0. 8 5
0. 0 0 8
1 0
. 1 6 9 5
0. 7 5
0. 0 1 4
1 1
. 1 4 6 9
. 6 5
0. 0 1 8
A b bre viati o ns:   C T R L = C o ntr ol; 
; his t. = hist orical; H R = hazar d 
rati o; Pr = pr o ba bilit y ; pr os p = pr os pecti ve; S S = sy n o vial sarc o ma.
All sce nari os a b o ve ass u me treat me nt vers us c o ntr ol H R = 1 (i n b ot h t u m ors) s o t hat  Pr( Fi nal) 
re prese nts T ype I err or ( u n der j o i nt n ull). 
Ta ble 6. 5 pr o vi des o perati n g c haracteristics u n der sce nari os i n w hic h o nl y 1 t u mor be nefit s fr o m 
t he a d ditio n of  r a mu ci r u ma b t o c he mot h era p y.  F or e xa m ple , i n eac h S ce nario 1 2- 1 6, t he tr ue H R 
was set e q ual t o 1 i n S S b ut s o me val ue 
.  M o st n ota bl y, u n der ver y str o n g 
heter o ge neit y i n effect-size ( Sce nario 1 6) t he T y pe I Err or is still c o ntr olle d bel o w 2 % f or t he 
ne gat i ve t u m or ( S S) des pite t he Ba yesia n b orr o wi n g fr om a p ositive t u m or .  O n t he ot her ha n d, 
t he p o wer t o c o ncl u de s uccess i n t he p osit i ve t u m or ( wit h H R =. 5) is of c o urse l o wer t ha n w he n 
b ot h t u m ors be nefit b y t hat mar gi n (see Sce nari o 5) .  Vie we d fr o m a Ba yesia n pers pect i ve, t his is 
a n e x pecte d (a n d desira ble) attri b ute of t he m o del.  O bser vi n g ne gati ve res ults i n 1 s u bty p e 
s h o uld s o m e w hat discre dit p ositive o bser vat i ons i n t he ot her s u bty pe w hile p osit i ve res ults i n 
b ot h s u bty pes s h o ul d be rei nf orci n g. 
T a bl e 6 . 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
Sce n ari o 
N u m ber
Tr ue H az ar d R ati o
Pr( P ass I nteri m)
Pr( P ass Fi n al)
S S
S S
S S
1 2
1
0. 5 0
0. 0 0 8
1 3
1
0. 5 2
0. 0 0 7
1 4
1
0. 5 7
0. 0 1 1
1 5
1
0. 5 8
0. 0 1 2
1 6
1
0. 6 0
0. 0 1 5
A b bre viati o ns:  
; Pr = Pr o ba bilit y; S S = sy n o vial sarc o ma.
Ta ble 6. 6 pr o vi des o perati n g c haracteristics u n der t he sce nari o w here real -w orl d c o ntr ol s are n ot 
i nc or p orate d i n t he i nteri m a nal ysis. Rat her t ha n usi n g a Ga m ma( 1 0, 4 2. 7 8) pri or f or t he rate 
para m eters, a n o ni nf or mat i ve Ga m ma( 0. 1, 0. 1) pri or is use d. T he m ar gi nal prior f or t he s ha pe 
para m eter is ke pt as a U nif or m (. 5, 1. 5 ) as i n pre vi ous si m ulat i ons . T he pri or/ data c o nflict 
sce nari os (Ta ble 6. 4 ) are o mitte d fr o m t his si m ulati on .
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T a bl e 6. 6.
I m p a ct o n I nt eri m A n al y si s w h e n N o R W d at a i s In cl u d e d
I ncl u de R W
O utc o mes
N o R W O utc o mes
Sce n ari o 
N u m ber
Tr ue H az ar d R ati o
Pr( P ass I nteri m) 
Pr( P ass I nteri m)
S S
S S
S S
1 
1
0. 4 4
0. 3 9
2
0. 8
0. 6 7
0. 5 7
3
0. 7
0. 7 9
0. 6 9
4
0. 6
0. 8 9
0. 8
5
0. 5
0. 9 6
0. 8 9
6
0. 4
0. 9 9
0. 9 6
7
0. 3 3
0. 9 9
0. 9 8
1 2 
1
0. 5
0. 4 5
1 3 
1
0. 5 2
0. 4 8
1 4 
1
0. 5 7
0. 5
1 5 
1
0. 5 8
0. 5 3
1 6 
1
0. 6
0. 5 4
C o n d ucti n g t he i nteri m a nal ysis wi t ho ut i nc or p orati o n of hist orical c o ntr ol i nf or mat i on decreases 
t he pr o ba bilit y of pass i n g t he i nteri m f utility criteria (i.e. c o nti n ue e nr oll me nt i n a gi ve n t u m or). 
Secti o n 5. 1 .2 lists H R = 0. 3 3 i n b ot h t u m or t y pes as t he tar get sce nari o. T his is w here t he 
Ba yesia n a nal ysis reac hes 8 2 % p o wer f or a gi ve n t u m or t ype at t he fi nal a nal ysis. At  H R = 
0. 3 3 f or S S a n d 
, t he pr o ba bilit y of  passi n g t he i nteri m is decrease d b y o nl y 1 %.   W he n 
t he H Rs are e q ual ( Sce nari os 1 -7), t here is a m o dest decrease i n p o wer wit h t he l ar gest 
differe nce of  1 0 % occ urri n g at H R = 0. 7 0. A lar ger decrease i n p o wer at i nteri m ca n be see n i n 
Sce nari os 1 2 -1 6 w here t here is si g nifica nt heter o ge neit y bet wee n t u m or t y pes. W he n b ot h H R = 
