A Randomized Phase II Study of MCS110 Combined With Carboplatin and Gemcitabine in Advanced Triple Negative Breast Cancer (TNBC)
Phase: PHASE2
Conditions: Advanced Triple Negative Breast Cancer (TNBC) With High TAMs
Sponsor: Novartis Pharmaceuticals

Cli ni c al D e v el o p m e nt  
M C S 1 1 0 
O n c ol o g y Cli ni c al Pr ot o c ol C M C S 1 1 0 Z 2 2 0 1 / N C T 0 2 4 3 5 6 8 0 
A  ra n d o mi z e d p h a s e  II st u d y  of MC S 1 1 0  c o m bi n e d wit h 
c ar b o pl ati n  a nd  g e m cit a bi n e i n a dv a n c e d  T ri ple N e g ati v e 
Br e a st  Ca n c er  (T N B C)  
D o c u m e nt t y p e  
A m e n d e d Pr ot o c ol V er si o n  
E U D R A C T n u m b er  
2 0 1 5 -0 0 0 1 7 9 -2 9  
V er si o n n u m b er  
0 6  (Cl e a n ) 
D e v el o p m e nt p h a s e  
II 
D o c u m e nt st at u s  
Fi n al  
R el e a s e d at e  
1 1 -O ct -2 0 1 7
Pr o p ert y of N o v arti s  
C o nf i d e nti al  
M a y n ot b e u s e d, di v ul g e d, p u blis h e d, or ot h er wi s e di s cl o s e d  
wit h o ut t h e c o n s e nt of N o v arti s  
T e m pl at e v er si o n 0 2 -D e c -2 0 1 3  

N o v artis  
C o nfi d e nti al  
P a g e 2 
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol  N o. C M C S 1 1 0 Z 2 2 0 1  
 
T a bl e of c o nt e nt s  
Ta ble of c o nte nts  ..........................................................................................................2  
List of a p p e n dic es  .........................................................................................................7  
List of fi g ures  ...............................................................................................................7  
List of ta bles  .................................................................................................................7  
List of a b bre viati o ns  .....................................................................................................9  
Gl oss ary of ter ms ........................................................................................................1 1  
A m e n d me nt 6 ( 1 1 -O ct -2 0 1 7) ......................................................................................1 3  
A m e n d me nt 5 ( 0 4 -Ma y -2 0 1 7) .....................................................................................1 6  
A m e n d me nt 4 ( 2 0 -Se p -2 0 1 6) ......................................................................................1 8  
A m e n d me nt 3  ( 0 8-Apr -2 0 1 6) ......................................................................................2 0  
A m e n d me nt 2 ( 8 -O ct -2 0 1 5) ........................................................................................2 4  
A m e n d me nt 1 ( 4 -Mar -2 0 1 5 ) .......................................................................................3 0  
Pr ot o c ol s u m m ary  .......................................................................................................3 1  
1  
Ba c k gr o u n d  ................................................................................................................3 3  
1. 1  
O v ervie w of dise ase pat h o ge n esis, e pi d e mi ol o g y a n d c urre nt tre at m e nt  .............3 3  
1. 1. 1  
T h e i m m u n o m o d ulat ory (I M) su bt y p e of T N B C ................................3 3  
1. 2  
O v ervie w of t he r ole of th e i m m u n e s yste m i n breast ca nc er..............................3 4  
1. 2. 1  
T u m or asso ciate d ma cro p h a ges i n bre ast c a nc er  ................................3 4  
1. 2. 2  
I m m u n o m o d ulati o n a n d c h e m ot h era p y resp o ns e i n breast c a n cer .......3 5  
1. 3  
I ntr o d u cti o n t o i n v esti gati o nal tre at me nt(s) a n d oth er st u d y treat m e nt(s) ............3 6  
1. 3. 1  
O v ervie w of M C S 1 1 0 .......................................................................3 6  
1. 3. 2  
O v ervie w of car b o plati n ...................................................................4 1  
1. 3. 3  
O v ervie w of ge m cita bi ne  ..................................................................4 2  
1. 4  
O v ervie w of c o m bi n ati o n treat m e nt ..................................................................4 2  
1. 4. 1  
N o n -cli nic al .....................................................................................4 2  
1. 4. 2  
Cli nic al  ............................................................................................4 2  
1. 4. 3  
P ote ntial f or dru g -dr u g i ntera cti o ns  ...................................................4 3  
1. 4. 4  
E x p ecte d o verla p pi n g t o xicities  ........................................................4 3  
2  
Rati o n ale  ....................................................................................................................4 4  
2. 1  
St u d y rati o nale  a n d p ur p os e .............................................................................4 4  
2. 2  
Rati o n ale f or t h e st u d y d esi g n  ..........................................................................4 4  
2. 3  
Rati o n ale f or d os e a n d re gi m e n s ele cti o n  ..........................................................4 5  
2. 3. 1  
Rati o n ale f or d os e a n d re gi m e n f or c arb o pla ti n a n d ge mcita bi ne ........4 5  
2. 3. 2  
Rati o n ale f or d os e a n d re gi m e n f or M C S 1 1 0  .....................................4 5  
2. 4  
Rati o n ale f or c h oic e of c o m bi nati o n dru gs  ........................................................4 7  

N o v artis  
C o nfi d e nti al  
P a g e 3 
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol  N o. C M C S 1 1 0 Z 2 2 0 1  
 
2. 5  
Rati o n ale f or c h oic e of c o m p arat ors dru gs  ........................................................4 7  
3  
O bje cti ves a n d e n d p oi nts  ............................................................................................4 7  
4  
St u d y d esi g n  ...............................................................................................................4 9  
4. 1  
D es cri ptio n of stu d y desi g n  ..............................................................................4 9  
4. 2  
D efi niti o n of e n d of t h e st u d y  ...........................................................................5 0  
4. 3  
Earl y st u d y ter mi nati o n  ....................................................................................5 0  
5  
P o p ulati o n  ..................................................................................................................5 1  
5. 1  
Patie nt p o p ulati o n  ............................................................................................5 1  
5. 2  
I n cl usio n criteria ..............................................................................................5 1  
5. 3  
E x cl usio n criteria  .............................................................................................5 1  
6  
Tre at m e nt  ...................................................................................................................5 3  
6. 1  
St u d y treat m e nt ................................................................................................5 3  
6. 1. 1  
D osi n g re gi m e n  ................................................................................5 3  
6. 1. 2  
A n cillar y tre at me nts  .........................................................................5 4  
6. 1. 3  
Tre at m e nt d urati o n  ...........................................................................5 5  
6. 2  
D os e m o dific ati o ns  ..........................................................................................5 5  
6. 2. 1  
D os e m o dific ati o n a n d d os e d ela y  .....................................................5 5  
6. 2. 2  
F oll o w -u p t o xicities..........................................................................5 8  
6. 2. 3  
A ntici p ate d risks a n d s afet y c o n c erns  ................................................5 8  
6. 3  
C o n c o mita nt m e dic atio ns  .................................................................................5 8  
6. 3. 1  
Per mitte d c o nc o mita nt t hera p y ..........................................................5 8  
6. 3. 2  
Per mitte d c o nc o mita nt t hera p y re q uiri n g c a uti o n  ...............................5 9  
6. 3. 3  
Pr o hi bite d c o n c o mita nt t hera p y .........................................................5 9  
6. 4  
Patie nt n u m beri n g, treat m e nt assi g n m e nt or ra n d o miz ati o n  ...............................5 9  
6. 4. 1  
Patie nt n u m beri n g  ............................................................................5 9  
6. 4. 2  
Tre at m e nt assi g n me nt a n d ra n d o mizati o n ..........................................6 0  
6. 5  
St u d y dr u g pre parati o n a n d disp e ns ati o n  ...........................................................6 0  
6. 5. 1  
St u d y dr u g pa c k a gi n g a n d la b eli n g ....................................................6 0  
6. 5. 2  
Dr u g s u p pl y a n d stora ge  ...................................................................6 0  
6. 5. 3  
St u d y treat m e nt c o m plia n ce a n d a cc o u nta bilit y  .................................6 1  
6. 5. 4  
Dis p osal a n d d estru cti o n  ...................................................................6 1  
7  
Visit s c h e d ule a n d ass ess m e nts....................................................................................6 1  
7. 1  
St u d y flo w a n d visit sc h e d ule  ...........................................................................6 1  
7. 1. 1  
M ole c ular p re-s cree ni n g ...................................................................6 5  
7. 1. 2  
Scre e nin g  .........................................................................................6 5  
7. 1. 3  
Tre at m e nt p erio d  ..............................................................................6 6  

N o v artis  
C o nfi d e nti al  
P a g e 4 
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol  N o. C M C S 1 1 0 Z 2 2 0 1  
 
7. 1. 4  
Dis c o nti n uati o n of stu d y tre at m e nt ....................................................6 6  
7. 1. 5  
Wit h dra w al of c o ns e nt......................................................................6 7  
7. 1. 6  
F oll o w -u p peri o d ..............................................................................6 7  
7. 1. 7  
L ost t o f oll o w -u p ..............................................................................6 8  
7. 2  
Ass ess me nt ty pes  .............................................................................................6 8  
7. 2. 1  
Effic ac y ass ess m e nts  ........................................................................6 8  
7. 2. 2  
Saf ety a n d t olera bilit y ass ess m e nts  ...................................................6 9  
7. 2. 3  
P h ar m a c o ki n etics, p h ar ma c o d y n a mics ( C S F -1)  
 
 ...............................................................................7 2  
7. 2. 4  
Bi o m ark ers ......................................................................................7 7  
8  
Saf ety m o nit orin g a n d re p ortin g  ..................................................................................8 0  
8. 1  
A d vers e e v e nts  ................................................................................................8 0  
8. 1. 1  
D ef i n iti o ns a n d re p orti n g ..................................................................8 0  
8. 1. 2  
La b orat or y a b n or m alities  ..................................................................8 1  
8. 2  
Seri o us a d v ers e e v e nts  .....................................................................................8 2  
8. 2. 1  
D efi niti o ns  .......................................................................................8 2  
8. 2. 2  
Re p ortin g  .........................................................................................8 3  
8. 3  
Pre g n a n cies  .....................................................................................................8 4  
8. 4  
War ni n gs a n d prec a uti o ns  ................................................................................8 4  
8. 5  
Ste eri n g C o m mittee  .........................................................................................8 4  
9  
D ata c olle cti o n a n d m a n a ge me nt  .................................................................................8 5  
9. 1  
D ata c o nfid e ntialit y  .........................................................................................8 5  
9. 2  
Site m o nit orin g  ................................................................................................8 5  
9. 3  
D ata c olle cti o n .................................................................................................8 6  
9. 4  
D ata bas e m a na ge m e nt a n d q ualit y c o ntrol  ........................................................8 6  
1 0  Statistic al m et h o ds a n d d ata a nal ysis  ...........................................................................8 7  
1 0. 1  A n al ysis s ets ....................................................................................................8 7  
1 0. 1. 1  
F ull A n al ysis Set  ..............................................................................8 7  
1 0. 1. 2  
Saf ety Set .........................................................................................8 7  
1 0. 1. 3  
Per -Pr ot o c ol Set  ...............................................................................8 8  
1 0. 1. 4  
P h ar m ac o ki n etic a nal ysis s et .............................................................8 8  
1 0. 2  Patie nt d e m o gra p hics/ot h er bas eli ne c h aracteristics...........................................8 8  
1 0. 3  Tre at m e nts (st u d y tre at me nt, c o n c o mita nt th era pies, c o m plia n ce)  ......................8 8  
1 0. 3. 1  
St u d y treat m e nt  ................................................................................8 8  
1 0. 3. 2  
C o n c o mita nt m e dic atio ns  .................................................................8 8  
1 0. 3. 3  
C o m plia n ce  ......................................................................................8 8  

N o v artis  
C o nfi d e nti al  
P a g e 5 
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol  N o. C M C S 1 1 0 Z 2 2 0 1  
 
1 0. 4  Pri m ar y o bje ctiv e .............................................................................................8 9  
1 0. 4. 1  
V aria ble  ...........................................................................................8 9  
1 0. 4. 2  
Statistic al h y p ot hesis, m o d el, a n d met h o d of a n alysis  ........................8 9  
1 0. 4. 3  
H a n dli n g of missi n g val u es/c e ns ori n g/ disc o nti n uati o ns  .....................8 9  
1 0. 4. 4  
S u p p orti v e a nal ys es  ..........................................................................9 0  
1 0. 5  Se c o n d ary o bje ctiv es  .......................................................................................9 0  
1 0. 5. 1  
Ot h er se c o n dar y effic ac y o bje cti ves  ..................................................9 0  
1 0. 5. 2  
Saf ety o bje ctiv es  ..............................................................................9 0  
1 0. 5. 3  
P h ar m ac o ki n etics  .............................................................................9 2  
1 0. 5. 4  
Bi o m ark ers ......................................................................................9 3  
 
9 4  
1 0. 7  I nteri m a n alysis ...............................................................................................9 4  
1 0. 8  Sa m ple siz e c alc ulati o n  ....................................................................................9 5  
1 1  Et hic al c o nsid erati o ns a n d a d mi nistrati v e pr oc e d ures  ...................................................9 6  
1 1. 1  Re g ulat or y a n d et hic al c o m plia n c e  ...................................................................9 6  
1 1. 2  Res p o nsi bilities o f t he i n v esti gat or a n d I R B/I E C/ R E B ......................................9 6  
1 1. 3  I nf or me d c o ns e nt pro ce d ures............................................................................9 6  
1 1. 4  Dis c o nti n uati o n of th e stu d y  .............................................................................9 7  
1 1. 5  P u blic ati o n of st u d y pr oto c ol a n d res ults ...........................................................9 7  
1 1. 6  St u d y d oc u me ntatio n, re c or d k ee pin g a n d rete nti o n of d o c u m e nts  .....................9 7  
1 1. 7  C o nfi de ntialit y of stu d y d o c u m e nts a n d patie nt re c ords  .....................................9 8  
1 1. 8  A u dits a n d i nsp ecti o ns  .....................................................................................9 8  
1 1. 9  Fi n a n cial dis clos ures  ........................................................................................9 8  
1 2  Pr ot o c ol a d h ere n ce ......................................................................................................9 8  
1 2. 1  A m e n d me nts to t he prot o c ol .............................................................................9 9  
1 3  Refere n c es (a vaila ble u p o n re q uest) ...........................................................................1 0 0  
1 4  A p pe n dic es ...............................................................................................................1 0 3  
1 4. 1  A p p e n di x 1: G ui d eli n es f or Res p o ns e, D urati o n of O v erall Res p o ns e, T T F, 
T T P, Pr o gressi o n -Fre e S ur viv al a n d O verall S urvi v al (b ase d o n R E CI S T 1. 1)  .1 0 3  
1 4. 1. 1  
I ntr o d u cti o n ...................................................................................1 0 5  
1 4. 1. 2  
Effic ac y ass ess m e nts  ......................................................................1 0 5  
1 4. 1. 3  
D efi niti o ns  .....................................................................................1 0 5  
1 4. 1. 4  
Dis e as e m eas ura bilit y  .....................................................................1 0 5  
1 4. 1. 5  
Eli gi bilit y b as e d o n m eas ura ble dise as e ...........................................1 0 6  
1 4. 1. 6  
Met h o ds of t u m or me asure me nt - ge n eral g ui d eli nes  .......................1 0 6  
1 4. 1. 7  
Bas eli n e d o c u m e ntati o n of tar get a n d n o n -tar get lesi o ns ..................1 0 8  

N o v artis  
C o nfi d e nti al  
P a g e 6 
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol  N o. C M C S 1 1 0 Z 2 2 0 1  
 
1 4. 1. 8  
F oll o w -u p e v al uati o n of tar get a n d n o n -tar get lesi o ns ......................1 0 9  
1 4. 1. 9  
F oll o w -u p a n d re c or di n g of lesio ns  .................................................1 0 9  
1 4. 1. 1 0  N o n -n o d al lesio ns  ..........................................................................1 0 9  
1 4. 1. 1 1  N o dal lesi o ns  .................................................................................1 0 9  
1 4. 1. 1 2  D eter mi nati o n of tar get lesi o n resp o ns e ...........................................1 1 0  
1 4. 1. 1 3  D eter mi nati o n of n o n -tar get lesio n res p o ns e ....................................1 1 2  
1 4. 1. 1 4  N e w lesio ns  ...................................................................................1 1 2  
1 4. 1. 1 5  E v al u atio n of o v erall lesi o n res p o nse  ..............................................1 1 3  
1 4. 1. 1 6  Effic ac y d efiniti o ns  ........................................................................1 1 3  
1 4. 1. 1 7  Best o v erall res p o nse  ......................................................................1 1 4  
1 4. 1. 1 8  Ti m e t o e v e nt varia bles ...................................................................1 1 6  
1 4. 1. 1 9  Pr o gressi o n- fre e sur viv al ................................................................1 1 6  
1 4. 1. 2 0  O v era ll sur viv al..............................................................................1 1 6  
1 4. 1. 2 1  Ti m e t o pr o gressio n ........................................................................1 1 7  
1 4. 1. 2 2  Ti m e t o treat m e nt f ail ure ................................................................1 1 7  
1 4. 1. 2 3  D urati o n of resp o ns e  ......................................................................1 1 7  
1 4. 1. 2 4  Ti m e t o  res p o nse ............................................................................1 1 8  
1 4. 1. 2 5  D efi niti o n of start a n d e n d dates f or ti m e t o e ve nt v aria bles  .............1 1 9  
1 4. 1. 2 6  H a n dli n g of p atie nts wit h n o n -me asura ble dise as e o nl y at bas eli ne ...1 2 0  
1 4. 1. 2 7  Se nsiti vit y a n alys es  ........................................................................1 2 1  
1 4. 1. 2 8  D ata ha n dli n g a n d pr o gra m mi n g r ules  .............................................1 2 2  
1 4. 1. 2 9  St u d y/ proje ct s p ecific d e cisio ns  ......................................................1 2 2  
1 4. 1. 3 0  E n d of tre at m e nt p has e c o m pletio n  .................................................1 2 3  
1 4. 1. 3 1  E n d of p ost -tre at m e nt f oll o w-u p (st u d y p has e c o m pleti o n) ...............1 2 3  
1 4. 1. 3 2  Me dic al v ali d atio n of pr o gra m m e d o v erall lesi o n resp o ns e  ..............1 2 4  
1 4. 1. 3 3  Pr o gra m mi n g r ules  .........................................................................1 2 4  
1 4. 1. 3 4  Calc ulati o n of ‘ti m e to e v e nt’ varia bles  ...........................................1 2 4  
1 4. 1. 3 5  I n c o m plete assess me nt d ates ...........................................................1 2 4  
1 4. 1. 3 6  I n c o m plete dates f or last k n o wn date p atie nt ali v e or d eat h ..............1 2 5  
1 4. 1. 3 7  N o n -tar get lesi o n resp o ns e..............................................................1 2 5  
1 4. 1. 3 8  St u d y/ proje ct s p ecific pr o gra m mi n g ................................................1 2 5  
1 4. 1. 3 9  C e ns ori n g re aso n............................................................................1 2 5  
1 4. 1. 4 0  Refere n c es (a vaila ble u p o n re q uest)  ................................................1 2 6  
 

N o v artis  
C o nfi d e nti al  
P a g e 7 
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol  N o. C M C S 1 1 0 Z 2 2 0 1  
 
Li st of a p p e n di c e s  
Effic a c y g ui d eli n es (e. g. Res p o ns e E v al u ati o n Criteria i n S oli d T u m ors ( R E CI S T)  
Li st of fi g ur e s  
Fi g ure 1 - 1 
Tri ple n e gati ve bre ast c a n c er  ............................................................3 4  
Fi g ure 1 - 2 
Ma cr o p h a ge p olariz ati o n a n d f u ncti o n ...............................................3 5  
Fi g ure 1 - 3 
C S F -1 R  i n hi biti o n le a ds t o T A M d e pleti o n, i n cre as e d TI Ls a n d 
e n ha nc e d c he m ot h era p y resp o ns e .....................................................3 6  
Fi g ure 2 - 1 
Pre dicte d p o p ulati o n m e a n s er u m c o n ce ntrati o n pr ofiles of f re e 
M C S 1 1 0 f oll o wi n g 1 0 m g/ k g Q 3 W i v i nf usi o n wit h a n d wit h o ut a n 
a d diti o n al d ose o n C1 D 8 ..................................................................4 6  
Fi g ure 4 - 1 
O v ervie w of st u d y d esi g n  .................................................................4 9  
Fi g ure 4 - 2 
St u d y visit fl o w  ................................................................................5 0  
Fi g ure 6 - 1 
St u d y Dru g A d mi nistrati o n  ...............................................................5 4  
 
Li st of t a bl e s  
Ta ble 1 - 1 
Cli nic al trials wit h M C S 1 1 0  .............................................................3 9  
Ta ble 2 - 1 
C o m p aris o n of o bs er ve d e x p os ure i n c y n o m ol g us m o n k e ys a n d 
h e alt h y v ol u nte ers vers us pre dicte d e x p osure in C M C S 1 1 0 Z 2 2 0 1  ......4 7  
Ta ble 3 - 1 
O bje cti ves a n d relate d e n d p oints  .......................................................4 8  
Ta ble 6 - 1 
D os e a n d treat m e nt s c h e d ule .............................................................5 3  
Ta ble 6 - 2 
D os e m o dific ati o ns a n d a cti o n f or t o xicities s us pe cte d t o b e relate d 
t o M C S 1 1 0 ......................................................................................5 6  
Ta ble 6 - 3 
D os e m o dific ati o ns f or h e m at ol o gic al t o xicities s us pe cte d t o b e 
relate d to car b o/ ge m .........................................................................5 7  
Ta ble 6 - 4 
D os e m o dific ati o ns f or n o n -he mat ol o gic al t o xicities s us p ecte d t o 
b e relate d t o car b o/ ge m.....................................................................5 8  
Ta ble 7 - 1 
Visit e v alu ati o n s c h e d ule  ..................................................................6 3  
Ta ble 7 - 2 
I m a gi n g c olle ctio n pla n ....................................................................6 9  
Ta ble 7 - 3 
E C O G p erf or m a n ce status  ................................................................7 0  
Ta ble 7 - 4 
L o c al Cli nical La b orator y p ara m eters c olle cti o n pla n  ........................7 0  
Ta ble 7 - 5 
1 2 lea d E C G c olle cti o n pla n  .............................................................7 2  
Ta ble 7 - 6 
P h ar m a c o ki n etic ( M C S 1 1 0), C S F -1  
 s a m ple bl o o d 
c olle cti o n l o g (first 1 5 p atie nts) i n Ar m 1 ( n ot a p plic a ble after 
a p pro val of prot o c ol a me n d m e nt 6)  ...................................................7 3  
Ta ble 7 - 7 
P h ar m a c o ki n etic ( M C S 1 1 0), C S F -1  
 s a m ple bl o o d 
c olle cti o n l o g (s u bs e q u e nt p atie nts) i n Ar m 1 ( n ot a p plic a ble after 
a p pro val of prot o c ol a me n d m e nt 6) ...................................................7 4  

N o v artis  
C o nfi d e nti al  
P a g e 8 
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol  N o. C M C S 1 1 0 Z 2 2 0 1  
 
Ta ble 7 - 8 
P h ar m a c o ki n etic (c ar b o/ ge m) s a m ple bl o o d c olle cti o n l o g i n b ot h 
Ar m 1 a n d Ar m 2 ( n ot a p plic a ble after a p pr o v al of pr ot o c o l 
a m e n d me nt 6) ..................................................................................7 5  
Ta ble 7 - 9 
Bi o m ar k er s a m ple c olle cti o n pla n ( n ot a p plic a ble after a p pr o v al of 
pr ot oc ol a m e n d m e nt 6)  .....................................................................7 8  
Ta ble 1 0 - 1 
N o n -c o m p art me ntal p har m ac o ki n etic para meters ..............................9 2  
Ta ble 1 0 - 2 
Tr u e P F S h a zar d rati o a n d c orresp o n di n g p o wer ................................9 5  
Ta ble 1 4 - 1 
Res p o nse criteria f or tar get lesi o ns  ..................................................1 1 0  
Ta ble 1 4 - 2 
Res p o nse criteria f or n o n -tar get lesio ns ...........................................1 1 2  
Ta ble 1 4 - 3 
O v erall lesi o n resp o ns e at ea c h assess me nt ......................................1 1 3  
Ta ble 1 4 - 4 
O v erall lesi o n res p o ns e at e a c h ass ess m e nt: p atie nts wit h n o n -
tar get dis e ase o nl y ..........................................................................1 2 0  
Ta ble 1 4 - 5 
O p ti o ns f or e ve nt d ates use d in P F S, T T P, d urati o n of res p o ns e .......1 2 1  
 

N o v artis  
C o nfi d e nti al  
P a g e 9 
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol  N o. C M C S 1 1 0 Z 2 2 0 1  
 
Li st of a b br e vi ati o n s  
A d v a n c e d B C  
A d v a n c e d br e a st c a n c er  
 
 
A E  
A d v er s e E v e nt  
A L K  
A n a pl a sti c l y m p h o m a ki n a s e  
A L A T  
A s p art at e a mi n otr a nf er a s e  
A L T  
Al a ni n e a mi n otr a n sf er a s e/ gl ut a mi c p yr u vi c tr a n s a mi n a s e/ G P T  
A S A T  
A s p art at e tr a n s a mi n a s e  
A S T  
A s p art at e a mi n otr a n sf er a s e/ gl ut a mi c o x al o a c eti c tr a n s a mi n a s e/ G O T  
A U C  
Ar e a u n d er t h e c ur v e of pl a s m a/ s er u m dr u g c o n c e ntr ati o n v er s u s ti m e c ur v e s  
b.i. d.  
bi s i n di e m /t wi c e  a d a y 
c ar b o  
C ar b o pl ati n  
C D P  
Cli ni c al D e v el o p m e nt Pl a n  
C K  
Cr e ati ni n e ki n a s e  
C L  
Cl e ar a n c e  
C m a x  
P e a k  pl a s m a/ s er u m dr u g c o n c e ntr ati o n aft er a d mi ni str ati o n  
C M O & P S  
C hi ef M e di c al Offi c e a n d P ati e nt S af et y  
C R F  
C a s e R e p ort/ R e c or d F or m; t h e t er m  C R F c a n b e  a p pli e d t o eit h er E D C or P a p er  
C R O  
C o ntr a ct R e s e ar c h Or g a ni z ati o n  
C S F -1  
C ol o n y  sti m ul ati o n f a ct or -1  al s o c all e d M -C S F  
C S F -1 R  
C ol o n y sti m ul ati o n f a ct or -1 r e c e pt or  
C S R  
Cli ni c al st u d y r e p ort  
C S R a d d e n d u m  
A n a d d e n d u m t o Cli ni c al St u d y R e p ort ( C S R) t h at c a pt ur e s all t h e a d diti o n al i nf or m ati o n t h at 
i s n ot i n cl u d e d i n t h e C S R 
C T X -1  
C -t er mi n al t el o p e pti d e of t y p e I c oll a g e n, a b o n e r e a b s or pti o n m ar k er 
D B L  
D at a b a s e l o c k  
D DI  
Dr u g -dr u g i nt er a cti o n  
d F d U  
2', 2' -difl u or o -d e o x y uri di n e , t h e pri m ar y m et a b olit e of g e m cit a bi n e 
D L T  
D o s e Li miti n g T o xi cit y  
D O R  
D ur ati o n of r e s p o n s e  
E C G  
El e ctr o c ar di o gr a m  
E LI S A  
E n z y m e li n k e d i m m u n o s or b e nt a s s a y 
E R  
E str o g e n r e c e pt or  
F A S  
F ull A n al y si s S et  
F U  
F oll o w -u p  
g e m  
G e m cit a bi n e  
G G T  
G a m m a -gl ut a m yl tr a n s p e pti d a s e  
G M -C S F  
Gr a n ul o c yt e m a cr o p h a g e c ol o n y sti m ul ati n g f a ct or  
i v 
i ntr a v e n o u s(l y) 
H A  
H e alt h A ut h orit y  
H E R -2  
H u m a n E pi d er m al Gr o wt h F a ct or R e c e pt or -2  
H R  
H a z ar d r ati o  
H V  
H e alt h y v ol u nt e er  
I B 
I n v e sti g at or’ s Br o c h ur e 
I C H 
I nt er n ati o n al C o nf er e n c e o n H ar m o ni z ati o n 
I E C 
I n d e p e n d e nt Et hi c s C o m mitt e e 

N o v artis  
C o nfi d e nti al  
P a g e 1 0  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol  N o. C M C S 1 1 0 Z 2 2 0 1  
 
I M 
I m m u n o m o d ul at or y 
I R B 
I n stit uti o n al R e vi e w B o ar d 
L A R  
L u mi n al a n dr o g e n r e c e pt or  
L L O Q  
L o w er li mit of q u a ntit ati o n  
L M W H  
L o w m ol e c ul ar w ei g ht h e p ari n  
m A B  
M o n o cl o n al A nti b o d y  
M A P  
M a st er  A n al y si s Pl a n d o c u m e nt s pr oj e ct st a n d ar d s i n t h e st ati sti c al m et h o d s w hi c h will b e 
u s e d wit hi n t h e i n di vi d u al cli ni c al tri al R A P d o c u m e nt ati o n  
M -C S F  
M a cr o p h a g e c ol o n y sti m ul ati n g f a ct or al s o c all e d C S F -1  
M RI  
M a g n eti c r e s o n a n c e i m a gi n g  
M T D  
M a xi m u m  T ol er at e d D o s e  
o. d.  
o m ni a  di e / o n c e a  d a y 
O R  
O v er all R e s p o n s e  
O S  
O v er all S ur vi v al  
P A S  
P h ar m a c o ki n eti c A n al y si s S et  
P B M C  
P eri p h er al bl o o d m o n o n u cl e ar c ell s  
P D  
P h ar m a c o d y n a mi c s  
P E T  
P o sitr o n e mi s si o n t o m o gr a p h y  
P F S  
Pr o gr e s si o n Fr e e S ur vi v al  
P g R  
Pr o g e st er o n e r e c e pt or  
P K  
P h ar m a c o ki n eti c s  
p. o.  
p er o s / b y m o ut h/ or all y 
P HI  
Pr ot e ct e d H e alt h I nf or m ati o n  
P P S  
P er -Pr ot o c ol S et  
P R  
P arti al r e s p o n s e  
P V N S  
Pi g m e nt e d Vill o n o d ul ar S y n o viti s  
Q W  
O n c e -w e e kl y  
Q 3 W  
O n c e e v er y t hr e e w e e k s  
Q 4 W  
O n c e e v er y f o ur w e e k s  
R A P  
T h e R e p ort a n d A n al y si s Pl a n ( R A P) i s a r e g ul at or y d o c u m e nt w hi c h pr o vi d e s e vi d e n c e of 
pr e pl a n n e d a n al y s e s  
S A E  
S eri o u s A d v er s e E v e nt  
S D  
St a bl e di s e a s e  
T A M  
T u m or a s s o ci at e d m a cr o p h a g e  
TI L  
T u m or i nfiltr ati n g l y m p h o c yt e  
TI O  
T u m or i n d u c e d o st e ol y si s  
T N B C  
Tri pl e n e g ati v e br e a st c a n c er  
T R A P  
T artr at e -r e si st a nt a ci d p h o s p h at a s e 
U L O Q  
U p p er Li mit Of Q u a ntifi c ati o n  
w/ w o  
wit h/ wit h o ut  

N o v artis  
C o nfi d e nti al  
P a g e 1 1  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol  N o. C M C S 1 1 0 Z 2 2 0 1  
 
Gl o s s ar y of t er m s  
A s s e s s m e nt  
A  pr o c e d ur e u s e d t o g e n er at e d at a r e q uir e d b y t h e st u d y  
A dj u v a nt  
Tr e at m e nt t h at i s gi v e n i n a d diti o n t o t h e pri m ar y tr e at m e nt ( s ur g er y). C ur ati v e 
i nt e nt. 
A d v a n c e d br e a st c a n c er  
M et a st ati c or l o c all y a d v a n c e d br e a st c a n c er n ot a m e n a bl e t o c ur ati v e tr e at m e nt  b y 
s ur g er y or r a di ot h er a p y  
Bi ol o gi c S a m pl e s  
A  bi ol o gi c al s p e ci m e n i n cl u di n g, f or e x a m pl e, bl o o d ( pl a s m a, s er u m), s ali v a, ti s s u e, 
uri n e, st o ol, et c. t a k e n fr o m a st u d y s u bj e ct or st u d y p ati e nt  
C o ntr ol dr u g  
A  st u d y tr e at m e nt u s e d a s a c o m p ar at or t o r e d u c e a s s e s s m e nt bi a s, pr e s er v e 
bli n di n g of i n v e sti g ati o n al dr u g, a s s e s s i nt er n al st u d y v ali dit y, a n d/ or e v al u at e 
c o m p ar ati v e eff e ct s of t h e i n v e sti g ati o n al dr u g  
C o h ort  
A  gr o u p of n e wl y e nr oll e d p ati e nt s tr e at e d at a  s p e cifi c d o s e a n d r e gi m e n (i. e. 
tr e at m e nt  gr o u p) at t h e s a m e ti m e 
C y cl e s  
N u m b er  a n d ti mi n g or r e c o m m e n d e d r e p etiti o n s of t h er a p y ar e u s u all y e x pr e s s e d as 
n u m b er of d a y s ( e. g.: q 2 8 d a y s)  
D o s e l e v el  
T h e d o s e of dr u g gi v e n t o t h e p ati e nt (t ot al d ail y or w e e kl y et c.)  
E nr oll m e nt  
P oi nt/ti m e of p ati e nt e ntr y i nt o t h e st u d y; t h e p oi nt at w hi c h i nf or m e d c o n s e nt m u st 
b e  o bt ai n e d (i. e. pri or t o st arti n g a n y of t h e pr o c e d ur e s d e s cri b e d i n t h e pr ot o c ol)  
I n v e sti g ati o n al dr u g 
T h e st u d y tr e at m e nt w h o s e pr o p erti e s ar e b ei n g t e st e d i n t h e st u d y; t hi s d efi niti o n i s 
c o n si st e nt wit h U S C F R 2 1  S e cti o n 3 1 2. 3 a n d i s s y n o n y m o u s wit h “i n v e sti g ati o n al 
n e w dr u g.”  
I n v e sti g ati o n al tr e at m e nt 
Dr u g w h o s e pr o p erti e s ar e b ei n g t e st e d i n t h e st u d y a s w ell a s t h eir a s s o ci at e d 
pl a c e b o a n d a cti v e tr e at m e nt  c o ntr ol s ( w h e n a p pli c a bl e). T hi s al s o i n cl u d e s 
a p pr o v e d dr u g s u s e d o ut si d e of t h eir i n di c ati o n/ a p pr o v e d d o s a g e, or t h at ar e t e st e d 
i n a fi x e d c o m bi n ati o n. I n v e sti g ati o n al tr e at m e nt g e n er all y d o e s n ot i n cl u d e ot h er 
st u d y tr e at m e nt s a d mi ni st er e d a s c o n c o mit a nt b a c k gr o u n d t h er a p y r e q uir e d or 
all o w e d b y t h e pr ot o c ol w h e n u s e d i n wit hi n a p pr o v e d i n di c ati o n/ d o s a g e  
M e di c ati o n n u m b er  
A  u ni q u e i d e ntifi er o n t h e l a b el of e a c h st u d y tr e at m e nt p a c k a g e w hi c h i s li n k e d t o 
o n e of t h e tr e at m e nt  gr o u p s of a st u d y  
N e o a dj u v a nt  
T h er a p e uti c a g e nt s t h at ar e  gi v e n b ef or e t h e m ai n tr e at m e nt  ( oft e n s ur g er y). 
C ur ati v e i nt e nt.  
Ot h er st u d y tr e at m e nt  
A n y dr u g a d mi ni st er e d t o t h e p ati e nt a s p art of t h e r e q uir e d st u d y pr o c e d ur e s t h at 
w a s n ot i n cl u d e d i n t h e i n v e sti g ati o n al tr e at m e nt  
S u bj e ct N u m b er ( S u bj e ct 
N o.)  
A  u ni q u e i d e ntif yi n g n u m b er a s si g n e d t o e a c h p ati e nt/ s u bj e ct/ h e alt h y v ol u nt e er w h o 
e nr oll s i n t h e st u d y  
P eri o d  
A  s u b di vi si o n of t h e st u d y ti m eli n e; di vi d e s st a g e s i nt o s m all er f u n cti o n al s e g m e nt s 
s u c h a s s cr e e ni n g, b a s eli n e, titr ati o n, w a s h o ut, et c.  
Pr e m at ur e  p ati e nt  
wit h dr a w al  
P oi nt/ti m e w h e n t h e p ati e nt e xit s fr o m t h e st u d y pri or t o t h e pl a n n e d c o m pl eti o n of 
all st u d y tr e at m e nt  a d mi ni str ati o n a n d/ or a s s e s s m e nt s; at t hi s ti m e all st u d y 
tr e at m e nt  a d mi ni str ati o n i s di s c o nti n u e d a n d n o f urt h er a s s e s s m e nt s ar e pl a n n e d, 
u nl e s s t h e p ati e nt will b e  f oll o w e d f or pr o gr e s si o n a n d/ or s ur vi v al  
R a n d o mi z ati o n n u m b er  
A  u ni q u e tr e at m e nt i d e ntifi c ati o n c o d e a s si g n e d t o e a c h r a n d o mi z e d p ati e nt, 
c orr e s p o n di n g t o a s p e cifi c tr e at m e nt ar m a s si g n m e nt  
St a g e  r el at e d t o st u d y 
ti m eli n e 
A  m aj or s u b di vi si o n of t h e st u d y ti m eli n e; b e gi n s a n d e n d s wit h m aj or st u d y 
mil e st o n e s s u c h a s e nr oll m e nt, r a n d o mi z ati o n, c o m pl eti o n of tr e at m e nt, et c.  
St a g e  i n c a n c er  
T h e e xt e nt of a c a n c er i n t h e b o d y. St a gi n g i s u s u all y b a s e d o n t h e si z e of t h e 
t u m or, w h et h er l y m p h n o d e s c o nt ai n c a n c er, a n d w h et h er t h e c a n c er h a s s pr e a d 
fr o m t h e ori gi n al sit e t o ot h er p art s of t h e b o d y 
S t o p st u d y p arti ci p ati o n 
P oi nt/ti m e at  w hi c h t h e p ati e nt c a m e i n f or a fi n al e v al u ati o n vi sit or w h e n st u d y 
tr e at m e nt  w a s di s c o nti n u e d w hi c h e v er i s l at er 

N o v artis  
C o nfi d e nti al  
P a g e 1 2  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol  N o. C M C S 1 1 0 Z 2 2 0 1  
 
St u d y tr e at m e nt  
I n cl u d e s a n y dr u g or c o m bi n ati o n of dr u g s i n a n y st u d y ar m a d mi ni st er e d t o t h e 
p ati e nt  ( s u bj e ct) a s p art of t h e r e q uir e d st u d y pr o c e d ur e s, i n cl u di n g pl a c e b o a n d 
a cti v e dr u g r u n -i n s. 
I n s p e cifi c e x a m pl e s, it i s i m p ort a nt t o j u d g e i n v e sti g ati o n al tr e at m e nt c o m p o n e nt 
r el ati o n s hi p r el ati v e t o a st u d y tr e at m e nt  c o m bi n ati o n; st u d y tr e at m e nt i n t hi s c a s e 
r ef er s t o t h e i n v e sti g ati o n al a n d n o n-i n v e sti g ati o n al tr e at m e nt s i n c o m bi n ati o n. 
St u d y tr e at m e nt 
di s c o nti n u ati o n  
P oi nt/ti m e w h e n p ati e nt p er m a n e ntl y st o p s t a ki n g st u d y tr e at m e nt f or a n y r e a s o n  
S u p p orti v e tr e at m e nt  
R ef er s t o a n y tr e at m e nt r e q uir e d  b y t h e e x p o s ur e t o a st u d y tr e at m e nt,  e. g. 
pr e m e di c ati o n of vit a mi n s u p pl e m e nt ati o n a n d c orti c o st er oi d f or p e m etr e x e d 
di s o di u m.  
Tr e at m e nt gr o u p  
A  tr e at m e nt gr o u p d efi n e s t h e d o s e a n d r e gi m e n or t h e c o m bi n ati o n, a n d m a y 
c o n si st of 1 or m or e c o h ort s. C o h or t s ar e n ot e x p a n d e d, n e w c o h ort s ar e e nr oll e d. 
V ari a bl e  
I d e ntifi er u s e d i n t h e d at a a n al y si s; d eri v e d dir e ctl y or i n dir e ctl y fr o m d at a c oll e ct e d 
u si n g s p e cifi e d a s s e s s m e nt s at s p e cifi e d ti m e  p oi nt s  
Wit h dr a w al of C o n s e nt  
Wit h dr a w al of c o n s e nt o c c ur s o nl y w h e n a p ati e nt d o e s n ot w a nt t o p arti ci p at e i n t h e 
st u d y a n y l o n g er, a n d d o e s n ot w a nt a n y f urt h er vi sit s or a s s e s s m e nt s, a n d d o es n ot 
w a nt a n y f urt h er st u d y r el at e d c o nt a ct  

N o v artis  
C o nfi d e nti al  
P a g e 1 4  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol  N o. C M C S 1 1 0 Z 2 2 0 1  
 
•  
S ur vi v al F U a n d Dis e as e pr o gressi o n F U h a v e b e e n re m o ve d fr o m t h e st u d y d esi g n  
Se cti o n 4. 2 D efi niti o n of e n d of t he st u d y:  
•  
S ur vi v al f oll o w -u p h as b e e n re m o v e d  
T a ble 7 -1: Visit E v al u ati o n Sc he d ule:  
•  S ur vi v al F U a n d Dis e as e Pr o gressi o n F U h a v e b e e n re m o ve d  
•  C A 1 5 -3 s a m ple c olle cti o ns  h a ve b e e n re m o ve d  
•  Bi o m ar k er s a m ple c olle cti o ns  h a ve b e e n re m o ve d  
•  T u m or e v al u ati o n h as b e e n u p date d t o s p e cif y t h at t u m or e v al u ati o ns will b e p erf or m e d  
wit h a mi ni m u m of e v er y 1 2 w e e ks  
•  Ce ntral E C G e v al u ati o n at C 8 D 1 h as b e e n re pla ce d b y a l o c al e v al u ati o n  
•  P K s a m ple c olle cti o n  f or M C S 1 1 0 a n d c ar b o/ ge m, C S F-1 s a m ple c olle cti o n  
 
  h a v e b e e n re m o v e d  
Se cti o n 7. 1. 4 Dis c o nti n u ati o n of st u d y tr e at me nt  
•  
Se cti o n h as b e e n u p d ate d t o re m o v e Dis e as e pr o gressi o n F U  
Se cti o n 7. 1. 6 F oll o w -U p pe ri o d  
•  
Se cti o n h as b e e n u p d ate d t o re m o v e Dis e as e Pr o gressi o n F U a n d S ur vi v al F U  
Se c ti o n 7. 2. 1 Effic a c y ass ess me nts 
•  
Se cti o n h as b e e n u p d ate d t o s p e cif y t h at t u m or ass ess m e nts will b e p erf or m e d wit h a 
mi ni m u m of e v er y 1 2 w e e ks  
•  
Se c ti o n h as b e e n u p d ate d t o re m o v e t h e c e ntral re vie w of t h e ra di ol o gic al i m a gi n g 
Se cti o n 7. 2. 2. 5. 3  T u m o r m a r ke rs  
•  
Se cti o n h as b e e n u p d ate d t o s p e cif y t h at  foll o wi n g l o c al I R B/ E C a p pr o v al of pr ot o c ol 
a m e n d m e nt 6,  t u m or m ar k ers s a m ple  c olle cti o n  will n o  l o n ger b e  re q uire d  b y  t h e  
pr ot o c ol.  
Se ct i o n 7. 2. 2. 6. 1 Ele ctr oc ar di o g r a m 
•  
Se cti o n h as b e e n u p d ate d t o s p e cif y t h at t h e E C G at C 8 D 1 will b e re vie w e d l o c all y 
i nste a d of c e ntrall y  
Se cti o n 7. 2. 3. 1 Bl o o d s a m ple c olle cti o n  
•  
Se cti o n u p d ate d t o s p e cif y t h at foll o wi n g l o c al I R B/ E C a p pr o val of pr ot o c ol a m e n d m e nt 
6, P K  s a m ple  c olle cti o n  f or M C S 1 1 0  a n d c ar b o/ ge m will n o l o n ger b e re q uire d . I n 
a d diti o n, C S F-1  
 s a m ple c olle cti o n will n o l o n ger b e re q uire d.  
P K t a bles 7 -6, 7 -7 a n d 7 - 8 
•  
P K ta bles u p d ate d t o s p e cif y t h at P K s a m ples will n o l o n ger b e c olle cte d after a p pr o val of 
pr ot o c ol a m e n d me nt 6  

N o v artis  
C o nfi d e nti al  
P a g e 1 5  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol  N o. C M C S 1 1 0 Z 2 2 0 1  
 
Se cti o n 7. 2. 4 Bi o m a r ke rs  
•  
Se cti o n u p d ate d t o s p e cif y t h at f oll o wi n g l o c al I R B/ E C a p pr o val of pr ot o c ol a m e n d m e nt 
6, bi o m ar k er s a m ple c olle cti o ns will n o l o n ger b e re q uire d b y t h e pr ot oc ol.  
T a ble 7 -9 B i o m a r ke r s a m ple c olle cti o n pl a n 
•  
Ta ble  u p d ate d  t o  s p e cif y t h at bi o m ar k er s a m ples will n o  l o n ger  b e  colle cte d after 
a p pr o v al of pr ot o c ol a m e n d m e nt 6.  
Se cti o n 9. 3 D at a C olle cti o n a n d s e cti o n 9. 4 D at a b as e m a n a g e me nt a n d q u alit y c o ntr ol  
•  
Se cti o ns h a v e b e e n u p date t o s p e cif y t h at t h e E C G’s will b e re vie w e d c e ntrall y o nl y u ntil 
c y cle 4  
Se cti o n 1 0 St atistic al met h o d a n d d at a a n al ysis  
•  
Se cti o n h as b e e n u p d ate d re gar di n g t h e ti mi n g of t h e cli nic al st u d y  re p ort 
Se cti o n 1 0. 5. 1 Ot he r s e c o n d a r y effic ac y o bje cti ves  
•  
Se cti o n h as b e e n u p d ate d t o re m o v e t h e o v erall s ur vi v al  
Se cti o n 1 1. 5 P u blic ati o n of st u d y pr ot o c ol a n d r es ults  
•  
Se cti o n u p d ate d t o refle ct t h e m ost re c e nt p u blic ati o n p olic y fr o m N o v artis  
 
I R B/I E C 
A  c o p y  of  t his  a m e n d e d  pr ot o c ol  will  b e  s e nt  t o  t h e  I nstit uti o n al  Re vie w  B o ar d  
(I R Bs)/I n d e p e n d e nt Et hics C o m mitte e (I E Cs) a n d H e alt h A ut h orities. 
T h e  c h a n ges  d es cri b e d  i n  t his  a m e n d e d  pr ot o c ol  re q uire  I R B/I E C  a p pr o v al  pri or  t o  
i m ple m e ntati o n.  
T h e c h a n ges h erei n  affe ct t h e I nf or m e d C o ns e nt F or m f or t h e p atie nts. Sit e s ar e r e q uir e d t o 
u p d ate a n d s u b mit f or a p pr o v al a re vis e d I nf or me d C o ns e nt F or m t h a t ta k es i nt o a c c o u n t t h e 
c h a n ges d es cri b e d i n t his pr ot o c ol a m e n d m e nt.  

N o v artis  
C o nfi d e nti al  
P a g e 1 6  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol  N o. C M C S 1 1 0 Z 2 2 0 1  
 
S u m m ar y of pr e vi o u s a m e n d m e nt s  
A m e n d m e nt 5 ( 0 4 -M a y -2 0 1 7)  
A m e n d m e nt r ati o n al e  
T h e p ur p os e of t his a m e n d m e nt is t o a d dress re q ueste d c h a n ges fr o m a H e alt h A ut h orit y ( H A) 
re gar di n g t h e p ost-tre at m e nt c o ntra c e pti o n p eri o d f or c ar b o plati n a n d ge m cita bi n e.  
T h e  mi ni m u m  re q uire d  p ost -tre at m e nt  c o ntra c e pti o n  p eri o d  is  3 0  d a ys  p er  pr ot o c ol  
a m e n d m e nt 4. H o w e ver, l o c al v ariati o ns re gar di n g t h e re q uire d p ost -tre at me nt c o ntr a c e pti o n 
p eri o d  h a v e  b e e n  d ete cte d  i n  t h e  p artici p ati n g  c o u ntries’  a p pr o v e d  la b els  f or  t h e  
c h e m ot h era p y.  T h eref ore,  t h e  p ost -tre at m e nt  c o ntra c e pti o n  p eri o d  f or  c ar b o plati n  a n d  
ge m cita bi n e will b e u p d ate d t o f oll o w t h e l o c al a p pr o ve d la b els wit h a mi ni m u m f oll o w -u p o f 
3 0 d a ys.  F urt h er m ore, m o nt hl y uri n e pre g n a n c y tests m ust b e p erf or m e d d uri n g t h e p ost -
tre at m e nt c o ntra c e pti o n p eri o d a c c or di n g t o l o c al a p pr o v e d la b el. 
I n a d diti o n, a mi n or clarific ati o n h as b e e n m a d e a b o ut t h e ra di ol o gic al ass ess m e nts f oll o  wi n g 
a n ot h er H A re q u est.  
F urt h er m ore,  a  mi n or c orre cti o n  w as m a d e  t o  t h e  E C G f o ot n ote  ref ere n c e  i n  t h e  visit 
e v al u ati o n s c h e d ule ( Ta ble 7 -1).  
St u d y U p d ates  
T h e a m e n d e d pr ot o c ol v ersi o n 0 4 h as b e e n s u b mitte d t o H As a n d I R B/I E Cs. As of A pril 1 9 t h, 
2 0 1 7 , 33 p atie nts h a ve re c ei ve d st u d y tre at m e nt.  
C h a n g e s  t o pr ot o c ol  
Se cti o n 5. 3: E x cl usi o n c rite ri o n n u m be r 1 4:  
•  E x cl usi o n criteri o n 1 4 u p d ate d as f oll o ws: “ W o me n of c hil d -be ari n g p ote ntial, d efi n e d as 
all w o m e n p h ysi ol o gic all y c a p a ble of b e c o mi n g pre g n a nt, u nless t h e y are usi n g hi g hl y 
eff e cti v e m et h o ds of c o ntra ce pti o n d uri n g d osi n g of st u d y tre at m e nt a n d f or 9 0 d a ys after 
t h e last d os e of M C S 1 1 0, or f or 3 0 d a ys after t h e last d os e of c ar b o plati n a n d ge m cita bi n e 
or as re c o m m e n d e d p er t h e l o c al a p pr o v e d la b els f or c ar b o plati n a n d ge m cita bi n e, 
w hic h e v er h as t h e l o n gest d urati o n”.  
T a ble 7 -1: Visit e v al u ati o n s c he d ule:  
•  F o ot n ote 4 h as b e e n u p d ate d t o refle ct t h at a n y pre g n a n c y test i n t h e s af et y f oll o w -u p will 
b e re p orte d i n t h e s o urc e  d o c u m e ntati o n  a n d t h at mo nt hl y uri ne pre g n a nc y tests m ust b e 
p erf or m e d f or 9 0 d a ys after t h e last d os e of M C S 1 1 0 or f or 3 0 d a ys after t h e last d os e of 
c ar b o plati n a n d ge m cita bi ne or as re c o m me n d e d p er t h e l o c al a p pr o ve d la b el s f or 
c ar b o plati n a n d ge m cita b i ne, w hic he ver h as t h e l o n gest d urati o n. 
•  F o ot n ote 8 h as b e e n d elete d as all t h e i nf or m ati o n a b o ut t h e pre g n a nc y tests i n t h e s af et y 
f oll o w-u p is c a pt ure d i n f o ot n ote 4.  
Se cti o n 7. 2. 1 Effic a c y ass ess me nts : 

N o v artis  
C o nfi d e nti al  
P a g e 1 7  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol  N o. C M C S 1 1 0 Z 2 2 0 1  
 
•  
Se cti o n u p d ate d t o clarif y t h at ra di ol o gic al ass ess me nts o btai n e d f or p atie nts e nr oll e d o n  
st u d y will b e c e ntrall y c olle cte d a n d st ore d b y a n i m a gi n g C R O d esi g n at e d b y N o v artis 
f or a p ote ntial c e ntraliz e d bli n de d re vie w i n a d diti o n t o t h e l o c al as s e s s m e n t if  d e e  m e d 
n e c ess ar y.   
Se cti o n 7. 2. 2. 5. 6: Pr e g n a nc y  
•  Se cti o n u p d ate d t o s p e cif y t h at f or b ot h ar ms, if t h e p ost -tre at m e nt c o ntra c e pti o n p eri o d 
f or c ar b o plati n a n d ge m cita bi n e as p er t h e l o c al a p pr o v e d la b el is l o n ger t h a n 3 0 d a ys, 
a d diti o n al m o nt hl y uri n e pre g n a nc y tests m ust b e p erf or m e d u ntil t h e e n d of t h e p ost -
tre at m e nt c o ntra c e pti o n p eri o d.   
Se cti o n 8. 3: Pr e g n a ncies  
•  Se cti o n u p d ate d t o s p e cif y t h at a n y pre g n a ncies o c c urri n g after dis c o nti n uati o n of st u d y 
tre at m e nt ( u p t o 9 0 d a ys or d uri n g t h e p ost tre at m e nt c o ntrac e pti o n p eri o d as 
re c om m e n d e d p er t h e l o c al a p pr o ve d la b el s, w hic he ver h as t h e l o n gest d urati o n) m ust b e 
re p orte d t o N o v artis wit hi n 2 4 h o urs of le ar ni n g of its o c c urre nc e.  
Se cti o n 1 0. 4. 1:  V a ri a ble  
•  Se cti o n u p d ate d t o s p e cif y t h at if bli n de d c e ntral re vie w is p erf or m e d o n t h e ra di ol o gic al 
ass ess m e nts, t h e n a n al ys es s p e cifie d f or all effica c y e n d p oi nts b as e d o n l o c al ass ess m e nts  
will b e a d diti o n all y p erf or m e d o n t h e res p o ns e e v al u ati o ns fr o m t h e bli n d e d re vie w.  
I R B/I E C 
A  c o p y  of  t his  a m e n d e d  pr ot o c ol  will  b e  s e nt  t o  t h e  I nstit uti o n al  Re vie w  B o ar d  
(I R Bs)/I n d e p e n d e nt Et hics C o m mitte e (I E Cs) a n d H e alt h A ut h orities. 
T h e  c h a n ges  d es cri b e d  i n  t his  a m e n d e d  pr ot o c ol  re q uire  I R B/I E C  a p pr o v al  pri or  t o  
i m ple m e ntati o n.  
T h e c h a n ges h erei n  affe ct t h e I nf or m e d C o ns e nt F or m f or t h e p atie nts. Sit e s ar e r e q uir e d t o 
u p d ate a n d s u b mit f or a p pr o v al a re vis e d I nf or me d C o ns e nt F or m t h at ta k es i nt o a c c o u nt t h e 
c h a n ges d es cri b e d i n t his pr ot o c ol a m e n d m e nt.  

N o v artis  
C o nfi d e nti al  
P a g e 1 8  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol  N o. C M C S 1 1 0 Z 2 2 0 1  
 
A m e n d m e nt 4 ( 2 0 -S e p - 20 1 6) 
A m e n d m e nt r ati o n al e  
T h e m ai n p ur p os e of t his a m e n d m e nt is t o e xte n d t h e p ost -tre at m e nt c o ntra c e pti o n p eri o d 
fr o m 6 0 t o 9 0 d a ys f or p atie nts re c ei vi n g M C S 1 1 0. T h e p ost-tre at m e nt c o ntr a c e pti o n p eri o d 
w as  s et  t o  6 0  d a ys  b as e d  o n  P K  d ata  fr o m  t h e  h e alt h y  v ol u nte er  ( H V)  st u d y  
( C M C S 1 1 0 X 2 2 0 1) d e m o nstrati n g t h at 9 9 % of fre e M C S 1 1 0 w as eli mi n ate d b y t h at ti m e-
p oi nt. N e wl y o btai n e d P K d ata s u g gest t h at t h e m a xi m u m c o nc e ntrati o ns of fre e M C S 1 1 0 ar e 
sli g htl y hi g h er i n T N B C p atie nts t h a n i n H V. Si m ulati o ns pre dict th at 9 7 % of fre e M C S 1 1 0 
will b e eli mi n ate d after 6 0 d a ys i n p atie nts wit h T N B C  a n d t h at after 9 0  d a ys 9 9 % of fre e 
M C S 1 1 0  will b e eli mi n ate d , c orres p o n di n g t o a fre e M C S 1 1 0 c o n ce ntrati o n  of 7 n g/ m L  w hic h 
is b el o w t h e i n -vitr o I C 5 0 d eter mi n e d i n  t h e a cti vit y a n d p ote n c y ass a y (I C 5 0: 1 0 -2 0 n g/ m L, 
I B e diti o n 1 1 s e cti o n 4. 1. 1. 1). T h us, t h e p ost -tre at m e nt c o ntrac e pti o n p eri o d will b e ext e n d e d 
fr o m 6 0 d a ys t o 9 0 d a ys.  
A c c or di n gl y , t h e s af et y f oll o w-u p will als o b e e xte n d e d fr o m 6 0 t o  9 0 d a ys. D uri n g t h e s afet y 
f oll o w-u p, all A E’s a n d S A E’s, re gar dless of c a us alit y, will b e c olle cte d 3 0 a n d 9 0 d a ys aft er 
dis c o nti n u ati o n  of st u d y tre at m e nt . If a p atie nt starts  a n e w a ntic a n c er th era p y   d uri n g t h e 
s af et y  f oll o w-u p , o nl y A E’s a n d S A E’s s us p e c te d t o b e related t o st u d y tre at m e nt  a n d 
ass o ciate d c o n c o mita nt m e dic ati o ns will b e c olle cte d  fr o m t his ti m e p oi nt.  
I n or d er t o a d d fle xi bilit y, s af et y f oll o w-u ps m a y b e p erf or me d via tele p h o n e  c alls.  
Clarif yi n g te xt h as b e e n a d d e d t o t h e pr ot o c ol e m p h asizi n g t h at o n -tre at m e nt bi o psies o nl y 
s h o ul d b e ta k e n if m e dicall y f easi ble a c c or di n g t o t h e tre ati n g i n v esti gat or t o e ns ure p ati e nt ’ s 
s af et y.  F urt h er m ore,  c orre cti o ns  of  i nsi g nific a nt  t y p o gra p hic al  err ors  h a v e  b e e n  m a d e  
t hr o u g h o ut t h e pr ot o c ol.  
St u d y U p d ates  
T h e a m e n d e d pr ot o c ol v ersi o n 0 3 h as b e e n s u b mitte d t o H As a n d I R B/I E Cs. As of A u g ust 
1 6 t h, 2 0 1 6, 2 0  p atie nts h a v e re c ei v e d st u d y tre at m e nt.  
C h a n g e s  t o pr ot o c ol  
Se cti o n 4. 1  
D es c ri pti o n of st u d y desi g n , St u d y  Visit Fl o w ( Fi g 4-2)  
Se cti o n 7  - T a ble 7 - 1 Visit E v al u ati o n Sc he d ule  
Se cti o n 7. 1. 6 . F oll o w -U p Pe ri o d  
Se cti o n 7. 2. 2. 5. 6  Pr e g n a nc y  
Se cti o n 8. 1. 1 . A d v e rs e E v e nts D efi niti o ns a n d R e p o rti n g  
Se cti o n 8. 2. 2 . Se ri o us A d v e rs e E v e nts R e p o rti n g  
Se cti o n 1 0 . 5.2. 1 .A n al ysis S et a n d G r o u pi n g f o r t he A n al ys es   
•  All s e cti o ns liste d a b o v e u p date d t o refle ct t h e n e w s afet y f oll o w -u p p eri o d of 9 0 d a ys  

N o v artis  
C o nfi d e nti al  
P a g e 1 9  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol  N o. C M C S 1 1 0 Z 2 2 0 1  
 
Se cti o n 5. 3 E x cl usi o n C rite ri o n 1 4  
•  U p d ate d t o refle ct t h e 9 0 d a ys c o ntra ce pti o n p eri o d after t h e last d os e of M C S 1 1 0  a n d t h e 
3 0 d a ys c o ntra c e pti o n p eri o d after t h e last d os e of c ar b o plati n a n d ge m cita bi n e f or p atie nts 
n ot re c ei vi n g M C S 1 1 0 . 
T a ble 7 -1 Sc he d ule of E v al u ati o n, Se cti o n 7. 1. 6 F oll o w -U p pe ri o d, Se cti o n 8. 1. 1 A d v e r s e 
E v e nts D efi niti o ns a n d R e p o rti n g a n d Se cti o n 8. 2. 2 Se ri o us A d v e rs e E v e nts R e p o rti n g  
•  Ta ble a n d Se cti o ns c h a n ge d t o reflect t h at o n c e a p atie nt b e gi ns a n ot h er a nti -c a nc er 
t h era p y, o nl y A E’s a n d S A E’s s us p e cte d t o b e relate d t o t h e st u d y tre at m e nt a n d t h e 
ass o ciate d m e dic ati o ns will b e c olle cte d i n t h e f oll o w -u p p eri o d.  
Se cti o n 7. 1. 6 F oll o w -u p pe ri o d  
•  Se cti o n u p d ate d t o refle ct t h e o pti o n t o p erf or m t h e s af et y f oll o w -u p via tele p h o ne c all  
Se cti o n 7. 2. 2. 5. 6 Pr e g n a nc y  
•  U p d ate d t o refle ct t h at f or w o m e n of c hil d be ari n g p ote ntial d uri n g t h e s af et y f oll o w -u p 
p eri o d, uri n e  pre g n a n c y te sts are p erf or me d 3 0 , 6 0 a n d 9 0 d a ys after st o p pi n g M C S 1 1 0 i n 
Ar m 1  a n d 3 0 d a ys after st o p pi n g st u d y tre at m e nt i n Ar m 2 . 
Se cti o n 7. 2. 4 T a ble 7 -9 Bi o m a r ke r s a m ple c olle cti o n pl a n  
•  Ta ble is u p d ate d t o clarif y t h at bi o psies s h o ul d b e ta k e n if m e dic all y f e asi ble  
•  A d diti o n all y  a f o ot n ote h as b e e n a d de d t h at all bi o psies m ust b e c o n d ucte d b y a 
pr of essi o nal wit h e x p ertis e i n t h e pr o c e d ure  
I R B/I E C  
A  c o p y  of  t his  a m e n d e d  pr ot o c ol  will  b e  s e nt  t o  t h e  I nstit uti o n al  Re vie w  B o ar d  
(I R Bs)/I n d e p e n d e nt Et hics C o m mitte e (I E Cs) a n d H e alt h A ut h orities. 
T h e  c h a n ges  d es cri b e d  i n  t his  a m e n d e d  pr ot o c ol  re q uire  I R B/I E C  a p pr o v al  pri or  t o  
i m ple m e ntati o n.  
T h e c h a n ges h erei n  affe ct t h e I nf or m e d C o ns e nt F or m f or t h e p atie nts. Sit e s ar e r e q uir e d t o  
u p d ate a n d s u b mit f or a p pr o v al a re vis e d I nf or me d C o ns e nt F or m t h at ta k es i nt o a c c o u nt t h e 
c h a n ges d es cri b e d i n t his pr ot o c ol a m e n d m e nt.  

N o v artis  
C o nfi d e nti al  
P a g e 2 0  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol  N o. C M C S 1 1 0 Z 2 2 0 1  
 
A m e n d m e nt 3 ( 0 8 -A pr -2 0 1 6)  
A m e n d m e nt r ati o n al e  
T h e m ai n p ur p os e of t his a m e n d me nt is t o pr o vi d e a d diti o nal fle xi bilit y f or M C S 1 1 0 d o si n g 
b y i ntr o d u ci n g t h e o pti o n t o s ki p t h e a d diti o n al M C S 1 1 0 d os e o n C 1 D 8 f or s u bs e q u e nt 
p atie nts, s h o ul d a n y s afet y c o n cer ns b e re v e ale d u p o n re vie w of d ata fr o m t h e d osi n g re gi m e n 
c urre ntl y b ei n g e v al u ate d.  
T h e c urre nt st u d y d esi g n i n cl u d es  a n e arl y s af et y re vie w m e eti n g, w hic h will b e p erf or m e d 
after t h e first 9 p atie nts h a v e b e e n ra n d o miz e d a n d c o m plete d  2 tre at m e nt c y cles of eit h er 
M C S 1 1 0 + c ar b o plati n/ ge m cita bi ne or c ar b o plati n/ ge m cita bi ne al o n e, or dis c o nti n ue d e arli er 
d u e t o a n a d v ers e  e v e nt. N o v artis a n d st u d y i n v esti gat ors will e v al u ate cli nic al, P K a n d 
la b orat or y d ata at a j oi nt m e eti n g t o m a k e a n ass ess m e nt of t h e s afet y of b ot h st u d y ar m s. If  
s af et y c o n c er ns are n ote d, t h e o nl y c urre nt o pti o n is t o re d u c e t h e M C S 1 1 0 d o s e t o 5 m g/ k g  
a n d t o k e e p t h e a d diti o n al 5 m g/ k g d os e of M C S 1 1 0 o n C y cle 1 D a y 8. T his a m e n d m e nt 
i ntr o d u c es t h e o pti o n t o s ki p t h e a d diti o n al M C S 1 1 0 d os e o n C 1 D 8 f or s u bs e q ue nt p atie nts. If  
t h e d osi n g re gi m e n is c h a n ge d after t h e d ata re vie w, a n a d diti o n al s af et y re view will ta k e 
pla c e after 9 p atie nts h a v e b ee n ra n d o miz e d a n d c o m plete d 2 c y cles of eit h er M C S 1 1 0 ( p er 
t h e n e w d osi n g re gi m e n) + c ar b o plati n/ ge m cita bi n e or c ar b o plati n/ ge m cita bi n e al o n e. A n y 
s u bs e q u e nt c h a n ges of t h e M C S 1 1 0 d osi n g re gi m e n will b e f oll o w e d b y a n a d diti o n al s af et y 
re vie w p er t h e pr o c e d ure j ust d es cri b e d. T h e l o w est a c c e pte d M C S 1 1 0 d osi n g re gi m e n will b e 
2. 5 m g/ k g, wit h or wit h o ut t h e a d diti o n al d os e o n C 1 D 8.  
F urt h er m ore, ot h er u p d ates are b ei n g i m ple m e nte d i n t his pr ot o c ol a m e n d m e nt a s d e s cri b e d 
b el o w:  
•  T h e l o w est p ossi ble d os e re d u cti o n f or M C S 1 1 0 h as b e e n c h a n ge d fr o m 2. 5 m g/ k g t o 1 
m g/ k g t o all o w d os e re d u cti o ns f or t h e alter n ati v e l o w er M C S 1 1 0 d osi n g re gi m e ns.  
•  D os e d ela y ≤ 1 w e e k will b e p er mitte d f or a n y re aso n. I n c as e tre at m e nt c a n n ot b e 
d eli v ere d wit hi n t his ti m e fra m e t h e d os e will b e s ki p p e d.  
•  A n ote h as b e e n a d d e d t o clarif y t h at d os e re d u cti o ns f or h e m at ol o gic al t o xicit ies 
s us p e cte d t o b e relate d t o c ar b o/ ge m s h o ul d n ot b e p erf or me d b as e d o n n a dir c o u nts f or 
platelets or n e utr o p hils  
•  Clarific ati o n h as b e e n a d de d t h at all t u m or bi o psies are m a n d at or y a n d m a y o nl y b e 
o mitte d f or m e dic al or s af et y re as o ns.  
•  T h e o n -tre at m e nt bi o ps y s h o ul d b e ta k e n b et w e e n C 2 D 8 – C 3 D 1, b ut m a y b e d ela y e d t o a 
later ti m e p oi nt at t h e i n v esti gat or’s dis creti o n.  
I n a d diti o n, c orre cti o ns of i nsi g nific a nt t y p o gra p hic al err ors h a v e b ee n m a de t hr o u g h o ut t h e 
pr ot o c ol.  
St u d y U p d ates  
T h e a m e n d e d pr ot o c ol v ersi o n 0 2 h as b e e n s u b mitte d t o H As a n d I R B/I E Cs. As of 1 7 -M A R -
2 0 1 6, 8 p atie nts h a v e b e e n d os e d.  

