Conditions: Advanced Triple Negative Breast Cancer (TNBC) With High TAMs
Keywords: MCS110; carboplatin; gemcitabine; TNBC; TAMs
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 50
Healthy volunteers: no

Brief summary:
To determine whether MCS110 antibody therapy improves the efficacy of carboplatin and gemcitabine (carbo/gem) in advanced TNBC patients

Detailed description:

Arms:
arm 1: MCS110+carboplatin+gemcitabine arm 2: carboplatin+gemcitabine

Interventions: intervention 1: MCS110 intervention 2: carboplatin intervention 3: gemcitabine
Intervention descriptions: intervention 1: taken by I.V intervention 2: taken by I.V intervention 3: taken by I.V

Protocol document:
Prot_000.pdf: 
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  

SAP_001.pdf: 
Clinical Development 
MCS110 
CMCS110Z2201 / NCT02435680
A randomized phase II study of MCS110 combined with 
carboplatin and gemcitabine in advanced Triple Negative 
Breast Cancer (TNBC) 
Statistical Analysis Plan (SAP) 
Author: 
Trial Statistician, 
 (Amendment 1) 
Document type: 
SAP Documentation 
Document status: 
Final 
Release date: 
29-Oct-2018
Number of pages: 
35 
Property of Novartis 
For business use only 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


Novartis 
For business use only 
Page 2 
SAP  
 
CMCS110Z2201 
 
 
Document History – Changes compared to previous final version of SAP 
 
Date Time 
point 
Reason 
for 
update 
Outcome for update 
Section and title impacted 
(Current) 
23-
Aug-
2016 
Prior 
to 
LPFV 
Creation of 
final 
version 
N/A - First version 
NA 
20-
Oct-
2018 
after 
enrollment 
halt 
Enrollment 
Halt 
Amendment 1 
1.1 Study design 
1.2 Study objectives and endpoints 
2.5 Analysis of primary objective 
2.6 Analysis of the key secondary 
objective 
2.8 Safety analyses 
2.9 Pharmacokinetic endpoints: 
2.10 Biomarkers 
 
 


Novartis 
For business use only 
Page 3 
SAP  
CMCS110Z2201 
Table of contents 
Table of contents ..........................................................................................................3 
List of abbreviations .....................................................................................................5 
1 
Introduction ..................................................................................................................7 
1.1 
Study design ......................................................................................................7 
1.2 
Study objectives and endpoints...........................................................................9 
2 
Statistical methods ......................................................................................................10 
2.1 
Data analysis general information.....................................................................10 
2.1.1 
General definitions ...........................................................................10 
2.2 
Analysis sets....................................................................................................11 
2.3 
Patient disposition, demographics and other baseline characteristics ..................12 
2.3.1 
Patient disposition ............................................................................12 
2.3.2 
Basic demographic and background data ...........................................13 
2.3.3 
Medical history ................................................................................13 
2.3.4 
Prior antineoplastic therapy ..............................................................13 
2.3.5 
Diagnosis and extent of cancer..........................................................13 
2.3.6 
Protocol deviations ...........................................................................13 
2.4 
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance) ................................................................................................... 13 
2.4.1 
Study treatment / compliance ............................................................13 
2.4.2 
Prior, concomitant and post therapies ................................................15 
2.5 
Analysis of the primary objective .....................................................................15 
2.5.1 
Primary endpoint..............................................................................15 
2.5.2 
Statistical hypothesis, model, and method of analysis ........................15 
2.5.3 
Handling of missing values/censoring/discontinuations .....................16 
2.5.4 
Supportive analyses ..........................................................................16 
2.6 
Analysis of the key secondary objective ...........................................................16 
2.7 
Analysis of secondary efficacy objective(s) ......................................................17 
2.8 
Safety analyses ..............................................................................................  17 
2.8.1 
Adverse events (AEs) .......................................................................19 
2.8.2 
Deaths .............................................................................................19 
2.8.3 
Laboratory data ................................................................................19 
2.8.4 
Other safety data ............................................................................  20 
2.9 
Pharmacokinetic endpoints.............................................................................21 
2.10 
Biomarkers ......................................................................................................23 
2.11 
Other Exploratory analyses ............................................................................25 
2.12 
Interim analysis ...............................................................................................25 


Novartis 
For business use only 
Page 4 
SAP  
 
CMCS110Z2201 
 
3 
Sample size calculation ...............................................................................................27 
4 
Change to protocol specified analyses..........................................................................27 
5 
Appendix....................................................................................................................27 
5.1 
Baseline ..........................................................................................................27 
5.2 
Handling of missing and partial dates ...............................................................28 
5.3 
Construction of waterfall graphs.......................................................................28 
5.4 
Imputation rules...............................................................................................29 
5.4.1 
Study drug .......................................................................................29 
5.4.2 
AE date imputation...........................................................................29 
5.4.3 
Medication/therapy date imputation ..................................................29 
5.5 
Laboratory parameters derivations....................................................................30 
5.6 
Statistical models .............................................................................................30 
5.6.1 
Primary analysis ...............................................................................30 
5.6.2 
Operating Characteristics..................................................................31 
5.7 
Rule of exclusion criteria of analysis sets..........................................................33 
6 
Reference ...................................................................................................................35 


Novartis 
For business use only 
Page 5 
SAP  
 
CMCS110Z2201 
 
List of abbreviations 
AE 
Adverse event 
ALT 
Alanine aminotransferase/glutamic pyruvic transaminase/GPT 
AST 
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT 
ATC 
Anatomical Therapeutic Classification 
AUC 
Area Under the Curve 
BDM 
Biometrics and Data Management 
CR 
Complete response 
CRO 
Contract Research Organization 
CSF-1 
Colony stimulation factor – 1, also called M-CSF 
CSP 
Clinical study protocol 
CSR 
Clinical study report 
CTC 
Common Toxicity Criteria 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTX-I 
C-terminal telopeptide of type I collagen, a bone reabsorption marker 
DAR 
Dose administration record 
DBL 
Database lock 
DI 
Dose intensity 
DMC 
Data Monitoring Committee  
DOR 
Duration of response 
DRI 
Drug reference listing 
ECG 
Electrocardiogram 
FAS 
Full Analysis Set 
eCRF 
Electronic Case Report Form 
HR 
Hazard ratio 
IHC 
Immunohistochemistry 
INR 
International normalized ratio 
LLN 
Lower Limit of Normal 
LLOQ 
Lower limit of quantificaton 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI 
National Cancer Institute 
ORR 
Overall respolnse rate 
OS 
Overall Survival 
PD 
Pharmacodynamics 
PDI 
Planned dose intensity 
PDS 
Programming Datasets Specifications 
PFS 
Progression-Free Survival 
PK 
Pharmacokinetics 
PPS 
Per-Protocol Set 
PR 
Partial response 
PRO 
Patient-reported Outcomes 
QoL 
Quality of Life 
RAP 
Report and Analysis Process 


Novartis 
For business use only 
Page 6 
SAP  
 
CMCS110Z2201 
 
RDI 
Relative Dose Intensity 
RECIST 
Response Evaluation Criteria in Solid Tumors  
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Stable disease 
SGOT 
Serum glutamic oxaloacetic transaminase 
SGPT 
Serum glutamic pyruvic transaminase 
SI 
International System of Units 
SOC 
System Organ Class 
SSD 
Study specification document 
TAM 
Tumor-associated macrophages 
TFLs 
Tables, Figures, Listings 
TIL 
Tumor-infiltrating lymphocytes 
TNBC 
Triple Negative Breast Cancer 
ULN 
Upper Limit of Normal 
WHO 
World Health Organization 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 
Introduction 
This Statistical Analysis Plan (SAP) provides detailed statistical methodology for the analysis 
of data from study CMCS110Z2201 that will be presented in the Clinical Study Report (CSR). 
The output shells (in-text and post-text) accompanying this document can be found in the Table 


Novartis 
For business use only 
Page 7 
SAP  
 
CMCS110Z2201 
 
Figure Listing (TFL) shells document. The specifications for derived variable and datasets can 
be found in the Programming Datasets Specifications (PDS) document. 
All changes to the planned analysis described in this document required before or after the 
clinical database lock will be made through an amendment or addendum, respectively. Note 
that obvious corrections will be made at the time of analysis to address minor formatting or 
spelling mistakes present in the TFL shells document without the need to amend. 
The SAP, TFL shells and PDS documents may also serve as a reference for the creation of any 
outputs required outside of the CSR, e.g., IB updates, abstracts, posters, presentations, 
manuscripts and management updates. Data used for these analyses will have a status aligned 
to the database lock guidance. 
This document uses CMCS110Z2201 study protocol version 06 as a reference. Novartis has 
halted the recuitment of the study as of June 16th, 2017 due to challenging enrollment and rapid 
evolution of the therapeutic landscape. Importantly, the recruitment halt was not a consequence 
of any safety concern. The changes to the protocol planned statistical analyses and to the 
original SAP are described in Section 4.  
 
1.1 
Study design 
This is a phase II, randomized (2:1), two-arm, open-label multi-center, study of patients with 
advanced TNBC. As shown in Figure 1-1, patients will be randomized in a ratio of 2:1 to Arm 
1 (MCS110 + carbo/gem) and Arm 2 (carbo/gem). No stratification factor will be used. 
Figure 1-1 
Overview of study design 
 
 
An early safety review meeting will take place when nine patients have been randomized and  
completed two cycles of either MCS110 + carbo/gem or carbo/gem alone, or discontinued 
earlier due to adverse event. If the dosing regimen is changed at this time, an additional safety 
review of the new dosing regimen will take place after six patients have been randomized and 


Novartis 
For business use only 
Page 8 
SAP  
 
CMCS110Z2201 
 
completed two cycles of MCS110 (per the new dosing regimen) + carbo/gem, or discontinued 
earlier due to an adverse event. Any subsequent MCS110 changes of the dosing regimen will 
be followed by an additional safety review per the procedure just described.  
Novartis clinical team and principal investigators will assess clinical, PK and laboratory data of 
all patients having received any treatment in the study before each of the meeting(s) to decide 
on the subsequent MCS110 dose regimen. One of the following dosing alternatives will be 
chosen:  
• If no safety concerns are noted during the safety review and the observed drug exposure is 
within that observed in cynomolgus monkeys and/or HV (clinical study protocol (CSP) 
Table 2-1), then the same MCS110 dose will be continued. 
• If safety concerns are noted, then the MCS110 dose will be reduced (from 10 mg/kg to 
5mg/kg, or from 5 mg/kg to 2.5 mg/kg) and the additional dose of MCS110 on C1D8 may 
be omitted, after review with the Steering Committee. 
Once a dosing regimen is agreed upon after the safety review meeting(s), all the subsequent 
patients randomized to Arm 1 will receive the confirmed dose. The study will continue until 52 
patients have been randomized to Arm 1 and treated at the dose level confirmed as the final 
recommended dose for MCS110 combined with carbo/gem. 
If there is no change to the MCS110 dosing regimen following the first safety review meeting, 
the total number of patients for this study will be 78. If the dosing regimen is changed, the total 
number of patients for the study may be approximately 110, as recruitment will continue during 
the decision making. 
After the early safety review(s), individual patient data will subsequently be reviewed on an 
ongoing basis and discussed with Investigators throughout the duration of the trial.  Aggregate 
safety data and the primary endpoint will be monitored quarterly by the study team. This data 
monitoring will be based on the available data in the clinical database at the respective time. 
The primary efficacy endpoint, progression free survival (PFS) as determined through the local 
Investigator’s tumor assessment per RECIST 1.1, will be analyzed according to the study arm 
patients are randomized to. Due to enrollment halt, formal hypothesis testing for the primary 
analysis including HR estimation with 90% credible interval will not be carried out for the CSR. 
Only Kaplan-Mayer (KM) curve between the MCS110 + carboplatin/gemcitabine arm and the 
carboplatin/gemcitabine alone arm will be presented. The analysis of the study data for the CSR 
will be done in one of the following approaches:  
• The CSR will be based on all patients’data at the end of the study, or 
• The study data will be analyzed and reported in the primary CSR based on all patients’
data up to the time when all patients have completed at least six cycles of treatment or 
discontinued the study. Any additional data for patients continuing to receive study 
treatment past the data cutoff date for the primary CSR, as allowed by the protocol, will be 
reported once end of study has been achieved. 
 