1, t he pr o ba bilit y of  inc orrectl y c o nt i n ui n g t he trial decreases fr om 0. 4 4 t o 0. 3 9. O verall, 
t he i nteri m a nal ysis retai ns s ufficie nt p o wer if R W E ca n n ot be i ncl u de d i n t he 
a nal ysis w hile n ot i ncreasi n g t he pr o ba bility o f pas si n g t he i nteri m u n der t he n ull case o f H R = 
1.
6. 6. 1. 7.
S e n siti vit y A n al y s e s f or Pri m ar y P r o gr e s si o n- Fr e e S ur vi v al E n d p oi nt
Besi des t he pri mar y a nal ysis o f P F S per Ba y esia n hierarc hical a nal ysis descri be d a b o ve, 
tra ditio n al (fre q ue ntist) assess me nts will be perf or me d t o pr o vi de a d diti onal c o nte xt .  N o n-
para m etric est i mates of s ur vi val c ur ves will be o btai ne d via t he met h o d of Ka pla n a n d Meier .  
T he ( u nstratifie d ) lo g ra n k test will be use d t o c o m pare treat me nt ar ms f or St u dies 
a n d 
J V 0 2 se paratel y a n d wit ho ut i nte gratio n of  hist oric al c o ntr ol data. 
F o ur se nsitivi t y a nal yes are pla n ne d wit hi n t he Ba yesia n fra me w or k :  ( 1) hist orical c o ntr ol pri ors 
base d o n f or mal e x pert elicitat i on will be use d i n lie u of t he p o wer pri ors c o nstr uct e d fr o m R W 
data ( 2) b orr o wi n g bet wee n t u mors will  be re mo v e d ( 3) wea kl y i nf or mati ve pri ors will be use d 
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f or c o ntr ol P F S a n d ( 4) t he bet wee n-t u mor b orr o wi n g a n d hist orical c o ntr ol b orr o wi n g will be 
r e mo ve d s o t hat se parate Wei b ull m o dels wit h wea kl y  inf or m ati ve priors will be use d. 
Se n sitivi t y t o usi n g “ missi n g” as a le vel f or matc hi n g v ari a bles (Ta ble 6. 2) will als o be
e val uate d. T he mat c hi n g al g orit h m will be rer u n usi n g o nl y  t h e c o mplete case p o p ulat i on of
hist ori cal patie nts. A n y pr os pecti vel y ra n d o mize d pati e nt wi t h missi n g val ues i n o ne or m ore of 
matc hi n g varia bles will be e xcl u de d fr o m t he matc hi n g al g orit h m b ut will be still i ncl u de d i n t he 
Ba yesia n a nal ysis o f P F S. T he Ba yesia n Wei b ull m o del will be refit a n d t he ass ociate d i m pact o n 
statistical i nfere nce will be st u die d.
Se nsit i vity t o t he c h oice of hist orical c o ntr ol s u bject matc hi n g al g orit h m will als o be e val uate d.  
Besi des t he pr o pe nsit y- base d met h o d c o rres p o n di n g t o t he pri mar y a nal ysis, a nearest-nei g h b or 
( Ma hala n obis) metric -base d matc hi n g a p pr oac h will be i m ple me nte d f or matc hi n g hist orical 
c o ntr ol p atie nts for i ncl usi o n i nt o t he prior distri b uti o ns .  T he ass ociate d i m pact o n statistical 
i nfere nce will be st u di e d.
6. 6. 1. 8.
E x p ert Eli cit ati o n of C o ntr ol P r o gr e s si o n- Fr e e S ur vi v al
F or mal pri or elicitati o n o f lea di n g e x perts i n 
 a n d S S will be c o n d ucte d t o o btai n 
c haracterizat i on of e x pecte d P F S o utc o mes o n c he m ot hera p y  in t he rel a pse d setti n g .  T he 
elicitatio n i nter vie ws (a p pr o xi matel y  1 h o ur) are t o be c o n d ucte d wit h eac h e x pert i n di vi d uall y 
per a c o m m o n pr ot oc ol (see t e mplate i n A p pe n di x 2 ).  T he res ults will be s y nt hesize d acr oss t he 
e x perts t o o btai n pri or distri b ut i ons t o be use d i n se nsit i vity a nal ysis o f P F S (see Secti o n 6. 6. 1. 7 ). 
6. 6. 2.
S e c o n d ar y Effi c a c y A n al y s e s
O verall res p o nse rate ( O R R) 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).  T he c o nfir mat i on of C R a n d P R is re q uire d.  T he O R R f or eac h 
st u d y ar m, wit h 80 % CI ( per 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 
se paratel y for St u di es 
