A Phase 1b/2, Open Label, Dose Escalation Study of Margetuximab in Combination With Pembrolizumab in Patients With Relapsed/Refractory Advanced HER2+ Gastroesophageal Junction or Gastric Cancer
Phase: PHASE1
Conditions: Gastric Cancer, Stomach Cancer, Esophageal Cancer
Sponsor: MacroGenics

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
C LI NI C A L T RI A L P R O T O C O L : C P -M G A H 2 2 -0 5  
P R O T O C O L A M E N D M E N T 6   
St u d y Title:  
A P hase 1 b/ 2, O pe n La bel, D ose Escalati o n St u d y of Mar get u xi ma b 
i n C o m bi nati o n wit h Pe m br oliz u ma b i n Patie nts wit h 
Rela pse d/ Refract or y A d va nce d H E R 2 + Gastr oes o p ha geal J u ncti o n or 
Gastric Ca ncer  
St u d y N u m ber:   
C P -M G A H 2 2 -0 5  
St u d y P h ase:    
P hase 1 b/ 2  
Pr o d uct N a me:    
Mar get u xi ma b i n c o m bi nati o n wit h pe m br oliz u ma b ( K E Y T R U D A
® ) 
Pr o d uct 
N u m ber:  
M G A H 2 2  
I N D N u m ber: 
 
I n dic ati o n:   
R ela pse d/refract or y a d va nce d, metastatic H E R 2 + gastr oes o p ha geal 
j u ncti o n ( G EJ) or gastric ca ncer ( G C) 
C o or di n ati n g 
Pri nci p al 
I n vesti g at or: 
 
 
  
 
 
S p o ns or:  
 
 
Macr o Ge nics, I nc.  
9 7 0 4 Me dical Ce nter Dri ve  
R oc k ville, M D 2 0 8 5 0  
U S A  
S p o ns or ’s 
Me dic al 
M o nit or:  
 
Macr o Ge nics, I nc.  
9 7 0 4 Me dical Ce nter Dri ve  
R oc k ville, M D 2 0 8 5 0  
U S A  
 
 
C o nfi de nti alit y St ate me nt  
T his d oc u me nt is c o nfi de ntial. It c o ntai ns pr o priet ar y i nf or mati o n of Macr o Ge nics, I nc. t h at 
ca n o nl y be use d f or t he p ur p ose of re vie wi n g or perf or mi n g t his st u d y. A n y use, vie wi n g or 
discl os ure of s uc h i nf or mati o n t hat is n ot a ut h orize d i n writi n g b y t he S p o ns or is strictl y 
pr o hi bite d.  
 
 
C o nfi d e nti al
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Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
 
C o nfi d e nti al
P a g e   
2   
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Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
T A B L E  O F C O N T E N T S  
S P O N S O R SI G N A T U R E S  ....................................................................................................... 9  
 