N o v artis  
C o nfi d e nti al  
P a g e 2 1  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol  N o. C M C S 1 1 0 Z 2 2 0 1  
 
C h a n g e s  t o pr ot o c ol  
Se cti o n 2. 2  
R ati o n ale f o r st u d y desi g n  
•  U p d ate d t o refle ct t h e  n e w d osi n g alter n ati v es f or M C S 1 1 0 a n d t h e p ote ntial a d diti o n al 
s af et y re vie w m e eti n gs 
Se cti o n 4. 1  
D es c ri pti o n of st u d y desi g n  
•  
U p d ate d t o refle ct t h e n e w d osi n g alter n ati v es f or M C S 1 1 0 a n d t h e p ote nti al a d diti o n al 
s af et y re vie w m e eti n gs 
Se cti o n 5. 3  E x cl usi o n c rite ri a  #1 4  
•  
U p d ate d t o c orre ct a t y p o: W o m e n of c hil d -be ari n g p ote ntial are all o w e d t o p artici p ate i n  
t h e trial if t h e y are usi n g hi g hl y eff e cti v e m et h o ds of c o ntrac e pti o n d uri n g d osi n g of stu d y 
tre at m e nt a n d f or 6 0 d a ys after t h e last d os e of M C S 1 1 0 (c h a n ge d fr o m 9 0 d a ys t o 6 0 
d a ys)  
Se cti o n 6. 1. 1  D osi n g r e gi me n  
•  T his s e cti o n i n cl u di n g Ta ble 6 - 1 ( D os e a n d tre at m e nt s c h e d ule) h as b e e n u p d ate d t o 
refle ct t h e n e w d osi n g o pti o ns after t h e s afet y re vie ws: p ossi bilit y t o s ki p t h e C 1 D 8 
M C S 1 1 0 d os e a n d n e w tre at m e nt gr o u p a d de d ( 2. 5 m g/ k g f or M C S 1 1 0).  
Se cti o n 6. 2. 1  D os e m o dific ati o ns a n d d os e del a y   
•  
U p d ate d t o refle ct t h at t h e s t u d y tre at m e nt m a y b e d ela y e d b y ≤ 1 w e e k fr o m t h e e x p ecte d 
d a y of t h e n e xt st u d y tre at m e nt a d mi nistrati o n f or a n y re as o n. If st u d y tre at m e nt c a n n ot 
b e gi v e n wit hi n t his ti m e fra m e d u e t o p ersisti n g t o xicit y, t h e d os e s h o ul d b e s ki p pe d. 
•  
U p d ate d t o refle ct t h at t h e M C S 1 1 0 d os e c a n b e re d u ce d b y 3 d os e le v els if t h e p atie nt is 
i n t h e M C S 1 1 0 1 0 m g/ k g tre at m e nt gr o u p. 
•  
U p d ate d l o w est p ossi ble d os e re d ucti o n  f or M C S 1 1 0 fr o m 2. 5 m g/ k g t o 1 m g/ k g. 
Se cti o n 6. 2. 1. 1  - T a ble 6 - 2 D os e m o dific ati o ns a n d a cti o ns f o r t o xicities s us pe cte d t o b e 
r el ate d t o M C S 1 1 0  
•  
A t y p o h as b e e n c orre cte d: i n c as e of Gra d e 3 A L T ele v ati o n t h e c h e m ot h era p e utic a ge nts 
s h o ul d b e re d u c e d b y 2 0 % a n d if re c urri n g b y a n a d diti o n al 2 0 %, i n a c c or d a n c e wit h t h e 
ori gi n al p u blic ati o n b y  O’ S h a u g h n ess y 2 0 1 1 .  
Se cti o n 6. 2. 1. 1  - T a ble 6 - 3 D os e m o dific ati o ns f o r he m at ol o gic al t o xicities s us pe cte d t o 
be r el ate d t o c a r b o/ g e m  
•  
N ote a d d e d t o refle ct t h at t h e d os e re d u cti o ns s h o ul d n ot b e p erf or m e d b as e d o n n a dir 
c o u nts of n e utr o p hils a n d platelets  
Se cti o n 6. 4. 2  Tr e at me nt assi g n me nt a n d r a n d o miz ati o n  
•  
T otal n u m b er of p atie nts if t h e d ose is c h a n ge d aft er t h e s afet y re vie w m e eti n gs h as b e e n 
re e v al u ate d t o a p pr o xi m atel y  1 1 0 (i n cl u di n g 2 a d diti o n al s af et y c o h orts of 9 p atie nts).  
Se cti o n 7  - T a ble 7 - 1 Visit E v al u ati o n Sc he d ule  

N o v artis  
C o nfi d e nti al  
P a g e 2 2  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol  N o. C M C S 1 1 0 Z 2 2 0 1  
 
•  
Pre g n a n c y test s e cti o n u p d ate d f or 3 0 a n d 6 0 d a ys s afet y f oll o w u p t o refle ct t h at t h e t e st 
will o nl y b e re p orte d i n s o urc e d oc u me nt a n d n ot i n t h e C R F  
•  
F o ot n ote h as b e e n a d d e d t o clarif y t h at t h e M C S 1 1 0 C 1 D 8 d ose m a y b e o mitt e d af t er a 
s af et y re vie w m e eti n g  
•  
P h o n e c all f or s ur vi v al f oll o w -u p h as b e e n m o v e d t o t h e s ur vi v al f oll o w-u p ( F U ) (t o 
c orre ct f or a t y p o)  
Se cti o n 7. 2. 2. 5. 6  Pr e g n a nc y  
•  
Clarific ati o n a d d e d t h at t h e pre g n a n c y tests at 3 0 a n d 6 0 d a ys s afet y f oll o w -u p m a y b e a 
uri n e test i nste a d of a s er u m pre g n a n c y test a n d will b e re c or d e d o nl y i n t h e s o urc e 
d o c u m e ntati o n, n ot i n t h e C R F.  
Se cti o n 7. 2. 3. 1  Bl o o d s a m ple c olle cti o n a n d h a n dli n g  
•  
F o ot n ote  a d d e d  i n  Ta ble 7 - 6 a n d Ta ble 7 - 7 t o refle ct t h at if  t h e a d diti o n al d os e of  
M C S 1 1 0  o n  C 1 D 8  is  o mitte d  t h e  p ost -d os e C 1 D 8 P K s a m ple c olle cti o n s h o ul d b e 
s ki p p e d 
Se cti o n 7. 2. 4  Bi o m a r ke rs  
•  
Clarific ati o n h as b e e n a d d e d t h at all bi o psies i n Ta ble 7 - 9 are m a n d at or y a n d m ust b e 
o btai n e d if m e dic all y f e asi ble.  
T a ble 7 - 9 Bi o m a r ke r s a m ple c olle cti o n pl a n  
•  
Clarific ati o n h as b e e n a d de d t h at if o btai ni n g t h e bi o ps y is n ot m e dic all y f e asi ble b et w ee n 
C 2 D 8 a n d C 3 D 1, t h e bi o ps y m a y b e c olle cte d at a later ti m e p oi nt at t h e i n v esti gat ors 
dis creti o n.  
Se cti o n 8. 2. 2  Se ri o us A d v e rs e E v e nts - R e p o rti n g  
•  
U p d ate d a c c or di n gl y t o t h e n e w s eri o us a d vers e e v e nts g ui d a n c e  
•  
U p d ate d t o refle ct t h at t h e S A Es h a v e t o b e c olle cte d, re gar dless of s us p ecte d c a u s alit y , 
u ntil at le ast 6 0 d a ys after t h e p atie nt h as st o p pe d st u d y tre at m e nt . 
Se cti o n 8. 5  Ste e ri n g C o m mitte e  
•  
Clarific ati o n h as b e e n a d de d t h at after t h e e arl y s af et y re vie w(s), i n di vi d u al p ati e nt d at a 
will s u bs e q u e ntl y b e re vie w e d o n a n o n g oi n g b asis a n d dis c uss e d wit h I n v esti gat ors 
t hr o u g h o ut t h e d urati o n of t h e trial. 
Se cti o n 1 0  St atistic al met h o ds a n d d at a a n al ysis  
•  
As t h ere m a y b e m ulti ple tre at m e nt gr o u ps wit hi n Ar m 1, t h e d ata s u m m ariz e d or list e d 
“ b y st u d y ar m ” h as b e e n c h a n ge d t o “ b y Ar m a n d tre at m e nt gr o u p ”.  
•  
T h e s e nte n c e  “D ata fr o m p atie nts e nr olle d b ef ore t h e s af et y re vie w tre ate d at a d osi n g 
le v el diff ere nt fr o m t h e c o nfir m e d o n e will b e a n al y z e d as a se p arate gr o u p f or all t h e 
a n alysis u nless s p e cifie d ot h er wis e ” h as b e e n d elete d, as t h ere mi g ht b e m ulti pl e s af et y 
re vie ws a n d i n a d diti o n t his s e nte n c e is alre a d y c o v ere d b y t h e last s e nte n c e fr o m t h e 

N o v artis  
C o nfi d e nti al  
P a g e 2 3  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol  N o. C M C S 1 1 0 Z 2 2 0 1  
 
pre vi o us p ara gra p h “ d ata will b e a n al y z e d a n d/ or pres e nte d s e p arat el y f or e a c h st u d y 
ar m a n d tre at m e nt gr o u p.  
Se cti o n 1 0. 4  Pri m a r y o bje cti v e  
•  
Clarific ati o n a d d e d t h at f or si m plicit y, t hr o u g h o ut t his s e cti o n, t h e M C S 1 1 0 + c ar b o/ g e m 
ar m will b e us e d t o ref er t o p atie nts ra n d o miz e d t o Ar m 1 at t h e M C S 1 1 0 fi n al c o nfir me d 
d os e.  
Se cti o n 1 0. 5. 2. 1  A n al ysis s et a n d g r o u pi n g f o r t he a n al ys es  
•  
D efi niti o ns of o n -tre at m e nt p eri o d a n d p ost -tre at m e nt p eri o d u p date d t o refle ct t h e s af et y 
f oll o w-u p of 6 0 d a ys  
Se cti o n 1 0. 7  I nte ri m a n al ysis 
•  
U p d ate d t o refle ct t h e a d diti o n of a s u bs e q u e nt s af et y re vie w m e eti n g if t h e d osi n g 
re gi m e n is c h a n ge d after a s afet y re vie w m e eti n g. 
•  
U p d ate d t o clarif y t h at a d e cisi o n t o st o p t h e trial e arl y ( n ot f or effic ac y) m a y b e m a d e b y 
t h e Ste eri n g C o m mitte e. 
I R B/I E C  
A  c o p y  of  t his  a m e n d e d  pr ot o c ol  will  b e  s e nt  t o  t h e  I nstit uti o n al  Re vie w  B o ar d  
(I R Bs)/I n d e p e n d e nt Et hics C o m mitte e (I E Cs) a n d H e alt h A ut h orities. 
T h e  c h a n ges  d es cri b e d  i n  t his  a m e n d e d  pr ot o c ol  re q uire  I R B/I E C  a p pr o v al  pri or  t o  
i m ple m e ntati o n.  
T h e c h a n ges h erei n  affe ct t h e I nf or m e d C o ns e nt F or m f or t h e p atie nts. Sit e s ar e r e q uir e d t o 
u p d ate a n d s u b mit f or a p pr o v al a re vis e d I nf or me d C o ns e nt F or m t h at ta k es i nt o a c c o u nt t h e 
c h a n ges d es cri b e d i n t his pr ot o c ol a m e n d m e nt.  

N o v artis  
C o nfi d e nti al  
P a g e 2 4  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol  N o. C M C S 1 1 0 Z 2 2 0 1  
 
A m e n d m e nt 2  ( 8-O ct -2 0 1 5)  
A m e n d m e nt r ati o n al e  
T h e m ai n p ur p os e of t his a m e n d m e nt is t o all o w s af et y m o nit ori n g of cre ati n e ki n as e ( C K) 
ele v ati o ns p er l o c al g ui d eli n es, t o m o dif y t h e la n g u a ge o n T u m or ass o ciate d m a cr o p h a ges 
( T A M) c o nte nt f or p atie nt s ele cti o n, a n d  t o  i m ple m e nt re q u este d  c h a n ges fr o m  H e alt h  
A ut h orities ( H A).  
I n pre vi o us M C S 1 1 0 st u dies, al d olas e testi n g h as b e e n us e d t o r ule o ut m us cle d a m a ge i n 
p atie nts wit h C K ele v ati o ns. H o w e v er, t h e al d olas e ass a y is n o l o n ger a v aila ble i n s e v eral 
p artici p ati n g c o u ntries a n d t h us, will b e re pla c e d b y re c o m m e n d ati o ns t o r ule o ut m us cle 
d a m a ge  ( m y ositis/r h a b d o m y ol ysis)  a c c or di n g  t o  l o c al  g ui d eli n es  ( Ta ble  6 -2  D os e  
m o dific ati o ns a n d a cti o n f or t o xicities s us p e cte d t o b e relate d t o M C S 1 1 0). T h e al d olas e 
testi n g at ti m e of C K ele v ati o n will o nl y b e p erf or m e d if re q uire d b y l o c al g ui d eli n es. 
Res e arc h c o n d u cte d at N o v artis esta blis h e d a n i m m u n o hist o c h e mic al ass a y, C D 1 6 3, f or 
e v al u ati n g T A Ms i n Tri ple n e gati v e bre ast c a n c er ( T N B C ). T h ere after, a n e xter n al la b w as 
c o ntra cte d f or t h e c e ntral testi n g of T A Ms. A c orrelati o n st u d y w as p erf or m e d at t h e e xt er n al 
la b t o e ns ure t h at t h e s a m e p atie nt p o p ulati o n w as i d e ntifie d usi n g t h e t w o diff ere nt ass a y 
platf or ms.  T h e  T A M c ut off  d eter mi n e d  d uri n g ass a y  v ali d ati o n  at t h e  e xter n al la b  f or 
i d e ntif yi n g  p atie nts  wit h  a  hi g h  T A M  c o nte nt ( 4 0 %  of  T N B C) diff ere d  fr o m  t h e  o n e  
d eter mi n e d at N o v artis, w hic h c a n b e e x plai n e d b y w ell -k n o w n te c h nical differe nc es b et w e e n 
ass a y platf or ms. T h e diff ere nt c ut off v al u es w ere str o n gl y a n d si g nific a ntl y c orrelate d a n d 
t h us, b ot h ass a y platf or ms i d e ntified t h e s a m e p atie nt p o p ulati o n. A c c or di n gl y, t o a c c o u nt f or 
te c h nic al diff ere nc es b et w e e n platf or ms t h e pre vi o usl y pr o vi d e d c ut-off h a s b e e n r e m o v e d 
a n d re pla c e d b y “ hi g h T A M c o nte nt”. 
T h e f oll o wi n g c h a n ges h a v e b ee n i m ple me nte d t o t h e pr ot o c ol at t h e re q u est of H A’s: 
•  “ H y p ers e nsiti vit y t o m o n ocl o n al a nti b o dies ” h as b e e n a d de d as a n e x cl usi o n criteri o n t o 
re d u c e t h e ris k of h y p ers e nsiti vit y re a cti o ns t o M C S 1 1 0. A d diti o nall y, la n g u a ge re gar di n g 
m o nit ori n g of p ote ntial h y pers e nsiti vit y re a cti o ns h as b e e n i n c or p orate d.  
•  P h os p h ate testi n g h as b e e n a d d e d t o r o uti n e c h e mistr y d u e t o pre cli nical fi n di n gs of 
h y p o p h osp hate mia.  
•  C h a n ge i n e x cl usi o n criteria # 1 1 t o i n cre as e A N C  fr o m < 1. 0 x 1 0 9/ L t o < 1. 5 x 1 0 9/ L t o 
ali g n wit h t h e s u m m ar y of pr o d uct c h ara cteristics ( S m P C) of  ge m cita bi n e  f or a p pr o ve d 
i n dic ati o ns.  
•  P h e n yt oi n m e dic ati o n will b e c a uti o n e d f or p atie nts p artici pati n g i n t h e st u d y si n c e it h as 
b e e n d es cri b e d t h at c o nc o mita nt c ar b o plati n tre at m e nt m a y d e cre as e t h e s er u m le v el of 
p h e n yt oi n.  
•  D os e m o dific ati o ns/a cti o ns f or “ Ot h er s Gra d e ≥ 3 t o xicities s us p e cte d t o b e relate d t o 
st u d y dr u gs w ere missi n g a n d h a v e b e e n a d d e d ( Ta bles 6 -2, 6 -3, 6 -4).  
•  A d diti o n al la n g u a ge o n t h e c o nti n u o us s af et y re vie w a n d a g gre gati o n of s afet y d ata t h at 
will b e o n g oi n g t hr o u g h o ut t h e d urati o n of t h e st u d y h as b e e n a d de d t o t h e pr ot oc ol 
( Se cti o n 8. 5). 

N o v artis  
C o nfi d e nti al  
P a g e 2 5  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol  N o. C M C S 1 1 0 Z 2 2 0 1  
 
A n a d diti o n al d os e re d u cti o n le v el ( 2. 5 m g/ k g) h as b e e n a d de d f or p atie nts wit h starti n g d os es 
of 1 0 m g/ k g t o ali g n t h e l o w est p er mitte d M C S 1 1 0 d os e le v el f or all p atie nts.  Th e w or di n g 
w as c h a n ge d fr o m “ 5 0 % of ori gi n al starti n g d os e ” t o “ 5 0 % of t h e pre vi o us d os e” i n t h e d o s e 
m o dific ati o n ta bles t o all o w f or t h e a d diti o nal d os e re d u cti o n of M C S 1 1 0.  
Q u a ntitati o n of circ ulati n g C D 1 4 + C D 1 6 + a n d C D 1 4 + C D 1 6 - m o n o c ytes usi n g fl o w c yt o me try  
h as b e e n re m o v e d fr o m t h e pr ot o c ol as it h as s h o w n hi g h ass a y v aria bilit y i n a pre vi o us st u d y 
wit h M C S 1 1 0 a n d t h us, is of l o w v al u e as a p h ar m a c o d y na mic ( P D) m ar k er.  
B o n e s c a n h as b e e n a d de d as a b as eli n e t u m or ass ess m e nt if cli nic all y i n dic ate d, t o a d h er e t o 
t h e N C C N G ui d eli n es 2 0 1 5 ( Pri n ci ples of M o nit ori n g Metastatic Dis e as e). 
T h e  st u d y  p o p ulati o n  will  b e  e x p a n d e d  t o  i n cl u d e  p atie nts  w h o  h a v e  re c ei v e d  pri or  
a dj u v a nt/ n e oa dj u v a nt tre at m e nt c o ntai ni n g c ar b o plati n, cis plati n a n d/ or ge m c it a b i n e if  t h e y  
are c o nsi d ere d n ot refra ct or y t o t h e dr u gs. N ot refract or y is d efi n e d as rela ps e or pr o gr e s si o n 
of dis e as e o c c urri n g > 1 2 m o nt hs after last a d mi nistrati o n of t h e dr u gs. All o wi n g p atie nts t h a t 
are n ot refra ct or y t o c ar b o plati n, ge m cita bi n e a n d/ or ge m cita bi n e t o p artici p ate i n t h e st u d y 
will f a cilitate e nr oll m e nt si n c e c ar b o plati n, cis pla ti n a n d/ or is c urre ntl y ofte n gi v e n i n t h e 
a dj u v a nt s etti n g.  
Clarific ati o n h as b e e n m a de re gar di n g t h e arc hi val t u m or s a m ple. T h e arc hi v al t u m or s a m pl e 
s h o ul d b e pr o vi d e d o nl y if o btai n e d at t h e ti m e of i nitial dia g n osis. If t h e t u m or s a m pl e fr o m 
t h e i nitial dia g n osis is us e d as t h e n e wl y o btai n e d t u m or s a m ple ( < 6 m o nt hs), a n a d diti o n al 
arc hi v al t u m or s a m ple is n ot n e e d e d.  
T h e ti m e wi n d o w f or C 1 D 1 5 “ 1 6 8 h p ost start of i nf usi o n of C 1 D 8 ” P K of M C S 1 1 0 w as 
i n c orre ctl y s p e cifie d as 2 4 h o urs a n d h as b e e n c orre cte d t o 8 h o urs. 
T h e u ns c h e d ule d a n d E O T P K s a m pli n gs f or c ar b o/ ge m w ere c o nsi d ere d re d u n da nt a n d will 
t h eref ore b e re m o ve d. 
Clarific ati o n t h at r a di ol o gic al ass ess m e nts p erf or m e d as p art of sta n d ar d of c are pri or t o 
si g ni n g i nf or m e d  c o ns e nt m a y  b e  us e d  if  p erf or m e d  wit hi n  2 8  d a ys of  t h e  first d os e  
a d mi nistere d.  
I nste a d of v a g u e la n g u a ge “ after t h e pri m ar y C S R c ut-off d ate is re a c h e d ”, S p e cifi c c ut -off 
(c y cle 8) is pr o vi d e d t o d etail t h e E C G c olle cti o n pla n. 
N e w pre g n a n c y g ui d eli n es h a ve b e e n i m ple m e nte d.  
I n a d diti o n, c orre cti o ns of i nsi g nific a nt t y p o gra p hic al err ors h a v e b ee n m a de t hr o u g h o ut t h e 
pr ot o c ol.  
St u d y U p d at e s  
T h e a m e n d e d pr ot o c ol v ersi o n 0 1 h as b e e n s u b mitte d t o H As a n d I R B/I E Cs. O n e p ati e nt h a s 
b e e n d os e d s o f ar.  
C h a n g e s  t o pr ot o c ol  
Se cti o n 2. 1  St u d y r ati o n ale a n d p ur p os e  

N o v artis  
C o nfi d e nti al  
P a g e 2 6  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol  N o. C M C S 1 1 0 Z 2 2 0 1  
 
•  Re m o v al of t h e f oll o wi n g s e nte n ces: “ E xte nsi v e w or k p erf or m e d at N o v artis h as 
esta blis h e d a n i m m u n o hist oc h e mic al ass a y f or e v al uati n g T A Ms. A T A M c o nte nt of 1 5 % 
of t h e t u m or are a, or a b o v e, i d e ntifie d 4 0 % of T N B C as T A M hi g h a n d t h e rest as T A M 
l o w. I n t his st u d y o nl y p atie nts wit h a p pr o xi m atel y 1 5 % T A M c o nte nt or hi g h er, as 
d eter mi n e d b y a c e ntral la b orat or y, will b e i n cl u d e d. T h e fi n al c ut -off f or t h e T A M 
c o nte nt le v el will b e d eter mi n e d d uri n g test v ali d ati o n at t h e c e ntral l a b orat or y”. 
•  A d diti o n of t h e f oll o wi n g s e nte n ce: “ T h e ass ess m e nt of T A M c o nte nt will b e o btai n e d 
t hr o u g h s u b missi o n of s a m ples t o a N o v artis d esi g n ate d la b orat or y w h ere I H C f or C D 1 6 3 
( m ar k er of T A M) will b e p erf or m e d. ” 
Se cti o n 5. 2 I ncl usi o n c rite ri a  
•  “ A p pr o x i m atel y 1 5 % of T A Ms or a b o v e ” h as b e e n re m o ve d fr o m i n cl usi o n criteri o n # 2. 
Se cti o n 5. 3 E x cl usi o n c rite r i a 
•  C h a n ge i n e x cl usi o n criteri o n # 1 t o all o w  pri or us e of c ar b o plati n, cis plati n or 
ge m cita bi n e as a dj u v a nt or n e o a dj u v a nt c h e m ot h era p y (if > 1 2 m o nt hs h as p ass e d si n c e 
last a d mi nistrati o n). 
•  C h a n ge i n e x cl usi o n criteri o n # 2 t o a d d “ h y pers e nsiti vit y t o m o n o cl o n al a nti b o dies ” a n d 
t o re m o v e “ pri or us e of c ar b o plati n, cis plati n, ge m cita bi n e”.  
•  C h a n ge i n e x cl usi o n criteria # 1 1 t o i n cre as e A N C f r o m < 1. 0 x1 0 9/ L t o < 1. 5 x 1 09/ L 
•  C h a n ge i n e x cl usi o n criteria # 1 5 t o i m ple m e nt t h e n e w c o ntra c e pti o n g ui d eli n es  
Se cti o n 6. 1. 2. 1 A ncill a r y tr e at me nts f o r M C S 1 1 0  
•  “ M o nit ori n g f or h y p ers e nsiti vit y re a cti o ns a c c or di n g t o l o c al g ui d eli n es ” h as b e e n a d de d.  
Se cti o n 6. 2. 1 D os e m o dific ati o ns a n d d os e del a y  
•  T h e f oll o wi n g s e nte n c e h as b ee n a d de d: “ T h e c h e m ot hera p y c a n b e d os e re d u c e d b y 2 
d os e le v els ( -2 0 % a n d -4 0 %, res p ecti v el y) w h ereas M C S 1 1 0 c a n b e d os e re d uc e d b y 2 or 
1 d os e le v els d e p e n di n g o n starti n g d os e (fr o m 1 0 m g/ k g  t o 5 m g / k g t o 2. 5 m g/ k g or fr o m 
5 m g/ k g t o 2. 5 m g/ k g). ”  
Se cti o n 6. 2. 1. 1 T a ble 6 -2: D os e m o dific ati o ns a n d a cti o n f o r t o xicities s us pe cte d t o be 
r el ate d t o M C S 1 1 0  
•  Ma n d at or y al d olas e testi n g at ti m e of C K ele v ati o n h as b e e n re m o v e d  
•  G ui d eli n es f or f urt h er e v al u ati o n of p atie nts wit h C K ele v ati o n a n d s y m pt o ms or ele v ate d 
le v els of cre ati ni n e, C K-M B or tr o p o ni n I/ T, t o r ule o ut m y ositis/r h a b d o m y ol ysis 
a c c or di n g t o l o c al g ui d eli n es h a v e b e e n a d de d. 
•  Clarific ati o n w as m a d e t h at c h e m ot h era p y m a y b e res u m e d at pre vi o us d os e after re c o very 
of C K -M B, tr o p o ni n (I or T) a n d cre ati ni n e (c o m bi n e d wit h Gra d e ≥ 3 C K ele v ati o n).  
•  Se cti o n f or Ot h er Gra d e ≥ 3 t o xicities h as b e e n a d d e d t o t h e ta ble  
•  “ 5 0 % of ori gi n al starti n g d os e ” w as c h a n ge d t o “ 5 0 % of t h e pre vi o us d os e ” 
Se cti o n 6. 2. 1. 1 T a ble 6 -3: D os e m o dific ati o ns f o r he m at ol o gic al t o xicities s us pe cte d t o b e 
r el ate d t o c a r b o/ g e m 
•  Se cti o n f or Ot h er Gra d e ≥ 3 t o xicities h as b e e n a d d e d t o t h e ta ble  
•  N o n -h e m at ol o gic al t o xicities re m o v e d fr o m t h e f o ot n ote t o c orre ct a n err or.  

N o v artis  
C o nfi d e nti al  
P a g e 2 7  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol  N o. C M C S 1 1 0 Z 2 2 0 1  
 
Se cti o n 6. 2. 1. 1 T a ble 6 -4: D os e m o dific ati o ns f o r n o n -he m at ol o gic al t o xicities s us pe cte d 
t o be r el ate d t o c a r b o/ g e m 
•  Se cti o n f or Ot h er Gra d e ≥ 3 t o xicities h as b e e n a d d e d t o t h e ta ble  
•  F o ot n ote a d d e d: “ As s o o n as re q uire me nts f or n o n -h e m at ol o gic al t o xicities are Gra d e ≤1 
or b as eli n e, st u d y tre at m e nt s h o ul d b e d eli v ere d ”.  
•   “ 5 0 % of ori gi n al starti n g d os e ” w as c h a n ge d t o “ 5 0 % of t h e pre vi o us d os e  
Se cti o n 6. 3. 2 Pe r mitte d c o nc o mit a nt t he r a p y r e q uiri n g c a uti o n 
•   Ca uti o n f or i n cre as e d ris k of s eiz ure wit h c o nc o mita nt c ar b o plati n a n d p he n yt oi n h as 
b e e n a d d e d t o t his s e cti o n.  
Se cti o n 7. 1, St u d y fl o w a n d visit s c he d ule  
•  Se nte n c e a d d e d: “ Ra di ol o gic al ass ess m e nts p erf or me d as p art of sta n dar d of c are p ri or t o 
si g ni n g i nf or m e d c o ns e nt m a y b e us e d if p erf or me d wit hi n 2 8 d a ys of t h e first d os e 
a d mi nistere d  
Se cti o n 7. 1, T a ble 7 -1: Visit e v al u ati o n s c he d ule  
•  Si n c e t h e pre g n a n c y test is p erf or m e d d uri n g t h e s cre e ni n g p eri o d, wit hi n 3 d a ys of t h e 
first d os e, t he pre g n a n c y test at C 1 D 1 is n ot n e c ess ar y a n d a f o ot n ote h as b e e n a d d e d f or 
clarific ati o n.  
•  Pre g n a n c y test a d d e d at 3 0 d a ys s afet y f oll o w -u p.  
•  A d diti o n of a s af et y f oll o w -u p at 6 0 d a ys after t h e last d os e of st u d y tre at m e nt, as w ell as 
relate d ass ess m e nts, i n cl u di n g a pre g n a n c y test. 
Se cti o n 7. 1 . 6 F oll o w-u p pe ri o d:  
•  A d diti o n of 6 0 d a ys s afet y f oll o w -u p a n d ass o ciate d ass ess m e nts.  
Se cti o n 7. 1. 1 M ole c ul a r pr e -sc r ee ni n g  
•  “ A p pr o xi m atel y 1 5 % of T A Ms or a b o v e ” h as b e e n re m o ve d fr o m t his s e cti o n a n d 
re pla c e d b y hi g h TA M c o nte nt p er c e ntral ass ess me nt.  
Se cti o n 7. 2. 1 Effic a c y Ass ess me nts  
•  Se nte n c e a d d e d: “ Ra di ol o gic al ass ess m e nts p erf or me d as p art of sta n dar d of c are pri or t o 
si g ni n g i nf or m e d c o ns e nt m a y b e us e d if p erf or me d wit hi n 2 8 d a ys of t h e first d os e 
a d mi nistere d. ”  
Se cti o n 7. 2. 1, T a ble 7 -2: I m a gi n g c olle cti o n pl a n  
•  B o n e s c a n h as b e e n a d de d  as a b as eli n e/s cree ni n g e v al u ati o n (if cli nic all y i n dic ate d)  
Se cti o n 7. 2. 2. 5, T a ble 7 -4: L o c al l a b o r at or y p a r a mete rs  
•  P h os p h ate testi n g h as b e e n a d d e d  
•  C D 1 4 + C D 1 6 + / C D 1 4 + C D 1 6 - m o n o c ytes testi n g h as b e e n re m o v e d  
•  C h a n ge re gar di n g t h e al d olas e testi n g w hic h will o nl y b e p erf or m e d if re q uire d t o r ule o ut 
m y ositis/r h a b d o m y ol ysis p er l o c al g ui d eli n es  
•  M y o gl o bi n (s er u m or uri n e) a d d e d: t o b e p erf or m e d o nl y if re q uire d t o r ule o ut 
m y ositis/r h a b d o m y ol ysis p er l o c al g ui d eli n es  

N o v artis  
C o nfi d e nti al  
P a g e 2 8  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol  N o. C M C S 1 1 0 Z 2 2 0 1  
 
Se cti o n 7. 2. 2. 6. 1 E C Gs a n d Se cti o n 9. 3 D at a C olle cti o n  
•  C h a n ge m a d e t o c e ntral E C G re vie w. T h e i n d e p e n d e nt re vie w of t h e E C G’s b y a c e ntral 
la b orat or y will o c c ur u p t o c y cle 8 i n cl u d e d. After c y cle 8, E C Gs will b e p erf or me d at t h e 
dis creti o n of t h e i n v esti gat or, re c or d e d o n a l o c al E C G C R F p a ge a n d will n ot b e re vie w e d 
b y t h e c e ntral la b orat or y.  E o T E C G’s are m a n d at or y b ut will n ot b e re vie w e d c e ntrall y.  
Se cti o n 7. 2. 3. 1, T a bles 7 -6 a n d 7 -7: M C S 1 1 0 P K s a m ple c olle cti o n l o g  
•  Sc h e d ule d ti m e c h a n ge d fr o m 1 6 8 ( ± 2 4 h) t o 1 6 8 ( ± 8 h) at C 1 D 1 5  
Se cti o n 7. 2. 3. 1, T a ble 7 -8: C a r b o/ G e m P K s a m ple c olle cti o n l o g  
•  E O T a n d U ns c h e d ule d ti m e p oi nts h a v e b ee n re m o v e d.  
Se cti o n 7. 2. 4, T a ble 7 -9 Bi o m a r ke r s a m ple c olle cti o n pl a n  
•  Clarific ati o n h as b e e n a d de d t h at t h e arc hi v al t u m or h as t o b e pr o vi d e d o nl y if a v aila ble 
a n d s h o ul d b e fr o m t h e i nitial dia g n osis.  
•  Clarific ati o n h as b e e n a d de d t o t h e f o ot n ote t h at t h e arc hi v al t u m or s a m ple fr o m t h e i nitial 
dia g n osis is n ot re q uir e d if t h e n e wl y o btai n e d t u m or s a m ple is fr o m t h e i nitial dia g n osis.  
Se cti o n 8. 5 Ste e ri n g C o m mitte e  
•  T h e f oll o wi n g te xt h as b e e n a d d e d t o t h is s e cti o n: “ After t h e i nitial s af et y re vie w, 
i n di vi d u al p atie nt d ata will s u bs e q ue ntl y b e re vie w e d o n a n o n g oi n g b asis a n d a g gre gate 
s af et y d ata a n d t h e pri m ar y e n d p oi nt will b e m o nit ore d q u arterl y b y t h e st u d y te a m a n d 
dis c uss e d wit h i n v esti gat ors a cr oss  t h e d urati o n of t h e trial. T h e d ata re vie w a n d a n al ysis 
will b e b as e d o n t h e a v aila ble d ata i n t h e cli nic al d ata bas e (s e e Se cti o n 1 0.7) at t h e 
res p e cti v e ti m e. ” 
Se cti o n 1 0. 5. 3. 1. 1 B asic T a bles, Fi g ur es a n d Listi n gs  
•  T h e a n al ysis pla n f or circ ulati n g  C D 1 4 + m o n oc ytes a n d C D 1 4 + C D 1 6 + m o n o c ytes  h as 
b e e n re m o v e d.  
Se cti o n 1 0. 7 I nte ri m A n al ysis  
T h e f oll o wi n g te xt h as b e e n a d d e d:  
Effic a c y a n d s afet y d ata will b e re vie w e d o n a re g ular b asis as m e nti o ne d i n Se cti o n  8. 5. T his 
d ata m o nit ori n g will n ot c o nstit ute a f or m al i nteri m a n al ysis of t h e pri m ar y e n d p oi nt si n c e n o  
d e cisi o n t o st o p t h e st u d y e arl y will b e ta k e n f oll o wi n g t h e re vie w of t his d ata.  
A n al ys es pr o d u ce d f or t his re vie w will i n cl u d e b ut m a y n ot b e li mite d t o:  
1.  A n al ysis of pri m ar y effic a c y e n d p oi nt  
2.   T h e f oll o wi n g s af et y s u m m aries a n d listi n gs:  
Tre at m e nt -e m er ge nt A Es re gar dless of st u d y dr u g relati o ns hi p  

N o v artis  
C o nfi d e nti al  
P a g e 2 9  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol  N o. C M C S 1 1 0 Z 2 2 0 1  
 
•  A Es le a di n g t o p er m a n e nt dis c o nti n uati o n of st u d y dr u g  
•  A Es re q uiri n g d os e a dj ust m e nt or st u d y dr u g i nterr u pti o n  
•  S A Es re gar dless of st u d y dr u g  relati o ns hi p 
3.  S u m m aries of k e y b as eli ne c h aracteristics  
O ut p uts t o b e pr o d u c e d f or t h e m o nit ori n g will b e i d e ntifie d i n t h e R A P.  
C h a n ges t o s p e cific s e cti o ns of t h e pr ot o c ol are s h o w n i n t h e tra c k c h a n ges v ersi o n of t h e 
pr ot o c ol usi n g stri k e t hr o u g h re d f o nt f or d eleti o ns a n d re d u n derli n e d f or i ns erti o ns.  
I R B/I E C  
A  c o p y  of  t his  a m e n d e d  pr ot o c ol  will  b e  s e nt  t o  t h e  I nstit uti o n al  Re vie w  B o ar d  
(I R Bs)/I n d e p e n d e nt Et hics C o m mitte e (I E Cs) a n d H e alt h A ut h orities. 
T h e  c h a n ges  d es cri b e d  i n  t h is  a m e n d e d  pr ot o c ol  re q uire  I R B/I E C a p pr o v al  pri or  t o  
i m ple m e ntati o n.  
T h e c h a n ges h erei n  affe ct t h e I nf or m e d C o ns e nt. Sites are re q uire d t o u p d ate a n d s u b mit f or 
a p pr o v al a re vis e d I nf or m e d C o ns e nt t h at ta k es i nt o a c c o u nt t h e c h a n ges d es cri b e d i n t his 
pr ot o c ol  a m e n d me nt. 

N o v artis  
C o nfi d e nti al  
P a g e 3 0  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol  N o. C M C S 1 1 0 Z 2 2 0 1  
 
A m e n d m e nt 1  ( 4-M ar -2 0 1 5)  
A m e n d m e nt r ati o n al e  
T h e m ai n re a s o n f or t his a m e n d m e nt is t o a d d m ore s p e cific g ui d a nc e f or d os e m o difi c ati o n s 
f or C K ele v ati o n  s us p e cte d t o b e relate d t o M C S 1 1 0, f oll o wi n g H e alt h A ut h orit y fe e d-b ac k . 
F urt h er m ore, a clarific ati o n h as b e e n a d d e d re gar di n g s e v ere p eri or bital e d e ma . 
C h a n g e s  t o t h e pr ot o c ol  
•  Ta ble 6 -2 ( D os e m o dific ati o ns a n d a cti o n f or t o xicities s us p e cte d t o b e relate d t o 
M C S 1 1 0) h as b e e n a m e n d e d t o pr o vi de m ore s p e cific g u i d a nc e i n c as e of C K ele v ati o n 
a n d s e v ere p eri or bital e d e ma. 
C h a n ges t o s p e cific s e cti o ns of t h e pr ot o c ol are s h o w n i n t h e tra c k c h a n ges v ersi o n of t h e 
pr ot o c ol usi n g stri k e t hr o u g h re d f o nt f or d eleti o ns a n d re d u n derli n e f or i ns erti o ns. A c o p y of 
t his a m e n d e d pr ot o c ol will b e s e nt t o t h e I nstit uti o n al Re vie w B o ar d (I R Bs)/I n d e p e n d e nt 
Et hics C o m mitte e (I E Cs) a n d H e alt h A ut h orities. T h e c h a n ges d es cri b e d i n t his a m e n d e d 
pr ot o c ol re q uire I R B/I E C a p pr o v al pri or t o i m ple m e ntati o n.  
T h e c h a n ges h erei n d o n ot affect t h e I nf or m e d C o nse nts.  

N o v artis  
C o nfi d e nti al  
P a g e 3 1  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol  N o. C M C S 1 1 0 Z 2 2 0 1  
 
Pr ot o c ol s u m m ar y  
Pr ot o c ol n u m b er  
C M C S 1 1 0 Z 2 2 0 1  
Titl e  
A  r a n d o mi z e d p h a s e II st u d y of M C S 1 1 0  c o m bi n e d wit h c ar b o pl ati n a n d g e m cit a bi n e i n 
a d v a n c e d Tri pl e N e g ati v e Br e a st C a n c er ( T N B C)  
Bri ef titl e  
Effi c a c y st u d y of M C S 1 1 0  gi v e n wit h c ar b o pl ati n a n d g e m cit a bi n e i n a d v a n c e d T N B C.  
S p o n s or a n d Cli ni c al 
P h a s e  
N o v arti s  
P h a s e II  
I n v e sti g ati o n t y p e 
Dr u g  
St u d y t y p e  
I nt er v e nti o n al 
P ur p o s e a n d r ati o n al e  
T o d et er mi n e w h et h er M C S 1 1 0  a nti b o d y t h er a p y i m pr o v e s t h e effi c a c y of c ar b o pl ati n 
a n d g e m cit a bi n e ( c ar b o/ g e m) i n a d v a n c e d T N B C p ati e nt s  
Pri m ar y O bj e cti v e( s)  
T h e pri m ar y o bj e cti v e i s t o a s s e s s t h e a nti -t u m or a cti vit y of M C S 1 1 0  c o m bi n e d wit h 
c ar b o/ g e m c o m p ar e d t o c ar b o/ g e m al o n e i n a d ult p ati e nt s wit h T N B C  c a n c er.  
S e c o n d ar y O bj e cti v e s  
C h ar a ct eri z e t h e s af et y a n d t ol er a bilit y of M C S 1 1 0  gi v e n i n c o m bi n ati o n wit h 
c ar b o/ g e m.  
C h ar a ct eri z e P K  of M C S 1 1 0  w h e n c o m bi n e d wit h c ar b o/ g e m  
C h ar a ct eri z e P K  of c ar b o/ g e m i n t h e pr e s e n c e a n d a b s e n c e of M C S 1 1 0.  
C h ar a ct eri z e P D  eff e ct of M C S 1 1 0  w h e n c o m bi n e d wit h c ar b o/ g e m  
T o a s s e s s t h e a nti -t u m or a cti vit y of M C S 1 1 0  gi v e n i n c o m bi n ati o n wit h c ar b o/ g e m a s 
m e a s ur e d b y a d diti o n al effi c a c y m e a s ur e s.  
St u d y d e si g n  
T hi s st u d y i s a p h a s e II, o p e n -l a b el, r a n d o mi z e d st u d y of M C S 1 1 0 i n c o m bi n ati o n wit h 
c ar b o/ g e m ( Ar m  1) v er s u s c ar b o/ g e m al o n e ( Ar m  2) i n p ati e nt s wit h a d v a n c e d T N B C 
wit h o n e or m or e e arl y s af et y r e vi e w s . 
P o p ul ati o n  
W o m e n wit h a d v a n c e d T N B C w h o s e t u m or s c o nt ai n a hi g h c o nt e nt of t u m or a s s o ci at e d 
m a cr o p h a g e s ( T A M s).  
I n cl u si o n crit eri a 
● A d ult w o m e n ( ≥ 1 8 y e ar s of a g e) wit h a d v a n c e d T N B C.  
● Hi st ol o gi c al or c yt ol o gi c al e vi d e n c e of e str o g e n -r e c e pt or n e g ati v e ( E R-), 
pr o g e st er o n e r e c e pt or n e g ati v e ( P g R -) a n d h u m a n e pi d er m al gr o wt h f a ct or-2 r e c e pt or 
n e g ati v e ( H E R 2 -) Br e a st  C a n c er b y l o c al l a b or at or y t e sti n g, b a s e d o n l a st a v ail a bl e 
t u m or ti s s u e. 
 
● E R/ P g R  n e g ati vit y t o f oll o w l o c al g ui d eli n e s  
 
● If I H C H E R 2 2 +, a n e g ati v e FI S H t e st i s r e q uir e d   
● A p r e -tr e at m e nt t u m or bi o p s y d e m o n str ati n g hi g h T A M c o nt e nt a s a s s e s s e d p er t h e 
c e ntr al l a b or at or y . 
● P ati e nt s m u st h a v e:  
At  l e a st o n e m e a s ur a bl e l e si o n p er R E CI S T  1. 1.  ( N ot e: M e a s ur a bl e  l e si o n s i n cl u d e l yti c 
or mi x e d (l yti c + bl a sti c) b o n e l e si o n s, wit h a n i d e ntifi a bl e s oft ti s s u e c o m p o n e nt t h at 
m e et s  t h e m e a s ur a bilit y crit eri a)  

N o v artis  
C o nfi d e nti al  
P a g e 3 2  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol  N o. C M C S 1 1 0 Z 2 2 0 1  
 
E x cl u si o n crit eri a  
● Pri or c h e m ot h er a p y f or a d v a n c e d B C. Pr e vi o u s a dj u v a nt/ n e o a dj u v a nt c h e m ot h er a p y 
i s all o w e d. 
● T h er a p y f or u n d erl yi n g m ali g n a n c y wit hi n 2 w e e k s pri or t o st art of st u d y tr e at m e nt:  
 
● C h e m ot h er a p y, bi ol o gi c t h er a p y ( a nti b o di e s a n d bi ol o gi c all y t ar g et e d s m all 
m ol e c ul e s)  
 
● R a di ot h er a p y  
 
● M aj or s ur g er y  
● P ati e nt s r e c ei vi n g c o n c o mit a nt i m m u n o s u p pr e s si v e a g e nt s or c hr o ni c c orti c o st er oi d s 
( ≥1 0 m g of  pr e d ni s o n e  or e q ui v al e nt) at t h e ti m e  of fir st st u d y d o s e.  
● Cli ni c all y si g nifi c a nt c ar di o v a s c ul ar di s e a s e s u c h a s u n c o ntr oll e d or s y m pt o m ati c 
arr h yt h mi a s, c o n g e sti v e h e art f ail ur e, or m y o c ar di al i nf ar cti o n wit hi n 6 m o nt h s of 
s cr e e ni n g.  
● K n o w n hi st or y of h u m a n i m m u n o d efi ci e n c y vir u s or a cti v e i nf e cti o n wit h h e p atiti s vir us 
or a n y u n c o ntr oll e d a cti v e s y st e mi c i nf e cti o n.  
● P ati e nt s wit h t h e f oll o wi n g l a b or at or y v al u e s d uri n g s cr e e ni n g a n d  o n D a y 1 pr e -d o s e:  
 
● A b s ol ut e N e utr o p hil C o u nt ( A N C) < 1. 5 x 1 0 9/ L 
 
● H e m o gl o bi n < 9 g/ d L  
 
● Pl at el et s < 1 0 0 x 1 0 9/ L 
 
● S er u m  cr e ati ni n e > 1. 5  x U L N  
 
● S er u m  t ot al bilir u bi n > 1. 5  x U L N  
 
● A S T/ S G O T a n d  A L T/ S G P T > 3. 0 x U L N  
I n v e sti g ati o n al a n d 
r ef er e n c e t h er a p y 
M C S 1 1 0,  c ar b o pl ati n a n d g e m cit a bi n e  
Effi c a c y a s s e s s m e nt s  
T u m or a s s e s s m e nt p er R E CI S T  v. 1. 1  
S af et y a s s e s s m e nt s  
I n ci d e n c e a n d s e v erit y of A E s a n d S A E s,  i n cl u di n g c h a n g e s i n l a b or at or y v al u e s, vit al 
si g n s a n d E C G s.  
Ot h er a s s e s s m e nt s  
M C S 1 1 0  a n d c ar b o/ g e m p h ar m a c o ki n eti c a s s e s s m e nt s.  
P h ar m a c o d y n a mi c m ar k er s i n bl o o d a n d t u m or  
D at a a n al y si s  
T h e pri m ar y effi c a c y e n d p oi nt i s pr o gr e s si o n fr e e s ur vi v al ( P F S) b a s e d o n l o c al 
I n v e sti g at or a s s e s s m e nt, a s d efi n e d i n R E CI S T 1. 1.  T h e h a z ar d r ati o ( H R) f or P F S 
b et w e e n  t h e M C S 1 1 0 +  c ar b o/ g e m ar m  a n d t h e c ar b o/ g e m ar m will b e e sti m at e d.  
 O n e or m or e  e arl y s af et y r e vi e w s will b e  p erf or m e d t o pr o vi d e g ui d a n c e o n c o nti n u e d 
s af e M C S 1 1 0  d o si n g aft er a s s e s s m e nt of P K,  cli ni c al a n d l a b or at ory d at a . 
K e y w or d s  
M C S 1 1 0;  c ar b o pl ati n; g e m cit a bi n e; T N B C; T A M s  

N o v artis  
C o nfi d e nti al  
P a g e 3 3  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol  N o. C M C S 1 1 0 Z 2 2 0 1  
 
1  
B a c k gr o u n d 
1. 1  
O v er vi e w of di s e a s e p at h o g e n e si s, e pi d e mi ol o g y a n d c urr e nt 
tre at m e nt  
Bre ast c a n c er is t h e m ost c o m m o n c a n cer a m o n g w o m e n w orl d wi d e, wit h a n esti m at e d 1. 3 8 
milli o n n e w c as es i n 2 0 0 8, a n d it is als o t h e m ost c o m m o n c a us e of c a n cer d e at h i n w o m e n, 
wit h  4 5 8, 0 0 0  d e at hs ( Ferla y G L O B O C A N 2 0 0 8 ). Tri ple-n e gati v e bre ast c a n c er ( T N B C) 
a c c o u nts f or a p pr o xi m atel y 1 5 % of n e wl y dia g n ose d breast c a n cers, b ut d u e t o its a g gr e s si v e 
n at ure a dis pr o p orti o nate n u m b er ( 2 5 %) of T N B C are re p orte d i n t h e m etastatic s etti n g ( Care y 
2 0 0 6, D a hl b er g 2 0 0 9 ). 
T N B C is c h ara cteriz e d b y la c k of e x pressi o n of t h e estr o ge n ( E R) a n d pr o gester o n e ( P R) 
re c e pt ors a n d la c k of o v ere x pressi o n of t h e h u m a n e pi d er m al gr o wt h f a ct or re c e pt or 2 
( H E R 2).  T h e  cli nic al  c o urs e  of  T N B C  is  ass o ciate d  wit h  a  hi g h  pr o b a bilit y  of  dista nt  
m etastas es, es p e ciall y t o t h e l u n g a n d brai n ( D e nt 2 0 0 7 ). C urre ntl y, t h ere are n o tar gete d 
t h era pies f or t his bre ast c a n c er s u bt yp e a n d t h e o nl y tre at m e nt o pti o n is c h e m ot her a p y.  E v e n 
t h o u g h s e v eral st u dies s u g gest t h at T N B C is a hi g hl y c h e m os e nsiti v e dis eas e, pr o g n o sis still 
re m ai ns p o or wit h a s h orter dis e as e fre e i nter v al after i nitial t h era p y a n d a m ore a g gressi v e 
cli nic al c o urs e i n t h e m etastatic s etti n g ( Care y 2 0 0 7, Lie dt k e 2 0 0 8, F o ul k es 2 0 1 0 ). M ost 
p atie nts re c ei v e a nt hra c ycli n es a n d ta x a n es i n t h e a dj u v a nt s etti n g a n d n o f urt h er st a n d ar d of 
c are t h era p y e xists f or p atie nts  wit h m etastatic T N B C ( N C C N 2 0 1 4, E S M O g ui d eli n es 2 0 1 4 ). 
H o w e v er, e m er gi n g d ata s u g gest t h at plati n u m s alts (ie, cis plati n a n d c ar b o plati n) a r e  h i g h l y  
a cti v e  i n  e arl y  a n d  a d v a n c e d  T N B C,  a n d  t h eref ore  wi d el y  us e d  i n  t h e  cli nic al  s etti n g 
(O’ S h a u g h n ess y  2 0 1 1,  v o n  Mi n c k witz  2 0 1 4 ).  Me dia n  s ur vi v al  f or  m etastatic  T N B C  is  
a p pr o xi m atel y 1 y e ar, m a ki n g T N B C a dis e as e wit h hi g h u n m et m e dic al n e e d ( K assa m 2 0 0 9 ). 
1. 1. 1  
T h e i m m u n o m o d ul at or y  (I M) s u bt y p e  of T N B C  
Re c e ntl y 6 diff ere nt s u bt y p es of T N B C w ere d es cri b e d usi n g ge n e e x pressi o n pr ofili n g: t w o 
b as al -li k e, o n e m es e n c h y m al, o n e m es e n c h y m al ste m-li k e, o ne l u mi n al a n dr o ge n re c e pt or 
( L A R) a n d o n e i m m u n o m o d ulat or y (I M) s u bt y p e (Le h m a n n 2 0 1 1 ). O n g oi n g a n d e m er gi n g 
tre at m e nt a p pr o a c hes i n cl u de s ele cte d tar gete d t h era pies f or e a c h u ni q ue s u bt y p e. 
T h e I M s u bt y p e c o m pris es a p pr o xi m atel y 2 5 % of all T N B C a n d is c h ara cteriz e d b y a n 
ele v ate d e x pressi o n of ge n es i n v ol v e d i n i m m u n e c ell si g n ali n g s u c h as T -c ell f u n cti o n , 
i m m u n e tra ns cri pti o n a n d i nterfer o n res p o ns e (Le h m a n n 2 0 1 4 ). F urt h er m ore, t h e I M s u bt y p e 
e x hi bits a s u bsta ntiall y hi g h er c o nte nt of t u m or i nfiltrati n g l y m p h o c ytes ( TI Ls) as w ell as 
t u m or ass o ciate d m a cr o p h a ges ( T A Ms) t h a n ot h er T N B C s u bt y p es (Ma h m o u d 2 0 1 2 a n d 
Vi n a y a k A S C O 2 0 1 4 ). T h e cli nic al c o urs e of I M s e e ms m ore f a v ora ble wit h si g nific a ntl y 
l o n ger ti m e t o rela ps e c o m p are d t o ot h er T N B C s u bt y p es (Tes c h e n d orff 2 0 0 7, Le h m a n n 
2 0 1 1 ).  
F ort y p erc e nt of T N B C h a v e hi g h t u m or i nfiltrati o n of T A Ms ( T A M hi g h) ( Y u a n 2 0 1 4 ). T h e 
T A M hi g h s u bs et is e nric h e d f or I M, c a pt uri n g 7 5 % of all I M .  

N o v artis
C o nfi d e nti al
P a g e 3 4
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol  N o. C M C S 1 1 0 Z 2 2 0 1  
 
Fi g ur e 1- 1 
Tri pl e n e g ati v e br e a st c a n c er  
F ort y p er c e nt of T N B C p ati e nt s ar e T A M hi g h. S e v e nt y -fiv e p er c e nt of I M ar e f o u n d wit hi n t h e T A M 
hi g h c at e g or y. ( L e h m a n n 2 0 1 1 a n d Y u a n 2 0 1 4 ). 
1. 2  
O v er vi e w of t h e r ol e of t h e i m m u n e s y st e m i n br e a st c a n c er  
1. 2. 1  
T u m or a s s o ci at e d  m a cr o p h a g e s i n br e a st c a n c er  
T h e t u m or micr o e n vir o n m e nt pla ys a n i m p orta nt r ole i n bre ast c a nc er pr o gressi o n. A m o n g t he 
m a n y c ell t y p es ass o ciate d wit h t h e t u m or micr oe n vir o n m e nt, T A Ms are t h e m ost i n f l u e nti a l 
f or bre ast c a n c er pr o gressi o n b y pr o m oti n g a n gi o ge n esis, t u m or gr o wt h a n d diss e mi n ati o n 
(Le e k 1 9 9 6, P ollar d 2 0 0 4, O b ei d 2 0 1 3 ). F urt h er m ore, T A Ms h a v e a n i m m u n os u p pressi v e 
eff e ct b y i n hi biti n g t h e C D 8 + c yt ot o xic T -c ells (N o y 2 0 1 4 ). Hi g h t u m or i nfiltrati o n of T A Ms 
is ass o ciate d wit h p o or c h e m oth era p y res p o ns e a n d pr o g n osis i n bre ast c a n c er ( D e N ar d o 
2 0 1 1, Y u a n 2 0 1 4 ).  
Ma cr o p h a ges are diff ere ntiate d i nt o t w o m ai n gr o u ps: t h e M 1 a n d M 2 m a cr o p h a ges.  M 1 
m a cr o p h a ges h a v e a n i m p orta nt r ole of t h e i m m u n e s yste m b y pr ote cti n g a gai nst t u m or c ells 
w h ere as M 2 m a cr o p h a ges pr o m ote t u m or gr o wt h. T A Ms are d efi n e d as M 2 m a cr o p h a ges 
wit h p ote nt i m m u n os u p pressi v e f u ncti o ns ( Ma nt o v a ni 2 0 0 2 ). Ma cr o p ha ges are p o larize d i n t o  
T A Ms b y sti m ulati o n of m a cr o p h a ge c ol o n y sti m ulati n g f a ct or ( M -C S F, C S F -1) or ster oi ds 
(J a g ui n 2 0 1 3, O b ei d 2 0 1 3). Se e Fi g ure 1 - 2. 

N o v artis
C o nfi d e nti al
P a g e 3 5
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol  N o. C M C S 1 1 0 Z 2 2 0 1  
 
Fi g ur e 1- 2 
M a cr o p h a g e p ol ari z ati o n a n d f u n cti o n  
 
C S F -1 sti m ul ati o n p ol ari z e s m a cr o p h a g e s i nt o T A M s, t h u s pr o m oti n g t u m or gr o wt h, a n gi o g e n e si s a n d 
i m m u n e s u p pr e s si o n (T a c k e 2 0 0 6, J a g ui n 2 0 1 3, M a nt o v a ni 2 0 0 2 ).  
1. 2. 2  
I m m u n o m o d ul ati o n  a n d c h e m ot h er a p y  r e s p o n s e i n br e a st c a n c er 
Tra diti o n all y, bre ast c a n c er h as n ot b e e n re gar d e d as a n i m m u n o ge nic t u m or t y p e. H o w e v er, 
t o d a y t h e intera cti o n b et w e e n i m m u ne c ells a n d t u m or c ells is a c k n o wle d ge d as critic al f or its 
d e v el o p m e nt a n d pr o gressi o n ( d e Viss er 2 0 0 6 ).  
C h e m ot h era p e utic  a ge nts m e diate  t h eir a ntic a n c er a cti vit y  n ot o nl y  b y  d ire ct  c yt ot o xic  
a ntic a n c er a cti vit y, b ut als o t hr o u g h i n d u c e d i m m u n o ge nic res p o ns e ( G hiri n g h elli 2 0 0 9, 
D e n k ert 2 0 1 0, Mattar oll o 2 0 1 1 ). I m m u ne a cti v ati o n is c o m m o nl y e v al u ate d b y ass essi n g TI Ls 
or C D 8 + T -c ells (L oi 2 0 1 3, D e n k ert 2 0 1 4 ). T h e pres e nc e of TI Ls at dia g n osis c orrelates wit h 
p at h ol o gic al res p o ns e, dis e as e fre e i nter v al a n d o v erall s ur vi v al after n e o a dj u v a nt/ a dj u v a nt 
c h e m ot h era p y, p artic ularl y  i n T N B C a n d H E R 2 + B C w h ere TI Ls are m ost fre q u e ntl y f o u n d 
(West 2 0 1 1, L oi 2 0 1 3, A d a ms 2 0 1 4 ).  
T h us, i m pr o v e d effic a c y fr o m c h e m ot hera p y s h o ul d b e a c hie ve d b y si m ulta n e o us a cti v ati o n 
of t h e i m m u n e s yste m. T his c o nc e pt h as b e e n s u p p orte d b y a pre cli nic al m o us e m o d el w h er e 
c o n c o mita nt c ar b o plati n a n d T A M d e pleti o n ( C S F -1 R bl o c k a d e) le a d t o e n h a n c e d r e s p o n s e 
a n d a cli nic al st u d y i n w hic h t u m or bi o psies fr o m p atie nts tre ate d wit h a C S F -1 R a nti b o d y 
dis pla y e d T A M  d e pleti o n  as  w ell  as  a cti v ate d  T -c ell  c o m p ositi o n  ( C D 8 +/ C D 4 +  rati o)  
(D e N ar d o 2 0 1 1, Ries 2 0 1 4 ).  

N o v artis
C o nfi d e nti al
P a g e 3 6
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol  N o. C M C S 1 1 0 Z 2 2 0 1  
 
Fi g ur e 1- 3 
C S F -1 R i n hi biti o n l e a d s t o T A M d e pl eti o n, i n cr e a s e d TI L s a n d 
e n h a n c e d c h e m ot h er a p y r e s p o n s e  
( A) T h er a p y wit h C S F-1 R a nti b o d y a s si n gl e a g e nt or c o m bi n e d wit h p a clit a x el l e a d s t o T A M d e pl eti o n. 
T h e c o n c e pt w a s st u di e d u si n g m ulti pl e d o s e l e v el s i n v ari o u s s oli d t u m or s ( d e pict e d a b o v e i n diff er e nt 
c ol or s) ( Ri e s 2 0 1 4 ). ( B) C S F-1 R i n hi biti o n i n cr e a s e s t h e l y m p h o c yt e i nfiltr ati o n ( TI L s) i n mi c e wit h 
M C 3 8 c ol o n c a n c er x e n o gr aft s ( Ri e s 2 0 1 4 ) ( C) C S F -1 R i n hi biti o n e n h a n c e s r e s p o n s e t o c ar b o pl ati n i n 
mi c e wit h ort h ot o pi c P y M T ( br e a st c a n c er) x e n o gr aft s ( D e N a r d o, 2 0 1 1). 
1. 3  
I ntr o d u cti o n t o i n v e sti g ati o n al  tr e at m e nt( s)  a n d ot h er st u d y 
tr e at m e nt( s) 
1. 3. 1  
O v er vi e w of M C S 1 1 0  
M C S 1 1 0  is  a  hi g h -affi nit y,  h u m a niz e d  m o n o cl o n al  a nti b o d y  dire cte d  a gai nst  h u m a n  
m a cr o p h a ge c ol o n y sti m ulati n g f a ct or ( M -C S F; als o k n o w n as c ol o n y -sti m ulati n g f a ct or-1 
[ C S F- 1]). C S F -1 bi n ds t o t h e re c e pt or t yr osi n e ki nas e C S F -1 R ( C S F -1 Re c e pt or) t o dri v e t h e 
diff ere ntiati o n, mi grati o n a n d s ur vi val of tiss u e m a cr o p ha ges. M C S 1 1 0 n e utrali z e s m ulti pl e 
f or ms of h u m a n C S F-1 a n d i n hi bits t h eir eff e ct  o n m o n o c ytes a n d m a cr o p h a ges. Se e I B  
(I n v esti gat or’s Br o c h ure) f or a d diti o nal pre cli nic al d ata.  