a n d J V 0 2 .  C o m paris o n bet wee n e x peri me ntal a n d c o ntr ol ar ms will 
be perf or m e d se paratel y bet wee n St u di es
 a n d J V 0 2 usi n g Fis her ’s e xact test wit h 1-side d 
le vel . 1.
T he C R r at e is defi ne d as t he n u m ber of patie nts w h o ac hieve a best o verall res p o nse of C R
di vi de d b y t he t otal n u m ber of patie nts ra n d o mize d t o t he c orres p o n di n g treat me nt ar m (I T T 
p o p ul at i on).  T he c o nfir mati o n o f C R is re q uire d.  T he C R rate f or eac h st u d y  ar m, wi t h 8 0 % 
fre q ue ntist CI, will be s u m marize d se paratel y for St u di es 
a n d J V 0 2.
D urati o n of  res p o nse is defi ne d as t he ti me fr o m t he date meas ure me nt criteria f or C R or P R 
( w hic he ver is first rec or de d) are first met u ntil t he first date t hat disease is rec urre nt or o bjecti ve 
pr o gressi o n is o bser ve d, per R E CI S T 1. 1, or t he date of dea t h fr o m a n y ca use i n t he a bse nce of 
o bj ect i vel y deter mi ne d disease pr o gressi o n or rec urre nce. D o R will be calc ulate d o nl y f or 
pati e nts wit h c o nfir me d P R or C R. D o R will be s u m marize d f or eac h treat me nt ar m usi n g 
descri pt i ve statistics.  
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6. 7.
Bi o a n al yti c al a n d P h ar m a c o ki n eti c/ P h ar m a c o d y n a mi c M et h o d s
Pl a n ne d P K a n d P K/ p har mac o d y na mic ( P D) a nal yses are s pecifie d i n a se parate sta n dal o ne 
P K/ P D a nal ysis pla n .  
6. 8.
S af et y A n al y s e s
S af et y a nal yses will be base d o n t he safet y p o p ul atio n s.  Safety a nal yses will be c o n d ucte d 
se paratel y for St u di es 
a n d J V 0 2.
6. 8. 1.
E xt e nt of E x p o s ur e
T he n u m ber of d ose a dj ust me nt s ( d ose o missi ons, re d ucti o ns, dela ys, a n d i ncreases), t he n u m ber 
of  c ycles recei ve d, t he d urati o n of t hera p y, t he c u m ulati ve d ose, a n d d ose i nte nsity/relat i ve d ose 
i nte nsit y will be s u m marize d b y treat me nt ar m f or St u di es 
a n d J V 0 2 se paratel y.  D ose 
i nte nsit y is defi ne d as act ual c u m ulati ve a m o u nt of dr u g ta ke n/ d urati o n of treat me nt.  Relat i ve 
d ose i nte nsit y is calc ulate d as (act ual a m o u nt of dr u g ta ke n/a m o u nt of dr u g prescri be d) * 1 0 0 %.
6. 8. 2.
A d v er s e E v e nt s
A d verse e ve nt ( A E) ver bat i m ter ms will be pr o vi de d b y t he i n vesti gat ors a n d t he n will be 
ma p pe d b y  Lill y or its desig nee t o c orres p o n di n g ter mi n o l og y  wit hi n t he Me dical Dicti onar y  for 
Re g ulat or y  Act i vities ( Me d D R A) L o wer Le vel ter m ( L L T) dict i onar y .  T he i n vesti gat or will 
use C o m m o n Ter mi n o l og y  Crit eria for A d verse E ve nts ( C T C A E) versi o n 4. 0 ( N CI 2 0 0 9) t o 
assi g n A E se verit y gra des.
Pre -e xist i n g c o n diti ons are defi ne d as A Es t hat be gi n b ut d o n ot res ol ve b ef or e t he first dose of 
st u d y dr u g i n eac h st u d y p erio d or e ve nts t hat occ ur aft er i nf or me d c o nse nt a n d res ol ve bef ore
t he first d ose of st u d y dr u g.  Pre -e xisti n g c o n dit i ons will be prese nte d b y patie nt a n d ca n be 
c o m bi ne d wit h t he list i n g of A Es, s o t hat t he hist or y of t he pre-e xist i n g c o n diti ons/ A Es ca n be 
trace d.
A treat me nt -e mer ge nt a d verse e ve nt ( T E A E) is defi ne d as a n e ve nt t hat first occ urre d or 
w orse ne d i n C T C A E gra de aft er t he first d ose of st u d y treat me nt .  T he Me d D R A L L T will be 
use d i n t he treat me nt -e mer ge nt c o mp ut ati o n.  
A d verse e ve nts ( A Es) will be s u m marize d b y ma xi m u m C T C A E gra de ( preferre d ter m [ P T ]
wi t hi n s yste m or ga n classificat i on [ S O C ]).  S u m maries o f A Es will i ncl u de :