1.2 
Study objectives and endpoints 
Objectives and related endpoints are described in Table 1-1 below. 


Novartis 
For business use only 
Page 9 
SAP  
 
CMCS110Z2201 
 
Table 1-1 
Objectives and related endpoints 
Objective 
Endpoint 
Analysis 
Primary 
 
 
To assess the anti-tumor activity of 
MCS110 combined with 
carboplatin/gemcitabine (carbo/gem) 
compared to carbo/gem alone 
PFS as per RECIST v1.1 (by local investigator 
assessment) 
Refer to 
Section 2.5 
Secondary 
 
 
Characterize the safety and 
tolerability of MCS110 given in 
combination with carbo/gem 
Safety: adverse event (AEs), serious adverse 
events (SAEs) 
Tolerability: Dose interruptions, reductions and 
dose intensity 
Refer to 
Section 2.8 
Characterize PK of MCS110 when 
combined with carbo/gem 
Serum concentration of free MCS110 and derived 
PK parameters  
Refer to 
Section 2.9 
Characterize PK of carbo and gem in 
the presence and absence of 
MCS110. 
Plasma concentration of carboplatin, gemcitabine 
and dFdU (the primary metabolite of gem), and 
derived PK parameters 
Refer to 
Section 2.9 
Characterize PD effect of MCS110 
when combined with carbo/gem 
Total CSF-I circulating levels, and serum CTX-I in 
blood. 
TAM and TIL content in pre- and post-dose tumor 
biopsies 
Refer to 
Section 2.10 
To assess the anti-tumor activity of  
MCS110 given in combination with  
carbo/gem as measured by additional 
efficacy measures 
Tumor response per RECIST v1.1 (by local 
investigator assessment): Overall Response Rate 
(ORR), Duration of Response (DOR), and Clinical 
Benefit Rate (Complete Response (CR) + Partial 
Response (PR) + Stable Disease (SD) ≥ 6 months)  
Refer to 
Section 2.7 


Novartis 
For business use only 
Page 10 
SAP  
 
CMCS110Z2201 
 
2 
Statistical methods 
This section and its subsections can be imported to section 9.7 of the CSR after the analyses 
have been conducted. The text will be changed to the past tense when imported into the CSR.  
2.1 
Data analysis general information 
The data will be analyzed by Novartis personnel and/or designated CRO(s) using SAS version 
9.4, and for Bayesian modeling, R version 3.0.2 or later and WinBUGS14. PK parameters will 
be calculated using non-compartmental methods available in Pharsight Phoenix version 6.4. 
The study data will be analyzed and reported (in a primary CSR if final DBL has not occurred) 
based on all patient data either at the end of the study or up to the time when all patients have 
completed at least six cycles of treatment or discontinued the study. Additional data for patients 
continuing to receive study treatment past the data cutoff date of the primary CSR, as allowed 
by the protocol, will be reported in the final CSR once all patients have either completed or 
discontinued the study. However, only a selection of key outputs (indicated in the TFL shells 
document) will be provided for the final CSR. 
Data from participating centers in this study protocol will be combined, so that an adequate 
number of patients will be available for analysis. No center effect will be assessed. The data 
will be summarized with respect to demographic and baseline characteristics, efficacy 
observations and measurements, safety observations and measurements, and all relevant 
pharmacokinetic (PK) and pharmacodynamics (PD) measurements using descriptive statistics 
(n, mean, standard deviation, median, minimum, and maximum) for quantitative data and 
contingency tables (frequencies and percentages) for qualitative data. 
2.1.1 
General definitions  
Study drug and study treatment 
The investigational drug refers to MCS110, the Novartis anti-CSF-1 recombinant humanized 
monoclonal antibody. The investigational treatment refers to carbo/gem with or without 
MCS110.  
Date of first/last administration of study drug and study treatment 
The date of first (last) administration of study treatment is derived as the first (last) date when 
a non-zero dose of any component of study treatment was administered and recorded on the 
Dosage Administration Record (DAR) eCRF. For the sake of simplicity, the date of first (last) 
administration of study treatment will also be referred as start (last) date of study treatment. 
Study day 
The study day for all assessments/events will be calculated using the date of randomization as 
reference for FAS or the start date of study treatment as reference for all other analysis sets. For 
assessments/events occurring on or after the start date of study treatment, study day will be 
calculated as: 
Study day (days) = Event date – Start date of study treatment + 1 


Novartis 
For business use only 
Page 11 
SAP 
 
CMCS110Z2201 
 
Therefore, the first day of study treatment is study day 1. 
For all assessment/events occurring prior to the start of the study treatment, study day will be 
negative and will be calculated as: 
Study day (days) = Event date – Start date of study treatment 
Study day will be displayed in the data listings. 
On-treatment assessment/event 
An on-treatment assessment/event is defined as any assessment/event obtained in the time 
interval from the start date of study treatment until the last date of study treatment + 30 days 
inclusive. 
2.2 
Analysis sets 
The number (%) of patients in each of the defined analysis set will be summarized using the 
FAS. 
Full Analysis Set 
The Full Analysis Set (FAS) comprises all patients to whom study treatment has been assigned 
by randomization. According to the intention to treat principle, patients will be analyzed 
according to the treatment to which they have been assigned during the randomization 
procedure. 
Unless otherwise specified the FAS will be the default analysis set used for all analyses and 
listing of raw data. 
Safety Set 
The safety set includes all patients who received at least one dose of MCS110 or carboplatin or 
gemcitabine for Arm 1, at least one dose of carboplatin or gemcitabine for Arm 2. The statement 
that a patient had no AEs (on the AE eCRF) constitutes a valid safety assessment. 
Patients will be classified according to treatment received, where treatment received is defined 
as: 
• The treatment assigned if it was received at least once, or 
• The first treatment received when starting therapy with study treatment if the assigned 
treatment was never received. 
The safety set will be the primary population for all safety related endpoints. 
Pharmacokinetic analysis set 
The pharmacokinetic analysis set (PAS) consists of all patients who have an evaluable 
pharmacokinetic (PK) profile (e.g., Cycle 1, Cycle 4, etc). A profile is considered evaluable if 
all of the following conditions are satisfied: 
• Patient receives the planned treatment on the profile day 
• Patient provides at least one primary PK parameter 


Novartis 
For business use only 
Page 12 
SAP 
 
CMCS110Z2201 
 
The PAS will be used for summaries of PK concentration data, PK parameters 
 
.  Patients will be analyzed according to the 
planned treatment. Patients may be removed from PK analysis on an individual basis depending 
on the number of available blood samples.  These patients will be identified at the time of 
analysis. 
2.3 
Patient disposition, demographics and other baseline 
characteristics 
Summaries and listings described in this section will be based on the FAS. 
2.3.1 
Patient disposition 
The FAS will be used for the patient disposition summary tables and listings. The following 
will be tabulated: 
• Number (%) of randomized patients who are treated and who are untreated,  
• Number (%) of patients who are still on-treatment (based on non-completion of the ‘End 
of Treatment’ page), 
• Number (%) of patients who discontinued treatment (based on completion of the ‘End of 
Treatment’ page with discontinuation date and reason entered), 
• Primary reasons for study treatment discontinuation (based on discontinuation reason 
entered in the ‘End of Treatment’ page), 
• Number (%) of patients who discontinued from post-treatment follow-up (based on 
completion of the ‘End of Post Treatment Phase Disposition’ page with discontinuation 
date and reason entered), 
• Primary reasons for post-treatment follow-up discontinuation (based on discontinuation 
reason entered in the ‘End of Post Treatment Phase Disposition’ page). 
2.3.2 
Basic demographic and background data 
Demographic data including age, predominant race, ethnicity, height, weight and ECOG 
performance status will be listed and summarized by study arm and treatment group. In addition, 
child bearing potential will be listed, and age (<65, 65-<85, ≥85 years) category summarized.  
2.3.3 
Medical history 
Medical history and current medical conditions will be coded using the latest Medical 
Dictionary for Regulatory Activities (MedDRA) terminology available at the time of reporting. 
Medical history and current (ongoing) medical conditions, including cancer-related conditions 
and symptoms will be listed. 
2.3.4 
Prior antineoplastic therapy 
Prior anti-neoplastic therapy will be summarized and listed for medication, radiotherapy and 
surgery. 
The number (%) of patients who received, in total and separately, any prior anti-neoplastic 
medication, radiotherapy or surgery will be summarized. 


Novartis 
For business use only 
Page 13 
SAP 
 
CMCS110Z2201 
 
The summary of prior anti-neoplastic medications will include the total number of regimens 
(note: there can be more than one medication per regimen), setting at last medication, time (in 
days) between end of last medication to start of study treatment, and reason for discontinuation 
at last medication. The last medication is defined based on the last end date of all prior regimen 
components. Prior antineoplastic medications will also be summarized by Anatomical 
Therapeutic Chemical (ATC) class, and preferred term. 
The summary of prior anti-neoplastic radiotherapy will include the radiotherapy locations 
(including all locations recorded for each patient), and setting at last radiotherapy. 
The summary of prior anti-neoplastic surgery will include the time (in months) between the last 
surgery (non-biopsy procedure) to start of study treatment and procedure at last surgery. 
2.3.5 
Diagnosis and extent of cancer 
The summary and listing of diagnosis and extent of cancer (disease history) will include primary 
site of cancer, details of tumor histology/cytology, histological grade, stage at initial diagnosis, 
time (in months) from initial diagnosis of primary site to start of study treatment, time (in 
months) from most recent recurrence/relapse or progression to start of study treatment, time (in 
months) from initial diagnosis of primary site to first recurrence/relapse or progression, current 
stage of cancer, current extent of disease (metastatic sites), BRCA1 mutation, and BRCA2 
mutation. 
2.3.6 
Protocol deviations 
The FAS will be used for the protocol deviation summary tables and listings. The number (%) 
of patients with any CSR-reportable protocol deviation will be tabulated by the deviation 
category (entry criteria not satisfied; wrong treatment or incorrect dose; developed withdrawal 
criteria, but not withdrawn; took an excluded concomitant medication; others). The full list of 
protocol deviations are documented in the Study Specification Document (SSD). Protocol 
deviations leading to exclusion from analysis sets are specified in Section 5.7. 
2.4 
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance) 
The Safety set will be used for all medication data summaries and listings. 
2.4.1 
Study treatment / compliance 
2.4.1.1 
Study treatment 
Last date of exposure to study drug MCS110 = last date of administration of MCS110 + 20 days 
Last date of exposure to study drug carbo = last date of administration of carbo + 20 days 
Last date of exposure to study drug gem = last date of administration of gem + 20 days 
Last date of exposure to study treatment is the maximum of the last date of exposure to each 
study drug. 
Dose administered (mg/kg) for MCS110 = Dose prescribed (mg/kg) * Total volume 
administered (mL) / Total volume planned to be administered (mL) 


Novartis 
For business use only 
Page 14 
SAP 
 
CMCS110Z2201 
 
Dose administered (AUC2) for carbo = Dose prescribed (AUC2) * Total volume administered 
(mL) / Total volume planned to be administered (mL) 
Dose administered (mg/m2) for gem = Dose prescribed (mg/m2) * Total volume administered 
(mL) / Total volume planned to be administered (mL) 
Planned dose is the dose level of a study drug assigned during randomization. 
Definitions of duration of exposure, cumulative dose, actual dose intensity (DI), planned dose 
intensity (PDI), relative dose intensity (RDI), percentage of cycles the planned/intended dose 
was received, as well as intermediate calculations, are as follows: 
• Duration of exposure (days) to study drug/treatment: last date of exposure to study 
drug/treatment − first date of study drug/treatment + 1 (periods of interruption are not 
excluded) 
• Cumulative dose (mg/kg for MCS110, mg/m2 for gem, AUC2 for carbo): sum of all doses 
of study drug taken by a patient 
• Cumulative planned dose (mg/kg for MCS110, mg/m2 for gem, AUC2 for carbo): sum of 
all doses of study drug that was intended to have been taken during the treated period by a 
patient 
• Percentage of cycles at planned dose: 100 × number of cycles at planned dose ⁄ number of 
cycles scheduled per protocol during treatment period 
• DI (mg/kg for MCS110, mg/m2 for gem, AUC2 for carbo): cumulative dose (mg/kg for 
MCS110, mg/m2 for gem, AUC2 for carbo) ⁄ planned number of doses patient should have 
taken  
• PDI (mg/kg for MCS110, mg/m2 for gem, AUC2 for carbo): cumulative planned dose 
(mg/kg for MCS110, mg/m2 for gem, AUC2 for carbo) ⁄ planned number of doses patient 
should have taken 
• RDI (%): 100 × DI  ⁄ PDI  
All the above variables will be calculated for MCS110, carboplatin and gemcitabine separately. 
The duration of exposure to each study drugs and study treatment (including categories: <=3, 
3-<=6, 6-<=9,  9-<=12, 12-<=15, 15-<=18 >18 weeks) will be summarized. In addition, the 
cumulative dose, DI, and RDI (including categories: <0.5, 0.5-<0.75, 0.75-<0.9, 0.9-<1.1, ≥1.1) 
will be summarized for each study drug. The number (%) of patients who have dose reductions 
and interruptions, and the corresponding reasons, will be provided for each study drug. The 
number of dose reductions and interruptions per patient will be summarized for each study drug. 
All doses of the study treatment along with reasons for any dose change will be listed. 
Dose interruption: If a dose is given more than 6 days after the scheduled day of dosing, it is 
considered a dose interruption.  
Dose reduction: A non-zero actual dose that is less than the immediate previous non-zero actual 
dose (if not the first dose) and below the treatment received dose, where treatment received is 
defined in Section 2.2. 