N o v artis  
C o nfi d e nti al  
P a g e 3 7  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol  N o. C M C S 1 1 0 Z 2 2 0 1  
 
1. 3. 1. 1  
N o n -cli ni c al e x p eri e n c e  
1. 3. 1. 1. 1  N o n -cli ni c al p h ar m a c ol o g y  
I n vitr o p h a r m a c ol o g y  
I n vitr o, t h e a bilit y of M C S 1 1 0 t o n e utraliz e t h e a cti vit y of C S F-1 w as esta blis h e d u si n g t w o 
diff ere nt ass a ys.  T h e  first ass a y  i n v ol v e d  C S F - 1-d e p e n d e nt pr olif erati o n  of  t h e  m o us e  
m y el o ge n o us le u k e mia c ell li n e M -N F S -6 0.  T his c ell li n e res p o n ds t o v ari o us re c o m bi n a nt 
f or ms of C S F-1, as w ell as C S F -1 f or ms pres e nt i n s er u m, i n m e di u m c o n diti o n e d b y t u m or 
c ell li n es, a n d o n t h e c ell s urf a c e. M C S 1 1 0 p ote ntl y i n hi bite d t h e pr oliferati o n of M -N F S -6 0 
c ells i n res p o ns e t o all h u m a n f or ms of C S F -1 teste d. Cell pr olif erati o n i n res p o ns e t o 1 0 
n g/ m L re c o m bi n a nt h u m a n C S F -1 c o ul d b e  c o m pletel y bl o c k e d b y M C S 1 1 0. M C S 1 1 0 bl o c ks 
t h e a cti vit y of c y n o m ol g us C S F-1 b ut h as n o a bilit y t o n e utr aliz e re c o m bi n a nt m o us e C S F -1. 
T h e s e c o n d ass a y, i n vitr o oste o clast o ge n esis, w as s et u p t o refle ct t h e pri n ci p al i n viv o 
f u n cti o n of C S F-1: re g ulati o n of t h e s ur vi val, pr oliferati o n a n d differe ntiati o n of c e lls o f t h e 
m o n o n u cle ar p h a g o c yte li n e a ge. M C S 1 1 0 i n d u c e d p ote nt i n hi biti o n of t h e oste o clast o ge n e sis 
pr o c ess  as  w ell  as  t h e  m or p h ol o gic al  c h a n ges  ass o ciate d  wit h  t h e  diff ere ntiati o n  i nt o  
oste o clasts.  
I n viv o p h a r m a c ol o g y  
Gi v e n (a) t h e la c k of a cti vit y a gai nst m o us e C S F -1, a n d ( b) t h e li k el y i m m u n e r e s p o n s e t h at 
w o ul d  d e v el o p  wit h  l o n g -ter m d osi n g of mic e wit h a h u m a niz e d m o n o cl o n al A nti b o d y 
( m A b), i n viv o effic a c y st u dies i n h u m a n t u m or c ell x e n o graft m o d e ls w ere c o n d u ct e d u si n g 
t w o s urr o gate m A bs rat h er t h a n M C S 1 1 0 its elf.  T h es e t w o s urr o gate m A bs w ere 5 A 1, a rat 
m o n o cl o n al  I g G 1 a nti b o d y  w hic h  n e utraliz es  m o us e  ( h ost)  C S F -1,  a n d  5 H 4,  a  m o us e  
m o n o cl o n al  I g G 1  a nti b o d y  w hic h  n e utraliz es  h u m a n  (t u m or -d eri v e d)  C S F -1.  Usi n g  a  
c o m bi n ati o n of t h es e t w o m A bs, i n hi biti o n of t u m or -i n d u c e d oste ol ysis w as d e m o nstr at e d i n 
mic e  i nje cte d  i ntrati biall y  wit h  a  h u m a n  bre ast  c a n c er  c ell  li n e  ( M D A -M B -2 3 1 L u c). 
Tre at m e nt wit h a c o m bi n ati o n of n e utralizi n g a nti b o dies dire cte d a gai n st b ot h t h e h ost m o us e 
s o urc e of C S F-1 a n d h u m a n t u m or -deri v e d C S F -1 h a d t h e l o w est m e a n oste ol ytic s c ore a n d a 
re d u c e d n u m ber of i n di vi d ual a ni m als wit h cle arl y e vi d e nt b o ne lesi o ns.  
T o  e v al u ate  t h e  c o m p ete n c e  of  T A Ms  f or  si g n ali n g  via  t h e  C S F 1/ C S F 1 R  p at h w a y, 
m a cr o p h a ges fr o m s p o nta n e o us t u m ors arisi n g i n M M T V -P y M T mic e w ere a n al y z e d f or 
C S F 1 R  e x pressi o n  b y  fl o w  c yt o m etr y.  C D 4 5 + C D 1 1 b + F 4/ 8 0 +  p ositi v e  T A Ms  stai n e d  
p ositi v el y f or C S F 1 R w hile C D 4 5 − t u m or c ells s h o w e d n o e x pressi o n of t h e re c e pt or. T h e 
f u n cti on al d e p e n d e n c e of T A Ms o n si g n ali n g m e diate d b y t h e C S F 1/ C S F 1 R p at h w a y w as 
ass ess e d after 6 d a ys of tre at m e nt wit h t h e 5 A 1 A nti M C S F a nti b o d y t o s h o w a si g nific a nt 
re d u cti o n  i n  m a cr o p h a ges  ( C D 4 5+ C D 1 1 b + F 4/ 8 0 +  c ells)  s u g gesti n g  a  f u n cti o n al  
i nter d e p e n d e n c y b et w e e n C S F 1 a n d C S F 1 R i n re g ulati n g T A Ms i n t his bre ast c a n c er m o d el 
(Stra c h a n 2 0 1 3 ). 
1. 3. 1. 1. 2  N o n - cli ni c al p h ar m a c o ki n eti c s a n d p h ar m a c o d y n a mi c s  
T h e  pre cli nic al  p h ar m a c o ki n etics  ( P K)  a n d  p h ar m a c o d y n a mics  ( P D)  of  M C S 1 1 0  w ere  
e v al u ate d i n c y n o m ol g us m o n k e ys f oll o wi n g si n gle i ntra v e n o us (i. v) b ol us i nje cti o n of 0. 2, 2 

N o v artis  
C o nfi d e nti al  
P a g e 3 8  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol  N o. C M C S 1 1 0 Z 2 2 0 1  
 
or 2 0 m g/ k g, or m ulti ple w e e kl y i v b ol us i nje cti o ns of 1 0 m g/ k g f or 3 w e e ks a n d 2, 2 0 o r 1 0 0 
m g/ k g f or u p t o 1 3 w e e ks.  Fre e M C S 1 1 0 ( u n b o u n d t o tar g et C S F-1) e x hi bite d d os e -d e p e n de nt 
P K, wit h d e cre asi n g cle ara n c e ( C L) a n d i n cre asi n g m e a n resi de n ce ti m e ( M R T) or ef f e cti v e 
t 1/ 2  w h e n  d os e  i n cre as e d.  T h e  P K pr ofiles of  fre e  M C S 1 1 0  w ere  n ota bl y  n o nli n e ar at 
c o n c e ntrati o ns b el o w  a p pr o xi m atel y 2 0 μ g/ m L, pres u m a bl y d u e t o tar get -m e diate dis p ositi o n . 
I n t h e 1 3-w e e k st u d y, 2 o ut of 2 2 a ni m als teste d h a d a nti -dr u g a nti b o dies d ete ct e d i n s er u m, 
w hic h c orrelate d wit h l o w er M C S 1 1 0 e x p osure at t h e c orres p o n di n g ti m e p oi nts. F or P D, ti m e 
a n d d os e d e p e n d e nt i n cre as e i n  t otal C S F-1 w as o bs er v e d i n t h e 1 3 -w e e k st u d y f oll o wi n g 
M C S 1 1 0 a d mi nistrati o n, pres u m a bl y d u e t o sl o w er cle ara n c e of t h e C S F -1 after it f or m e d 
i m m u n e  c o m ple x es  wit h  M C S 1 1 0,  i n dic ati n g  tar get  e n ga ge m e nt.  D e cre as es  i n  ot h er  
d o w nstre a m bi o m ar k ers s u c h as circ ulati n g m o n o c ytes a n d s er u m N T x w ere als o o bs er v e d 
f oll o wi n g M C S 1 1 0 a d mi nistrati o n. 
1. 3. 1. 1. 3  N o n -cli ni c al t o xi c ol o g y  
T h e c y n o m ol g us m o n ke y w as s ele cte d as t h e rele v a nt s p e cies f or t o xic ol o g y st u die s b e c a us e 
M C S 1 1 0 s h o w e d si milar f u n cti o n al a cti vit y a gai nst c y n o m ol g us m o n k e y a n d h u m a n C S F -1 i n 
i n vitr o bi o ass a ys. I n c y n o m ol g us m o n k e y st u dies t h ere w ere n o s e v ere t o xic ol o gi c al eff e cts 
i n a n y a ni m al gi v e n M C S 1 1 0 i ntra v e n o usl y as a si n gle d os e or as m ulti ple d os es o n ce w e e kl y 
u p t o 1 3 w e e ks a n d u p t o d os es of 1 0 0 m g/ k g, s h o wi n g g o o d t olera bilit y of M C S 1 1 0 gi v e n 
s yste mic all y.  Mil d  i n cre as es  i n  li v er  e n z y m es  w ere  s e e n  i n  all  st u dies  wit h o ut  
hist o p at h ol o gic al c orrelates,  w hic h  res ol v e d  wit h  cle ara n c e  of  t h e  dr u g. T his i n cl u d e d  
c o nsiste nt mil d/ m o d erate,  d os e -d e p e n d e nt i n cre as es i n la ctate  d e h y dr o ge n as e ( L D), mil d 
i n cre as es i n A S T, a n d mi ni m al i n cre as es i n ga m m a -gl uta m yl tra ns pe pti d as e  ( G G T) a n d A L T. 
All  p ara m eters ret ur n e d t o b as eli n e le v els wit h t h e cle ara n c e of M C S 1 1 0 fr o m t h e s er u m. T h e 
m ost li k el y c a us e of t h es e i n cre as es is re d u ce d cle ara n ce rate of t h e s er u m e n z y m es d u e t o t h e 
di mi nis h e d n u m b ers of K u pff er c ells i n t h e li v er. T hi s w as d e m o nstrate d i n c y n o m ol g us 
m o n k e y  st u d y  wit h  a  si n gle  i ntra v e n o us d os e  of  M C S 1 1 0, w hic h  s h o w e d  a  d e cre as e d  
cle ara n c e of histi di n e-ta g ge d cre ati n e ki n as e i nje cte d i n p arallel t o M C S 1 1 0. After 1 3 w e e kl y 
d os es, mi ni m al or mil d i nterstitial e d e m a w as s e e n i n m ulti ple or ga ns hist o p at h ol o gic all y i n 
all d os e gr o u ps, i n cl u di n g t h e l o w -d os e gr o u p. Alt h o u g h p eri or bital s w elli n g w as o bs er v e d t o 
o c c ur s p ora dic all y i n all gr o u ps (i n cl u di n g c o ntr ols), t h e i n cre as e d i n ci d e n ce a n d s e v erit y of 
p eri or bital s w elli n g o bs er v e d at 1 0 0 m g/ k g s u g geste d a relati o ns hi p of t his effect t o M C S 1 1 0 
a d mi nistrati o n. N o i nterstitial or p eri or bital e d e m a w as pres e nt at t h e e n d of t h e re c o v er y 
p eri o d s h o wi n g t h e re v ers al of t his effe ct. All ot h er effe cts s e e n, s u c h a s b o n e m or p h ol o g y 
c h a n ges a n d  m o n o c yte  d e pleti o n  w ere  d u e  t o  t h e  e x p e cte d  p h ar m a c ol o gic al eff e cts of  
M C S 1 1 0. T h e d ata s u p p ort t h e i ntra v e n o us us e of M C S 1 1 0 i n cli nic al trials at t h e d os es 
s ele cte d (Se cti o n 2. 3. 2 ). 
1. 3. 1. 2  Cli ni c al e x p eri e n c e  
T hre e cli nic al trials wit h M C S 1 1 0 h a v e b e e n i nitiate d.  

N o v artis  
C o nfi d e nti al  
P a g e 3 9  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol  N o. C M C S 1 1 0 Z 2 2 0 1  
 
T a bl e 1- 1 
Cli ni c al tri al s wit h M C S 1 1 0  
Tri al  
St u d y t y p e  
St u d y o bj e cti v e s  
P ati e nt s  
M C S 1 1 0  d o s e r a n g e 
a n d s c h e d ul e  
M C S 1 1 0 A 2 1 0 1  
Cl o s e d  
Fir st i n h u m a n, 
d o s e e s c al ati o n  
M T D, s af et y, 
P K/ P D,  p r eli mi n ar y  
effi c a c y  
Pr o st at e c a n c er wit h 
b o n e m et a st a s e s,  n = 3  
0. 0 1 m g/ k g e v er y 1 4  d a y s  
M C S 1 1 0 X 2 1 0 1  
C o m pl et e d  
H e alt h y 
v ol u nt e er s, 
d o s e e s c al ati o n  
M T D, s af et y, P K/ P D  
H e alt h y, n = 5 2  
0. 0 1 -2 0  m g/ k g, 1 -2 i v 
i nf u si o n s e v er y 2 1-5 6 
d a y s  
M C S 1 1 0 X 2 2 0 1  
O n g oi n g  
Effi c a c y st u d y  
S af et y, t ol er a bilit y, 
P K/ P D,  effi c a c y  
Pi g m e nt e d Vill o n o d ul ar 
S y n o viti s ( P V N S), n = 1 6  
1 0  m g/ k g, 1 -4 i v 
i nf u si o n s e v er y 2 8 d a y s 
Brief i nf or m ati o n o n cli nic al e x perie nc e of M C S 1 1 0 will b e pr o vi d e d b el o w. F or a d diti o n al 
i nf or m ati o n, ple as e refer t o t h e I n v esti gat or’s Br o c h ure (I B). 
1. 3. 1. 2. 1  C M C S 1 1 0 A 2 1 0 1, a fir st i n h u m a n cli ni c al tri al  
C M C S 1 1 0 A 2 1 0 1  w as a  first i n  h u m a n  st u d y  i n  pr ostate  c a n c er wit h  b o n e  m etastas e s, 
d esi g n e d t o e v al u ate s af et y, t olera bilit y a n d M T D of M C S 1 1 0. M C S 1 1 0 w as a d mi nist er e d at 
d os es 0. 0 1 m g/ k g re p e ate d e v er y 2 w e e ks i n a 2 8 d a y c y cle f or a t otal of 3 c y cles. T h e st u d y 
w as cl os e d after 3 p atie nts d u e t o pri oritiz ati o n wit hi n N o v artis. N o M T D w as esta blis h e d.  
Cli nic al s afet y a n d t ole r a bilit y  
M C S 1 1 0  w as  w ell -t olerate d  a n d  all  p atie nts  c o m plete d  t h e  3-c y cle tre at m e nt. T h e o nl y 
a d v ers e e v e nt s us pe cte d t o b e relate d t o M C S 1 1 0 w as a n i nf usi o n re a cti o n wit h c hills ( Gr a d e 
1), diz zi n ess ( Gra d e 2) a n d  h y p ote nsi o n ( Gra d e 2). T h e i nf usi o n re a cti o n starte d 1 h o ur aft er 
c o m pleti n g t h e first i nf usi o n a n d laste d f or 1 h o ur. N o i nf usi o n re a cti o ns w ere n ote d f oll o win g 
s u bs e q u e nt i nf usi o ns f or t h e s a m e p atie nt or i n t h e t w o ot h er p atie nts. N o D L Ts w ere re p orte d  
a m o n g t h e 3 p atie nts tre ate d wit h M C S 1 1 0.  
Cli nic al p h a r m a c o ki netics  
F or m al  P K  a n al ysis  w as  n ot  c o n d u cte d  d u e  t o  s m all  n u m b er  of  s er u m  s a m ples  wit h  
m e as ura ble c o n c e ntrati o ns. F oll o wi n g bi w e e kl y i v i nf usi o n of 0. 0 1 m g/ k g M C S 1 1 0 t o 3 
p atie nts, C m a x of fre e M C S 1 1 0 w as o bs er v e d at 5 mi n utes p ost t h e e n d of i nf usi o n, wit h 
m e dia n of 2 1 9 a n d 1 0 6 n g/ m L d uri n g t h e first a n d si xt h i nf usi o n, res p ecti v el y. Fre e M C S 1 1 0 
s er u m c o n c e ntrati o n d e creas e d ra pi dl y a n d w as o nl y m e as ura ble u p t o 2 h o urs aft er i nf u si o n 
i n t h e m ajorit y of s a m ples. N o a c c u m ulati o n w as o bs er v e d at t his d os e le v el. I m m u n o ge nicit y  
w as ass ess e d i n all p atie nts, a n d a nti -M C S 1 1 0 a nti b o dies w ere n ot d ete cte d.  
Cli nic al p h a r m a c o d y n a mics  
N o c o nsiste nt c h a n ges i n m o n oc yte c o u nt w ere o bs er ve d i n t h e 3 p atie nts tre ate d. All p atie nts’ 
p eri p h eral m o n o c ytes w ere wit hi n 7 0 % of b as eli n e le v els t hr o u g h o ut t h e st u d y.  
Cli ni c al effi c a c y  
Bi ol o gic a cti vit y of M C S 1 1 0 w as n ot o bs er v e d. N o c o nsiste nt dire cti o n of c h a n ge w as s e e n i n 
b o n e m ar k ers.  

N o v artis  
C o nfi d e nti al  
P a g e 4 0  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol  N o. C M C S 1 1 0 Z 2 2 0 1  
 
1. 3. 1. 2. 2  C M C S 1 1 0 X 2 1 0 1, a cli ni c al tri al i n h e alt h y v ol u nt e er s  
C M C S 1 1 0 X 2 1 0 1 w as a p h as e I st u d y d esi g n e d t o e v al u ate s af et y, t olera bilit y a n d M T D of 
M C S 1 1 0 i n 5 2 h e alt h y v ol u nte ers ( H V). M C S 1 1 0 w as d eli v ere d t o 2 7 H V at i n cre asi n g si n gle 
d os es fr o m 0. 0 1 -2 0 m g/ k g. A d diti o n all y, 6 H V re c ei v e d 2 d os es ( 5 m g/ k g) gi v e n 2 1 d a ys 
a p art, a n d a n ot h er 6 re c ei ve d 2 d oses ( 1 0 m g/ k g) gi v e n 5 6 d a ys a p art.  
Cli nic al s afet y a n d t ole r a bilit y  
As y m pt o m atic a n d re v ersi ble cre ati n e ki n as e ( C K) ele v ati o ns w ere s e e n i n 1 5 of 5 2 H V. T h e 
C K ele v ati o n di d n ot a p p e ar t o refle ct m us cle d a m a ge si n c e n eit h er tr o p o ni n T ( m ar k er f or 
c ar dia c m us cle d a m a ge) n or al d olas e ( m ar ker f or s k eletal m us cle tiss u e d a ma ge) w as ele v ate d. 
T h e C K ele v ati o ns are t h o u g ht t o b e c a us e d b y t h e p h ar m a c ol o gic al effe ct of M C S 1 1 0.  
Mil d p eri or bital e d e m a, w as o bs er v e d i n 4 of 5 2 H V a n d w as tra nsie nt, lasti n g b et w e e n 2 a n d 
1 5 8 d a ys. N o n e of t h e s u bjects w h o prese nte d wit h p eri or bital e d e m a h a d d e vel o pe d a nti -dr u g 
a nti b o dies. T h e d os e li miti n g t o xicit y w as i d e ntifie d at 2 0 m g/ k g, b as e d o n C K ele v ati o ns 
e x c e e di n g m ore t h a n 5 ti m es t h e u p p er li mit of n or m al. T h e re c o m m e n d e d d os e f or f ut ure 
st u dies w as s et at 1 0 m g/ k g. 
Cli nic al p h a r m a c o ki netics  
F oll o wi n g i ntra v e n o us a d mi nistrati o n of M C S 1 1 0 i n h e alt h y v ol u nte ers, s er u m fre e M C S 1 1 0 
e x hi bite d c o n c e ntrati o n/ d os e -de p e n de nt P K, wit h d e cre asi n g C L (cle ara n c e) a n d i n cr e a si n g 
M R T ( m e a n resi d e n c e ti m e) or eff e cti v e t 1/ 2 w h e n d os es i n cre as e d fr o m 0. 0 1 t o 2 0 m g/ k g 
a cr oss 8 d os e le v els. T h e s h a p e of t h e s er u m fre e M C S 1 1 0 P K pr ofiles i n dic ate d t ar get 
m e diate d  dis p ositi o n,  w h ere  t h e  M C S 1 1 0  c o n c e ntrati o n  d e cli n e d  m ore  ra pi dl y  at  
c o n c e ntrati o ns l o w er t h a n a p pr o xi m atel y 1 0 μ g/ m L. T his w as pres u m a bl y d u e t o bi n di n g of  
M C S 1 1 0  t o  t h e  tar get,  s u g gesti n g  t h at  s er u m  fre e  M C S 1 1 0  c o n c e ntrati o ns  a b o v e  
a p pr o xim atel y  1 0  μ g/ m L  is re q uire d t o s at urate circ ulati n g C S F -1. At t h e 1 0 m g/ k g si n gle 
d os e le v el, M C S 1 1 0 c o n c e ntrati o ns w ere m ai ntai ne d a b o ve 1 0 μ g/ m L f or u p t o 4 2 d a ys p ost -
d os e.  As  e x p e cte d,  t otal C S F -1  e x hi bite d  d os e -d e p e n d e nt i n cre as e i n plas m a f oll o wi n g 
M C S 1 1 0 tre at m e nt, pres u m a bl y d u e t o sl o w er cle ara n c e of C S F -1 after it f or m e d i m m u n e 
c o m ple x es  wit h  M C S 1 1 0,  i n dic ati n g  s u c c essf ul  tar get  e n ga ge m e nt.  T h e  t otal  C S F -1 
c o n c e ntrati o n re a c h e d plate a u at t h e si n gle -d os e le v el at or a b o ve 1 0 m g/ k g, a n d it m ai ntai n e d 
at t h e plate a u f or at le ast 4 2 d a ys at t h e 1 0 m g/ k g d os e.  
Cli nic al p h a r m a c o d y n a mics  
E x p e cte d p h ar m a c ol o gic al res p o ns es w ere o bs er v e d i n d o w nstre a m bi o m ar k ers i n cl u di n g 
d os e -d e p e n d e nt d e creas es i n circ ulati n g C D 1 4 + or C D 1 4 + C D 1 6 + m o n oc ytes a n d C -ter mi n al 
tel o p e pti d e of t y p e I c olla ge n ( C T X-1), a b o n e res or pti o n m ar ker. I n a d diti o n, d os e -de pe n de nt 
i n cre as es i n C K w ere o bs er v e d. Si m ulati o n of ste a d y-state d os e-res p o ns e relati o ns hi ps f or 
bi o m ar k ers s h o w e d t h at wit h t h e o n c e -e ver y-4 w e e k ( Q 4 W) i v a d mi nistrati o n of M C S 1 1 0, t he 
res p o ns e of P D bi o m ar kers ( C D 1 4 + a n d C D 1 4 + C D 1 6 + m o n o c ytes, a n d C T X-1) w as e x pe cte d 
t o b e cl os e t o m a xi m al at t h e d os es at or a b o v e 5 m g/ k g a n d mi ni m al at d os e s at or b el o w 1 
m g/ k g.  

N o v artis  
C o nfi d e nti al  
P a g e 4 1  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol  N o. C M C S 1 1 0 Z 2 2 0 1  
 
1. 3. 1. 2. 3  C M C S 1 1 0 X 2 2 0 1, a p h a s e II st u d y i n pi g m e nt e d vill o n o d ul ar  s y n o viti s  
C M C S 1 1 0 X 2 2 0 1 is a n o n g oi n g p h as e II st u d y d esi g n e d t o e v al u ate s af et y, t olera bilit y a n d 
effic a c y wit h M C S 1 1 0 i n pi g m e nte d vill o n o d ular s y n o vitis ( P V N S). P V N S is a b e ni g n t u m or 
c o nsisti n g of m a cr o p ha ges a n d m ulti n u cle ate d gia nt c ells, m o st c o m m o nly l o c at e d t o j oi nts. 
Fi v e p atie nts w ere e nr olle d i n t h e first p art of t h e st u d y ( Part A) wit h si n gle i nje cti o ns ( 1 0 
m g/ k g) a n d 1 1 are pla n n e d t o p artici p ate i n t h e re p e at -d os e st u d y ( Part B) wit h 4 i nje cti o ns o f  
M C S 1 1 0 ( 1 0 m g/ k g) re p e ate d e v er y 2 8 d a ys.  
Cl i nic al s afet y a n d t ole r a bilit y 
As of A u g ust 2 0 1 4, t h e preli mi n ar y d ata o n re p orte d A Es, wit h s us p ecte d relati o n t o t h e dr u g, 
i n cl u d e t h e f oll o wi n g: k n e e art hral gia, C K ele v ati o n, a m ylas e ele v ati o n (all of m o d erate 
gra d e), a n d i nfl u e n z a s y m pt o ms, li p as e ele v ati o n, A S T/ G G T ele v ati o n, h y p ote nsi o n a n d 
e d e m a (all of mil d gra d e).  
Cli nic al p h a r m a c o ki netics  
P K a n al ysis is o n g oi n g. Preli mi n ar y d ata of t h e first 3 p atie nts wit h si n gle i v i nf usi o n of 1 0 
m g/ k g i n t h e o n g oi n g st u d y s u g geste d si milar P K as i n H V.  
Cli nic al p h a r m a c o d y n a mics  
Preli mi n ar y d ata fr o m t h e o n g oi n g st u d y i n P V N S p atie nts s h o w e d a n e x p e cte d d e cre as e i n 
m o n o c ytes a n d C T X -1, w hile a n i n cre as e w as s e e n i n C K. Ma xi m u m v al u es are ge n erall y 
o bs er v e d at D a y 2 8 or D a y 4 3 a n d t h e n ret ur ni n g b a c k t o b a s eli ne. 
Cli nic al effic a c y  
O n e si n gle i nje cti o n ( 1 0 m g/ k g) res ulte d i n si g nific a nt ( 3 0 -5 0 %) t u m or re d u cti o ns ( M RI) i n 
all ( 4) p atie nts re c ei vi n g t h e dr u g.  
1. 3. 2  
O v er vi e w of c ar b o pl ati n  
Car b o plati n is a n al k ylati n g a ge nt w hic h a cts b y pr o d u ci n g cr oss-li n ki n g g u a ni n e b as es i n 
D N A d o u ble -h eli x stra n ds, t h ere b y pre ve nti n g tra ns cri pti o n a n d re plic ati o n. T h e m e c h a nis m 
of a cti o n is n ot c ell -c y cle s p e cific ( Mc E v o y 2 0 0 0 ).  
T h e m aj or r o ute of eli mi n ati o n of c ar b o plati n is re n al e x creti o n. Patie nts wit h n or m al re n al 
f u n cti o n e x crete 7 1 % of t h e d os e wit hi n 2 4 h o urs. Dr u g i ntera cti o ns wit h a mi n o gl y c o si d e s, 
p h e n yt oi n a n d w arf ari n h a ve b e e n re p orte d a n d c o n c o mita nt us e is c a uti o n e d ( Mc E v o y 2 0 0 0 ). 
T h e m ai n t o xicities of c ar b o plati n are m y el osu p pressi o n, n a use a/ v o miti n g, n e p hr ot o xicit y a n d 
p eri p h eral n e ur o pat h y. H y pers e nsiti vit y re a cti o ns h a v e b e e n re p orte d, p artic ularl y w h e n u s e d 
i n c o m bi n ati o n or after re p eate d e x p os ure (Mc E v o y 2 0 0 0, Mar k m a n 1 9 9 9 ).  
Car b o plati n is a p pr o v e d f or us e al o n e or c o m bi n e d wit h ot h er dr u gs i n o v aria n c a n c er a n d 
n o n -s m all l u n g c a n c er, b ut wi d el y us e d als o i n ot h er m ali g n a ncies s u c h as h e a d n e c k c a n c er, 
ger m c ell t u m ors, bre ast c a n c er a n d ot h ers. N u m er o us d osi n g s c h e d ules e xist a n d d e p e n d o n 
dis e as e, res p o ns e e x p e ctati o ns a n d c o n c o mita nt t h era p y (N C C N 2 0 1 4, E S M O G ui d eli n es 
2 0 1 4 ).  

N o v artis  
C o nfi d e nti al  
P a g e 4 2  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol  N o. C M C S 1 1 0 Z 2 2 0 1  
 
1. 3. 3  
O v er vi e w of g e m cit a bi n e  
G e m cita bi n e  is  a  p yri mi di n e  a n al o g  w hic h  is  m eta b oliz e d  t o  t w o  a cti v e  m eta b olites,  
ge m cita bi n e di p h os p hate a n d ge m cita bi ne tri p h osp hate. T h e c yt ot o xic effects of ge m cit a bi n e 
are  e x erte d  t hr o u g h  i n c or p orati o n  of  ge m cita bi n e  tri p h os p h ate  i nt o  D N A,  r es ulti n g i n  
i n hi biti o n of D N A s y nt h esis a n d i n d u cti o n of a p o pt osis. G e m cita bi n e is c ell -c y cle p h as e 
s p e cific ( S a n d G 1/ S-p h as es) ( Gri n d e y 1 9 9 0, Eli Lill y 1 9 9 9 ). 
G e m cita bi n e is ra pi dl y m eta b oliz e d b y c yti di n e d e a mi nas es i n li v er, ki d n e y, bl o o d a n d ot h er 
tiss u e (Gil b ert 2 0 0 6 ). Dr u g eli mi n ati o n is m e diate d m ai nl y t hr o u g h re n al e x creti o n. Wit hi n 
o n e w e e k of a d mi nistrati o n 9 2 % t o 9 8 % of t h e d os e w as re c o v ere d, al m ost e ntirel y i n t h e 
uri n e ( Eli Lill y 1 9 9 9 ). 
T h e  m ai n  t o xicities  of  ge m cita b i n e  are  ele v ate d  li v er e n z y m es  [as p artate  tra ns a mi n as e  
(A S A T )/  as p artate  a mi n otra nf eras e  (A L A T) ] a n d a n a plastic  l y m p h o m a  ki n as e   (A L K ), 
n a us e a/ v o miti n g,  pr otei n/ h e m at uria, d ys p n e a, ras h  a n d  m y el os u p pressi o n  ( M o ore 1 9 9 2, 
Merte ns 1 9 9 3, L u n d 1 9 9 4 ). 
G e m cita bi n e is a p pr o v e d f or us e al o n e or wit h ot h er dr u gs i n p a n cre atic c a n c er, o v aria n 
c a n c er, n o n -s m all l u n g c a n c er a n d bre ast c a n c er. T h e m ost c o m m o nl y us e d s c h e d ule f or 
ge m cita bi n e is a d mi nistrati o n o n d a ys 1 a n d 8 of e a c h 2 1 -d a y c y cle, b ut t h ere are s e v eral 
o pti o ns ( N C C N 2 0 1 4, E S M O G ui d eli n es 2 0 1 4 ).  
1. 4  
O v er vi e w of c o m bi n ati o n tr e at m e nt  
1. 4. 1  
N o n -cli ni c al  
N o  pre cli nic al  d ata  e xist  f or  t h e  c o m bi n ati o n  of  M C S 1 1 0  wit h  c ar b o/ ge m.  H o w e v er,  
pre cli nic al d ata fr o m ot h er c o m p o u n ds tar geti n g t h e C S F -1/ C S F 1 R si g n ali n g p at h w a y i n 
c o m bi n ati o n wit h c h e m ot h era p y (c ar b o plati n, p a clita xel) s u p p orts t h e st u d y c o n c e pt of  t his 
trial (D e N ar d o 2 0 1 1 ). Se e Se cti o n 2. 1 . 
1. 4. 2  
Cli ni c al  
T h e st u d y starte d e nr oll m e nt i n A u g ust 2 0 1 5.  After t h e e nr oll m e nt h alt i n J u n e  2 0 1 7 , L P F T 
o c c urre d o n J ul y 1 7 th, 2 0 1 7. Thirt y -f o ur p atie nts h a v e b e e n tre ate d wit h M C S 1 1 0 at 1 0 m g/ k g  
Q 3 W (wit h  or  wit h o ut  a n a d diti o n al d os e  of  M C S 1 1 0  o n  C 1 D 8 ) i n  c o m bi n ati o n  wit h  
c ar b o/ ge m . 
T h e m ost c o m m o n a d v erse e v e nts o bs er v e d s us pe cte d t o b e relate d t o M C S 1 1 0 are p eri or bital 
e d e m a, ele v ate d cre ati n e ki n as e a n d ele v ate d li v er e n z y m es . F or a d diti o n al i nf or m ati o n, 
ple as e ref er t o t h e M C S 1 1 0 I n v esti gat or’s br o c h ure.  
After t h e first e arl y s af et y re vie w m e eti n g i n Ma y 2 0 1 6, it w as d e ci d e d t o re m o v e t h e 
a d diti o n al d os e of M C S 1 1 0 1 0 m g/ k g o n C 1 D 8 i n or d er t o i m pr o v e  t olera bilit y. N o i m m e diate 
s af et y c o n c er ns wit h t h e c urre nt dosi n g w ere i d e ntifie d.   
A n a d diti o n al Saf et y re vie w m e eti n g t o o k pla c e i n Ma y 2 0 1 7. Safet y d ata i n di c at e d t h at t h e 
d osi n g re gi m e n  of  M C S 1 1 0  1 0  m g/ k g wit h o ut t h e  a d diti o n al d os e  o n  C 1 D 8  w as b ette r 
t olerate d  re gar di n g  A Es  a n d  d os e  d ela ys/i nterr u pti o ns  t h a n  t h e  re gi m e n  i n cl u di n g  a n  

N o v artis  
C o nfi d e nti al  
P a g e 4 3  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol  N o. C M C S 1 1 0 Z 2 2 0 1  
 
a d diti o n al C 1 D 8 d os e. T h us, t h e esta blis he d d osi n g re gi m e n f or M C S 1 1 0 i n c o m bi n ati o n wit h 
c ar b o/ ge m is 1 0 m g/ k g Q 3 W.  
I n a d diti o n, cli nic al d ata fr o m a trial c o m bi ni n g C S F-1 R bl o c k a d e (a nti b o d y) wit h p a clit a x el 
d e m o nstrate d r o b ust T A M d e pleti o n. N o d ata w as pr o vi de d f or a nti -t u m or a cti vit y or t o xicit y. 
(Ries 2 0 1 4 ). Se e Se cti o n 2. 1 . 
1. 4. 3  
P ot e nti al  f or dr u g -dr u g i nt er a cti o n s  
S p e cific st u dies t o i n v esti gate dr u g -dr u g i ntera cti o ns ( D DI) h a v e n ot b e e n c o n d u cte d wit h 
M C S 1 1 0. A nti b o dies t h at m o d ulate c yt o ki n es, w hic h m a y re g ulate c yt o c hr o m e P 4 5 0 ( C Y P) 
e n z y m es, m a y c a us e  D DI wit h s m all m ole c ule dr u gs b e c a us e of t h e p ote ntial t o alter C Y P-
m e diate d m eta b olis m (Le e et al 2 0 1 0 ; H u a n g et al 2 0 1 0 ). H o w e v er,  M C S 1 1 0 s p e cific all y 
n e utraliz es C S F -1 a n d h e n c e, it is n ot e x p e cte d t o m o d ulate c yt o ki n es. I n a d diti o n, as a n 
a nti b o d y, M C S 1 1 0 is eli mi n ate d t hr o u g h pr otei n c ata b olis m a n d tar get -m e diate d dis p o siti o n . 
T h eref ore ,  M C S 1 1 0  is  n ot  a ntici p ate d  t o  b e  dire ctl y  eli mi n ate d t hr o u g h  h e p atic/re n al  
m eta b olis m a n d e x creti o n, t o c o m p ete wit h t h e eli mi n ati o n of c ar b o a n d ge m, w hic h are 
m ai nl y eli mi n ate d t hr o u g h m eta b olis m ( ge m) a n d re n al e x creti o n ( ge m a n d c ar b o). T h eref ore, 
t h e ris k of D DI b et w e e n M C S 1 1 0 a n d c ar b o or ge m is a ntici p ate d t o b e l o w. N e v ert h eless, P K 
of c ar b o a n d ge m i n t h e pres e n c e a n d a bse n ce of M C S 1 1 0 will b e c h ara cteriz e d i n t his st u d y 
t o ass ess t h e D DI, if a n y, b et w e e n M C S 1 1 0 a n d c ar b o or ge m (Se cti o n 1 0. 5. 3 ).  
1. 4. 4  
E x p e ct e d o v erl a p pi n g t o xi citi e s  
As y m pt o m atic a n d tra nsie nt C K ele v ati o ns w ere fre q u e ntl y s e e n i n cli nic al st u dies wit h 
M C S 1 1 0.  Tra nsie nt i n cre as es  of  Gra d e  1 -2  A S T w ere  o bs er v e d  as  w ell,  w h ere as  A L T 
ele v ati o ns w ere o nl y s e e n i n o c c asi o nal p atie nts. T h e i n cre ase of e n z y m es d oes n ot a p p e ar t o 
refle ct m us cle d a m a ge si n c e m ar k ers f or c ar dia c or s k eletal m us cle d a m a g e w er e e v al u at e d 
a n d  f o u n d  n or m al.  F urt h er m ore,  is olate d  C K/ A S T ele v ati o n  is n ot c o nsiste nt wit h  li v er 
d a m a ge ( Kris h n a m urt h y 2 0 0 9 ). T h e ele v ati o n of e n z y m es is c o nsi d ere d a p h ar m a c ol o gic al 
eff e ct of M C S 1 1 0 re d u ci n g t h e n u m b er of li v er m a cr o p h a ges ( K u pff er c ells), le a di n g t o 
re d u c e d cle ara n ce rate. 
Gra d e 1 -2 ele v ati o ns of A S T/ A L T are c o m m o nl y s e e n  d uri n g tre at m e nt wit h ge m cita bi n e, 
w h ere as  Gra d e  3 -4  t o xicit y  is  rare .  H o w e v er,  t h es e  i n cre as es  are  s el d o m  of  cli nic al  
si g nific a n c e a n d t h ere is n o e vi d e n ce of i n cre asi n g h e p atic t o xicit y wit h eit h er l o n ger d urati o n 
of ge m cita bi n e tre at m e nt or c u m ulati v e d os e ( A a pr o 1 9 9 8 a n d Eli Lill y 1 9 9 9 ). F D A a p pr o v e d 
pres cri bi n g i nf or m ati o n  d o es n ot re c o m m e n d a n y d os e m o dific ati o ns of ge m cit a bi n e u nl e ss 
Gra d e 3 -4 li v er t o xicit y is re p orte d, at w hic h 5 0 % d os e re d ucti o n or wit h h ol di n g of t h e dr u g is 
pr o p os e d.  
E v e n t h o u g h A L T ele v ati o n is rare wit h M C S 1 1 0 it is fre q u e ntl y s e e n wit h a d mi nistr a ti o n o f  
ge m cita bi n e. D u e t o t h e p ote ntial ris k of o v erla p pi n g li v er e n z y me ele v ati o n s, o nl y p ati e nts 
wit h n or m al li v er f u n cti o n a n d wit h o ut k n o w n c hr o nic li v er or h e art dis e as e ar e eli gi bl e f or 
e nr oll m e nt. Se e Se cti o n 5. 2 . F urt h er m ore, p atie nts will b e c aref ull y m o nit ore d re gar di n g t h e ir 
li v er e n z y m es d uri n g t h e st u d y a n d i nstr u cti o ns f or d os e m o dific ati o ns are pr o vi d e d. Se e 
Se cti o n 6. 2. 1. 1 . 

N o v artis  
C o nfi d e nti al  
P a g e 4 4  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol  N o. C M C S 1 1 0 Z 2 2 0 1  
 
2  
R ati o n al e 
2. 1  
St u d y r ati o n al e  a n d p ur p o s e  
N o s u bsta ntial pr o gress h as b e e n m a de i n t h e tre at m e nt of T N B C a n d t h e pr o g n osis r e m ai n s 
p o or ( F o ul k es 2 0 1 0 ). C urre ntl y, c h e m ot h era p y is t h e o nl y tre at m e nt o pti o n. Alt h o u g h T N B C 
is a c h e m os e nsiti v e dis e as e a n d a s u bs et of c h e m o res p o n d ers h as a n e x c elle nt pr o g n osis, t h e 
m aj orit y of p atie nts ra pi dl y  rela ps es (Lie dt k e 2 0 0 8 ). C urre nt tre at m e nt strate g y i n T N B C ai ms 
at f urt h er i m pr o vi n g t h e effic a c y of c h e m ot hera p y. 
Pre cli nic al a n d cli nic al d ata s u g gest t h at T N B C is a hi g hl y i m m u n o ge nic s oli d t u m or a n d t h at 
i m m u n o m o d ulati o n m a y le a d t o e n h a n c e d c h e m ot h era p y res p o ns e a n d i m pr o v e d p atie nt 
o utc o m e. C S F -1 R i n hi biti o n le a ds t o i n cre as e d l y m p h oc yte i nfiltrati o n a n d e n ha nc e d res p o ns e 
t o  c ar b o plati n  i n  x e n o graft m o d els (D e N ar d o 2 0 1 1  a n d  Ries 2 0 1 4 ). F urt h er m ore, T A M 
d e pleti o n is a c hie v e d i n p atie nts tre ate d wit h C S F -1 R dire cte d t h era p y ( Ries 2 0 1 4 ) (Se cti o n 
1. 2 , Fi g ure  1 - 3).  Ra n d o miz e d  p h as e  III trials s h o w t h at a d di n g c ar b o plati n  t o  sta n d ar d  
c h e m ot h era p y si g nific a ntl y i n cre as es t h e res p o ns e rate i n T N B C, p artic ularl y i n t h os e wit h 
hi g h a m o u nts of TI Ls ( Vi n a y a k 2 0 1 4, v o n Mi n c k witz 2 0 1 4 ).  
T h e tar gete d st u d y p o p ulati o n will i n cl u d e p atie nts w h ose t u m ors c o ntai n hi g h i m m u n ol o gic al 
i nfiltrates of T A Ms ( T A M hi g h). A re c e nt p u blic ati o n i d e ntifie d 4 0 % of T N B C as T A M h i g h  
a n d d e m o nstrate d t h at T A M hi g h h a d a si g nific a ntl y w ors e o utc o m e t h a n T A M l o w ( Y u a n 
2 0 1 4 ). T h e ass ess m e nt of T A M c o nte nt will b e o btai n e d t hr o u g h s u b missi o n of s a m pl e s t o a 
N o v artis d esi g n ate d la b orat or y w h ere I H C f or C D 1 6 3 ( m ar k er of T A M) will b e p erf or m e d.  
T h e s ele cti o n  strate g y is e x p e cte d t o i d e ntif y a p pr o xi matel y 4 0 % of T N B C p ati e nts a s T A M 
hi g h a n d e nric h e d f or t h e I M s u bt y p e (Le h m a n n 2 0 1 1 a n d Y u a n 2 0 1 4 ). (Se cti o n 1. 1. 1 ). 
T h e p ur p os e of t his st u d y is t o d eter mi n e if d e pleti o n of T A Ms i n d u c e d b y M C S 1 1 0 i m pr o ves 
t h e res p o ns e t o t h e c h e m ot hera pe utic a ge nts c ar b o plati n a n d ge m cita bi n e (c ar b o/ ge m). 
2. 2  
R ati o n al e f or t h e st u d y d e si g n  
T his st u d y is a p h as e II, o p e n -la b el, ra n d o miz e d st u d y of M C S 1 1 0 i n c o m bi n ati o n wit h 
c ar b o/ ge m ( Ar m 1) v ers us c ar b o/ ge m al o n e ( Ar m 2) i n  p atie nts wit h a d v a n c e d T N B C. T h e 
st u d y will tar get T N B C p atie nts wit h T A M hi g h t u m ors wit h n o pri or c h e m ot h era p y i n t h e 
a d v a n c e d s etti n g.  
T h e t w o -ar m st u d y is d esi g n e d t o pr o vi d e a preli mi n ar y c o m paris o n of t h e cli nic al effic a c y a s 
w ell as s af et y a n d t olera bilit y b et w e e n t h e t w o tre at m e nt c o m bi n ati o ns ( Ar m 1 vs Ar m 2). 
Hist oric al d ata  o n  effic a c y  a n d  s af et y  are  a v aila ble  f or t h e  c h e m ot h era p y  re gi m e n  i n  
m etastatic T N B C, b ut n ot f or t h e tar gete d p atie nt p o p ulati o n (I M) w hic h m a y h a v e a m ore 
f a v ora ble pr o g n osis. A ra n d o mize d st u d y d esi g n w as s ele cte d t o all o w f or e v al u ati o n of t h e 
p ote ntial cli nic al b e n efit of  a d di n g M C S 1 1 0 t o c ar b o plati n/ ge m cita bi n e i n t his p artic ular 
s u bs et of T N B C. 
T h e st u d y d esi g n i n cl u d es o n e or m ore e arl y s afet y re vie w s. T h e first s afet y r e v i e  w m e e ti n g 
will b e p erf or m e d after t h e first 9 p atie nts  h a v e re c ei v e d 2 c y cles of eit h er M C S 1 1 0 + 
c ar b o/ ge m or c ar b o/ ge m al o n e, or dis c o nti n ue d e arlier d u e t o a n a d vers e e ve nt. If t h e d o si n g 
re gi m e n is c h a n ge d at t his ti m e, a n a d diti o nal s af et y re vie w will ta k e pla c e after 9 p atie nts 

N o v artis  
C o nfi d e nti al  
P a g e 4 5  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol  N o. C M C S 1 1 0 Z 2 2 0 1  
 
h a v e b e e n ra n d o miz e d a n d c o m plete d t w o c y cles of eit h er M C S 1 1 0 (at t h e n e w d osi n g 
re gi m e n) + c ar b o/ ge m or c ar b o/ ge m al o n e, or dis c o nti n u e d e arlier d u e t o a n a d v ers e e v e nt.  
A n y s u bs e q u e nt c h a n ges of t h e M C S 1 1 0  d osi n g re gi m e n will b e f oll o w e d b y a n a d diti o n al 
s af et y re vie w p er t h e pr o c e d ure j ust d es cri b e d.  
N o v artis cli nic al te a m a n d st u d y i n v esti gat ors will e v al u ate cli nic al, P K a n d la b orat or y d ata a t 
a j oi nt m e eti n g t o m a k e a n ass ess m e nt of t h e s af et y of b ot h  st u d y ar ms. If s afet y c o nc er ns ar e 
n ote d, t h e n t h e M C S 1 1 0 d os e will b e  re d u c e d (fr o m 1 0 m g/ k g t o 5 m g/ k g or fr o m 5 m g/ k g t o 
2. 5 m g/ k g)  wit h or wit h o ut a n a d diti o n al d os e of M C S 1 1 0 o n C y cle 1 D a y 8  (Se c ti o n 4. 1). 
E nr oll m e nt of a d diti o n al p atie nts will n ot b e st o p p e d d uri n g t h e s afet y re vie w p eri o d.  
T h e pri m ar y o bje cti v e of t his st u d y is t o e v al u ate t h e eff e ct o n cli nic al a cti vit y of a d di n g 
M C S 1 1 0 t o c ar b o plati n/ ge m cita bi n e, o n e of t h e re c o m m e n de d tre at m e nt o pti o ns i n  t h e  f ir st -
li n e s etti n g f or a d v a n c e d T N B C. T h e ra n d o miz e d d esi g n mi ni miz es all o c ati o n bias, b ala n ci n g 
b ot h k n o w n a n d u n k n o w n pr o g n ostic f a ct ors i n t h e assi g n m e nt of tre at m e nts. Patie nts will b e 
ra n d o miz e d  i n  a  rati o  of  2: 1  ( M C S 1 1 0  + c ar b o/ ge m: c ar b o/ ge m) t o  all o w  f or a  lar ger 
pr o p orti o n of p atie nts t o re c ei v e t h e st u d y dr u g a n d h e n c e a n i n cre as e d c h a n c e f or b e n efit 
fr o m t h e c o m bi n ati o n. T his will als o all o w f or s ufficie nt p atie nts t o c h ara cteriz e t h e s af et y 
pr ofile of t h e M C S 1 1 0 + c ar b o/ ge m c o m bi nati o n.  
F or t h e d etaile d statistic al m et h o ds, refer t o Se cti o n 1 0 . 
2. 3  
R ati o n al e f or d o s e a n d r e gi m e n s el e cti o n  
2. 3. 1  
R ati o n al e f or d o s e a n d r e gi m e n f or c ar b o pl ati n a n d g e m cit a bi n e  
N o sta n d ar d of c are t h era p y e xists f or a d v a n c e d T N B C. H o w e v er, p u blis h e d d ata fr o m 
ra n d o miz e d  p h as e  II  a n d  p h as e  III  trials  d e m o nstrate  effic a c y  a n d  t olera bilit y  usi n g  
c ar b o plati n/ ge m cita bi ne i n t h e 1 st- 3r d li n e m etastatic s etti n g (O’ S h a u g h n ess y 2 0 1 1 ). T h e d os es 
a n d tre at m e nt c y cles will f oll o w t h e a b o v e m e nti o n e d p u blis h e d re gi m e ns wit h c ar b o plati n 
( A U C 2) a n d ge m cita bi n e ( 1 0 0 0 m g/ m2) a d mi nistere d o n d a ys 1 a n d 8 i n 2 1-d a y c y cles.  
2. 3. 2  
R ati o n al e f or d o s e a n d r e gi m e n f or M C S 1 1 0  
In t h e H V st u d y ( St u d y C M C S 1 1 0 X 2 1 0 1), > 5 -f ol d as y m pt o m atic C K ele v ati o n w as i d e ntifie d 
wit h si n gle i v i nf usi o ns of M C S 1 1 0 at t h e d os e of 2 0 m g/ k g. T h e re c o m m e n d e d d os e f or 
s u bs e q u e nt tre at m e nt w as s et at 1 0 m g/ k g w h ere M C S 1 1 0 w as w ell t olerate d. T h e P K a n d 
t otal C S F-1 c o n c e ntrati o n d ata s u g gest t h at circ ulati n g C S F -1 w as s at urate d f or a p pr o xi m ately 
6 w e e ks f oll o wi n g a si n gle d os e of 1 0 m g/ k g (Se cti o n 1. 3. 1. 2. 2 ). P D bi o m ar k er res p o ns e 
(m o n o c ytes a n d C T X -1)  w as pre dicte d t o b e cl os e t o m a xi m al  wit h d os es at or a b o v e 5 
m g/ k g, b as e d o n H V d ata.   Si g nific a nt t u m or v ol u m e re d u cti o ns w ere a c hie v e d i n P V N S 
p atie nts ( St u d y C M C S 1 1 0 X 2 2 0 1) usi n g 1 0 m g/ k g as si n gle i v i nf usi o n. A re p e at -d os e p h a s e 
of t h e st u d y is c urre ntl y o n g oi n g t o e v al u ate t h e t olera bilit y a n d effic ac y of 4 i v i nf usi o ns of  
1 0 m g/ k g M C S 1 1 0 e v er y 4 w e e ks ( Q 4 W).  Preli mi n ar y d ata wit h si n gle i v i nf usi o n of 1 0 
m g/ k g i n t h e o n g oi n g st u d y s u g gest t h at t h e P K pr ofile of M C S 1 1 0 a n d circ ulati n g C S F -1 
le v els are si milar i n P V N S p atie nts a n d i n H V. 
I n t his st u d y, p atie nts will re c ei v e M C S 1 1 0 Q 3 W at a d os e of 1 0 m g/ k g i v b as e d o n s afety a n d 
effic a c y d ata i n H V a n d P V N S p atie nts . T h e 3 -w e e k c y cle is c h os e n t o c o or di n ate wit h t h e 

N o v artis  
C o nfi d e nti al  
P a g e 4 6  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol  N o. C M C S 1 1 0 Z 2 2 0 1  
 
a d mi nistrati o n c y cle of t h e c h e m ot h era p y (c ar b o/ ge m). I n a d diti o n, c o m p are d t o t h e 4 -w e e k 
c y cle us e d i n t h e o n g oi n g st u d y of P V N S p atie nts, t h e 3 -w e e k c y cle m a y i m pr o v e tr e at m e nt 
b e n efit d u e t o p ote ntiall y hi g h er C S F -1 le v els i n T N B C p atie nts t h a n i n H V or P V N S p atie nts.  
All p atie nts will re c ei v e a n a d diti o n al 1 0 m g/ k g d os e of M C S 1 1 0 o n C y cle 1 D a y 8. T h e 
rati o n ale f or a d di n g a n a d diti o nal d os e is t o re a c h ste a d y state e arlier, t h us a c hie vi n g a f a st er  
a n d m ore c o nti n u o us i n hi biti o n of C S F-1. I n pre cli nic al m o d els c o nti n u o us i n hi biti o n of t h e 
C S F 1 -R p at h w a y is ess e ntial t o m ai ntai n effic aci o us T A M d e pleti o n as a n a ntic a n c er t h e r a p y 
(Stra c h a n 2 0 1 3 ). 
M C S 1 1 0 c o n c e ntrati o ns are pre dicte d t o re a c h ste a d y -state at We e k 6 i nste a d of We e k 1 2 
wit h a n a d diti o n al  d os e o n C y cle 1 D a y 8, b as e d o n t h e p o p ulati o n P K m o d el d e vel o pe d f r o m  
H V d ata ( Fi g ure 2 - 1). A c hie vi n g a f aster T A M d e pleti o n a n d, t h us e n ha n c e d c h e m ot h er a p y 
effic a c y m a y b e of cli nic al i m p orta n ce i n T N B C gi v e n t h e a g gressi v e cli nic al c o urs e.  
Fi g ur e 2- 1 
Pr e di ct e d p o p ul ati o n m e a n s er u m c o n c e ntr ati o n pr ofil e s of fr e e 
M C S 1 1 0 f oll o wi n g 1 0 m g/ k g Q 3 W i v i nf u s i o n wit h a n d wit h o ut an 
a d diti o n al d o s e  o n C 1 D 8  
 
N ot e: Pr e di cti o n i s b a s e d o n p o p ul ati o n P K m o d el i n M o d eli n g & Si m ul ati o n r e p ort of St u d y 
C M C S 1 1 0 X 2 1 0 1.  
F oll o wi n g a d mi nistrati o n of 1 0 m g/ k g Q 3 W of M C S 1 1 0 wit h a n a d diti o n al C 1 D 8 d o s e, it is 
pre dicte d t h at C m a x will b e a c hie v e d 5 w e e ks s o o ner t h a n wit h o ut t h e a d diti o nal C 1 D 8 d o s e 
(Fi g ure 2 - 1). T h e C m a x a n d ste a d y-state A U C of M C S 1 1 0 is pre dicte d t o b e a p pr o xi m atel y 2 -
f ol d l o w er t h a n t h at o bs er v e d i n H V tre ate d wit h a si n gle d os e of 2 0 m g/ k g si n gle d os e, a n d 
a p pr o xi m atel y 1 9 f ol d l o w er f or C m a x a n d 1 0 -f ol d l o w er f or A U C t h a n t h at o bs er v e d i n 
c y n o m ol g us m o n ke ys d os e d re p e ate dl y at 1 0 0 m g/ k g ( Ta ble 2 - 1).  
Bas e d o n cli nic al e x p erie n ce wit h M C S 1 1 0, t h e s h ort ti m e t o C m a x, a n d t h e esti m ate d s af et y 
m ar gi ns f or e x p os ure, a d os e re gi m e n of 1 0 m g/ k g e v er y 2 1 d a ys wit h a n a d diti o n al d o s e o n 
C 1 D 8 w as s ele cte d.  

N o v artis  
C o nfi d e nti al  
P a g e 4 7  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol  N o. C M C S 1 1 0 Z 2 2 0 1  
 
T a bl e 2- 1 
C o m p ari s o n of o b s er v e d e x p o s ur e i n c y n o m ol g u s m o n k e y s a n d 
h e alt h y v ol u nt e er s v er s u s pr e di ct e d e x p o s ur e i n C M C S 1 1 0 Z 2 2 0 1  
St u d y  
D o s e r e gi m e n 
(i v i nf u si o n) 
A U C 
( µ g* d a y/ m L) 
C m a x   
( µ g 
/ m L) 
E x p o s ur e m ar gi n a 
R el ati v e t o 
m o n k e y  
A U C  7 d a y, s s 
R el ati v e 
t o H V 
A U C 0 -i nf 
R el ati v e t o 
m o n k e y 
C m a x  
R el ati v e 
t o H V 
C m a x  
1 3 -w e e k 
t o xi c ol o g y 
( c y n o m ol g u s 
m o n k e y) b 
1 0 0  m g/ k g Q W  
2 9 0 2 5  
 ( A U C7 d ay, s s )c 
5 1 5 6  
- 
- 
- 
- 
C M C S 1 1 0 X 2 1 0 1  
( H V) d 
2 0 m g/ k g  
si n gl e d o s e  
6 4 5 0  
( A U C0 -i nf) 
4 4 6  
- 
- 
- 
- 
C M C S 1 1 0 Z 2 2 0 1  
( Pr e di ct e d d at a)e 
1 0  m g/ k g Q 3 W 
wit h a n   
a d diti o n al 
d o s e of 1 0 
m g/ k g o n 
C 1 D 8  
2 8 9 6  
( A U C0- 2 1 d ay, 
C 1 ) 
2 7 2  
1 0  
2. 2  
1 9  
1. 6  
2 9 9 8 
( A U C2 1 d ay, s s ) 
9. 7  
2. 2  
s s: st e a d y st at e, A U C 0- i nf: A U C fr o m ti m e z ero t o i nfi nit y; A U C 7 d ay, s s : A U C  fr o m ti m e z er o t o 7 d a y s d uri n g st e a d y 
st at e A U C 0- 2 1 d ay, C 1 : A U C fr o m ti m e zer o t o 2 1 d a y s d uri n g C y cl e 1; A U C 2 1 d ay, s s : A U C fr o m ti m e z er o t o 2 1 d a y s 
d uri n g st e a d y st at e.  
a M e a n  o b s er v e d e x p o s ur e i n m o n k e y or H V di vi d e d b y m e a n pr e di ct e d e x p o s ur e of C M C S 1 1 0 Z 2 2 0 1  
b D at a  ar e  fr o m pr e cli ni c al s af et y st u d y r e p ort of 1 3 -W e e k G L P st u d y i n c y n o m ol g u s m o n k e y s.  
c A v er a g e of m e a n m al e a n d f e m al e D a y 8 5 A U C 0- tl ast of n o n -r e c o v er y a ni m al s fr o m st art of i nf u si o n t o t h e l a st 
m e a s ur e d s a m pli n g ti m e  p oi nt ( 7 d a y)   
d D at a  ar e  fr o m cli ni c al st u d y r e p ort of St u d y C M C S 1 1 0 X 2 1 0 1. 
 
e A U C  a n d C m a x  c al c ul at e d u si n g p o p ul ati o n m e a n c o n c e ntr ati o n pr ofil e si m ul at e d b y t h e p o p ul ati o n P K m o d el 
fr o m M o d eli n g & Si m ul ati o n r e p ort of  St u d y C M C S 1 1 0 X 2 1 0 1.  
2. 4  
R ati o n al e f or c h oi c e of c o m bi n ati o n dr u g s  
Car b o/ ge m w as c h os e n as o n e of s e v eral tre at m e nt re gi m e ns us e d i n a d va n ce d T N B C. A l o w -
m o d eratel y e m et o ge nic d osi n g re gi m e n will b e us e d, w hic h aff or ds t h e a d va nta ge of littl e or 
n o ster oi ds, a tre at m e nt t h at c o ul d p ote ntiall y a cti v ate T A Ms ( Se cti o n 1. 2. 1 ). I n pre cli nic al 
m o d els, c ar b o plati n c o m bi n e d wit h T A M d e pleti n g dr u gs le a d t o e n h a n c e d c h e m ot h era p y 
res p o ns e (D e N ar d o 2 0 1 1 ) 
2. 5  
R ati o n al e f or c h oi c e of c o m p ar at or s dr u g s  
Car b o/ ge m  h as  a  d o c u m e nte d  hi g h  effic a c y  i n  m etastatic  T N B C  a n d  is  o n e  of  t h e  
re c o m m e n d e d tre at m e nt o pti o ns i n t h e first-li n e m etastatic s etti n g (O’ S h a u g h n ess y 2 0 1 1, 
N C C N 2 0 1 4, E S M O 2 0 1 4 ). 
3 
O bj e cti v e s a n d e n d p oi nt s  
O bje cti v es a n d relate d e n d p oi nts are d es cri be d i n Ta ble 3 - 1 b el o w.  

N o v artis  
C o nfi d e nti al  
P a g e 4 8  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol N o. C M C S 1 1 0 Z 2 2 0 1  
 
T a bl e 3- 1 
O bj e cti v e s a n d r el at e d e n d p oi nt s  
O bj e cti v e  
E n d p oi nt  
A n al y si s  
Pri m ar y  
 
R ef er t o  S e cti o n 1 0. 4  
T o a s s e s s t h e a nti -t u m or a cti vit y of M C S 1 1 0  c o m bi n e d wit h 
c ar b o pl ati n/ g e m cit a bi n e ( c ar b o/ g e m) c o m p ar e d t o c ar b o/ g e m al o n e  
P F S  a s p er R E CI S T  v 1. 1 ( b y l o c al i n v e sti g at or a s s e s s m e nt)  
 
S e c o n d ar y  
 
R ef er t o  S e cti o n 1 0. 5  
C h ar a ct eri z e  t h e s af et y a n d t ol er a bilit y of M C S 1 1 0  gi v e n i n 
c o m bi n ati o n wit h c ar b o/ g e m  
S af et y:  a d v er s e e v e nt ( A E s), s eri o u s a d v er s e e v e nt s ( S A E s)  
T ol er a bilit y: D o s e i nt err u pti o n s, r e d u cti o n s a n d d o s e i nt e n sit y  
R ef er t o  S e cti o n 1 0. 5. 2   
C h ar a ct eri z e P K  of M C S 1 1 0  w h e n c o m bi n e d wit h c ar b o/ g e m  
S er u m  c o n c e ntr ati o n of fr e e M C S 1 1 0  a n d d eri v e d P K p ar a m et er s  
R ef er t o  S e cti o n 1 0. 5. 3  
C h ar a ct eri z e P K  of c ar b o a n d g e m i n t h e pr e s e n c e a n d a b s e n c e of 
M C S 1 1 0.  
Pl a s m a  c o n c e ntr ati o n of c ar b o pl ati n, g e m cit a bi n e a n d d F d U (t h e 
pri m ar y m et a b olit e of g e m), a n d d eri v e d P K p ar a m et er s  
R ef er t o  S e cti o n 1 0. 5. 3  
C h ar a ct eri z e  P D  eff e ct of M C S 1 1 0  w h e n c o m bi n e d wit h c ar b o/ g e m  
T o t al C S F -I  cir c ul ati n g l e v el s, s er u m C T X-I a n d cir c ul ati n g m o n o c yt es i n 
bl o o d.  
T A M  a n d TI L c o nt e nt i n pr e - a n d p o st -d o s e t u m or bi o p si e s  
R ef er t o  S e cti o n 1 0. 5. 4  
T o a s s e s s t h e a nti -t u m or a cti vit y of M C S 1 1 0  gi v e n i n c o m b i n ati o n 
wit h  c ar b o/ g e m a s m e a s ur e d  b y a d diti o n al effi c a c y m e a s ur e s  
T u m or r e s p o n s e p er R E CI S T v 1. 1 ( b y l o c al i n v e sti g at or a s s e s s m e nt): 
O v er all R e s p o n s e R at e ( O R R), D ur ati o n of R e s p o n s e ( D O R)  a n d 
Cli ni c al B e n efit R at e ( C o m pl et e R e s p o n s e ( C R) +  P arti al R e s p o n s e 
( P R) + Sta bl e Di s e a s e ( S D) ≥ 6 m o nt h s)  
R ef er t o  S e cti o n 1 0. 5. 1  

N o v artis  
C o nfi d e nti al  
P a g e 4 9  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol N o. C M C S 1 1 0 Z 2 2 0 1  
 
4 
St u d y d e si g n  
4. 1  
D e s cri pti o n of st u d y d e si g n  
T his is a p h as e II, ra n d o miz e d ( 2: 1), t w o -ar m, o pe n -la b el m ulti-c e nter, st u d y of p atie nts wit h 
a d v a n c e d T N B C ( Se cti o n 5. 2 ). 
Fi g ur e 4- 1 
O v er vi e w of st u d y d e si g n  
 
A n e arl y s af et y re vie w m e eti n g will ta k e pla c e w h e n 9 p atie nts h a v e b e e n ra n d o miz e d  a n d 
c o m plete d  2 c y cles of eit h er M C S 1 1 0 + c ar b o/ ge m or c ar b o/ ge m al o n e, or dis c o nti n u e d 
e arlier d u e t o a n a d v ers e e v e nt. If t h e d osi n g re gi m e n is c h a n ge d at t his ti m e, a n ad diti o n al 
s af et y re vie w of  t he n e w d osi n g  re gi m e n will ta k e pla c e after 9 p atie nts h a v e b e e n ra n d o mize d 
a n d c o m plete d 2 c y cles of M C S 1 1 0 ( p er t h e n e w d osi n g re gi m e n)  + c ar b o/ ge m or c ar b o/ g e m 
al o n e , or dis c o nti n u ed e arlier d u e t o a n a d v ers e e v e nt. A n y s u bs e q u e nt M C S 1 1 0 c h a n g e s of 
t h e d osi n g re gi m e n will b e f oll o w e d b y a n a d diti o n al s af et y re vie w p er t h e pr o c e d ure j ust 
d es cri b e d.   
N o v artis cli nic al te a m a n d pri n ci p al i n v esti gat ors will ass ess cli nic al, P K a n d la b orat o r y d a t a 
of all p at ie nts h a vi n g re c ei v e d a n y tre at m e nt i n t h e st u d y b ef ore e a c h of t h e m e eti n g(s) t o 
d e ci d e o n t h e s u bs e q u e nt M C S 1 1 0 d os e re gi m e n. O n e of t h e f oll o wi n g d osi n g alter n ati v es 
will b e c h os e n:  
•  If n o s af et y c o n cer ns are n ote d d uri n g t h e s af et y re vie w a n d t h e o bs er v e d dr u g e x p os ure is 
wit hi n t h at o bs er v e d i n c y n o m ol g us m o n k e ys a n d/ or H V ( Ta ble 2 - 1), t h e n t h e s a m e 
M C S 1 1 0 d os e will b e c o nti n u e d.  
•  If s af et y c o n c er ns are n ote d, t h e n t h e M C S 1 1 0 d os e will b e re d u c e d (fr o m 1 0 m g/ k g t o 5 
m g/ k g, or fr o m 5 m g/ k g t o 2. 5 m g/ k g)  a n d t h e a d ditio n al d os e of M C S 1 1 0 o n C 1 D 8 m a y  
b e o mitte d , after re vie w wit h t h e Ste eri n g C o m mitte e (s e e Se cti o n 8. 5 ). 
O n c e a d os i n g re gi m e n is a gre e d u p o n after t h e s afet y re vie w m e eti n g(s), all t h e s u b s e q u e nt  
p atie nts ra n d o miz e d t o Ar m 1 will re c ei v e t h e c o nfir m e d d os e . T h e st u d y will c o n ti n u e u ntil 

N o v artis  
C o nfi d e nti al  
P a g e 5 1  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol N o. C M C S 1 1 0 Z 2 2 0 1  
 
5  
P o p ul ati o n 
5. 1  
P ati e nt p o p ul ati o n  
W o m e n wit h a d v a n c e d ( m etastatic or l o c all y a d va nc e d B C n ot a m e n a ble t o c urati v e tre at m e nt 
b y s ur ger y or ra di ot h era p y) T N B C will b e  c o nsi d ere d f or p artici p ati o n i n t his st u d y. All 
p atie nts will h a v e a n e wl y o btai n e d t u m or s a m ple ta k e n fr o m a n a p pr o priate t u m or site  at t h e 
pre- s cre e ni n g visit. T h e t u m or s a m ple will b e ass ess e d re gar di n g T A M c o nte nt. O nl y p atie nts 
w h os e t u m ors h a v e a hi g h c o nte nt of T A Ms will b e e nr olle d i n t h e tre at m e nt p art of t h e st u d y.  
T h e i n v esti gat or or d esi g n e e m ust e ns ure t h at o nl y p atie nts w h o m e et all t h e f oll o wi n g 
i n cl usi o n a n d n o n e of t h e e x cl usi o n criteria are offere d tre at m e nt i n t h e st u d y.  
5. 2  
I n cl u si o n criteri a  
Patie nts eli gi ble f or i n cl usi o n i n t his st u d y h a v e t o m e et all  of t h e f oll o wi n g criteria:  
Writte n i nf or m e d c o ns e nt m ust b e o btai ne d pri or t o a n y s cre e ni n g pr o c e d ures.  
1.  A d ult w o m e n ( ≥ 1 8 y e ars of a ge) wit h a d v a n c e d T N B C.  
2.  Hist ol o gic al or c yt ol o gic al e vi d e n c e of estr o ge n -rec e pt or n e gati v e ( E R-), pr o gester o n e 
re c e pt or n e gati v e ( P g R-) a n d h u m a n e pi d er m al gr o wt h f a ct or-2 re c e pt or n e gati v e ( H E R 2 -) 
B C b y l o c al la b orat or y testi n g, b as e d o n last a v aila ble t u m or tiss u e.  
•  E R/ P g R  n e gati vit y t o f oll o w l o c al g ui d eli n es  
•  If I H C H E R 2 2 +, a n e gati v e FI S H test is re q uire d  
3.  A pre -tre at m e nt t u m or bi o ps y d e m o nstrati n g hi g h T A M c o nte nt as ass ess e d p er t h e c e ntral 
la b orat or y  
4.  Ra di ol o gic al or o bje cti v e e vi d e nc e of re c urre n ce or pr o gressi o n pri or t o e nr oll m e nt  
5.  Pati e nts m ust h a v e: 
•  At le ast o n e m e a s ura ble lesi o n p er R E CI S T 1. 1. ( N ote: Me as ura ble lesi o ns i n cl u de 
l ytic or mi x e d (l ytic + blastic) b o n e lesi o ns, wit h a n i d e ntifia ble s oft tiss u e c o m p o ne nt 
t h at m e ets t h e m e as ura bilit y criteria) 
or  
•  B o n e lesi o ns: n o n -m e as ura bl e l ytic or mi x e d (l ytic +blastic ) i n t h e a bs e n c e of 
m e as ura ble dis e as e as d efi ne d a b o ve. Patie nts wit h o nl y n o n -m eas ura ble lesi o ns (e. g. 
ple ural eff usi o n, as cites) a n d n o l ytic or mi x e d b o ne lesi o ns are n ot eli gi ble.  
6.  E C O G Perf or m a n c e Stat us 0 - 2 
7.  Patie nts m u st si g n i nf or m e d c o ns e nt b ef ore a n y st u d y-s p ecific m ole c ular pre-s cre e ni n g 
a n d s cre e ni n g pr o c e d ures 
5. 3  
E x cl u si o n crit eri a  
Patie nts eli gi ble f or t his st u d y m ust n ot m e et a n y  of t h e f oll o wi n g criteria:  
1.  Pri or c h e m ot h era p y f or a d va n ce d B C. Pre vi o us a dj u va nt/ n e oa dj u v a nt c h e m ot hera p y is 
all o w e d  (car b o plati n, cis plati n or ge m cita bi n e o nl y  if > 1 2 m o nt hs h as p ass e d si n c e last 
a d mi nistrati o n ). 
N ote : A c h e m ot h era p y li n e o nl y c o u nts if b ei n g gi v e n f or ≥ 2 1 d a ys.  