S u m mar y  of all T E A Es

S u m mar y  of all T E A Es relate d t o st u d y tr e at me nt 

S u m mar y  of all T E A Es l ea di n g t o d ose a dj ust me nt

S u m mar y  of all A Es res ulti n g i n disc o nti n uati on fro m  st u d y treat me nt 

S u m mar y  of A d verse E ve nts of S pecial I nterest 
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6. 8. 3.
D e at h s, S eri o u s A d v er s e E v e nt s, Ot h er Si g nifi c a nt A d v er s e 
E v e nt s
All deat hs t hat occ ur d uri n g t he st u d y , withi n 3 0 da ys of t he st u d y  treat me nt disc o nti n uati on, as 
well as t he ca use of deat h, will be s u m marize d a n d liste d.
S eri o us a d verse e ve nts ( S A Es) are t h ose e ve nts t hat res ult i n deat h, are life -t hreate ni n g, re q uire 
or pr ol o n g h os pi t ali z atio n, res ul t i n persiste nt or si g nifica nt disa bility/ i nca pacity,  or ca use 
c o n ge nital a n o ma l y/ birt h defect.  S A Es will be ta b ulate d b y  S O C, P T ter ms, a n d relati ons hi p t o 
st u d y dr u g.
6. 8. 4.
Cli ni c al L a b or at or y E v al u ati o n
All rele va nt he mat ol o g y  a n d c he mistr y la b orat or y val ues will be gra de d acc or di n g t o C T C A E 
Versi o n 4.  S hift ta bl es s h o wi n g t he c ha n ge fr o m baseli ne t o t he w orst gra de o n st u d y will be 
prese nte d. 
6. 8. 5.
Vit al Si g n s a n d Ot h er P h y si c al Fi n di n g s
T e m perat ure, bl o o d press ure, p ulse rate, wei g ht a n d E aster n C o o perati ve O nc o l og y  
G r o u p/Kar n ofs k y / La ns k y p erf or m a nce sc ore (as a p plica ble) will be s u m marize d b y c o h ort a n d 
o verall.
6. 8. 6.
El e ctr o c ar di o gr a m s
L ocal  electr ocar di o gra ms ( E C Gs) will be s u m marize d b y  c ycle a n d o verall.  T he s u m mar y b y 
c ycle will classif y patie nts as ha vi n g n or mal or ab n or m al.  A d ditio n all y, Q T, R R, a n d Q R S 
i nter vals will als o be c o llecte d a n d Q Tc F will be calc ulate d base d o n t hese para meters.  A Es t hat 
c o uld be ass ociate d wit h a b n or mal E C Gs will be prese nte d, if a p pr o priate.   
6. 9.
S u b gr o u p A n al y s e s
D ue t o sa m ple -size li mitat i ons, n o f or mal statistic al t ests of  treat me nt effect b y s u b gr o u p will be 
pres pe cifie d.  H o we ver, d escri pt i ve statistics f or pri mar y a n d sec o n dar y efficac y meas ures will  
be pr o vi de d b y  tr e at me nt ar m wit hi n t he f oll owi n g s u b gr o u ps f or St u dies
 a n d J V 02 
se paratel y:

A ge ( < 1 8 vs. ≥1 8)

Li ne of t hera p y  (sesc o n d li ne vs. t hir d li ne a n d a b o ve)

T i me-t o-Rela pse
o
o
St u d y  J V 0 2:  < 2. 5 yr s vs. ≥2. 5 yr s

Metastatic disease at rela pse ( y es vs. n o)

T u m or si ze at i nit ial dia g n osis
o
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St u d y  J V 0 2:  < 5 c m vs. ≥5 c m
6. 1 0. Pr ot o c ol Vi ol ati o n s
I mp orta nt pr ot oc ol de viat i ons t hat p ote ntiall y c o m pr o mise t he data i nte grit y a n d patie nts’ safet y 
will be liste d.   T hese de viat i ons will i ncl u de t h ose defi ne d b y:

I nf or me d c o nse nt

I ncl usi on/ e xcl usi o n criteria

I n vesti gati onal p r o d uct

St u d y  p r oce d ures

A d mi nistrati ve/ o versi g ht

S af et y

Ot her
O n t he basis of t he disc ussi o n wi t h t he st u d y t e a m, t he detaile d descri pt i on of eac h de viat i on 
wi t hi n t he a b o ve cate g or y a n d t he met h o d t o i de ntif y eac h de viat i on will  be liste d i n a se parate 
d oc u m e nt – B usi ness Pr ocess D oc u me nt :  I mp orta nt Pr ot oc ol  De viatio ns.
6. 1 1. I nt eri m A n al y s e s 
St u di es 
a n d J V 0 2 are u n bli n de d .  Safet y 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 ds f or St u dies 
 a n d J V 0 2. 
D ue t o t he nat ure of t he Ba yesia n hierarc hical a nal ysis o f P F S ( w hic h i ncl u des a f or mal 
mec ha nis m f or a da pti ve b orr o wi n g o n effect -size bet wee n S t u dies 
 a n d J V 0 2), ti mi n g of t he 
pre pl a n ne d i nteri m a nal ysis o f P F S i s base d o n t he t otal n u m ber of P F S e ve nts o bser ve d acr oss 
b ot h St u dies 
 a n d J V 0 2.  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 ies
a n d J V 0 2 wi t h a mi ni m u m of 8 
e ve nts i n eac h st u d y.  W hile a si n gle j o i nt Ba yesia n hierarc hical m o del will be fit t o t he P F S data 
fr om b ot h St u dies 
 a n d J V 0 2, st u d y s pecific f utility co ncl usi o n s will be ma de base d o n 
t u mor -specific o ut p ut o btai ne d fr om t he Ba yesia n m o del.  
 
 
, 
Li ke wise, at t he i nteri m f ut ility l oo k, t he Ba y esia n 
a nal ysis m ust pr o vi de a mi ni m u m o f 6 0 % c o nfi de nce i n treat me nt s u peri orit y ( P F S 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.
T he i nteri m f ut ility a nal ysis o f P F S will utilize e xactl y t he sa me Ba yesia n hierarc hical m o del 
(incl u di n g t he hist orical c o nt r ol matc hi n g al g orit h m) as f or t he pri mar y a nal ysis.  Re gar di n g
hi st orical c o ntr ol matc hi n g at i nteri m, t he met h o d ol o g y is i de ntical t o t hat s pecifie d f or t he 
pri mar y  a nal ysis i n Secti on 6. 6. 1. 5 , e xce pt it is p ossi ble t hat ˂ 2 0 patie nts will ha ve e nr o lle d o n 
eac h treat me nt ar m of St u di es 
 a n d J V 0 2 as of t he i nteri m a nal ysis.  He nce , ˂2 0 hist orical 
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c o ntr ol p atie nts ma y be matc he d per t u mor, b ut t he p o wer pri or para m eter will still be e q ual t o 
. 5.  
If fe wer t ha n 1 0 real w orl d hist orical c o ntr ol s u bjects are a vaila ble wi t hi n a gi ve n t u mor t y pe as 
of  t he data base l oc k f or t he i nteri m f ut ility a nal ysis , t he c o ntr ol ar m (for t hat st u d y ) will n ot be 
a u g me nte d wit h r e al-w orl d data. T he m o del t o assess i nteri m f utility ( Sect i on 6. 6. 1. 2 ) w o ul d 
t heref ore be fit usi n g o nl y pr os pecti ve l y ra n d omize d pati e nts a n d t he n o ni nf or mat i ve h y per pri ors 
f or   ,   ,   , a n d   prese nte d i n Secti o n 6. 6. 1. 3 .
6. 1 2. A n n u al R e p ort A n al y s e s
T he f o ll owi n g re p orts are nee de d as re q ueste d f or a n n ual re p orti n g p ur p oses :
De vel o p me nt Safet y U p date Re p ort:

C u m ulat i ve S u bject E x p os ure b y A ge Gr o u p a n d Se x

C u m ulat i ve S u bject E x p os ure b y Racial Gr o u p

Esti mate d C u m ulati ve S u bject E x p os ure

E x p os ure I nf or mat i on

List i n g of Disc o nti n uati ons D ue t o A E d uri n g t he Re p orti n g Perio d

List i n g of S u bjects W h o Die d d uri n g t he Re p orti n g Peri o d
Cli nical I n vest i gat or’s Br oc h ure (I B):

List i n g a n d S u m mar y of S A E

List i n g a n d S u m mar y of Deat h

List i n g a n d S u m mar y of T E A E (a n d b y maxi m u m C T C A E gra de)

List i n g a n d S u m mar y of Patient  Dis p ositi on

List i n g a n d S u m mar y of St u d y Dr u g A djust m e nt
Ot her re p orts ma y  be re q ueste d if dee me d a p pr o priate f or t he I B.
6. 1 3. Cli ni c al Tri al R e gi str y A n al y s e s
A d dit i onal a nal yses will be perf or me d f or t he p ur p o se of f ulfilli n g t he Cli nical Trial Re gistr y 
( C T R) re q uire me nts.
A nal yses pr o vi de d f or t he C T R re q uire me nts i ncl u de t he f o ll owi n g:

S u m mar y  of A Es, pr o vide d as a dataset w hic h will be c o n verte d t o a n X M L file.  
B ot h S A Es a n d ‘ Ot her’ A Es will be s u m marize d b y Me d D R A P T wit hi n tr e at me nt 
gr o u p.