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N S O F  T E R M S  ...........................................1 1  
1  
S Y N O P SI S  .................................................................................................................. 1 6  
2  
B A C K G R O U N D I N F O R M A TI O N  ............................................................................ 3 2  
2. 1  
Disease Bac k gr o u n d ........................................................................................... 3 2  
2. 1. 1  
Gastr oes o p ha geal J u ncti o n Ca ncer a n d Gastric C a ncer  ........................... 3 2  
2. 1. 2  
H E R 2 + Gastr oes o p h a geal J u ncti o n Ca ncer or Gastric Ca ncer  ................ 3 2  
2. 2  
Bac k gr o u n d o n P D -1 .......................................................................................... 3 4  
2. 2. 1  
P D -1  ......................................................................................................... 3 4  
2. 3  
St u d y A ge nt Bac k gr o u n d  ................................................................................... 3 5  
2. 3. 1  
Mar get u xi ma b  .......................................................................................... 3 5  
2. 3. 1. 1  
Mar get u xi ma b Cli nical E x perie nce  ................................................ 3 5  
2. 3. 2  
Pe m br oliz u ma b Bac k gr o u n d a n d Cli nical Trials  ..................................... 3 7  
2. 3. 2. 1  
Safet y  .............................................................................................. 3 8  
2. 4  
Rati o nale f or C o m bi ni n g Mar get u xi ma b a n d Pe m br oliz u ma b  .......................... 3 9  
2. 5  
Rati o nale f or D ose Sel ecti o n  ............................................................................. 3 9  
2. 5. 1  
D ose Escalati o n P hase ( Part A)  ................................................................ 3 9  
2. 5. 1. 1  
Pe m br oliz u ma b ............................................................................... 3 9  
2. 5. 1. 2  
Mar g et u xi ma b ................................................................................ 4 0  
2. 5. 2  
C o h ort E x pa nsi o n P hase ( H E R 2 + G EJ/ G C a n d H E R 2 + 
G C -I H C3 +) ( Parts B –  C)  ........................................................................ 4 2  
3  
S T U D Y P U R P O S E A N D O B J E C TI V E S ................................................................... 4 3  
3. 1  
Pri mar y O bj ecti ves ............................................................................................. 4 3  
3. 2  
Sec o n d ar y O bj ecti ves ......................................................................................... 4 3  
3. 3  
E x pl orat or y O bjecti ves  ...................................................................................... 4 3  
4  
T RI A L D E SI G N  ......................................................................................................... 4 5  
4. 1  
O verall St u d y Desi g n a n d Pla n  .......................................................................... 4 5  
4. 1. 1  
Ge neral St u d y Desi g n  .............................................................................. 4 5  
4. 1. 2  
D ose Escalati o n P hase ( Part A)  ................................................................ 4 6  
4. 1. 3  
C o h ort E x pa nsi o n P hase  .......................................................................... 4 6  
4. 1. 3. 1  
C o h ort E x pa nsi o n P hase ( Part B)  ................................................... 4 6  
4. 1. 3. 2  
C o h ort E x pa nsi o n P hase ( Part C)  ................................................... 4 7  
4. 1. 4  
Efficac y F oll o w -u p Peri o d  ....................................................................... 4 7  
4. 2  
D ose Li miti n g To xicit y  ...................................................................................... 4 8  
4. 2. 1  
Defi niti o ns  ................................................................................................ 4 8  
4. 2. 2  
He mat ol o gi c D ose Li miti n g To xicit y  ...................................................... 4 8  
C o nfi d e nti al
P a g e   
3   
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Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
4. 2. 3  
N o n -He mat ol o gic D os e Li miti n g To xicit y  .............................................. 4 9  
4. 2. 4  
He patic N o n -He mat ol o gi c D ose Li miti n g To xicit y  ................................. 5 0  
4. 3  
D ose Escalati o n R ules ........................................................................................ 5 0  
4. 4  
R ules f or Treat me nt Disc o nti n uati o n  ................................................................. 5 1  
4. 5  
G ui deli nes f or D ose M o dificati o ns  .................................................................... 5 2  
4. 5. 1  
D ose Dela ys  ............................................................................................. 5 2  
4. 6  
Rati o nale f or St u d y Desi g n  ................................................................................ 5 3  
4. 7  
St u d y D urati o n  ................................................................................................... 5 3  
4. 7. 1  
Patie nt Accr ual  ......................................................................................... 5 3  
4. 7. 2  
Defi ni ti o n of E n d of Trial ........................................................................ 5 3  
5  
S E L E C TI O N A N D WI T H D R A W A L O F P A TI E N T S  ................................................ 5 4  
5. 1  
I n cl usi o n Criteria ............................................................................................... 5 4  
5. 2  
E xcl us i o n Criteria .............................................................................................. 5 6  
5. 3  
Wit h dra wal of Patie nt fr o m t he St u d y  ............................................................... 5 9  
5. 3. 1  
G ui deli nes f or St u d y Disc o nti n uati o n  ...................................................... 6 0  
6  
S T U D Y T R E A T M E N T S  ............................................................................................ 6 1  
6. 1  
Descri pti o n of Treat me nts a n d St u d y Dr u g a n d S u p plies  .................................. 6 1  
6. 1. 1  
Mar get u xi ma b  .......................................................................................... 6 1  
6. 1. 2  
Pe m br oli z u ma b ........................................................................................ 6 1  
6. 2  
Dr u g Pre parati o n  ................................................................................................ 6 2  
6. 2. 1  
Ge neral G ui deli nes a n d Preca uti o ns  ........................................................ 6 2  
6. 2. 2  
Pe m br oliz u ma b Pre parati o n  ..................................................................... 6 2  
6. 2. 3  
Mar get u xi ma b Pre parati o n  ....................................................................... 6 2  
6. 2. 4  
Place b o or C o ntr ol  ................................................................................... 6 2  
6. 3  
St u d y Dr u g A d mi nistrati o n  ................................................................................ 6 2  
6. 3. 1  
Pe m br oliz u ma b A d mi nistrati o n  ............................................................... 6 3  
6. 3. 2  
Mar get u xi ma b A d mi nistrati o n  ................................................................. 6 3  
6. 4  
Selecti o n a n d Ti mi n g of D ose f or Eac h Patie nt  ................................................. 6 3  
6. 5  
P ote ntial A d verse E ve nts a n d S u p p orti ve Care Meas ures  ................................. 6 3  
6. 5. 1  
I nf usi o n-Relate d Reacti o ns I ncl u di n g C yt o ki ne R elease 
S y n dr o me  ................................................................................................. 6 3  
6. 5. 1. 1  
Gra di n g of I nf usi o n Reacti o ns  ....................................................... 6 4  
6. 5. 1. 2  
Pre me dicati o ns a n d Pr o p h yla xis  .................................................... 6 4  
6. 5. 1. 3  
Ma na ge me nt of O bser ve d I nf usi o n Reacti o ns  ............................... 6 5  
6. 5. 2  
I m m u ne-Relate d A d verse E ve nts  ............................................................. 6 8  
6. 5. 2. 1  
Diarr hea or C olitis  .......................................................................... 6 9  
6. 5. 2. 2  
He patic To xicit y  ............................................................................. 7 0  
6. 5. 2. 2. 1  
Ele vati o ns i n Tra ns a mi nases  .......................................................... 7 0  
C o nfi d e nti al
P a g e   
4   
of   
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Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
6. 5. 2. 2. 2  
Ele vati o ns i n Total Bilir u bi n  .......................................................... 7 1  
6. 5. 2. 3  
P ne u m o nitis  .................................................................................... 7 2  
6. 5. 2. 4  
Der mat ol o gic To xicit y  .................................................................... 7 2  
6. 5. 2. 5  
Ne p hritis/ Re nal Fail ure  .................................................................. 7 3  
6. 5. 2. 6  
I m m u ne-Me diate d H y p o p h ysitis  .................................................... 7 4  
6. 5. 2. 7  
T h yr oi d To xicit y  ............................................................................. 7 4  
6. 5. 2. 8  
Ty p e 1 Dia betes Mellit us  ................................................................ 7 5  
6. 5. 2. 9  
Ot her I m m u ne -Rel ate d A Es  ........................................................... 7 5  
6. 5. 3  
Car di ot o xicities of S pecific I nterest  ......................................................... 7 6  
6. 5. 3. 1  
Decrease d Left Ve ntric ul ar Ejecti o n Fracti o n  ................................ 7 6  
6. 5. 3. 2  
M y ocar ditis ..................................................................................... 7 6  
6. 6  
Met h o d of Assi g ni n g Patie nts t o Treat me nt Gr o u ps  .......................................... 7 7  
6. 7  
Bli n di n g .............................................................................................................. 7 7  
6. 8  
C o nc o mita nt T hera p y  ......................................................................................... 7 7  
6. 9  
Restri cti o ns ........................................................................................................ 7 9  
6. 9. 1  
Pri or T hera p y  ........................................................................................... 7 9  
6. 9. 2  
Fl ui d a n d F o o d I nta ke  .............................................................................. 7 9  
6. 9. 3  
Patie nt Acti vit y Restricti o ns  .................................................................... 7 9  
6. 1 0  
Treat me nt C o m plia nce  ....................................................................................... 7 9  
6. 1 1  
Pac ka gi n g a n d La b eli n g  ..................................................................................... 7 9  
6. 1 1. 1  
Pe m br oliz u ma b  ........................................................................................ 7 9  