N o v artis  
C o nfi d e nti al  
P a g e 5 2  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol N o. C M C S 1 1 0 Z 2 2 0 1  
 
2.  K n o w n h y p ers e nsiti vit y t o c ar b o plati n, cis plati n, ge m cita b i n e, M C S 1 1 0 or ot h er 
m o n o cl o n al a nti b o dies . A n ot her m ali g n a nc y wit hi n t hre e y e ars pri or t o si g ni n g of 
i nf or m e d c o ns e nt, wit h t h e e x c e pti o n of a d e q u atel y tre ate d i n sit u c arci n o m a of a n y t y p e, 
b as al or s q u a m o us c ell s ki n c a n cer, a n d a n y m ali g n a n c y c o nsi d ere d t o b e i n d ole nt a n d 
t h at h as n e v er re q uire d t h era p y. Patie nts wit h a sta ble m ali g n a n c y m a y b e c o nsi dere d f or 
i n cl usi o n after dis c ussi o n wit h t h e s p o ns or 
3.  Patie nts wit h a pri m ar y C N S t u m or or C N S t u m or i n v ol v e m e nt. H o w e ver, p atie nts wit h 
m etastatic C N S t u m ors m a y p artici p ate i n t his st u d y if  t h e p atie nt is: 
•  N e ur ol o gic all y sta ble  
•  D o es n ot re q uire ster oi ds  
•  H as re c o v ere d fr o m l o c al tre at m e nt s u c h as ra diati o n a n d/ or s ur ger y.  
4.  T h era p y f or u n derl yi n g m ali g n a n c y wit hi n 2 w e e ks pri or t o start of st u d y tre at m e nt: 
•  C h e m ot h era p y, bi ol o gic t h era p y (a nti b o dies a n d bi ol o gic all y tar gete d s m all 
m ole c ules)  
•  Ra di ot h era p y  
•  Maj or s ur ger y  
5.  Pres e n c e of ≥ C T C A E gra d e 2 t o xicit y (e x c e pt al o p ecia d u e t o pri or c a n c er t h era p y).  
6.  Patie nts re c ei vi n g c o n c o mita nt i m m u n os u p pressi v e a ge nts or c hr o nic c ortic oster oi ds 
( ≥1 0 m g of  pre d nis o ne  or e q ui vale nt) at t h e ti m e of first d os e of st u d y dr u g.  
7.  Se v ere a n d / or u n c o ntr olle d m e dical c o n diti o ns t h at i n t h e i n v esti gat or’s o pi ni o n c o ul d 
aff e ct t h e s afet y of t h e i n di vi d u al or i m p air t h e ass ess m e nt of st u d y res ult.  
8.  Cli nic all y si g nific a nt c ar di o v asc ular dis e as e s u c h as u n c o ntr olle d or s y m pt o matic 
arr h yt h mias, c o n gesti v e h e art f ail ure, or m y oc ar dial i nf arcti o n wit hi n 6 m o nt hs of 
s cre e ni n g. 
9.  K n o w n hist or y of h u ma n i m m u n o d eficie nc y vir us or a cti v e i nf ecti o n wit h h e p atitis vir us 
or a n y u n c o ntr olle d a cti v e s yste mic i nf ecti o n.  
1 0.  Patie nts wit h t h e f oll o wi n g la b orat or y v al u es d uri n g s cre e ni n g a n d o n D a y 1 pre -d os e:  
•  A bs ol ute N e utr o p hil C o u nt ( A N C) < 1. 5 x 1 0 9/ L 
•  H e m o gl o bi n < 9 g/ d L  
•  Platelets < 1 0 0 x 1 0 9/ L 
•  Ser u m cre ati ni n e > 1. 5 x U L N  
•  Ser u m t otal bilir u bi n > 1. 5 x  U L N  
•  A S T/ S G O T a n d A L T/ S G P T  > 3. 0 x U L N  
1 1.  Patie nts u n willi n g or u n a ble t o c o m pl y wit h t h e pr ot o c ol.  
1 2.  Partici p ati o n i n p arallel i n v esti gati o n al dr u g or d e vic e st u dies  
1 3.  Pre g n a nt or n ursi n g (la ctati n g) w o m e n, w h ere pre g n a n c y is d efi ne d as t h e state of a 
f e m ale after c o nc e pti o n a n d u ntil t h e ter mi n ati o n of gestati o n, c o nfir me d b y a p ositi v e 
h C G la b orat or y test.  
1 4.  W o m e n of c hil d -b e ari n g p ote ntial, d efi n e d as all w o m e n p h ysi ol o gic all y c a p a ble of 
b e c o mi n g pre g n a nt, u nless t h e y are usi n g hi g hl y effecti v e m et h o ds of c o ntra ce pti o n 
d uri n g d osi n g of st u d y tre at m e nt a n d f or  9 0  d a ys after t h e last d os e of M C S 1 1 0  or f or  3 0 

N o v artis  
C o nfi d e nti al  
P a g e 5 3  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol N o. C M C S 1 1 0 Z 2 2 0 1  
 
d a ys after t h e last d os e of c ar b o plati n a n d ge m cita bi n e or as re c o m m e n d e d p er t h e l o c al 
a p pr o v e d la b els f or c ar b o plati n a n d ge m cita bi n e, w hic h e v er h as t h e l o n gest d urati o n . 
Hi g hl y Eff e cti v e c o ntra ce pti o n m et h o ds  i n cl u d e: 
•  T otal a bsti n e n c e ( w h e n t his is i n li n e wit h t h e pref erre d a n d us u al lif est yle of t h e 
s u bje ct. Peri o dic a bsti n e n ce (e. g., c ale n dar, o v ulati o n, s y m pt ot her m al, p ost-o v ulati o n 
m et h o ds) a n d wit h dra w al are n ot a c c e pta ble m et h o ds of c o ntra ce pti o n  
•  Fe m ale steriliz ati o n ( h a v e h a d s ur gic al bilateral o o p h orect o m y wit h or wit h o ut 
h ystere ct o m y) , t otal h ystere ct o m y or t u b al li gati o n at le ast si x w e e ks b ef ore ta ki n g 
st u d y tre at m e nt. I n c as e of o o p h ore ct o m y al o n e, o nl y w h e n t h e re pr o d ucti v e stat us of 
t h e w o m a n h as b e e n c o nfir m e d b y f oll o w u p h or m o ne le v el ass ess m e nt  
•  Male steriliz ati o n (at le ast 6 m o nt hs pri or t o s cre e ni n g). F or f e m ale s u bje cts o n t h e 
st u d y, t h e v as e ct o miz e d m ale p art ner s h o ul d b e t h e s ole p art n er f or t h at s u bje ct  
•  Us e of oral, i nje cte d or i m pla nte d h or m o nal m et h o ds of c o ntra c e pti o n or pla c e me nt of 
a n i ntra uteri n e d e vic e (I U D) or i ntra uteri n e s yste m (I U S), or ot h er  
f or ms of h or m o n al c o ntra ce pti o n t h at h a v e c o m para ble effic a c y (f ail ure rate < 1 %), f or 
e x a m ple h or m o ne v a gi n al ri n g or tra ns d er m al h or m o n e c o ntra ce pti o n.  
I n c as e of us e of oral c o ntra c e pti o n w o m e n s h o ul d h a v e b e e n sta ble o n t h e s a m e pill f or a 
mi ni m u m of 3 m o nt hs b ef ore ta ki n g st u d y tre at m e nt.  
W o m e n are c o nsi d ere d p ost -m e n o p a us al a n d n ot of c hil d b e ari n g p ote ntial if t h e y h a v e h a d 1 2 
m o nt hs of n at ur al (s p o nta n e o us) a m e n orr h e a wit h a n a p pr o priate cli nic al pr ofile (e. g. a ge 
a p pr o priate, hist or y of v as o m ot or s y m pt o ms) or h a v e h a d s ur gic al bilateral o o p h ore ct o m y 
( wit h or wit h o ut h ystere ct o m y), t otal h ysterect o m y or t u b al li gati o n at le ast si x w e e ks a g o . I n 
t h e c as e of o o p h ore ct o m y al o ne, o nl y w h e n t h e re pr o d u cti v e stat us of t h e w o m a n h a s b e e n 
c o nfir m e d b y f oll o w u p h or m o n e le v el ass ess m e nt is s h e c o nsi d ere d n ot of c hil d b e ari n g 
p ote ntial.  
6  
Tr e at m e nt 
6. 1  
St u d y tr e at m e nt  
T h e i n v esti gati o n al dr u g ref ers t o M C S 1 1 0, t h e N o v artis C S F -1 re c o m bi n a nt h u m a niz e d 
m o n o cl o n al a nti b o d y. T h e I n v esti gati o n al tre at m e nt ref ers t o c ar b o/ ge m wit h or wit h o ut 
M C S 1 1 0.  
6. 1. 1  
D o si n g r e gi m e n  
T a bl e 6- 1 
D o s e a n d tr e at m e nt s c h e d ul e  
St u d y Dr u g & 
C o m bi n ati o n 
tr e at m e nt s 
P h ar m a c e uti c al  f or m a n d 
r o ut e of a d mi ni str ati o n 
D o s e  
Fr e q u e n c y a n d/ or R e gi m e n  
M C S 1 1 0  
I ntr a v e n o u s i nf u si o n 
1 0 m g/ k g  ,5 m g/ k g  or 
2. 5 m g/ k g  
D a y 1, wit h or wit h o ut 
a d diti o n al d o s e at C 1 D 8  
G e m cit a bi n e  
I ntr a v e n o u s i nf u si o n 
1 0 0 0 m g/ m 2 
D a y s 1 & 8  
C ar b o pl ati n  
I ntr a v e n o u s i nf u si o n 
A U C 2  
D a y s 1 & 8  

N o v artis  
C o nfi d e nti al  
P a g e 5 4  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol N o. C M C S 1 1 0 Z 2 2 0 1  
 
After re vie wi n g t h e  cli nic al,  P K  a n d  la b orat or y  d ata  o btai n e d  fr o m  t h e  s af et y  re vie w  
m e eti n g s, t h e M C S 1 1 0 d os e m a y b e re d u c e d, a n d/ or t h e a d diti o n al d os e o n  C 1 D 8 m a y b e 
o mitte d.  (Se cti o n 2. 2  a n d Se cti o n 4. 1 ). T h e d os es of M C S 1 1 0, c ar b o/ ge m will b e c alc ulate d o n 
D a y  1  at e a c h  c y cle.  T h e  c alc ulati o ns will b e b as e d o n w ei g ht f or M C S 1 1 0, cre ati ni n e 
cle ara n c e (a c c or di n g t o i nstit uti o n al g ui d eli n es) f or c ar b o a n d b o d y s urfa c e are a f or ge m.  
A p h ar m a c y m a n u al will b e pr o vi d e d wit h d etails a b o ut h o w t o a d mi nister M C S 1 1 0 . 
Fi g ur e 6- 1 
St u d y Dr u g A d mi ni str ati o n  
 
6. 1. 2  
A n cill ar y tr e at m e nt s  
6. 1. 2. 1  A n cill ar y tr e at m e nt s f or M C S 1 1 0  
T h e m ost c o m m o n si d e -effe cts fr o m M C S 1 1 0 i n cl u de p eri or bital e d e m a a n d C K el e v ati o n, 
b ot h of w hic h d o n ot re q uire a n y tre at m e nt.  
Mil d i nf usi o n re a cti o ns w ere re p orte d i n 2 p atie nts w h ere all s y m pt o ms ( diz zi n ess, c hills, 
h y p ote nsi o n) res ol v e d wit hi n 1 h o ur . O n e p atie nt w as re-c h alle n ge d wit h M C S 1 1 0 a n d di d n ot 
h a v e a n y i nf usi o n re a cti o ns d uri n g s u bs e q u e nt i nf usi o ns. Patie nts s h o ul d b e m o nit ore d f or 
h y p ers e nsiti vit y  re a cti o ns  a c c or di n g  t o  l o c al  g ui d eli n es.  A p pr o priate  tre at m e nt  f or  
h y p ers e nsiti vit y re a cti o ns  s h o ul d b e a v aila ble at b e dsi d e a n d a p h ysicia n re a dil y a v aila ble. 
Pr o p h yla xis t o pre v e nt i nf usi o n re a cti o ns is o nl y re c o m m e n d e d f or s u bs e q u e nt d os es i n 
p atie nts w h o pre vi o usl y e x p erie n ce d a n i nf usi o n re a cti o n t o M C S 1 1 0.  
6. 1. 2. 2  
A n cill ar y tr e at m e nt s f or c ar b o pl ati n  a n d g e m cit a bi n e  
6. 1. 2. 2. 1  N a u s e a  
A l o w -d os e c ar b o plati n d osi n g re gi m e n will b e us e d wit h a l o w t o m o d erate ris k  f o r e  m e sis. 
All p atie nts s h o ul d re c ei v e a nti -e m etic pre- a n d p ost-m e dic ati o n a c c or di n g t o l o c al g ui d eli n es, 

N o v artis  
C o nfi d e nti al  
P a g e 5 5  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol N o. C M C S 1 1 0 Z 2 2 0 1  
 
b ut ster oi ds s h o ul d b e us e d wit h m o d erati o n. T h e t otal ster oi d d ose p er tre at m e nt c y cle s h o ul d 
n ot e x c e e d 1 6 m g of d e x a met h as o ne or e q ui v ale nt.  
6. 1. 2. 2. 2  H y p er s e n siti vit y  r e a cti o n s 
H y p ers e nsiti vit y  re a cti o ns  c a us e d  b y  c ar b o plati n  h a v e  b e e n  re p orte d,  b ut  are  rare.  
Pre m e dic ati o n t o pre v e nt h y pers e nsiti vit y re a cti o ns is n ot re c o m m e n de d, b ut m a y b e us e d p er 
l o c al re c o m m e n d ati o n. Pr o p h ylactic ster oi ds s h o ul d b e a v oi d e d. 
6. 1. 3  
Tr e at m e nt d ur ati o n  
Patie nt m a y c o nti n u e tre at m e nt wit h t h e st u d y dr u g u ntil p atie nt e x p erie n c es u n a c c e pta ble 
t o xicit y,  dis e as e  pr o gressi o n  a n d/ or  tre at m e nt  is  dis c o nti n u e d  at  t h e  dis creti o n  of  t h e  
i n v esti gat or  or  t h e p atie nt. Patie nts w h o h a v e dis e as e pr o gressi o n  a n d h a v e e vi d e n c e of 
cli nic al b e n efit, s u c h as dis e as e s hri n k a ge at ot h er sites or s y m pt o m atic i m pr o v e m e nt, m a y 
c o nti n u e st u d y tre at m e nt.  
6. 2  
D o s e m o difi c ati o n s  
6. 2. 1  
D o s e m o difi c ati o n a n d d o s e d el a y  
F or  p atie nts  w h o  are  u n a ble  t o  t olerate  t h e  pr ot o c ol -s p e cifie d  d osi n g  s c h e d ule,  d os e  
a dj ust m e nts a n d a p pr o priate s u p p orti v e t h era pies are p er mitte d. T h e f oll o wi n g g ui d eli n es 
s h o ul d b e f oll o w e d a n d t h es e c h a n ges m ust b e re c or d e d o n t h e D os a ge A d mi nistrati o n Re c or d 
e C R F. 
T h e criteria f or d os e m o dificati o ns of t h e st u d y tre at m e nt f or t o xicities c o nsi d ere d  s u s p e ct e d 
t o  b e  relate d (s us p e cte d  i n cl u d es p ossi bl y, pr o b a bl y  or d efi nitel y  relate d) t o  t h e st u d y 
m e dic ati o n tre at m e nt  are o utli n e d i n Ta ble 6 - 2, Ta ble 6 - 3 a n d Ta ble 6 - 4. St u d y t re at m e nt m a y 
b e d ela y e d b y ≤ 1 w e e k fr o m t h e e x pe cte d d a y of t h e n e xt st u d y tre at m e nt a d mi nistra ti o n f or 
a n y  re as o n.  I f st u d y tre at m e nt c a n n ot b e gi v e n wit hi n t his ti m e fra m e d u e t o p ersisti n g 
t o xicit y, t h e d os e s h o ul d b e s ki p p e d. Patie nts re q uiri n g a d os e d ela y of > 3 w e e ks f or a st u d y 
tre at m e nt relate d t o xicit y s h o ul d b e dis c o nti n u e d fr o m t h e st u d y tre at m e nt. If t h e p atie nt is 
cle arl y b e n efiti n g fr o m t h e st u d y tre at m e nt a n d i n t h e o pi ni o n of t h e i n v esti gat or it is i n t h e 
p atie nt’s b est i nterest t o c o nti n u e t h e st u d y tre at m e nt, after dis c ussi o n wit h N o v artis, t h e 
p atie nt m a y re m ai n o n st u d y tre at m e nt. Patie nts w h o dis c o nti n ue fr o m t h e st u d y f or a st u d y 
dr u g -relate d A E or a n a b n or m al la b orat or y v al u e m ust b e f oll o w e d as d es cri be d i n Se cti o n 8 .  
If, after i nterr u pti o n of t h e st u d y tre at m e nt a n d res ol uti o n, t h e st u d y tre atm e nt is r e s u m e d at 
t h e s a m e d os e f oll o wi n g t h e criteria i n Ta ble 6 - 2, Ta ble 6 - 3, Ta ble 6 - 4 a n d t h e s a m e t o xi cit y 
re o c c urs wit h t h e s a m e or w ors e s e v erit y, t h e d os e of t h e c h e m ot h era p y a n d/ or M C S 1 1 0  
s h o ul d b e re d u c e d  as f oll o ws . T h e c h e m ot hera p y c a n b e d os e re d u ce d b y 2 d os e le v els ; -2 0 % 
a n d -4 0 %  of t h e ori gi n al d os e  w h ereas  M C S 1 1 0  c a n b e d os e r e d u ce d b y 3, 2 or 1  d os e l e v el s 
d e p e n di n g o n t h e starti n g d os e (fr o m 1 0 m g/ k g t o 5 m g / k g t o 2. 5 m g/ k g t o 1 m g/ k g, or fr o m 5 
m g/ k g t o 2. 5 m g/ k g  t o 1 m g/ k g, or fr o m 2. 5 m g/ k g t o 1 m g/ k g). 
F or e a c h p atie nt, o n c e a d os e le v el re d u cti o n h as o c c urre d, t h e d os e le v el m ust n ot b e re -
es c alate d d uri n g s u bs e q u e nt tre at m e nt c y cles. If m ore t h a n 2 d ose re d ucti o ns of c ar b o  a n d/ or  
ge m , or M C S 1 1 0  d os es b el o w 1. 0  m g/ k g, are n e e d e d , t h e res p e cti v e st u d y dr u g(s) will b e 

N o v artis  
C o nfi d e nti al  
P a g e 5 6  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol N o. C M C S 1 1 0 Z 2 2 0 1  
 
dis c o nti n u e d . Patie nts w h o dis c o nti n ue d 1 or 2 dr u gs i n t h e Ar m 1 re gi m e n or 1 dr u g o nl y i n 
t h e Ar m 2 re gi m e n d u e t o t o xicit y m a y c o nti n u e wit h t h e re m ai n d er of dr u gs assi g n e d at 
ra n d o miz ati o n u p o n dis c ussi o n wit h t h e N o v artis Me dic al M o nit or. 
T h e i nter v al of M C S 1 1 0 i nf usi o n s h o ul d b e pr ol o n ge d b y  u p t o 1 w e e k t o c o or di n ate wit h a n y 
d ela y e d c h e m ot h era p y tre at m e nt. If c h e m ot h era p y is d ela y e d m ore t h a n 1 w e e k, b ut less t h a n 
3 w e e ks, i n v esti gat ors s h o ul d dis c uss wit h N o v artis h o w t o re -start a n d c o or di n at e tr e at m e nt 
i n t h e i n v esti gati o n al tre at m e nt ar m.  
6. 2. 1. 1   
Do s e m o difi c ati o n s a n d a cti o n f or t o xi citi e s s u s p e ct e d t o b e r el at e d t o 
st u d y tr e at m e nt  
T a bl e 6- 2 
D o s e m o difi c ati o n s a n d a cti o n f or t o xi citi e s s u s p e ct e d t o b e r el at e d t o 
M C S 1 1 0 
T o xi cit y  
C T C A E Gr a d e  
A cti o n  
C K el e v ati o n  
Gr a d e ≥3  
( C K > 5 x U L N) 
M o nit or C K -M B, tr o p o ni n (I or T) a n d cr e ati ni n e . 
● If C K -M B  a n d  tr o p o ni n (I or T) ar e n or m al , cr e ati ni n e < 1. 5 x 
b a s eli n e a n d p ati e nt a s y m pt o m ati c, m ai nt ai n d o s e l e v el.  
● If C K -M B  a n d  tr o p o ni n (I or T ) ar e a b n or m al or  cr e ati ni n e ( > 1 . 5 x 
b a s eli n e a n d >  U L N) or p ati e nt s y m pt o m ati c, wit h h ol d dr u g s a n d 
e x pl or e alt er n ati v e c a u s e s f or el e v at e d C K  (f or e x a m pl e m y o siti s a n d 
r h a b d o m y ol y si s) a c c or di n g t o l o c al g ui d eli n e s.  
Aft er r e c o v er y of C K -M B,  tr o p o ni n (I or T) a n d cr e ati ni n e t o Gr a d e 1 
or b a s eli n e, st u d y tr e at m e nt m a y b e r e s u m e d : c h e m ot h er a p y at  
pr e vi o u s d o s e s a n d M C S 1 1 0 at 5 0 % a of t h e pr e vi o u s  d o s e   
P eri or bit al 
e d e m a  
Gr a d e ≥3  
( s e v er e) 
H ol d M C S 1 1 0.  
C o n s ult ati o n of a n o p ht h al m ol o gi st m a y b e  c o n si d er e d b y  t h e 
i n v e sti g at or. 
Aft er  r e c o v er y t o Gr a d e 1 or b a s eli n e, M C S 1 1 0  m a y b e  r e s u m e d at 
5 0 % a of t h e pr e vi o u s  d o s e.   
H e p ati c  
Gr a d e ≥ 3  
(t ot al bilir u bi n > 3 x U L N 
or  A L T > 5 x U L N ) 
 
or  
 
t ot al bilir u bi n  gr a d e ≥ 2 
wit h A L T gr a d e ≥ 2  
H ol d st u d y tr e at m e nt (i n cl u di n g c h e m ot h er a p y) u ntil r e s ol v e d t o ≤ 
Gr a d e 1  or b a s eli n e.  
Aft er r e c o v er y st u d y tr e at m e nt m a y b e r e s u m e d p er t h e i n v e sti g at or’ s 
di s cr eti o n: c h e m ot h er a p e uti c a g e nt s r e d u c e d b y 2 0 % a n d M C S 1 1 0 
b y 5 0 % a of t h e pr e vi o u s d o s e.   
 
E n d tr e at m e nt  a n d di s c o nti n u e p ati e nt fr o m st u d y.  
I nf u si o n 
r el at e d 
r e a cti o n 
Gr a d e 1  
(tr a n si e nt fl u s hi n g or 
r a s h, dr u g f e v er < 3 8° C/  < 
1 0 0. 4° F)  
Sl o w d o w n i nf u si o n r at e t o 5 0 %  of pr e vi o u s r at e.  
C o n si d er pr e m e di c ati o n at s u b s e q u e nt i nf u si o n s wit h a nti -hi st a mi n e 
( di p h e n h y dr a mi n e 5 0 m g or e q ui v al e nt) a n d a c et a mi n o p h e n ( 1 g).  
P ati e nt s m u st b e o b s er v e d f or at l e a st 3 h o ur s aft er e a c h s u b s e q u e nt 
i nf u si o n b ef or e di s c h ar g e. 
 
Gr a d e 2  
(fl u s hi n g, r a s h, urti c ari a, 
d y s p n e a,  
dr u g f e v er 
≥3 8. 5° C/ ≥1 0 1. 3° F)  
I nt err u pt t h e i nf u si o n of M C S 1 1 0. 
A d mi ni st er a nti -hi st a mi n e s or c orti c o st er oi d s.  
Aft er  r e c o v er y of s y m pt o m s, r e s u m e i nf u si o n at a sl o w e r r at e ( 5 0 % of 
pr e vi o u s r at e). If n o f urt h er s y m pt o m s a p p e ar, c o m pl et e t h e 
a d mi ni str ati o n.  
P ati e nt s m u st b e o b s er v e d f or at l e a st 3 h o ur s aft er e a c h s u b s e q u e nt 
i nf u si o n b ef or e di s c h ar g e. 
 
Gr a d e 3  
( s y m pt o m ati c 
br o n c h o s p a s m, w/ w o 
urti c ari a b; all er g y- r el at e d 
e d e m a/ a n gi o -e d e m a; 
I m m e di at el y st o p M C S 1 1 0  i nf u si o n a n d di s c o nti n u e p ati e nt fr o m 
st u d y.  
A d mi ni st er a nti -hi st a mi n e s or c orti c o st er oi d s. E pi n e p hri n e c a n b e 
i n di c at e d w h e n w h e e zi n g a n d 
a n a p h yl a xi s of a c ut e lif e -t hr e at e ni n g n at ur e i s pr e s e nt b ut s h o ul d b e 

N o v artis  
C o nfi d e nti al  
P a g e 5 7  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol N o. C M C S 1 1 0 Z 2 2 0 1  
 
T o xi cit y  
C T C A E Gr a d e  
A cti o n  
h y p ot e n si o n c) a n d  
Gr a d e 4  ( a n a p h yl a xi s d) 
c h o s e n c a uti o u sl y.  
P ati e nt s m u st b e  o b s er v e d a s p er l o c al g ui d eli n e s b ef or e di s c h ar g e.  
Ot h er s 
( e x c e pt f or 
f ati g u e a n d 
al o p e ci a)  
Gr a d e ≥ 3  
H ol d M C S 1 1 0.  
Aft er  r e c o v er y t o Gr a d e ≤1  or b a s eli n e, M C S 1 1 0  m a y b e  r e s u m e d at 
5 0 % a of t h e pr e vi o u s  d o s e . 
aE x c e pt f or d o s e r e d u cti o n s of M C S 1 1 0  d o s e of 2. 5  m g/ k g: i n t hi s c a s e, t h e d o s e will b e r e d u c e d t o M C S 1 1 0  1 
m g/ k g
 
b Urti c ari a wit h m a nif e st ati o n s of all er gi c or h y p er s e n siti vit y r e a cti o n i s gr a d e d a s All er gi c  
r e a cti o n/ h y p er s e n siti vit y. 
c D efi n e d b y a s y st oli c pr e s s ur e dr o p  ≥ 3 0 m m  H g  
d D efi n e d a s v a s c ul ar c oll a p s e a n d s h o c k ( bl o o d pr e s s ur e < 9 0  m m  H g, u nr e s p o n si v e t o I V fl ui d s) b eli e v e d t o b e 
all er gi c i n ori gi n, wit h or wit h o ut a nt e c e d e nt r e s pir at or y di str e s s a n d o c c urri n g wit hi n 3 0 mi n ut e s of i niti ati o n of 
M C S 1 1 0  i nf u si o n.  C ut a n e o u s m a nif e st ati o n s i n cl u d e pr urit u s, urti c ari a or a n gi o e d e m a.  
T a bl e 6- 3 
D o s e m o difi c ati o n s f or h e m at ol o gi c al t o xi citi e s s u s p e ct e d t o b e 
r el at e d t o c ar b o/ g e m 
T o xi cit y  
A E  
A cti o n  
H e m at ol o gi c al t o xi cit y a 
D 1 b of e a c h c y cl e  
n e utr o p e ni a  
or  
t hr o m b o c yt o p e ni a  
A N C < 1. 0 x 1 0 9/ L 
or  
pl at el et s < 1 0 0 x 1 0 9/ L 
H ol d b ot h dr u g s u ntil A N C ≥ 1. 0 x 1 0 9/ L a n d pl at el et s 
≥1 0 0 x 1 0 9/l,  t h e n d eli v er tr e at m e nt. 
Fir st e pi s o d e:  r e d u c e c ar b o pl ati n a n d g e m cit a bi n e b y 
2 0 % of ori gi n al st arti n g d o s e.  
S e c o n d e pi s o d e :  r e d u c e b ot h dr u g s b y 4 0 % of 
ori gi n al st arti n g d o s e.  
D 8 b of e a c h c y cl e  
n e utr o p e ni a  
or  
t hr o m b o c yt o p e ni a  
A N C 0. 7 5 - < 1. 0 x 1 0 9/ L  
or  
pl at el et s 7 5 - < 1 0 0 x 1 0 9/ L  
R e d u c e c ar b o pl ati n a n d g e m cit a bi n e b y 2 0 % of D 1 
d o s e.  
n e utr o p e ni a  
or  
t hr o m b o c yt o p e ni a 
A N C < 0. 7 5 x 1 0 9/ L  
or  
pl at el et s <  7 5 x 1 0 9/ L 
H ol d b ot h dr u g s a n d d o n ot m a k e u p d o s e.  
At  a n y ot h er ti m e p oi nt  
fe bril e n e utr o p e ni a  
A N C < 1. 0 x 1 0 9/l wit h a  si n gl e 
t e m p er at ur e  of > 3 8. 3  º C 
( 1 0 1 º F) or a s u st ai n e d 
t e m p er at ur e  of > = 3 8  º C 
( 1 0 0. 4  º F) f or m or e t h a n o n e 
h o ur.   
Fir st e pi s o d e:  r e d u c e c ar b o pl ati n a n d g e m cit a bi n e b y 
2 0 % of ori gi n al st arti n g d o s e.  
S e c o n d e pi s o d e :  r e d u c e b ot h dr u g s b y 4 0 % of 
ori gi n al st arti n g d o s e.  
 t hr o m b o c yt o p e ni a 
Pl at el et s < 2 5 x 1 0 9/ L  
or  
pl at el et s <  5 0 x 1 0 9/ L wit h 
bl e e di n g  
Fir st e pi s o d e:  r e d u c e c ar b o pl ati n a n d g e m cit a bi n e b y 
2 0 % of ori gi n al st arti n g d o s e.  
S e c o n d e pi s o d e :  r e d u c e b ot h dr u g s b y 4 0 % of 
ori gi n al st arti n g d o s e.  
O t h er s 
Gr a d e ≥ 3  
Fir st e pi s o d e:  r e d u c e c ar b o pl ati n a n d g e m cit a bi n e b y 
2 0 % of ori gi n al st arti n g d o s e.  
S e c o n d e pi s o d e :  r e d u c e b ot h dr u g s b y 4 0 % of 
ori gi n al st arti n g d o s e.  
aA s s o o n a s r e q uir e m e nt s f or h e m at ol o gi c al p ar a m et er s ar e r e a c h e d st u d y tr e at m e nt s h o ul d b e d eli v er e d.  
bD o s e r e d u cti o n s s h o ul d b e p erf or m e d b a s e d o n D 1 or D 8  l a b s, n ot b a s e d o n n a dir c o u nt s of n e utr o p hil s a n d 
pl at el et s , u nl e s s f or t o xi citi e s d e s cri b e d u n d er “ At a n y ot h er ti m e p oi nt” a b o v e.  

N o v artis  
C o nfi d e nti al  
P a g e 5 8  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol N o. C M C S 1 1 0 Z 2 2 0 1  
 
T a bl e 6- 4 
D o s e m o difi c ati o n s f or n o n -h e m at ol o gi c al t o xi citi e s s u s p e ct e d t o b e 
r el at e d t o c ar b o/ g e m 
T o xi cit y  
C T C A E Gr a d e  
A cti o n a 
N o n -h e m at ol o gi c al t o xi cit y  
P n e u m o niti s  
Gr a d e ≥ 2  
( s y m pt o m ati c, m e di c al 
i nt er v e nti o n i n di c at e d) 
Di s c o nti n u e g e m cit a bi n e pr o m ptl y. Tr e at m e nt wit h 
st er oi d s s h o ul d b e i niti at e d a s p er l o c al g ui d eli n e s.  
H e p ati c  
Gr a d e ≥ 3  
(t ot al bilir u bi n > 3 x U L N 
or A L T > 5 x U L N ) 
 
or  
 
t ot al bilir u bi n gr a d e ≥ 2 
wit h A L T gr a d e ≥ 2  
H ol d tr e at m e nt (i n cl u di n g M C S 1 1 0) u ntil r e s ol v e d t o ≤ 
Gr a d e 1  or b a s eli n e. Aft er  r e c o v er y st u d y tr e at m e nt m a y 
b e  r e s u m e d p er t h e i n v e sti g at or’ s di s cr eti o n: 
c h e m ot h er a p e uti c a g e nt s r e d u c e d b y 2 0 % a n d M C S 1 1 0 
b y  5 0 % b of t h e pr e vi o u s d o s e.  
 
E n d tr e at m e nt  a n d di s c o nti n u e p ati e nt fr o m st u d y.  
Ot h er s  
( e x c e pt f or f ati g u e a n d 
al o p e ci a)  
Gr a d e ≥ 3  
Fir st e pi s o d e:  r e d u c e c ar b o pl ati n a n d g e m cit a bi n e b y 
2 0 % of ori gi n al st arti n g d o s e.  
S e c o n d e pi s o d e :  r e d u c e b ot h dr u g s b y 4 0 % of ori gi n al 
st arti n g d o s e.  
aA s s o o n a s r e q uir e m e nt s f or n o n -h e m at ol o gi c al t o xi citi e s ar e Gr a d e < 1  or b a s eli n e, st u d y tr e at m e nt  s h o ul d b e 
d eli v er e d.  
bE x c e pt f or d o s e r e d u cti o n s of M C S 1 1 0  d o s e of 2. 5  m g/ k g: i n t hi s c a s e, t h e d o s e will b e r e d u c e d t o M C S 1 1 0  1 
m g/ k g  
6. 2. 2  
F oll o w -u p t o xi citi e s  
Patie nts w h os e tre at m e nt is i nterr u pte d or p er m a ne ntl y dis c o nti n ue d d ue t o a n a d v er s e e v e nt 
or cli nic all y si g nific a nt la b orat or y v al u e m ust b e f oll o we d u p at le ast o n c e e v er y 7 d a y s ( or 
m ore fre q u e ntl y if re q uire d b y i nstit uti o nal pra ctic es, or if cli nic all y i n di c a t e d) f or 3 0  d a y s, 
a n d s u bs e q u e ntl y at a p pr o xi m atel y 3 0 d a y i nter v als, u ntil res ol uti o n or sta biliz ati o n of t h e 
e v e nt, w hic h e v er c o m es first.  
6. 2. 3  
A nti ci p at e d ri s k s a n d s af et y c o n c er n s  
Se e Se cti o n 1. 4. 3  a n d  Se cti o n 1. 4. 4 .  
6. 3  
C o n c o mit a nt m e di c ati o n s  
6. 3. 1  
P er mitt e d c o n c o mit a nt  t h er a p y  
I n ge n eral, c o n c o mita nt m e dicati o ns a n d t h era pies d ee m e d n e c ess ar y f or t h e s u p p orti v e  c ar e  
(e. g.  s u c h  as  a nti-e m etics,  a nti-diarr h e a)  a n d  s af et y  of  t h e  p atie nt  are  all o w e d.  T h e  
a d mi nistrati o n of bis p h osp h o nates is p er mitte d.  
T h e p atie nt m ust b e t ol d t o n otif y t h e i n v esti gati o n al site a b o ut a n y n e w m e dic ati o ns, h er b al 
re m e dies a n d dietar y su p ple m e nts h e/s h e ta k es after t h e start of  t h e st u d y tre at m e nt. All 
m e dic ati o ns  ( ot h er  t h a n  st u d y  tre at m e nt)  a n d  si g nific a nt  n o n -dr u g t h era pies (i n cl u di n g 
p h ysic al t h era p y, h er b al/ nat ural m e dic ati o ns a n d bl o o d tra nsf usi o ns) a d mi nistere d d uri n g t h e 
st u d y m ust b e liste d o n t h e Pri or a n d C o n c o mita nt Me dic ati o ns or t h e S ur gic al a n d Me dic al 
Pr o c e d ures e C R F. Pri or a nti n e o plastic t h era pies i n cl u di n g m e dic ati o ns, ra di ot h era p y, a n d 
s ur ger y  are  t o  b e  re c or d e d  o n  t h e  s e p arate  Pri or A nti n e o plastic  T h era p y  e C R F d uri n g 

N o v artis  
C o nfi d e nti al  
P a g e 5 9  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol N o. C M C S 1 1 0 Z 2 2 0 1  
 
scre e ni n g. Me dic ati o n e ntries s h o ul d b e s p ecific t o tra d e n a m e, d os e a n d u nit, t h e f r e q u e n c y 
a n d r o ute of a d mi nistrati o n, t h e start a n d dis c o nti n u ati o n d ate a n d t h e re as o n f or t h era p y.  
6. 3. 2  
P er mitt e d c o n c o mit a nt  t h er a p y r e q uiri n g c a uti o n  
A ntic o a g ulati o n is p er mi tte d if t h e p atie nts are alre a d y at sta ble d os es of l o w m ole c ular 
w ei g ht h e p ari n ( L M W H) f or > 2 w e e ks at ti m e of first d os e. H o w e ver, o n g oi n g a ntic o a g ul a nt 
t h era p y  s h o ul d  b e  te m p oraril y  dis c o nti n u e d  t o  all o w  t u m or  bi o ps y  a c c or di n g  t o  t h e  
i nstit uti o n al g ui d eli n es. 
C o n c o mita nt tre at m e nt wit h w arf ari n s o di u m or a n y ot h er c o u m ari n -d eri vati v e a ntic o a g ula nts 
s h o ul d b e c a uti o n e d d u e t o p ote ntial dr u g i ntera cti o n wit h c ar b o plati n.  
Si n c e t h e re n al eff e cts of n e p hr ot o xic c o m p o u n ds m a y b e p ote ntiate d b y c ar b o pl ati n, dr u gs 
wit h n e p hr ot o xicit y s h o ul d b e u s e d wit h c a uti o n. A mi n o gl y c osi d es a n d p h e n yt oi n h a v e b e e n 
re p orte d t o h a v e i ntera cti o n wit h c ar b o plati n a n d s h o ul d b e us e d wit h c a uti o n. C o n c o mit a nt 
a d mi nistrati o n of c ar b o plati n a n d p he n yt oi n m a y c a us e d e cre as ed le v els of s er u m p h e n yt oi n. 
T his m a y le a d t o re a p p e ara n c e of s eiz ures a n d m a y re q uire a n i n creas e of p h e n yt oi n d os a ges.  
Ster oi ds us e d i nter mitte ntl y as a nti -e m etics are all o w e d b ut s h o ul d b e us e d wit h c a uti o n. 
Pref era bl y, ster oi ds s h o ul d o nl y b e a d mi nistere d b ef ore  c h e m ot hera p y tre at m e nt t o mi ni mi z e 
t h e  us e  of  ster oi ds.  T h e  t otal  d os e  p er  tre at m e nt  c y cle  s h o ul d  n ot  e x c e e d  1 6  m g  of  
d e x a m et h as o n e or e q ui v ale nt.  
Stati ns s h o ul d b e us e d wit h c a uti o n si n c e C K ele v ati o ns are c o m m o nl y s e e n.  
6. 3. 3  
Pr o hi bit e d c o n c o mit a nt  t h er a p y  
A n y ot h er a ntic a n c er or i n v esti gati o n al tre at m e nt is n ot p er mitte d w hile o n st u d y tre at m e nt. 
A d diti o n all y, ot h er bi ol o gics (e g: a nti b o dies a n d pr otei ns) a n d i m m u n os u p pressi ve m e dicatio n 
are n ot p er mitte d w hile o n t his st u d y.  
C o n c o mita nt c hr o nic c ortic oster oi ds ( ≥1 0  m g of  pre d nis o n e  or e q ui v ale nt) are n ot all o w e d 
( Se e Se cti o n 5. 3 ). 
Tre at m e nt wit h h e m at o p oietic c ol o n y -sti m ulati n g gr o wt h f a ct ors (e. g. G-C S F, m a y n ot b e 
i nitiate d u nless t h e i n v esti gat or d e e ms it n e c ess ar y. H e m at o p oetic c ol o n y-sti m ulati n g f a c t o r s 
m a y c o u ntera ct t h e effects of M C S 1 1 0.  
T h e us e of li v e v a c ci n es is n ot all o w e d t hr o u g h t h e w h ole d urati o n of t h e st u d y.  
6. 4  
P ati e nt n u m b eri n g, tr e at m e nt a s si g n m e nt or r a n d o mi z ati o n  
6. 4. 1  
P ati e nt n u m b eri n g  
Ea c h p atie nt is i d e ntifie d i n t h e st u d y b y a S u bje ct N u m b er ( S u bje ct N o.), t h at is assi g n e d 
w h e n t h e p atie nt is first e nr olle d f or pre -s cre e ni n g a n d is retai n e d as t h e pri m ar y i d e ntifier f or 
t h e p atie nt t hr o u g h o ut his/ h er e ntire p artici p ati o n i n t h e trial. T h e S u bje ct N o. c o nsists of  t h e 
Ce nter N u m b er ( Ce nter N o.) (as assi g n e d  b y  N o v artis t o  t h e  i n v esti gati v e  site) wit h  a  
s e q u e ntial p atie nt n u m ber s uffi x e d t o it, s o t h at e a c h s u bje ct is n u m b ere d u ni q uel y a cr os s t h e 
e ntire  d ata b as e.  U p o n  si g ni n g t h e  M ole c ula r pre-s cre e ni n g I nf or m e d C o ns e nt F or m, t h e 

N o v artis  
C o nfi d e nti al  
P a g e 6 0  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol N o. C M C S 1 1 0 Z 2 2 0 1  
 
p atie nt is assi g n e d t o t h e n e xt s e q u e ntial S u bje ct N o. a v aila ble t o t h e i n v esti gat or t hr o u g h t h e 
Ora cle Cli nic al R D C i nterf a c e.  
6. 4. 2  
Tr e at m e nt a s si g n m e nt a n d r a n d o mi z ati o n  
All eli gi ble  p atie nts will b e ra n d o miz e d i n a 2: 1 rati o t o eit h er Ar m 1 (i n v esti gati o n al ar m): 
M C S 1 1 0 + c ar b o/ ge m Or Ar m 2 (c o ntr ol ar m): c ar b o/ ge m. If t h ere is n o c h a n ge i n t h e 
M C S 1 1 0 d os e after t h e first e arl y s af et y re vie w m e eti n g, t h e t otal n u m b er of p atie nts f or t h is 
st u d y will b e 7 8. If t h e d os e is c h a n ge d, t h e t otal n u m b er of p atie nts f or t h e st u d y m a y b e 
a p pr o xi m atel y - 11 0 , as t h e re cr uit m e nt c o nti n u es d uri n g t h e d e cisi o n m a ki n g. 
T h e ra n d o miz ati o n will b e d o n e via I nteracti v e Res p o ns e Te c h n ol o g y (I R T). T h e i n v esti ga t o r 
or  his/ h er  d ele gate  will  c o nta ct  t h e  I R T  after  c o nfir mi n g t h at t h e p atie nt f ulfills all t h e 
i n cl usi o n/e x cl usi o n criteria. T h e I R T will assi g n a ra nd o miz ati o n n u m b er t o t h e p atie nt, w hic h 
will b e us e d t o li n k t h e s u bje ct t o a tre at m e nt ar m.  T h e ra n d o miz ati o n n u m b ers will b e 
ge n erate d usi n g t h e f oll o wi n g pr o c e d ure t o e ns ure t h at tre at m e nt assi g n m e nt is u n bi a s e d a n d 
c o n c e ale d fr o m s u bje cts a n d i n v esti gat or staff.  
A p atie nt ra n d o miz ati o n list will b e pr o d u c e d b y t h e I R T pr o vi d er usi n g a v ali d ate d s yste m 
t h at a ut o m ates t h e ra n d o m assi g nm e nt of tre at m e nt ar ms t o ra n d o miz ati o n n u m bers.  
6. 5  
St u d y dr u g pr e p ar ati o n a n d di s p e n s ati o n  
6. 5. 1  
St u d y dr u g p a c k a gi n g  a n d l a b eli n g  
St u d y dr u g – M C S 1 1 0  
M C S 1 1 0 is pr o vi d e d i n a 1 0 ml glass vial e a c h c o ntai ni n g 1 5 0 m g M C S 1 1 0 as a 2 0 m g/ ml 
c o n c e ntrate f or s ol uti o n f or i nf usi o n. 
Me dic ati o n la b els will b e c o d e d, pri nte d i n t h e l o c al la n g u a ge, a n d will c o m pl y wit h l o c al 
re g ulat or y re q uire m e nts. T h e st ora ge c o n diti o ns f or st u d y dr u g will b e pr o vi d e d o n t h e 
m e dic ati o n la b el.  
C a r b o pl ati n/ g e mcit a bi ne  
C o m m erciall y a v aila ble c ar b o plati n a n d ge m cita bi n e will b e s o urc e d l o c all y b y e a c h st u d y 
site. G e n eric c ar b o plati n a n d ge m cita bi n e m a y b e us e d f or st u d y tre at m e nt.  
6. 5. 2  
Dr u g s u p pl y  a n d st or a g e  
St u d y dr u g – M C S 1 1 0  
Ple as e ref er t o t h e P h ar m a c y Ma n u al f or i nf or m ati o n re gar di n g  t h e M C S 1 1 0 pre p arati o n a n d 
st ora ge. 
C a r b o pl ati n a n d g e mcit a bi ne  
Car b o a n d ge m s h o ul d b e st ore d a n d pre p are d a c c or di n g t o t h e i nstr u cti o ns o n t h e p a c k a ge 
i ns ert or s u m m ar y of pr o d u ct c h ara cteristics of t h e c o m m ercial s u p pl y. T h e pre p arati o n 
(i n cl u di n g all pre- a n d p ost-i nf usi o n a nti-e metics m e dic ati o n) a n d dis p os al of c ar b o/ ge m m ust 
b e i n a c c or d a n c e wit h l o c al i nstit uti o n al g ui d eli n es.  

N o v artis  
C o nfi d e nti al  
P a g e 6 1  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol N o. C M C S 1 1 0 Z 2 2 0 1  
 
6. 5. 3  
St u d y tr e at m e nt c o m pli a n c e  a n d a c c o u nt a bilit y  
6. 5. 3. 1  
St u d y tr e at m e nt c o m pli a n c e  
C o m plia n c e will b e ass ess e d b y t h e i n v esti gat or a n d/ or st u d y p ers o n nel at e a c h p ati e nt visit 
a n d i nf or m ati o n will b e c a pt ure d i n t h e Dr u g A c c o u nta bilit y F or m. T his i nf or m ati o n m ust b e 
c a pt ure d i n t h e s o urc e d o c u m e nt at e a c h p atie nt visit. Re c or ds of st u d y m e dic ati o n us e d, 
d os a ges a d mi nistere d, a n d d osi n g p eri o d  will b e k e pt d uri n g t h e st u d y.  
All st u d y m e dic ati o ns will b e a d mi nistere d t o t h e p atie nt b y t h e st u d y site staff. C o  m pli a n c e 
will b e ass ure d b y a d mi nistrati o n of t h e st u d y tre at m e nt u n der t h e s u p er visi o n of I n v esti g at or 
or his/ h er d esi g n e e.  
6. 5. 3. 2  
St u d y tr e at m e nt a c c o u nt a bilit y  
T h e i n v esti gat or or d esi g n e e m ust m ai ntai n a n a c c urate re c or d of t h e s hi p m e nt a n d dis pe nsi n g 
of  st u d y  tre at m e nt  ( M C S 1 1 0  a n d  c ar b o/ ge m)  a c c or di n g  t o  l o c al  i nstit uti o n al  dr u g  
a c c o u nta bilit y pr o c ess es. Dr u g a c c o u nta bilit y will b e n ote d b y t h e fiel d m o nit or d uri n g site 
visits a n d at t h e c o m pleti o n of t h e st u d y.  
At st u d y cl os e -o ut, a n d, as a p pr o priate d uri n g t h e c o urs e of t h e st u d y, t h e i n v esti gat or will 
ret ur n  all us e d  a n d  u n us e d  st u d y  tre at m e nt, p a c k a gi n g, dr u g la b els, a n d  a  c o p y of t h e 
c o m plete d dr u g a c c o u nta bilit y le d ger t o t h e N o v artis a d dress pr o vi d e d i n t h e i n v esti gat or 
f ol d er at e a c h site. 
6. 5. 4  
Di s p o s al a n d d e str u cti o n  
T h e st u d y dr u g s u p pl y c a n b e d estr o y e d at t h e l o c al N o v artis f acilit y, Dr u g S u p pl y gr o u p or 
t hir d p art y, as a p pro priate  
7 
Vi sit s c h e d ul e a n d a s s e s s m e nt s  
7. 1  
St u d y fl o w a n d vi sit s c h e d ul e  
Ta ble 7 - 1 lists all of t h e ass ess m e nts a n d i n dic ates wit h a n “ X ”, t h e visits w h e n t h e y are 
p erf or m e d. All d ata o btai n e d fr o m t h es e as s ess m e nts m ust b e s u p p orte d i n t h e p atie nt’s s o urce 
d o c u m e ntati o n.  
N o C R F will b e us e d as a s o urc e d o c u m e nt.  
T h e ta ble i n dic ates w hic h ass ess m e nts pr o d u c e d ata t o b e e ntere d i nt o t h e cli nic al d ata b as e 
( D) or re m ai n i n s o urc e d o c u me nts o nl y ( S) (“ Cate g or y ” c ol u m n) 
T h e pre -s cre e ni n g ass ess m e nt a n d all s cre e ni n g ass ess m e nts s h o ul d b e c o m pl et e d wit hi n 2 8 
d a ys b ef ore C 1 D 1, e x ce pt t h e pre g n a n c y test w hic h m ust b e p erf or m e d wit hi n 3 d a y s b ef or e 
C 1 D 1.  
Ass ess m e nts w hic h are i n dic ate d t o b e p erf or me d at Scre e ni n g/ b as eli ne a n d o n C y cle  1 D a y 1 
n e e d o nl y t o b e re p e ate d at C y cle 1 D a y 1 if t h e Scre e ni n g/ b as eli n e ass ess me nt w as m ore t h a n 
3 d a ys e arlier.  

N o v artis  
C o nfi d e nti al  
P a g e 6 2  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol N o. C M C S 1 1 0 Z 2 2 0 1  
 
R a di ol o gic al ass ess m e nts p erf or m e d as p art of sta n d ar d of c are pri or t o si g ni n g i nf or m e d 
c o ns e nt m a y b e us e d if p erf or m e d wit hi n 2 8 d a ys of t h e first d os e a d mi nistere d.  

N o v artis  
C o nfi d e nti al  
P a g e 6 3  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol N o. C M C S 1 1 0 Z 2 2 0 1  
 
T a bl e 7- 1 
Vi sit e v al u ati o n s c h e d ul e  
 
C at e g or y  
Pr ot o c ol 
S e cti o n  
Pr e -S cr e e ni n g  
S cr e e ni n g  
Tr e at m e nt p eri o d  
F oll o w -u p p h a s e  
C y cl e 1  
C y cl e 2  
S u b s e q u e nt c y cl e s  
E n d of Tr e at m e nt  
3 0 d a y s af et y 
/( pr e g n a n c y) F U 
6 0 d a y pr e g n a n c y 
F U  
9 0 d a y s af et y 
/( pr e g n a n c y) F U 
D a y of c y cl e  
 
 
 
 
1  
2  
4  
8  
1 5  
1  
8  
1  
2  
4  
8  
1 5  
 
 
 
 
M o l. Pr e -S cr e e ni n g I C F  
D  
7. 1. 1  
x  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
M ai n I C F  
D  
7. 1. 2  
 
x  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
P ati e nt hi st or y  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
I n cl u si o n/ e x cl u si o n crit eri a 
D  
 
 
x  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
M e di c al Hi st or y  
D  
7. 1. 2. 2  
 
x  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
D e m o gr a p hi c s  
D  
7. 1. 2. 2   
x  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Di a g n o s e d at e s a n d st a g e s f or 
pri m ar y a n d a d v a n c e d di s e a s e  
D 
7. 1. 2. 2   
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pri or a nti n e o pl a sti c  
D  
7. 1. 2. 2   
 
x  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pri or/ c o n c o mit a nt m e di c ati o n s 
a n d N o n dr u g t h er a p y  
D 
7. 1. 2. 2   
 
x 
C o nti n u o u sl y  
R a n d o mi z ati o n  
D  
 
 
x  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
P h y si c al e x a mi n ati o n  
S  
7. 2. 2. 1  
 
x  
x  
 
 
 
 
x  
 
x  
 
 
 
 
x  
 
 
 
P erf or m a n c e st at u s  
D  
7. 2. 2. 4  
 
x  
x  
 
 
 
 
x  
 
x  
 
 
 
 
x  
 
 
 
H ei g ht  
D  
7. 2. 2. 3  
 
x  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
W ei g ht  
D  
7. 2. 2. 3   
 
x  
x  
 
 
 
 
x  
 
x  
 
 
 
 
x  
 
 
 
Vit al si g n s  
D  
7. 2. 2. 2  
 
x  
x  
x  
x  
x  
x  
x  
x  
x 1 
x 1 
x 1 
x 1 
x 1 
x  
 
 
 
H e m at ol o g y  
D  
7. 2. 2. 5. 1  
 
x  
x  
 
 
x  
x  
x  
x  
x  
 
 
x  
 
x  
 
 
 
C h e mi str y  
D  
7. 2. 2. 5. 2  
 
x  
x  
 
 
x  
x  
x  
x  
x  
 
 
x 2 
 
x  
 
 
 
T h yr oi d P a n el  
D  
7. 2. 2. 5. 5  
 
x  
O nl y if cli ni c all y si g nifi c a nt a c c or di n g t o t h e PI  
x  
 
 
 

N o v artis  
C o nfi d e nti al  
P a g e 6 4  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol N o. C M C S 1 1 0 Z 2 2 0 1  
 
 
C at e g or y  
Pr ot o c ol 
S e cti o n  
Pr e -S cr e e ni n g  
S cr e e ni n g  
Tr e at m e nt p eri o d  
F oll o w -u p p h a s e  
C y cl e 1  
C y cl e 2  
S u b s e q u e nt c y cl e s  
E n d of Tr e at m e nt  
3 0 d a y s af et y 
/( pr e g n a n c y) F U 
6 0 d a y pr e g n a n c y 
F U  
9 0 d a y s af et y 
/( pr e g n a n c y) F U 
D a y of c y cl e  
 
 
 
 
1  
2  
4  
8  
1 5  
1  
8  
1  
2  
4  
8  
1 5  
 
 
 
 
C o a g ul ati o n  
D  
7. 2. 2. 5. 4  
 
x  
O nl y if cli ni c all y si g nifi c a nt a c c or di n g t o t h e PI  
x  
 
 
 
Pr e g n a n c y t e st  
D/ S 4 
7. 2. 2. 5. 6  
 
x 3 
 
 
 
 
 
x  
 
x  
 
 
 
 
x  
X  
X  
X  
T u m or e v al u ati o n  a s p er 
R E CI S T v 1. 1  
( C T c h e st/ a b d o m e n/ p el vi s + 
r el e v a nt)- M RI o r P E T/ C T m a y 
b e  u s e d i n st e a d of C T s c a n s  
D 
7. 2. 1  
 
x 
 
 
 
 
 
 
 
At a mi ni m u m e v er y 1 2 
w e e k s ( 4 c y cl e s)  
x 
 
 
 
E C G  
D  
7. 2. 2. 6. 1  
 
x  
x 5 
 
 
 
 
 
 
O nl y C 4 D 1 5 a n d C 8 D 1 5 
x  
 
 
 
A d v er s e e v e nt s  
D  
8. 1. 1  
X 6  
C o nti n u o u sl y  
C o nti n u o u sl y 8 
St u d y dr u g/tr e at m e nt 
a d mi ni str ati o n  
D 
6. 2  
 
 
 
M C S 1 1 0  a d mi ni str ati o n  
D  
6. 2. 1  
 
 
x  
 
 
X 7 
 
x  
 
x  
 
 
 
 
 
 
 
 
C ar b o/ g e m a d mi ni str ati o n  
D  
6. 2. 1   
 
 
x  
 
 
x  
 
x  
x  
x  
 
 
x  
 
 
 
 
 
A nti n e o pl a sti c t h er a pi e s si n c e 
di s c o nti n u ati o n of st u d y 
tr e at m e nt 
 
 
 
 
 
 
C o nti n u o u sl y  
1:  Vit al si g n s f or t h e s u b s e q u e nt c y cl e s: t o b e p erf or m e d o n t h e d a y s of d o si n g - if n o d o si n g, t o b e p erf or m e d w h e n t h er e i s a  P K  ti m e p oi nt  
2:  F or t h e C h e mi str y at  d a y 8 of t h e s u b s e q u e nt c y cl e s, o nl y t h e s er u m cr e ati ni n e i s m a n d at e d  
3:  S cr e e ni n g pr e g n a n c y t e st m u st b e p erf or m e d wit hi n 3 d a y s b ef or e fir st d o s e a d mi ni str ati o n  
4:  C at e g or y S f or a n y s af et y  F U pr e g n a n c y t e st. M o nt hl y uri n e pr e g n a n c y t e st s m u st b e  p erf or m e d f or 9 0 d a y s aft er  t h e l a st d o s e of M C S 1 1 0  or f or 3 0 d a y s aft er  t h e l a st 
d o s e of c ar b o p l ati n a n d g e m cit a bi n e or a s r e c o m m e n d e d p er t h e l o c al a p pr o v e d l a b el s f or c ar b o pl ati n a n d g e m cit a bi n e, w hi c h e v er h a s t h e l o n g e st d ur ati o n. 
5:  O nl y f or p ati e nt s r e c ei vi n g M C S 1 1 0 i n c o m bi n ati o n wit h c ar b o/ g e m  
6: Pr e -s cr e e ni n g pr o c e d ur e r el at e d S A E’ s  o nl y  
7: T h e M C S 1 1 0  C 1 D 8  d o s e m a y b e o mitt e d aft er  a d e ci si o n t o c h a n g e t h e r e gi m e n h a s b e e n m a d e  at a s af et y  r e vi e w m e eti n g  
8:  If a p ati e nt st art s a n e w a nti c a n c er t h er a p y d uri n g t h e s af et y f oll o w -u p, o nl y A E’ s or S A E’ s  s u s p e ct e d t o b e  r el at e d t o st u d y tr e at m e nt a n d a s s o ci at e d c o n c o mit a nt 
m e di c ati o n s will b e c oll e ct e d fr o m t hi s ti m e p oi nt.  

N o v artis  
C o nfi d e nti al  
P a g e 6 5  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol N o. C M C S 1 1 0 Z 2 2 0 1  
 
7. 1. 1  
M ol e c ul ar pr e -s cr e e ni n g  
O nl y  p atie nts w h os e  t u m ors h a v e  a  hi g h  T A M c o nte nt p er c e ntral ass ess m e nt  will  b e  
c o nsi d ere d eli gi ble f or t h e st u d y ( Se cti o n 2. 1  a n d  Se cti o n 4. 1 ). T he ass ess m e nt of  T A M 
c o nte nt will b e o btai n e d t hr o u g h s u b missi o n of s a m ples t o a N o v artis d esi g n at e d l a b or at or y 
w h ere I H C f or C D 1 6 3 ( m ar k er of T A M) will b e p erf or m e d. T h e c e ntral testi n g will b e 
p erf or m e d o n n e wl y o btai n e d t u m or s a m ples ( < 6 m o nt hs ol d). Pa tie nts will b e as k e d  t o  si g n  
a n d d ate a n I R B/I E C a p pr o v e d “ M ole c ular pre -s cre e ni n g i nf or m e d c o nse nt f or m.” 
T h e pre -s cre e ni n g res ults fr o m c e ntral testi n g f or all p atie nts ( w h et h er t h e p atie nt is eli gi ble or 
n ot f or t h e st u d y) will b e c o m m u nic ate d t o t h e res p e cti v e st u d y c e nter.  
If c o nfir m e d t h at t h e p atie nt’s t u m or h as a hi g h T A M c o nte nt t h e p atie nt m a y si g n t h e st u d y’ s 
m ai n i nf or m e d c o ns e nt t o b e gi n s cre e ni n g pr o ce d ures.  
7. 1. 2  
S cr e e ni n g  
T h e st u d y I R B/I E C a p pr o v e d I C F m ust b e si g n e d a n d d ate d pri or t o c o n d ucti n g  a n y s cre e ni n g 
pr o c e d ures t h at are n ot p erf or m e d as p art of t h e p atie nt‘s sta n d ar d of c are.  
Patie nts  will  b e  e v al u ate d  a gai nst  st u d y  i n cl usi o n  a n d  e x cl usi o n  criteria  a n d  s af et y  
ass ess m e nts. F or d etails of ass ess m e nts, refer t o Ta ble 7 - 1. 
Scre e ni n g ass ess m e nts , m ust b e re p e ate d if p erf or m e d o utsi d e of t h e s p e cifie d s cre e ni n g 
wi n d o ws. T h e pre -s cre e ni n g ass ess me nt a n d all s cre e ni n g ass ess me nts s h o ul d b e c o m pl et e d 
wit hi n 2 8 d a ys b e f ore C 1 D 1, e x c e pt t h e pre g n a n c y test w hic h m ust b e p erf or m e d wit hi n 3 
d a ys b ef ore C 1 D 1.  
7. 1. 2. 1  
I nf or m ati o n t o b e c oll e ct e d o n s cr e e ni n g f ail ur e s 
S u bje ct s w h o si g n e d a n I nf or m e d C o nse nt F or m b ut f aile d t o b e starte d o n tre at m e nt f or a n y 
re as o n  will b e  c o nsi d ere d  a s cre e n  f ail ure. B ot h  s u bje cts w h o  si g n e d  a  m ole c ular pre -
s cre e ni n g I C F b ut are c o nsi d ere d i n eli gi ble after m ole c ular pre -scre e ni n g, as w ell as s u bj e cts 
w h o  are  f o u n d  n ot eli gi ble  after si g ni n g t h e  m ai n  st u d y  c o ns e nt will b e  c o nsi d ere d  as 
s cre e ni n g f ail ures, a n d d ata will b e h a n dle d i n t h e s a m e m a n ner. 
T h e m ole c ular pre -s cre e ni n g f ail ures or s cre e ni n g f ail ure s will b e e ntere d o n t h e Scre e ni n g 
P h as e Dis p ositi o n Pa ge.  
T h e d e m o gra p hic i nf or m ati o n, i nf or me d c o ns e nt, a n d I n cl usi o n/ E x cl usi o n p a ges m ust als o b e 
c o m plete d f or Scre e n Fail ure s u bje cts. N o ot h er d ata will b e e ntere d i nt o t h e cli nic al d ata b a s e 
f or s u bje cts w h o are s cre e n f ail ures, u nless t h e s u bject e x p erie n ce d a Seri o us A d v er s e E v e nt 
d uri n g t h e Scre e ni n g P h as e (s e e Se cti o n 8  f or S A E re p orti n g d etails) or a S A E p ossi bl y 
relate d t o a st u d y pr o c e d ure d uri n g t h e pre-m olec ular s cre e ni n g p h as e  
7. 1. 2. 2  
P ati e nt d e m o gr a p hi c s  a n d ot h er b a s eli n e  c h ar a ct eri sti c s  
D ata t o b e c olle cte d will i n cl u d e ge n eral p atie nt d e m o gra p hics, rele va nt m e dic al hist or y a n d 
c urre nt m e dic al c o n diti o ns, dia g n osis a n d e xte nt of t u m or, d etails of pri or a nti -n e o plastic 
tre at m e nts a n d a n y ot h er ass ess m e nts t h at are d o n e f or t h e p ur p os e of d eter mi ni n g eli gi bilit y 
f or i n cl usi o n i n t h e st u d y. All m e dic ati o ns a n d si g nific a nt n o n-dr u g t h era pies (i n cl u di n g 

N o v artis  
C o nfi d e nti al  
P a g e 6 6  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol N o. C M C S 1 1 0 Z 2 2 0 1  
 
h er b al m e dici n es, p h ysic al t h era p y a n d bl o o d tra nsf usi o ns) ta k e n wit hi n 4 w e e ks pri or t o f ir st 
d os e of st u d y dr u g m ust b e re c or de d o n t h e e C R F.  
7. 1. 3  
Tr e at m e nt p eri o d  
A tre at m e nt c y cle is d efi n e d as 2 1 d a ys.  Ple as e ref er t o Ta ble 7 - 1 f or d etails of t h e ti mi n g of  
re q uire d ass ess m e nts a n d Se cti o n 7. 1  f or visit wi n d o ws. 
Patie nts will b e tre ate d u ntil p atie nt e x p erie n c es u n a c c e pta ble t o xicit y, pr o gressi v e dis e as e 
a n d/ or tre at m e nt are dis c o nti n ue d at t h e dis creti o n of t h e i n v esti gat or or wit h dra w al of c o nse nt 
as d es cri b e d i n Se cti o n 7. 1. 4  a n d Se cti o n 7. 1. 5 . 
Patie nts w h o dis c o nti n u e d 1 or 2 dr u gs  i n t h e Ar m 1 re gi m e n or 1 dr u g o nl y i n t h e Ar m 2 
re gi m e n d u e t o t o xicit y m a y c o nti n u e wit h t h e re m ai n d er of dr u gs assi g n e d at ra n d o mi z ati o n 
u p o n dis c u ssi o n wit h t h e N o v artis Me dic al M o nit or. 
Patie nts w h o h a v e dis e as e pr o gressi o n a n d h a v e e vi d e nc e of cli nic al b e n efit, s u c h a s dis e a s e 
s hri n k a ge at ot h er sites or s y m pt o m atic i m pr o v e m e nt, m a y c o nti n u e st u d y tre at m e nt u p o n 
d o c u m e nte d dis c ussi o n wit h t h e N o v a rtis m e dic al m o nit or. 
F or d etails of ass ess m e nts, refer t o Ta ble 7 - 1. 
7. 1. 4  
Di s c o nti n u ati o n of st u d y tr e at m e nt  
Patie nts m a y v ol u ntaril y dis c o nti n u e fr o m t h e st u d y tre at m e nt f or a n y re as o n at a n y ti m e. If  a 
p atie nt d e ci d es t o dis c o nti n u e fr o m t h e st u d y tre at m e nt, t h e i n v esti gat or m ust m a k e e v er y 
eff ort (e. g. tele p h o n e, e -m ail, letter) t o d eter mi n e t h e pri m ar y re as o n f or t his d e cisi o n a n d 
re c or d t his i nf or m ati o n i n t h e p atie nt’s c h art a n d o n t h e a p pr o priate C RF p a ges. T h e y m a y b e 
c o nsi d ere d wit h dra wn if t h e y state a n i nte nti o n t o wit h dra w, f ail t o ret ur n f or visits, or b e c o me 
l ost t o f oll o w-u p f or a n y ot h er re as o n.  
T h e i n v esti gat or s h o ul d dis c o nti n u e st u d y tre at m e nt f or a gi v e n p atie nt if, o n b ala nc e, h e/s h e 
b e lie v es t h at c o nti n u ati o n w o ul d b e d etri m e ntal t o t h e p atie nt’s w ell-b ei n g.  
St u d y tre at m e nt m a y b e dis c o nti n ue d if a n y of t h e f oll o wi n g o c c ur:  
•  A d v ers e e v e nt  
•  L ost t o f oll o w -u p  
•  Dis e as e pr o gressi o n  
•  P h ysicia n’s d e cisi o n  
•  St u d y ter mi n ate d b y t h e s p o ns or  
•  S u bje ct/ g u ar dia n d e cisi o n  
•  Pr ot o c ol d e viati o n  
•  Te c h nic al pr o ble ms  
St u d y tre at m e nt will b e dis c o nti n u e d if a n y of t h e f oll o wi n g o c c ur:  
•  D e at h  
•  Pre g n a n c y  

N o v artis  
C o nfi d e nti al  
P a g e 6 7  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol N o. C M C S 1 1 0 Z 2 2 0 1  
 
At t h e ti m e p atie nts dis c o nti n u e st u d y tre at m e nt, a visit s h o ul d b e s c h e d ule d as s o o n as 
p ossi ble, a n d wit hi n 1 4 d a ys  of t h e last d os e of st u d y dr u g or wit hi n 1 4 d a ys of t h e d e cisi o n t o 
p er m a n e ntl y dis c o nti n ue st u d y tre at m e nt, at w hic h ti m e all of t h e ass ess m e n ts list e d  f or t h e 
E O T visit will b e p erf or m e d ( Ta ble 7 - 1). If t h e d e cisi o n t o wit h dra w t h e p atie nt o c c urs at a 
re g ularl y s c h e d ule d visit, t h at visit m a y b e c o me t h e E O T visit rat h er t h a n h a vi n g t h e  p a ti e n t 
ret ur n f or a n a d diti o n al visit. A n E n d of Tre at m e nt P h as e Dis p ositi o n C R F p a ge s h o ul d b e 
c o m plete d,  gi vi n g  t h e  d ate  a n d  re as o n  f or  st o p pi n g  t h e  st u d y  tre at m e nt.  E n d  of  
tre at m e nt/ Pre m at ure wit h dra w al visit is n ot c o nsi d ere d as t h e e n d of t h e st u d y. 
Patie nts w h o dis c o nti n u e st u d y tre at m e nt s h o ul d N O T b e c o nsi d ere d wit h dra w n fr o m t h e 
st u d y. T h e y s h o ul d ret ur n f or t he ass ess m e nts i n dicate d i n Se cti o n 7. 1. 6 . If t h e y f ail t o r et ur n 
f or t h es e ass ess m e nts f or u n k n o w n re as o ns, e v er y eff ort (e. g. tele p h o n e, e m ail, letter) s h o ul d 
b e m a d e t o c o nta ct t h e m as s p e cifie d i n Se cti o n 7. 1. 7 .  
7. 1. 4. 1  R e pl a c e m e nt  p oli c y  
Patie nts will n ot b e re pla c e d.  
7. 1. 5  
Wit h dr a w al of c o n s e nt  
Patie nts m a y v ol u ntaril y wit h dra w c o ns e nt t o p artici p ate i n t h e st u d y f or a n y re as o n at a n y 
ti m e. Wit h dra w al of c o ns ent o c c urs o nl y w h e n a p atie nt d o es n ot w a nt t o p artici p ate i n t h e 
st u d y a n y l o n ger, a n d d o es n ot w a nt a n y f urt h er visits or ass ess m e nts, a n d d o es n ot w a nt a n y 
f urt h er st u d y relate d c o nta ct.  
N o v artis will c o nti n u e t o retai n a n d us e all res e arc h res ults t h a t h a v e alre a d y b e e n c oll e ct e d 
f or t h e st u d y e v al u ati o n. All bi ol o gic al s a m ples t h at h a v e alre a d y b e e n c olle cte d m a y b e 
retai n e d a n d a n al y z e d at a later d ate ( or as p er mitte d b y l o c al re g ulati o ns).  
If a p atie nt wit h dra ws c o ns e nt, t h e i n v esti gat or m ust m a k e e v er y eff ort (e. g. tele p h o ne, e-m ail, 
letter) t o d eter mi n e t h e pri m ar y re as o n f or t his d e cisi o n a n d re c or d t his i nf or m ati o n. 
St u d y tre at m e nt m ust b e dis c o nti n ue d a n d n o f urt h er ass ess me nts c o n d ucte d.  
F urt h er  atte m pts  t o  c o nta ct  t h e  p atie nt  are  n ot  all o w e d  u nless  s af et y  fi n di n gs  re q uire  
c o m m u nic ati o n or f oll o w u p.  
7. 1. 6  
F oll o w -u p p eri o d  
All p atie nts m ust h a v e s af et y e v al u ati o ns 3 0 d a ys  a n d 9 0 d a ys after t h e last d os e of st u d y 
tre at m e nt. It is u p t o t h e i n v esti gat or t o d e ci d e if t h e p atie nt s h o ul d c o m e b a c k t o t h e cli nic f or 
t h e s af et y f oll o w-u p or if t h e f oll o w-u p  c a n b e p erf or me d via a telep h o n e c all. I nf or m ati o n 
relate d t o A Es  (i n cl u di n g c o n c o mita nt m e dic ati o n ta k e n f or o n g oi n g  A Es) a n d o n g oi n g a nti -
n e o plastic tre at m e nts will b e c olle cte d f or 9 0 d a ys after t h e last d os e of st u d y tre at m e nt ( Ta ble 
7- 1 ). O n c e a p atie nt b e gi ns a n ot h er a nt i-c a n cer t h era p y, o nl y  A E’s a n d S A E’s s us p e cte d t o b e  
relate d t o t h e st u d y tre at m e nt a n d t h e as s o ciate d m e dic ati o ns will b e c olle cte d.  
A nti n e o plastic t h era pies si n c e dis c o nti n uati o n of st u d y dr u g will b e c olle cte d d uri n g t h e s a f ety 
f oll o w-u p p eri o d.  