Novartis 
For business use only 
Page 15 
SAP 
 
CMCS110Z2201 
 
2.4.1.2 
Compliance 
Compliance to the study treatment within each study arm/treatment group will be assessed by 
the number of dose reductions, number of dose interruptions and percent of cycles received 
planned dose for all the study drugs separately in summary tables by study arm and treatment 
group for the safety set.  
2.4.2 
Prior, concomitant and post therapies 
Concomitant therapies are defined as any medications (excluding study treatment, prior 
antineoplastic treatments) and significant non-drug therapies (including physical therapy and 
blood transfusions) administered in the study and are recorded in the Concomitant 
Medications/significant non-drug therapies eCRF. These therapies will be coded using the 
WHO Drug Reference Listing (WHO DRL) dictionary that employs the WHO Anatomical 
Therapeutic Chemical (WHO ATC) classification system. 
Any concomitant therapies starting prior to or after the start of study treatment will be listed. 
Concomitant and significant non-drug therapies will be summarized by ATC class and preferred 
term. These summaries will include 1) medications or therapies starting on or after the start of 
study treatment but starting no later than 90 days after last dose of study treatment and 2) 
medications or therapies starting prior to the first dose of study treatment and continuing after 
the start of study treatment. 
The imputation of a concomitant medication start date will follow the same conventions as for 
an AE start date (see Section 5.4.3 for more details). No imputation will be performed for 
concomitant medication end dates. 
Anti-neoplastic therapies since discontinuation of study drug will be listed.  
2.5 
Analysis of the primary objective 
The primary objective is to assess the anti-tumor activity of MCS110 combined with 
carboplatin/gemcitabine compared to carboplatin/gemcitabine in adult patients with triple 
negative breast cancer.  
2.5.1 
Primary endpoint 
The primary efficacy endpoint is progression-free survival (PFS) based on local Investigator 
assessment, as defined in RECIST v1.1. PFS is defined as the time from the date of 
randomization to the date of the first radiologically documented PD or death due to any cause.  
Due to enrollment halt, formal hypothesis testing for the primary endpoint including hazard 
ratio for PFS with 90% credible interval between the MCS110 + carbo/gem arm and the 
carbo/gem arm (as detailed out in Section 2.5.2) will not be carried out. Only Kaplan-Meier 
curve by treatment arms will be presented.  
2.5.2 
Statistical hypothesis, model, and method of analysis  
The primary efficacy endpoint, PFS as determined through the local Investigator’s tumor 
assessment per RECIST 1.1, will be analyzed according to the study arm patients are 
randomized to. However, due to enrollment halt, formal hypothesis testing as sepcified below 


Novartis 
For business use only 
Page 16 
SAP 
 
CMCS110Z2201 
 
including estimation of HR and 90% confidence interval will not be carried out. PFS will be 
presented 
graphically 
using 
Kaplan-Meier 
plots 
for 
both 
the 
MCS110 
+ 
carboplatin/gemcitabine arm and the carboplatin/gemcitabine arm. 
The primary analysis of the study is based on the estimation of the hazard ratio between the 
MCS110 + carboplatin/gemcitabine arm and the carboplatin/gemcitabine alone arm and related 
one-sided 90% credible interval of the HR. 
The following double criteria will be used in order to conclude that there is clinical and 
statistical evidence of efficacy of the MCS110 + carboplatin/gemcitabine combination 
treatment compared to the carboplatin/gemcitabine alone treatment: 
• the estimated hazard ratio (posterior median) is equal or less than 0.7 (i.e 30% reduction in 
risk of PFS event with MCS110 + carboplatin/gemcitabine arm compared to the 
carboplatin/gemcitabine arm), 
• the upper bound of the one-sided 90% credible interval of the HR is below 1. 
Estimated HR for the MCS110 + carboplatin/gemcitabine arm compared to the 
carboplatin/gemcitabine arm along with the one-sided 90% confidence interval will be 
produced 
2.5.3 
Handling of missing values/censoring/discontinuations 
If a patient has not progressed or is not known to have died at the date of analysis cut-off or has 
received any further anticancer therapy, PFS will be censored at the date of the last adequate 
tumor evaluation before the cut-off date or before the start of the new anticancer therapy date, 
whichever is earlier, as defined in the in the RECIST v1.1 (CSP Appendix 1). Clinical 
deterioration will not be considered as a qualifying event for progression.  
In particular, PFS will be censored at the last adequate tumor assessment if one of the following 
occurs: absence of event; the event occurs after a new anticancer therapy is given; the event 
occurred after two or more missing tumor assessments. Any response assessment is considered 
to be adequate if the assessment was perfomed and the outcome of the assessment was other 
than ‘unknown’. 
Patients without baseline tumor assessment or any tumor assessment after the start date of study 
treatment will be censored at the date of randomization in the primary analysis, but will be 
excluded in the PPS for sensitivity analysis, if performed. 
2.5.4 
Supportive analyses 
NA  
2.6 
Analysis of the key secondary objective 
NA 
2.7 
Analysis of secondary efficacy objective(s) 
ORR is defined as the proportion of patients with a best overall resonse of complete response 
(CR) or partial response (PR) per RECIST v1.1. 


Novartis 
For business use only 
Page 17 
SAP 
 
CMCS110Z2201 
 
CBR is defined as the proportion of patients with a best overall response of complete response 
(CR) or partial response (PR) or stable disease (SD) ≥ 6 months per RECIST v1.1. 
Both CR and PR must be confirmed by repeat assessments performed not less than 4 weeks 
after the criteria for response are first met. The next scheduled assessment may be used for 
purposes of confirmation of response. BOR for each patient is determined from the sequence 
of overall lesion responses according to the following rules: 
• CR = at least two determinations of CR at least 4 weeks apart before progression. 
• PR = at least two determinations of PR or better at least 4 weeks apart before progression (and 
not qualifying for a CR). 
• SD = at least one SD assessment (or better) > 5 weeks after start of treatment (and not 
qualifying for CR or PR). 
• PD = progression ≤ 12 weeks after start of treatment (and not qualifying for CR, PR or SD). 
• UNK = all other cases (i.e. not qualifying for confirmed CR or PR and without SD after more 
than 6 weeks or progression within the first 12 weeks) 
Unconfirmed PR and unconfirmed CR are considered as stable disease (SD) if > 5 weeks after 
start of treatment, otherwise considered as unknown. Patients who are of unknown clinical 
response or have no post-baseline tumor assessment will be treated as non-responders. 
Only tumor assessments performed before the start of any further anti-neoplastic therapies (i.e., 
any additional secondary anti-neoplastic therapy or anti-cancer surgery) will be considered in 
the assessment of BOR. Further anti-neoplastic therapies will be identified via protocol 
deviations or from the data collected on ‘Anti-neoplastic therapies since discontinuation of 
study drug’ as appropriate. Clinical deterioration will not be considered as documented disease 
progression.  
The best overall response will usually be determined from response assessments undertaken 
while on treatment. As a default, any assessments taken more than 90 days after the last dose 
of study treatment will not be included in the best overall response derivation. If any alternative 
cancer therapy is taken while on study any subsequent assessments would be excluded from the 
best overall response determination. 
Individual lesion measurements will be listed along with the overall lesion response and Best 
Overall response (BOR).  
Among patients with a confirmed PR or CR per RECIST 1.1, DOR is defined as the time from 
first documented response (PR or CR) to the date of first documented disease progression (PD) 
or death due to any cause. If a patient has not had an event, DOR is censored in the same way 
as PFS, at the date of last adequate tumor assessment. 
DOR will be presented descriptively using Kaplan Meier plots for the two study arms. In 
addition, the median DOR will be presented.  
2.8 
Safety analyses 
The assessment of safety is based on the type and frequency of Adverse Events (AEs) as well 
as on the number of laboratory values that fall outside of pre-determined ranges (Common 


Novartis 
For business use only 
Page 18 
SAP 
 
CMCS110Z2201 
 
Toxicity Criteria for Adverse Events (CTCAE) grading limits or normal ranges as appropriate). 
Other safety data include electrocardiogram and vital signs. 
The safety set will be used for summaries and listings of safety data. 
The overall observation period will be divided into three mutually exclusive segments: 
1. Pre-treatment period: from day of patient’s informed consent to the day before first dose 
of study medication, 
2. On-treatment period: from day of first dose of study medication to 30 days after last dose 
of study medication, 
3. Post-treatment period: starting at Day 31 after last dose of study medication. 
The safety summary tables will primarily be based on all data from the on-treatment period, 
which is collected no later than 30 days after study treatment discontinuation. However, in the 
listings all safety assessments will be listed and those collected after study treatment 
discontinuation will be flagged.  
2.8.1 
Adverse events (AEs) 
AEs will be coded and graded using the latest version of MedDRA and CTCAE, respectively, 
available at the time of reporting. If CTCAE grading does not exist for an AE, grades 1, 2, 3, or 
4 corresponding to the severity of mild, moderate, severe, and life-threatening, respectively, 
will be used. CTCAE grade 5 (death) will not be used in this study. Death information will be 
collected on the “Death” eCRF page. 
All AEs will be listed. All AE summaries will be summarized (frequency counts and 
percentages) by system organ class and/or preferred term, and maximum severity grades, unless 
noted otherwise. 
The following AE summaries will be produced: 
• AEs regardless of study drug relationship (including CTC grade 3/4) 
• AEs suspected to be study drug related (including CTC grade 3/4) 
• AEs regardless of study drug relationship leading to discontinuation of study drug 
• AEs suspected to be study drug related leading to discontinuation of study drug 
• AEs regardless of study drug relationship requiring dose adjustment or study drug 
interruption 
• AEs suspected to be study drug related requiring dose adjustment or study drug 
interruption 
• AEs which are not SAEs regardless of study drug relationship 
• SAEs regardless of study drug relationship 
• SAEs suspected to be study drug related 
A patient with multiple CTC grades for an AE will be summarized under the maximum CTC 
grade recorded for the event. A subject with multiple occurrences of an AE is counted only once 
in the AE category (e.g. system organ class, preferred term). 


Novartis 
For business use only 
Page 19 
SAP 
 
CMCS110Z2201 
 
EudraCT and clinicaltrials.gov requirements for AEs and Deaths summaries 
For the legal requirements of clinicaltrials.gov and EudraCT, two required tables on treatment-
emergent adverse events which are not serious adverse events with an incidence greater than 
5% and on treatment emergent SAEs and SAEs suspected to be related to study treatment will 
be provided by SOC and PT on the safety set population. This analysis will be done after the 
final database lock. 
If for a same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT: 
• a single occurrence will be counted if there is  ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE 
• more than one occurrence will be counted if there is > 1 day gap between the end date of 
the preceding AE and the start date of the consecutive AE 
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE. 
The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT. 
 
2.8.2 
Deaths 
All deaths will be listed, with post-treatment deaths flagged. The following summaries of deaths 
will be produced: 
• On-treatment deaths with cause of death by preferred term 
• All deaths with cause of death by primary system organ class and preferred term 
2.8.3 
Laboratory data 
Laboratory data will be converted into SI units and classified (by Novartis statistical 
programming) into CTC grades according to CTCAE v4.03. Grade 5 will not be used. 
Change from baseline criteria will not be used in derivation of CTC grade. A Grade 0 CTC 
grade will be set when laboratory value is: 
• Within LLN and ULN and grading in both direction, 
• Below ULN and grading in hyper direction, 
• Above LLN and grading in hypo direction. 
Laboratory data for which a CTC grading does not exist will be classified into low, normal, or 
high based on local laboratory normal ranges as applicable. 
The following summaries will be produced for hematology and biochemistry parameters: 
• For parameters with CTC grades: Shifts from baseline to the worst post-baseline CTC  
grade (Each patient will be counted only for the worst grade observed post-baseline.)  
• For parameters with no CTC grades defined: Shifts from baseline to the worst post-
baseline using low/normal/high classifications, based on laboratory normal ranges 


Novartis 
For business use only 
Page 20 
SAP 
 
CMCS110Z2201 
 
The following listings will be produced: 
• Listing of patients with laboratory abnormalities of CTC grade 3 and 4 
• Listing of all laboratory data with values flagged to show the corresponding CTCAE 
grades if applicable and the classifications relative to the laboratory normal ranges 
Table 2-1 and Table 2-2 list all laboratory parameters that will be summarized. 
Table 2-1 
Laboratory parameters for which CTCAE grades are defined 
Hematology and 
coagulation 
Biochemistry 
White Blood Cells 
(WBC) 
↑↓ 
Creatinine 
↑ 
Hemoglobin 
↑↓ 
Sodium 
↑↓ 
Platelets  
↓ 
Potassium  
↑↓ 
Absolute Neutrophils 
↓ 
Calcium 
↑↓ 
Absolute Lymphocytes 
↑↓ 
Alkaline phosphatase 
↑ 
International normalized 
ratio (INR) 
↑ 
Albumin 
↓ 
 
 
AST (SGOT) 
↑ 
 
 
ALT (SGPT) 
↑ 
 
 
Bicarbonate 
↓ 
 
 
Total Bilirubin 
↑ 
 
 
Creatine kinase (CK) 
↑ 
 
 
Uric Acid 
↑ 
 
 
Blood plasma Glucose 
↑↓ 
 
 
Phosphate 
↓ 
↑ Indicates that CTC grade increases as the parameter increases. 
↓ Indicates that CTC grade increases as the parameter decreases. 
Table 2-2 
Laboratory parameters (without CTCAE grades) for which lab 
reference ranges are defined 
Hematology and 
coagulation 
Biochemistry 
Prothrombin time (PT) 
Blood urea nitrogen (BUN) 
 
Urea 
2.8.4 
Other safety data 
2.8.4.1 
ECG and cardiac imaging data 
Baseline for ECG analysis is defined as the average of all available ECG measurements 
associated with the baseline assessment. Scheduled study day 1 pre-dose ECGs will be 
considered to have been obtained prior to study drug administration if dosing time is missing.  