A n A E i s c o nsi dere d ‘ Seri o us’ w het her or n ot it is a T E A E.
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
A n A E i s c o nsi dere d i n t he ‘ Ot her’ cate g or y if it is b ot h a T E A E a n d is n ot seri o us.  
F or eac h S A E a n d ‘ Ot her’ A E, f or eac h ter m a n d treat me nt gr o u p, t he f oll o wi n g are 
pr o vi de d:
o
t he n u m ber of partici pa nts at ris k of a n e ve nt
o
t he n u m ber of partici pa nts w h o e x perie nce d eac h e ve nt ter m
o
t he n u m ber of e ve nts e x perie nce d

C o nsiste nt wit h w w w. Cli nical Trials. g o v re q uire me nts, ‘ Ot her’ A Es t hat occ ur i n ˂ 5 % 
of  p atie nts/s u bjects i n e ver y tr e at me nt gr o u p ma y n ot be i ncl u de d if a 5 % t hres h ol d is 
c h ose n ( 5 % is t he mi ni m u m t hres h o l d).

A E re p ortin g is c o nsiste nt wit h ot her d oc u me nt discl os ures, e. g., t he cli nical st u d y 
re p ort ( C S R), ma n uscri pts, a n d s o f ort h. 
I n a d diti on, a partici pa nt fl o w will be create d t hat will descri be h o w ma n y e nr olle d pat ient s 
c o mplete d t he st u d y , a n d f or t h ose w h o di d n ot, t he fre q ue nc y of eac h reas o n f or n ot c o m pleti n g.  
T his a nal ysis will be base d o n st u d y  disc o nti n uati on, n ot treat m e nt disc o nti n uati on.  A patie nt 
will be i de nt ifie d as ha vi n g c o m p lete d t he st u d y if t he patie nt has recei ved ≥1 d ose of st u d y dr u g 
a n d ha ve ≥1 p ost baseli ne t u m or assess me nt at t he ti me of t he fi nal a nal ysis .
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7.
R ef er e n c e s
A b o u har b S, et  al. S y n o vial sarc o ma: e val uati o n of res p o nse t o treat me nt wit h ge mcita bi ne a n d 
d oceta xel. A S C O A n n ual Meet i n g p oster. J Cli n O nc ol. 2 0 1 4; 3 2: 5s. (s u p pl; a bstr 1 0 5 6 4).
Cl o p per , CJ, et al. 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 .
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.
L u n n D, et al. T he B U G S b o o k: a practical i ntr o d ucti o n t o Ba yesia n a nal ysis. L o n d o n: C ha p ma n 
a n d Hall/ C R C; 2 0 1 2.
Pl u m mer M.   J A G S Versi o n  4. 3. 0 user ma n ual. 2 0 1 7
S k ol ni k J M, et al. S h orte ni n g t he ti meli ne of pe diatric 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.
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A p p e n di x 1.
J A G S C o d e f or B a y e si a n Hi er ar c hi c al M o d el of 
Pri m ar y  P F S E n d p oi nt
T he a p pr o xi mate p osteri or di stri b utio n c orres p o n di n g t o t he Ba y esia n hierarc hical m o del o f t he
pri mar y  P F S e n d p oi nt is t o be o btai ne d via Mar k o v C hai n M o nte Carl o ( M C M C) si m ulati o n
usi n g J A G S ( Pl u m mer 2 0 1 7) .  T he J A G S scri pt f or t he Ba yesia n m o del is pr o vi de d bel o w.
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A p p e n di x 2.
Pri or Eli cit ati o n Pr ot o c ol
Pri or I nf or m ati o n Elicit ati o n Pr ot oc ol
D ate :  
Pr oject I de ntifiers
C o m p o u n d :  Ra m ucir u ma b 
I n dic ati o n:  S y n o vial Sarc o ma 
 
P atie nt p o p ul ati o n :  Pe diatric pat ient s a n d yo u n g a d ul ts (a ge ≤3 0 years) wit h rela pse d, 
rec urre nt, or pr o gressi ve s y n ovial sarc o ma or 
T her a pe utic are a :  O nc o l og y
E n d p oi nts:

Pr o gressi o n -Free S ur vi val ( P F S)
E x pert:
N a me: 
Affili ati o n: 
E m ail: 
P h o ne:  
F acilit at or: 
N a me: 
Affili ati o n: 
E m ail: 
Setti n g of Elicit ati o n :  Tel ec o nfere nce 
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1.  I nte nti o n of t he Pri or Elicit ati o n E xercise
St u di es 
 J 1 S-M C -J V 0 2 are pla n ne d ra n d o mize d P hase 2 st u dies e val uati n g 
r a mu ci r u ma b i n c o m bi nati on wi t h c he mot h era p y vers us c he mot h era p y alo n e i n pe diatri c patie nts 
a n d yo u n g a d ul ts wit h r ela pse d, rec urre nt, or pr o gressi ve s y n o vial sarc o ma ( S S) or 
 