6. 1 1. 2  
Mar ge t u xi ma b .......................................................................................... 8 0  
6. 1 2  
St ora ge a n d Acc o u nt a bilit y  ................................................................................ 8 0  
6. 1 2. 1  
Pe m br oliz u ma b  ........................................................................................ 8 0  
6. 1 2. 2  
Mar ge t u xi ma b .......................................................................................... 8 0  
6. 1 2. 3  
Acc o u nti n g f or t he Materials  ................................................................... 8 0  
6. 1 3  
I n v esti gati o nal Pr o d uct Dis p ositi o n at E n d of St u d y ......................................... 8 1  
7  
S T U D Y P R O C E D U R E S  ............................................................................................ 8 2  
7. 1  
I nf or me d Co nse nt ............................................................................................... 8 2  
7. 2  
Me dical Hist or y  ................................................................................................. 8 2  
7. 3  
Pri or a n d C o nc o mita nt Me dicati o ns  .................................................................. 8 2  
7. 4  
P h ysical E x a mi nati o n ......................................................................................... 8 3  
7. 5  
Vital Si g ns  .......................................................................................................... 8 3  
7. 6  
Cli nical La b orat or y Tests  ................................................................................... 8 3  
7. 6. 1  
La b orat or y Para meters  ............................................................................. 8 4  
7. 6. 2  
Sa m ple C ollecti o n, St ora ge, a n d S hi p pi n g  .............................................. 8 5  
7. 7  
T u m or Bi o ps y S peci me ns  .................................................................................. 8 5  
7. 7. 1  
Sa m ples f or H E R 2 a n d P D -L 1 Testi n g  .................................................... 8 5  
C o nfi d e nti al
P a g e   
5   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
7. 7. 1. 1  
Arc hi val T u m or Bi o ps y S peci me ns ................................................ 8 5  
7. 7. 1. 2  
Ma n dat or y Baseli ne T u m or Bi o ps y a n d O pti o nal Fres h 
Paire d T u m or Bi o ps y S peci me ns  ................................................... 8 5  
7. 8  
Car diac E val u ati o ns  ........................................................................................... 8 6  
7. 8. 1  
1 2 -Lea d Electr ocar di o gra ms  .................................................................... 8 6  
7. 8. 2  
M ulti gate d Ac q uisiti o n Ve ntric ul o gra p h y Sca n ni n g a n d 
Ec h ocar di o gra p h y  .................................................................................... 8 8  
7. 9  
Safet y Assess me nts  ............................................................................................ 8 8  
7. 9. 1  
Criteria f or E val uati o n  ............................................................................. 8 8  
7. 9. 2  
A d verse E ve nt: Defi niti o ns  ...................................................................... 8 9  
7. 9. 2. 1  
A d verse E ve nt  ................................................................................ 8 9  
7. 9. 2. 2  
A d ve rse Dr u g Reacti o n .................................................................. 8 9  
7. 9. 2. 3  
A d verse E ve nt of S pecial I nterest  .................................................. 8 9  
7. 9. 2. 4  
Treat me nt E mer ge nt A d verse E ve nt  ............................................... 8 9  
7. 9. 2. 5  
Seri o us A d verse E ve nts  .................................................................. 9 0  
7. 9. 2. 6  
I m me diatel y R e p orta ble E ve nt ....................................................... 9 0  
7. 9. 3  
A d verse E ve nts of S peci al I nt erest  .......................................................... 9 1  
7. 9. 4  
Perf or mi n g A d verse E ve nt Assess me nts  .................................................. 9 2  
7. 9. 5  
Re p orti n g of A d verse E ve nts t o t he S p o ns or  ........................................... 9 3  
7. 9. 5. 1  
C ha n ges i n Cli nical La b orat or y Para m eters  ................................... 9 4  
7. 9. 5. 2  
O ver d ose ......................................................................................... 9 5  
7. 9. 5. 2. 1  
Pe m br oliz u ma b ............................................................................... 9 5  
7. 9. 5. 2. 2  
Mar get u xi ma b  ................................................................................ 9 5  
7. 9. 6  
N oti ficati o n t o t he S p o ns or of E ve nts Re q uiri n g I m me diate 
Re p orti n g  .................................................................................................. 9 6  
7. 9. 7  
E mer ge n c y U n bli n di n g  ............................................................................ 9 6  
7. 1 0  
Efficac y, I m m u n o ge nicit y, P har mac o ki n etic, a n d P har mac o d y na mic 
Assess me nts  ....................................................................................................... 9 6  
7. 1 0. 1  
Efficac y Assess me nts  ............................................................................... 9 6  
7. 1 0. 1 . 1 
Ra di ol o gic E val u ati o n: Treat me nt of Patie nts 
Acc or di n g t o Pri nci ples of I m m u ne -Relate d Res p o nse 
Criteria  ............................................................................................ 9 6  
7. 1 0. 1. 2  
O bjecti ve Res p o nse a n d Res p o nse D urati o n  .................................. 9 7  
7. 1 0. 1. 3  
Pr o gressi o n -Free S ur vi val ( P F S)  .................................................... 9 8  
7. 1 0. 1. 4  
O verall S ur vi val  ............................................................................. 9 8  
7. 1 0. 2  
Im m u n o ge nicit y  ....................................................................................... 9 8  
7. 1 0. 3  
P har mac o ki netics  ..................................................................................... 9 8  
7. 1 0. 4  
P har mac o d y na mics/ Bi o mar kers  .............................................................. 9 9  
7. 1 1  
Ot her St u d y Pr oce d ures  ................................................................................... 1 0 0  
C o nfi d e nti al
P a g e   
6   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
7. 1 1 . 1 
Ce ntral La b orat or y E val u ati o ns  ............................................................. 1 0 0  
7. 1 1. 2  
Sa m ple Rete nti o n a n d F urt her Testi n g  ................................................... 1 0 0  
7. 1 2  
A p pr o priate ness of Meas ure me nts  ................................................................... 1 0 1  
7. 1 2. 1  
Rati o nale f or Use of I m m u ne Res p o nse Criteria  ................................... 1 0 1  
8  
S T U D Y A C TI VI TI E S  ............................................................................................... 1 0 2  
8. 1  
Scree ni n g Peri o d  .............................................................................................. 1 0 2  
8. 2  
Re gistrati o n  ...................................................................................................... 1 0 2  
8. 3  
E n d of Treat me nt Visit  ..................................................................................... 1 0 2  
9  
P L A N N E D S T A TI S TI C A L M E T H O D S  .................................................................. 1 0 3  
9. 1  
Ge neral C o nsi derati o ns  .................................................................................... 1 0 3  
9. 2  
De ter mi nati o n of Sa m ple Size ......................................................................... 1 0 3  
9. 2. 1  
A nal ysis P o p ulati o ns  .............................................................................. 1 0 4  
9. 3  
De m o gra p hics a n d Baseli ne C haract eristics  .................................................... 1 0 5  
9. 4  
Safet y E n d p oi nt(s)  ........................................................................................... 1 0 5  
9. 4. 1  
A d ve rse E ve nts ...................................................................................... 1 0 5  
9. 4. 2  
La b orat or y Val ues  .................................................................................. 1 0 6  
9. 4. 3  
Ot her Safet y E n d p oi nts  .......................................................................... 1 0 6  
9. 5  
Efficac y E n d p oi nts  ........................................................................................... 1 0 6  
9. 6  
Ot her Ass ess me nts or A nal yses  ....................................................................... 1 0 7  
1 0  
Q U A LI T Y C O N T R O L A N D A S S U R A N C E  ........................................................... 1 0 8  
1 0. 1  
M o nit ori n g, A u diti n g a n d I ns p ecti o ns  ............................................................. 1 0 8  
1 0. 2  
Data C ollecti o n a n d Ma na ge me nt  .................................................................... 1 0 9  
1 1  
A D MI NI S T R A TI V E C O N SI D E R A TI O N S ...............................................................1 1 0  
1 1. 1  
I nstit uti o nal Re vie w B oar d (I R B) or I n de pe n de nt Et hics C o m mittee 
(I E C) A p pr o val..................................................................................................1 1 0  
1 1. 2  
Et hical C o n d uct of t he St u d y  ............................................................................ 1 1 1  
1 1. 3  
Patie nt I nf or mati o n a n d C o nse nt  ...................................................................... 1 1 1  
1 1. 4  
Patie nt C o nfi de ntialit y  ......................................................................................1 1 2  
1 1. 5  
Case Re p ort F or ms a n d St u d y Rec or ds  ............................................................1 1 2  
1 1. 6  
Access t o S o urce D oc u m e ntati o n  .....................................................................1 1 2  
1 1. 7  
Rete nti o n of Data  ..............................................................................................1 1 2  
1 1. 8  
Fi na ncial Discl os ur e ..........................................................................................1 1 3  
1 1. 9  
P u blicati o n a n d Discl os ure P olic y  ....................................................................1 1 3  
1 1. 1 0  
Disc o nti n uati o n of t he St u d y or St u d y Sites  .....................................................1 1 3  
1 1. 1 0. 1  
Disc o nti n uati o n of St u d y Sites  ................................................................1 1 3  
1 1. 1 0. 2  
Disc o nti n uati o n of t he St u d y  ..................................................................1 1 3  
1 1. 1 1  
I d e ntificati o n of t he C o or di nati n g Pri nci pal I n vesti gat or .................................1 1 4  
1 2  
R E F E R E N C E LI S T  ...................................................................................................1 1 5  
C o nfi d e nti al
P a g e   
7   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
 