N o v artis  
C o nfi d e nti al  
P a g e 6 8  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol N o. C M C S 1 1 0 Z 2 2 0 1  
 
7. 1. 7  
L o st t o f oll o w -u p  
F or p atie nts w h os e stat us is u n cle ar b e ca use t h e y fail t o a p p e ar f or st u d y visits wit h o ut stati n g 
a n i nte nti o n t o wit h dra w c o ns e nt, t h e i n v esti gat or s h o ul d s h o w " d u e dili ge n c e" b y c o nt a cti n g 
t h e p atie nt, f a mil y or f a mil y p h ysicia n as a gre e d i n t h e i nf or m e d c o nse nt a n d b y d o c u me nti n g 
i n t h e s o urc e d o c u m e nts ste ps ta k e n t o c o nta ct t h e p atie nt, e. g. d ates of tele p h o n e c alls, 
re gistere d letters, etc. A p atie nt s h o ul d n ot b e c o nsi d ere d l ost t o f oll o w-u p u ntil d u e dili g e n c e 
h as b e e n c o m plete d. Patie nts l ost t o f oll o w u p s h o ul d b e re c or d e d as s u c h o n t h e a p pr o pri at e 
Dis p ositi o n C R F.  
7. 2  
A s s e s s m e nt t y p e s  
7. 2. 1  
Effi c a c y a s s e s s m e nt s  
T u m or res p o ns e will b e d eter mi n e d l o c all y a c c or di n g t o Res p o ns e E v al u ati o n Criteria i n S oli d 
T u m ors ( R E CI S T) v 1. 1 ( A p p e n di x 1 ). T h e l o c al i n v esti gat or’s ass ess me nt will b e us e d f or t h e 
pri m ar y e n d p oi nt a n al ysis a n d f or tre at m e nt d e cisi o n m a ki n g.  
T u m or e v al u ati o ns will b e p erf or m e d at b as eli n e wit hi n 2 8 d a ys b ef ore start of tre at m e n t. All 
p atie nts m ust u n d er g o C T wit h i. v. c o ntrast of t h e c h est, a b d o me n, a n d p el vis . R a di ol o gi c al 
ass ess m e nts p erf or m e d as p art of sta n d ar d of c are pri or t o si g ni n g i nf or m e d c o ns e nt m a y b e 
us e d if p erf or me d wit hi n 2 8 d a ys of t h e first d os e a d mi nistere d.  
If t h ere are cli nic al si g ns of dis e as e els e w h ere, f or e x a m ple p ai n, p al p a bl e n o d e s et c. , t h e s e 
a re as s h o ul d b e e v al u ate d wit h b o ne s c a n, b o ne X- ra y, C T or M RI. P E T/ C T m a y b e us e d o nl y 
if  t h e C T is of  si milar dia g n ostic q u alit y as a C T p erf or m e d wit h o ut P E T, i n cl u di n g t h e 
utiliz ati o n of oral a n d i ntra v e n o us c o ntrast m e dia. If a p atie nt is i nt olera nt of i o di n e-b as e d 
c o ntrast a ge nts, C Ts m a y b e p erf or m e d wit h o ut c o ntrast; h o w e v er, M RI m a y b e us e d t o 
e v al u ate sites of dis e as e w h ere a C T wit h o ut i. v. c o ntrast is n ot a d e q uate. Visi ble s ki n lesi o n s 
a n d e asil y p al p a ble s u b c uta ne o us t u m ors m a y b e m e as ure d b y p h ysic al e x a mi n ati o n u si n g a 
r uler or c ali p ers. Ultras o u n d s h o ul d n ot b e us e d t o m e as ure sites of dis e as e.  
S u bs e q u e nt t u m or e v al u ati o ns will b e p erf or m e d at le ast e v er y 1 2 w e e ks ( 4 c y cl e s) . T u m or 
e v al u ati o ns will b e p erf or me d at t h e E O T visit. If t h e last pri or t u m or e v al u ati o n w a s wit hi n 
3 0 d a ys of E O T or o bje cti v e e vi d e nc e of pr o gressi v e dis eas e  h as alre a d y b e e n d o c u m e nt e d, 
t h e n t u m or e v al u ati o ns d o n ot n e e d t o b e re p e ate d at E O T. Se e Ta ble 7 - 1 f or d etails.  
T u m or e v al u ati o ns after t h e b as eli ne ass ess m e nt will i n cl u d e e v al u ati o n of all sites of dis e a s e 
i d e ntifie d at b as eli n e, usi n g t h e s a m e te c h ni q u e t h at w as us e d at b as eli n e. If t h ere w as n o 
e vi d e n c e of dis eas e i n a b o d y re gi o n o utsi d e of t h e c h est , a b d o m e n  a n d p el vis  at b as eli n e, t h a t 
re gi o n d o es n ot n e e d t o b e i m a ge d at s u bs e q ue nt ass ess m e nts u nless t h ere is cli nic al c o n c er n 
f or a n e w lesi o n i n t h at b o d y re gi o n.  
All C Rs a n d P Rs M U S T b e c o nfir m e d b y a s e c o n d ass ess me nt n ot e arlier t h a n 2 8 d a ys af t er 
th e criteria f or res p o ns e are first m et.  

N o v artis  
C o nfi d e nti al  
P a g e 6 9  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol N o. C M C S 1 1 0 Z 2 2 0 1  
 
T a bl e 7- 2 
I m a gi n g c oll e cti o n pl a n 
Pr o c e d ur e  
S cr e e ni n g/  
B a s eli n e  
D uri n g Tr e at m e nt or Di s e a s e  Pr o gr e s si o n  F U  
C T* wit h c o ntr a st 
e n h a n c e m e nt  ( C h e st, 
A b d o m e n, P el vi s)  
M a n d at e d  
M a n d at e d, at a mi ni m u m e v er y 1 2 w e e k s ( 4 c y cl es ), u ntil di s e a s e 
pr o gr e s si o n.  
E n d of tr e at m e nt.  
B o n e s c a n , b o n e x -r a y, 
C T or M RI  
If cli ni c all y 
i n di c at e d 
M a n d at e d  (e x c e pt b o n e s c a n s, o nl y p er i n v e sti g at or’ s di s cr eti o n ) if 
fi n di n g s at s cr e e ni n g. At a  mi ni m u m e v er y  1 2 w e e k s ( 4 c y cl e s) u ntil 
di s e a s e pr o gr e s si o n.  
E n d of tr e at m e nt.  
* M RI or P E T/ C T m a y b e u s e d i n st e a d of C T s c a n s, a s d e s cri b e d a b o v e. 
7. 2. 2  
S af et y a n d t ol er a bilit y a s s e s s m e n t s 
Saf et y  will  b e  m o nit ore d  b y  ass essi n g p h ysic al  e x a mi n ati o n,  vital  si g ns,  w ei g ht,  E C O G  
p erf or m a nc e stat us, la b orat or y e v al u ati o ns, 1 2 -le a d E C G i n tri plic ate as w ell as c o ll e c ti n g o f  
t h e a d v ers e e v e nts at e v er y visit. F or d etails o n A E c olle cti o n a n d re p orti n g, ref er t o Se cti o n 8 . 
7. 2. 2. 1  
P h y si c al e x a mi n ati o n  
A c o m plete  p h ysic al e x a mi n ati o n  m ust b e  p erf or m e d  a c c or di n g t o  t h e  visit e v al u ati o n  
s c h e d ule i n Ta ble 7 - 1. 
Ass ess m e nts w hic h are i n dic ate d t o b e p erf or me d at Scre e ni n g/ b as eli ne a n d o n C y cle 1 D a y 1 
n e e d o nl y t o b e re p e ate d at C y cle 1 D a y 1 if t h e Scre e ni n g/ b as eli n e ass ess me nt w as m ore t h a n 
3 d a ys e arlier.  
T h e e x a mi n ati o n will i n cl u d e t h e e x a mi n ati o n of ge n eral a p p e ara n c e, s ki n, bre asts, n e c k 
(i n cl u di n g t h yr oi d), e y es, e ars, n os e, t hr o at, l u n gs, h e art, a b d o m e n, b a c k, l y m p h n o d e s, a n d 
e xtre mities, v as c ular a n d n e ur ol o gic al. I n a d diti o n, if i n dic ate d b as e d o n m e dic al hist or y 
a n d/ or s y m pt o ms, re ctal, e xte r n al ge nitalia, a n d p el vic e x a ms will b e p erf or me d. 
P h ysic al e x a mi n ati o n will b e p erf or m e d o n t h e s c h e d ule d d a y, e v e n if st u d y tre at m e nt is b ei n g 
wit h h el d. M ore fre q u e nt e x a mi n ati o ns m a y b e p erf or me d at t h e dis creti o n of t h e I n v esti g at or 
a n d if m e dic all y i n dic ate d.  
Si g nific a nt fi n di n gs t h at w ere pres e nt pri or t o t h e si g ni n g of i nf or m e d c o ns e nt m ust b e 
i n cl u d e d i n t h e Me dic al Hist or y p a ge o n t h e p atie nt’s C R F. Si g nific a nt n e w fi n di n gs t h at 
b e gi n or w ors e n after i nf or me d c o ns e nt m ust b e re c or de d o n  t h e A d v ers e E v e nt p a g e of  t h e 
p atie nt’s C R F.  
7. 2. 2. 2  
Vit al si g n s  
Vital si g ns ( b o d y te m p erat ure, p uls e rate, bl o o d press ure) will b e ass ess e d a c c or di n g t o t h e 
visit e v al u ati o n s c h e d ule i n Ta ble 7 -1.   
Vital si g n s ( b o d y te m p erat ure, p uls e rate, bl o o d pressure) will b e ass ess e d pre -d os e f or Ar m 1 
a n d Ar m 2. I n a d diti o n f or Ar m 1, bl o o d press ure p ost -d os e M C S 1 1 0 (at t h e e n d of M C S 1 1 0 
i nf usi o n) will b e ass ess e d. 

N o v artis  
C o nfi d e nti al  
P a g e 7 0  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol N o. C M C S 1 1 0 Z 2 2 0 1  
 
Bl o o d press ure s h o ul d b e ass esse d after 5 mi n utes rest. T h e vital si g ns m ust b e ass ess e d i n t h e 
s a m e p ositi o n d uri n g t h e st u d y (eit h er sitti n g or s u pi n e). 
Vital si g ns s h o ul d b e ass ess e d o n t h e s c he d ule d d a y, e ve n if st u d y tre at m e nt is b ei n g wit h h eld. 
M ore fre q u e nt e x a mi n ati o ns m a y b e p erf or m e d at t h e dis creti o n o f t h e I n v esti gat or a n d if 
m e dic all y i n dic ate d.  
7. 2. 2. 3  
H ei g ht a n d w ei g ht  
H ei g ht a n d b o d y w ei g ht  (i n i n d o or cl ot hi n g, b ut wit h o ut s h o es) will b e m e as ure d a c c or di n g t o 
t h e visit e v al u ati o n s c h e d ule i n Ta ble 7 - 1. 
7. 2. 2. 4  
P erf or m a n c e st at u s  
E C O G p erf or m a nc e stat us will b e ass ess e d a c c or di n g t o Ta ble 7 - 3 a n d a c c or di n g t o t h e visit 
e v al u ati o n s c h e d ule i n Ta ble 7 -1.  
T a bl e 7- 3 
E C O G p erf or m a n c e st at u s  
Gr a d e  
E C O G St at u s  
0  
F ull y a cti v e, a bl e t o c arr y o n all pr e -di s e a s e p erf or m a n c e wit h o ut r e stri cti o n  
1 
R e stri ct e d i n p h y si c all y str e n u o u s a cti vit y b ut a m b ul at or y a n d a bl e t o c arr y o ut w or k of a  li g ht or 
s e d e nt ar y n at ur e ( e. g., li g ht h o u s e w or k, offi c e w or k)  
2 
A m b ul at or y a n d c a p a bl e of all s elf -c ar e b ut u n a bl e t o c arr y o ut a n y w or k a cti viti e s. U p a n d a b o ut m or e 
t h a n 5 0 %  of w a ki n g ho ur s  
3  
C a p a bl e of o nl y li mit e d s elf -c ar e, c o nfi n e d t o b e d or c h air m or e t h a n 5 0 % of w a ki n g h o ur s  
4  
C o m pl et el y di s a bl e d. C a n n ot c arr y o n a n y s elf -c ar e. T ot all y c o nfi n e d t o b e d or c h air  
7. 2. 2. 5  
L a b or at or y e v al u ati o n s  
All la b orat or y p ara m eters ass ess e d f or s afet y p ur p os es will b e e v al u ate d l o c all y, at t h e site.  
U ns c h e d ule d ass ess me nt c a n b e p erf or me d if cli nic all y i n dic ate d.  
Ref er t o Ta ble 7 - 4 f or a s u m m ar y of t h e p ara m eters t o b e e v al u ate d a c c or di n g t o Ta ble 7 - 1 
T a bl e 7- 4 
L o c al Cli ni c al L a b or at or y p ar a m et er s c o ll e cti o n pl a n 
T e st C at e g or y  
T e st N a m e  
H e m at ol o g y  
H e m o gl o bi n, Pl at el et s, W hit e bl o o d c ell s ( W B C) wit h Diff er e nti al C o u nt ( N e utr o p hil s, 
L y m p h o c yt e s, M o n o c yt e s, B a s o p hil s, E o si n o p hil s)  
C h e mi str y  
Al b u mi n, Al k ali n e p h o s p h at a s e, A L T ( S G P T), A S T ( S G O T), Bi c ar b o n at e, C al ci u m, P h o s p h at e, 
C hl ori d e, Cr e ati ni n e, S o di u m, P ot a s si u m, Cr e ati n e ki n a s e ( C K),  T ot al Bilir u bi n, Ur e a or B U N, 
Uri c A ci d, Bl o o d pl a s m a G l u c o s e ( n o n-f a sti n g) 
C K -M B b a s eli n e a n d Tr o p o ni n (I or T)  b a s eli n e  
If C K > 5  x U L N: C K-M B  (i s o e n z y m e of C K),  Tr o p o ni n (I or T), 
If r e q uir e d t o r ul e o ut m y o siti s/r h a b d o m y ol y si s p er l o c al g ui d eli n e s: A l d ol a s e, M y o gl o bi n  
T u m or M ar k er s  
C A 1 5 -3  
C o a g ul ati o n  
Pr ot hr o m bi n ti m e ( P T) or I nt er n ati o n al n or m a li z e d r ati o [I N R] 
T h yr oi d  
T S H - if a b n or m al t a k e fr e e T 3 a n d T 4  
Uri n e  
If r e q uir e d t o r ul e o ut m y o siti s/r h a b d o m y ol y si s p er l o c al g ui d eli n e s: M y o gl o bi n  

N o v artis  
C o nfi d e nti al  
P a g e 7 1  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol N o. C M C S 1 1 0 Z 2 2 0 1  
 
7. 2. 2. 5. 1  H e m at ol o g y  
Ple as e ref er t o Ta ble 7 - 4 f or a list of tests t o b e p erf or m e d. F or ti mi n g of ass ess m e nts, refer t o  
Ta ble 7 - 1. 
7. 2. 2. 5. 2  Cli ni c al C h e mi str y  
Ple as e ref er t o Ta ble 7 - 4 f or a list of tests t o b e p erf or m e d. F or ti mi n g of ass ess m e nts, refer t o  
Ta ble 7 - 1. 
7. 2. 2. 5. 3  T u m or M ar k er s  
Ple as e ref er t o Ta ble 7 - 4 f or a list of tests t o b e p erf or m e d. F or ti mi n g of ass ess m e nts, refer t o  
Ta ble 7 - 1. 
F oll o wi n g l o c al I R B/ E C a p pr o v al of pr ot o c ol a m e n d me nt 6, t u m or m ar k er  s a m ple c oll e cti o n 
will n o l o n ger b e re q uire d b y t h e pr ot o c ol.  
7. 2. 2. 5. 4  C o a g ul ati o n  
C o a g ulati o n p a n el o utli n e d i n Ta ble 7 - 4 will b e p erf or m e d as p er t h e ass ess m e nt s c h e d ul e i n 
Ta ble 7 - 1. 
7. 2. 2. 5. 5  T h yr oi d  
T h yr oi d p a n el o utli n e d i n Ta ble 7 - 4 will b e p erf or m e d as p er t h e ass ess m e nt s c h e d ule i n  
Ta ble 7 - 1. 
7. 2. 2. 5. 6  Pr e g n a n c y  
All f e m ales of c hil d be ari n g p ote ntial will h a v e a s er u m pre g n a n c y test at s cre e ni n g wit hi n ≤ 3  
d a ys b ef ore first d os e of st u d y tre at m e nt. D uri n g t h e st u d y, a s er u m pre g n a n c y test s h o ul d b e 
d o n e at d a y 1 of e v er y c y cle  starti n g at C y cle 2 , a n d a t e n d of tre at m e nt. 
If a p atie nt b e c o m es pre g n a nt, st u d y tre at m e nt s h o ul d b e dis c o nti n u e d i m m e di at el y a n d t h e 
p atie nt s h o ul d b e dis c o nti n u e d fr o m t h e st u d y. Se e Se cti o n 8. 3  f or pre g n a n c y re p orti n g. 
D uri n g t h e s af et y f oll o w -u p, a uri n e pre g n a n c y test m ust b e p erf or m e d 3 0, 6 0 a n d 9 0 d a y s 
after  st o p pi n g  M C S 1 1 0  f or  w o m e n  of  c hil d b e ari n g  p ote ntial  i n  Ar m  1 .  W o m e n  of  
c hil d b e ari n g p ote ntial i n Ar m 2 will h a v e a uri n e pre g n a n c y test p erf or m e d at le ast 3 0 d a ys 
after st o p pi n g st u d y tre at m e nt . F or b ot h ar ms, if t h e p ost -tre at m e nt c o ntra ce pti o n p eri o d f or 
c ar b o plati n a n d ge m cita bi ne as p er l o c al a p pr o ve d la b el is l o n ger t h a n 3 0 d a ys, m o nt hl y uri n e 
pre g n a n c y tests m ust b e p erf or m e d u ntil t h e e n d of t h e p ost -tre at m e nt c o ntra ce pti o n p eri o d.  If  
t h e p atie nt is n ot c o mi n g t o t h e cli nic f or t h e f oll o w-u p visits, a pre g n a n c y test s h o ul d b e 
p erf or m e d at h o m e or at a l o c al d o ct or’s offic e at e a c h of t h e f oll o w -u p ti m e  p oi nts d escri b e d  
a b o v e a n d t h e res ults will b e c o m m u nic ate d t o t h e site staff.  T h e f oll o w -u p  pr e g n a n c y t e sts 
will b e re c or d e d o nl y i n t h e s o urc e d o c u m e ntati o n, n ot i n t h e C R F .  

N o v artis  
C o nfi d e nti al  
P a g e 7 2  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol N o. C M C S 1 1 0 Z 2 2 0 1  
 
7. 2. 2. 6  
C ar di a c A s s e s s m e nt s  
7. 2. 2. 6. 1  El e ctr o c ar di o gr a m  ( E C G)  
A sta n d ar d 1 2 le a d E C G will b e p erf or m e d as p er t h e ass ess m e nt s c h e d ule i n T a bl e 7 - 1 a n d 
Ta ble 7 - 5. O nl y s cre e ni n g a n d E o T EC Gs are re q uire d i n p atie nts assi g n e d t o Ar m 2. Bl o o d 
s a m ples s c h e d ule d at t h e s a m e ti m e p oi nt s h o ul d b e ta k e n after t h e E C Gs are c o m plete d. T h e 
E C Gs o n C 1 D 1, C 4 D 1 a n d C 8 D 1 m ust b e p erf or me d i n tri plic ate.  
T a bl e 7- 5 
1 2 l e a d E C G c oll e cti o n pl a n  
C y cl e  
D a y  
Ti m e  
S cr e e ni n g  
-1 4 t o -1  
A n yti m e ( all p ati e nt s)  
1  
1  
* Pr e-d o s e ( Ar m  1 o nl y)  
1  
1  
* 1 h ( ± 5 mi n) h o ur p o st e n d of M C S 1 1 0  i nf u si o n ( Ar m 1 o nl y)  
4  
1  
* Pr e-d o s e ( Ar m  1 o nl y)  
4  
1  
* 1 h ( ± 5 mi n) h o ur p o st e n d of M C S 1 1 0  i nf u si o n ( Ar m 1 o nl y)  
8  
1  
* Pr e-d o s e ( Ar m  1 o nl y)  
8  
1  
* 1 h ( ± 5 mi n) h o ur p o st e n d of M C S 1 1 0  i nf u si o n ( Ar m 1 o nl y)  
E o T  
- 
A n yti m e ( all p ati e nt s)  
U n s c h e d ul e d **  
- 
A n yti m e ( all p ati e nt s ) 
*  E C G s P erf or m e d i n tri pli c at e. 
**if  o n t h e s a m e  d a y a s a P K  s a m pl e, bl o o d s h o ul d b e c oll e ct e d j u st aft er a n E C G p erf or m e d d u e t o a n 
u n e x p e ct e d c ar di a c si g n al.  
All E C Gs  (u p t o c y cle 4 i n cl u d e d) will b e i n d e p e n d e ntl y re vie w e d b y a c e ntral la b orat or y. 
I nstr u cti o ns f or t h e c olle cti o n a n d tra ns missi o n  of E C Gs t o t h e c e ntral E C G la b orat or y will b e 
pr o vi d e d i n t h e E C G Ma n u al.  
E C G s at c y cle 8 will b e p erf or m e d l o c all y a n d re c or d e d o n a l o c al E C G C R F p a ge. After 
c y cle 8, E C Gs will b e p erf or m e d at t h e dis creti o n of t h e i n v esti gat or a n d will b e re c or d e d o n a 
l o c al E C G C R F p a ge.  T h es e E C Gs will n ot b e re vie w e d b y t h e c e ntral la b orat or y.   
E o T E C G’s  are m a n d at or y a n d will b e re vie w e d l o c all y.  
Cli nic all y si g nific a nt a b n or m alitie s pres e nt at s cre e ni n g s h o ul d b e re p orte d o n t h e Me dic al 
Hist or y C R F p a ge. N e w or w ors e n e d cli nic all y si g nific a nt fi n di n gs o c c urri n g aft er i nf or m e d 
c o ns e nt m ust b e  re c or d e d  o n  t h e  A d v ers e  E v e nts C R F p a ge. All eli gi bilit y  a n d  p atie nt 
m a n a ge m e nt d e cisi o ns s h o ul d b e m a de b as e d o n t h e l o c al re a di n g of t h e E C G.  
7. 2. 3  
P h ar m a c o ki n eti c s,  p h ar m a c o d y n a mi c s  ( C S F -1) 
 
T o ass ess P K, P D ( C S F -1) 
 of M C S 1 1 0, bl o o d s a m ples will b e c oll e ct e d 
i n Ar m 1 t o d eter mi n e fre e M C S 1 1 0 c o n ce ntrati o n i n s er um, t otal C S F -1 le v els i n plas m a,  
 
. T o ass ess P K of c ar b o a n d g e m, bl o o d 
s a m ples will b e c olle cte d i n b ot h Ar m 1 a n d Ar m 2 t o d eter mi n e plas m a c o n c e ntrati o ns of 
c ar b o, ge m a n d 2', 2' -difl u or o -d e o x y uri di n e ( d F d U), t h e pri m ar y m eta b olite of ge m.  

N o v artis  
C o nfi d e nti al  
P a g e 7 3  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol N o. C M C S 1 1 0 Z 2 2 0 1  
 
7. 2. 3. 1  Bl o o d s a m pl e c oll e cti o n a n d h a n dli n g  
I n Ar m 1, f or t h e first 1 5 p atie nts, s erial bl o o d s a m ples will b e c olle cte d i n C y cle 1 a n d 4, a n d 
pre- d os e a n d s p ars e bl o o d s a m ples will b e c olle cte d i n C y cle 2, 3 a n d 5 -8 (s e e d etails i n Ta ble  
7- 6 ). F or s u bs e q u e nt p atie nts, s p arse bl o o d s a m ples will b e c olle cte d (s e e d etails i n T a bl e 7 -
7 ). N ote: If t h e M C S 1 1 0 d os e is re d u c e d a n d/ or t h e a d diti o nal d os e o n  C 1 D 8 is o mitt e d , t h e 
first 1 5 p atie nts of t h e n e w d os e re gi m e n will b e f oll o wi n g t h e s a m pli n g s c h e d ule i n Ta bl e 7 -
6 , a n d t h e s u bs e q u e nt p atie nts of t h e n e w d os e re gi m e n will f oll o w t h e s a m pli n g s c h e d ul e i n 
Ta ble 7 - 7. 
I n b ot h Ar m 1 a n d 2, s erial bl o o d s a m ples will als o b e c olle cte d i n C y cle 1 a n d 4 (s e e d etails in 
Ta ble 7 - 8). 
All bl o o d s a m ples will b e c olle cte d b y eit h er dire ct v e ni p u n ct ure or a n i n d w elli n g c a n n ula 
i ns erte d i n a f ore ar m v ei n c o ntra-lateral t o t h e site of dr u g i nf usi o n t o a v oi d p ote nti al l o s s of 
d os e or c o nta mi n ati o n of bl o o d s a m ples. At e a c h s p e cifie d ti m e -p oi nt, 2 m L bl o o d s a m ple 
will b e c olle cte d f or e a c h a nal y te of M C S 1 1 0, C S F-1  
 ( Ta ble 7 - 6 t o 7- 7 ), a n d 1 m L 
bl o o d s a m ple will b e c olle cte d f or e a c h a n al yte of c ar b o a n d ge m ( Ta ble 7 - 8). C o m plete 
i nstr u cti o ns  f or  s a m ple  pr o c essi n g,  h a n dli n g  a n d  s hi p m e nt  will  b e  pr o vi d e d  i n  t h e  
[ C M C S 1 1 0 Z 2 2 0 1 La b orat or y Ma n ual]. 
T h e e x a ct d ate a n d cl o c k ti m es of st u d y dr u g a d mi nistrati o n a n d bl o o d s a m ple c olle cti o n wi ll 
b e re c or d e d o n t h e a p pr o priate e C R F. A n y s a m pli n g iss u es s h o ul d b e n ote d o n t h e e C R F a n d 
o n a p pr o priate s o urce d o c u m e ntati o n.  
F oll o wi n g  l o c al  I R B/ E C  a p pr o v al  of  pr ot o c ol  a m e n d m e nt  6,  p h ar m a c o ki n etic  s a m ple 
c olle cti o n f or M C S 1 1 0 will n o l o n ger b e re q uire d b y t h e pr ot o c ol. I n a d diti o n, C S F -1  
 
 s a m ples will n o l o n ger b e c olle cte d. 
T a bl e 7- 6 
P h ar m a c o ki n eti c ( M C S 1 1 0), C S F -1  
 s a m pl e bl o o d c oll e cti o n 
l o g (fir st 1 5 p ati e nt s) i n Ar m 1 ( n ot a p pli c a bl e aft er a p pr o v al of 
pr ot o c ol a m e n d m e nt 6)  
C y cl e  
D a y  
S c h e d ul e d Ti m e  
( S a m pli n g wi n d o w)a 
D o s e 
R ef er e n c e  I D  
( M C S 1 1 0)b  
P K S a m pl e 
N o 
( M C S 1 1 0)b  
C S F -1 
S a m pl e 
N o b  
 
1  
1  
Pr e -d o s e ( 0 h) d 
1 0 1  
1 0 1  
2 0 1  
1  
1  
1 h ( ± 5 mi n) p o st e n d of i nf u si o n  
1 0 1  
1 0 2  
2 0 2  
1  
2  
2 4  h ( ± 2 h) p o st st art of i nf u si o n  
1 0 1  
1 0 3  
2 0 3  
1  
4  
7 2  h ( ± 6 h) p o st st art of i nf u si o n  
1 0 1  
1 0 4  
2 0 4  
1 
8  
Pr e -C 1 D 8  d o s e ( 0 h) d / 1 6 8 h p o st 
C 1 D 1 d o s e  
1 0 2/ 1 0 1 e 
1 0 5  
2 0 5  
1 
8 f 
1 h ( ± 5 mi n) p o st e n d of i nf u si o n of 
C 1 D 8 d o s e  
1 0 2  
1 0 6  
- 
1 
1 5  
1 6 8  h ( ± 8 h) p o st st art of i nf u si o n of 
C 1 D 8 d o s e  
1 0 2  
1 0 7  
2 0 6  
2 
1 
Pr e -C 2  d o s e ( 0 h) d / 3 3 6  h p o st C 1 D 8 
d o s e  
1 0 3/ 1 0 2 e 
1 0 8  
2 0 7  
3 
1 
Pr e -C 3  d o s e ( 0 h) d / 5 0 4  h p o st C 2 
d o s e  
1 0 4/ 1 0 3 e 
1 0 9  
2 0 8  
4 
1 
Pr e -C 4  d o s e ( 0 h) d / 5 0 4  h p o st C 3 
d o s e  
1 0 5/ 1 0 4 e 
1 1 0  
2 0 9  

N o v artis  
C o nfi d e nti al  
P a g e 7 4  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol N o. C M C S 1 1 0 Z 2 2 0 1  
 
C y cl e  
D a y  
S c h e d ul e d Ti m e  
( S a m pli n g wi n d o w)a 
D o s e 
R ef er e n c e  I D  
( M C S 1 1 0)b  
P K S a m pl e 
N o 
( M C S 1 1 0)b  
C S F -1 
S a m pl e 
N o b  
4 
1 
1 h ( ± 5 mi n) p o st e n d of i nf u si o n of 
C 4 d o s e  
1 0 5  
1 1 1  
- 
4 
2 
2 4  h ( ± 2 h) p o st st art of i nf u si o n of 
C 4 d o s e  
1 0 5  
1 1 2  
- 
4 
4 
7 2 h ( ± 6 h) p o st st art of i nf u si o n of 
C 4 d o s e  
1 0 5  
1 1 3  
- 
4 
8 
1 6 8  h ( ± 8  h) p o st st art of i nf u si o n of 
C 4 d o s e  
1 0 5  
1 1 4  
2 1 0  
4 
1 5  
3 3 6  h ( ± 2 4  h) p o st st art of i nf u si o n of 
C 4 d o s e  
1 0 5  
1 1 5  
2 1 1  
5 
1 
Pr e -C 5  d o s e ( 0 h) d / 5 0 4  h p o st C 4 
d o s e  
1 0 6/ 1 0 5 e 
1 1 6  
2 1 2  
6 
1 
Pr e -C 6  d o s e ( 0 h) d / 5 0 4  h p o st C 5 
d o s e  
1 0 7/ 1 0 6 e 
1 1 7  
2 1 3  
7 
1 
Pr e -C 7  d o s e ( 0 h) d / 5 0 4  h p o st C 6 
d o s e  
1 0 8/ 1 0 7 e 
1 1 8  
2 1 4  
8 
1 
Pr e -C 8  d o s e ( 0 h) d/ 5 0 4  h p o st C 7 
d o s e  
1 0 9/ 1 0 8 e 
1 1 9  
2 1 5  
8 
1 
1 h ( ± 5 mi n)  p o st e n d of i nf u si o n of 
C 8 d o s e  
1 0 9  
1 2 0  
- 
E O T  
- 
5 0 0 0  
6 0 0 0  
U n s c h e d ul e d  g 
- 
1 0 0 1 +  
2 0 0 1 +  
a Ti m e r el ati v e t o M C S 1 1 0  d o s e. Bl o o d s a m pl e s ( 2 m L  f or e a c h a n al yt e) ar e t o b e  c oll e ct e d fr o m t h e ar m  c o ntr a -
l at er al t o t h e i nf u si o n sit e. 
b D o s e r ef er e n c e I D  a n d P K  s a m pl e N o. ar e f or i nt er n al N o v arti s pr o c e s s e s o nl y.  
 
 
d Pr e -d o s e bl o o d s a m pl e s s h o ul d b e c oll e ct e d pri or t o st art of M C S 1 1 0  i nf u si o n.  
e T h e fir st d o s e r ef er e n c e I D  i s f or t h e fir st d o s e a d mi ni st er e d p o st t h e s a m pl e c oll e cti o n; t h e s e c o n d d o s e 
r ef er e n c e I D i s f or t h e l a st d o s e a d mi ni st er e d pri or t o t h e s a m pl e coll e cti o n.  
f If t h e a d diti o n al d o s e of M C S 1 1 0 o n  C 1 D 8 i s o mitt e d , t h e p o st -d o s e s a m pl e at C 1 D 8  s h o ul d  b e s ki p p e d.  
g U n s c h e d ul e d bl o o d s a m pl e s will b e u ni q u el y a n d s e q u e nti all y n u m b er e d a s 1 0 0 1,  1 0 0 2,  et c. f or M C S 1 1 0  P K 
s a m pl e, a n d 2 0 0 1,  2 0 0 2,  et c. f or C S F -1 s a m pl e, a n d  3 0 0 1, 3 0 0 2, et c. f or
. 
T a bl e 7- 7 
P h ar m a c o ki n eti c ( M C S 1 1 0), C S F -1  
 s a m pl e bl o o d c oll e cti o n 
l o g ( s u b s e q u e nt p ati e nt s) i n Ar m 1 ( n ot a p pli c a bl e aft er a p pr o v al of 
pr ot o c ol a m e n d m e nt 6)  
C y cl e  
D a y  
S c h e d ul e d Ti m e  
( S a m pli n g wi n d o w)a 
D o s e 
R ef er e n c e  I D  
( M C S 1 1 0)b  
P K S a m pl e 
N o 
( M C S 1 1 0)b  
C S F -1 
S a m pl e 
N o b  
1  
1  
Pr e -d o s e ( 0 h) d 
1 0 1  
1 0 1  
2 0 1  
1  
1  
1 h ( ± 5 mi n) p o st e n d of i nf u si o n  
1 0 1  
1 0 2  
2 0 2  
1 
8   
Pr e -C 1 D 8  d o s e ( 0 h) d / 1 6 8 h p o st 
C 1 D 1 d o s e  
1 0 2/ 1 0 1 e 
1 0 5  
2 0 5  
1 
8  f 
1 h ( ± 5 mi n) p o st e n d of i nf u si o n of 
C 1 D 8 d o s e  
1 0 2  
1 0 6  
- 
1 
1 5  
1 6 8  h ( ±  8 h) p o st st art of i nf u si o n of 
C 1 D 8 d o s e  
1 0 2  
1 0 7  
2 0 6  
2 
1 
Pr e -C 2  d o s e ( 0 h) d / 3 3 6  h p o st 
C 1 D 8 d o s e  
1 0 3/ 1 0 2 e 
1 0 8  
2 0 7  
3  
1  
Pr e -C 3  d o s e ( 0 h) d / 5 0 4  h p o st C 2 
1 0 4/ 1 0 3 e 
1 0 9  
2 0 8  

N o v artis  
C o nfi d e nti al  
P a g e 7 5  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol N o. C M C S 1 1 0 Z 2 2 0 1  
 
C y cl e  
D a y  
S c h e d ul e d Ti m e  
( S a m pli n g wi n d o w)a 
D o s e 
R ef er e n c e  I D  
( M C S 1 1 0)b  
P K S a m pl e 
N o 
( M C S 1 1 0)b  
C S F -1 
S a m pl e 
N o b  
 
d o s e  
4 
1 
Pr e -C 4  d o s e ( 0 h) d / 5 0 4  h p o st C 3 
d o s e  
1 0 5/ 1 0 4 e 
1 1 0  
2 0 9  
4 
1 
1 h ( ± 5 mi n) p o st e n d of i nf u si o n of 
C 4 d o s e  
1 0 5  
1 1 1  
- 
4 
8 
1 6 8  h ( ± 8  h) p o st st art of i nf u si o n of 
C 4 d o s e  
1 0 5  
1 1 4  
2 1 0  
4 
1 5  
3 3 6  h ( ± 2 4  h) p o st st art of i nf u si o n of 
C 4 d o s e  
1 0 5  
1 1 5  
2 1 1  
5 
1 
Pr e -C 5  d o s e ( 0 h) d / 5 0 4  h p o st C 4 
d o s e  
1 0 6/ 1 0 5 e 
1 1 6  
2 1 2  
6 
1 
Pr e -C 6  d o s e ( 0 h) d / 5 0 4  h p o st C 5 
d o s e  
1 0 7/ 1 0 6 e 
1 1 7  
2 1 3  
7 
1 
Pr e -C 7  d o s e ( 0 h) d / 5 0 4  h p o st C 6 
d o s e  
1 0 8/ 1 0 7 e 
1 1 8  
2 1 4  
8 
1 
Pr e -C 8  d o s e ( 0 h) d/ 5 0 4  h p o st C 7 
d o s e  
1 0 9/ 1 0 8 e 
1 1 9  
2 1 5  
8 
1 
1 h ( ± 5 mi n)  p o st e n d of i nf u si o n of 
C 8 d o s e  
1 0 9  
1 2 0  
- 
E O T  
- 
5 0 0 0  
6 0 0 0  
U n s c h e d ul e d  g 
- 
1 0 0 1 +  
2 0 0 1 +  
a Ti m e r el ati v e t o M C S 1 1 0  d o s e. Bl o o d s a m pl e s ( 2 m L  f or e a c h a n al yt e) ar e t o b e  c oll e ct e d fr o m t h e ar m  c o ntr a -
l at er al t o t h e i nf u si o n sit e. 
b D o s e r ef er e n c e I D  a n d P K  s a m pl e N o. ar e f or i nt er n al N o v arti s pr o c e s s e s o nl y.  
 
 
d Pr e -d o s e bl o o d s a m pl e s s h o ul d b e c oll e ct e d pri or t o st art of M C S 1 1 0  i nf u si o n.  
e T h e fir st d o s e r ef er e n c e I D  i s f or t h e fir st d o s e a d mi ni st er e d p o st t h e s a m pl e c oll e cti o n; t h e s e c o n d d o s e 
r ef er e n c e I D i s f or t h e l a st d o s e a d mi ni st er e d pri or t o t h e s a m pl e coll e cti o n.  
f If t h e a d diti o n al d o s e of M C S 1 1 0 o n  C 1 D 8 i s o mitt e d, t h e  p o st -d o s e s a m pl e at C 1 D 8  s h o ul d  b e s ki p p e d.  
g U n s c h e d ul e d bl o o d s a m pl e s will b e u ni q u el y a n d s e q u e nti all y n u m b er e d a s 1 0 0 1,  1 0 0 2,  et c. f or M C S 1 1 0  P K 
s a m pl e, a n d 2 0 0 1,  2 0 0 2,  et c. f or C S F -1 s a m pl e, a n d  3 0 0 1, 3 0 0 2, et c. f or
. 
F oll o wi n g  l o c al  I R B/ E C  a p pr o v al  of  pr ot o c ol  a m e n d m e nt  6,  p h ar m a c o ki n etic  s a m ple 
c olle cti o n f or  c ar b o/ ge m will n o l o n ger b e re q uire d b y t h e pr ot oc ol.  
T a bl e 7- 8 
P h ar m a c o ki n eti c ( c ar b o/ g e m) s a m pl e bl o o d c oll e cti o n l o g i n b ot h Ar m 
1 a n d Ar m 2  ( n ot a p pli c a bl e aft er a p pr o v al of pr ot o c ol a m e n d m e nt 6) 
C y cl e  
D a y  
S c h e d ul e d Ti m e  
( S a m pli n g wi n d o w)a 
D o s e 
R ef er e n c e 
I D ( g e m)b  
P K 
S a m pl e 
N o ( g e m) b  
D o s e 
R ef er e n c e 
I D ( c ar b o)b  
P K S a m pl e 
N o ( c ar b o) b  
1  
1  
Pr e -d o s e ( 0 h) c 
2 0 1  
4 0 1  
3 0 1  
5 0 1  
1  
1  
E n d of G e m i nf u si o n ( ± 5 mi n)  
2 0 1  
4 0 2  
- 
- 
1  
1  
E n d of C ar b i nf u si o n ( ± 5 mi n)  
2 0 1  
4 0 3  
3 0 1  
5 0 2  
1 
1 
2 h ( ± 1 0 mi n) p o st st art of i nf u si o n of 
g e m d o s e  
2 0 1  
4 0 4  
3 0 1  
5 0 3  
1 
1 
3 h ( ± 1 0 mi n) p o st st art of i nf u si o n of 
g e m d o s e  
2 0 1  
4 0 5  
3 0 1  
5 0 4  
1 
1 
5 h ( ± 3 0 mi n) p o st st art of i nf u si o n of 
g e m d o s e  
2 0 1  
4 0 6  
3 0 1  
5 0 5  
1  
2  
2 4  h ( ± 2 h) p o st st art of i nf u si o n of 
2 0 1  
4 0 7  
3 0 1  
5 0 6  

N o v artis  
C o nfi d e nti al  
P a g e 7 6  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol N o. C M C S 1 1 0 Z 2 2 0 1  
 
C y cl e  
D a y  
S c h e d ul e d Ti m e  
( S a m pli n g wi n d o w)a 
D o s e 
R ef er e n c e 
I D ( g e m)b  
P K 
S a m pl e 
N o ( g e m) b  
D o s e 
R ef er e n c e 
I D ( c ar b o)b  
P K S a m pl e 
N o ( c ar b o) b  
g e m d o s e  
4  
1  
Pr e -d o s e ( 0 h) c 
2 0 2  
4 0 8  
3 0 2  
5 0 7  
4  
1  
E n d of C 4 D 1  g e m i nf u si o n ( ± 5 mi n)  
2 0 2  
4 0 9  
- 
- 
4  
1  
E n d of C 4 D 1  c ar b i nf u si o n ( ± 5 mi n)  
2 0 2  
4 1 0  
3 0 2  
5 0 8  
4 
1 
2 h ( ± 1 0 mi n) p o st st art of i nf u si o n of 
C 4 D 1 g e m d o s e  
2 0 2  
4 1 1  
3 0 2  
5 0 9  
4 
1 
3 h ( ± 1 0 mi n) p o st st art of i nf u si o n of 
C 4 D 1 g e m d o s e  
2 0 2  
4 1 2  
3 0 2  
5 1 0  
4 
1 
5 h ( ± 3 0 mi n) p o st st art of i nf u si o n of 
C 4 D 1 g e m d o s e  
2 0 2  
4 1 3  
3 0 2  
5 1 1  
4 
2 
2 4  h ( ± 2 h) p o st st art of i nf u si o n of 
C 4 D 1 g e m d o s e  
2 0 2  
4 1 4  
3 0 2  
5 1 2  
a Bl o o d s a m pl e s ( 1 m L  f or g e m a n d 1  m L f or c ar b o) ar e t o b e c oll e ct e d fr o m t h e ar m  c o ntr a -l at er al t o t h e i nf u si o n 
sit e.  
b D o s e r ef er e n c e I D  a n d P K  s a m pl e N o. ar e f or i nt er n al N o v arti s pr o c e s s e s o nl y.  
c Pr e -d o s e bl o o d s a m pl e s h o ul d b e c oll e ct e d pri or t o st art of g e m i nf u si o n f or g e m P K s a m pl e, a n d pri or t o st art of 
c ar b o i nf u si o n f or c ar b o P K s a m pl e, r e s p e cti v el y.  
7. 2. 3. 2  
A n al yti c al m et h o d s  
Fr e e M C S 1 1 0  
Fre e M C S 1 1 0 ( u n b o u n d dr u g) will b e d eter mi n e d i n s er u m b y a v ali d ate d E n z y m e Li n k e d 
I m m u n os or b e nt Ass a y ( E LI S A) wit h a l o w er li mit of q u a ntific ati o n ( L L O Q) at 2 0 n g/ m L a n d  
a n u p p er li mit of q u a ntific ati o n ( U L O Q) at 1 0 0 0 n g/ m L. T h e E LI S A m et h o d us es C S F -1 as 
t h e c a pt ure re a ge nt a n d a n a nti-h u m a n I g G c o nj u gate as t h e d ete cti o n re a ge nt.  T h e d etaile d 
m et h o d  d es cri pti o ns  o f  t h e  fre e  M C S 1 1 0  ass a y  will b e  i n cl u d e d  i n  t h e  c orres p o n di n g 
bi o a n al ytic al d ata re p ort.  
T ot al C S F - 1 
T otal  C S F -1  will  b e  d eter mi n e d  i n  plas m a  ( K 2  E D T A)  b y a v ali d ate d E n z y m e Li n k e d 
I m m u n o S or b e nt Ass a y ( E LI S A) wit h a n a ntici p ate d L L O Q at 1. 5 n g/ m L a n d a n U L O Q at 4 8 
n g/ m L.  
T h e E LI S A m et h o d us es a g o at a nti -h u m a n C S F -1 a nti b o d y as t h e c a pt ure re a ge nt a n d a 
ra b bit  a nti-h u m a n  C S F -1 a n d a g o at a nti -ra b bit c o nj u gate as t h e d ete cti o n re a ge nts. T h e 
d etaile d m et h o d d es cri pti o ns of t h e t otal C S F -1 ass a ys will b e i n c l u d e d i n t h e c orr e s p o n di n g 
bi o a n al ytic al d ata re p ort.  

N o v artis  
C o nfi d e nti al  
P a g e 7 7  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol N o. C M C S 1 1 0 Z 2 2 0 1  
 
C a r b o  
Plas m a ( K 2 E D T A) c o n c e ntrati o n of c ar b o plati n will b e d eter mi n e d b y a v ali d ate d ass a y 
usi n g ultra -filtrati o n a n d a n al ysis of t h e filtrate b y li q ui d c hr o m at o gra p h y - ta n d e m m ass 
s p e ctr o m etr y ( L C-M S/ M S) wit h a n a ntici p ate d L L O Q at 2 n g/ m L usi n g 5 0 μ L of plas m a. T h e  
d etaile d m et h o d d es cri pti o ns of t h e c ar b o plati n ass a y will b e i n cl u d e d i n t h e c orr e s p o n di n g 
bi o a n al ytic al d ata re p ort.  
G e m a n d d F d U  
Plas m a ( Lit hi u m H e p ari n) c o n c e ntrati o n of ge m  a n d d F d U (t h e pri m ar y m eta b olite) will b e 
d eter mi n e d b y a v ali d ate d c o n c o mita nt ass a y usi n g pr otei n pre ci pitati o n a n d a n al ysis of 
re c o nstit ute d s a m ple b y L C-M S/ M S wit h a nti ci p ate d L L O Qs at 0. 5 n g/ m L f or ge m cita bi n e 
a n d 5 n g/ m L f or d F d U usi n g 5 0 μ L of plas m a. T h e d etaile d m et h o d d es cri pti o ns of  t h e g e m 
a n d d F d U ass a y will b e i n cl u d e d i n t h e c orres p o n di n g bi o a nal ytic al d ata re p ort.  
7. 2. 4  
Bi o m ar k er s  
F oll o wi n g l o c al I R B/ E C a p pr o v al of  pr ot o c ol a m e n d m e nt 6, bi o m ar k er s a m ple c olle cti o ns 
will n o l o n ger b e re q uire d b y t h e pr ot o c ol.  
As o utli n e d i n Ta ble 7 - 9, bi o m ar k er a n al ys es will b e us e d t o i n v esti gate t h e effe ct of M C S 1 1 0 
at t h e m ole c ular a n d c ell ular le v el t o d eter mi n e h o w b as eli n e bi o m ar ker stat us a n d/ or c h a n ge s 
fr o m b as eli n e v al u es m a y relate t o e x p os ure, cli nic al o utc o me, a n d/ or resista n ce m e c ha nis ms. 
T h e c o n c e pt f or t his st u d y is t h at i n d u cti o n of a n i m m u ne res p o ns e t o c h e m ot h era p y m a y le a d 
t o  e n h a n c e d  t u m or  res p o ns es.  M C S 1 1 0  is  a n  a nti b o d y  dire cte d  t o w ar ds  C S F-1  w hic h  
s u p press es t h e d e v el o p m e nt a n d s ur vi v al of T A Ms. M ore o v er, s e veral st u dies h a v e s h o w n t hat 
T A M d e pleti o n le a ds t o i n d u cti o n of a n i m m u n e res p o ns e b y a cti v ati o n of C D 8 + T -c ells 
(D e N ar d o  2 0 1 1, Ries 2 0 1 4 ). O nl y p atie nts wit h a hi g h c o nte nt of T A Ms ( C D 1 6 3 +), t h e tar g et 
c ell f or M C S 1 1 0, i n t h eir t u m or tiss u e will b e eli gi ble f or p artici p ati o n i n t his st u d y.  
Cli nic al st u dies h a v e s h o w n t h at c h e m ot h era p y res p o nse is hi g h er i n p atie nts w h o s e t u m or s 
h a v e hi g h TI L c o nte nt ( v o n Mi n c k wietz 2 0 1 4 ). A d diti o n all y, it h as b e e n s h o wn i n pre cli ni c al 
m o d els t h at a b asic le v el of TI Ls is n e e d e d t o get a n a d diti o n al eff e ct of T A M d e pleti o n 
re gar di n g i m m u n o ge nic res p o ns e a n d e n h a n c e d c h e m ot h era p y res p o ns e (R uffell, 2 0 1 4 ). T h us, 
TI L c o u nts as d eter mi n e d b y C D 8 pr otei n e x pr essi o n will als o b e e x a mi ne d i n p r e  a n d p o st -
d os e t u m or s a m ples.  
All bi o psies i n Ta ble 7 - 9 are m a n d at or y a n d  m ust b e o btai n e d , if m e dic all y f e asi ble. 
W hile t h e g o al of t h e bi o m ar k er ass ess m e nts is t o pr o vi d e s u p p orti v e d ata f or t h e cli nic al 
st u d y, t h ere m a y b e circ u msta n c es w h e n a d e cisi o n is m a d e t o st o p a c olle cti o n, or n ot 
p erf or m or dis c o nti n u e a n a n al ysis d u e t o eit h er pra ctic al or strate gic re as o ns (e. g., i n a d e q uate 
s a m ple n u m b er, iss u es relate d t o t h e q u alit y of t h e s a m ple or iss u es relate d t o  t h e  a s s a y  t h a t 
pre cl u d e a n al ysis, i m p ossi bilit y t o p erf or m c orrelati v e a n al ys es, etc.). T h eref or e, d e p e n di n g 
o n t h e res ults o btai n e d d uri n g t h e st u d y, s a m ple c olle cti o n a n al ysis m a y b e o mi tte d at t h e 
dis creti o n of N o v artis.  

N o v artis  
C o nfi d e nti al  
P a g e 8 1  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol N o. C M C S 1 1 0 Z 2 2 0 1  
 
A d v ers e e v e nts will b e ass ess e d a n d gra d e d a c c or di n g t o t h e C o m m o n Ter mi n ol o g y Crit eri a 
f or A d v ers e E v e nts ( C T C A E) v ersi o n 4. 0 3.  
If C T C A E gra di n g d o es n ot e xist f or a n a d v ers e e v e nt, t h e s e v erit y of mil d, m o derate, s e v er e, 
a n d lif e -t hre ate ni n g, c orres p o n di n g t o  Gra d es 1 - 4, will b e us e d. C T C A E Gra d e 5 ( d e at h) will 
n ot b e us e d i n t his st u d y  b ut is c olle cte d as a s eri o us n ess criteria ; rat h er, i nf or m ati o n a b o ut 
d e at hs will b e c olle cte d t h o u g h a D e at h f or m.  
T h e o c c urre n c e of a d v ers e e v e nts s h o ul d b e s o u g ht b y n o n -directi v e q uesti o ni n g of t h e p atie nt 
(s u bje ct) d uri n g t h e s cre e ni n g pr o c ess after si g ni n g i nf orm e d c o ns e nt a n d at e a c h visit d uri n g 
t h e st u d y. A d v ers e e v e nts als o m a y b e d ete cte d w h e n t h e y are v ol u nte ere d b y t h e p atie nt 
(s u bje ct) d uri n g t h e s cre e ni n g pr o c ess or b et w e e n visits, or t hr o u g h p h ysic al e x a mi n ati o n, 
la b orat or y  test,  or ot h er ass ess m e nts. As f ar as p ossi ble, e a c h a d v ers e e v e nt s h o ul d b e 
e v al u ate d t o d eter mi n e:  
1.  T h e s e v erit y gra d e ( C T C A E Gra d e 1 -4)  
2.  Its d urati o n ( Start a n d e n d d ates) 
3.  Its relati o ns hi p t o t h e st u d y tre at m e nt ( Re as o n a ble p ossi bilit y t h at A E is relate d: N o, Y es) 
4.  A cti o n ta k e n wit h r es p e ct t o st u d y or i n v esti gati o n al tre at m e nt ( n o ne, d os e a dj uste d, 
te m p oraril y i nterr u pte d, p er m a ne ntl y dis c o nti n ue d, u n k n o w n, n ot a p plic a ble) 
5.  W h et h er m e dic ati o n or t h era p y w as gi v e n ( n o c o nc o mita nt m e dic ati o n/ n o n -dr u g t h era p y, 
c o n c o mita nt m e dic ati o n/ n o n- dr u g t h era p y) 
6.  O utc o m e ( n ot re c o v ere d/ n ot res ol v e d, re c o vere d/res ol v e d, re c o veri n g/res ol vi n g, 
re c o v ere d/res ol v e d wit h s e q u ela e, fatal, u n k n o w n) 
7.  W h et h er it is s eri o us, w h ere a s eri o us a d v erse e v e nt ( S A E) is d efi n e d as i n Se cti o n 8. 2. 1  
a n d w hic h s eri o us n ess criteria h a v e b e e n m et   
All a d v ers e e v e nts s h o ul d b e tre ate d a p pr o priatel y. If a c o n c o mita nt m e dic ati o n or n o n -dr u g 
t h era p y is gi v e n, t his a cti o n s h o ul d b e re c or de d o n t h e A d v ers e E v e nt C R F. 
O n c e a n a d v ers e e v e nt is d ete cte d, it s h o ul d b e f oll o w e d u ntil its res ol uti o n or u ntil it is 
j u d ge d t o b e p er m a n e nt, a n d ass ess me nt s h o ul d b e m a d e at e a c h visit ( or m ore fr e q u e ntl y, if  
n e c ess ar y) of a n y c h a n ges i n s e v erit y, t h e s us p e cte d relati o ns hi p t o t h e st u d y tr e at m e nt, t h e 
i nter v e nti o ns re q uire d t o tre at it, a n d t h e o utc o m e. 
Pr o gressi o n of m ali g n a n c y (i n cl u di n g f atal o utc o mes), if d o c u m e nte d b y u s e of a p pr o pri at e 
m et h o d (f or e x a m ple, as p er R E CI S T criteria f or s oli d t u m ors), s h o ul d n ot b e re p orte d as a 
s eri o us a d v ers e e v e nt. 
A d v ers e e v e nts s e p arate fr o m t h e pr o gressi o n of m ali g n a nc y (e x a m ple, d e e p v ei n t hr o m b osis 
at t h e ti m e of pr o gressi o n or h e m o pt ysis c o nc urre nt wit h fi n di n g of dis e as e pr o gressi o n) will 
b e re p orte d as p er us u al g ui d eli n es us e d f or s u c h e v e nts wit h pr o p er attri b uti o n re gar di n g 
relate d n ess t o t h e dr u g. 
8. 1. 2  
L a b or at or y a b n or m aliti e s  
8. 1. 2. 1  
D efi niti o n a n d r e p orti n g  
La b orat or y a b n or malities t h at c o nstit ute a n A d v ers e e v e nt i n t h eir o w n ri g ht (ar e c o n si d er e d 
cli nic all y si g nific a nt, i n d u c e cli nic al si g ns or s y m pt o ms, re q uire c o n c o mita nt t h era p y or 

N o v artis  
C o nfi d e nti al  
P a g e 8 2  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol N o. C M C S 1 1 0 Z 2 2 0 1  
 
re q uire  c h a n ges i n  st u d y  tre at m e nt), s h o ul d  b e  re c or d e d  o n  t h e  A d v ers e  E ve nts  C R F.  
W h e n e v er p ossi ble, a dia g n osis, rat h er t h a n a s y m pt o m s h o ul d b e pr o vi d e d (e. g. a n e mia 
i nste a d of l o w h e m o gl o bi n). La b orat or y a b n or m alities t h at m e et t h e criteria f or A d v ers e 
E v e nts s h o ul d b e f oll o we d u ntil t h e y h a v e ret ur n e d t o n or m al or a n a d e q u ate e x pl a n ati o n of 
t h e a b n or m alit y is f o u n d. W h e n a n a b n or m al la b orat or y or test res ult c orres p o n ds t o a 
si g n/s y m pt o m of a n alre a d y re p orte d a d vers e e v e nt, it is n ot n e c ess ar y t o s e p aratel y re c or d t h e 
la b/test res ult as a n a d diti o n al e v e nt. 
La b orat or y a b n or malities, t h at d o n ot m e et t h e d efi niti o n of a n a d vers e e v e nt, s h o ul d n ot b e 
re p orte d  as  a d v ers e  e v e nts.  A  Gra d e  3  or  4  e v e nt  (s e v ere)  as  p er  C T C A E  d o es  n ot  
a ut o m atic all y i n dic ate a S A E u nless it m e ets t h e d efi niti o n of s eri o us as d efi n e d b el o w a n d/ o r 
as p er i n v esti gat or’s dis creti o n. A d os e h ol d or m e dic ati o n f or t h e la b a b n or m alit y m a y b e 
re q uire d b y t h e pr ot o c ol i n w hic h c as e t h e la b a b n or m alit y w o ul d still, b y d efi niti o n, b e a n 
a d v ers e e v e nt a n d m ust b e re p orte d as s u c h.  
8. 2  
S eri o u s a d v er s e e v e nt s  
8. 2. 1  
D efi niti o n s  
Seri o us a d v ers e e v e nt ( S A E) is d efi n e d as o n e of t h e f oll o wi n g:  
•  Is f atal or lif e-t hre ate ni n g 
•  Res ults i n p ersiste nt or si g nific a nt dis a bilit y/i n c a pa cit y  
•  C o nstit utes a c o n ge nital a n o m al y/ birt h d efe ct  
•  Is m e dic all y si g nific a nt, i. e., d efi n e d as a n e v e nt t h at je o p ar diz es t h e p atie nt or m a y 
re q uire m e dic al or s ur gic al i nter v e nti o n t o pre v e nt o n e of t h e o utc o m es liste d a b o v e 
•  Re q uires i n p atie nt h os pitaliz ati o n or pr ol o n gati o n of e xisti n g h os pitaliz ati o n,  
•  N ote t h at h os pitaliz ati o ns f or t h e f oll o wi n g re as o ns s h o ul d n ot b e re p orte d as s eri o us 
a d v ers e e v e nts: 
•  R o uti n e tre at m e nt or m o nit ori n g of t h e st u die d i n dic ati o n, n ot ass o ciate d wit h a n y 
d eteri orati o n i n c o n diti o n  
•  Ele cti v e or pre -pla n n e d tre at m e nt f or a pre -e xisti n g c o n diti o n t h at is u nrelate d t o t h e 
i n dic ati o n u n d er st u d y a n d h as n ot w ors e ne d si n c e si g ni n g t h e i nf or m e d c o ns e nt  
•  S o cial re as o ns a n d res pite c are i n t h e a bs e nc e of a n y d eteri orati o n i n t h e p atie nt’s ge n eral 
c o n diti o n  
•  N ote t h at tre at m e nt o n a n e m er ge n c y o ut patie nt b asis t h at d o es n ot res ult i n h os pital  
a d missi o n a n d i n v ol ves a n e v e nt n ot f ulfilli n g a n y of t h e d efi niti o ns of a S A E gi v e n a b o v e 
is n ot a s eri o us a d v ers e e v e nt 
Pr o gressi o n of u n d erl yi n g m ali g n a n c y is n ot re p orte d as a n a d v ers e e v e nt if it is cle arl y 
c o nsiste nt wit h t h e s us p e cte d pr o gressi o n of t h e u n d erl yi n g c a n c er as d efi n e d b y R E CI S T 
criteria,  or  ot h er  criteria  as  d eter mi n e d  b y  pr ot o c ol.  H os pitaliz ati o n  d u e  s olel y  t o  t h e  
pr o gressi o n of u n derl yi n g m ali g n a n c y s h o ul d N O T b e re p orte d as a s eri o us a d v erse e v e nt.  
Cli nic al s y m pt o ms of pr o gressi o n m a y b e re p orte d as a d v ers e e v e nts if t h e s y m pt o m c a n n ot 
b e d eter mi n e d as e x cl usi vel y d ue t o t h e pr o gressi o n of t h e u n d erl yi n g m ali g n a n c y, or d o es n ot 
fit t h e e x p e cte d p atter n of pr o gressi o n f or t h e dis e as e u n der st u d y. 