Novartis 
For business use only 
Page 21 
SAP 
 
CMCS110Z2201 
 
The following summary will be provided for each applicable ECG parameter: 
• Number (%) of patients having notable ECG values according to Table 2-3. 
Table 2-3 
Criteria for notable ECG values 
ECG parameter 
Criteria for notable ECG values 
QT, QTcF, QTcB (ms) 
New value of > 450 ms, > 480 ms, > 500 ms 
Increase from baseline of > 30 ms, > 60 ms 
HR (bpm) 
Increase from baseline > 25% and to a value > 100 bpm 
Decrease from baseline > 25% and to a value < 50 bpm 
PR (ms) 
Increase from baseline > 25% and to a value > 200 ms 
New value of > 200 ms 
QRS (ms) 
Increase from baseline > 25% and to a value > 120 ms 
New value of > 120 ms 
Patients with any notable ECG values will be listed. 
2.8.4.2 
Vital signs 
Vital sign parameters collected are systolic and diastolic blood pressure (mmHg), pulse rate 
(beats per minute), respiratory rate (breaths per minute), body temperature (°C), and weight 
(kg). Vital sign values considered notably abnormal are defined in Table 2-4. 
Table 2-4 
Criteria for notable vital sign values 
Vital sign 
Criteria for clinically notable vital sign values 
Systolic blood pressure 
[mmHg] 
≥180 mmHg/≤90 mmHg with increase/decrease from baseline of 
≥20 mmHg 
Diastolic blood pressure 
[mmHg] 
≥105 mmHg/≤50 mmHg with increase/decrease from baseline of 
≥15 mmHg 
Pulse rate [bpm] 
≥100 bpm/≤50 bpm with increase/decrease from baseline of >25% 
Body temperature [°C] 
≥ 39.1 
Weight [kg] 
≥10% decrease/increase from baseline 
Vital signs shift table based on values classified as notable low, normal, notable high or notable 
(high and low) at baseline and worst post-baseline will be produced. 
Patients with any clinically notable vital sign value will be listed. 
2.9 
Pharmacokinetic endpoints   
All PK analyses will be performed based on the PAS. Only PK blood samples with the date and 
time and for which the last prior dose dates and times are adequately recorded will be included 
in the PK analyses. Missing concentration values will be reported as is in data listings. 
Concentration values below Lower limit of quantitation (LLOQ: 20 ng/mL for free MCS110; 
1.5 ng/mL for total CSF-1; 2 ng/mL for carboplatin; 0.5 ng/mL for gemcitabine; and 5 ng/mL 
for dFdU) will be handled as zero in summary statistics, and reported as is in data listings. Any 
missing pharmacokinetic parameter data will not be imputed.  


Novartis 
For business use only 
Page 22 
SAP 
 
CMCS110Z2201 
 
PK parameters will be calculated using noncompartmental methods and summarized as 
described in Table 2-5. The PK parameters considerd primary are AUCinf, AUCtau, AUClast, 
Cmax, and Tmax. Other PK parameters (CL, Vz, T1/2) are considered as secondary.  
Table 2-5 
PK parameters – descriptive statistics 
Parameters 
Descriptive statistics 
AUCinf, AUCtau, AUClast, Cmax, 
Tmax, CL, Vz and T1/2 
Mean, standard deviation, CV% mean, geometric mean, 
CV% geometric mean, median, minimum and maximum 
CV% = coefficient of variation (%) = sd/mean*100 
CV% geometic mean = sqrt (exp (variance for log transformed data)-1)*100 
Descriptive statistics (mean, standard deviation, CV% or median (range)) will be presented for 
all parameters by analyte, study arm and study cycle/day. When a geometric mean is presented, 
it will be stated as such. Zero concentrations will not be included in the geometric mean 
calculation. Since Tmax and T1/2 are generally evaluated by a nonparametric method, median 
values and ranges will be presented for these parameters. All primary PK parameters will be 
listed. 
 
 
 
Descriptive graphical plots of individual and mean serum/plasma concentration versus time 
profiles of free MCS110, total CSF-1 and other PD biomarkers (e.g. CTX-1,  and monocytes) 
will be generated.  
2.10 
Biomarkers 
2.10.1 
Introduction 
As a project standard, Novartis biostatistics and statistical programming will analyze only 
biomarkers collected in the clinical database.
 
 
 
 
 
 
There may be circumstances when a decision is made to stop sample collection, or not perform 
or discontinue the analysis of blood / archival tumor samples / fresh tumor biopsies / fine needle 
aspirates due to either practical or strategic reasons (e.g. issues related to the quality and/or 
quantity of the samples or issues related to the assay). Under such circumstances, the number 
of samples may be inadequate to perform a rigorous data analysis and the available data will 
only be listed and potentially summarized. 
2.10.2 
Outline of the data analysis 
Additional analyses that may be performed after the completion of the final (end-of-study) CSR 
will be documented in separate reports. These analyses may include but are not limited to the 
meta-analysis of data from this study combined with data from other studies or the analysis of 


Novartis 
For business use only 
Page 23 
SAP 
 
CMCS110Z2201 
 
biomarkers generated from samples collected during the study but analyzed after the database 
lock and completion of the CSR. The data analysis will be described in an addendum of the 
SAP or in a stand-alone analysis plan document, as appropriate. 
 
Only analysis specified in the secondary objectives may be performed and reported depending 
on the quality and/or quantity of the samples collected.  
2.10.3 
Biomarker objectives 
The biomarker objectives and corresponding endpoints are described in Section 1.2.  
2.10.4 
Biomarker analysis data set 
The Full Analysis Set will be used for all biomarker analysis. Unless otherwise specified, all 
statistical analyses of biomarker data will be performed on patients with biomarker data. 
Assessment of associations between biomarker and safety data will be conducted using the 
Safety Set. 
2.10.4.1 List of biomarkers evaluated and the collection time points 
Table 2-6 
Sample biomarker summary table 
Sample 
Type 
Visit/Time 
point 
Volume 
Marker 
Purpose 
Method 
Data
set 
Tumor 
samples 
 
 
 
 
 
 
Newly 
obtained 
tumor 
sample  
Pre-
screening 
FFPE tumor 
block/freshly
-cut sections 
of newly 
obtained 
biopsy 
or 
3-6 passes 
of newly 
obtained 
tumor 
biopsy 
CD163  
expression 
Patient selection and PD 
marker 
 
To determine TAM 
content 
Immunohist
o-chemistry 
IHC 
Newly 
obtained 
tumor 
sample  
Screening *  
 
Between 
C2D8 and 
C3D1 ** 
FFPE tumor 
block/freshly
-cut sections 
of newly 
obtained 
biopsy 
or 
3-6 passes 
of newly 
obtained 
tumor 
biopsy 
CD8, CD163  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
To evaluate CD163+ 
TAMs as a PD marker 
To evaluate whether 
specific immune 
populations (CD8+ TILs) 
 
  
 
 
 
 
Immunohist
ochemistry 
 
 
 
 
 
 
 
 
 
 
 
IHC 
 
 
 
 
 
 
 
 
 
 
 


Novartis 
For business use only 
Page 24 
SAP 
 
CMCS110Z2201 
 
Sample 
Type 
Visit/Time 
point 
Volume 
Marker 
Purpose 
Method 
Data
set 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
Blood 
samples 
 
 
 
 
 
 
Blood 
serum 
Pre-dose 
sample: 
C1D1  pre-
dose  
 
and  
 
C1D2, 
C1D4, 
C1D8, 
C1D15, C2-
8D1  
6 mL 
(minimum) 
CTX-I
 
 
 
 
 
To evaluate  bone 
resorption 
 
 
  
ELISA/MSD 
(Meso Scale 
Discovery) 
MSD 
* Using remaining tissue from newly obtained pre-screening tumor biopsy 
** If obtaining of the biopsy is not medically feasible between C2D8 and C3D1, the biopsy may be collected at a 
later time point at the investigator’s discretion. 
*** Not required if tumor sample from the initial diagnosis is used as the newly obtained tumor sample.  
Note 1: On days and time points when biomarker and pharmacokinetic blood samples are being collected, the 
PK sample must be drawn first. 
 
 
2.10.4.2 Data handling principles 
All measurements below their respective LLOQs or missing data will be labeled as such in the 
concentration data listings. Measurements below the LLOQ will be treated as zero in summary 
statistics. Change from baseline analyses will only be performed on patients with measurable 
samples and pre- and post-treatment time points. 


Novartis 
For business use only 
Page 25 
SAP 
 
CMCS110Z2201 
 
2.10.4.3 Data analysis principles 
2.10.4.3.1 
Analysis sets 
The FAS will be used for all analyses. Patients with measureable tumor samples will be 
identified in the summaries and relevant proportions will be calculated against this number of 
patients. 
2.10.4.3.2 
Basic tables, figures and listings 
Assessment of pharmacodynamic biomarkers 
The extent of TAM suppression and TIL increase will be assessed by IHC in pre- and post-
treatment formalin-fixed paraffin embedded tissue obtained during the study, when feasible. 
For this purpose, the TAM and TIL content will be compared with baseline levels by producing 
a summary table with the descriptive statistics. Data will also be listed by patient for all these 
markers. 
 
 Furthermore, the PD effect of 
MCS110 when combined with carboplatin/gemcitabine will also be characterized by assessing 
the total CSF-1 circulating levels, serum CTX-1 and circulating monocytes in blood. Both 
summary statistics and listings will be produced. 
2.10.4.3.3 
Advanced analysis methods 
A logistic regression model will be used to determine whether the baseline mutation status (e.g. 
BRCA), protein expression levels (e.g. S-CSF-1 levels), cell content (e.g. TAM levels, TIL 
levels) are potentially correlated with clinical response to the combination of MCS110 and 
carboplatin/gemcitabine. Kaplan-Meier estimates of PFS by mutational status and treatment 
will also be produced. 
2.11 
Other Exploratory analyses 
There are no other exploratory analyses planned. 
2.12 
Interim analysis 
When the first 9 patients randomized in the study have completed two cycles of treatment or 
discontinue earlier due to adverse event, Novartis and principal investigators will have a safety 
review meeting to review clinical, PK and laboratory data and to decide on the dose for study 
continuation (CSP Section 2.2 and Section 4.1). If the monitoring of the study data requires a 
decision to be taken on the continuation of the study, then the relevant data will be 
communicated to the Steering Committee (CSP Section 8.5). 