LI S T O F T A B L E S   
Ta ble  1  
Mar get u xi ma b P har mac o ki netics at Stea d y State –  6 m g/ k g, 
1 0  m g/ k g, 1 5  m g/ k g, 1 8  m g/ k g –  C P -M G A H 2 2 -0 1  ..................................... 4 1  
Ta ble  2  
Mar get u xi ma b D ose Escalati o n C o h orts  ...................................................... 4 6  
Ta ble  3  
Pe m br oliz u ma b Pr o d uct Descri pti o ns  .......................................................... 6 1  
Ta ble  4  
Cli nical La b orat or y Tests  .............................................................................. 8 4  
Ta ble  5  
I m m u n o ge nicit y Bl o o d Sa m pli n g Sc he d ule ( Parts A, B, a n d C)  ................. 9 8  
Ta ble  6  
P har mac o ki netics Bl o o d Sa m pli n g Sc he d ule f or Mar get u xi ma b  ................. 9 9  
Ta ble  7  
Res p o nse Rates a n d 9 5 % C o nfi de nce I nter vals  ......................................... 1 0 4  
 
LI S T O F A P P E N DI C E S   
A P P E N DI X 1  
TI M E A N D E V E N T S S C H E D U L E: D O S E E S C A L A TI O N 
( P A R T A) 
A P P E N DI X 2  
TI M E A N D E V E N T S S C H E D U L E: C O H O R T E X P A N SI O N 
P H A S E ( P A R T S B –  C)  
A P P E N DI X 3  
T A B L E O F L A B O R A T O R Y T E S TI N G B L O O D V O L U M E S 
( D O S E E S C A L A TI O N P H AS E –  P A R T A)  
A P P E N DI X 4  
T A B L E O F L A B O R A T O R Y T E S TI N G B L O O D V O L U M E S 
( C O H O R T E X P A N SI O N P HA S E –  P A R T S B - C)  
A P P E N DI X 5  
C E N S O RI N G R U L E S F O R P F S  
A P P E N DI X 6  
E A S T E R N C O O P E R A TI V E O N C O L O G Y G R O U P ( E C O G ) 
P E R F O R M A N C E S T A T U S  
A P P E N DI X 7  
R E CI S T 1. 1 G UI D E LI N E S  
A P P E N DI X 8  
I M M U N E-R E L A T E D R E CI S T G UI D E LI N E S  
A P P E N DI X 9  
P RI N CI P A L I N V E S TI G A T O R ’S A G R E E M E N T  
 