N o v artis  
C o nfi d e nti al  
P a g e 8 3  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol N o. C M C S 1 1 0 Z 2 2 0 1  
 
S y m pt o m atic  d eteri orati o n  m a y  o c c ur i n  s o m e p atie nts. I n t his sit u ati o n, pr o gressi o n is 
e vi d e nt i n t h e p atie nt’s cli nic al s y m pt o ms, b ut is n ot s u p p orte d b y t h e t u m or m e a s ur e m e nts. 
Or, t h e dis e as e pr o gressi o n is s o e vi d e nt t h at t h e i n v esti gat or m a y ele ct n ot t o p erf or m f urt h er 
dis e as e ass ess m e n ts. I n s u c h c as es, t h e d eter mi n ati o n of cli nic al pr o gressi o n is b as e d o n 
s y m pt o m atic d eteri orati o n. T h es e d eter mi nati o ns s h o ul d b e a rare e x c e pti o n a s e v er y eff ort 
s h o ul d b e m a d e t o d o c u m e nt t h e o bje cti v e pr o gressi o n of u n derl yi n g m ali g n a n c y. 
If t h ere is a n y u n c ertai nt y a b o ut a n a d vers e e v e nt b ei n g d u e o nl y t o t h e dis e as e u n d er st u d y, it 
s h o ul d b e re p orte d as a n A E or S A E. 
8. 2. 2  
R e p orti n g  
T o e ns ure p atie nt s af et y, e v er y S A E, re gar dless of s us p e cte d c a us alit y, o c c urri n g after t h e 
p atie nt h as pr o vi d e d i nf or me d c o n s e nt a n d u ntil at le ast  9 0 d a ys after t h e p atie nt h as st o p p e d 
st u d y tre at m e nt m ust b e re p orte d t o N o v artis wit hi n 2 4 h o urs of le ar ni n g of its o c c urre n ce.  
A n y S A Es e x p erie n c e d after t his 9 0 d a ys p eri o d or o n ce a p atie nt b e gi ns a n ot h er a nti -c a n c er 
tre at m e nt s h o ul d o nl y b e re p orte d t o N o v artis if t h e i n v esti gat or s us pe cts a c a usal relati o ns hi p 
t o t h e st u d y tre at m e nt. Re c urre nt e pis o d es, c o m plic ati o ns, or pr o gressi o n of t h e i nitial S A E 
m ust b e re p orte d as f oll o w -u p t o t h e ori gi n al e pis o d e  wit hi n 2 4 h o urs of t h e i n v esti gat or 
re c ei vi n g  t h e  f oll o w-u p  i nf or m ati o n. A n  S A E o c c urri n g at a  diff ere nt ti m e  i nter v al or 
ot h er wis e c o nsi d ere d c o m pletel y u nrelate d t o a pre vi o usl y re p orte d o n e s h o ul d b e r e p ort e d 
s e p aratel y as a n e w e v e nt. 
I nf or m ati o n a b o ut all S A Es is c olle cted a n d re c or d e d o n t h e Seri o us A d v ers e E v e nt Re p ort 
F or m; all a p plic a ble s e cti o ns of t h e f or m m ust b e c o m plete d i n or d er t o pr o vi d e a cli ni c all y 
t h or o u g h re p ort. T h e i n v esti gat or m ust ass ess a n d re c or d t h e relati o nshi p of e a c h S A E t o e a c h 
s p e cific st u d y tre at m e nt (if t h ere is m ore t h a n o n e st u d y tre at m e nt), c o m plete t h e S A E Re p o rt 
F or m  i n  E n glis h,  a n d  s u b mit t h e  c o m plete d  f or m wit hi n 2 4 h o urs t o N o v artis. D etaile d 
i nstr u cti o ns re gar di n g t h e s u b missi o n pr oc ess a n d re q uire m e nts f or si g n at ures are t o b e f o u n d 
in t h e i n v esti gat or f ol d er pr o vi d e d t o e a c h site.  
 F oll o w -u p i nf or m ati o n is s u b mitte d i n t h e s a m e w a y as t h e ori gi n al S A E Re p ort.  Ea c h re -
o c c urre n c e, c o m plic ati o n, or pr o gressi o n of t h e ori gi n al e v e nt s h o ul d b e re p orte d as a f oll o w -
u p t o t h at e v e nt re gar dless of w h e n it o c c urs. T h e f oll o w -u p i nf or m ati o n s h o ul d d es cri b e 
w h et h er t h e e v e nt h as res ol v e d or c o nti n u es, if a n d h o w it w as tre ate d, w h et h er t h e bli n d w a s 
br o k e n or n ot, a n d w h et her t h e p atie nt c o nti n ue d or wit h dre w fr o m st u d y p artici p ati o n.  
If t h e S A E is n ot pre vi o usl y d o c u m e nte d i n t h e I n v esti gat or’s Br o c h ure or Pa c k a ge I ns ert 
( n e w o c c urre n c e) a n d is t h o u g ht t o b e relate d t o t h e N o v artis st u d y tre at m e nt, a n o n c ol o g y 
N o v artis C hief Me dic al Offic e a n d Patie nt Saf et y (C M O & P S ) d e p art m e nt ass o ciate m a y 
ur ge ntl y re q uire f urt h er i nf or m ati o n fr o m t h e i n v esti gat or f or H e alt h A ut h orit y re p orti n g. 
N o v artis m a y n e e d t o iss u e a n I n v esti gat or N otific ati o n (I N), t o i nf or m all i n v esti gat ors 
i n v ol v e d  i n  a n y  st u d y  wit h  t h e  s a m e  dr u g t h at t his S A E h as b e e n  re p orte d. S us p e cte d 
U n e x p e cte d Seri o us A d v ers e Re a cti o ns ( S U S A Rs) will b e c olle cte d a n d re p orte d t o t h e 
c o m p ete nt  a ut h orities  a n d  rele v a nt  et hics  c o m mitte es  i n  a c c or d a n c e  wit h  Dire cti v e  
2 0 0 1/ 2 0/ E C or as p er n ati o n al re g ulat or y re q uire me nts i n p artici p ati n g  c o u ntries.  

N o v artis  
C o nfi d e nti al  
P a g e 8 4  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol N o. C M C S 1 1 0 Z 2 2 0 1  
 
8. 3  
Pr e g n a n ci e s  
T o e ns ure p atie nt s af et y, e a c h pre g n a n c y o c c urri n g w hile t h e p atie nt is o n st u d y tre at m e nt 
m ust b e re p orte d t o N o v artis wit hi n 2 4 h o urs of le ar ni n g of its o c c urre nc e.  
F urt h er m ore, a n y pre g n a n cies o c c urri n g after dis c o nti n u ati o n of st u d y tre at m e nt ( u p t o 9 0 
d a ys or d uri n g t h e  p ost tre at m e nt c o ntra c e pti o n  p eri o d  as re c o m m e n d e d  p er t h e  l o c al 
a p pr o v e d la b els, w hic h e v er h as t h e l o n gest d urati o n) m ust b e re p orte d t o N o v artis wit hi n 2 4 
h o urs of le ar ni n g of its o c c urre n c e.  
T h e  pre g n a n c y  s h o ul d b e f oll o w e d u p t o d eter mi n e o utc o m e, i n cl u di n g s p o nta n e o us or 
v ol u ntar y ter mi n ati o n, d etails of t h e birt h, a n d t h e prese n ce or a bs e nc e of a n y birt h d ef e cts, 
c o n ge nital a b n or m alities, or m ater nal a n d/ or n e w b or n c o m plic ati o ns.   
Pre g n a n c y  s h o ul d  b e  re c or d e d o n a Cli nic al Trial Pre g n a n c y F or m a n d re p orte d b y t h e 
i n v esti gat or t o t h e o n c ol o g y N o v artis C hief Me dic al Offic e a n d Patie nt Saf et y  (C M O & P S ). 
Pre g n a n c y f oll o w -u p s h o ul d b e re c or d e d o n t h e s a m e f or m a n d s h o ul d i n cl u d e a n ass e s s m e nt 
of  t h e  p ossi ble  rela ti o ns hi p  t o  t h e  st u d y  tre at m e nt a n y  pre g n a n c y  o utc o m e. A n y  S A E 
e x p erie n c e d d uri n g pre g n a nc y m ust b e re p orte d o n t h e S A E Re p ort F or m.  
If a pre g n a n c y o c c urs w hile o n st u d y tre at m e nt, t h e n e w b or n will b e f oll o w e d f or at l e a st 3 
m o nt hs.  
8. 4  
W ar ni n g s  a n d pr e c a uti o n s 
N o e vi d e n c e a v aila ble at t h e ti m e of t h e a p pr o val of t his st u d y pr ot oc ol i n dic ate d t h at s p e ci al 
w ar ni n gs or pre c a uti o ns w ere a p pr o priate, ot h er t h a n t h os e n ote d i n t h e pr o vi d e d I n v esti g at or 
Br o c h ure. A d diti o n al s af et y i nf or m ati o n c olle cte d b et w e e n I B u p d ates will b e c o m m u ni c at e d 
i n t h e f or m of I n v esti gat or N otific ati o ns. T his i nf or m ati o n will b e i n cl u d e d i n t h e p atie nt 
i nf or m e d c o ns e nt a n d s h o ul d b e dis c uss e d wit h t h e p atie nt d uri n g t h e st u d y as n e e de d. 
8. 5  
St e eri n g C o m mitt e e  
D uri n g t h e s af et y re vie w (s), s af et y pr ofiles of all t h e p atie nts w h o re c ei v e tre at m e nt i n t h e 
st u d y will b e re vie w e d. T h e d etaile d pr o c e d ure  of t h e s af et y re vie w m e eti n gs are s p e cifi e d i n 
Se cti o n 4. 1 . After t h e e arl y s af et y re vie w(s), i n di vi d u al p atie nt d ata will s u bs e q u e ntl y b e 
re vie w e d o n a n o n g oi n g b asis a n d dis c uss e d wit h I n v esti gat ors t hr o u g h o ut t h e d urati o n of t h e 
trial. Ag gre gate s af et y d ata a n d t h e pri m ar y e n d p oi nt will b e m o nit o re d q u arterl y b y t h e st u d y 
te a m. T his d ata m o nit ori n g will b e b as e d o n t h e a v aila ble d ata i n t h e cli nic al d ata b as e ( s e e 
Se cti o n 1 0. 7 ) at t h e res p e cti v e ti m e. 
A  Ste eri n g  C o m mitte e  c o nstit ute d  of  m e m b ers  of  t h e  N o v artis  Tra nslati o n al  Cli nic al  
O n c ol o g y  Le a d ers hi p Te a m will b e f or m e d f or t his st u d y. If t h e m o nit ori n g of t h e st u d y d at a 
re q uires a d e cisi o n t o b e ta k e n o n t h e c o nti n u ati o n of t h e st u d y, t h e n t h e rel e v a nt d at a ( e. g., 
s af et y  d ata  or  pri m ar y  a n al ysis  a n d  pre dicti v e  pr o b a bilit y  of  s u c c ess  ( P P O S) )  will  b e  
c o m m u nic ate d t o t h e Ste eri n g C o m mitte e f or d e cisi o n m a ki n g p ur p os es. 

N o v artis  
C o nfi d e nti al  
P a g e 8 5  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol N o. C M C S 1 1 0 Z 2 2 0 1  
 
9 
D at a c oll e cti o n a n d m a n a g e m e nt  
9. 1  
D at a c o nfi d e nti alit y  
I nf or m ati o n a b o ut st u d y s u bjects will b e k e pt c o nfi d e ntial a n d m a n a ge d u n d er t h e a p pli c a bl e 
la ws a n d re g ulati o ns. T h os e re g ulati o ns re q uire a si g n e d s u bje ct a ut h oriz ati o n i nf or mi n g t h e 
s u bje ct of t h e f oll o wi n g: 
•  W h at pr ote cte d h e alt h i nf or m ati o n ( P HI) will b e c olle cte d fr o m s u bje cts i n t his st u d y  
•  W h o will h a v e a c c ess t o t h at i nf or m ati o n a n d w h y  
•  W h o will us e or dis cl os e t h at i nf or m ati o n 
•  T h e ri g hts of a res e arc h s u bje ct t o re v o ke t h eir a ut h oriz ati o n f or us e of t h eir P HI.  
I n t h e e v e nt t h at a s u bje ct re v o k es a ut h oriz ati o n t o c olle ct or us e P HI, t h e i n v esti gat or, b y 
re g ulati o n, retai ns t h e a bilit y t o us e all i nf or m ati o n c olle cte d pri or t o t h e re v o cati o n of s u bje ct 
a ut h oriz ati o n. F or s u bje cts t h at h a v e re v o k e d a ut h oriz ati o n t o c olle ct or us e P HI, atte m pts 
s h o ul d b e m a d e t o o btai n p er missi o n t o c olle ct f oll o w-u p s af et y i nf or m ati o n (e. g. h as t h e 
s u bje ct e x p erie n c e d a n y n e w or w ors e ne d A Es) at t h e e n d of t h eir s c h e d ule d st u d y p eri o d.  
T h e d ata c olle cti o n s yste m f or t his st u d y us es b uilt -i n s e c urit y f eat ures t o e n cr y pt all d a t a f o r 
tra ns missi o n i n b ot h dire cti o ns, pre v e nti n g u n a ut h oriz e d a c c ess t o c o nfi d e ntial p artici p a nt 
i nf or m ati o n. A c cess t o t h e s yste m will b e c o ntr olle d b y a s e q u e n ce of i n di vi d u all y a s si g n e d 
us er i d e ntific ati o n c o d es a n d p ass w or ds, m a d e a v aila ble o nl y t o a ut h oriz e d p ers o n n el w h o 
h a v e c o m plete d prere q uisite trai ni n g.  
Pri or t o e nteri n g k e y s e nsiti v e p ers o n all y i d e ntifia b le i nf or m ati o n ( S u bje ct I nitials a n d  e x a c t 
D ate of Birt h), t h e s yste m will pr o m pt site t o v erif y t h at t his d ata is all o w e d t o b e c olle cte d. If  
t h e site i n dic ates t h at c o u ntr y r ules or et hics c o m mitte e sta n dar ds d o n ot p er mit c oll e c ti o n  o f 
t h es e ite ms, t h e s yste m will n ot s olicit S u bje ct I nitials. Y e ar of birt h will b e s olicite d (i n t h e  
pla c e of e x a ct d ate of birt h) t o esta blis h t h at t h e s u bje ct s atisfies pr ot o c ol a ge re q uire m e nts  
a n d t o e n a ble a p pr o priate a ge -relate d n or m al ra n ges t o b e us e d i n ass essi n g lab orat or y test  
res ults. 
9. 2  
Sit e m o nit ori n g  
Bef ore st u d y i nitiati o n, at a site i nitiati o n visit or at a n i n v esti gat or’s m e eti n g, N o v artis 
p ers o n n el ( or d esi g n ate d C R O) will re vie w t h e pr ot o c ol a n d C R Fs wit h t h e i n v esti gat or s a n d 
t h eir staff.  D uri n g t h e  st u d y,  th e fiel d m o nit or will visit t h e site re g ularl y t o c h e c k t h e 
c o m plete n ess of p atie nt re c or ds, t h e a c c ura c y of e ntries o n t h e C R Fs, t h e a d h ere n c e t o t h e 
pr ot o c ol t o G o o d Cli nic al Pra ctic e, t h e pr o gress of e nr oll m e nt, a n d t o e ns ure t h at st u d y 
tre at m e nt is b ein g st ore d, dis p e ns e d, a n d a c c o u nte d f or a c c or di n g t o s p e cific ati o ns. K e y st u d y 
p ers o n n el m ust b e a v aila ble t o assist t h e fiel d m o nit or d uri n g t h es e visits.  
T h e i n v esti gat or m ust m ai ntai n s o urc e d o c u m e nts f or e a c h p atie nt i n t h e st u d y, c o n sisti n g of  
c as e a n d visit n otes ( h os pital or cli nic m e dic al re c or ds) c o ntai ni n g d e m o gra p hic a n d m e di c al 
i nf or m ati o n,  la b orat or y  d ata,  ele ctr o c ar di o gra ms,  a n d  t h e  res ults  of  a n y  ot h er  tests  or  
ass ess m e nts. All i nf or m ati o n re c or d e d o n C R Fs m ust b e tra c e a ble t o s o urc e d oc u me nt s i n t h e 
p atie nt's file. T h e i n v esti gat or m ust als o k e e p t h e ori gi n al si g n e d i nf or m e d c o ns e nt f or m (a 
si g n e d c o p y is gi v e n t o t h e p atie nt). 

N o v artis  
C o nfi d e nti al  
P a g e 8 6  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol N o. C M C S 1 1 0 Z 2 2 0 1  
 
T h e i n v esti gat or m ust gi v e t h e m o nit or a c c ess t o all rele v a nt s o urc e d o c u m e nts t o c o nfir m 
t h eir c o nsiste n c y wit h t h e C R F e ntries. N o v artis m o nit ori n g sta n d ar ds re q uire f ull v erific ati o n 
f or t h e pres e n c e of i nf or m e d c o ns e nt, a d h ere n c e t o t h e i n cl usi o n/e x cl usi o n criteria a n d 
d o c u m e ntati o n of S A Es. A d diti o n al c h e c ks of t h e c o nsiste n c y of t h e s o urc e d ata wit h t h e 
C R Fs are p erf or m e d a c c or di n g t o t h e st u d y -s pe cific m o nit ori n g pla n. 
9. 3  
D at a c oll e cti o n  
F or st u dies usi n g Ele ctr o nic D ata Ca pt ure ( E D C), t h e d esi g n ate d i n v esti gat or staff will e n t e r 
t h e d ata re q uire d b y t h e pr ot o c ol i nt o t h e Ele ctr o nic Cas e Re p ort F or ms (e C R F). T h e e C R Fs 
h a v e b e e n b uilt usi n g f ull y v ali d ate d s e c ure w e b -e n a ble d s oft w are t h at c o nf or ms t o 2 1 C F R 
Part 1 1 re q uire m e nts, I n vesti gat or site staff will n ot b e gi v e n a c c ess t o t h e E D C s y st e  m u n til 
t h e y h a v e b e e n trai n e d. A ut o m atic v ali d ati o n pr o gra ms c h e c k f or d ata dis cre p a n cies i n t h e 
e C R Fs a n d, all o w m o dificati o n or v erific ati o n of t h e e ntere d d ata b y t h e i n v esti gat or staff.  
T h e Pri n ci p al I n v esti gat or is res p o nsi ble f or ass uri n g t h at t h e d ata e ntere d i nt o e C R F is 
c o m plete, a c c urate, a n d t h at e ntr y a n d u p dates are p erf or me d i n a ti m el y m a n n er.  
P K s a m ples dra w n d uri n g t h e c o urs e of t h e st u d y will b e c olle cte d b y i n vesti gati o n al sites a n d 
a n al y z e d b y N o v artis d ele gate d c e ntral La b orat or y. 
Bi o m ar k er s a m ples dra w n d uri n g t h e c o urs e of t h e st u d y will b e c olle cte d b y i n ve s ti g ati o n al 
sites a n d a n al y z e d b y a N o v artis-desi g n ate d la b orat or y.  
All  E C Gs  ( u p t o c y cle 4 i n cl u d e d) c olle cte d  p er ass ess m e nt s c h e d ule Ta ble 7 - 5 will b e 
i n d e p e n d e ntl y re vie w e d b y a c e ntral la b orat or y.  C y cle 8 ( o nl y f or p atie nts i n Ar m 1) a n d E o T  
E C G’s will b e re vie w e d l o c all y . After c y cle 8 , E C Gs will b e p erf or me d at t h e dis creti o n of the 
i n v esti gat or, re p orte d o n a l o c al E C G C R F p a ge a n d n ot b e re vie w e d c e ntrall y.   
 Ra di ol o gic al ass ess m e nts o btai n e d f or p atie nts e nr olle d o n st u d y m a y b e c e ntrall y c oll e ct e d 
b y a n i m a gi n g C R O d esi g n ate d b y N o v artis a n d m a y b e ass ess e d c e ntrall y i n a d diti o n t o t h e 
l o c al ass ess m e nt if d e e m e d n e c ess ar y. T h e i n v esti gator’s staff will b e i nstr u cte d o n h o w t o 
s e n d d ata fr o m t h es e ra di ol o gic al ass ess me nts t o a C R O f or c e ntral re vie w w h e n n e e de d. 
9. 4  
D at a b a s e m a n a g e m e nt a n d q u alit y c o ntr ol  
F or st u dies usi n g e C R Fs, N o v artis p ers o n n el ( or d esi g n ate d C R O) will re vie w t h e d ata e nte re d 
b y i n v esti gati o n al staff f or c o m plete n ess a n d a c c ura c y. Ele ctr o nic d ata q u eries stati n g t h e 
n at ure of t h e pr o ble m a n d re q u esti n g clarific ati o n will b e cre ate d f or dis cre p a n cies a n d 
missi n g  v al u es  a n d  s e nt  t o  t h e  i n v esti gati o n al  site  via  t h e  E D C  s yste m.  D esi g n ate d 
i n v esti gat or site staff is re q uire d t o res p o n d pr o m ptl y t o q u eries a n d t o m a k e a n y n e c e s s ar y 
c h a n ges t o t h e d ata.  
C o n c o mita nt tre at m e nts a n d pri or m e dicati o ns e ntere d i nt o t h e d ata b as e will b e  c o d e d u si n g 
t h e  W H O  Dr u g  Dicti o n ar y ,  w hic h  e m pl o ys  t h e  A n at o mic al  T h era p e utic  C h e mic al  
classific ati o n s yste m. Me dic al hist or y/c urre nt m e dic al c o n diti o ns a n d a d v ers e e v e n ts will b e 
c o d e d usi n g t h e Me dic al dicti o n ar y f or re g ulat or y a cti vities ( Me d D R A) ter mi n ol o g y.  
P K,  bi o m ar k er s a m ples a n d E C G d ata  (o nl y u nt il c y cle 4 f or E C G) will b e pr o c ess e d c e ntrally 
a n d t h e res ults will b e s e nt ele ctr o nic all y t o N o v artis ( or a d esi g n ate d C R O).  

N o v artis  
C o nfi d e nti al  
P a g e 8 7  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol N o. C M C S 1 1 0 Z 2 2 0 1  
 
F or E D C st u dies, after d ata b as e l o c k, t h e i n v esti gat or will re c ei v e a C D -R O M or p a p er c o pies 
of t h e p atie nt d ata f or arc hi vi n g at  t h e i n v esti gati o n al site. 
Ra n d o miz ati o n c o des will b e tra c k e d usi n g a n I ntera cti v e Res p o ns e Te c h n ol o g y. T h e s y st e m 
will b e s u p plie d b y a v e n d or.  
1 0  
St ati sti c al m et h o d s a n d d at a a n al y si s  
T h e d ata will b e a n al y z e d b y N o vartis.  
It is pla n n e d t h at t h e d ata fr o m p artici p ati n g c e nters i n t his pr ot o c ol will b e c o m bi n e d, s o  t h a t 
a n a d e q u ate n u m ber of p atie nts will b e a v aila ble f or a nal ysis. T h e d ata will b e s u m m ari z e d 
wit h  res p e ct  t o  d e m o gra p hic  a n d  b as eli n e  c h ara cteristics,  effic a c y  o bs er v ati o ns  a n d  
m e as ure m e nts, s afet y o bs er v ati o ns a n d m e as ure me nts, a n d all rele v a nt p h ar m ac o ki n eti c a n d 
p h ar m a c o d y n a mic  m e as ure m e nts  usi n g  d es cri pti v e  statistics  ( q u a ntitati v e  d ata)  a n d  
c o nti n ge n c y ta bles ( q u alitati v e d ata). I n all c as es, d ata will b e a n al y z e d a n d/ or pres e nte d 
s e p aratel y f or e a c h st u d y ar m a n d tre at m e nt gr o u p.  
T h e a n al ysis of st u d y d ata f or t h e cli nic al st u d y re p ort ( C S R) will b e d o n e i n o n e of t h e 
f oll o wi n g a p pr o a c hes:  
•  T h e C S R will b e b as e d o n all p atie nts ’  d ata at t h e e n d of t h e st u d y, or  
•  T h e st u d y d ata will b e a n al y z e d a n d re p orte d i n t h e pri m ar y C S R b as e d o n all p atie nts ’
d ata u p t o t h e ti m e w h e n all p atie nts h a v e  c o m plete d at le ast si x c y cles of tre at m e nt or 
dis c o nti n u e d t h e st u d y.  A n y a d diti o nal d ata f or  p atie nts c o nti n ui n g t o re c ei v e st u d y 
tre at m e nt p ast t h e d ata c ut off d ate f or t h e pri m ar y C S R, as all o w e d b y t h e pr ot o c ol, will be 
re p orte d o n c e e n d of st u d y h as b e e n a c hie v e d. 
1 0. 1  
A n al y si s s et s  
1 0. 1. 1  
F ull A n al y si s S et  
T h e  F ull  A n al ysis  Set  ( F A S)  c o m pris es  all  p atie nts t o  w h o m  st u d y  tre at m e nt h as b e e n  
assi g n e d b y ra n d o miz ati o n. A c c or di n g t o t h e i nte nti o n t o tre at pri n ci ple, p atie nts will b e 
a n al y z e d  a c c or di n g  t o  t h e  tre at m e nt  t o  w hic h  t h e y  h a v e  b e e n  assi g n e d  d uri n g  t h e  
ra n d o miz ati o n pr oc e d ure. 
U nless ot h er wis e s p e cif ie d t h e F A S will b e t h e d ef a ult a n al ysis s et us e d f or all a n a l y s e s a n d 
listi n g of ra w d ata. 
1 0. 1. 2  
S af et y S et  
T h e s af et y s et i n cl u d es all p atie nts w h o re c ei v e d at le ast o n e d os e of M C S 1 1 0 or c ar b o pl ati n 
or ge m cita bi n e f or ar m 1, at le ast o n e d os e of c ar b o plati n o r ge m cita bi n e f or ar m 2. T h e 
state m e nt t h at a p atie nt h a d n o A Es ( o n t h e A E e C R F) c o nstit utes a v ali d s af et y ass ess me nt.  
Patie nts will b e classifie d a c c or di n g t o tre at m e nt re c ei v e d, w h ere tre at m e nt re c ei v e d is d efine d 
as: 
•  T h e tre at m e nt assi g n e d if it w as r e c ei v e d at le ast o n c e, or  

N o v artis  
C o nfi d e nti al  
P a g e 8 8  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol N o. C M C S 1 1 0 Z 2 2 0 1  
 
•  T h e first tre at m e nt re c ei v e d w h e n starti n g t h era p y wit h st u d y tre at m e nt if t h e assi g n e d 
tre at m e nt w as n e v er re c ei v e d. 
T h e s af et y s et will b e t h e pri m ar y p o p ulati o n f or all s af et y relate d e n d p oi nts.  
1 0. 1. 3  
P er -Pr ot o c ol S et  
T h e Per -Pr ot o c o l Set ( P P S) will c o nsist of a s u bs et of p atie nts i n t h e F A S w h o h a v e a n 
a d e q u ate t u m or ass ess m e nt at b as eli n e, a f oll o w -u p t u m or ass ess me nt ≥6 w e e ks after st arti n g 
tre at m e nt ( u nless dis e as e pr o gressi o n is o bs er v e d b ef ore t h at ti m e), a n d n o m aj or pr ot o c ol 
d e viati o ns.  
All m aj or pr ot o c ol d e viati o ns le a di n g t o e x cl usi o n fr o m t h e P P S will b e d etaile d i n t h e 
Re p orti n g a n d A n al ysis Pla n ( R A P).  
T h e P P S  will d efi n e t h e p atie nts us e d i n t h e s e nsiti vit y a n al ysis of t h e pri m ar y e n d p oi nt.  
If t h e P P S a n d t h e F A S are i d e ntic al, t h e n a n al ys es d es cri b e d b y t h e P P S b el o w will n ot b e 
p erf or m e d. 
1 0. 1. 4  
P h ar m a c o ki n eti c  a n al y si s  s et  
T h e  p h ar m a c o ki n etic  a n al ysis  s et  ( P A S)  c o nsists  of  all  p atie nts  w h o  h a v e  e v al u a ble  
p h ar m a c o ki n etic ( P K) d ata . T h e P A S will b e us e d f or s u m m aries of P K c o n c e ntrati o n d ata, 
P K p ara m eters 
. Patie nts m a y b e 
re m o v e d fr o m P K a n al ysis o n a n i n di vi d u al b asis d e p e n di n g o n t h e n u m ber of a v aila ble bl o o d 
s a m ples. T h es e p atie nts will b e i d e ntifie d at t h e ti m e of a n al ysi s. 
1 0. 2  
P ati e nt d e m o gr a p hi c s/ ot h er b a s eli n e c h ar a ct eri sti c s  
D e m o gra p hic a n d ot h er b as eli n e d ata  will b e s u m m ariz e d d es cri pti v el y b y st u d y ar m  a n d 
tre at m e nt gr o u p. 
1 0. 3  
T r e at m e nt s ( st u d y tr e at m e nt,  c o n c o mit a nt  t h er a pi e s, 
c o m pli a n c e)  
1 0. 3. 1  
St u d y tr e at m e nt  
D urati o n of e x p os ure t o st u d y tre at m e nt i n c y cles, as w ell as a ct u al t otal d os es, a ct u al d os e 
i nte nsities,  a n d  relati v e  d os e  i nte nsities  of  all  st u d y  dr u gs  will  b e  s u m m ariz e d  usi n g  
d es cri pti v e statistics b y st u d y  ar m a n d tre at m e nt gr o u p f or t h e s afet y s et. 
1 0. 3. 2  
C o n c o mit a nt m e di c ati o n s  
C o n c o mita nt m e dic ati o ns a n d si g nific a nt n o n -dr u g t h era pies pri or t o a n d after t h e start of  t h e 
st u d y tre at m e nt will b e liste d a n d s u m m ariz e d b y st u d y ar m a n d tre at m e nt gr o u p f or t h e s af ety 
s et b y A T C ( A n at o mic al t h era p e utic c h e mic al classific ati o n s yste m) ter m. 
1 0. 3. 3  
C o m pli a n c e  
C o m plia n c e t o t h e pr ot o c ol will b e ass ess e d b y t h e n u m b er a n d pr o p orti o n of p atie nts wit h 
pr ot o c ol d e viati o ns. T h es e will b e i d e ntifie d pri or t o d ata b as e l o c k a n d w ill b e liste d a n d 

N o v artis  
C o nfi d e nti al  
P a g e 8 9  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol N o. C M C S 1 1 0 Z 2 2 0 1  
 
s u m m ariz e d b y st u d y ar m a n d tre at m e nt gr o u p. C o m plia n ce t o t h e st u d y tre at m e nt wit hi n e ac h 
st u d y ar m will b e ass ess e d b y t h e n u m b er of d ose re d ucti o ns, n u m b er of d o s e i nt err u pti o n s 
a n d p erc e nt of c y cles re c ei v e d pla n n e d d os e f or all t h e st u d y dr u gs s e p aratel y i n s u m m ar y 
ta bles b y st u d y ar m a n d tre at m e nt gr o u p f or t h e s afet y s et. 
1 0. 4  
Pri m ar y o bj e cti v e  
T h e  pri m ar y  o bje cti v e  is  t o  ass ess  t h e  a nti -t u m or a cti vit y  of  M C S 1 1 0  c o m bi n e d  wit h  
c ar b o plati n/ ge m cita bi n e c o m p are d t o c ar b o plati n/ ge m cita bi n e i n a d ult p atie nts wit h tri ple 
n e gati v e bre ast c a n c er . F or si m plicit y, t hr o u g h o ut t his s e cti o n, t h e M C S 1 1 0 +c ar b o/ g e m ar m 
will b e us e d t o ref er t o p atie nts ra n d o miz e d t o Ar m 1 at t h e M C S 1 1 0 fi n al c o nfir m e d d os e . 
1 0. 4. 1  
V ari a bl e  
T h e pri m ar y effic ac y e n d p oi nt is pr o gressi o n fre e s ur vi v al ( P F S) b as e d o n l o c al I n v e sti g a t or 
ass ess m e nt, as d efi ne d i n R E CI S T 1. 1. T h e h a z ar d rati o ( H R) f or P F S b et w e e n t h e M C S 1 1 0 + 
c ar b o/ ge m ar m a n d t h e c ar b o/ ge m ar m will b e esti m ate d.  N ote: if bli n d e d c e ntral re vie w is 
p erf or m e d, t h e n a n al ys es s p e cifie d f or all effica c y e n d p oi nts b as e d o n l o c al ass ess m e nts will 
b e a d diti o n all y p erf or m e d o n t h e res p o ns e e v al u ati o ns fr o m t h e bli n de d re vie w.  
1 0. 4. 2  
St ati sti c al h y p ot h e si s,  m o d el, a n d m et h o d of a n al y si s  
T h e pri m ar y effic a c y e n d p oi nt, P F S as d eter mi n e d t hr o u g h t h e l o c al I n v esti gat or’s t u m or 
ass ess m e nt p er R E CI S T 1. 1,  will b e  a n al y z e d  a c c or di n g t o  t h e  st u d y  ar m  p atie nts  are  
ra n d o miz e d t o. 
T h e pri m ar y a n al ysis of t h e st u d y is b as e d o n t h e esti m ati o n of t h e h a z ar d rati o ( H R) b et w e e n 
t h e M C S 1 1 0 + c ar b o plati n/ ge m cita bi n e ar m a n d t h e c ar b o plati n/ gem cita bi n e al o n e ar m a n d 
relate d o n e-si d e d 9 0 % c o nfi de nc e i nter val of t h e H R.  
T h e f oll o wi n g d o u ble criteria will b e us e d i n or d er t o c o n cl u d e t h at t h ere is cli nic al a n d 
statistic al e vi d e n c e  of  effic a c y  of  t h e  M C S 1 1 0  + c ar b o plati n/ ge m cita bi n e  c o m bi n ati o n  
treat m e nt c o m p are d t o t h e c ar b o plati n/ ge m cita bi n e al o ne tre at m e nt:  
•  t h e esti m ate d h a z ar d rati o ( p osteri or m e dia n) is e q u al or less t h a n 0. 7 (i. e 3 0 % re d u cti o n in 
ris k of P F S e v e nt wit h M C S 1 1 0 + c ar b o plati n/ ge m cita bi ne ar m c o m pare d t o t h e 
c ar b o plati n/ ge m cita bi ne ar m),  
•  t h e up p er b o u n d of t h e o n e -si d e d 9 0 % cre di ble i nter v al of t h e H R is b el o w 1.  
I n a d diti o n, esti m ate d H R f or t h e M C S 1 1 0 + c ar b o plati n/ ge m cita bi n e ar m c o m p are d t o t h e 
c ar b o plati n/ ge m cita bi ne ar m al o n g wit h t h e o n e -si de d 9 0 % cre di ble i nter v al will b e pr o d u c e d. 
M ore o v er, K a pla n -Meier pl ots will b e a d o pte d i n or d er t o pres e nt P F S gra p hic al o ut p uts f or 
b ot h t h e M C S 1 1 0 + c ar b o plati n/ ge m cita bi n e ar m a n d t h e c ar b o plati n/ ge m cita bi n e ar m.  
1 0. 4. 3  
H a n dli n g of mi s si n g v al u e s/ c e n s ori n g/ di s c o nti n u ati o n s  
If  a  p atie nt h as  n ot h a d  a n  e v e nt,  P F S is  c e ns ore d  at t h e  d ate  of  last a d e q u ate  t u m or 
ass ess m e nt, as d efi n e d i n t h e i n t h e R E CI S T 1. 1 ( A p p e n di x 1 ). Patie nts f or w h o m n o b est 
o v erall res p o ns e  c a n  b e  ass ess e d  at t h e  ti m e  of  t h e pri m ar y a n al ysis will b e tre ate d as 
tre at m e nt f ail ures i n t h e a n al ysis of O R R. T h e re as o n f or dis c o nti n u ati o n fr o m st u d y will b e 

N o v artis  
C o nfi d e nti al  
P a g e 9 0  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol N o. C M C S 1 1 0 Z 2 2 0 1  
 
s u m m ariz e d a n d liste d, al o n g wit h d ates of first a n d last st u d y dr u g tre at m e nt, d urati o n of 
e x p os ure t o st u d y dr u g tre at m e nt a n d d ate of dis c o nti n uati o n f or e a c h p atie nt.  
Ot h er missi n g d ata will si m pl y b e n ote d as missi n g o n a p pr o priate ta bles/listi n gs.  
1 0. 4. 4  
S u p p orti v e a n al y s e s  
T h e P P S  will b e us e d i n a s u p p orti v e a n al ysis of t h e pri m ar y e n d p oi nt.  
 s u p p orti v e a nal ys es will b e c o n d ucte d if a p pr o priate a n d  d e fi n e d  
i n t h e R A P. 
1 0. 5  
S e c o n d ar y o bj e cti v e s  
1 0. 5. 1  
Ot h er s e c o n d ar y effi c a c y o bj e cti v e s  
R es p o ns e :  I n di vi d u al  lesi o n  m e as ure m e nts  will  b e  liste d  al o n g wit h  t h e  o v erall  lesi o n  
res p o ns e a n d Best O v erall res p o ns e. O R R a nd C B R will b e s u m m ariz e d b y st u d y ar m a n d 
tre at m e nt gr o u p wit h a c c o m p a n yi n g 9 5 % c o nfi de nc e i nter v als.  
D O R:  D O R will  b e pres e nte d d es cri pti v el y usi n g K a pla n Meier pl ots b y tre at m e nt gr o u p . I n 
a d diti o n, t h e m e dia n D O R a n d c orres p o n di n g 9 5 % c o nfi d e n ce i nter v al will b e pres e nte d.  
1 0. 5. 2  
S af et y o bj e cti v e s  
1 0. 5. 2. 1  A n al y si s s et a n d gr o u pi n g f or t h e a n al y s e s  
F or all s af et y a n al ys es, t h e s af et y s et will b e us e d. All listi n gs a n d ta bles will b e pres e n t e d  b y  
st u dy ar m a n d tre at m e nt gr o u p. 
T h e o v erall o bs er v ati o n p eri o d will b e di vi d e d i nt o t hre e m ut u all y e x cl usi v e s e g m e nts:  
•  pre- tre at m e nt p eri o d: fr o m d a y of p atie nt’s i nf or m e d c o ns e nt t o t h e d a y b ef ore first d os e 
of st u d y m e dic ati o n  
•  o n -tre at m e nt p eri o d: fr o m d a y of first d os e of st u d y m e dicati o n t o 9 0 d a ys after last d os e 
of st u d y m e dic ati o n  
•  p ost -tre at m e nt p eri o d: starti n g at d a y 9 1 after last d os e of st u d y m e dic ati o n.  
1 0. 5. 2. 2  A d v er s e e v e nt s ( A E s)  
S u m m ar y ta bles f or a d v ers e e v e nts ( A Es) h a v e t o i n cl u de o nl y A Es t h at starte d  or w or s e n e d 
d uri n g  t h e  o n -tre at m e nt  p eri o d,  t h e  tr e at m e nt-e m er g e nt A Es .  H o w e v er,  all s af et y  d ata  
(i n cl u di n g t h os e fr o m t h e pre a n d p ost-tre at m e nt p eri o ds) will b e liste d a n d t h os e c olle cte d 
d uri n g t h e pre -tre at m e nt a n d p ost-tre at m e nt p eri o d are t o b e fla gge d.  
T h e i n ci d e n c e of tre at m e nt -e mer ge nt a d vers e e ve nts ( n e w or w ors e ni n g fr o m b aseli n e) will b e 
s u m m ariz e d b y s yste m or ga n class a n d or preferre d ter m, s e verit y ( b as e d o n C T C A E gra d e s), 
t y p e of a d v ers e e v e nt, relati o n t o st u d y tre at m e nt b y st u d y ar m a n d tre at m e nt gr o u p. 
D e at hs re p orta ble as S A Es a n d n o n -fatal s eri o us a d vers e e v e nts will b e liste d b y  p a ti e n t a n d  
ta b ulate d b y t y p e of a d v erse e v e nt a n d st u d y ar m a n d tre at m e nt gr o u p. 

N o v artis  
C o nfi d e nti al  
P a g e 9 1  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol N o. C M C S 1 1 0 Z 2 2 0 1  
 
1 0. 5. 2. 3  L a b or at or y a b n or m aliti e s  
F or la b orat or y  tests c o v ere d  b y  t h e  C o m m o n  Ter mi n ol o g y Criteria f or A d v ers e E v e nts 
( C T C A E) v ersi o n 4. 0 3, t h e st u d y’s bi ostatistic al a n d re p orti n g te a m will gra d e la b orat or y d ata 
a c c or di n gl y. F or la b orat or y tests c o vere d b y C T C A E, a  Gra d e 0 will b e assi g n e d f or all n o n -
missi n g v al u es n ot gra d e d as 1 or hi g h er. Gra d e 5 will n ot b e us e d.  
F or la b orat or y tests w h ere gra d es are n ot d efi n e d b y C T C A E, res ults will b e gra d e d b y t h e 
l o w/ n or m al/ hi g h classific ati o ns b ase d o n la b orat or y n or mal ra n ges. 
T h e  f oll o wi n g b y -tre at m e nt s u m m aries will b e ge n erate d s e p aratel y f or h e m at ol o g y  a n d 
bi o c h e mistr y la b orat or y tests:  
•  fre q u e n c y ta ble f or n e wl y o cc urri n g o n-tre at m e nt gra d es 3 or 4 
•  s hift ta bles usi n g C T C A E gra d es t o c o m p are b as eli n e t o t h e w orst o n -tre at m e nt v al u e 
•  f or la b orat or y tests w h ere C T C A E gra d es are n ot d efi n e d, s hift ta bles usi n g t h e 
l o w/ n or m al/ hi g h/(l o w a n d hi g h) classificati o n t o c o m p are b as eli ne t o t h e w orst o n -
tre at m e nt v al u e  
•  listi n g of all la b orat or y d ata wit h v al u es fla g ge d t o s h o w t h e c orres p o n di n g C T C A E 
gra d es a n d t h e classific ati o ns relati v e t o t h e la b orat or y n or mal ra n ges  
I n a d diti o n t o t h e a b o v e m e nti o ne d ta bles a n d listi n gs, ot h er e x pl orat or y a n al ys es, f or e xa m ple 
fi g ures pl otti n g tim e c o urs e of ra w or c h a n ge i n la b orat or y tests o v er ti m e or b o x pl ots mi g ht 
b e s p e cifie d i n t h e R A P.  
1 0. 5. 2. 4  Ot h er s af et y  d at a  
E C G 
•  s hift ta ble b as eli n e t o w orst o n-tre at m e nt res ult f or o verall ass ess m e nts 
•  listi n g of E C G e v al u ati o ns f or all p atie nts wit h at le ast o n e a b n or m alit y. 
Vit al si g n s  
D efi niti o ns of n ota bl y a b n or m al res ults h a ve t o p art of t h e C D P, M A P, C S P a n d R A P.  
•  s hift ta ble b as eli n e t o w orst o n-tre at m e nt res ult 
•  ta ble wit h d es cri pti v e statistics at b as eli n e, o n e or s e v eral p ost-b aseli n e ti m e p oi nts a n d 
c h a n ge fr o m b as eli n e t o t his/t h es e p ost -bas eli ne ti m e p oi nts.  
1 0. 5. 2. 5  S u p p orti v e a n al y s e s f or s e c o n d ar y o bj e cti v e s  
A n y s u p p orti v e a n al ys es t h at are c o nsi d ere d a p pr o priate f or s e c o n d ar y v aria bles will b e 
d es cri b e d i n t h e R A P pri or t o D B L.  
1 0. 5. 2. 6  T ol er a bilit y  
T olera bi lit y of st u d y dr u g tre at m e nt will b e ass ess e d b y s u m m arizi n g t h e n u m ber of tre at m e nt 
d os e i nterr u pti o ns a n d d os e re d u cti o ns. Re aso ns f or d os e i nterr u pti o n a n d d os e re d ucti o ns will 
b e liste d b y p atie nt a n d s u m m ariz e d.  

N o v artis  
C o nfi d e nti al  
P a g e 9 4  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol N o. C M C S 1 1 0 Z 2 2 0 1  
 
Ass ess me nt of p h a r m a c o d y n a mic bi o m a r ke rs  
T h e e xte nt of T A M s u p pressi o n a n d TI L i n cre as e will b e ass ess e d b y I H C i n pr e - a n d p o st -
tre at m e nt f or m ali n-fi x e d p araffi n e m b e d de d tiss u e o btai n e d d uri n g t h e st u d y, w h e n f e a si bl e. 
F or t his p ur p os e,  t h e  T A M a n d  TI L c o nte nt will b e  c o m p are d  wit h  b as eli n e  le v els b y  
pr o d u ci n g a s u m m ar y ta ble wit h t h e d es cri pti v e statistics of t h e H-s c ores. T h e H-s c ore d ata 
will als o b e liste d b y p atie nt f or all t h es e m ar k ers. Besi d es, t h e T A M a n d TI L c o nte nt i n 
pri m ar y arc hi v al tiss u e a n d t h e pre -tre at m e nt bi o ps y will als o b e c o m p are d a n d pr e s e nt e d i n 
t he  si milar  w a y.  F urt h er m ore,  t h e  P D  eff e ct  of  M C S 1 1 0  w h e n  c o m bi n e d  wit h  
c ar b o plati n/ ge m cita bi n e will als o b e c h ara cteriz e d b y ass essi n g t h e t otal C S F -1 circ ulati n g 
le v els, s er u m C T X-1 a n d circ ulati n g m o n o c ytes i n bl o o d. B ot h s u m m ar y statistics a n d listi n gs 
will b e pr o d u c e d.  
1 0. 5. 4. 3. 3  
A d v a n c e d a n al y si s m et h o d s  
A l o gistic re gressi o n m o d el will b e us e d t o d eter mi n e w h et h er t h e b as eli n e m utati o n stat us 
(e. g. B R C A), pr otei n e x pressi o n le v els (e. g. S-C S F -1 le v els), c ell c o nte nt (e. g. T A M le v els, 
TI L le v els) are p ote ntiall y c orrelate d wit h cli nic al res p o ns e t o t h e c o m bi n ati o n of M C S 1 1 0 
a n d  c ar b o plati n/ ge m cita bi n e.  K a pla n -Meier  esti m ates  of  P F S  b y  m utati o n al  stat us  a n d  
tre at m e nt will als o b e pr o d u c e d. 
1 0. 7  
I nt eri m a n al y si s 
W h e n t h e first 9 p atie nts ra n d o miz e d  i n t h e st u d y h a ve c o m plete d t w o c y cles of tr e at m e nt or 
dis c o nti n u e e arlier d u e t o a d v ers e e v e nt, N o v artis a n d pri n ci p al i n v esti gat ors will h a v e a 
s af et y re vie w m e eti n g t o re vie w cli nic al, P K a n d la b orat or y d ata a n d t o d e ci d e o n t h e d os e f or 
st u d y c o nti n u ati o n (Se cti o n 2. 2  a n d  Se cti o n 4. 1 ). If t h e d osi n g re gi m e n is c h a n g e d aft er t h e 
first s af et y re vie w m e eti n g, a n a d diti o n al s af et y re vie w f or t his n e w tre at m e nt re gi m e n will 
ta k e pla c e after 9 p atie nts h a v e b e e n ra n d o miz e d  a n d c o m plete d t w o c y cles of eit h er M C S 1 1 0 
(at t h e n e w d osi n g re gi m e n) + c ar b o/ ge m or c ar b o/ ge m al o n e, or dis c o nti n ue d e arli er d u e t o 
a d v ers e e v e nts . A n y s u bs e q ue nt M C S 1 1 0 c h a n ges of t h e d osi n g re gi m e n will b e f oll o w e d b y 
a n a d diti o n al s af et y re vie w(s) after 9 p atie nts h a v e b e e n  ra n d o miz e d a n d c o m plete d t w o 
c y cles of eit h er M C S 1 1 0 (at t h e n e w d osi n g re gi m e n) + c ar b o/ ge m or c ar b o/ ge m al o n e, or 
dis c o nti n u e d e arlier d ue t o a d v erse e v e nts.  
If t h e m o nit ori n g of t h e st u d y d ata re q uires a d e cisi o n t o b e ta k e n o n t h e c o nti n u ati o n of t h e 
st u d y, t h e n t h e rele v a nt d ata will b e c o m m u nic ate d t o t h e Ste eri n g C o m mitte e ( Se cti o n 8. 5 ). 
O ut p uts t o b e pr o d u c e d f or t h e  s afet y re vie w will b e i d e ntifie d i n t h e R A P. 
Effic a c y  a n d  s af et y  d ata  will b e  re vie w e d  o n  a  re g ular b asis  as  m e nti o n e d  i n  Se cti o n  
 8. 5.  T his d ata m o nit ori n g will n ot c o nstit ute a f or m al i nteri m a n al ysis of t h e pri m ar y e n d p oint 
si n c e n o d e cisi o n t o st o p t h e st u d y e arl y f or effic a c y will b e ta k e n f oll o wi n g t h e re vie w of t his 

N o v artis  
C o nfi d e nti al  
P a g e 9 5  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol N o. C M C S 1 1 0 Z 2 2 0 1  
 
d ata.  ( N ote: e arl y st o p pi n g m a y b e re c o m m e n d e d b y t h e Ste eri n g C o m mitte e f or s af et y or 
f utilit y p ur p os es.) 
A n al ys es pr o d u ce d f or t his re vie w will i n cl u d e b ut m a y n ot b e li mite d t o:  
•  A n al ysis of pri m ar y effic a c y e n d p oi nt  
•  T h e f oll o wi n g s af et y s u m maries a n d listi n gs:  
Tre at m e nt -e m er ge nt A Es re gar dless of st u d y dr u g relati o ns hi p 
•  A Es le a di n g t o p er m a n e nt dis c o nti n uati o n of st u d y dr u g  
•  A Es re q uiri n g d os e a dj ust m e nt or st u d y dr u g i nterr u pti o n  
•  S A Es re gar dless of st u d y dr u g relati o ns hi p  
•  S u m m aries of k e y b as eli ne c h aracteristics  O ut p uts t o b e pr o d u c e d f or m o nit ori n g will b e 
i d e ntifie d i n t h e R A P. 
1 0. 8  
S a m pl e si z e c al c ul ati o n  
F or  t his  trial,  i nf or m ati o n  c urre ntl y  a v aila ble  c o mi n g  fr o m  O’ S h a u g h n ess y  2 0 1 1   f or 
c ar b o plati n/ ge m cita bi ne  (s e e Se cti o n 1. 1 ) h as b e e n us e d i n or d er t o s et u p t h e crit eri a w hi c h 
will  n e e d  t o  b e  s atisfie d  t o  c o nsi d er  a  cli nic all y  rele v a nt  effic a c y  of  t h e  M C S 1 1 0  + 
c ar b o plati n/ ge m cita bi n e  c o m bi n ati o n  tre at m e nt c o m p are d  t o  t h e  c ar b o plati n/ ge m cita bi n e  
al o n e tre at m e nt. A n esti m ati o n of at le ast 3 0 % re d u cti o n i n ris k of P F S e v e nt wit h M C S 1 1 0 + 
c ar b o plati n/ ge m cita bi n e  c o m p are d  t o  t h e  c ar b o plati n/ ge m cita bi n e  al o n e  ar m,  or  
c orres p o n di n gl y,  a n  esti m ate d  P F S  H R  ≤  0. 7  w o ul d  b e  c o nsi d ere d as cli nic all y rele v a nt. 
Besi d es, it w o ul d b e c o nsi d ere d as statistic al si g nific a nt if t h e u p per b o u n d o f t h e  o n e -si d e d 
9 0 % CI of t h e H R is b el o w 1. As m e nti o n e d i n Se cti o n 1 0.4. 2 , t his d o u ble criteria will b e use d 
i n or d er t o c o n cl u d e t h at t h ere is cli nic al a n d statistic al e vi d e n ce of effic a c y of t h e M C S 1 1 0 + 
c ar b o/ ge m c o m bi n ati o n tre at m e nt c o m p are d t o t h e c ar b o/ ge m al o ne tre at m e nt.  
U n d er t h e ass u m pti o n t h at s u bje ct a c cr ual (e ntr y) o c c urs i n t h e  first 1 4 m o nt hs, t h e st u d y lasts 
f or 2 2 m o nt hs wit h a n u nif or m a c cr u al p atter n a cr oss m o nt hs (all p eri o ds e q u al) a n d t h e 
dr o p o ut rate wit h t h e ass u m pti o n of c e ns ori n g at ti m e 0 b ei n g e q u al t o 1 0 %, it is esti m ate d 
t h at a o n e -si d e d l o gra n k test wit h a t y p e-1 err or e q u al t o 1 0 %, wit h a p pr o xi m atel y 5 8 P F S 
e v e nts a n d a n o v erall s a m ple siz e of 7 8 p atie nts ( 5 2 i n t h e M C S 1 1 0 + c ar b o plati n/ ge m cita bi ne  
ar m a n d 2 6 i n t h e c ar b o plati n/ ge m cita bi n e  al o n e ar m) a c hie v es t h e res ults pres e nte d i n t h e 
f oll o wi n g Ta ble 1 0 - 2. 
T a bl e 1 0 - 2 
Tr u e P F S h a z ar d r ati o a n d c orr e s p o n di n g p o w er  
Tr u e h a z ar d r ati o ( Alt er n ati v e h y p ot h e si s)  
Pr o b a bilit y of c o n cl u di n g effi c a c y ( p o w er)  
0. 4  
9 8 %  
0. 5  
9 0 %  
0. 6  
7 2 %  
0. 7  
5 0 %  
1. 0  
9 %  
T h e a n al ysis h as b e e n p erf or me d wit h P A S S 2 0 0 8 a n d R -pr oje ct 2. 1 3. 2.  

N o v artis  
C o nfi d e nti al  
P a g e 9 6  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol N o. C M C S 1 1 0 Z 2 2 0 1  
 
1 1  
Et hi c al c o n si d er ati o n s a n d a d mi ni str ati v e pr o c e d ur e s  
1 1. 1  
R e g ul at or y a n d et hi c al c o m pli a n c e  
T his cli nic al st u d y w as d esi g n e d, s h all b e i m ple m e nte d a n d re p orte d i n a c c or d a n c e wit h t h e 
I C H H ar m o niz e d Tri p artite G ui d eli n es f or G o o d Cli nic al Pra ctic e, wit h a p plic a ble l o c al 
re g ulati o ns (i n cl u di n g E ur o p e a n Dire cti v e 2 0 0 1/ 2 0/ E C a n d U S C o d e of Fe d eral R e g ul ati o ns 
Title 2 1), a n d  wit h t h e et hic al pri n ci ples lai d d o w n i n t h e D e clarati o n of H elsi n ki.  
1 1. 2  
R e s p o n si biliti e s  of t h e i n v e sti g at or a n d I R B/I E C/ R E B  
T h e pr ot o c ol a n d t h e pr o p os e d i nf or m e d c o ns e nt f or m m ust b e re vie w e d a n d a p pr o v e d b y a 
pr o p erl y  c o nstit ute d  I nstit uti o n al Re vie w B o a r d/I n d e p e n d e nt Et hics C o m mitte e/ Res e arc h 
Et hics  B o ar d  (I R B/I E C/ R E B)  b ef ore  st u d y  start.  Pri or  t o  st u d y  start,  t h e  i n v esti gat or  is  
re q uire d t o si g n a pr ot o c ol si g n at ure p a ge c o nfir mi n g his/ h er a gre e m e nt t o c o n d uct t h e st u d y 
i n a c c or d a n c e wit h t h es e d o c u me nts a n d all of t h e i nstr u cti o ns a n d pr o c e d ur e s f o u n d i n t his 
pr ot o c ol a n d t o gi v e a c c ess t o all rele v a nt d ata a n d re c or ds t o N o v artis m o nit ors, a u dit ors, 
N o v artis  Cli nic al  Q u alit y  Ass ura n c e  re pres e ntati v es,  d esi g n ate d  a ge nts  of  N o v artis,  
I R Bs/I E Cs/ R E Bs a n d re g ulat or y a ut h orities as re q uire d.  
1 1. 3  
I nf or m e d c o n s e nt pr o c e d ur e s 
Eli gi ble p atie nts m a y o nl y b e i n cl u d e d i n t h e st u d y after pr o vi di n g writte n ( wit n ess e d, w h er e 
re q uire d b y la w or re g ulati o n), I R B/I E C/ R E B-a p pr o v e d i nf or me d c o ns e nt  
I nf or m e d c o ns e nt m ust b e o btai ne d b ef ore c o n d ucti n g a n y st u d y-s pe cif ic pr o c e d ur e s  ( i. e .  a ll 
of t h e pr o c e d ures d es cri b e d i n t h e pr ot o c ol). T h e pr o c ess of o btai ni n g i nf or m e d c o ns e nt 
s h o ul d b e d o c u me nte d i n t h e p atie nt s o urce d o c u m e nts. T h e d ate w h e n a s u bje ct’ s I nf or m e d 
C o ns e nt w as a ct u all y o btai n e d will b e c a pt ure d i n t h eir C R Fs.  
N o v artis will pr o vi d e t o i n v esti gat ors, i n a s e p arate d o c u m e nt, a pr o p os e d i nf or m e d c o n s e nt 
f or m (I C F) t h at is c o nsi d ere d a p pr o priate f or t his st u d y a n d c o m plies wit h t h e I C H G C P 
g ui d eli n e a n d re g ulat or y re q uire m e nts. A n y c h a n ges t o t his I C F s u g geste d b y t h e i n v esti g at or 
m ust b e a gre e d t o b y N o v artis b ef ore s u b missi o n t o t h e I R B/I E C/ R E B, a n d a c o p y of t h e 
a p pr o v e d v ersi o n m ust b e pr o vi de d t o t h e N o v artis m o nit or after I R B/I E C/ R E B a p pr o v al.  
W o m e n of c hil d b e ari n g p ote ntial s h o ul d b e i nf or m e d t h at ta ki n g t h e st u d y m e di c ati o n m a y 
i n v ol v e u n k n o w n ris ks t o t h e f et us if pre g n a nc y w ere t o o c c ur d uri n g t h e st u d y a n d a gre e t h at 
i n or d er t o p artici p ate i n t h e st u d y t h e y m ust a d h ere t o t h e c o ntra c e pti o n re q uire m e nt f or t h e 
d urati o n of t h e st u d y. If t h ere is a n y q u esti o n t h at t h e p atie nt will n ot relia bl y c o m pl y, t h e y 
s h o ul d n ot b e e ntere d i n t h e st u d y. 
A d diti o n al c o ns e nt f or m (if a p plic a ble) 
S u b -st u dies a n d st u dies wit h a n o pti o n al E x pl orat or y Bi o m ar k er c o m p o n e nt will h a v e a 
s e p arate c o ns e nt f or m c o veri n g t h os e st u dies. T his f or m will b e a d a pte d f or e a c h St u d y b a s e d 
o n a sta n d ar d te m plate us e d gl o b all y f or all St u dies. T h es e i nf or m e d c o ns e nt f or ms will b e 
s u b mitte d  f or et hic al a p pr o v al t o get h er wit h  t h e  St u d y  Pr ot o c ol a n d t h e m ai n i nf or m e d 
c o ns e nt f or m of t h e St u d y. If a s u bje ct o pts n ot t o p artici p ate i n t h e o pti o n al ass ess m e nts, t his 
i n n o w a y aff e cts t h e s u bject’s a bilit y t o p artici p ate i n t h e m ai n res e arc h st u d y. 

N o v artis  
C o nfi d e nti al  
P a g e 9 7  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol N o. C M C S 1 1 0 Z 2 2 0 1  
 
1 1. 4  
Di s c o nti n u ati o n of t h e st u d y  
N o v artis res er v es t h e ri g ht t o dis c o nti n u e t his st u d y u n d er t h e c o n diti o ns s p e cifie d i n t h e 
cli nic al st u d y a gre e m e nt. S p e cific c o n diti o ns f or ter mi n ati n g t h e st u d y are o utli n e d i n  Se cti o n 
4. 3 . 
1 1. 5  
P u bli c ati o n of st u d y pr ot o c ol a n d r e s ult s  
N o v artis is c o m mitte d t o f oll o wi n g hi g h et hic al sta n d ar ds f or re p orti n g st u d y res ults f or its 
i n n o v ati v e m e dici n e, i n cl u di n g t h e ti m el y c o m m u nic ati o n a n d p u blic ati o n of cli nic al trial 
res ults , w h ate v er t h eir o utc o m e.  
N o v artis ass ures  t h at t h e k e y d esi g n ele m e nts of t his pr ot o c ol will b e p oste d   o n t h e p u bli cl y 
a c c essi ble d ata b as e , e. g. w w w. cli nic altrials. g o v , b ef ore st u d y start. I n a d diti o n, res ults of 
i nter v e nti o n al cli nic al trials i n a d ult p atie nts are p oste d o n w w w. n o v artis cli nic altri a ls. c o  m , a 
p u blicl y a c c essi ble d ata b as e of cli nic al st u d y res ults wit hi n 1 y e ar of st u d y c o m pleti o n  
(i. e., L P L V),  , t h os e f or i nter v e nti o n al cli nic al trials i n v ol vi n g p e diatric p ati nts wit hi n 6 
m o nt hs of st u d y c o m pleti o n . 
N o v artis  f oll o ws  t h e  I C MJ E  a ut h ors hi p  g ui d eli n es ( w w w.ic mje. or g ) a n d  ot h er s p e cific  
g ui d eli n es of t h e j o ur n al or c o n gress t o w hic h t h e p u blic ati o n will b e s u b mitte d.  
A ut h ors will n ot re c ei v e re m u n erati o n f or t h eir writi n g of a p u blic ati o n, eit h er d ir e c tl y  fr o  m 
N o v artis or t hr o u g h t h e p r of essi o n al m e dic al writi n g a ge n c y. A ut h or(s) m a y b e r e q u est e d t o 
pres e nt  p oster  or  oral  pres e ntati o n  at  s cie ntific  c o n gress;  h o w e v er,  t h ere  will  b e  n o  
h o n orari u m pr o vi d e d f or s u c h pres e ntati o ns.  
As p art of its c o m mit m e nt t o f ull tra ns p are n c y i n p u blic ati o ns, N o v artis s u p p orts t h e f ull 
dis cl os ure of all f u n di n g s o urc es f or t h e st u d y a n d p u blic ati o ns, as w ell as a n y a ct u al a n d 
p ote ntial c o nflicts of i nterest of fi n a n cial a n d n o n -fi n a n cial n at ure b y all a ut h or s, i n cl u di n g 
m e dic al writi n g/e dit orial s u p p ort, if  a p plic a ble.  
F or t h e N o v artis G ui d eli n es f or t h e P u blic ati o n of Res ults fr o m N o vartis -s p o ns ore d Res e arc h, 
ple as e ref er t o w w w. n o vartis. c o m .  
1 1. 6  
St u d y d o c u m e nt ati o n, r e c or d k e e pi n g a n d r et e nti o n of 
d o c u m e nt s  
Ea c h p artici p ati n g site will m ai ntai n a p pr o priate m e dic al a n d res e arc h re c or ds f or t his trial, i n 
c o m plia n c e  wit h  Se cti o n  4. 9  of  t h e  I C H  E 6  G C P,  a n d  re g ulat or y  a n d  i nstit uti o n al  
re q uire m e nts f or t h e pr ote cti o n of c o nfi d e ntialit y of s u bje cts. As p art of p artici p ati n g i n a 
N o v artis -s p o ns ore d st u d y, e a c h site will p er mit a ut h oriz e d re pres e ntati v es of t h e  s p o ns o r( s) 
a n d re g ulat or y a ge n cies t o e x a mi n e (a n d w h e n re q uire d b y a p plic a ble la w, t o c o p y) cli ni c al 
re c or ds f or t h e p ur p os es of q u alit y ass ura n c e re vie ws, a u dits a n d e v al u ati o n of t h e st u d y 
s af et y a n d pr o gress. 
S o urc e d ata are all i nf or m ati o n, ori gi n al re c or ds of cli nic al fi n di n gs, o bs er v ati o ns, or ot h er 
a cti vities  i n  a  cli nic al  trial  n e c ess ar y  f or  t h e  re c o nstr u cti o n  a n d  e v al u ati o n  of  t h e  trial.  
E x a m ples of t h es e ori gi n al d o c u m e nts a n d d ata re c or ds i n cl u de, b u t are n ot li mite d t o, h os pital 
re c or ds,  cli nic al  a n d  offic e  c h arts,  la b orat or y  n otes,  m e m ora n d a,  s u bje cts’  diaries  or  

N o v artis  
C o nfi d e nti al  
P a g e 9 8  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol N o. C M C S 1 1 0 Z 2 2 0 1  
 
e v al u ati o n  c h e c klists,  p h ar m a c y  dis p e nsi n g  re c or ds,  re c or d e d  d ata  fr o m  a ut o m ate d  
i nstr u m e nts,  c o pies  or  tra ns cri pti o ns  c ertifie d  after  v erific ati o n  as  b ei n g  a c c urate  a n d  
c o m plete, micr ofic h es, p h ot o gra p hic n e gati v es, micr ofil m or m a g n etic m e dia, x -ra ys, a n d 
s u bje ct files a n d re c or ds k e pt at t h e p h ar m a c y, at t h e la b orat ories, a n d m e dic o -te c h nic al 
d e p art m e nts i n v ol ve d i n t h e cli nic al trial.  
D a ta c olle cti o n is t h e res p o nsi bilit y of t h e cli nic al trial staff at t h e site u n d er t h e s u p er visi o n of 
t h e site Pri n ci p al I n v esti gat or. T h e st u d y c as e re p ort f or m ( C R F) is t h e pri m ar y d ata c olle cti o n 
i nstr u m e nt  f or  t h e  st u d y.  T h e  i n v esti gat or  s h o ul d  e ns ure  th e  a c c ura c y,  c o m plete n ess,  
le gi bilit y, a n d ti m eli n ess of t h e d ata re p orte d i n t h e C R Fs a n d all ot h er re q uire d re p orts. D a t a 
re p orte d o n t h e C R F, t h at are d eri v e d fr o m s o urc e d o c u m e nts, s h o ul d b e c o nsist e nt wit h t h e 
s o urc e d o c u m e nts or t h e dis cre p a n cies s h o ul d b e e x plai n e d. All d ata re q u este d o n t h e C R F 
m ust b e re c or d e d. A n y missi n g d ata m ust b e e x plai n e d. A n y c h a n ge or c orre cti o n t o a p a p er 
C R F s h o ul d b e d ate d, i nitiale d, a n d e x plai n e d (if n e c ess ar y) a n d s h o ul d n ot o bs c ure t h e 
ori gi n al  e ntr y.  F or  ele ctr o nic  C R Fs a n a u dit trail will b e m ai ntai n e d b y t h e s yste m. T h e 
i n v esti gat or s h o ul d retai n re c or ds of t h e c h a n ges a n d c orre cti o ns t o p a per C R Fs. 
T h e i n v esti gat or/i nstit uti o n s h o ul d m ai ntai n t h e trial d o c u m e nts as s p e cifie d i n Ess e ntial 
D o c u m e nts f or t h e  C o n d u ct  of a Cli nic al Trial (I C H E 6 Se cti o n 8) a n d as re q uire d b y 
a p plic a ble re g ulati o ns a n d/ or g ui d eli n es. T h e i n v esti gat or/i nstit uti o n s h o ul d ta k e m e as ur e s t o  
pre v e nt a c ci d e ntal or pre m at ure d estr u cti o n of t h es e d oc u m e nts.  
Ess e ntial d o c u m e nts ( writte n a n d ele ct r o nic) s h o ul d b e retai n e d f or a p eri o d of n ot l e s s t h a n 
fifte e n ( 1 5) y e ars fr o m t h e c o m pleti o n of t h e Cli nic al Trial u nless S p o ns or pr o vi d e s writt e n 
p er missi o n t o dis p os e of t h e m or, re q uires t h eir rete nti o n f or a n a d diti o n al p eri o d of ti m e 
b e c a us e of a p pl ic a ble la ws, re g ulati o ns a n d/ or g ui d eli nes. 
1 1. 7  
C o nfi d e nti alit y  of st u d y d o c u m e nt s a n d p ati e nt r e c or d s  
T h e i n v esti gat or m ust e ns ure a n o n y mit y of t h e p atie nts; p atie nts m ust n ot b e i d e ntifie d b y 
n a m es i n a n y d o c u m e nts s u b mitte d t o N o v artis. Si g n e d i nf or me d c o ns e nt f or m s a n d p ati e nt 
e nr oll m e nt l o g m ust b e k e pt strictl y c o nfi d e ntial t o e n a ble p atie nt i d e ntific ati o n at t h e site.  
1 1. 8  
A u dit s  a n d i n s p e cti o n s  
S o urc e d ata/ d o c u m e nts m ust b e a v aila ble t o i ns p e cti o ns b y N o v artis or d esi g n e e or H e alt h 
A ut h orities.  
1 1. 9  
Fi n a n ci al di s cl o s ur e s  
Fi n a n cial dis cl os ures s h o ul d b e pr o vi d e d b y st u d y p ers o n nel w h o are dire ctl y i n v ol ve d i n t h e 
tre at m e nt or e v al u ati o n of p atie nts at t h e site - pri or t o st u d y start.  
1 2  
Pr ot o c ol a d h er e n c e  
I n v esti gat ors as c ertai n t h e y will a p pl y d u e dili ge n c e t o a v oi d pr ot oc ol d e vi ati o ns. U n d er n o 
circ u msta n c es s h o ul d t h e i n v esti gat or c o nta ct N o v artis or its a ge nts, if a n y, m o nit ori n g t h e 
st u d y t o re q u est a p pr o val of a pr ot o c ol d e viati o n, as n o a ut h oriz e d d e viati o ns are p er mitte d. If  
t h e i n v esti gat or f e els a pr ot o c ol d e viati o n w o ul d i m pr o ve t h e c o n d uct of t h e st u d y t his m u st 

N o v artis  
C o nfi d e nti al  
P a g e 9 9  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol N o. C M C S 1 1 0 Z 2 2 0 1  
 
b e c o nsi d ere d a pr ot o c ol a m e n d m e nt, a n d u nless s u c h a n a m e n d m e nt is a gre e d u p o n b y 
N o v artis a n d  a p pr o v e d  b y  t h e  I R B/I E C/ R E B it c a n n ot b e  i m ple m e nte d. All si g nific a nt 
pr ot o c ol d e viati o ns will b e re c or d e d a n d re p orte d i n t h e C S R.  
1 2. 1  
A m e n d m e nt s t o t h e pr ot o c ol  
A n y c h a n ge or a d diti o n t o t h e pr ot o c ol c a n o nl y b e m a d e i n a writte n pr ot o c ol a m e n d m e nt t hat 
m ust b e a p pr o v e d b y N o v artis, H e alt h A ut h orities w h ere re q uire d, a n d t h e I R B/I E C/ R E B. 
O nl y  a m e n d m e nts  t h at  are  re q uire d  f or  p atie nt  s af et y  m a y  b e  i m ple m e nte d  pri or  t o  
I R B/I E C/ R E B  a p pr o v al.  N ot wit hsta n di n g  t h e  n e e d  f or  a p pr o v al  of  f or m al  pr ot o c ol  
a m e n d m e nts, t h e i n v esti gat or is e x p e cte d t o ta k e a n y i m m e diate a cti o n re q uire d f or t h e s af et y 
of a n y p atie nt i n cl u d e d  i n t his st u d y, e v e n if t his a cti o n re pres e nts a d e viati o n fr o m t h e 
pr ot o c ol. I n s u c h c as es, N o v artis s h o ul d b e n otifie d of t his a cti o n a n d t h e I R B/I E C at t h e st u d y 
site s h o ul d b e i nf or m e d a c c or di n g t o l o c al re g ulati o ns (e. g. U K re q uires t h e n otific ati o n o f 
ur ge nt s af et y m e as ures wit hi n 3 d a ys) b ut n ot later t h a n 1 0 w or ki n g d a ys.  