Novartis 
For business use only 
Page 26 
SAP 
 
CMCS110Z2201 
 
Outputs to be produced for the safety review has been identified in a separate RAP document 
(MCS110Z2201 Steering Committee Charter and Interim Analysis RAP). 
Efficacy and safety data will be reviewed on a regular basis as mentioned in CSP Section 
8.5. This data monitoring will not constitute a formal interim analysis of the primary endpoint 
since no decision to stop the study early will be taken following the review of this data. 
Analyses produced for this review will include: 
1. Analysis of primary efficacy endpoint 
2. The following safety summaries and listings: 
•  Treatment-emergent AEs regardless of study drug relationship 
• AEs leading to permanent discontinuation of study drug 
• AEs requiring dose adjustment or study drug interruption 
• SAEs regardless of study drug relationship 
3. Summaries of key baseline characteristics  
3 
Sample size calculation 
For this trial, information currently available coming from O’Shaughnessy 2011 for 
carboplatin/gemcitabine (see CSP Section 1.1) has been used in order to set up the criteria which 
will need to be satisfied to consider a clinically relevant efficacy of the MCS110 + 
carboplatin/gemcitabine combination treatment compared to the carboplatin/gemcitabine alone 
treatment. An estimation of at least 30% reduction in risk of PFS event with MCS110 + 
carboplatin/gemcitabine compared to 
the 
carboplatin/gemcitabine alone arm, 
or 
correspondingly, an estimated PFS HR ≤ 0.7 would be considered as clinically relevant. 
Besides, it would be considered as statistical significant if the upper bound of the one-sided 
90% CI of the HR is below 1. As mentioned in CSP Section 10.4.2, this double criteria will be 
used in order to conclude that there is clinical and statistical evidence of efficacy of the MCS110 
+ carbo/gem combination treatment compared to the carbo/gem alone treatment. 
Under the assumption that subject accrual (entry) occurs in the first 14 months, the study lasts 
for 22 months with an uniform accrual pattern across months (all periods equal) and the dropout 
rate with the assumption of censoring at time 0 being equal to 10%, it is estimated that a one-
sided logrank test with a type-1 error equal to 10%, with approximately 58 PFS events and an 
overall sample size of 78 patients (52 in the MCS110 + carboplatin/gemcitabine arm and 26 in 
the carboplatin/gemcitabine alone arm) achieves the results presented in the following Table 3-
1. 
Table 3-1 
True PFS hazard ratio and corresponding power 
True hazard ratio (Alternative hypothesis) 
Probability of concluding efficacy (power) 
0.4 
98% 
0.5 
90% 
0.6 
72% 
0.7 
50% 
1.0 
9% 
The analysis has been performed with PASS 2008 and R-project 2.13.2. 


Novartis 
For business use only 
Page 27 
SAP 
 
CMCS110Z2201 
 
4 
Change to protocol specified analyses 
 As a result, the primary objective, to assess the anti-tumor activity of MCS110 combined with 
carboplatin and gemcitabine (carbo/gem), will not be reached. Therefore, the formal hypothesis 
testing including estimation of HR and 90% credit interval will not be performed. Analysis of 
OS will be removed.
 
Only summary tables 
and listings of PK endpoints and biomarkers will be presented.  
The following section have been updated in comparison to first SAP 
Section 2.1.1 General definitions 
• Definition of on-treatment assessment/event 
Section 2.5 Analysis of the primary objective 
• Formal hypothesis testing of the primary objective will not be performed. HR and 90% 
credit interval will not be presented. Only K-M curve will be produced by treatment 
arms(MCS110 + carbo/gem VS. carbo/gem only). 
Section 2.6 Analysis of the key secondary objective 
• OS will not be analyzed due to removal of survival follow-up.  
Section 2.8 Safety analyses 
• Defintion of on-treatment period changed from including 90 days to 30 days after last 
dose in line with all other IO studies and reporting standards.  
  
 
 
 
Section 2.10 Biomarkers  
 
• 
 
 
• Advanced analysis such as logistic regression model will not be applied.  
Section 2.12 No interim analysis will be carried out.  
 
5 
Appendix 
5.1 
Baseline 
Baseline is the last available and valid assessment performed or value measured within 28 days 
before the first administration of study treatment, unless otherwise stated under the related 
assessment section. Baseline can be the day before first treatment administration or the same 


Novartis 
For business use only 
Page 28 
SAP 
 
CMCS110Z2201 
 
day as first treatment administration if a pre-dose assessment/value is available (e.g., ECG, PK 
samples, samples for biomarkers). 
If time is recorded for the first treatment dose and for a specific assessment performed the day 
of first dose, this assessment will be considered as baseline only if it is actually performed 
before the first dose, as checked using both times. 
If time is not recorded, a specific assessment performed the day of first dose administration will 
be considered as baseline if, according to protocol, it should be performed before the first dose. 
Patients with no data on a particular parameter before the first treatment administration will 
have a missing baseline for this parameter. 
Computation of baseline for ECG, biomarker and other endpoints are described in each specific 
section. 
5.2 
Handling of missing and partial dates 
For patients not known to have died prior to the cut-off date: 
All events (e.g. AEs and concomitant medications) that started before or on the cut-off date, 
and with end date missing or after the cut-off date will be reported as continuing at the cut-off 
date. For these events, the end date will not be imputed. 
For patients known to have died prior to or on the cut-off date: 
All events (e.g. AEs and concomitant medications) that started before or on the cut-off date, 
and with end date missing or after the cut-off date will have the end date imputed to the date of 
death. For these events, the imputed end date will not appear in the listings. 
If imputation of an end date is required for a specific analysis (e.g. a dose administration record 
with missing end date, or last date of study treatment is after the cut-off date), the end date will 
be imputed to the cut-off date in order to calculate e.g., the duration of exposure to study 
treatment. The imputed date will be displayed and flagged in the listings. 
5.3 
Construction of waterfall graphs 
Waterfall graphs will be used to depict anti-tumor activity. These plots will display the best 
percentage change from baseline in the sum of diameters of target lesions for each patient.  
Note: Patients without any valid assessments to calculate a percentage change from baseline 
value will be excluded from the graphs. Assessments with an unknown overall response will be 
included as long as the sum of diameters of target lesions is correctly computed on the same 
lesions assessed at baseline. 
Patients will be ordered in the graph from left (worst change) to right (best change). 
1. Bars above the horizontal axis (0%) representing tumor growth, 
2. Bars under the horizontal axis (0%) representing tumor shrinkage. 
A special symbol (e.g. ∗) will be added below the bottom of respective bars for confirmed 
RECIST response (CR or PR), with corresponding specificatons in footnote. The total number 
of patients displayed in the graph (n) over the total number of patients in the FAS (N) will be 


Novartis 
For business use only 
Page 29 
SAP 
 
CMCS110Z2201 
 
shown. The best overall response (BOR) will be shown above each of the displayed bars in the 
graph. Symbols will be used to differentiate groups of interest, i.e. study arm. A horizontal 
threshold line at -30% will be shown.  
5.4 
Imputation rules 
5.4.1 
Study drug 
Dose administration record with missing or partial dates are not acceptable, and should always 
be queried. The start and end dates for each DAR are expected to be the same. 
5.4.2 
AE date imputation 
A missing AE start date will be imputed using the following logic matrix described in Table 5-
1. 
Table 5-1 
Imputation rules for a partially missing AE start date 
 
AEM MISSING 
AEM < TRTM 
AEM = TRTM 
AEM > TRTM 
AEY MISSING 
No imputation 
No imputation 
No imputation 
No imputation 
AEY < TRTY 
(D) 
(C) 
(C) 
(C) 
AEY = TRTY 
(B) 
(C) 
(B) 
(A) 
AEY > TRTY 
(E) 
(A) 
(A) 
(A) 
AEM: Month AE started; AEY: Year AE started 
TRTM: Month treatment started; TRTY: Year treatment started 
Table 5-2 is the legend to the logic matrix shown in Table 5-1 and details the relationship of 
AE start date to study treatment start date. 
Table 5-2 
Imputation legend and AE/treatment start date relationship 
 
AE start date relationship 
Imputation 
(A) 
After treatment start or Uncertain 
01MONYYYY 
(B) 
Uncertain 
TRTSTD+1 
(C) 
Before treatment start 
15MONYYYY 
(D) 
Before treatment start 
01JULYYYY 
(E) 
After treatment start 
01JANYYYY 
Before treatment start: Partial date indicates AE start date is prior to treatment start date. 
After treatment start: Partial date indicates AE start date is after treatment start date. 
Uncertain: Partial date insufficient to determine relationship of AE start date to treatment start date. 
No imputation will be performed for AE end dates. 
5.4.3 
Medication/therapy date imputation 
5.4.3.1 
Prior antineoplastic therapy date imputation 
The imputation of a prior therapy start date will follow the same conventions as for an AE start 
date (see Section 5.4.2 AE date imputation), with the exception that scenario (B) will be 
replaced to be ‘Start date of study treatment – 1’. 


Novartis 
For business use only 
Page 30 
SAP 
 
CMCS110Z2201 
 
For missing end date imputation: 
Imputated date = min (start date of study treatment, last day of the month), if day is missing; 
Imputated date = min (start date of study treatment, 31DEC), if both month and day are missing. 
If the end date is not missing, and the imputated start date is after the end date, use the end date 
as the imputated start date. 
If both the start date and the end date are imputated and if the imputated start date is after the 
imputated end date, use the imputated end date as the imputation for the start date. 
5.4.3.2 
Concomitant medication date imputation 
The imputation of a concomitant medication start date will follow the same conventions as for 
an AE start date (see Section 5.4.2 AE date imputation). No imputation will be performed for 
concomitant medication end dates. 
5.4.3.3 
Post antineoplastic therapy date imputation 
Post therapies date imputation should not have to be considered. Any data entered in the eCRF 
pages are considered as starting after the last treatment, after being queried and verified. 
5.5 
Laboratory parameters derivations 
Serum creatinine clearance is derived according to the Cockcroft-Gault equation: (140-age 
(years)) × weight (kg) (× 1.04 if female) / (serum creatinine (umol/L)).  
Corrected Calcium (mg/dL) = 0.8 × (Normal Albumin (g/dL) – Albumin (g/dL)) + Serum 
Calcium (mg/dL), where normal albumin is 4 g/dL. 
5.6 
Statistical models 
5.6.1 
Primary analysis 
In the following, the statistical model and prior distributions for the Bayesian Cox proportional 
hazard (PH) model will be described. We consider here the use of historical data of the same 
patient population to enrich the chemo arm (Arm 2). 
5.6.1.1 
Model Specification 
The primary analysis of progression free survival (PFS) will be based on a Bayesian Cox PH 
model. This model will be used to estimate the hazard ratio for PFS of Arm 1 vs. Arm 2. This 
model assumes that the hazard function of individual in Arm i (MCS110 + chemo or chemo 
only) can be expressed as 
                                                   𝜆𝜆𝑖𝑖(t) = λ0(𝑡𝑡)𝑒𝑒𝛽𝛽𝑋𝑋𝑖𝑖         
Here λ0(𝑡𝑡) is the baseline hazard (or hazard for chemo arm), 𝑋𝑋𝑖𝑖 indicates the treatment arm 
membership (0 for chemo and 1 for MCS110 + chemo) and β denotes the log hazard ratio (HR) 
between MCS110+chemo arm and the chemo arm. Furthermore baseline or chemo arm hazard 
function λ0(𝑡𝑡) is modeled via a piece-wise exponential model. This is a semi-parametric model 


Novartis 
For business use only 
Page 31 
SAP 
 
CMCS110Z2201 
 
which subdivides time into reasonably small K intervals and assumes that the baseline hazard 
is constant in each interval. i.e.,  
 
                                                                                         for 
Note that the λCk refers to hazard for unit time (per day). Sampling model (or likelihood) under 
this framework can be constructed using Poisson distribution. In this model for each of the K 
time intervals, the number of events in the chemo arm (rCk) and MCS110+chemo arm (rTk) 
follow Poisson distributions with interval-specific hazards λCk. Under the proportional hazards 
assumption it follows that  
 
Chemo data:    
 
rCk ~ ~ Poisson(eCk λCk), 
 
MCS110+chemo data: 
rTk  ~ Poisson(eTk eβ λCk), 
where eCk and eTk are risk sets for event in the chemo and MCS110+chemo arm, respectively, 
in interval 
]
,
(
1
k
k
I
I −
 and Lk is the length of the k-th interval.  
The study plans to enroll approximately 78 patients to accrue 58 events for the primary  analysis 
of PFS endpoint. This study will be considered successful if there is sufficient evidence that the 
combination of MCS110 with chemotherapy is superior to chemotherapy only in PFS based on 
the evaluation criteria, i.e.: 
• Posterior probability (HR >1) < 10%, and 
• Posterior median HR ≤ 0.7. 
5.6.1.2 
Prior distribution 
The Bayesian approach requires the specification of prior distributions for the model 
parameters. In this section we illustrate the specification of weakly informative prior for interval 
specific hazards (λk’s) using relevant data for chemo arm from publications and non-informative 
prior for log hazard ratio (β). 
5.6.1.2.1 Prior for Log Hazard Ratio (β)   
The prior distribution for the log hazard ratio β was assumed non-informative, β ~ N(mean=0, 
sd=10). 
5.6.1.2.2 Prior Derivation for Interval Specific Hazard (λk ‘s) 
A weakly informative prior for log(λCk)  as N(mean = -1.892569, sd = 5) will be used for 
interval specific hazards (λk‘s) to reflect the historical hazard rate for the chemo arm but 
allowing for considerable prior uncertainty to handle possible prior-data conflict to the chemo 
arm in the current trial. 
5.6.2 
Operating Characteristics 
The purpose of this section is to present the operating characteristics of the proposed design 
under various scenarios. The data for the chemo arm are simulated such that for some scenarios 
they are in alignment with the historical control data and for the others, they are not. Different 
]
,
(
   