C o nfi d e nti al
P a g e   
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Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
S P O N S O R SI G N A T U R E S   
St u d y Title:  
A P hase 1 b/ 2, O pe n La bel, D ose Escalati o n St u d y of 
Mar get u xi ma b i n C o m bi nati o n wit h Pe m br oliz u ma b i n Patie nts 
wit h  Rela pse d/ Refract or y A d va nce d H E R 2 + Gastr oes o p ha ge al 
J u ncti o n or Gastric Ca ncer 
St u d y N u m ber:    
C P -M G A H 2 2 -0 5  
 
T his cli nical st u d y pr ot oc ol has bee n a p pr o ve d b y t he S p o ns or:  
Si g ne d:  
See A p pe n de d Electr o nic Si g n at ure P a ge  
Date:  
 
 
 
Vice Presi de nt, Cli nical De vel o p me nt  
 
Macr o Ge nics, I nc.  
9 7 0 4 Me dical Ce nter Dri ve  
R oc k ville, M D 2 0 8 5 0  
 
 
   
 
Si g ne d:  
See A p pe n de d Electr o nic Si g n at ure P a ge  
Date:  
 
 
 
Direct or, Bi ostatistics  
 
Macr o Ge nics, I nc.  
9 7 0 4 Me dical Ce nter Dri ve  
R oc k ville, M D 2 0 8 5 0  
 
   
 