N o v artis  
C o nfi d e nti al  
P a g e 1 0 0  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol N o. C M C S 1 1 0 Z 2 2 0 1  
 
1 3  
R ef er e n c e s ( a v ail a bl e u p o n r e q u e st)  
A a pr o M, Marti n C, H att y S ( 1 9 9 8) G e m cita bi n e --a s af et y re vie w. A ntic a nc er Dr u gs. 
9( 3): 1 9 1 -2 0 1  
A d a ms S, Gra y R, D e m aria S, et al. ( 2 0 1 4) Pr o g n ostic V al u e of T u m or -I nfiltrati n g 
L y m p h o c ytes i n Tri ple -N e gati v e Bre ast Ca n cers Fr o m T w o P h as e III Ra n d o miz e d A dj u v a nt 
Bre ast Ca n c er Trials: E C O G 2 1 9 7 a n d E C O G 1 1 9 9. J Cli n O n c ol 3 2: 2 9 5 9 -2 9 6 6  
Care y L, D e es C, Sa w y er L et al. ( 2 0 0 7) T h e Tri ple N e gati v e  Para d o x: Pri m ar y T u m or  
C h e m os e nsiti vit y of Bre ast Ca n c er S u bt y p es. Cli n Ca n c er Res 1 3( 8): 2 3 2 9 -2 3 3 4  
Care y L, Per o u C, Li v as y C et al. ( 2 0 0 6) Ra c e, Bre ast Ca n c er S u bt y p es, a n d S ur vi v al i n t h e 
Car oli n a Bre ast Ca n c er St u d y. J A M A, J u n e 7, 2 0 0 6 V ol. 2 9 5, N o. 2 1  
D a hl b er g L, L u n d k vist J, Li n d m a n H et al. ( 2 0 0 9) H e alt h c are c osts f or tre at m e nt of 
diss e mi n ate d bre ast c a nc er. E ur o p e a n J o ur n al of Ca n cer 4 5: 1 9 8 7 -1 9 9 1  
D e Viss er K, Eic hte n A a n d C o uss e ns L ( 2 0 0 6) Para d o xic al r oles of t h e i m m u n e s yste m 
d uri n g c a n c er d e v el o p m e nt. N at Re v Ca n c er 6( 1): 2 4 -3 7  
D e N ar d o D, Bre n n a n D, Re x h e p aj E, et al. ( 2 0 1 1) Le u k o c yte c o m ple xit y pre dicts bre ast 
c a n c er s ur vi v al a n d f u ncti o nall y re g ulates res p o ns e t o c h e m ot h era p y. Ca n cer Dis c o v. 1, 5 4 – 6 7  
D e n k ert C, L oi bl S, N os k e A, et al. ( 2 0 1 0)  T u m or -ass ociate d l y m p h o c ytes as a n i n d e p e n de nt 
pre dict or of res p o ns e t o n e oa dj u v a nt c h e m ot hera p y i n bre ast c a nc er. J Cli n O n c ol 2 8( 1): 1 0 5-
1 3  
D e n k ert C, v o n Mi n c k witz G, Bras e J C et al. ( 2 0 1 4) T u m or-I nfiltrati n g L y m p h oc ytes a n d 
Res p o ns e t o N e o a dj u v a nt C h e m ot h era p y Wit h or Wit h o ut Car b o plati n i n H u m a n E pi d er m al 
Gr o wt h Fa ct or Re c e pt or 2 -P ositi v e a n d Tri ple -N e gati v e Pri m ar y Bre ast Ca n c ers . J Cli n 
O n c ol.  
D e nt R, Tr u d e a u M, Pritc h ar d K et al. ( 2 0 0 7) Tri ple-N e gati v e Bre ast Ca n c er: Cli nic al 
Fe at ures a n d Patter ns of Re c urre nc e. Cli n Ca n c er Res 1 3: 4 4 2 9 -4 4 3 4.  
Eli Lill y Ca n a d a I n c. G e m z ar Pr o d u ct M o n o gra p h. T or o nt o, O ntari o; 1 9 A u g ust 1 9 9 9.  
E S M O G ui d eli n es 2 0 1 4. Car d os o F, H ar b e c k N, Fall o wfiel d L et al. ( 2 0 1 2) L o c all y re c urre nt 
or m etastatic bre ast c a n c er: E S M O Cli nic al Pra ctic e G ui d eli n es f or dia g n osis, tre at m e nt a n d 
f oll o w-u p. A n nals of O n c ol o g y 2 3 ( S u p ple m e nt 7): vii 1 1 – vii 1 9  
Ferla y J, S hi n H R, Bra y F, et al. ( 2 0 0 8) Esti m ates of w orl d wi de b ur de n of c a nc er i n 2 0 0 8: 
G L O B O C A N 2 0 0 8. nt. J. Ca n c er: 1 2 7, 2 8 9 3 – 2 9 1 7  
F o ul k es  W, S mit h I a n d Reis -Fil h o J ( 2 0 1 0) Tri ple -N e gati v e Bre ast Ca n c er. N E n gl J Me d 
3 6 3: 1 9 3 8 -4 8  
G hiri n g h elli F, A p et o h L, Tes niere A, et al. ( 2 0 0 9) A cti v ati o n of t h e N L R P 3 i nfla m m as o me in 
d e n dritic c ells i n d u c es I L -1 b eta -de pe n d e nt a d a pti v e i m m u nit y a gai nst t u m ors. N at Me d 
1 5( 1 0): 1 1 7 0 -8  
Gil b ert J, Sala v a g gi o n e O, Ji Y, et al. ( 2 0 0 6) G e m cita bi n e p h ar m a c o ge n o mics: c yti di n e 
d e a mi n as e a n d d e o x yc yti d ylate d e a mi n as e ge n e res e q ue nci n g a n d f u ncti o nal ge n o mics. Cli n 
Ca n c er Res 1 2: 1 7 9 4 -1 8 0 3  

N o v artis  
C o nfi d e nti al  
P a g e 1 0 1  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol N o. C M C S 1 1 0 Z 2 2 0 1  
 
Gri n d e y G,  H ertel L a n d Pl u n k ett W ( 1 9 9 0)  C yt ot o xicit y a n d a ntit u m or a cti vit y of 2',2' -
difl u or o d e o x y c yti di n e ( G e m cita bi n e). Ca n c er I n vest 8( 2): 3 1 3  
H u a n g S, Z h a o H, Le e J, et al ( 2 0 1 0) T h era p e utic pr otei n -dr u g i ntera cti o ns a n d i m plic ati o ns 
f or dr u g d e v el o p m e nt. Cli nic al P h ar m a c ol o g y & T h era p e utics; 8 7: 4 9 7-5 0 3.  
J a g ui n M, H o ul b ert N, Far d el O, et al. ( 2 0 1 3) P olariz ati o n pr ofiles of h u m a n M-C S F 
ge n erate d m a cr o p h a ges a n d c o m p aris o n of M 1 -m ar k ers i n classic all y a cti v ate d m a cr o p ha ges 
fr o m G M-C S F a n d M -C S F ori gi n. Cell ular I m m u n ol o g y 2 8 1: 5 1 – 6 1  
K ass a m F, E nri g ht K, D e nt R et al. ( 2 0 0 9) Tri ple -N e gati v e Bre ast Ca n c er: I m plic ati o ns f or 
Cli nic al Pra ctic e a n d Trial D esi g n. Cli nic al Bre ast Ca n c er 9( 1): 2 9 -3 3  
Kris h n a m urt h y S, K ore n blat K a n d Sc ott M ( 2 0 0 9) Persiste nt I n cre as e i n As p artate 
A mi n otra nsf eras e i n a n As y m pt o matic Patie nt. Cli nic al C h e mistr y 5 5( 8) 1 5 7 3 – 1 5 7 7  
Le e J, Z h a n g L, Me n A, et al ( 2 0 1 0) C Y P -m e diate d t h era pe utic pr otei n -dr u g i ntera cti o ns 
Cli nic al fi n di n gs, pr o p os e d m e c ha nis ms a n d re g ulat or y i m plic ati o ns. Cli nic al 
P h ar m a c o ki n etics; 4 9: 2 9 5 -3 1 0  
Le e k R, Le wis C, W hite h o us e R, et al. ( 1 9 9 6) Ass o ciati o n of m a cr o p h a ge i nfiltrati o n wit h 
a n gi o ge n esis a n d pr o g n osis i n i n v asi ve bre ast c arci n o ma. Ca n cer Res. 5 6( 2 0): 4 6 2 5 - 9 
Le h m a n n B a n d Piete n p ol J ( 2 0 1 4) I d e ntific ati o n a n d us e of bi o m ar kers i n tre at m e nt strate gies 
f or tri ple n e gati v e bre ast c a n c er s u bt y p es. J Pat h ol 2 3 2( 2): 1 4 2– 1 5 0.  
Le h m a n n B, Ba u er J, C h e n x et al. ( 2 0 1 1) I d e ntific ati o n of h u m a n tri ple-n e gati v e bre ast 
c a n c er s u bt y p es a n d pre cli nic al m o dels f or s ele cti o n of tar gete d t h era pies. J Cli n I n v est. 
1 2 1( 7): 2 7 5 0 -6 7  
Lie dt k e C, Ma z o u ni C, H ess K et al. ( 2 0 0 8) Res p o ns e t o N e o a dj u v a nt T h era p y a n d L o n g -
Ter m S ur vi v al i n Patie nts Wit h Tri ple -N e gati v e Bre ast Ca n c er. J Cli n O n c ol 2 6( 8): 1 2 7 5 -8 1  
L oi S ( 2 0 1 3) T u m or -i nfiltrati n g l y m p h o c ytes, breast c a n cer s u bt y p es a n d t h era p e utic effic a c y. 
O n c oI m m u n ol o g y 2: 7(e 2 4 7 2 0): 1 - 3 
L u n d B, H a ns e n O, T h eila d e K, et al. ( 1 9 9 4) P h as e II St u d y of G e m cita bi n e ( 2', 2' -
Difl u or o d e o x yc yti di n e) i n  Pre vi o usl y Tre ate d O v aria n Ca nc er Patie nts. J N atl Ca n c er I nst 
8 6( 2 0): 1 5 3 0 - 3 
Ma h m o u d S, Le e A, C Pais h E, et al. ( 2 0 1 2) T u m o ur -i nfiltrati n g m a cr o p h a ges a n d cli nic al 
o utc o m e i n bre ast c a n c er. J Cli n Pat h ol 6 5: 1 5 9-1 6 3  
Ma nt o v a ni A, S o z z a ni S, L o c ati M, et al . ( 2 0 0 2) Ma cr o p h a ge p olariz ati o n: t u m or-ass o ciate d 
m a cr o p h a ges as a p ara di g m f or p olariz e d M 2 m o n o n ucle ar p ha g o c ytes. Tre n ds I m m u n ol. 
2 3( 1 1): 5 4 9 -5 5  
Mar k m a n M, K e n n e d y A, We bster K, et al. ( 1 9 9 9) Cli nic al f e at ures of h y pers e nsiti vit y 
re a cti o ns t o c ar b o platin. J Cli n O n c ol. 1 7( 4): 1 1 4 1  
Mattar oll o S, L oi S, D uret H, et al. ( 2 0 1 1) Pi v otal r ole of i n n ate a n d a d a pti v e i m m u nit y i n 
a nt hra c y cli n e c h e m ot hera p y of esta blis h e d t u m ors. Ca n c er Res. 7 1( 1 4): 4 8 0 9 -2 0  
Mc E v o y, G K, e dit or ( 2 0 0 0) A m eric a n H os pital F or m ular y Ser vic e Dr u g I nf or mati o n. 
A m eric a n S o ciet y of H e alt h S yste m  

N o v artis  
C o nfi d e nti al  
P a g e 1 0 2  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol N o. C M C S 1 1 0 Z 2 2 0 1  
 
Merte ns W, Eis e n h a u er E, M o ore M, et al. ( 1 9 9 3) G e m cita bi n e i n a d v a nc e d re n al c ell 
c arci n o m a. A p h as e II st u d y of t h e N ati o n al Ca n c er I nstit ute of Ca n a d a Cli nic al Trials Gr o u p. 
A n n O n c ol. 1 9 9 3 A pr; 4( 4 ): 3 3 1- 2 
M o ore D, Pa z d ur R, D a u g h ert y K, et al. ( 1 9 9 2) P h as e II st u d y of ge m cita bi n e i n a d v a nc e d 
c ol ore ctal a d e n o carci n o ma. I n v est N e w Dr u gs 1 0( 4): 3 2 3 -5.  
N ati o n al C o m pre h e nsi v e Ca nc er N et w or k ( N C C N) 2 0 1 4  
N o y R a n d P ollar d J W ( 2 0 1 4) T u m or -Ass ociate d Ma cr o p h a ges: Fr o m Me c h a nis ms t o 
T h era p y. I m m u nit y 4 1( 1): 4 9 -6 1  
O’ S h a u g h n ess y J, Os b or ne C, Pi p p e n J ( 2 0 1 1) I ni p ari b pl us C h e m ot h era p y i n Metastatic 
Tri ple -N e gati v e Bre ast Ca n c er. N E n gl J Me d 3 6 4: 2 0 5 -1 4  
O b ei d E, N a n a d a R, F u Y X, et al. ( 2 0 1 3) T h e r ole of t u m or -ass o ciate d m a cr o p h a ges i n bre ast 
c a n c er pr o gressi o n ( Re vie w). I nter n ati o n al J o ur n al of O n c ol o g y 4 3: 5 -1 2  
P ollar d J W ( 2 0 0 4) T u m o ur -e d u cate d m a cr o p ha ges pr o m ote t u m o ur pr o gressi o n a n d 
m etastasis. N at Re v Ca n c er 4( 1): 7 1 - 8 
Ries C, Ca n n arile M, H o v es S, et al. ( 2 0 1 4) Tar geti n g t u m or -ass o ciate d m a cr o p ha ges wit h 
a nti-C S F -1 R a nti b o d y re v e als a strate g y f or c a n cer t h era p y. Ca n c er Cell 2 5( 6): 8 4 6 -5 9  
R uff ell B, C h a n g -Stra c h a n, C h a n V, et al. ( 2 0 1 4) Ma cr o p ha ge I L -1 0 Bl o c ks C D 8 + T Cell -
D e p e n d e nt Res p o ns es t o C h e m ot hera p y b y S u p pressi n g I L -1 2  E x pressi o n i n I ntrat u m oral 
D e n dritic Cells. Ca n c er Cell 2 6, 6 2 3 – 6 3 7  
Stra c h a n D, R uff ell B, O ei Y, et al. ( 2 0 1 3) C S F 1 R i n hi biti o n d ela ys c er vical a n d m a m m ar y 
t u m or gr o wt h i n m uri n e m o d els b y atte n u ati n g t h e t ur n o v er of t u m or-ass ociate d m a c r o p ha ges 
a n d e n h a n ci n g i nfiltrati o n b y C D 8 + T c ells. O n c oi m m u n ol o g y 2( 1 2):e 2 6 9 6 8  
Ta c k e F, Gi n h o u x F, J a k u b zic k C, et al. ( 2 0 0 6) I m m at ure m o n oc ytes a c q uire a nti ge ns fr o m 
ot h er c ells i n t h e b o n e m arr o w a n d pres e nt t h e m t o T c ells after m at uri n g i n t h e p eri p h er y. J 
E x p Me d. 2 0 3( 3): 5 8 3 -9 7  
Tes c h e n d orff A, Mire m a di A, Pi n d er S, et al. ( 2 0 0 7) A n i m m u n e res p o nse ge n e e x pressi o n 
m o d ule i d e ntifies a g o o d pr o g n osis s u bt y p e i n estr o ge n re c e pt or n e gati v e bre ast c a n cer. 
G e n o m e Bi ol. 2 0 0 7; 8( 8): R 1 5 7  
Vi n a y a k S, Gra y R, A d a ms S, et al. ( 2 0 1 4) Ass o ciati o n of i n cre as e d t u m or -i nfiltrati n g 
l y m p h o c ytes ( TI Ls) wit h i m m u n o m o d ulat or y (I M) tri ple-n e gati v e bre ast c a nc er ( T N B C) 
s u bt y p e a n d res p o ns e t o n e o a dj u va nt plati n u m-bas e d t h era p y i n Pr E C O G 0 1 0 5. 2 0 1 4 A S C O 
A n n u al Me eti n g J Cli n O n c ol 3 2: 5s  
v o n Mi n c k witz G, Sc h n e e w eiss A, L oi bl S et al. ( 2 0 1 4) N e o a dj u va nt c ar b o plati n i n p atie nts 
wit h tri ple -n e gati v e a n d H E R 2 -p ositi v e e arl y bre ast c a n c er ( G e p ar Si xt o; G B G 6 6): a 
ra n d o mis e d p h as e 2 trial. La n c et O n c ol. 1 5( 7): 7 4 7-5 6  
West N, Mil n e K, Tr u o n g P, et al. ( 2 0 1 1) T u m or -i nfiltrati n g l y m p h o c ytes pre dict res p o ns e t o 
a nt hra c y cli n e -bas e d c h e m ot hera p y i n estr o ge n re c e pt or -ne gati v e bre ast c a nc er. Bre ast Ca n c er 
Res e arc h 1 3( R 1 2 6): 1 -1 3  
Y u a n Z Y, L u o R Z, Pe n g RJ, et al. ( 2 0 1 4) Hi g h i nfiltrati o n of t u m or -ass o ciate d m a cr o p h a ges 
i n tri ple-n e gati v e bre ast c a n c er is ass o ciate d wit h a hi g h er ris k of dista nt m etastasis. 
O n c o Tar gets a n d T h era p y 7: 1 4 7 5 – 1 4 8 0  

N o v artis  
C o nfi d e nti al  
P a g e 1 0 4  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol N o. C M C S 1 1 0 Z 2 2 0 1  
 
Gl o s s ar y  
C R  
C o m pl et e r e s p o n s e  
C R F  
C a s e R e p ort F or m  
C S R  
Cli ni c al St u d y R e p ort  
C T  
C o m p ut e d t o m o gr a p h y  
D F S  
Di s e a s e -fr e e s ur vi v al 
e C R F  
El e ctr o ni c C a s e R e p ort F or m  
F P F V  
Fir st p ati e nt fir st vi sit  
G B M  
Gli o bl a st o m a m ultif or m e  
M RI  
M a g n eti c r e s o n a n c e i m a gi n g  
L P L V  
L a st p ati e nt l a st vi sit  
O S  
O v er all s ur vi v al  
P D  
Pr o gr e s si v e di s e a s e  
P F S  
Pr o gr e s si o n -fr e e s ur vi v al 
P R  
P arti al r e s p o n s e  
R A P  
R e p orti n g a n d A n al y si s Pl a n  
R E CI S T  
R e s p o n s e E v al u ati o n Crit eri a i n S oli d T u m or s  
S D  
St a bl e di s e a s e  
S O D  
S u m of Di a m et er  
T T F  
Ti m e t o tr e at m e nt f ail ur e  
T T P  
Ti m e t o pr o gr e s si o n  
U N K  
U n k n o w n  

N o v artis  
C o nfi d e nti al  
P a g e 1 0 5  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol N o. C M C S 1 1 0 Z 2 2 0 1  
 
1 4. 1. 1  
I ntr o d u cti o n 
T h e p ur p os e of t his d o c u m e nt is t o pr o vi d e t h e w or ki n g d efi niti o ns a n d r ules n e ce s s ar y f or a 
c o nsiste nt a n d efficie nt a n al ysis of effic a c y f or o n c ol o g y st u dies i n s oli d t u m ors. T his 
d o c u m e nt is b as e d o n t h e R E CI S T criteria f or t u m or res p o ns es ( T h erass e et al 2 0 0 0 ) a n d t h e 
re vis e d R E CI S T 1. 1 g ui d eli n es (Eis e n h a u er et al 2 0 0 9 ). 
T h e effic a c y ass ess me nts d escri b e d i n  Se cti o n 1 4.1. 2  a n d t h e d efi niti o n of b e st r e s p o n s e  i n 
Se cti o n 1 4. 1. 1 7  are b as e d o n t h e R E CI S T 1. 1  criteria b ut als o gi v e m ore d etaile d i nstr u c ti o n s  
a n d r ules f or d eter mi n ati o n of b est res p o ns e. Se cti o n 1 4. 1. 1 8  is s u m m arizi n g t h e “ti m e t o 
e v e nt” v aria bles a n d r ules w hic h are m ai nl y d eri v e d fr o m i nter n al dis c ussi o ns  a n d re g ul at or y 
c o ns ultati o ns , as t h e R E CI S T criteria d o n ot d efi n e t h es e v aria bles i n d etail. Se cti o n 1 4. 1. 2 8  
of t his g ui d eli n e d es cri b es d ata h a n dli n g a n d pr o gra m mi n g r ules. T his s e cti o n is t o b e ref erre d 
t o i n  t h e  R A P  ( Re p orti n g  a n d  A n al ysis  Pla n)  t o  pr o vi d e  f urt h er  d etails  n e e d e d  f or  
pr o gra m mi n g.  
1 4. 1. 2  
Effi c a c y a s s e s s m e nt s  
T u m or e v al u ati o ns are m a d e b as e d o n R E CI S T criteria ( T h erass e et al 2 0 0 0 ), N e w G ui d eli nes 
t o E v al u ate t h e Res p o ns e t o Tre at m e nt i n S oli d T u m ors, J o ur nal of N ati o n al Ca n c er I nstit ut e, 
V ol.  9 2; 2 0 5 -1 6  a n d  re vis e d  R E CI S T g ui d eli n es ( v ersi o n  1. 1) ( Eis e n h a u er et al 2 0 0 9 ) 
E ur o p e a n J o ur n al of Ca n cer; 4 5: 2 2 8 -2 4 7.  
1 4. 1. 3  
D efi niti o n s  
1 4. 1. 4  
Di s e a s e m e a s ur a bilit y  
I n or d er t o e v al u ate t u m ors t hr o u g h o ut a st u d y, d efi niti o ns of m e as ura bilit y are re q uire d i n 
or d er t o classif y lesi o ns a p pr o priatel y at b as eli n e. I n d efi ni n g m e as ura bilit y, a disti n cti o n als o  
n e e ds t o b e m a d e b et w e e n n o d al lesi o ns ( p at h ol o gic al l y m p h n o des) a n d n o n -n o d al lesi o ns.  
•  Me as ur a ble dis e as e  - t h e pres e n c e of at le ast o n e m e as ura ble n o dal or n o n -n o dal lesi o n. 
If t h e m e as ura ble dis e as e is restricte d t o a s olitar y lesi o n, its n e o plastic n at ure s h o ul d b e 
c o nfir m e d b y c yt ol o g y/ hist ol o g y. 
F or p atie nts wit h o ut m e as ura ble dis e as e s e e Se cti o n 1 4. 1.2 6 . 
Me as ur a ble lesi o ns  ( b ot h n o d al a n d n o n-n o d al)  
•  Me as ura ble n o n -n o d al  - As a r ule of t h u m b, t h e mi ni m u m siz e of a m e as ura ble n o n -n o d al 
tar get lesi o n at b as eli n e s h o ul d b e n o less t h a n d o u ble t h e slic e t hic k n ess or 1 0 m m 
w hic h e v er is gre ater - e. g. t h e mi ni m u m  n o n -n o d al lesi o n siz e f or C T/ M RI wit h 5 m m c uts 
will b e 1 0  m m, f or 8 m m c o nti g u o us c uts t h e mi ni m u m siz e will b e 1 6  m m.  
•  L ytic b o n e lesi o ns or mi x e d l ytic -blastic lesi o ns wit h i d e ntifia ble s oft tiss u e c o m p o ne nts, 
t h at c a n b e e v al u ate d b y C T/ M RI, c a n b e c o nsi dere d as m e as ura ble lesi o ns, if t h e s oft 
tiss u e c o m p o n e nt m e ets t h e d efi niti o n of m e as ura bilit y. 
•  Me as ura ble n o d al lesi o ns (i. e. l y m p h n o d es) - L y m p h n o des ≥1 5 m m i n s h ort a xis c a n b e 
c o nsi d ere d f or s ele cti o n as tar get lesi o ns. L y m p h n o d es m e as uri n g ≥1 0 m m a n d < 1 5 m m 
are c o nsi d ere d n o n-m e as ura ble. L y m p h n o d es s m aller t h a n 1 0 m m i n s h ort a xis at 

N o v artis  
C o nfi d e nti al  
P a g e 1 0 6  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol N o. C M C S 1 1 0 Z 2 2 0 1  
 
b as eli n e, re gar dless of t h e slic e t hic k ness, are n or m al a n d n ot c o nsi d ere d i n dicati v e of 
dis e as e.  
•  C ystic lesi o ns : 
•  Lesi o ns t h at m e et t h e criteria f or ra di o gra p hic all y d efi n e d si m ple c ysts (i. e., s p h erical 
str u ct ure wit h a t hi n, n o n-irre g ular, n o n-n o d ular a n d n o n -e n ha nci n g w all, n o 
s e ptati o ns, a n d l o w C T d e nsit y [ w ater-li ke] c o nte nt)  s h o ul d n ot b e c o nsi dere d as 
m ali g n a nt lesi o ns ( n eit h er m e as ura ble n or n o n -me as ura ble) si n c e t h e y are, b y 
d efi niti o n, si m ple c ysts.  
•  ‘ C ystic lesi o ns’ t h o u g ht t o re pres e nt c ystic m etastas es c a n b e c o nsi dere d as 
m e as ura ble lesi o ns, if t h e y m e et t h e  d efi niti o n of m e as ura bilit y d es cri b e d a b o v e. 
H o w e v er, if n o n c ystic lesi o ns are pres e nt i n t h e s a m e p atie nt, t h es e are preferre d f or 
s ele cti o n as tar get lesi o ns. 
•  N o n -m e as ura ble lesi o ns - all ot h er lesi o ns  are c o nsi d ere d n o n-m eas ura ble, i n cl u di n g s m all 
lesio ns (e. g. l o n gest dia m eter < 1 0 m m wit h C T/ M RI or p at h ol o gic al l y m p h n o d es wit h ≥ 
1 0 t o < 1 5 m m s h ort a xis), as w ell as tr ul y n o n -m e as ura ble lesi o ns e. g., blastic b o ne 
lesi o ns, le pt o m e ni n ge al dis e as e, as cites, ple ural/ p ericar dial eff usi o n, i nfla m m at or y bre ast 
dis e as e, l y m p h a n gitis c utis/ p ul m o nis, a b d o mi nal m ass es/a b d o mi n al or ga n o m e gal y 
i d e ntifie d b y p h ysic al e x a m t h at is n ot m e as ura ble b y re pr o d uci ble i m a gi n g te c h ni q u es. 
1 4. 1. 5  
Eli gi bilit y b a s e d o n m e a s ur a bl e di s e a s e  
If n o m e as ura ble lesi o ns are i d e ntifie d at b as eli n e, t h e p atie nt m a y b e all o w e d t o e nter t h e 
st u d y  i n  s o m e  sit u ati o ns (e. g.  i n  P h as e  III st u dies w h ere  P F S is t h e  pri m ar y  e n d p oi nt). 
H o w e v er, it is re c o m m e n d e d t h at p atie nts b e e x cl u d e d fr o m trials w h ere t h e m ai n f o c u s is o n 
t h e  O v erall Res p o ns e  Rate  ( O R R). G ui d a n c e o n h o w p atie nts wit h j ust n o n-m e as ura ble 
dis e as e at b as eli n e will b e e v al u ate d f or res p o ns e a n d als o h a n dle d i n t h e statistic al a n al ys es is 
gi v e n i n Se cti o n 1 4. 1. 2 6 . 
1 4. 1. 6  
M et h o d s of t u m or m e a s ur e m e nt   - g e n er al g ui d eli n e s  
I n t his d o c u m e nt, t h e ter m “ c o ntrast” ref ers t o i ntra v e n o us (i. v) c o ntrast. 
T h e f oll o wi n g c o nsi d erati o ns are t o b e m a d e w h e n e v al u ati n g t h e t u m or:  
•  All m e as ure m e nts s h o ul d b e ta k e n a n d re c or de d i n m etric n otati o n  ( m m), usi n g a r uler or 
c ali p ers. All b as eli n e e v al u ati o ns s h o ul d b e p erf or m e d as cl os el y as p ossi ble t o t h e 
b e gi n ni n g of tre at m e nt a n d n e ver m ore t h a n 4 w e e ks b ef ore t h e b e gi n ni n g of t h e 
tre at m e nt. 
•  I m a gi n g-b as e d e v al u ati o n is pref erre d t o e v al uati o n b y cli nic al e x a mi n at i o n w h e n b ot h 
m et h o ds h a v e b e e n us e d t o ass ess t h e a ntit u m or effect of a tre at m e nt.  
•  F or o pti m al e v al u ati o n of p atie nts, t h e s a m e m et h o ds of ass ess m e nt a n d te c h ni q u e s h o ul d 
b e us e d t o c h ara cteriz e e a c h i d e ntifie d a n d re p orte d lesi o n at b as eli n e a n d d uri n g f oll o w -
u p. C o ntrast -e n h a nc e d C T of c h est, a b d o m e n a n d p el vis s h o ul d prefera bl y b e p erf or me d 
usi n g a 5 m m slic e t hic k n ess wit h a c o nti g u o us re c o nstr u cti o n al g orit h m. C T/ M RI s c a n 
slic e t hic k n ess s h o ul d n ot e x ce e d 8 m m c uts usi n g a c o nti g u o us re c o nstr ucti o n alg orit h m. 
If, at b as eli n e, a p atie nt is k n o w n t o h a v e a m e dic al c o ntrai n dic ati o n t o C T c o ntrast or 
d e v el o ps a c o ntrai n dic ati o n d uri n g t h e trial, t h e f oll o wi n g c h a n ge i n i m a gi n g m o d alit y will 

N o v artis  
C o nfi d e nti al  
P a g e 1 0 7  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol N o. C M C S 1 1 0 Z 2 2 0 1  
 
b e a c c e pte d f or f oll o w u p: a n o n -c o ntrast C T of c h est ( M RI n ot re c o m m e n d e d d u e t o 
res pirat or y artif a cts) pl us c o ntrast-e n h a n ce d M RI of a b d o m e n a n d p el vis. 
•  A c h a n ge i n m et h o d ol o g y c a n b e d efi ne d as eit h er a c h a n ge i n c o ntrast us e (e. g. k e e pi n g 
t h e s a m e te c h ni q u e, li k e C T, b ut s witc hi n g fr o m wit h t o wit h o ut c o ntrast us e or vic e -versa, 
re gar dless of t h e j ustific ati o n f or t h e c h a n ge) or a c h a n ge i n te c h ni q u e (e.g. fr o m C T t o 
M RI, or vic e -v ers a), or a c h a n ge i n a n y ot h er i m a gi n g m o d alit y. A c h a n ge i n m et h o d ol o gy 
will r es ult b y d ef a ult i n a U N K o v erall lesi o n res p o ns e ass ess m e nt. H o w e ver, a n ot h er 
res p o ns e ass ess m e nt t h a n t h e N o v artis c alc ulate d U N K res p o ns e m a y b e a c c e pte d fr o m the 
i n v esti gat or or t h e c e ntral bli n d e d re vie w er if a d efi niti v e res p o ns e ass ess m e nt c a n b e 
j ustifie d, b as e d o n t h e a v aila ble i nf or m ati o n. 
•  F D G -P E T : c a n c o m ple m e nt C T s c a ns i n ass essi n g pr o gressi o n ( p artic ularl y p ossi ble f or 
‘ n e w’ dis e as e). N e w lesi o ns o n t h e b asis of F D G-P E T i m a gi n g c a n b e i d e ntifie d a c c or di n g 
t o t h e f oll o wi n g al g orit h m: 
•  N e gati v e F D G -P E T at b as eli n e, wit h a p ositi v e F D G -P E T at f oll o w -u p is a si g n of P D 
b as e d o n a n e w lesi o n.  
•  N o F D G -P E T  at b as eli n e wit h a p ositi v e F D G -P E T at f oll o w -u p:  
•  If t h e p ositi v e F D G-P E T at f oll o w -u p c orres p o n ds t o a n e w site of dis e as e c o nfir m e d b y 
C T, t his is P D.  
•  If t h e p ositi v e F D G-P E T at f oll o w -u p is n ot c o nfir m e d as a n e w site of dis e as e o n C T, 
a d diti o n al f oll o w -u p C T are n e e d e d t o d eter mi n e if t h ere is tr ul y pr o gressi o n o c c urri n g at 
t h at Site (if s o, t h e d ate of P D will b e t h e d ate of t h e i nitial a b n or m al C T s c a n). 
•  If t h e p ositi v e F D G-P E T at f oll o w -u p c orres p o n ds t o a pre -e xisti n g site of dis e as e o n C T 
t h at is n ot pr o gressi n g o n t h e b asis of t h e a n at o mic i m a ges, t his is n ot P D. 
•  C hest x -r a y : Lesi o ns o n c h est x-ra y are a c c e pta ble as m e as ura ble lesi o ns w h e n t h e y are 
cle arl y d efi n e d a n d s urr o u n de d b y a erate d l u n g. H o w e ver, C T is pref era ble.  
•  Ultr as o u n d : W h e n t h e pri m ar y e n d p oi nt of t h e st u d y is o bje cti v e res p o nse e v al uati o n, 
ultras o u n d ( U S) s h o ul d n ot b e us e d t o m e as ure t u m or lesi o ns. It is, h o w e v er, a p ossi ble 
alter n ati v e t o cli nic al m e as ure m e nts of s u p erficial p al p a ble l y m p h n o des, s u bc uta n e o us 
lesi o ns a n d t h yr oi d n o d ules. U S mi g ht als o b e us ef ul t o c o nfir m t h e c o m plete 
dis a p p e ara n ce of s u p erficial lesi o ns us uall y ass ess e d b y cli nic al e x a mi n ati o n.  
•  E n d os c o p y a n d l a p a r os c o p y : T h e utiliz ati o n of e n d os c o p y a n d la p ar os c o p y f or o bje cti v e 
t u m or e v al u ati o n h as n ot y et b e e n f ull y a n d wi d el y v ali d ate d. T h eir us es i n t his s p e cific 
c o nte xt re q uire s o p histic ate d e q ui p me nt a n d a hi g h le v el of e x pertis e t h at m a y o nl y b e 
a v aila ble i n s o m e c e nters. T h eref ore, t h e utiliz ati o n of s u c h te c h ni q ues f or o bjecti v e t u m or 
res p o ns e s h o ul d b e restricte d t o v ali d ati o n p ur p oses i n s p e cializ e d c e nters. H o w e v er, s u c h 
te c h ni q u es c a n b e us ef ul i n c o nfir mi n g c o m plete p at h ol o gic al res p o ns e w h e n bi o psies are 
o btai n e d.  
•  T u m o r m a r ke rs : T u m or m ar k ers al o n e ca n n ot b e us e d t o ass ess res p o ns e. H o w e v er, 
s o m e dis e as e s p e cific a n d m ore v ali d ate d t u m or m ar k ers (e. g. C A-1 2 5 f or o v aria n c a nc er, 
P S A f or pr ostate c a n c er, al p ha -F P, L D H a n d Beta -h C G f or testic ular c a nc er) c a n b e 
i nte grate d as n o n-tar get dis e as e. If m ar k ers are i nitiall y a b o v e t h e u p p er n or m al li mit t h e y 
m ust n or m aliz e f or a p atie nt t o b e c o nsi dere d i n c o m plete cli nic al res p o ns e w h e n all 
lesi o ns h a v e dis a p p eare d. 

N o v artis  
C o nfi d e nti al  
P a g e 1 0 8  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol N o. C M C S 1 1 0 Z 2 2 0 1  
 
•  C yt ol o g y a n d hist ol o g y : C yt ol o g y a n d hist ol o g y c a n b e us e d t o differe ntiate b et w ee n P R 
a n d C R in rare c as es (i. e., after tre at m e nt t o differe ntiate b et w e e n resi d ual b e ni g n lesi o ns 
a n d resi d u al m ali g n a nt lesi o ns i n t u m or t y p es s u c h as ger m c ell t u m ors). C yt ol o gic 
c o nfir m ati o n of n e o plastic n at ure of a n y eff usi o n t h at a p p ears or w ors e ns d uri n g tre at m e nt 
is re q uire d w h e n t h e m e as ura ble t u m or h as m et t h e criteria f or res p o ns e or sta ble dis e as e. 
U n d er s u c h circ u msta nc es, t h e c yt ol o gic e x a mi n ati o n of t h e fl ui d c olle cte d will p er mit 
diff ere ntiati o n b et w ee n res p o ns e a n d sta ble dis e as e (a n eff usi o n m a y b e a si d e effe ct of the 
tre at m e nt) or pr o gressi v e dis e as e (if t h e n e o plastic ori gi n of t h e fl ui d is c o nfir me d). 
•  Cli nic al e x a mi n ati o n : Cli nic al lesi o ns will o nl y b e c o nsi d ere d m e asura ble w h e n t h e y are 
s u p erficial (i. e., s ki n n o d ules a n d p al pa ble l y m p h n o d es). F or t h e c as e of s ki n lesi o ns, 
d o c u m e ntati o n b y c ol or p h ot o gra p h y, i n cl u di n g a r uler t o esti m ate t h e siz e of t h e lesi o n, is 
re c o m m e n d e d. 
1 4. 1. 7  
B a s eli n e  d o c u m e nt ati o n  of t ar g et a n d n o n -t ar g et l e si o n s 
F or t h e e v al u ati o n of lesi o ns at b as eli n e a n d t hr o u g h o ut  t h e st u d y, t h e lesi o ns are classifi e d at 
b as eli n e as eit h er tar get or n o n -tar get lesi o ns: 
•  T a r g et lesi o ns : All m e as ura ble lesi o ns ( n o dal a n d n o n-n o dal) u p t o a m a xi m u m of fi v e 
lesi o ns i n t otal (a n d a m a xi m u m of t w o lesi o ns p er or ga n), re pres e ntati v e of all i n v ol v e d 
or ga ns s h o ul d b e i d e ntifie d as tar get lesi o ns a n d re c or d e d a n d m e as ure d at b as eli n e. Tar get 
lesi o ns s h o ul d b e s ele cte d o n t h e b asis of t h eir siz e (lesi o ns wit h t h e l o n gest dia m eter) a n d 
t h eir s uita bilit y f or a c c urate re p e ate d m e as ure m e nts (eit h er b y i m a gi n g te c h ni q ues or 
cli nic all y). Ea c h tar get lesi o n m ust b e u ni q u el y a n d s e q ue ntiall y n u m bere d o n t h e C R F 
(e v e n if it resi d es i n t h e s a m e or ga n). 
Mi ni m u m t ar g et l e si o n si z e at b a s eli n e  
•  N o n -n o d al t a r g et : N o n-n o d al tar get lesi o ns i d e ntifie d b y m et h o ds f or w hic h slic e 
t hic k n ess is n ot a p plic a ble (e. g. cli nic al e x a mi n ati o n, p h ot o gra p h y) s h o ul d b e at le ast 1 0 
m m i n l o n gest dia m eter. Se e Se cti o n 1 4. 1. 4 . 
•  N o d al t a r g et : Se e Se cti o n 1 4. 1. 4 . 
A s u m of dia m eters (l o n g a xis f or n o n -n o dal lesi o ns, s h ort a xis f or n o dal) f or all tar get lesi o n s 
will b e c alc ulate d a n d re p orte d as t h e b as eli ne s u m of dia m eters ( S O D). T h e b as eli n e s u m of  
dia m eters will b e us e d as ref ere n c e b y w hic h t o c h ara cteriz e t h e o bje cti v e t u m or res p o ns e. 
Ea c h tar get lesi o n i d e ntifie d at b as eli ne m ust b e f oll o w e d at e a c h s u bs e q u e nt e v al u ati o n a n d 
d o c u m e nte d o n e C R F . 
•  N o n -t a r g et lesi o ns: All ot h er lesi o ns are c o nsi d ere d  n o n -tar get lesi o ns, i. e. lesi o ns n ot 
f ulfilli n g t h e criteria f or tar get lesi o ns at b as eli n e. Pres e n c e or a bs e n ce or w ors e ni n g of 
n o n -tar get lesi o ns s h o ul d b e ass ess e d t hr o u g h o ut t h e st u d y; m e as ure m e nts of t h es e lesi o ns 
are n ot re q uire d.  M ulti ple n o n -tar get lesi o ns i n v ol v e d i n t h e s a m e or ga n c a n b e ass ess e d as 
a gr o u p a n d re c or d e d as a si n gle ite m (i. e. m ulti ple li v er m etastas es). Ea c h n o n -tar get 
lesi o n i d e ntifie d at b as eli n e m ust b e f oll o w e d at e a c h s u bs e q ue nt e v al u ati o n a n d 
d o c u m e nte d o n e C R F.  

N o v artis  
C o nfi d e nti al  
P a g e 1 0 9  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol N o. C M C S 1 1 0 Z 2 2 0 1  
 
1 4. 1. 8  
F oll o w -u p e v al u ati o n of t ar g et a n d n o n- t ar g et l e si o n s 
T o ass ess t u m or res p o ns e, t h e s u m of dia m eter s f or all tar get lesi o ns will b e c alc ulate d (at 
b as eli n e a n d t hr o u g h o ut t h e st u d y). At e a c h ass ess me nt res p o ns e is e v al u ate d first s e p ar at el y 
f or t h e tar get (Ta ble 1 4 - 1) a n d n o n -tar get lesi o ns (Ta ble 1 4 - 2) i d e ntifie d at b as eli n e. T h es e 
e v al u ati o ns are t h e n us e d t o c alc ulate t h e o verall lesi o n res p o ns e c o nsi d eri n g b ot h t h e t ar g et 
a n d n o n -target  lesi o ns t o get h er (Ta ble 1 4 - 3) as w ell as t h e pres e n c e or a bs e n c e of n e w lesi o ns. 
1 4. 1. 9  
F oll o w -u p a n d r e c or di n g of l e si o n s  
At e a c h visit a n d f or e a c h lesi o n t h e a ct u al d ate of t h e s c a n or pr o c e d ure w hic h w a s u s e d f or 
t h e e v al u ati o n of e a c h s p e cific lesi o n s h o ul d b e re c or d e d. T his a p plies t o tar get a n d n o n-tar get 
lesi o ns as w ell as n e w lesi o ns t h at are d ete cte d. At t h e ass ess m e nt visit all of t h e s e p arate 
lesi o n e v al u ati o n d ata are e x a mi n e d b y t h e i n v esti gat or i n or d er t o d eri v e t h e o v erall visit 
res p o ns e. T h eref ore all s u c h d ata a p plic a ble t o a p artic ular visit s h o ul d b e ass ociate d wit h t h e 
s a m e ass ess m e nt n u m ber. 
1 4. 1. 1 0  N o n - no d al le si o n s  
F oll o wi n g tre at m e nt, lesi o ns m a y h a v e l o n gest dia m eter m e as ure m e nts s m aller t h a n t h e i m a ge 
re c o nstr u cti o n i nter v al. Lesi o ns s m aller t h a n t wic e t h e re c o nstr u cti o n i nter v al are s u bje ct t o 
s u bsta ntial “ p artial v ol u m e ” effects (i. e., siz e m a y b e u n d eresti m ate d b e ca us e of t h e dist a n c e 
of t h e c ut fr o m t h e l o n gest dia m eter; s u c h lesi o ns m a y a p p ear t o h a v e res p o n d e d or pr o gresse d 
o n s u bs e q u e nt e x a mi nati o ns, w h e n, i n f a ct, t h e y re m ai n t h e s a m e siz e).  
If t h e lesi o n h as c o m pletel y dis a p p eare d, t h e lesi o n siz e s h o ul d b e re p orte d as 0 m m. 
M e as ure m e nts of n o n -n o dal tar get lesi o ns t h at b e c o m e 5 m m  or less i n l o n ge st di a m et er ar e 
li k el y t o b e n o n-re pr o d uci ble. T h eref ore, it is re c o m m e n de d t o re p ort a d ef a ult v al u e of 5 m m, 
i nste a d of t h e a ct u al m e as ure m e nt. T his d ef a ult v al u e is d eri v e d fr o m t h e 5  m m C T slic e 
t hic k n ess ( b ut s h o ul d n ot b e c h a n ge d wit h v ar yi n g C T slic e t hic k n ess). A ct ual m e a s ur e m e nt 
s h o ul d b e gi v e n f or all lesi o ns lar ger t h a n 5 m m i n l o n gest dia m eter irres p e cti v e of slic e 
t hic k n ess/re c o nstr u cti o n i nter v al. 
I n ot h er c as es w h ere t h e lesi o n c a n n ot b e relia bl y m e as ure d f or re as o ns ot h er t ha n its siz e 
(e. g.,  b or d ers of  t h e  lesi o n  are  c o nf o u n d e d  b y  n ei g h b ori n g a n at o mic al str u ct ures), n o  
m e as ure m e nt s h o ul d b e e ntere d a n d t h e lesi o n c a n n ot b e e v al uate d.  
1 4. 1. 1 1  N o d al l e si o n s  
A n o d al lesi o n less t h a n 1 0 m m i n siz e b y s h ort a xis is c o nsi d ere d n or m al. L y m p h n o d e s ar e 
n ot e x p e cte d t o dis a p p ear c o m pletel y, s o a “ n o n -z er o siz e ” will al w a ys p ersist.  
M e as ure m e nts of n o d al tar get lesi o ns t h at b e c o m e 5 m m or less i n s h ort a xis are li k el y t o b e  
n o n -re pr o d uci ble. T h eref ore, it is re c o m m e n de d t o re p ort a d ef a ult v al u e of 5 m m, i n ste a d of 
t h e a ct u al m e as ure m e nt. T his d ef a ult v al u e is d eri v e d fr o m t h e 5  m m C T slic e t hic k n e s s ( b u t 
s h o ul d n ot b e c h a n ge d wit h v ar yi n g C T slic e t hic k n ess).A ct ual m e as ure me nt s h o ul d b e gi v e n 
f or all lesi o ns lar ger t h a n 5 m m i n s h ort a xis  irres p e cti v e of slic e t hic k n ess/re c o nstr u cti o n 
i nter v al. 

N o v artis  
C o nfi d e nti al  
P a g e 1 1 0  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol N o. C M C S 1 1 0 Z 2 2 0 1  
 
H o w e v er, o n c e a tar get n o d al lesi o n s hri n ks t o less t h a n 1 0 m m i n its s h ort a xis, it will b e 
c o nsi d ere d n or mal f or res p o ns e p ur p os e d eter mi n ati o n. T h e l y m p h n o de m e a s ur e m e nts will 
c o nti n u e t o b e re c or d e d t o all o w t h e v al u es t o b e i n cl u de d i n t h e s u m of dia m et er s f or t ar g et 
lesi o ns, w hic h m a y b e re q uire d s u bse q ue ntl y f or res p o ns e d eter mi n ati o n. 
1 4. 1. 1 2  D et er mi n ati o n of t ar g et l e si o n r e s p o n s e  
T a bl e 1 4 - 1 
R e s p o n s e crit eri a f or t ar g et l e si o n s  
R e s p o n s e Crit eri a  
E v al u ati o n of t ar g et l e si o n s  
C o m pl et e R e s p o n s e ( C R):  
Di s a p p e ar a n c e of all n o n -n o d al t ar g et l e si o n s. I n a d diti o n, a n y p at h ol o gi c al l y m p h 
n o d e s a s si g n e d a s t ar g et l e si o n s m u st h a v e a r e d u cti o n i n s h ort a xi s t o < 1 0  m m 1 
P arti al R e s p o n s e ( P R):  
At l e a st a 3 0 % d e cr e a s e i n t h e s u m of di a m et er of all t ar g et l e si o n s, t a ki n g a s 
r ef er e n c e t h e b a s eli n e s u m  of di a m et er s. 
Pr o gr e s si v e Di s e a s e ( P D): 
At l e a st a 2 0 % i n cr e a s e i n t h e s u m of di a m et er of all m e a s ur e d t ar g et l e si o n s, 
t a ki n g a s r ef er e n c e t h e s m all e st s u m of di a m et er of all t ar g et l e si o n s r e c or d e d at 
or aft er  b a s eli n e. I n a d diti o n t o t h e r el ati v e i n cr e a s e of 2 0 %,  t h e s u m  m u st al s o 
d e m o n s tr at e a n a b s ol ut e i n cr e a s e of at  l e a st 5 m m2. 
St a bl e Di s e a s e ( S D):  
N eit h er s uffi ci e nt s hri n k a g e t o q u alif y f or P R or C R n or a n i n cr e a s e i n l e si o n s 
w hi c h w o ul d q u alif y f or P D.  
U n k n o w n ( U N K)  
Pr o gr e s si o n h a s n ot b e e n d o c u m e nt e d a n d o n e or m or e t ar g et l e si o n s h a v e n ot 
b e e n a s s e s s e d or h a v e b e e n  a s s e s s e d u si n g a diff er e nt m et h o d t h a n b a s eli n e. 3 
1. S O D  f or C R  m a y n ot b e z er o w h e n n o d al l e si o n s ar e p art of t ar g et l e si o n s 
2. F oll o wi n g a n i niti al C R, a P D  c a n n ot b e a s si g n e d if all n o n-n o d al t ar g et l e si o n s ar e sti ll n ot pr e s e nt a n d all n o d al 
l e si o n s ar e < 1 0  m m  i n si z e. I n t hi s c a s e, t h e t ar g et l e si o n r e s p o n s e i s C R 
3. M et h o d ol o g y c h a n g e S e e S e cti o n 1 4. 1. 6 . 
N ot e s o n t ar g et l e si o n r e s p o n s e  
R e a p pe a r a nc e of lesi o ns : If t h e lesi o n a p p e ars at t h e s a m e a n at o mic al l o c ati o n w h ere a tar get 
lesi o n h a d pre vi o usl y dis a p p e are d, it is a d vis e d t h at t h e ti m e p oi nt of lesi o n dis a p p e ara n c e 
(i. e., t h e “ 0 m m ” re c or di n g) b e re-e v al u ate d t o m a k e s ure t h at t h e le si o n w as n ot a ct u all y 
pres e nt a n d/ or n ot vis u aliz e d f or te c h nic al re as o ns i n t his pre vi o us ass ess m e nt. If it is n ot 
p ossi ble t o c h a n ge t h e 0 v al u e, t h e n t h e i n v esti gat or/ra di ol o gist h as t o d e ci d e b et w e e n t h e 
f oll o wi n g t hre e p ossi bilities: 
•  T h e lesi o n is a n e w lesi o n, i n w hic h c as e t h e o v erall t u m or ass ess m e nt will b e c o nsi d ere d 
as pr o gressi v e dis e as e  
•  T h e lesi o n is cle arl y a re a p p e ara n c e of a pre vi o usl y dis a p pe are d lesi o n, i n w hic h c as e t h e 
siz e of t h e lesi o n h as t o b e e ntere d i n t h e C R F a n d t h e t u m or ass ess m e nt will re m ai n b as e d 
o n t h e s u m of t u m or m e as ure m e nts as pres e nte d i n Ta ble 1 4 - 1 a b o ve (i. e., a P D will b e 
d eter mi n e d if t h ere is at le ast 2 0 % i n cre as e i n t h e s u m of dia m eters of all  m e as ure d tar get 
lesi o ns, ta ki n g as ref ere n c e t h e s m allest s u m of dia m eters of all tar get lesi o ns re c or d e d at or 
af ter b as eli n e wit h at le ast 5 m m i n cre as e i n t h e a bs ol ute s u m of t h e dia m eters). Pr o p er 
d o c u m e ntati o n s h o ul d b e a v aila ble t o s u p p ort t his d e cisi o n.  T his a p plies t o p atie nts w h o 
h a v e n ot a c hie v e d tar get res p o ns e of C R. F or p atie nts w h o h a ve a c hie v e d C R, ple a s e refer 
t o last b ullet i n t his s e cti o n. 
•  F or t h os e p atie nts w h o h a v e o nl y o ne tar get lesi o n at b as eli n e, t h e re a p p e ara nc e of t h e 
tar get lesi o n w hic h dis a p p e are d pre vi o usl y, e v e n if still s m all, is c o nsi d ere d a P D. 

N o v artis  
C o nfi d e nti al  
P a g e 1 1 1  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol N o. C M C S 1 1 0 Z 2 2 0 1  
 
•  Missi n g me as ur e me nts : I n c as es w h ere m e as ure m e nts are missi n g f or o ne or m ore tar get 
lesi o ns it is s o m eti m es still p ossi ble t o assi g n P D b as e d o n t h e m e as ure me nts of t h e 
re m ai ni n g lesi o ns. F or e x a m ple, if t h e s u m of dia m eters f or 5 tar get lesi o ns at b as eli n e is 
1 0 0  m m at b as eli n e a n d t h e s u m of dia meters f or 3 of t h os e lesi o ns at a p ost -b as eli ne visit 
is 1 4 0 m m ( wit h d ata f or 2 ot h er lesi o ns missi n g) t h e n a P D s h o ul d b e assi g n e d. H o w e ver, 
i n ot h er c as es w h ere a P D c a n n ot d efi nitel y b e attri b ute d, t h e tar get lesi o n res p o nse w o ul d 
b e U N K.  
•  N o d al lesi o n de c r e as e t o n o r m al siz e : W h e n n o d al dis e ase is i n cl u d e d i n t h e s u m of tar get 
lesi o ns a n d t h e n o d es d e cre as e t o “ n or m al” siz e t h e y s h o ul d still h a v e a m e as ure m e nt 
re c or d e d o n s c a ns. T his m e as ure m e nt s h o ul d b e re p orte d e v e n w h e n t h e n o des are n or mal 
i n or d er n ot t o o v erstate pr o gressi o n s h o ul d it b e b as e d o n i n cre as e i n t h e siz e of n o des. 
•  Lesi o ns s plit :  I n s o m e circ u msta n c es, dis e as e t h at is m e as ura ble as a tar get lesi o n at 
b as eli n e a n d a p p e ars t o b e o n e m ass c a n s plit t o b e c o m e t w o or m ore s m aller s u b -lesio ns. 
W h e n t his o c c urs, t h e dia m eters (l o n g a xis - n o n -n o d al lesi o n, s h ort a xis - n o d al lesi o ns) of 
t h e t w o s plit lesi o ns s h o ul d b e a d d e d t o get h er a n d t h e s u m re c ord e d i n t h e dia m eter field o n 
t h e c as e re p ort f or m u n d er t h e ori gi n al lesi o n n u m ber. T his v al ue will b e i n cl u d e d i n t h e 
s u m of dia m eters w h e n d eri vi n g tar get lesi o n res p o nse. T h e i n di vi d u al s plit lesi o ns will n ot 
b e c o nsi d ere d as n e w lesi o ns, a n d will n ot a ut o m atic all y tri g ger a P D d esi g n ati o n.  
•  Lesi o ns c o ales c e d : C o n v ers el y, it is als o p ossi ble t h at t w o or m ore lesi o ns w hic h w ere 
disti n ctl y s e p arate at b as eli n e b e c o m e c o nfl u e nt at s u bs e q u e nt visits. W h e n t his o c c urs a 
pla n e b et w e e n t h e ori gi n al lesi o ns m a y b e m ai ntai n e d t h at w o ul d ai d i n o btai ni n g dia m eter 
m e as ure m e nts of e a c h i n di vi d ual lesi o n. If t h e lesi o ns h a v e tr ul y c o ales ce d s u c h t h at t h e y 
are n o l o n ger s e p ara ble, t h e m a xi m al dia m eters (l o n g a xis - n o n -n o dal lesi o n, s h ort a xis - 
n o d al lesi o ns) of t h e “ m er ge d lesi o n ” s h o ul d b e us e d w h e n c alc ulati n g t h e s u m of 
dia m eters f or tar get lesi o ns. O n t h e  c as e re p ort f or m, t h e dia meter of t h e “ m er ge d lesi o n” 
s h o ul d be re c or d e d f or t h e siz e of o n e of t h e ori gi n al lesi o ns w hile a siz e of “ 0 ” m m s h o ul d 
b e e ntere d f or t h e re m ai ni n g lesi o n n u m bers w hic h h a v e c o ales ce d.  
•  T h e me as ur e me nts f o r n o d al lesi o ns , e v e n if less t h a n 1 0 m m i n siz e, will c o ntri b ute t o 
t h e c alc ulati o n of tar get lesi o n res p o ns e i n t h e us u al w a y wit h sli g ht m o dific ati o ns. 
•  Si n c e lesi o ns less t h a n 1 0 m m are c o nsi d ere d n or m al, a C R f or tar get lesi o n res p o ns e 
s h o ul d b e assi g n e d w h e n all n o d al tar get lesi o ns s hri n k t o less t h a n 1 0 m m a n d all 
n o n -n o d al tar get lesi o ns h a v e dis a p pe are d.  
•  O n c e a C R tar get lesi o n res p o ns e h as b e e n assi g n e d a C R will c o nti n u e t o b e 
a p pr o priate (i n t h e a bs e n ce of missi n g d ata) u ntil pr o gressi o n of tar get lesi o ns.  
•  F oll o wi n g a C R, a P D c a n s u bs e q u e ntl y o nl y b e assi g n e d f or tar get lesi o n res p o ns e if 
eit h er a n o n -n o d al tar get lesi o n “re a p pe ars” or if a n y si n gle n o d al lesi o n is at le ast 1 0 
m m a n d t h ere is at le ast 2 0 % i n cre as e i n s u m of t h e dia meters of all n o d al tar get 
lesi o ns relati v e t o n a dir wit h at le ast 5 m m i n cre as e i n t h e a bs ol ute s u m of t h e 
dia m eters.  

N o v artis  
C o nfi d e nti al  
P a g e 1 1 2  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol N o. C M C S 1 1 0 Z 2 2 0 1  
 
1 4. 1. 1 3  D et er mi n ati o n  of n o n -t ar g et l e si o n r e s p o n s e 
T a bl e 1 4 - 2 
R e s p o n s e crit eri a f or n o n -t ar g et l e si o n s 
R e s p o n s e Crit eri a  
E v al u ati o n of n o n -t ar g et l e si o n s 
C o m pl et e R e s p o n s e ( C R):  
Di s a p p e ar a n c e of all n o n -t ar g et l e si o n s. I n a d diti o n, all l y m p h n o d e s a s si g n e d a 
n o n -t ar g et l e si o n s m u st b e n o n -p at h ol o gi c al i n si z e ( < 1 0 m m  s h ort a xi s)  
Pr o gr e s si v e Di s e a s e ( P D):  
U n e q ui v o c al pr o gr e s si o n of e xi sti n g n o n -t ar g et l e si o n s.1 
N o n -C R/ N o n -P D:  
N eit h er C R  n or P D  
U n k n o w n ( U N K)  
Pr o gr e s si o n h a s n ot b e e n d o c u m e nt e d a n d o n e or m or e n o n -t ar g et l e si o n s h a v e 
n ot b e e n a s s e s s e d or h a v e b e e n a s s e s s e d u si n g a diff er e nt m et h o d t h a n b a s eli n e.  
1. Alt h o u g h a cl e ar pr o gr e s si o n of n o n-t ar g et l e si o n s o nl y i s e x c e pti o n al, i n s u c h cir c u m st a n c e s, t h e o pi ni o n of t h e 
tr e ati n g p h y si ci a n d o e s pr e v ail a n d t h e pr o gr e s si o n st at u s s h o ul d b e c o nfir m e d l at er o n b y t h e r e vi e w p a n el ( or 
st u d y c h air).  
N ot e s o n n o n -t ar g et l e si o n r e s p o n s e 
•  T h e res p o ns e f or n o n -tar get lesi o ns is C R  o nl y if all n o n -tar get n o n-n o d al lesi o ns w hic h 
w ere e v al u ate d at b as eli n e are n o w all a bs e nt a n d wit h all n o n -tar get n o dal lesi o ns 
ret ur n e d t o n or m al siz e (i. e. < 1 0 m m). If a n y of t h e n o n -tar get lesi o ns are still pres e nt, or 
t h ere are a n y a b n or m al n o dal lesi o ns (i. e. ≥ 1 0 m m) t h e res p o ns e c a n o nl y b e ‘ N o n -
C R/ N o n -P D ’ u nless a n y of t h e lesi o ns w as n ot ass ess e d (i n w hic h c as e res p o nse is U N K ) 
or t h ere is u n e q ui v o cal pr o gressi o n of t h e n o n -tar get lesi o ns (i n w hic h c as e res p o ns e is 
P D ). 
•  U n e q ui v o c al pr o gressi o n:  T o a c hie v e “ u n e q ui v o cal pr o gressi o n ”  o n t h e b asis of n o n -tar get 
dis e as e t h ere m ust b e a n o v erall le v el of s u bsta ntial w ors e ni n g i n n o n -tar get dis e as e s u c h 
t h at, e v e n i n pres e n c e of C R, P R or S D i n tar get dis e as e, t h e o v erall t u m or b ur de n h as 
i n cre as e d s ufficie ntl y t o m erit dis c o nti n u ati o n of t h era p y. A m o d est “i n cre as e ” i n t h e siz e 
of o n e or m ore n o n -tar get lesi o ns is us u all y n ot s ufficient t o q u alif y f or u ne q ui v oc al 
pr o gressi o n stat us. T h e d esi g n ati o n of o v erall pr o gressi o n s olel y o n t h e b asis of c h a n ge i n 
n o n -tar get dis e as e i n t h e f a c e of C R, P R or S D of tar get dis e as e is t h eref ore e x pe cte d t o b e 
rare. In or d er f or a P D t o b e assi g n e d o n  t h e b asis of n o n-tar get lesi o ns, t h e i n cre as e i n t h e 
e xte nt of t h e dis e as e m ust b e s u bsta ntial  ev e n i n c as es w h ere t h ere is n o m e as ura ble 
dis e as e at b as eli n e. If t h ere is u n e q ui v oc al pr o gressi o n of n o n-tar get lesi o n(s), t h e n at le ast 
o n e of t h e n o n -tar get lesi o ns m ust b e assi g n e d a stat us of “ W orse n e d ”. W h ere p ossi ble, 
si milar r ules t o t h os e d es cri b e d i n Se cti o n 1 4.1. 1 2  f or assi g ni n g P D f oll o wi n g a C R f or t h e 
n o n -tar get lesi o n res p o ns e i n t h e pres e n c e of n o n-tar get lesi o ns n o dal lesi o ns s h o ul d b e 
a p plie d.  
1 4. 1. 1 4  N e w l e si o n s  
T h e a p p e ara n c e of a n e w lesi o n is al w a ys ass o ciate d wit h Pr o gressi v e Dis e as e ( P D) a n d h as to 
b e re c or d e d as a n e w lesi o n i n t h e N e w Lesi o n C R F p a ge.  
•  If a n e w lesi o n is e q ui v o c al, f or e x a m ple b e ca us e of its s m all siz e, c o nti n u e d t h era p y a n d 
f oll o w-u p e v al uati o n will clarif y if it re pres e nts tr ul y n e w dis e as e. If re p e at s c a ns c o nfir m 
t h ere is d efi nitel y a n e w lesi o n, t h e n pr o gressi o n s h o ul d b e d e clare d usi n g t h e d ate of t h e 
first o bs er v ati o n of t h e lesi o n. 