)
(
1
0
k
k
ck
I
I
t
t
−
∈
= λ
λ
K
k
,.....,
2,1
=


Novartis 
For business use only 
Page 32 
SAP 
 
CMCS110Z2201 
 
magnitudes of efficacy are also considered, e.g, no efficacy, moderate efficacy and substantial 
efficacy under different scenarios. Type I error rate and power for this design under different 
scenarios will be investigated as mentioned in detail in the next section. 
5.6.2.1 Scenarios investigated 
In order to investigate the operating characteristics, data are simulated under the scenarios as 
described in Table 5-3. 
Table 5-3 
Different Scenarios of Operating Characteristics simulations 
Scenario# 
Current control 
aligned with prior? 
Efficacy 
Magnitude 
Median PFS, 
chemo arm 
(months) 
Median PFS, 
MCS110+chemo 
arm (months) 
True  
Hazard Ratio 
1 
Yes 
No efficacy 
4.6 
4.6 
1 
2 
Yes 
Substantial 
4.6 
9.2 
0.5 
3 
Yes 
Moderate  
4.6 
6.6 
0.7 
4 
No 
No efficacy 
6 
6 
1 
5 
No 
Substantial  
6 
12 
0.5 
6 
No 
Moderate 
6 
8.6 
0.7 
As shown in the Table 5-3, chemo data are simulated to be aligned with the prior for scenarios 
1-3. Different magnitudes of efficacy will be tested in these three scenarios by varying the true 
hazard ratio. For scenario 1, hazard ratio 1 means that there is no efficacy. The simulation output 
in this case provides Type I error rate. For the other two scenarios, powers are obtained.  
Similarly for scenarios 4-6, chemo data not aligned with prior are simulated and scenario 4 is 
the case with no efficacy where the simulation result provides Type I error rate. 
5.6.2.2 Simulation study description 
Each of the above described scenarios is investigated based on simulated data over 1000 trials. 
The following assumptions are made in order to run these simulations: 
1. The time to event (PD or death), censoring time and accrual time are all assumed to follow 
exponential distribution. For all the above scenarios the accrual is assumed to be 6 patients 
per month. 
2. The End of Study is assumed to be on the day of the 58th event.  
Simulation is performed in the following steps: 
Step 1:  
Based on the assumed distributions of time to event and accrual time, PFS data are simulated 
for patients in the MCS110+chemo arm and chemo arm (randomization ratio 2:1) sequentially 
until the required number of events (58 events) is reached. 
Step 2:  
The simulated data is then transformed as the number of patients at risk and number of events 
in different time intervals for each treatment arm similar to historical data. But the total number 
of interval in the simulation depends on maximum event/censored time.  


Novartis 
For business use only 
Page 33 
SAP 
 
CMCS110Z2201 
 
Step 3:  
As mathematical closed form are not tractable, hence, posterior distributions for the log(HR) 
from Bayesian Cox PH model are computed via MCMC combining the weakly informative 
prior with the simulated transformed data.  
Step 4:  
Claim positive result for the Bayesian method if {Posterior median HR ≤ 0.7 and posterior 
Prob(HR>1)  <  0.1}. 
Step 5:  
Repeat step 1-4 for 1000 trials. Calculate the rate of positive results. 
5.6.2.3 Simulation study results 
Table 5-4 shows the operating characteristics for the six scenarios. 
Table 5-4 
Operating characteristics for the six scenarios 
Scenario 
Median PFS 
chemo arm 
(months) 
Median PFS 
MCS110+chemo 
arm 
(months) 
HR 
Type I error/ 
Power 
Estimated HR 
1 
4.6 
4.6 
1 
0.089 
1.056 
2 
4.6 
9.2 
0.5 
0.878 
0.531 
3 
4.6 
6.6 
0.7 
0.465 
0.742 
4 
6 
6 
1 
0.088 
1.051 
5 
6 
12 
0.5 
0.886 
0.522 
6 
6 
8.6 
0.7 
0.497 
0.736 
Results from Table 5-4 show that the Bayesian Cox PH model using weakly informative prior 
yields reasonable 1-sided type I error (0.088-0.089) and power (0.465-0.886) under different 
scenarios in alignment between current and historical data. 
5.7 
Rule of exclusion criteria of analysis sets 
The rules for subject classification in the analysis sets (FAS, Safety, PPS, and PAS) based on 
protocol deviation specifications (Table 5-5) and non-protocol deviation classification criteria 
(Table 5-6), are described below. 
Table 5-5 
Protocol deviations that cause subjects to be excluded 
Deviation 
ID 
Description of Deviation 
Exclusion from 
Analysis Set 
INCL02 
Patient must have histological or cytological evidence of 
estrogen-receptor negative (ER-), progesterone receptor negative 
(PgR-) and human epidermal growth factor-2 receptor negative 
PPS 


Novartis 
For business use only 
Page 34 
SAP 
 
CMCS110Z2201 
 
Deviation 
ID 
Description of Deviation 
Exclusion from 
Analysis Set 
(HER2-) BC by local laboratory testing, based on last available 
tumor tissue. 
INCL03 
Patient must provide a pre-treatment tumor biopsy demonstrating 
high TAM content  as assessed per the central laboratory  
(approximately  15% of TAMs or above) (under PA1) 
PPS 
INCL05 
Patient must have at least one measurable lesion per RECIST 1.1 
( including lytic or mixed bone lesions with an identifiable soft 
tissue component that meets the measurability criteria) or non-
measurable bone lesions in the absence of measurable disease. 
PPS 
INCL09 
Patient must provide a pre-treatment tumor biopsy demonstrating 
high TAM content  as assessed per the central laboratory (under 
PA 2) 
PPS 
EXCL07 
Patient must not receive concomitant immunosuppressive agents 
or chronic corticosteroids (≥10 mg of prednisone or equivalent) 
at the time of first dose of study drug.  
PPS 
EXCL18 
Patient must not participate in parallel investigational drug or 
device studies. 
PPS 
EXCL24 
Patient must not have had a prior chemotherapy ( given for ≥ 21 
days) for advanced BC- and patients must not have had a prior 
chemotherapy with carboplatin, cisplatin or gemcitabine in the 
adjuvant or neoadjuvant setting if less then 12 months have 
passed since the last administration (under PA 2) 
PPS 
COMD01 
Patient received another anticancer or investigational treatment 
while on study treatment. 
PPS 
COMD02 
Patient received concomitant chronic corticosteroids (≥10 mg 
of prednisone or equivalent) while on study. 
PPS 
COMD03 
Patient received other biologics ( (eg: antibodies and proteins) or 
immunosuppressive medication while on study. 
PPS 
TRT01 
Misrandomization: Patient received investigational treatment 
which was different from the one assigned by the randomization 
system  
PPS 
OTH03 
Method used to evaluate lesions has changed from baseline 
method 
PPS 
OTH05 
Patient with no PK sample collected 
PAS 
 
Table 5-6 
Subject Classification 
Non-PD criteria that cause subjects to be excluded 
Exclusion from 
Analysis Set 
No informed consent 
Not randomized 
FAS 
No informed consent 
Not randomized 
Safety Set 


Novartis 
For business use only 
Page 35 
SAP 
 
CMCS110Z2201 
 
Non-PD criteria that cause subjects to be excluded 
Exclusion from 
Analysis Set 
No study treatment taken 
No valid post-baseline safety assessment 
Not in FAS 
No adequate tumor assessment at baseline 
No follow-up tumor assessment ≥6 weeks after starting treatment nor 
PD < 6 weeks 
PPS 
No evaluable PK data 
PAS 
6 
Reference 
O’Shaughnessy J, Osborne C, Pippen J (2011) Iniparib plus Chemotherapy in Metastatic 
Triple-Negative Breast Cancer. N Engl J Med 364:205-14 
 


Clinical Development 
MCS110 
CMCS110Z2201 / NCT02435680
A randomized phase II study of MCS110 combined with 
carboplatin and gemcitabine in advanced Triple Negative 
Breast Cancer (TNBC) 
Statistical Analysis Plan (SAP) 
Author: 
Trial Statistician, 
 
Document type: 
SAP Documentation 
Document status: 
Final 
Release date: 
20-March-2020
Number of pages: 
18 
Property of Novartis 
For business use only 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


Novartis 
For business use only 
Page 2 
SAP 
 
CMCS110Z2201 
 
 
Document History – Changes compared to previous final version of SAP 
 
Date 
Time point 
Reason for update 
Outcome for 
update 
Section and title 
impacted (Current) 
20-
March-
2020 
Prior to final 
DB lock 
Creation of final 
version 
N/A – First version NA 
 
 
 


Novartis 
For business use only 
Page 3 
SAP 
 
CMCS110Z2201 
 
Table of contents 
 
 
Table of contents ..........................................................................................................3 
List of abbreviations .....................................................................................................5 
Introduction ..................................................................................................................7 
1.1 
Study design ......................................................................................................7 
1.2 
Study objectives and endpoints...........................................................................7 
2 
Statistical methods ........................................................................................................7 
2.1 
Data analysis general information.......................................................................7 
2.1.1 
General definitions .............................................................................7 
2.2 
Analysis Set.......................................................................................................8 
2.3 
Patient Disposition , Demographics and Other Baseline Characteristics ...............8 
2.3.1 
Patient disposition ..............................................................................8 
2.3.2 
Basic demographic and background data .............................................8 
2.3.3 
Medical History .................................................................................8 
2.3.4 
Prior antineoplastic therapy ................................................................9 
2.3.5 
Diagnosis and extent of cancer............................................................9 
2.3.6 
Protocol deviations .............................................................................9 
2.4 
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance) .......................................................................................................9 
2.4.1 
Study treatment / compliance ..............................................................9 
2.4.2 
Prior, concomitant and post therapies ..................................................9 
2.5 
Analysis of the primary objective .......................................................................9 
2.5.1 
Primary endpoint................................................................................9 
2.5.2 
Statistical hypothesis, model, and method of analysis ........................10 
2.5.3 
Handling of missing values/censoring/discontinuations .....................10 
2.5.4 
Supportive analyses ..........................................................................10 
2.6 
Analysis of the key secondary objective ...........................................................10 
2.7 
Analysis of secondary efficacy objective(s) ......................................................10 
2.8 
Safety analyses ................................................................................................10 
2.8.1 
Adverse events (AEs) .......................................................................10 
2.8.2 
Deaths .............................................................................................11 
2.8.3 
Laboratory data ................................................................................11 
2.8.4 
Other safety data ..............................................................................12 
2.9 
Pharmacokinetic analysis .................................................................................12 
2.10 
Biomarkers ......................................................................................................12 
2.11 
Exploratory analyses ........................................................................................12 
2.12 
Interim analysis ...............................................................................................12 


Novartis 
For business use only 
Page 4 
SAP 
 
CMCS110Z2201 
 
3 
Sample size calculation ...............................................................................................12 
4 
Change to protocol specified analyses – CSR Section 9.8.3 ..........................................12 
5 
Appendix....................................................................................................................12 
5.1 
Baseline ..........................................................................................................12 
5.2 
Handling of missing and partial dates ...............................................................13 
5.3 
Construction of waterfall graphs.......................................................................13 
5.4 
Imputation rules...............................................................................................14 
5.4.1 
Study drug .......................................................................................14 
5.4.2 
AE date imputation...........................................................................14 
5.4.3 
Medication/therapy date imputation ..................................................14 
5.5 
Laboratory parameters derivations....................................................................15 
5.6 
Statistical models .............................................................................................15 
5.6.1 
Primary analysis ...............................................................................15 
5.6.2 
Operating Characteristics..................................................................16 
6 
Reference ...................................................................................................................18 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Novartis 
For business use only 
Page 5 
SAP 
 
CMCS110Z2201 
 
List of abbreviations 
AE 
Adverse event 
ALT 
Alanine aminotransferase/glutamic pyruvic transaminase/GPT 
AST 
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT 
ATC 
Anatomical Therapeutic Classification 
AUC 
Area Under the Curve 
BDM 
Biometrics and Data Management 
CR 
Complete response 
CRO 
Contract Research Organization 
CSF-1 
Colony stimulation factor – 1, also called M-CSF 
CSP 
Clinical study protocol 
CSR 
Clinical study report 
CTC 
Common Toxicity Criteria 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTX-I 
C-terminal telopeptide of type I collagen, a bone reabsorption marker 
DAR 
Dose administration record 
DBL 
Database lock 
DI 
Dose intensity 
DMC 
Data Monitoring Committee  
DOR 
Duration of response 
DRI 
Drug reference listing 
ECG 
Electrocardiogram 
FAS 
Full Analysis Set 
eCRF 
Electronic Case Report Form 
HR 
Hazard ratio 
IHC 
Immunohistochemistry 
INR 
International normalized ratio 
LLN 
Lower Limit of Normal 
LLOQ 
Lower limit of quantificaton 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI 
National Cancer Institute 
ORR 
Overall respolnse rate 
OS 
Overall Survival 
PD 
Pharmacodynamics 
PDI 
Planned dose intensity 
PDS 
Programming Datasets Specifications 
PFS 
Progression-Free Survival 
PK 
Pharmacokinetics 
PPS 
Per-Protocol Set 
PR 
Partial response 
PRO 
Patient-reported Outcomes 
QoL 
Quality of Life 
RAP 
Report and Analysis Process 