C o nfi d e nti al
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Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
C o nfi d e nti al
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Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N S O F  T E R M S                          
A D A  
A nti -dr u g a nti b o dies  
A D C C  
A nti b o d y -de pe n de nt cell -me diate d c yt ot o xicit y  
A D R  
A d verse dr u g reacti o n 
A E  
A d verse e ve nt  
A E SI  
A d verse e ve nt of s pecial i nterest  
A L B  
Al b u mi n  
A L K -P    
Al kali ne p h os p hatase  
A L T  
Ala ni ne a mi n otra nsferase ( S G P T)  
A N C  
A bs ol ute ne utr o p hil c o u nt  
A nti -C T L A -4    
C yt ot o xic T l y m p h oc yte ass ociate d pr otei n 4 a nti b o d y  
A nti -P D -1    
Pr o gra m me d cell deat h pr otei n 1 a nti b o d y  
A nti -P D -L 1    
Pr o gra m me d deat h li ga n d 1a nti b o d y  
A P T T  
Acti vate d partial t hr o m b o plasti n ti me  
A S T  
As partate a mi n otra nsferase ( S G O T)  
A U C  
Area u n der t he c ur ve  
B U N  
Bl o o d urea nitr o ge n  
° C 
De grees Celsi us  
Ca  
Calci u m  
C B C  
C o m plete bl o o d c o u nt  
C D R  
C o m pli me ntar y -deter mi ni n g re gi o n  
C F R  
C o de of Fe deral Re g ulati o ns  
C H F  
C o n gesti ve heart fail ure  
CI  
C o nfi de nce i nter val  
Cl  
C hl ori de  
C L  
Plas ma cleara nce  
C N S  
Ce ntral ner v o us s yste m  
c C R 
C o nfir me d c o m plete res p o nse  
C R  
C o m plete res p o nse  
C o nfi d e nti al
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Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
C R S  
C yt o ki ne release s y n dr o me  
C S R  
Cli nical st u d y re p ort  
C T  
C o m p ute d t o m o gra p h y  
C T C A E    
C o m m o n ter mi n ol o g y criteria f or a d verse e ve nts  
ct D N A 
Circ ulati n g T u m or D N A  
C T L A -4    
C yt ot o xic T l y m p h oc yte a nti ge n 4  
D B P  
Diast olic bl o o d press ure  
d L  
Deciliter  
D L T  
D ose -li miti n g t o xicit y 
D R A E  
Dr u g -relate d a d verse e ve nt 
E C G  
Electr ocar di o gra m  
E A P  
E x pa n de d access pr o gra m  
E C O G  
Easter n C o o perati ve O nc ol o g y Gr o u p  
e C R F 
Electr o nic case re p ort f or m  
E LI S A  
E nz y me -li n ke d i m m u n os or be nt assa y 
E OI  
E n d of I nf usi o n 
E U  
E ur o pea n U ni o n  
Fcγ R  
Fc ga m ma rece pt or  
F D A  
F o o d a n d Dr u g A d mi nistrati o n  
F F P E  
F or mali n -fi xe d paraffi n-e m be d de d 
FI S H  
Fl u oresce nce i n sit u h y bri dizati o n  
G C  
Gastric ca ncer  
G C P  
G o o d Cli nical Practice  
G EJ  
Gastr oes o p ha geal j u ncti o n ca ncer  
G L P  
G o o d La b orat or y Practice  
H C  
Hea v y c hai n  
h C G  
H u ma n c h ori o nic g o na d otr o pi n  
Hct  
He mat ocrit  
H E E N T    
Hea d, e yes, ears, t hr oat, nec k  
H g b  
He m o gl o bi n  
C o nfi d e nti al
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Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
HI P A A    
Healt h I ns ura nce P orta bilit y a n d Acc o u nta bilit y Act  
H P V  
H u ma n pa pill o ma vir us  
I B 
i n vesti gat or’s br oc h ure  
I C H 
I nter nati o nal C o nfere nce o n Har m o nisati o n 
I C F 
I nf or me d C o nse nt F or m 
I E C 
I n de pe n de nt Et hics C o m mittee 
I g 
I m m u n o gl o b uli n 
I H C 
I m m u n o hist oc he mistr y 
I L 
I nterle u ki n 
ir A E 
I m m u ne-relate d a d verse e ve nt 
ir C R 
I m m u ne-relate d c o m plete res p o nse 
ir P D 
I m m u ne-relate d pr o gressi ve disease 
ir P R 
I m m u ne-relate d partial res p o nse 
ir R C 
I m m u ne-relate d res p o nse criteria 
I R B 
I nstit uti o nal Re vie w B oar d 
I R E 
I m me diatel y Re p orta ble E ve nt 
I S H 
I n-sit u h y bri dizati o n 
I U D 
I ntra uteri ne de vice 
I V 
I ntra ve n o us 
K  
P otassi u m  
K g  
Kil o gra m  
L C  
Li g ht c hai n  
L D H  
Lactate de h y dr o ge nase  
L V E F  
Left ve ntric ular ejecti o n fracti o n  
M A D  
Ma xi m u m a d mi nistere d d ose  
mc g or µ g    
Micr o gra m  
M C H  
Mea n c or p usc ular he m o gl o bi n  
M C H C    
Mea n c or p usc ular he m o gl o bi n c o nce ntrati o n  
M C V  
Mea n c or p usc ular v ol u me  
Me d D R A    
Me dical Dicti o nar y f or Re g ulat or y Acti vities  
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Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
M g  
Milli gra m  
M H C  
Maj or hist oc o m pati bilit y class  
m L  
Milliliter  
M m  
Milli meter  
Msec  
Millisec o n d  
M RI  
Ma g netic res o na nce i ma gi n g  
M T D  
Ma xi m u m t olerate d d ose  
M U G A    
M ulti -gate d ac q uisiti o n 
Na  
S o di u m  
N CI  
Nati o nal Ca ncer I nstit ute  
N K  
Nat ural Killer  
N S AI D    
N o n -ster oi dal a nti-i nfla m mat or y dr u g 
N S C L C    
N o n -s mall cell l u n g ca ncer 
N Y H A  
Ne w Y or k Heart Ass ociati o n  
O R R  
O bjecti ve res p o nse rate  
O S  
O verall S ur vi val  
Pa p  
Pa pa nic ola o u  
P B M C  
Peri p heral bl o o d m o n o n uclear cells  
P C R  
P ol y merase c hai n reacti o n  
P D  
P har mac o d y na mics, or Pr o gressi ve Disease  
P D -1  
Pr o gra m me d cell deat h pr otei n 1  
P D -L 1  
Pr o gra m me d deat h li ga n d 1  
P F S  
Pr o gressi o n -free s ur vi val 
P K  
P har mac o ki netics  
P O  
Orall y  
P R  
Partial res p o nse  
P T  
Pr ot hr o m bi n ti me  
Q  
I nter-c o m part me nt cleara nce  
Q 3 W  
E ver y 3 wee ks  
Q W  
E ver y wee k  
C o nfi d e nti al
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Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
R A N K -L    
Rece pt or -acti vat or of n uclear fact or ka p pa B li ga n d  
R B C  
Re d bl o o d cell  
R E CI S T    
Res p o nse E val uati o n Criteria i n S oli d T u m ors  
R P 2 D  
Rec o m me n de d P hase 2 D ose  
S A E  
Seri o us a d verse e ve nt  
S B P  
S yst olic bl o o d press ure  
S C  
S u bc uta ne o us  
S C C H N    
S q ua m o us cell ca ncer of t he hea d a n d nec k  
S D  
Sta ble disease  
S G O T  
Ser u m gl uta mic o xal oacetic tra nsa mi nase  
S G P T  
Ser u m gl uta mic p yr u vic tra nsa mi nase  
S O C  
S yste m Or ga n Class  
T 1/ 2 α 
Distri b uti o n half -life 
T 1/ 2 β  
Ter mi nal half -life 
T 4  
T h yr o xi ne  
T C R  
T -cell rece pt or 
T E A E  
Treat me nt -e mer ge nt a d verse e ve nt  
Tre gs  
Re g ulat or y T -cells 
T S H  
T h yr oi d sti m ulati n g h or m o ne  
U L N  
U p per li mit of n or mal  
U S  
U nite d States  
U S P  
U nite d States P har mac o peia  
V c 
Ce ntral v ol u me  
V 1  
V ol u me of distri b uti o n of t he ce ntral c o m part me nt  
V p 
Peri p heral v ol u me  
V S S  
V ol u me of distri b uti o n at stea d y state  
W B C  
W hite bl o o d cell  
 
 
C o nfi d e nti al
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Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
1    
S Y N O P SI S   
S p o ns or:  Macr o Ge nics, I nc.  
I N D N u m ber:   
 