N o v artis  
C o nfi d e nti al  
P a g e 1 1 3  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol N o. C M C S 1 1 0 Z 2 2 0 1  
 
•  If n e w dis e as e is o bs er v e d i n a re gi o n w hic h w as n ot s c a n ne d at b as eli ne  or w h ere t h e 
p artic ular b as eli n e s c a n is n ot a v aila ble f or s o me re as o n, t h e n t his s h o ul d b e c o nsi dere d as 
a P D. T h e o n e e x c e pti o n t o t his is w h e n t h ere are n o b as eli ne s c a ns at all a v aila ble f or a 
p atie nt i n w hic h c as e t h e res p o ns e s h o ul d b e U N K, as f or a n y of t his p atie nt's ass ess m e nt 
(s e e Se cti o n 1 4. 1. 1 5 ). 
•  A l y m p h n o de is c o nsi de r e d as a “ ne w lesi o n ” a n d, t h eref ore, i n dic ati v e of pr o gressi ve 
dis e as e if t h e s h ort a xis i n cre as es i n siz e t o ≥ 1 0 m m f or t h e first ti m e i n t h e st u d y pl us 5 
m m a bs ol ute i n cre as e.  
F D G -P E T : c a n c o m ple m e nt C T s c a ns i n ass essi n g pr o gressi o n ( p artic ularl y p ossi ble f or 
‘ n e w’ dis e as e). Se e Se cti o n 1 4. 1. 6 . 
1 4. 1. 1 5  E v al u ati o n of o v er all l e si o n r e s p o n s e  
T h e e v al u ati o n of o v erall lesi o n res p o ns e at e a c h ass ess m e nt is a c o m p osite of t h e tar get 
lesi o n res p o ns e, n o n-tar get lesi o n res p o nse a n d pres e nc e of n e w lesi o ns a s s h o w n b el o w i n  
Ta ble 1 4 -3.  
T a bl e 1 4 - 3 
O v er all l e si o n r e s p o n s e at e a c h a s s e s s m e nt  
T ar g et l e si o n s  
N o n -t ar g et l e si o n s 
N e w L e si o n s  
O v er all  
l e si o n r e s p o n s e 
C R  
C R  
N o  
C R 1 
C R  
N o n -C R/ N o n -P D 3 
N o  
P R  
C R, P R, S D  
U N K  
N o  
U N K  
P R  
N o n -P D a n d n ot U N K  
N o  
P R 1 
S D  
N o n -P D a n d n ot U N K  
N o  
S D 1, 2 
U N K  
N o n -P D or U N K  
N o  
U N K 1 
P D  
A n y  
Y e s  o r N o  
P D  
A n y  
P D  
Y e s  o r N o  
P D  
A n y  
A n y  
Y e s  
P D  
1. T hi s o v er all l e si o n r e s p o n s e al s o a p pli e s w h e n t h er e ar e n o n o n -t ar g et l e si o n s i d e ntifi e d at b a s eli n e. 
2. O n c e c o nfir m e d P R w a s a c hi e v e d, all t h e s e a s s e s s m e nt s ar e c o n si d er e d P R. 
3. A s  d efi n e d i n S e cti o n 1 4. 1. 8 . 
If  t h ere  are  n o  b as eli n e  s c a ns  a v aila ble  at  all, t h e n t h e o v erall lesi o n res p o ns e at e a c h 
ass ess m e nt s h o ul d b e c o nsi dere d U n k n o wn ( U N K).  
If t h e e v al u ati o n of a n y of t h e tar get or n o n -tar get lesi o ns i d e ntifie d at b as eli n e  c o ul d  n o t b e 
m a d e d uri n g f oll o w -u p, t h e o v erall stat us m ust b e ‘ u n k n o wn’ u nless pr o gressi o n w as s e e n.  
I n s o m e circ u msta n c es it m a y b e diffic ult t o disti n g uis h resi d u al dis e as e fr o m n or m al tis s u e. 
W h e n t h e e v al u ati o n of c o m plete res p o ns e d e p e n ds o n t his d eter mi nati o n, it is re c o m m e n d e d 
t h at t h e resi du al lesi o n b e i n v esti gate d (fi n e n ee dle as pirate/ bi o ps y) t o c o nfir m t h e C R.  
1 4. 1. 1 6  Effi c a c y d efi niti o n s  
T h e  f oll o wi n g d efi niti o ns  pri m aril y  relate  t o  p atie nts  w h o  h a v e  m e as ura ble  dis e as e  at  
b as eli n e. Se cti o n 1 4. 1.2 6  o utli n es t h e s p ecial c o nsi d erati o ns t h at n e e d t o b e gi v e n t o p ati e nts 
wit h n o m e as ura ble dis e as e at b as eli ne i n or d er t o a p pl y t h e s a m e c o nc e pts.  

N o v artis  
C o nfi d e nti al  
P a g e 1 1 4  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol N o. C M C S 1 1 0 Z 2 2 0 1  
 
1 4. 1. 1 7  B e st o v er all r e s p o n s e  
T h e b est o v erall res p o ns e is t h e b est res p o ns e re c or d e d fr o m t h e start of t h e tre at m e nt u ntil 
dis e as e  pr o gressi o n/re c urre n c e  (ta ki n g  as  ref ere n c e  f or  P D  t h e  s m allest  m e as ure m e nts  
re c or d e d si n c e t h e tre at m e nt starte d). I n ge n eral, t h e p atie nt's b est res p o ns e assi g n m e nt will 
d e p e n d o n t h e a c hie ve me nt of b ot h m e as ure m e nt a n d c o nfir m ati o n criteria.  
T h e b est o v erall res p o ns e will us u all y b e d eter mi n e d fr o m res p o ns e ass ess me nts u n d ert a k e n 
w hile  o n  tre at m e nt.  H o w e v er,  if  a n y  ass ess m e nts  o c c ur after tre at m e nt wit h dra w al t h e  
pr ot o c ol s h o ul d s p e cific all y d es cri b e if t h es e will b e i n cl u d e d i n t h e d eter mi n ati o n of b est 
o v erall res p o ns e a n d/ or w h et her t h es e a d diti o nal ass ess me nts will b e re q uire d f or s e nsiti vit y 
or s u p p orti v e a n al ys es. As a d ef a ult, a n y ass ess me nts ta k e n m ore t h a n 3 0 d a ys aft er t h e l a st 
d os e of st u d y tre at m e nt will n ot b e i n cl u d e d i n  t h e b est o v erall res p o ns e d eri v ati o n. If a n y 
alter n ati v e  c a n c er t h era p y  is ta k e n  w hile  o n  st u d y  a n y  s u bs e q u e nt ass ess m e nts w o ul d  
or di n aril y b e e x cl u d e d fr o m t h e b est o v erall res p o ns e d eter mi n ati o n. If res p o ns e ass e s s m e nts 
ta k e n after wit h dra w al fr o m st u d y tre at m e nt a n d/ or alter nati v e t h era p y are t o b e i n cl u d e d i n 
t h e m ai n e n d p oi nt d eter mi nati o n, t h e n t his s h o ul d b e d es cri b e d a n d j ustifie d i n t h e pr ot o c ol. 
W h ere a st u d y re q uires c o nfir m ati o n of res p o ns e  (P R or C R ), c h a n ges i n t u m or m e as ure m e nts 
m ust b e c o nfir m e d b y re p e at ass ess m e nts t h at s h o ul d b e p erf or m e d n ot less t h a n 4 w e e ks after 
t h e criteria f or res p o ns e are first m et. 
L o n ger i nter v als m a y als o b e a p pr o priate. H o w e v er, t his m ust b e cle arl y state d i n t h e pr ot o c ol. 
T h e m ai n g o al of c o nfir m ati o n of o bje cti ve res p o ns e is t o a v oi d o v eresti m ati n g t h e r e s p o ns e 
rate o bs er v e d. I n c as es w h ere c o nfir mati o n of res p o ns e is n ot f e asi ble, it s h o ul d b e m a d e cle ar 
w h e n re p orti n g t h e o utc o m e of s u c h st u dies t h at t h e res p o ns es are n ot c o nfir m e d.  
•  -F or n o n -ra n d o miz e d trials w h ere res p o ns e is t h e pri m ar y e n d p oi nt, c o nfir m ati o n is 
n e e d e d.  
•  -F or trials i nte n d e d t o s u p p ort a c c elerate d a p pr o v al, c o nfir m ati o n is n e e de d  
•  F or all ot h er trials, c o nfir m ati o n of res p o ns e m a y b e c o nsi d ere d o pti o n al.  
T h e b est o v er all res p o ns e f or e a c h p atie nt is d eter mi n e d fr o m t h e s e q ue nc e of o v erall (lesi o n) 
res p o ns es a c c or di n g t o t h e f oll o wi n g r ules: 
•  C R = at le ast t w o d eter mi n ati o ns of C R at le ast 4 w e e ks a p art b ef ore pr o gressi o n  w h ere 
c o nfir m ati o n re q uire d or o n e d eter mi n ati o n of C R pri or t o pr o gressi o n w h ere c o nfir m ati o n 
n ot re q uire d  
•  P R = at le ast t w o d eter mi n ati o ns of P R or b etter at le ast 4 w e e ks a p art b ef ore pr o gressi o n 
(a n d n ot q u alif yi n g f or a C R) w h ere c o nfir m ati o n re q uire d or o n e d eter mi nati o n of P R 
pri or t o pr o gressi o n w h ere c o nfir m ati o n n ot re q uire d  
•  S D = at le ast o n e S D ass ess m e nt ( or b etter) > 6 w e e ks after ra n d o mizati o n/start of 
tre at m e nt (a n d n ot q u alif yi n g f or C R or P R). 
•  P D = pr o gressi o n ≤ 1 2 w e e ks after ra n d o miz ati o n/ start of tre at m e nt (a n d n ot q u alif yi n g 
f or C R, P R or S D). 
•  U N K = all ot h er c as es (i. e. n ot q u alif yi n g f or c o nfir m e d C R or P R a n d wit h o ut S D after 
m ore t h a n 6 w e e ks or e arl y pr o gressi o n wit hi n t h e first 1 2 w e e ks)  

N o v artis  
C o nfi d e nti al  
P a g e 1 1 5  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol N o. C M C S 1 1 0 Z 2 2 0 1  
 
O v erall lesi o n  res p o ns es of  C R m ust sta y  t h e  s a m e  u ntil pr o gressi o n  s ets i n, wit h  t h e  
e x c e pti o n of a U N K stat us. A p atie nt w h o h a d a C R c a n n ot s u bse q u e ntl y h a ve a l o w er st at u s 
ot h er t h a n a P D, e. g. P R or S D, as t his w o ul d i m pl y a pr o gressi o n b as e d o n o n e or m ore 
lesi o ns re a p p e ari n g, i n w hic h c as e t h e stat us w o ul d b ec o me a P D. 
O n c e a n o v erall lesi o n res p o ns e of P R is o bs er v e d ( w hic h m a y h a v e t o b e a c o nfir m e d P R 
d e p e n di n g o n t h e st u d y) t his assi g n m e nt m ust sta y t h e s a m e or i m pr o v e o v er ti m e u ntil 
pr o gressi o n  s ets i n,  wit h  t h e  e x c e pti o n  of  a n  U N K stat us. H o w e v er, i n  st u dies w h ere  
c o nfir m ati o n of res p o ns e is re q uire d, if a p atie nt h as a si n gle P R ( ≥3 0 % r e d u cti o n of t u m or 
b ur d e n c o m p are d t o b as eli n e) at o n e ass ess m e nt, f oll o w e d b y a < 3 0 % re d ucti o n fr o m b as eli ne 
at t h e n e xt ass ess m e nt ( b ut n ot ≥2 0 % i n cre as e fr o m pre vi o us s m allest s u m), t h e o bje cti v e 
stat us at t h at ass ess m e nt s h o ul d b e S D. O n c e a c o nfir m e d P R w as s e e n, t h e o v erall lesi o n 
res p o ns e s h o ul d b e c o nsi d ere d P R ( or U N K) u ntil pr o gressi o n is d o c u m e nt e d or t h e l e si o n s 
t otall y dis a p p e ar i n w hic h c as e a C R assi g n m e nt is a p plic a ble. I n st u dies w h ere co nfir m ati o n 
of res p o ns e is n ot re q uire d after a si n gle P R t h e o v erall lesi o n res p o ns e s h o ul d still b e 
c o nsi d ere d P R ( or U N K) u ntil pr o gressi o n is d o c u m e nte d or t h e lesi o n t otall y dis a p p e ars i n 
w hic h c as e a C R assi g n m e nt is a p plic a ble.  
E x a m ple: I n a c as e w h ere c o nfir m ati o n of res p o ns e is re q uire d t h e s u m of lesi o n dia m et er s is 
2 0 0  m m at b as eli n e a n d t h e n 1 4 0  m m - 1 5 0  m m - 1 4 0  m m - 1 6 0 m m - 1 6 0 m m at t h e 
s u bs e q u e nt visits.  Ass u mi n g t h at n o n-tar get lesi o ns di d  n ot pr o gress, t h e  o v erall lesi o n  
res p o ns e w o ul d b e P R - S D - P R - P R - P R. T h e s e c o n d ass ess me nt wit h 1 4 0 m m c o nfir ms the 
P R  f or  t his  p atie nt.  All  s u bs e q u e nt  ass ess m e nts  are  c o nsi d ere d  P R  e v e n  if  t u m or  
m e as ure m e nts d e cre as e o nl y b y 2 0 % c o m p are d t o b as eli n e ( 2 0 0  m m t o 1 6 0 m m) at t h e 
f oll o wi n g ass ess m e nts. 
If t h e p atie nt pr o gress e d b ut c o nti n ues st u d y tre at m e nt, f urt h er ass ess m e nts are n ot c o nsi d ere d 
f or t h e d eter mi n ati o n of b est o v erall res p o ns e. 
N ote : t h es e c as es m a y b e d es cri b e d as a s e p arate fi n di n g i n t h e C S R b ut n ot i n cl u d e d i n t h e 
o v erall res p o ns e or dis e as e c o ntr ol rates. 
T h e b est o v erall res p o ns e f or a p atie nt is al w a ys c alc ulate d, b as e d o n t h e s e q u e n ce of o v er all 
lesi o n res p o ns es. H o w e v er, t h e o v erall lesi o n res p o ns e at a gi v e n ass ess m e nt m a y b e pr o vi de d 
fr o m diff ere nt s o urc es: 
•  I n v esti gat or o v erall lesi o n res p o ns e 
•  Ce ntral Bli n d e d Re vie w o v erall lesi o n res p o ns e  
•  N o v artis c alc ulate d o v erall lesi o n res p o ns e ( b as e d o n m e as ure me nts fr o m eit h er 
I n v esti gat or or Ce ntral Re vie w) 
T h e  pri m ar y  a n al ysis  of  t h e  b est  o v erall  res p o ns e  will  b e  b as e d  o n  t h e  s e q u e n c e  of  
i n v esti gat or/c e ntral bli n d e d re vie w/c alc ulate d (i n v esti gat or)/c alc ulate d (c e ntral) o v erall lesi o n  
res p o ns es. 
Bas e d o n t h e p atie nts’ b est o v erall res p o ns e d uri n g t h e st u d y, t h e f oll o wi n g rates are t h e n 
c alc ulate d: 
O v e r all r es p o ns e r ate ( O R R)  is t h e pr o p orti o n of p atie nts wit h a b est o v erall res p o ns e of C R 
or P R. T his is als o ref erre d t o as ‘ O bje cti v e res p o ns e rate’ i n s o m e pr ot o c ols or p u blic ati o ns.  

N o v artis  
C o nfi d e nti al  
P a g e 1 1 6  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol N o. C M C S 1 1 0 Z 2 2 0 1  
 
Dis e as e c o ntr ol r ate  ( D C R) is t h e pr o p orti o n of p atie nts wit h a b est o v erall re s p o ns e of C R 
or P R or S D.  
A n ot h er a p pr o a c h is t o s u m m ariz e t h e pr o gressi o n rate at a c ertai n ti m e p oi nt after b as eli ne. In 
t his c as e, t h e f oll o wi n g d efi niti o n is us e d: 
E a rl y pr o g r essi o n r ate ( E P R)  is t h e pr o p orti o n of p atie nts wit h pr o gressi v e dis e as e wit hi n 
8 w e e ks of t h e start of tre at m e nt.  
T h e pr ot o c ol s h o ul d d efi ne p o p ulati o ns f or w hic h t h es e will b e c alc ulate d. T h e ti m e p oi nt f or 
E P R is st u d y s p e cific. E P R is us e d f or t h e m ulti n o mial d esi g ns of D e nt a n d Z e e ( 2 0 0 1)  a n d 
c o u nts all p atie nts w h o at t h e s p e cifie d ass ess m e nt (i n t his e x a m ple t h e ass ess me nt w o ul d b e 
at 8 w e e ks ± wi n d o w) d o n ot h a v e a n o v erall lesi o n res p o ns e of S D, P R or C R. Pati e nts wit h 
a n u n k n o w n ( U N K) ass ess m e nt at t h at ti m e p oi nt a n d n o P D b ef ore, will n ot b e c o u nte d as 
e arl y pr o gress ors i n t h e a n al ysis b ut m a y b e i n cl u d e d i n t h e d e n o mi n at or of t h e E P R rate, 
d e p e n di n g o n t h e a n al ysis p o p ulati o n us e d. Si milarl y w h e n e x a mi ni n g o v er all r e s p o ns e a n d 
dis e as e c o ntr ol, p atie nts wit h a b est o v erall res p o nse ass ess m e nt of u n k n o w n ( U N K) will n ot 
b e re gar d e d as “res p o n d ers ” b ut m a y b e i n cl u d e d i n t h e d e n o mi n at or f or O R R a n d D C R 
c alc ulati o n d e p e n di n g o n t h e a n al ysis p o p ulati o n (e. g. p o p ulati o ns b as e d o n a n I T T a p pr o ac h).  
1 4. 1. 1 8  Ti m e t o e v e nt v ari a bl e s  
T h e pr ot o c ol s h o ul d st ate w hic h of t h e f oll o wi n g v ari a bles is us e d i n t h at st u d y.  
1 4. 1. 1 9  Pr o gr e s si o n -fr e e s ur vi v al 
Us u all y  i n  all  O n c ol o g y  st u dies,  p atie nts  are  f oll o w e d  f or  t u m or  pr o gressi o n  after  
dis c o nti n u ati o n of st u d y m e dicati o n f or re as o ns ot h er t h a n pr o gressi o n or d e at h. If t his is n ot 
us e d, e. g. i n P h as e I or II st u dies, t his s h o ul d b e cle arl y state d i n t h e pr ot o c ol. N ote t h at 
ra n d o miz e d trials ( pref era bl y bli n d e d) are re c o m m e n d e d w h ere P F S is t o b e t h e pri m ar y 
e n d p oi nt.  
Pr o g r essi o n -fr e e s ur vi v al ( P F S) is t h e ti m e fr o m d ate of ra n d o miz ati o n/start of tre at m e n t t o  
t h e d ate of e v e nt d efi n e d as t h e first d o c u m e nte d pr o gressi o n or d e at h d u e t o a n y c a u s e. If  a 
p atie nt h as n ot h a d a n e v e nt, pr o gressi o n -free s ur vi v al is c e ns ore d at t h e d ate of last a d e q u at e 
t u m or ass ess m e nt. 
1 4. 1. 2 0  O v er all s ur vi v al  
All p atie nts s h o ul d b e f oll o w e d u ntil d e at h or u ntil p atie nt h as h a d a d e q u ate f oll o w -u p ti m e a s 
s p e cifie d i n t h e pr ot o c ol w hic h e v er c o m es first. T h e f oll o w-u p d ata s h o ul d c o nt ai n t h e d at e 
t h e p atie nt w as last s e e n ali v e / last k n o w n d ate p atie nt ali v e , t h e d ate of d e at h a n d t h e r e a s o n 
of d e at h (“ St u d y i n dic ati o n ” or “ Ot h er”).  
O v e r all s ur vi v al ( O S)  is d efi n e d as t h e ti m e fr o m d ate of ra n d o miz ati o n/start of tre at m e nt t o  
d ate of d e at h d u e t o a n y c a us e. If a p atie nt is n ot k n o w n t o h a v e die d, s ur vi v al will b e 
c e ns ore d at t h e d ate of last k n o w n d ate p atie nt ali v e . 

N o v artis  
C o nfi d e nti al  
P a g e 1 1 7  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol N o. C M C S 1 1 0 Z 2 2 0 1  
 
1 4. 1. 2 1  Ti m e t o pr o gr e s si o n  
S o m e st u dies mi g ht c o nsi d er o nl y d e at h relate d t o u n d erl yi n g c a n c er as a n e v e nt w hic h 
i n dic ates pr o gressi o n. I n t his c as e t h e v aria ble “ Ti m e t o pr o gressi o n” mi g ht b e us e d. T T P is 
d efi n e d as P F S e x c e pt f or d e at h u nrelate d t o u n d erl yi n g c a n cer.  
Ti me t o pr o g r essi o n ( T T P)  is t h e ti m e fr o m d ate of ra n d o miz ati o n/start of tr e a t m e nt t o  t h e 
d ate of e v e nt d efi n e d as t h e first d o c u m e nte d pr o gressi o n or d e at h d ue t o u n d erl yi n g c a n cer. If 
a p atie nt h as n ot h a d a n e v e nt, ti m e t o pr o gressi o n is c e ns ore d at t h e d ate of last a d e q u ate 
tu m or ass ess m e nt.  
1 4. 1. 2 2  Ti m e t o tr e at m e nt f ail ur e  
T his e n d p oi nt is ofte n a p pr o priate i n st u dies of a d v a n c e d dis e as e w h ere e arl y dis c o nti n u ati o n 
is t y pic all y relate d t o i nt olera n c e of t h e st u d y dr u g. I n s o m e pr ot o c ols, ti m e t o tre at m e nt 
f ail ure  m a y  b e  c o nsi d ere d  as  a  s e nsiti vit y  a n al ysis  f or  ti m e  t o  pr o gressi o n.  T h e  list  of  
dis c o nti n u ati o n re as o ns t o b e c o nsi dere d or n ot as tre at m e nt f ail ure m a y b e a d a pte d a c c or di n g 
t o t h e s p e cificities of t h e st u d y or t h e dis e ase. 
Ti me t o tr e at me nt f ail ur e ( T T F)  is t h e ti m e fr o m d ate of ra n d o miz ati o n/start of tre at m e nt t o  
t h e e arliest of d ate of pr o gressi o n, d ate of d e at h d u e t o a n y c a us e, or d ate of dis c o nti n u ati o n 
d u e t o re as o ns ot h er t h a n ‘ Pr ot o c ol vi olati o n’ or ‘ A d mi nistrati v e pr o ble ms’. T h e ti m e t o 
tre at m e nt f ail ure f or p atie nts w h o di d n ot e x p erie n c e tre at m e nt fail ure will b e c e ns ore d at l a st 
a d e q u ate t u m or ass ess m e nt.  
1 4. 1. 2 3  D ur ati o n of r e s p o n s e  
T h e  a n al ysis  of  t h e  f oll o wi n g v aria bles s h o ul d b e p erf or m e d wit h m u c h c a uti o n w h e n 
restricte d t o res p o n d ers si n c e tre at m e nt bias c o ul d h a v e b e e n i ntr o d u c e d . T h ere h a v e b e e n 
re p orts w h ere a tre at m e nt wit h a si g nific a ntl y hi g h er res p o ns e rate h a d a si g nific a ntl y s h ort er 
d urati o n of res p o ns e b ut w h ere t his pr o b a bl y pri m aril y refle cte d s ele cti o n bias w hic h is 
e x plai n e d as f oll o ws: It is p ost ulate d t h at t h ere are t w o gr o u ps of p atie nts: a g o o d ris k gr o u p 
a n d a p o or ris k gr o u p. G o o d ris k p atie nts te n d t o get i nt o res p o ns e re a dil y (a n d relati v el y 
q uic kl y) a n d te n d t o re m ai n i n res p o ns e after t h e y h a v e a res p o ns e. P o or ris k p atie nts t e n d t o 
b e diffic ult t o a c hie v e  a res p o ns e, m a y h a v e a l o n ger ti m e t o res p o n d, a n d te n d t o rela ps e 
q uic kl y w h e n t h e y d o res p o n d. P ote nt a ge nts i n d u c e a res p o ns e i n b ot h g o o d ris k a n d p o or 
ris k p atie nts. Less p ote nt a ge nts i n d u c e a res p o ns e m ai nl y i n g o o d ris k p atie nts o nl y.  T his is 
d e scri b e d i n m ore d etail b y M or ga n ( 1 9 8 8)  
It is re c o m m e n d e d t h at a n a n al ysis of all p atie nts ( b ot h res p o n d ers a n d n o n-res p o n d ers) b e 
p erf or m e d w h et h er or n ot a “ res p o n d ers o nl y” d es cri pti ve a n a l ysis is pres e nte d. A n a n al ysis of 
res p o n d ers  s h o ul d  o nl y  b e  p erf or m e d  t o  pr o vi d e  d es cri pti v e  statistics  a n d  e v e n  t h e n  
i nter prete d wit h c a uti o n b y e v al uati n g t h e res ults i n t h e c o nte xt of t h e o bs er v e d res p o nse rates. 
If a n i nf ere ntial c o m paris o n b et w e e n tre at m e nts is re q uire d t his s h o ul d o nl y b e p erf or m e d o n 
all p atie nts (i. e. n ot restricti n g t o “res p o n d ers ” o nl y) usi n g a p pr o priate statistic al m et h o ds s uc h 
as t h e te c h ni q u es d es cri b e d i n Ellis et al ( 2 0 0 8 ). It s h o ul d als o b e state d i n t h e pr ot o c ol if 
d urati o n of res p o ns e is t o b e c alc ulate d i n a d diti o n f or u nc o nfir m e d res p o ns e.  

N o v artis  
C o nfi d e nti al  
P a g e 1 1 8  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol N o. C M C S 1 1 0 Z 2 2 0 1  
 
F or s u m m ar y  statistics o n  “res p o n d ers ”  o nl y  t h e  f oll o wi n g d efi niti o ns are  a p pr o priate. 
( S p e cific d efi niti o ns f or a n all-p atie nt a n al ysis of t h es e e n d p oi nts are n ot a p pr o priate si n c e t h e 
stat us of p atie nts t hr o u g h o ut t h e st u d y is us u all y ta k e n i nt o a c c o u nt i n t h e a n al ysis).  
D ur ati o n of o v e r all r es p o ns e ( C R o r P R) : F or p atie nts wit h a C R or P R ( w hic h m a y h a v e t o 
b e c o nfir m e d t h e start d ate is t h e d ate of first d o c u me nte d res p o ns e ( C R or P R) a n d t h e e n d 
d ate a n d c e ns ori n g is d efi n e d t h e s a m e as t h at f or ti m e t o pr o gressi o n.  
T h e f oll o wi n g t w o d urati o ns mi g ht b e c alc ulate d i n a d diti o n f or a lar ge P h as e III st u d y i n 
w hic h a re as o n a ble n u m b e r of res p o n ders is s e e n. 
D ur ati o n of o v e r all c o m plete r es p o ns e ( C R) : F or p atie nts wit h a C R ( w hic h m a y h a v e t o b e 
c o nfir m e d) t h e start d ate is t h e d ate of first d oc u me nte d C R a n d t h e e n d d ate a n d c e ns ori n g is 
d efi n e d t h e s a m e as t h at f or ti m e t o pr o gressi o n.  
D ur ati o n of st a ble dis e as e ( C R/ P R/ S D) : F or p atie nts wit h a C R or P R ( w hic h m a y h a v e t o 
b e c o nfir m e d) or S D t h e start a n d e n d d ate as w ell as c e ns ori n g is d efi ne d t h e s a m e as t h at f or 
ti m e t o pr o gressi o n. 
1 4. 1. 2 4  Ti m e t o r e s p o n s e  
Ti me t o o v e r all r es p o ns e ( C R o r P R)  is t h e ti m e b et w e e n d ate of ra n d o miz ati o n/start of 
tre at m e nt u ntil first d o c u m e nte d  res p o ns e  ( C R or P R). T h e  res p o ns e  m a y  n e e d  t o  b e  
c o nfir m e d d e pe n di n g o n t h e t y p e of st u d y a n d its i m p orta n c e. W h ere t h e res p o nse n e e ds t o b e 
c o nfir m e d t h e n ti m e t o r es p o ns e is t h e ti m e t o t h e first C R or P R o bs er v e d.  
Alt h o u g h  a n  a n al ysis o n  t h e  f ull p o p ulati o n  is pref erre d  a  d es cri pti v e  a n al ysis m a y  b e  
p erf or m e d o n t h e “ res p o n d ers” s u bs et o nl y, i n w hic h c as e t h e res ults s h o ul d b e i nter prete d 
wit h c a uti o n a n d i n t h e c o nte xt of t h e o verall res p o ns e rates, si n c e t h e s a m e ki n d of s el e cti o n 
bias m a y  b e  i ntr o d u c e d  as d es cri b e d  f or d urati o n  of  res p o ns e  i n  Se cti o n 1 4. 1. 2 3 . It is 
re c o m m e n d e d  t h at a n  a n al ysis  of  all p atie nts  ( b ot h res p o n d ers a n d n o n-res p o n d ers) b e 
p erf or m e d w h et h er or n ot a “res p o n d ers o nl y ” d es cri pti v e a n al ysis is pres e nte d. W h ere a n 
i nf ere ntial statistic al c o m p aris o n is re q uire d, t h e n all p atie nts s h o ul d d efi nitel y b e i n cl u d e d i n  
t h e a n al ysis t o e ns ure t h e statistic al test is v ali d. F or a n al ysis i n cl u di n g all p atie nts, p atie nts 
w h o di d n ot a c hie v e a res p o ns e ( w hic h m a y h a ve t o b e a c o nfir m e d res p o ns e) will b e c e ns ore d 
usi n g o n e of t h e f oll o wi n g o pti o ns.  
•  at m a xi m u m f oll o w -u p (i. e. F P F V t o L P L V us e d f or t h e a n a l ysis) f or p atie nts w h o h a d a 
P F S  e v e nt (i. e. pr o gress e d or die d d u e t o a n y c a us e). I n t his c as e t h e P F S e v e nt is t h e 
w orst p ossi ble o utc o m e as it m e a ns t h e p atie nt c a n n ot s u bs e q u e ntl y res p o n d. Si n c e t h e 
statistic al a n al ysis us u all y m a k es us e of t h e ra n ki n g of ti m es t o res p o ns e it is s ufficie nt t o 
assi g n t h e w orst p ossi ble c e ns ori n g ti m e w hic h c o ul d b e o bs er ve d i n t h e st u d y w hic h is 
e q u al t o t h e m a xi m u m f oll o w-u p ti m e (i. e. ti m e fr o m F P F V t o L P L V)  
•  at last a d e q u ate t u m or ass ess m e nt d ate  ot h er wis e . I n this c as e p atie nts h a ve n ot y et 
pr o gress e d s o t h e y t h e oretic all y still h a v e a c h a n c e of res p o n di n g  
Ti me t o o v e r all c o m plete r es p o ns e ( C R)  is t h e ti m e b et w e e n d ates of ra n d o miz ati o n/start o f 
tre at m e nt u ntil first d o c u m e nte d C R. Si milar a n al ysis c o nsi derati o ns i n cl u di n g (if a p pr o priate) 
c e ns ori n g r ules a p pl y f or t his e n d p oi nt d es cri be d f or t h e ti m e t o o v erall res p o ns e e n d p oi nt.  

N o v artis  
C o nfi d e nti al  
P a g e 1 1 9  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol N o. C M C S 1 1 0 Z 2 2 0 1  
 
1 4. 1. 2 5  D efi niti o n of st art a n d e n d d at e s f or ti m e t o e v e nt v ari a bl e s  
A s s e s s m e nt  d at e  
F or e a c h ass ess m e nt (i. e. e v al u ati o n n u m b er), t h e ass essme nt d ate  is c alc ulate d a s t h e l at e st 
of  all  m e as ure m e nt  d ates  (e. g.  X -ra y,  C T-s c a n)  if  t h e  o v erall  lesi o n  res p o ns e  at  t h at  
ass ess m e nt is C R/ P R/ S D/ U N K. Ot h er wis e - if o v erall lesi o n res p o ns e is pr o gressi o n - t h e 
ass ess m e nt d ate is c alc ulate d as t h e e arliest d ate of all m e as ure me nt d ates at t h at e v al u ati o n 
n u m b er.  
St art d at e s  
F or all “ti m e t o e v e nt” v aria bles, ot h er t h a n d urati o n of res p o ns e, t h e ra n d o miz ati o n/ d at e of 
tre at m e nt start will b e us e d as t h e start d ate.  
F or t h e c alc ulati o n of d urati o n of res p o ns e t h e f oll o wi n g start d ate s h o ul d b e us e d:  
•  D ate of first d o c u m e nte d res p o ns e is t h e ass ess m e nt d ate of t h e first o v erall lesi o n 
res p o ns e of C R (f or d urati o n of o verall c o m plete res p o nse) or C R / P R (f or d urati o n of 
o v erall res p o ns e) res p ecti v el y, w h e n t his  stat us is later c o nfir m e d. 
E n d d at e s  
T h e e n d d ates w hic h are us e d t o c alc ulate ‘ti m e t o e v e nt’ v aria bles are d efi n e d as f oll o ws:  
•  D ate of d e at h ( d uri n g tre at m e nt as re c or de d o n t h e tre at m e nt c o m pleti o n p a ge or d uri n g 
f oll o w-u p as re c or de d o n t h e st u d y e v al u ati o n c o m pleti o n p a ge or t h e s ur vi v al f oll o w -u p 
p a ge).  
•  D ate of pr o gressi o n is t h e first ass ess m e nt d ate at w hic h t h e o v erall lesi o n res p o ns e w as 
re c or d e d as pr o gressi v e dis e as e. 
•  D ate of last a d e q u ate t u m or ass ess m e nt is t h e d ate t h e last t u m or ass ess m e nt wit h o v erall 
lesi o n res p o ns e of C R, P R or S D w hic h w as m a d e b ef ore a n e v e nt or a c e ns ori n g re as o n 
o c c urre d. I n t his c as e t h e last t u m or e v al u ati o n d ate at t h at ass ess m e nt is us e d. If n o p ost -
b as eli n e ass ess m e nts are a v aila ble ( b ef ore a n e v e nt or a c e ns ori n g re as o n o c c urre d) t h e 
d ate of ra n d o miz ati o n/start of tre at m e nt is us e d.  
•  D ate of n e xt s c h e d ule d ass ess m e nt is t h e d ate of t h e last a d e q uate t u m or ass ess me nt pl us 
t h e pr ot o c ol s p e cifie d ti m e i nter v al f or ass ess me nts. T his d ate m a y b e us e d if b a c k-d ati n g 
is c o nsi d ere d w h e n t h e e v e nt o c c urre d b e y o n d t h e a c c e pta ble ti m e wi n d o w f or t h e n e xt 
t u m or ass ess m e nt as p er pr ot o c ol (s e e Se cti o n 1 4.1. 2 6 ). 
E x a m ple  (if pr ot o c ol d efi n e d s c h e d ule of ass ess m e nts is 3 m o nt hs): t u m or ass ess m e nts at 
b as eli n e - 3 m o nt hs - 6 m o nt hs - missi n g - missi n g - P D. D ate of n e xt s c h e d ul e d a s s e s s m e nt 
w o ul d t h e n c orres p o n d t o 9 m o nt hs.  
•  D ate of dis c o nti n u ati o n  is t h e d ate of t h e e n d of tre at m e nt visit. 
•  D ate of last c o nta ct is d efi n e d as t h e last d ate t h e p atie nt w as k n o w n t o b e ali v e. T his 
c orres p o n ds t o t h e latest d ate f or eit h er t h e visit d ate, la b s a m ple d ate or t u m or ass ess me nt 
d ate. If a v aila ble, t h e last k n o w n d ate p atie nt ali v e  f r o m t he s ur vi v al f oll o w -u p p a ge is 
us e d. If n o s ur vi v al f oll o w -u p is a v aila ble, t h e d ate of dis c o nti n uati o n is us e d as last 
c o nta ct d ate.  

N o v artis  
C o nfi d e nti al  
P a g e 1 2 0  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol N o. C M C S 1 1 0 Z 2 2 0 1  
 
•  D ate of s e c o n d ar y a nti -c a nc er t h era p y is d efi n e d as t h e start d ate of a n y a d diti o n al 
(s e c o n d ar y) a nti n e o plastic t h era p y or s ur ger y. 
1 4. 1. 2 6  H a n d li n g of p ati e nt s wit h n o n-m e a s ur a bl e  di s e a s e  o nl y at b a s eli n e  
It is p ossi ble t h at p atie nts wit h o nl y n o n-m e as ura ble dis e as e pres e nt at b as eli n e are e ntere d 
i nt o t h e st u d y, eit h er b e c a us e of a pr ot o c ol vi olati o n or b y d esi g n (e. g. i n P h as e III st u dies 
wit h P F S  as t h e pri m ar y e n d p oi nt). I n s u c h c as es t h e h a n dli n g of t h e res p o ns e d at a r e q uir e s 
s p e cial c o nsi d erati o n wit h res p e ct t o i n cl usi o n i n a n y a n al ysis of e n d p oi nts b as e d o n t h e 
o v erall res p o ns e e v al u ati o ns.  
It is re c o m m e n de d t h at a n y p atie nts wit h o nl y n o n-me as ura ble dis e ase at b as eli n e s h o ul d b e 
i n cl u d e d i n t h e m ai n (I T T) a n al ysis of e a c h of t h es e e n d p oi nts. 
Alt h o u g h t h e te xt of t h e d efi niti o ns d es cri b e d i n t h e pre vi o us s e cti o ns pri m aril y relates t o 
p atie nts wit h m e as ura ble dis e as e at b as eli n e, p atie nts wi t h o ut m e as ura ble dis e as e s h o ul d als o 
b e i n c or p orate d i n a n a p pr o priate m a n ner. T h e o verall res p o ns e f or p atie nts wit h m e a s ur a bl e 
dis e as e is d eri v e d sli g htl y diff ere ntl y a c c or di n g t o Ta ble 1 4 -4.  
T a bl e 1 4 - 4 
O v er all l e si o n r e s p o n s e at e a c h a s s e s s m e nt : p ati e nt s wit h n o n-t ar g et 
di s e a s e o nl y  
N o n -t ar g et l e si o n s 
N e w L e si o n s  
O v er all l e si o n r e s p o n s e  
C R  
N o  
C R  
N o n -C R/ N o n -P D 1 
N o  
N o n -C R/ n o n -P D  
U N K  
N o  
U N K  
P D  
Y e s  o r N o  
P D  
A n y  
Y e s  
P D  
1 A s  d efi n e d i n S e cti o n 1 4. 1. 8 . 
I n ge n eral, t h e n o n -C R/ n o n -P D r es p o ns e  f or t h es e p atie nts is c o nsi d ere d e q ui vale nt t o a n S D 
res p o ns e i n e n d p oi nt d eter mi nati o n. I n s u m m ar y ta bles f or b est o v erall res p o ns e p atie nts wit h 
o nl y n o n -m e as ura ble dis e as e m a y b e hi g hli g hte d i n a n a p pr o priate f ashi o n e. g. i n p artic ular b y 
dis pla yi n g t h e s p e cific n u m b ers wit h t h e n o n - C R/ n o n-P D c ate g or y.  
I n c o nsi d eri n g h o w t o i n c or p orate d ata fr o m t h es e p atie nts i nt o t h e a n al ysis t h e i m p orta n c e t o 
e a c h e n d p oi nt of b ei n g a ble t o i d e ntif y a P R a n d/ or t o d eter mi n e t h e o c c urre n ce a n d ti mi n g of  
pr o gressi o n n e e ds t o b e ta k e n i nt o a c c o u nt.  
F o r O R R  it is re c o m m e n d e d t h at t h e m ai n (I T T) a n al ysis i n cl u d es d ata fr o m p atie nts wit h 
o nl y n o n -m e as ura ble dis e as e at b as eli n e, h a n dli n g p atie nts wit h a b est res p o ns e of C R as 
“res p o n d ers ” wit h res p e ct t o O R R a n d all ot h e r p atie nts as “ n o n -res p o n d ers ”. 
F o r P F S , it is a gai n re c o m m e n d e d t h at t h e m ai n I T T a n al ys es o n t h es e e n d p oi nts i n cl u d e all 
p atie nts wit h o nl y  n o n -m e as ura ble dis e as e at b as eli n e, wit h p ossi ble s e nsiti vit y a n al ys es 
w hic h e x cl u d e t h es e p artic ular p atie nts. E n d p oi nts s u c h as P F S w hic h are relia nt o n t h e 
d eter mi n ati o n a n d/ or ti mi n g of pr o gressi o n c a n i n c or p orate d ata fr o m p atie nts  wit h o nl y  n o n -
m e as ura ble dis e as e.  

N o v artis  
C o nfi d e nti al  
P a g e 1 2 1  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol N o. C M C S 1 1 0 Z 2 2 0 1  
 
1 4. 1. 2 7  S e n siti vit y a n al y s e s  
T his s e cti o n o utli n es t h e p ossi ble e v e nt a n d c e ns ori n g d ates f or pr o gressi o n , as w ell as  
a d dress es  t h e iss u es of missi n g t u m or ass ess m e nts d uri n g t h e st u d y. F or i nsta n c e, if o n e or 
m ore ass ess m e nt visits are miss e d pri or t o t h e pr o gressi o n e v e nt, t o w h at d ate s h o ul d t h e 
pr o gressi o n e v e nt b e assi g n e d ? A n d s h o ul d pr o gressi o n e v e nt b e i g n ore d if it o c c urre d af t er a 
l o n g p eri o d of a p atie nt b ei n g l ost t o f oll o w-u p ? It is i m p orta nt t h at t h e pr ot o c ol a n d R A P 
s p e cif y t h e pri m ar y a n al ysis i n d etail wit h res p e ct t o t h e d efi niti o n of e v e nt a n d c e ns ori n g 
d ates a n d als o i n cl u d e a d es cri pti o n of o n e or m ore s e nsiti vit y a n al ys es t o b e p erf or m e d.  
Bas e d o n d efi niti o ns o utli n e d i n Se cti o n 1 4. 1. 2 5 , a n d usi n g t h e draft F D A g ui d eli n e o n 
e n d p oi nts ( Cli nic al Trial E n d p oi nts f or t h e A p pr o v al of Ca n c er Dr u g s a n d Bi ol o gics, A pril 
2 0 0 5 ) as a ref ere n c e, t h e f oll o wi n g a n al ys es c a n b e c o nsi d ere d: 
T a bl e 1 4 - 5 
O pti o n s f or e v e nt  d at e s u s e d i n P F S, T T P, d ur ati o n of r e s p o n s e  
Sit u ati o n  
O pti o n s f or e n d -d at e ( pr o gr e s si o n or 
c e n s ori n g) 1 
( 1) = d ef a ult u nl e s s s p e cifi e d diff er e ntl y i n 
t h e pr ot o c ol or R A P 
O ut c o m e  
A  
N o b a s eli n e a s s e s s m e nt  
( 1) D at e  of r a n d o mi z ati o n/ st art of tr e at m e nt3 
C e n s or e d  
B  
Pr o gr e s si o n at or b ef or e n e xt s c h e d ul e d 
a s s e s s m e nt  
( 1) D at e  of pr o gr e s si o n 
( 2) D at e  of n e xt s c h e d ul e d a s s e s s m e nt2 
Pr o gr e s s e d  
Pr o gr e s s e d  
C 1  
Pr o gr e s si o n or d e at h aft er e x a ctl y o n e 
mi s si n g a s s e s s m e nt  
( 1) D at e  of pr o gr e s si o n ( or d e at h) 
( 2) D at e  of n e xt s c h e d ul e d a s s e s s m e nt2 
Pr o gr e s s e d  
Pr o gr e s s e d  
C 2  
Pr o gr e s si o n or d e at h aft er t w o or m or e 
mi s si n g a s s e s s m e nt s  
( 1) D at e of l a st a d e q u at e a s s e s s m e nt2 
( 2) D at e  of n e xt s c h e d ul e d a s s e s s m e nt2 
( 3) D at e  of pr o gr e s si o n ( or d e at h) 
C e n s or e d  
Pr o gr e s s e d  
Pr o gr e s s e d  
D  
N o pr o gr e s si o n  
( 1) D at e of l a st a d e qu at e a s s e s s m e nt  
C e n s or e d  
E  
Tr e at m e nt di s c o nti n u ati o n d u e t o ‘ Di s e a s e 
pr o gr e s si o n’ wit h o ut d o c u m e nt e d 
pr o gr e s si o n, i. e. cli ni c al pr o gr e s si o n b a s e d 
o n i n v e sti g at or cl ai m  
( 1) N/ A 
( 2) D at e  of di s c o nti n u ati o n ( vi sit d at e at w hi c h 
cli ni c al pr o gr e s si o n w a s d et er mi n e d)  
I g n or e d 
Pr o gr e s s e d  
F  
N e w  a nti c a n c er t h er a p y gi v e n  
( 1) D at e of l a st a d e q u at e a s s e s s m e nt 
( 2) D at e  of s e c o n d ar y a nti-c a n c er t h er a p y  
( 3) D at e  of s e c o n d ar y a nti-c a n c er t h er a p y  
( 4) N/ A 
C e n s or e d  
C e n s or e d  
E v e n t  
I g n or e d 
G  
D e at h s d u e t o r e a s o n ot h er t h a n 
d et eri or ati o n of ‘ St u d y i n di c ati o n’  
( 1) D at e of l a st a d e q u at e a s s e s s m e nt 
C e n s or e d 
( o nl y T T P a n d 
d ur ati o n of 
r e s p o n s e) 
1. = D efi niti o n s c a n b e f o u n d i n S e cti o n 1 4. 1. 2 5  
2. = Aft er  t h e l a st a d e q u at e t u m or a s s e s s m e nt. “ D at e  of n e xt s c h e d ul e d a s s e s s m e nt” i s d efi n e d i n S e cti o n 1 4. 1. 2 5. 
3. = T h e r ar e  e x c e pti o n t o t hi s i s if t h e p ati e nt di e s n o l at er t h a n t h e ti m e of t h e s e c o n d s c h e d ul e d a s s e s s m e nt a s 
d efi n e d i n t h e pr ot o c ol i n w hi c h c a s e t hi s i s a P F S  e v e nt at t h e d at e of d e at h. 
T h e pri m ar y a n al ysis a n d t h e s e nsiti vit y a n al ys es m ust b e s p e cifie d i n t h e pr ot o c ol. Cle arl y 
d efi n e if a n d w h y o pti o ns ( 1) are n ot us e d f or sit u ati o ns C, E a n d (if a p plic a ble) F.  
Sit u ati o n s C ( C 1 a n d C 2): Pr o gressi o n or d e at h after o n e or m ore missi n g ass ess m e nts: T h e 
pri m ar y a n al ysis is us u all y usi n g o pti o n s ( 1) f or sit u ati o ns C1 a n d C 2 , i. e. 

N o v artis  
C o nfi d e nti al  
P a g e 1 2 2  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol N o. C M C S 1 1 0 Z 2 2 0 1  
 
•  ( C 1) ta ki n g t h e a ct u al pr o gressi o n or d e at h d ate, i n t h e c as e of o nl y o n e missi n g 
ass ess m e nt. 
•  ( C 2) c e ns ori n g at t h e d ate of t h e last a d e q u ate ass ess m e nt, i n t h e c as e of t w o or m ore 
c o ns e c uti v e missi n g ass ess me nts.  
I n t h e c as e of t w o or missi n g ass ess m e nts (sit u ati o n C 2), o pti o n ( 3) m a y b e c o nsi d ere d j oi ntl y 
wit h o pti o n ( 1) i n sit u ati o n C 1 as s e nsiti vit y a n al ysis. A v aria nt of t his s e nsi ti vit y a n al ysis 
c o nsists of b a c k dati n g t h e d ate of e v e nt t o t h e n e xt s c h e d ule d ass ess m e nt a s pr o p o s e d wit h 
o pti o n ( 2) i n sit u ati o ns C 1 a n d C 2.  
Sit u ati o n  E:  Tr e at me nt  dis c o nti n u ati o n  d ue  t o  ‘ Dis e as e  pr o g r essi o n’  wit h o ut  
d o c u me nte d pr o g r essi o n : B y d ef a ult, o pti o n ( 1) is us e d f or sit u ati o n E  as p atie nts wit h o ut 
d o c u m e nte d  P D s h o ul d  b e  f oll o w e d  f or pr o gressi o n  after dis c o nti n u ati o n  of  tre at m e nt . 
H o w e v er, o pti o n ( 2) m a y b e us e d as s e nsiti vit y a n al ysis.  If pr o gressi o n is cl ai m e d b a s e d o n 
cli nic al d eteri orati o n i n ste a d of t u m or ass ess m e nt b y e. g. C T-s c a n, o pti o n ( 2) m a y b e us e d f or 
i n dic ati o ns wit h hi g h e arl y pr o gressi o n rate or diffic ulties t o ass ess t h e t u m or d u e t o cli ni c al 
d eteri orati o n.  
Sit u ati o n F: N e w c a nc e r t he r a p y gi v e n : t h e h a n dli n g of t his sit u ati o n m ust b e s p e cifie d i n 
d etail i n t h e pr ot o c ol. H o w e ver, o pti o n ( 1), i. e. c e ns ori n g at last a d e q u ate ass ess me nt m a y b e 
us e d as a d ef a ult i n t his c as e. 
A d diti o n al  s u g g e sti o n s  f or  s e n siti vit y  a n al y s e s  
Ot h er s u g gesti o ns f or a d dit i o n al s e nsiti vit y a n al ys es m a y i n cl u d e a n al ys es t o c h e c k f or 
p ote ntial bias i n f oll o w -u p s c h e d ules f or t u m or ass ess m e nts, e. g. b y assi g ni n g t h e d ates f or 
c e ns ori n g a n d e v e nts o nl y at s c h e d ule d visit d ates. T h e latter c o ul d b e h a n dle d b y re pla ci n g i n 
Ta ble  1 4 - 5 t h e “ D ate of last a d e q u ate ass ess m e nt” b y t h e “ D ate of pre vi o us s c h e d ule d 
ass ess m e nt (fr o m b as eli n e)”, wit h t h e f oll o wi n g d efi niti o n:  
•  D ate of pr e vi o us s c he d ule d ass ess me nt (fr o m b as eli ne)  is t h e d ate w h e n a t u m or 
ass ess m e nt w o ul d h a ve ta k e n pla c e, if t h e pr ot o c ol ass ess m e nt s c h e m e w as strictl y 
f oll o w e d fr o m b as eli ne, i m m e diatel y b ef ore or o n  t h e d ate of t h e last a d e q u ate t u m or 
ass ess m e nt.  
I n a d diti o n, a n al ys es c o ul d b e re p eate d usi n g t h e I n v esti gat ors’ ass ess m e nts of res p o ns e rat h er 
t h a n t h e c alc ulate d res p o ns e. T h e n e e d f or t h es e t y p es of s e nsiti vit y a n al ys es will d e p e n d o n 
t h e i n di vi d u al re q uire m e nts f or t h e s p e cific st u d y a n d dis e as e are a a n d h a v e t o b e s p e cifie d i n 
t h e pr ot o c ol or R A P d o c u m e ntatio n.  
1 4. 1. 2 8  D at a h a n dli n g a n d pr o gr a m mi n g r ul e s  
T h e f oll o wi n g s e cti o n s h o ul d b e us e d as g ui d a n c e f or d e v el o p m e nt of t h e pr ot o c ol, d ata 
h a n dli n g pr o c e d ures or pr o gra m mi n g re q uire m e nts (e. g. o n i n c o m plete d ates).  
1 4. 1. 2 9  St u d y/ pr oj e ct s p e cifi c d e ci si o n s  
F or e a c h st u d y ( or pr oje ct) v ari o us iss u es n e e d t o b e a d dress e d a n d s p e cifie d i n t h e pr ot o c ol or 
R A P d o c u m e ntati o n. A n y d e viati o ns fr o m pr ot o c ol m ust b e dis c usse d a n d d efi n e d at t h e latest 
i n t h e R A P d o c u m e ntati o n. 

N o v artis  
C o nfi d e nti al  
P a g e 1 2 3  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol N o. C M C S 1 1 0 Z 2 2 0 1  
 
T h e pr o p os e d pri m ar y a n al ysis a n d p ote ntial s e nsiti vit y a n al ys es s h o ul d b e dis c uss e d a n d 
a gre e d wit h t h e h e alt h a ut h orities a n d d o c u m e nte d i n t h e pr ot o c ol ( or at t h e latest i n  t h e  R A P 
d o c u m e ntati o n b ef ore d ata bas e l o c k).  
1 4. 1. 3 0  E n d of tr e at m e nt p h a s e c o m pl eti o n  
Patie nts m a y  v ol u ntaril y wit h dra w fr o m t h e st u d y tre at m e nt or m a y b e ta k e n off t h e st u d y 
tre at m e nt at t h e dis creti o n of t h e i n v esti gat or at a n y ti m e. F or p atie nts w h o are l ost t o f o ll o  w -
u p, t h e i n v esti gat or or d esi g n e e s h o ul d s h o w " d u e dili ge n c e" b y d o c u m e nti n g i n t h e s o urc e 
d o c u m e nts ste ps ta k e n t o c o nta ct t h e p atie nt, e. g., d ates of tele p h o ne c alls, re gister e d l ett er s, 
etc.  
T h e e n d of tre at m e nt visit a n d its ass o ciate d ass ess m e nts s h o ul d o c c ur wit hi n 7 d a ys of t h e 
last st u d y tre at m e nt. 
Patie nts m a y dis c o nti n u e st u d y tre at m e nt f or a n y of t h e f oll o wi n g re as o ns:  
•  A d v ers e e v e nt(s)  
•  L ost t o f oll o w -u p  
•  P h ysicia n d e cisi o n  
•  Pre g n a n c y  
•  Pr ot o c ol d e viati o n  
•  Te c h nic al pr o ble ms  
•  S u bje ct/ g u ar dia n d e cisi o n  
•  D e at h  
•  Pr o gressi v e dis e as e  
•  St u d y ter mi n ate d b y t h e s p o ns or  
•  N o n -c o m plia nt wit h st u d y tre at m e nt  
•  N o l o n ger re q uires tre at m e nt  
•  Tre at m e nt d urati o n c o m plete d as p er pr ot o c ol ( o pti o n al, t o b e us e d if o nl y a fi x e d n u m b er 
of c y cles is gi v e n)  
1 4. 1. 3 1  E n d of p o st -tr e at m e nt f oll o w-u p ( st u d y p h a s e c o m pl eti o n)  
E n d  of  p ost -tre at m e nt  f oll o w-u p  visit will b e  c o m plete d  after dis c o nti n u ati o n  of  st u d y  
tre at m e nt a n d p ost-tre at m e nt e v al u ati o ns b ut pri or t o c olle cti n g s ur vi v al f oll o w-u p.  
Patie nts m a y pr o vi d e st u d y p h as e c o m pleti o n i nf or m ati o n f or o n e of t h e f oll o wi n g re as o ns:  
•  A d v ers e e v e nt  
•  L ost t o f oll o w -u p  
•  P h ysicia n d e cisi o n  
•  Pre g n a n c y  
•  Pr ot o c ol d e viati o n  
•  Te c h nic al pr o ble ms  
•  S u bje ct/ g u ar dia n d e cisi o n  

N o v artis  
C o nfi d e nti al  
P a g e 1 2 4  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol N o. C M C S 1 1 0 Z 2 2 0 1  
 
•  D e at h  
•  N e w t h era p y  f or st u d y i n dic ati o n 
•  Pr o gressi v e dis e as e  
•  St u d y ter mi n ate d b y t h e s p o ns or  
1 4. 1. 3 2  M e di c al v ali d ati o n of pr o gr a m m e d o v er all l e si o n r e s p o n s e  
As R E CI S T  is v er y strict re gar di n g m e as ure m e nt m et h o ds (i. e. a n y ass ess m e nt wit h m or e or 
less s e nsiti v e m et h o d t h a n t h e o n e us e d t o ass ess t h e lesi o n at b as eli n e is c o nsi d ere d U N K) 
a n d n ot a v aila ble e v al u ati o ns (i. e. if a n y tar get or n o n -tar get lesi o n w as n ot e v al u ate d t h e 
w h ole o v erall lesi o n res p o ns e is U N K u nless re m ai ni n g lesi o ns q u alifie d f or P D), t h es e U N K 
ass ess m e nts m a y b e re -e v al u ate d b y cli nicia ns at N o v artis or e xter n al e x p erts. I n a d diti o n, 
d ata re vie w re p orts will b e a v aila ble t o i d e ntif y ass es s m e nts f or w hic h t h e i n v esti gat ors’ or 
c e ntral re a d er’s  o pi ni o n  d o es n ot m atc h  t h e  pr o gra m m e d  c alc ulate d  res p o ns e  b as e d  o n  
R E CI S T criteria. T his m a y b e q u erie d f or clarific ati o n. H o w e v er, t h e i n v esti gat or or c e ntral 
re a d er’s res p o ns e ass ess m e nt will n e v er b e o v err ule d.  
If N o v artis ele ct t o i n v ali d ate a n o v erall lesi o n res p o ns e as e v al u ate d b y t h e i n v esti gat or or 
c e ntral re a d er u p o n i nter n al or e xter n al re vie w of t h e d ata, t h e c alc ulate d o v erall lesi o n 
res p o ns e  at  t h at  s p e cific  ass ess m e nt  is  t o  b e  k e pt  i n  a  d atas et.  T his  m ust  b e  cle arl y  
d o c u m e nte d i n t h e R A P d o c u m e ntati o n a n d a gre e d b ef ore d ata bas e l o c k. T his d atas et s h o ul d 
b e cre ate d a n d st ore d as p art of t h e ‘ra w’ d ata.  
A n y dis c o nti n u ati o n d u e t o ‘ Dis e as e pr o gressi o n’ wit h o ut d o c u me ntati o n of pr o gr e s si o n b y  
R E CI S T criteria s h o ul d b e c aref ull y re vie w e d. O nl y p atie nts wit h d o c u me nte d d eteri orati o n of 
s y m pt o ms i n dic ati v e of pr o gressi o n of dis e as e s h o ul d h a ve t his re as o n f or dis c o nti n u ati o n of  
tre at m e nt or st u d y e v al u ati o n. 
1 4. 1. 3 3  Pr o gr a m mi n g r ul e s  
T h e f oll o wi n g s h o ul d  b e us e d f or pr o gra m mi n g of effica c y res ults:  
1 4. 1. 3 4  C al c ul ati o n  of ‘ti m e  t o e v e nt’ v ari a bl e s  
Ti m e t o e v e nt = e n d d ate - start d ate + 1 (i n d a ys) 
W h e n n o p ost -b as eli n e t u m or ass ess m e nts are a v aila ble, t h e d ate of ra n d o miz ati o n/start of 
tre at m e nt will b e us e d as en d d ate ( d urati o n = 1 d a y) w h e n ti m e is t o b e c e ns ore d at last t u m or 
ass ess m e nt, i. e. ti m e t o e v e nt v aria bles c a n n e ver b e n e gati v e. 
1 4. 1. 3 5  I n c o m pl et e a s s e s s m e nt d at e s 
All i n v esti gati o n d ates (e. g. X -ra y, C T s c a n) m ust b e c o m plete d wit h d a y, m o nt h a n d y e ar. 
If o ne or m ore i n v esti gati o n d ates are i n c o m plete b ut ot h er i n v esti gati o n d ates ar e a v ail a bl e, 
t his/t h es e i n c o m plete d ate(s) are n ot c o nsi d ere d f or c alc ulati o n of t h e ass ess m e nt d ate (a n d 
ass ess m e nt d ate is c alc ulate d as o utli n e d i n Se cti o n 1 4. 1. 2 5 ). If all m e as ure me nt d ates h a v e n o 
d a y re c or d e d, t h e 1 st of t h e m o nt h is us e d.  

N o v artis  
C o nfi d e nti al  
P a g e 1 2 5  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol N o. C M C S 1 1 0 Z 2 2 0 1  
 
If t h e m o nt h is n ot c o m plete d, f or a n y of t h e i n v esti gati o ns, t h e res pe cti v e ass ess me nt will b e 
c o nsi d ere d t o b e at t h e d ate w hic h is e x a ctl y b et w ee n pre vi o us a n d f oll o wi n g ass ess m e nt. If a 
pre vi o us a n d f oll o wi n g ass ess me nt is n ot a v aila ble, t his ass ess me nt will n ot b e u s e d f or a n y 
c alc ulati o n.  
1 4. 1. 3 6  I n c o m pl et e d at e s f or l a st k n o w n d at e p ati e nt ali v e  or d e at h  
All d ates m ust b e c o m plete d wit h d a y, m o nt h a n d y e ar. If t h e d a y is missi n g, t h e 1 5 t h of t h e 
m o nt h will b e us e d f or i n c o m plete d e at h d ates or d ates of last c o nta ct.  
1 4. 1. 3 7  N o n -t ar g et l e si o n r e s p o n s e 
If n o n o n -tar get lesi o ns are i d e ntifie d at b as eli n e (a n d t h eref ore n ot f oll o we d t hr o u g h o ut t h e 
st ud y), t h e n o n -tar get lesi o n res p o ns e at e a c h ass ess me nt will b e c o nsi d ere d ‘ n ot a p pli c a bl e 
( N A)’. 
1 4. 1. 3 8  St u d y/ pr oj e ct s p e cifi c pr o gr a m mi n g  
T h e sta n d ar d a n al ysis pr o gra ms n e e d t o b e a d a pte d f or e a c h st u d y/ pr oje ct . 
1 4. 1. 3 9  C e n s ori n g r e a s o n  
I n or d er t o s u m m ariz e t h e v ari o us re as o ns f or c e ns ori n g, t h e f oll o wi n g c ate g ories will b e 
c alc ulate d f or e a c h ti m e t o e v e nt v aria ble b as e d o n t h e tre at m e nt c o m pleti o n p a g e, t h e st u d y 
e v al u ati o n c o m pleti o n p a ge a n d t h e s ur vi v al p a ge.  
F or s ur vi v al t h e f oll o wi n g c e nsori n g re as o ns are p ossi bl e: 
•  Ali v e  
•  L ost t o f oll o w -u p  
F or P F S a n d T T P (a n d t h eref ore d urati o n of res p o ns es) t h e f oll o wi n g c e ns ori n g r e a s o n s ar e 
p ossi ble:  
•  O n g oi n g wit h o ut e v e nt  
•  L ost t o f oll o w -u p  
•  Wit h dre w c o ns e nt  
•  A d e q u ate ass ess m e nt n o l o n ger a v aila ble *  
•  E v e nt d o c u m e nte d after t w o or m ore missi n g t u m or ass ess me nts ( o pti o n al, s e e Ta ble 1 4 -5) 
•  D e at h d u e t o re as o n ot h er t h a n u n d erl yi n g c a n c er ( o nly us e d f or T T P a n d d ur ati o n of 
r es p o ns e) 
•  I nitiati o n of n e w a nti-c a n c er t h era p y 
* A d e q u ate ass ess m e nt is d efi n e d i n Se cti o n 1 4. 1. 2 5 . T his re as o n is a p plic a ble w h e n a d e q u at e 
e v al u ati o ns are missi n g f or a s p e cifie d p eri o d pri or t o d ata c ut -off ( or pri or t o a n y ot h er 
c e ns ori n g  re as o n)  c orres p o n di n g  t o  t h e  u n a v aila bilit y  of  t w o  or  m ore  pla n n e d  t u m or  
ass ess m e nts pri or t o t h e c ut -off d ate. T h e f oll o wi n g clarific ati o ns c o n c er ni n g t his re as o n 
s h o ul d als o b e n ote d: 

N o v artis  
C o nfi d e nti al  
P a g e 1 2 6  
A m e n d e d Pr ot o c ol V ersi o n 0 6 (Cl e a n)  
 
Pr ot o c ol N o. C M C S 1 1 0 Z 2 2 0 1  
 
•  T his m a y b e w h e n t h ere h as b e e n a d efi nite d e cisi o n t o st o p e v al u ati o n (e. g. 
re as o n =“ S p o ns or d e cisi o n” o n st u d y e v al u ati o n c o m pleti o n p a ge), w h e n p atie nts are n ot 
f oll o w e d f or pr o gressi o n after tre at m e nt c o m pleti o n or w h e n o nl y U N K ass ess me nts are 
a v aila ble j ust pri or t o d ata c ut - off). 
•  T h e re as o n " A d e q u ate ass ess m e nt n o l o n ger a v aila ble" als o pre vails i n sit u ati o ns w h e n 
a n ot h er c e ns ori n g re as o n (e. g. wit h dra w al of c o ns e nt, l oss t o f oll o w -u p or alter n ati v e a nti -
c a n c er t h era p y) h as o c c urre d m ore t h a n t h e s p e cifie d p eri o d f oll o wi n g t h e last a d e q uate 
ass ess m e nt.  
•  T his re as o n will als o b e us e d t o c e ns or i n c as e of n o b as eli n e ass ess m e nt.  
 
1 4. 1. 4 0  R ef er e n c e s  ( a v ail a bl e  u p o n r e q u e st)  
D e nt S, Ze e  ( 2 0 0 1) a p plic ati o n of a n e w m ulti n o mial p h as e II st o p pi n g r ule usi n g res p o ns e 
a n d e arl y pr o gressi o n, J Cli n O n c ol; 1 9: 7 8 5 -7 9 1  
Eis e n h a u er E , et al ( 2 0 0 9) N e w res p o ns e e v al u ati o n criteria i n s oli d t u m ors: re vis e d R E CI S T 
g ui d eli n e ( v ersi o n 1. 1). E ur o pe a n J o ur nal of Ca n c er, V ol. 4 5: 2 2 8 -4 7  
Ellis S, et al ( 2 0 0 8) A n al ysis of d urati o n of res p o ns e i n o n c ol o g y trials. C o nte m p Cli n Trials 
2 0 0 8; 2 9: 4 5 6 -4 6 5  
F D A G ui d eli n es: 2 0 0 5 Cli nic al Trial E n d p oi nts f or t h e A p pr o val of Ca n c er Dr u gs a n d 
Bi ol o gics, A pril 2 0 0 5  
F D A G ui d eli n es: 2 0 0 7 Cli nic al Trial E n d p oi nts f or t h e A p pr o val of Ca n c er Dr u gs a n d 
Bi ol o gics,  Ma y 2 0 0 7  
M or ga n T M ( 1 9 8 8) A n al ysis of d urati o n of res p o ns e: a pr o ble m of o n c ol o g y trials. C o nt Cli n 
Trials; 9: 1 1 -1 8  
T h erass e P, Ar b u c k S, Eis e n h a u er E, et al (2 0 0 0 ) N e w G ui d eli n es t o E v al u ate t h e Res p o ns e t o 
Tre at m e nt i n S oli d T u m ors, J o ur n al of N ati o nal Ca n c er I nstit ute, V ol. 9 2; 2 0 5 -1 6