Novartis 
For business use only 
Page 6 
SAP 
 
CMCS110Z2201 
 
RDI 
Relative Dose Intensity 
RECIST 
Response Evaluation Criteria in Solid Tumors  
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Stable disease 
SGOT 
Serum glutamic oxaloacetic transaminase 
SGPT 
Serum glutamic pyruvic transaminase 
SI 
International System of Units 
SOC 
System Organ Class 
SSD 
Study specification document 
TAM 
Tumor-associated macrophages 
TFLs 
Tables, Figures, Listings 
TIL 
Tumor-infiltrating lymphocytes 
TNBC 
Triple Negative Breast Cancer 
ULN 
Upper Limit of Normal 
WHO 
World Health Organization 
 


Novartis 
For business use only 
Page 7 
SAP 
 
CMCS110Z2201 
 
Introduction 
This Statistical Analysis Plan (SAP) provides detailed statistical methodology for the analysis 
of data from study CMCS110Z2201 that will be presented in the final Clinical Study Report 
(CSR). The output shells (in-text and post-text) accompanying this document can be found in 
the Tables, Figures and Listings (TFL) shells document. The specifications for derived variable 
and datasets can be found in the Programming Datasets Specifications (PDS) document. This 
version of the SAP is based on the Protocol Amendment 6. The final CSR will be written after 
the final database lock.  
The statistical analyses which are covered in the SAP for the primary CSR are not repeated 
within this document. Refer to the folloing documents stored in CREDI. 
/CREDI Projects/M/MCS110Z/CREDI Studies/MCS110Z2201/Administrative Files (study 
level)/RAP or RAMP Meeting - CMCS110Z2201_SAP_CSR_1_primary_final.docx 
https://webedi02.na.novartis.net:8443/webEDI02_non_SSO/drl/objectId/090095a88e6b01c2 
All changes to the planned analysis described in this document required before or after database 
lock will be made through an amendment or addendum, respectively. Note that obvious 
corrections will be made at the time of analysis to address minor formatting or spelling mistakes 
present in the TFL shells document without the need to amend. 
The SAP, TFL shells and PDS documents may also serve as a reference for the creation of any 
outputs required outside of the CSR, e.g., PSUR/DSUR, MTD/RDE declaration, IB updates, 
abstracts, posters, presentations, manuscripts and management updates. Data used for these 
analyses will have a status aligned to the database lock guidance.  
1.1 
Study design 
See the primary CSR SAP.  
1.2 
Study objectives and endpoints 
See the primary CSR SAP.  
2 
Statistical methods 
2.1 
Data analysis general information 
See the primary CSR SAP.  
2.1.1 
General definitions  
See the primary CSR SAP.  
2.1.1.1 
Study drug and study treatment 
See the primary CSR SAP.  
 


Novartis 
For business use only 
Page 8 
SAP 
 
CMCS110Z2201 
 
2.1.1.2 
Date of first/last administration of study treatment 
See the primary CSR SAP.  
2.1.1.3 
Study day 
See the primary CSR SAP.  
2.1.1.4 
On-treatment assessment/event  
See the primary CSR SAP. 
2.2 
Analysis Set 
See the primary CSR SAP. 
2.3 
Patient Disposition , Demographics and Other Baseline 
Characteristics 
Unless noted otherwise, summaries and listings described in this section will be based on the 
FAS. 
2.3.1 
Patient disposition 
The following will be tabulated: 
• Number (%) of randomized patients who are treated and who are untreated,  
• Number (%) of patients who discontinued treatment (based on completion of the ‘End of 
Treatment’ page with discontinuation date and reason entered), 
• Primary reasons for study treatment discontinuation (based on discontinuation reason 
entered in the ‘End of Treatment’ page), 
• Number (%) of patients who discontinued from post-treatment follow-up (based on 
completion of the ‘End of Post Treatment Phase Disposition’ page with discontinuation 
date and reason entered), 
• Primary reasons for post-treatment follow-up discontinuation (based on discontinuation 
reason entered in the ‘End of Post Treatment Phase Disposition’ page). 
 
A listing of study completion by treatment will be produced using the FAS. Screen failures 
will not be included. 
2.3.2 
Basic demographic and background data 
Demographic data including age, predominant race, ethnicity, height, weight and ECOG 
performance status will be listed and summarized by study arm and treatment group. In addition, 
child bearing potential will be listed, and age (<65, 65-<85, ≥85 years) category summarized.  
 
2.3.3 
Medical History 
No analysis of medical history will be performed for the final CSR. 


Novartis 
For business use only 
Page 9 
SAP 
 
CMCS110Z2201 
 
2.3.4 
Prior antineoplastic therapy 
No analysis of prior antineoplastic theray will be performed for the final CSR. 
2.3.5 
Diagnosis and extent of cancer 
No analysis of diagnosis of the extent of cancer will be performed for the final CSR. 
2.3.6 
Protocol deviations 
No analysis of protocol deviation will be performed for the final CSR. 
2.4 
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance) 
The safety set will be used for all summaries and listings of study treatment.  
2.4.1 
Study treatment / compliance 
2.4.1.1 
Study treatment 
See the primary CSR SAP. 
The duration of exposure to each study drugs and study treatment (including categories: <=3, 
3-<=6, 6-<=9,  9-<=12, 12-<=15, 15-<=18 >18 weeks) will be summarized. In addition, the 
cumulative dose, DI, and RDI (including categories: <0.5, 0.5-<0.75, 0.75-<0.9, 0.9-<1.1, ≥1.1) 
will be summarized for each study drug. The number (%) of patients who have dose reductions 
and interruptions, and the corresponding reasons, will be provided for each study drug. The 
number of dose reductions and interruptions per patient will be summarized for each study drug. 
2.4.1.2 
Compliance 
Compliance to the study treatment within each study arm/treatment group will be assessed by 
the number of dose reductions, number of dose interruptions and percent of cycles received 
planned dose for all the study drugs separately in summary tables by study arm and treatment 
group for the safety set.  
2.4.2 
Prior, concomitant and post therapies 
No analysis of prior, concomitant and post therapies will be performed for the final CSR. 
2.5 
Analysis of the primary objective 
The primary objective is to assess the anti-tumor activity of MCS110 combined with 
carboplatin/gemcitabine compared to carboplatin/gemcitabine in adult patients with triple 
negative breast cancer.  
2.5.1 
Primary endpoint 
See the primary CSR SAP. 


Novartis 
For business use only 
Page 10 
SAP 
 
CMCS110Z2201 
 
2.5.2 
Statistical hypothesis, model, and method of analysis 
See the primary CSR SAP. 
For final CSR, Kaplan-Meier plots will be reproduced and summarized by treatment arm. No 
formal hypothesis testing will be carried out. A summary table based on Kaplan-Meier estimates 
of PFS by treatment arm will also be presented.  
2.5.3 
 Handling of missing values/censoring/discontinuations 
See the primary CSR SAP. 
2.5.4 
Supportive analyses 
No supportive analysis will be performed for the final CSR. 
2.6 
Analysis of the key secondary objective 
NA. 
2.7 
Analysis of secondary efficacy objective(s) 
See the primary CSR SAP.  
Duration of response will be summarized and presented by treatment arm using Kaplan-Meier 
estimates.  
2.8 
Safety analyses 
The Safety set will be used for summaries and listings of safety. 
2.8.1 
Adverse events (AEs) 
Adverse events will be coded using the Medical dictionary for regulatory activities (MedDRA, 
version 20.1 or later) and assessed according to the Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.03, respectively.  
The CTCAE represents a comprehensive grading system for reporting the acute and late effects 
of cancer treatments. CTCAE grading is by definition a 5-point scale generally corresponding 
to mild, moderate, severe, life threatening, and death. CTCAE Grade 5 (death) is not used in 
this study; rather, information about deaths is summarized in a separate analysis. This grading 
system inherently places a value on the importance of an event, although there is not necessarily 
proportionality among grades (a grade 2 is not necessarily twice as bad as a grade 1). 
AE Summaries  
AE summaries will include all AEs occurring during on-treatment period. All AEs collected in 
the AE (e)CRF page will be listed along with the information collected on those AEs e.g. AE 
relationship to study drug, AE outcome etc. AEs starting during the post-treatment period will 
be flagged in the listings.  
AEs will be summarized by number and percentage of patients having at least one AE, having 
at least one AE in each primary system organ class (SOC) and for each preferred term (PT) 


Novartis 
For business use only 
Page 11 
SAP 
 
CMCS110Z2201 
 
using MedDRA coding. A patient with multiple occurrences of an AE will be counted only 
once in the respective AE category. A patient with multiple CTCAE grades for the same 
preferred term will be summarized under the maximum CTCAE grade recorded for the event. 
AE with missing CTCAE grade will be included in the ‘All grades’ column of the summary 
tables.  
In AE summaries the primary system organ class will be presented alphabetically and the 
preferred terms will be sorted within primary SOC in descending frequency. The sort order for 
the preferred term will be based on their frequency of “All grades” column, as reported in the 
“All patients” column. 
The following summaries will be produced for all AEs starting or worsenining during the on-
treatment periods by treatment: AEs by SOC and/or PT, summarized by severity, relationship, 
seriousness and leading to treatment discontinuation 
EudraCT and clinicaltrials.gov requirements for AEs and Deaths summaries 
For the legal requirements of clinicaltrials.gov and EudraCT, two required tables on-treatment 
adverse events which are not serious adverse events with an incidence greater than 5% and on-
treatment SAEs and SAEs suspected to be related to study treatment will be provided by SOC 
and PT on the safety set population. 
If for a same Subject, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT: 
• a single occurrence will be counted if there is  ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE 
• more than one occurrence will be counted if there is > 1 day gap between the end date of 
the preceding AE and the start date of the consecutive AE 
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE. 
The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT. 
2.8.2 
Deaths  
Separate summaries for on-treatment and all deaths (including post-treatment death) will be 
produced by treatment, system organ class and preferred term.  
All deaths will be listed for the safety set, post treatment deaths will be flagged.  
2.8.3 
Laboratory data 
No analysis of laboratory data will be performed for the final CSR.  


Novartis 
For business use only 
Page 12 
SAP 
 
CMCS110Z2201 
 
2.8.4 
Other safety data 
2.8.4.1 
ECG and cardiac imaging data 
No ECG and cardiac imaging data will be analyzed for the final CSR. 
2.8.4.2 
Vital signs 
No vital signs data will be analyzed for the final CSR.  
2.9 
Pharmacokinetic analysis  
No pharmacokinetic data will be analyzed for the final CSR. 
2.10 
Biomarkers 
See the primary CSR SAP. 
Tables with descriptive statistics summarizing the TAM and TIL content, circulating CSF-1 
level and serum CTX-1 level, at baseline and post-baseline will be provided. Data will be listed 
by patient for TAM and TIL content, as well as circulating CSF-1 level and serum CTX-1 level. 
Safety set will be used for all summaries and listings.  
2.11 
Exploratory analyses 
No exploratory analyses will be executed for the final CSR.  
2.12 
Interim analysis 
See the primary CSR SAP. 
3 
Sample size calculation 
See the primary CSR SAP. 
4 
Change to protocol specified analyses – CSR Section 9.8.3  
For the final CSR, only limited demographic, disposition, exposure, efficacy, biomarker and 
safety data will be analysed.  
 
5 
Appendix 
5.1 
Baseline 
Baseline is the last available and valid assessment performed or value measured within 28 days 
before the first administration of study treatment, unless otherwise stated under the related 
assessment section. Baseline can be the day before first treatment administration or the same 
day as first treatment administration if a pre-dose assessment/value is available (e.g., ECG, PK 
samples, samples for biomarkers). 