N a me of Fi nis he d Pr o d uct:  
Mar get u xi ma b ( M G A H 2 2)  
St u d y Title:  
A P hase 1 b/ 2, O pe n La bel, D ose Escalati o n St u d y of Mar get u xi ma b i n C o m bi nati o n wit h Pe m br oliz u ma b i n 
P atie nts wit h Rela pse d/ Refract or y A d va nce d H E R 2 + Gastr oes o p ha geal J u ncti o n or Gastri c Ca ncer.  
St u d y N u m b er:  
C P -M G A H 2 2 -0 5  
I n vesti g at or(s)/ Ce nters:  
T his st u d y will be e xec ute d at a p pr o xi matel y 2 9 i nstit uti o ns i n N ort h A merica a n d Asia e x p erie nce d i n 
ca ncer i m m u n ot hera p y a n d/ or t he c o n d uct of P hase 1 st u dies i n patie nts wit h gastr oes o p ha geal j u ncti o n 
( G EJ) or gastric ca ncer ( G C).  
St u d y P h ase:  P hase 1 b/ 2  
Pri m ar y O bjecti ves:   
T he pri mar y o bj ecti ves of t his st u d y are:  
  T o c haracterize t he safet y, t ol era bilit y, d ose -li miti n g t o xicities ( D L T), a n d ma xi m u m t olerate d 
d ose ( M T D) or ma xi m u m a d mi nistere d d ose ( M A D) (if n o M T D is defi ne d) of mar get u xi ma b 
w he n a d mi nistere d i ntra ve n o usl y (I V) e ver y 3 wee ks i n c o m bi nati o n wit h 2 0 0 m g 
pe m br oliz u ma b a d mi nistere d I V e ver y 3  wee ks t o patie nts wit h rela pse d/refract or y u nresecta ble 
l ocall y a d va nce d or metastatic H E R 2 + G EJ or gastric ca ncer ( G C).  
  T o i n vesti gate t he preli m i nar y a nti-t u m or acti vit y, as meas ur e d b y o bj ecti ve res p o nse rate 
( O R R) a n d res p o nse d urati o n, of mar get u xi ma b w he n a d mi nistere d I V e ver y 3 wee ks i n 
c o m bi nati o n wit h pe m br oliz u ma b a d mi nistere d I V e ver y 3 wee ks usi n g b ot h c o n ve nti o nal 
Res p o nse E val uati o n Cr iteria i n S oli d T u m ors ( R E CI S T) 1. 1 (A p pe n di x  7 ) a n d i m m u ne-relate d 
res p o nse criteria (ir R C) (A p pe n di x  8 ), i n patie nts t hat ha ve faile d first-li ne trast uz u ma b-
c o ntai ni n g re gi me ns . 
Sec o n d ar y O bjecti ves:   
Sec o n dar y o bj ecti ve of t his st u d y are:  
  T o i n vesti gate t he preli mi nar y effect o n o verall s ur vi val ( O S) a n d pr o gressi o n-free s ur vi val 
( P F S) of mar get u xi ma b a d mi nistere d I V e ver y 3 wee ks i n c o m bi nati o n wit h pe m br oliz u ma b 
a d mi nistere d I V e ver y 3 wee ks.  
  T o c haracterize t he p har mac o d y na mic ( P D) acti vit y of mar get u xi ma b w he n a d mi nistere d I V 
e ver y 3  wee ks i n c o m bi nati o n wit h pe m br oliz u ma b a d mi nist ere d I V e ver y 3 wee ks.  
  T o c haracterize t he p har mac o ki netics ( P K) a n d i m m u n o ge nicit y of mar get u xi ma b a d mi nistere d 
I V e ver y 3 wee ks i n c o m bi nati o n wit h pe m br oliz u ma b a d mi nistere d I V e ver y 3 wee ks.  
 