.  D ue t o m o dest sa m ple sizes ass ociate d wit h t he rarit y o f t he 2
i n dicati ons, a n o vel Ba yesia n desi g n will be utilize d w here b y e xist i n g k n o wle d ge re gar di n g 
e x pecte d patie nt o utc o me o n t he c o ntr ol re gi me ns will be directl y le vera ge d withi n t he statistical 
a nal ysis to a u g m e nt i nf or mat i on ge nerate d fr o m t he pr os pecti ve c o ntr ol ar ms .  T he e xist i n g 
k n o wl e d ge ta kes 2 f or ms:  ( 1) hist orical patie nt data fr o m retr os pecti ve c hart re vie ws a n d ( 2) 
e x pert o pi ni o n fr om w orl d lea ders i n t he treat me nt of t hese c o n dit i ons .  Pri or elicit ati o n is t he 
f or mal statistic al fra me w or k b y w hic h we assess/ d oc u me nt t he later s o urce of e xisti n g 
k n o wl e d ge, e x pert o pi ni o n, i n a ma n ner t hat all o ws its c o n versi o n i nto m at he matical o bjects, 
calle d pri or distri b uti o ns (see Fi g ure 1 bel o w), t hat ca n be f or mall y le vera ge d wit hi n a statist ical 
m o d el .  See H a m ps o n et al . ( 2 0 1 5) f or a n e xa m ple of a cli nical trial desi g n i n t he rare/ pe diatric 
setti n g le vera gi n g e x pert o pi ni o n directl y withi n a pres pecifie d pri mar y a nal ysis. 
2.  Pr oce d ures 
T he pri or elici t atio n e xercise is a n i nter vie w (c o n d ucte d via telec o nfere nce i n t he prese nt case) 
d uri n g w hic h q uest i ons of s pecialize d f or mat are as ke d of t he partici pat i n g e x pert(s).  T he 
i nter vie w q uest i ons are directe d at d oc u me ntati o n of ( 1) t he e x pert’s j u d ge me nt r e gar di n g t he 
m o st pla usi ble tr ue val ue f or a gi ve n e n d p o i nt of i nterest (e. g. me dia n P F S, O R R, O S i n s ome 
p o p ul at i on of patie nts recei vi n g s o me re gi me n of i nterest) a n d, i m p orta ntl y, ( 2) t he e x pert’s le vel 
of  c o nfi de nce/ u ncertai nty re gar di n g t hat o pi ni on . Lar ge u ncertai nt y re gar di n g e x pecte d patie nt 
o utc o m e is c o m mo n, a n d t he stati stical a nal ysis will full y  acc o u nt f or t his u ncertai nt y.  
Ul timatel y, t he 2 pi eces of i nf or mati o n ( 1) a n d ( 2) will defi ne a pr o ba bilit y distri b ut i on w hic h 
gra p hicall y  descri bes t he e x pert’s beliefs. 
Fi g ure 1 s h o ws e xa m ples of vari o us pri or distri b uti o ns re prese nt i n g differi n g e x pert beliefs (a n d 
ass ociate d u ncertai nt y)  for m e dia n P F S i n m o nt hs.  T he pea k ( m o de) of t he distri b ut i on ali g ns 
wi t h t he e x pert’s belief re gar di n g t he m ost -li kel y tr ue valu e .  Distri b ut i ons t hat stretc h o ver a 
wi de ra n ge of val ues (al o n g x -a xis) a n d o nl y reac h lo wer de nsit y val ues ( y -a xis) i n dicate lar ger 
u ncertai nt y .  Ver y  pea ke d distri b uti o ns t hat rest o ver a m ore narr o w ra n ge of val ues a n d attai n 
hi g h de nsit y i n dicate greater c o nfi de nce i n t he u n derl yi n g belief.  F or e xa m ple, pa nels (a) a n d ( b) 
of  Fi g ure 1 b ot h s h o w e x pert beliefs c orres p o n di n g t o a m ost -li kel y me dia n P F S val ue of 3 
m o nt hs, b ut wi t h s u bsta ntiall y greater u n derl yi n g u ncertai nty i n t hat assess me nt f or pa nel ( b). 
Li ke wise, pa nels (c) a n d ( d) b ot h s h o w e x pert beliefs c orres p o n di n g t o a m ost -li kel y me dia n P F S 
val ue e q ual t o 6 m o nt hs, b ut wit h s u bsta nt iall y greater u ncertai nty ass ociate d wit h t hat 
assess me nt f or pa nel ( d).
I n a n iterati ve fas hi on, t he pri or distri b ut i on i m plie d b y t he e x perts’ a ns wers will be dis pla ye d 
gra p hicall y  d uri n g t he i nter vie w, wit h a djust me nts bei n g ma de s yste mat icall y t o e ns ure t he 