Novartis 
For business use only 
Page 13 
SAP 
 
CMCS110Z2201 
 
If time is recorded for the first treatment dose and for a specific assessment performed the day 
of first dose, this assessment will be considered as baseline only if it is actually performed 
before the first dose, as checked using both times. 
If time is not recorded, a specific assessment performed the day of first dose administration will 
be considered as baseline if, according to protocol, it should be performed before the first dose. 
Patients with no data on a particular parameter before the first treatment administration will 
have a missing baseline for this parameter. 
Computation of baseline for ECG, biomarker and other endpoints are described in each specific 
section. 
5.2 
Handling of missing and partial dates 
For patients not known to have died prior to the cut-off date: 
All events (e.g. AEs and concomitant medications) that started before or on the cut-off date, 
and with end date missing or after the cut-off date will be reported as continuing at the cut-off 
date. For these events, the end date will not be imputed. 
For patients known to have died prior to or on the cut-off date: 
All events (e.g. AEs and concomitant medications) that started before or on the cut-off date, 
and with end date missing or after the cut-off date will have the end date imputed to the date of 
death. For these events, the imputed end date will not appear in the listings. 
If imputation of an end date is required for a specific analysis (e.g. a dose administration record 
with missing end date, or last date of study treatment is after the cut-off date), the end date will 
be imputed to the cut-off date in order to calculate e.g., the duration of exposure to study 
treatment. The imputed date will be displayed and flagged in the listings. 
5.3 
Construction of waterfall graphs 
Waterfall graphs will be used to depict anti-tumor activity. These plots will display the best 
percentage change from baseline in the sum of diameters of target lesions for each patient.  
Note: Patients without any valid assessments to calculate a percentage change from baseline 
value will be excluded from the graphs. Assessments with an unknown overall response will be 
included as long as the sum of diameters of target lesions is correctly computed on the same 
lesions assessed at baseline. 
Patients will be ordered in the graph from left (worst change) to right (best change). 
1. Bars above the horizontal axis (0%) representing tumor growth, 
2. Bars under the horizontal axis (0%) representing tumor shrinkage. 
A special symbol (e.g. ∗) will be added below the bottom of respective bars for confirmed 
RECIST response (CR or PR), with corresponding specificatons in footnote. The total number 
of patients displayed in the graph (n) over the total number of patients in the FAS (N) will be 
shown. The best overall response (BOR) will be shown above each of the displayed bars in the 
graph. Symbols will be used to differentiate groups of interest, i.e. study arm. A horizontal 
threshold line at -30% will be shown.  


Novartis 
For business use only 
Page 14 
SAP 
 
CMCS110Z2201 
 
5.4 
Imputation rules 
5.4.1 
Study drug 
Dose administration record with missing or partial dates are not acceptable, and should always 
be queried. The start and end dates for each DAR are expected to be the same. 
5.4.2 
AE date imputation 
A missing AE start date will be imputed using the following logic matrix described in Table 5-
1. 
Table 5-1 
Imputation rules for a partially missing AE start date 
 
AEM MISSING 
AEM < TRTM 
AEM = TRTM 
AEM > TRTM 
AEY MISSING 
No imputation 
No imputation 
No imputation 
No imputation 
AEY < TRTY 
(D) 
(C) 
(C) 
(C) 
AEY = TRTY 
(B) 
(C) 
(B) 
(A) 
AEY > TRTY 
(E) 
(A) 
(A) 
(A) 
AEM: Month AE started; AEY: Year AE started 
TRTM: Month treatment started; TRTY: Year treatment started 
Table 5-2 is the legend to the logic matrix shown in Table 5-1 and details the relationship of 
AE start date to study treatment start date. 
Table 5-2 
Imputation legend and AE/treatment start date relationship 
 
AE start date relationship 
Imputation 
(A) 
After treatment start or Uncertain 
01MONYYYY 
(B) 
Uncertain 
TRTSTD+1 
(C) 
Before treatment start 
15MONYYYY 
(D) 
Before treatment start 
01JULYYYY 
(E) 
After treatment start 
01JANYYYY 
Before treatment start: Partial date indicates AE start date is prior to treatment start date. 
After treatment start: Partial date indicates AE start date is after treatment start date. 
Uncertain: Partial date insufficient to determine relationship of AE start date to treatment start date. 
No imputation will be performed for AE end dates. 
5.4.3 
Medication/therapy date imputation 
5.4.3.1 
Prior antineoplastic therapy date imputation 
The imputation of a prior therapy start date will follow the same conventions as for an AE start 
date (see Section 5.4.2 AE date imputation), with the exception that scenario (B) will be 
replaced to be ‘Start date of study treatment – 1’. 
For missing end date imputation: 
Imputated date = min (start date of study treatment, last day of the month), if day is missing; 
Imputated date = min (start date of study treatment, 31DEC), if both month and day are missing. 


Novartis 
For business use only 
Page 15 
SAP 
 
CMCS110Z2201 
 
If the end date is not missing, and the imputated start date is after the end date, use the end date 
as the imputated start date. 
If both the start date and the end date are imputated and if the imputated start date is after the 
imputated end date, use the imputated end date as the imputation for the start date. 
5.4.3.2 
Concomitant medication date imputation 
The imputation of a concomitant medication start date will follow the same conventions as for 
an AE start date (see Section 5.4.2 AE date imputation). No imputation will be performed for 
concomitant medication end dates. 
5.4.3.3 
Post antineoplastic therapy date imputation 
Post therapies date imputation should not have to be considered. Any data entered in the eCRF 
pages are considered as starting after the last treatment, after being queried and verified. 
5.5 
Laboratory parameters derivations 
Serum creatinine clearance is derived according to the Cockcroft-Gault equation: (140-age 
(years)) × weight (kg) (× 1.04 if female) / (serum creatinine (umol/L)).  
Corrected Calcium (mg/dL) = 0.8 × (Normal Albumin (g/dL) – Albumin (g/dL)) + Serum 
Calcium (mg/dL), where normal albumin is 4 g/dL. 
5.6 
Statistical models 
5.6.1 
Primary analysis 
In the following, the statistical model and prior distributions for the Bayesian Cox proportional 
hazard (PH) model will be described. We consider here the use of historical data of the same 
patient population to enrich the chemo arm (Arm 2). 
5.6.1.1 
Model Specification 
The primary analysis of progression free survival (PFS) will be based on a Bayesian Cox PH 
model. This model will be used to estimate the hazard ratio for PFS of Arm 1 vs. Arm 2. This 
model assumes that the hazard function of individual in Arm i (MCS110 + chemo or chemo 
only) can be expressed as 
                                                   𝜆𝜆𝑖𝑖(t) = λ0(𝑡𝑡)𝑒𝑒𝛽𝛽𝑋𝑋𝑖𝑖         
Here λ0(𝑡𝑡) is the baseline hazard (or hazard for chemo arm), 𝑋𝑋𝑖𝑖 indicates the treatment arm 
membership (0 for chemo and 1 for MCS110 + chemo) and β denotes the log hazard ratio (HR) 
between MCS110+chemo arm and the chemo arm. Furthermore baseline or chemo arm hazard 
function λ0(𝑡𝑡) is modeled via a piece-wise exponential model. This is a semi-parametric model 
which subdivides time into reasonably small K intervals and assumes that the baseline hazard 
is constant in each interval. i.e.,  
 
                                                                                         for 
K
k
,.....,
2,1
=
]
,
(
   
)
(
1
0
k
k
ck
I
I
t
t
−
∈
= λ
λ


Novartis 
For business use only 
Page 16 
SAP 
 
CMCS110Z2201 
 
Note that the λCk refers to hazard for unit time (per day). Sampling model (or likelihood) under 
this framework can be constructed using Poisson distribution. In this model for each of the K 
time intervals, the number of events in the chemo arm (rCk) and MCS110+chemo arm (rTk) 
follow Poisson distributions with interval-specific hazards λCk. Under the proportional hazards 
assumption it follows that  
 
Chemo data:    
 
rCk ~ ~ Poisson(eCk λCk), 
 
MCS110+chemo data: 
rTk  ~ Poisson(eTk eβ λCk), 
where eCk and eTk are risk sets for event in the chemo and MCS110+chemo arm, respectively, 
in interval 
]
,
(
1
k
k
I
I −
 and Lk is the length of the k-th interval.  
The study plans to enroll approximately 78 patients to accrue 58 events for the primary  analysis 
of PFS endpoint. This study will be considered successful if there is sufficient evidence that the 
combination of MCS110 with chemotherapy is superior to chemotherapy only in PFS based on 
the evaluation criteria, i.e.: 
• Posterior probability (HR >1) < 10%, and 
• Posterior median HR ≤ 0.7. 
5.6.1.2 
Prior distribution 
The Bayesian approach requires the specification of prior distributions for the model parameters. 
In this section we illustrate the specification of weakly informative prior for interval specific 
hazards (λk’s) using relevant data for chemo arm from publications and non-informative prior 
for log hazard ratio (β). 
5.6.1.2.1 Prior for Log Hazard Ratio (β)   
The prior distribution for the log hazard ratio β was assumed non-informative, β ~ N(mean=0, 
sd=10). 
5.6.1.2.2 Prior Derivation for Interval Specific Hazard (λk ‘s) 
A weakly informative prior for log(λCk)  as N(mean = -1.892569, sd = 5) will be used for 
interval specific hazards (λk‘s) to reflect the historical hazard rate for the chemo arm but 
allowing for considerable prior uncertainty to handle possible prior-data conflict to the chemo 
arm in the current trial. 
5.6.2 
Operating Characteristics 
The purpose of this section is to present the operating characteristics of the proposed design 
under various scenarios. The data for the chemo arm are simulated such that for some scenarios 
they are in alignment with the historical control data and for the others, they are not. Different 
magnitudes of efficacy are also considered, e.g, no efficacy, moderate efficacy and substantial 
efficacy under different scenarios. Type I error rate and power for this design under different 
scenarios will be investigated as mentioned in detail in the next section. 


Novartis 
For business use only 
Page 17 
SAP 
 
CMCS110Z2201 
 
5.6.2.1 Scenarios investigated 
In order to investigate the operating characteristics, data are simulated under the scenarios as 
described in Table 5-3. 
Table 5-3 
Different Scenarios of Operating Characteristics simulations 
Scenario# 
Current control 
aligned with prior? 
Efficacy 
Magnitude 
Median PFS, 
chemo arm 
(months) 
Median PFS, 
MCS110+chemo 
arm (months) 
True  
Hazard Ratio 
1 
Yes 
No efficacy 
4.6 
4.6 
1 
2 
Yes 
Substantial 
4.6 
9.2 
0.5 
3 
Yes 
Moderate  
4.6 
6.6 
0.7 
4 
No 
No efficacy 
6 
6 
1 
5 
No 
Substantial  
6 
12 
0.5 
6 
No 
Moderate 
6 
8.6 
0.7 
As shown in the Table 5-3, chemo data are simulated to be aligned with the prior for scenarios 
1-3. Different magnitudes of efficacy will be tested in these three scenarios by varying the true 
hazard ratio. For scenario 1, hazard ratio 1 means that there is no efficacy. The simulation output 
in this case provides Type I error rate. For the other two scenarios, powers are obtained.  
Similarly for scenarios 4-6, chemo data not aligned with prior are simulated and scenario 4 is 
the case with no efficacy where the simulation result provides Type I error rate. 
5.6.2.2 Simulation study description 
Each of the above described scenarios is investigated based on simulated data over 1000 trials. 
The following assumptions are made in order to run these simulations: 
1. The time to event (PD or death), censoring time and accrual time are all assumed to follow 
exponential distribution. For all the above scenarios the accrual is assumed to be 6 patients 
per month. 
2. The End of Study is assumed to be on the day of the 58th event.  
Simulation is performed in the following steps: 
Step 1:  
Based on the assumed distributions of time to event and accrual time, PFS data are simulated 
for patients in the MCS110+chemo arm and chemo arm (randomization ratio 2:1) sequentially 
until the required number of events (58 events) is reached. 
Step 2:  
The simulated data is then transformed as the number of patients at risk and number of events 
in different time intervals for each treatment arm similar to historical data. But the total number 
of interval in the simulation depends on maximum event/censored time.  
Step 3:  
As mathematical closed form are not tractable, hence, posterior distributions for the log(HR) 
from Bayesian Cox PH model are computed via MCMC combining the weakly informative 
prior with the simulated transformed data.  


Novartis 
For business use only 
Page 18 
SAP 
 
CMCS110Z2201 
 
Step 4:  
Claim positive result for the Bayesian method if {Posterior median HR ≤ 0.7 and posterior 
Prob(HR>1)  <  0.1}. 
Step 5:  
Repeat step 1-4 for 1000 trials. Calculate the rate of positive results. 
5.6.2.3 Simulation study results 
Table 5-4 shows the operating characteristics for the six scenarios. 
Table 5-4 
Operating characteristics for the six scenarios 
Scenario 
Median PFS 
chemo arm 
(months) 
Median PFS 
MCS110+chemo 
arm 
(months) 
HR 
Type I error/ 
Power 
Estimated HR 
1 
4.6 
4.6 
1 
0.089 
1.056 
2 
4.6 
9.2 
0.5 
0.878 
0.531 
3 
4.6 
6.6 
0.7 
0.465 
0.742 
4 
6 
6 
1 
0.088 
1.051 
5 
6 
12 
0.5 
0.886 
0.522 
6 
6 
8.6 
0.7 
0.497 
0.736 
Results from Table 5-4 show that the Bayesian Cox PH model using weakly informative prior 
yields reasonable 1-sided type I error (0.088-0.089) and power (0.465-0.886) under different 
scenarios in alignment between current and historical data. 
6 
Reference 
O’Shaughnessy J, Osborne C, Pippen J (2011) Iniparib plus Chemotherapy in Metastatic 
Triple-Negative Breast Cancer. N Engl J Med 364:205-14