e x perts feel t he s ha pe a n d l ocat i on of t he distri b ut i o n are c o nsiste nt wit h t heir u n derl yi n g beliefs.
M ul tiple e x perts will partici pate i n t he e xercise via i n de pe n de nt i nter vie ws .  T he ra n ge of 
o pi ni o ns will t he n be c ollate d i nt o a si n gle pri o r distri b uti on t hat will ult i matel y s u p p ort 
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statistical a nal ysis o f t he pr os pecti ve st u d y res ults.  T he e x pert o pi ni o n will be de -i de ntifie d i n all 
re p orts/ disclos ures i n v o l vi n g its use (e. g., c o m m u nicat i ons t o re g ulat or y  a ge ncies, ma n uscri pts, 
cli nical st u d y  re p orts, etc.). 
Fi g ur e 1. E x a m pl e s of Pri or Di stri b uti o n s R e pr e s e nti n g V ari o u s E x p ert 
B eli ef s/ U n c ert ai nt y
3. I nter vie w C o nte nt
D uri n g t he i nter vie w, t he f o ll owi n g q uesti o ns will be as ke d of t he e x perts (se paratel y  for S S a n d 
a n d eac h c he m ot hera p y bac k b o ne/c o ntr ol re gi me n of i nterest):
( 1) Me dia n P F S o verall:
a.
I ma gi ne t hat 1 0 0 patie nts wit h rela pse d, refract or y , or pr o gressi ve [S S or 
] 
(a ge 3 0 years or less, i neli gi ble f or s ur ger y, wit h meas ura ble disease) e nr olle d o n 
a cli nical trial a n d were assi g ne d t o recei ve d [ bac k b o ne/c o ntr ol ].  F or si m plicit y,  
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i ma gi ne t hat all patie nts e nr olle d o n t he sa me da y.  H o w l o n g ( m o nt hs) w o ul d y o u 
e x pect it t o ta ke f or h alf of  t h ose patie nts t o ha ve t he P F S e ve nt?
b.
I n t he sce nari o fr om a. a b o ve, a part fr o m w hat y o u t hi n k t he m ostl y li kel y  time 
w o ul d be, w hat is t he m ost o pti mist ic ( b ut still reas o na ble) g uess f or t hat ti me t hat 
s o me o ne c o ul d gi ve?
( 2) A d dit i onal P F S Ti me
a.
C o nsi deri n g t he sce nari o a b o ve i n ( 1), f or t he s u b gr o u p of 5 0 patie nts t hat 
r e mai ne d pr o gressio n -free as of t he ti me yo u ga ve, h o w m uc h l o n ger w o ul d y o u 
e x pect it t o ta ke f or half of t he m t o ha ve t he P F S e ve nt (relati ve t o t he date of 
e nr o ll me nt)?
b.
W hat is t he m ost o pti mist ic b ut still reas o na ble g uess f or t hat ti me t hat s o me o ne 
c o uld gi ve?
T he f o ll owi n g ta ble ( Ta ble 1 - 1) will be fille d f or eac h patient  p o p ulati on se paratel y (s y n o vial 
sarc o ma a n d  
) a n d f or eac h re gi me n per t he q uesti o ns re gar di n g P F S o utli ne d a b o ve.  
N ote t hat ‘ C he m o O pt i ons O verall’ refers t o all c he m ot hera p y  o ptio ns t hat are use d i n t he 
r ela pse d setti n g wit h o ut re gar d f or li ne of t hera p y or prefere nce of i n di vi d ual e x perts or 
i nstituti o ns. 
T a bl e 1 - 1
I n dicati o n
C o ntr ol/ Bac k b o ne Re gi me n
Me dia n P F S i n I nitial 1 0 0
A d diti o nal Ti me i n Latter 5 0
M ost Li kel y
O pti mistic
M ost Li kel y
O pti mistic
S y n o vial 
Sarc o ma
C he m o O pti o ns O verall
Ge m/ D oc
Tra becte di n 
A b bre viati o ns :  Ge m = ge mcita bi ne; D oc = d oceta xel; 
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3.  P a pers a n d S u p p orti n g I nf or m ati o n
H a m ps o n, Li sa V, et al. " Elicitati on of  ex pert pri or o pi ni o n: a p plicat i on t o t he M Y P A N trial in 
c hil d h o o d p ol yarterit is n o d osa." P L o S O ne 1 0. 3 ( 2 0 1 5): e 0 1 2 0 9 8 1.
4. E x pert’s B ac k gr o u n d
[ T o be fille d per eac h e x pert c o ntracte d]
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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 9 - J a n - 2 0 2 2  1 4 : 2 4 : 0 0  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
P P D