 
C o nfi d e nti al
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Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
St u d y Des i g n: 
Ge ner al St u dy Desi g n  
T his st u d y is a P hase 1 b/ 2, o pe n -la bel, d ose escalati o n a n d c o h ort e x pa nsi o n st u d y desi g ne d t o c haracterize 
t he safet y, t olera bilit y, P K, P D, i m m u n o ge nicit y, a n d preli mi nar y a ntit u m or acti vit y of mar get u xi ma b 
a d mi nistere d I V e ver y 3 wee ks i n c o m bi nati o n wit h pe m br oliz u ma b a d mi nistere d I V e ver y 3 wee ks i n 
patie nts wit h rela pse d/refract or y  u nresecta ble l ocall y a d va nc e d or metastatic H E R 2 + G EJ or gastric ca ncer  
( G C). 
T he st u d y c o nsists of a D ose Esc al ati o n P h ase  ( P art A) t o deter mi ne t he M T D or M A D (if n o M T D is 
defi ne d) of escalati n g d oses of mar get u xi ma b a d mi nistere d i n c o m bi nati o n wit h a fi xe d d ose of 2 0 0 m g 
pe m br oliz u ma b, f oll o we d b y a C o h ort E x p a nsi o n P h ase  ( P arts B -C ) t o f urt her defi ne safet y a n d i nitial 
efficac y of t he c o m bi nati o n wit h t he mar get u xi ma b d ose esta blis he d i n t he first p hase. As of A me n d me nt 2, 
u p t o a p pr o xi matel y 2 5 a d diti o nal patie nts wit h gastric ca nc er ( G C)  o nl y will be a d de d t o t he C o h ort 
E x pa nsi o n P hase  (P art C  - se e “ St u d y P o p ulati o n” bel o w). B ot h mar get u xi ma b  a n d pe m br oliz u ma b will be 
a d mi nistere d o nce e ver y 3 we e ks. B ot h a ge nts will be a d mi nistere d o n t he sa me da y, wit h pe m br oliz u ma b 
a d mi nistere d first, f oll o we d b y mar get u xi ma b. Eac h c ycle of t hera p y is defi ne d as 3 wee ks, i n w hic h 
mar get u xi ma b a n d pe m br oliz u ma b will be gi ve n o n Da y  1. T u m or assess me nts will be perf or me d e ver y 6 
wee ks (i.e., f oll o wi n g 2 c ycles of treat me nt [ pri or t o d osi n g f or C ycles 3, 5, 7, etc.]) f or t he first 6 m o nt hs o n 
treat me nt; t hereafter, t u m or assess me nts will be perf or me d e ver y 1 2 wee ks u ntil d oc u me nt e d pr o gressi o n, 
i nitiati o n of alter nati ve a nti-ca ncer t hera p y, l ost t o f oll o w -u p, wit h dra wal of i nf or me d c o nse nt, deat h, or e n d 
of st u d y.    
Ass u mi n g patie nts re mai n cli nicall y sta ble, ha ve n ot e x perie nce d i m m u ne -relate d pr o gressi ve disease (ir P D), 
a n d d o n ot e x perie nce u nacce pta ble t o xicit y t hat necessitates per ma ne nt disc o nti n uati o n of b ot h st u d y dr u gs, 
treat me nt wit h t he c o m bi nati o n ma y c o nti n ue f or u p t o 2 years. F oll o wi n g u p t o 2 years of c o m bi nati o n 
treat me nt, t hera p y will be disc o nti n ue d a n d patie nts will be f oll o we d i n Efficac y F oll o w-u p Peri o d.    
F or patie nts w h o are ot her wise cli nicall y sta ble b ut ha ve met c o n ve nti o nal criteria f or pr o gressi ve disease 
( P D), t hera p y ma y be c o nti n ue d at t he discreti o n of t he i n vesti gat or pe n di n g c o nfir mati o n of pr o gressi o n at 
t he ne xt sc he d ule d t u m or assess me nt. T his a p pr oac h all o ws f or li mite d treat me nt of patie nts be y o n d i nitial 
ra di o gra p hic d oc u me ntati o n of disease pr o gressi o n, ass u mi n g t hat patie nts are t olerati n g t hera p y a de q uatel y 
a n d re mai n ot her wise cli nicall y sta ble des pite t his i nitial ra di o gra p hic e vi de nce of disease pr o gressi o n, a n d 
t hat t he i n vesti gat or feels t he patie nt ma y still deri ve be nefit fr o m c o nti n uati o n of t hera p y.  
F or patie nts i n w h o m pr o gressi o n is c o nfir me d at t he ne xt sc he d ule d t u m or assess me nt, t he criteria f or ir P D 
will ha ve bee n met, a n d treat me nt wit h mar get u xi ma b a n d pe m br oliz u ma b s h o ul d be disc o nti n ue d. T he 
patie nt s h o ul d be re m o ve d fr o m st u d y partici pati o n after c o m pleti o n of pr ot oc ol -s pecifie d f oll o w-u p (see 
Secti o n  8. 3  a n d A p pe n di x  1 , a n d  A p pe n di x  2 ). 
F oll o wi n g t he last d ose of b ot h st u d y dr u gs,  eac h patie nt will be f oll o we d f or b ot h P F S a n d O S d uri n g a n  
Effic ac y F oll o w u p Peri o d .  
D ose Esc al ati o n P h ase  ( P art A): 
T he g oal of t he D ose Escalati o n P hase  ( Part A) is t o i nitiall y c haracterize t he safet y a n d t olera bilit y of 
mar get u xi ma b a n d pe m br oliz u ma b a d mi nistere d i n c o m bi nati o n, a n d m ore s pecificall y t o d escri be t he D L Ts 
f or eac h d ose le vel st u die d a n d t o defi ne t he M T D or M A D (if n o M T D is defi ne d) base d o n t he fre q ue nc y of 
t he occ urre nce of d ose-li miti n g t o xicities ( D L Ts) i n eac h c o h ort d uri n g t he D L T E v al u ati o n Peri o d . 
F or t he p ur p oses of g ui di n g de cisi o ns re gar di n g d ose escalati o n, t he D L T E v al u ati o n Peri o d  is defi ne d as 
t he ti me f oll o wi n g a d mi nistrati o n of the first d ose of pe m br oliz u ma b u p t o t he da y of t he sec o n d pla n ne d 
a d mi nistrati o n of pe m br oliz u ma b (i.e., 2 1 da ys f oll o wi n g first d ose of pe m br oliz u ma b –  t he e n d of C ycle 1). 
C o nfi d e nti al
P a g e   
1 7   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
Mar get u xi ma b will be e val uat e d i n t w o se q ue ntial escalati n g d oses, 1 0 m g/ k g a n d 1 5 m g/ k g, i n c o m bi nati o n 
wit h 2 0 0 m g pe m br oliz u ma b i n c o h orts of 3 t o 6 patie nts eac h. If it is deter mi ne d t hat t he M T D is e xcee de d 
i n t he first d ose c o h ort, a d ose de-escalati o n c o h ort t o e val uat e a l o wer d ose of mar get u xi ma b ( 6 m g/ k g) i n 
c o m bi nati o n wit h 2 0 0 m g pe m br oliz u ma b will be e nr olle d. T he d ose escalati o n sc he ma is o utli ne d bel o w:  
C o h ort  
M ar get u xi m a b D ose  
Pe m br oliz u m a b D ose  
C o h ort -1  a 
6 m g/ k g  
2 0 0 m g  
C o h ort 1  b  
1 0 m g/ k g  
2 0 0 m g  
C o h ort 2  
1 5 m g/ k g  
2 0 0 m g  
a  
T o be e val uate d o nl y if t he starti n g d ose is  deter mi ne d t o e xcee d t he M T D.  
b   Starti n g d ose le vel  
 
A n i nter me diate d ose of mar get u xi ma b ma y be e x pl ore d d uri n g t he d ose escalati o n p orti o n of t he st u d y, 
base d o n re vie w of c u m ulati ve safet y, efficac y, a n d/ or P K data o n res pecti ve ar ms a n d base d u p o n a gree me nt 
bet wee n i n vesti gat ors a n d S p o ns or. T he Re g ulat or y A ge ncies a n d I nstit uti o nal Re vie w B o ar ds 
(I R Bs)/I n de pe n de nt Et hics C o m mittees (I E Cs) will be n otifi e d of a n y a d diti o nal d ose le vel t o be e val uate d.  
C o h ort E x p a nsi o n P h ase  ( P art B): 
T he g oals f or t his e x pa nsi o n p orti o n of t he st u d y i ncl u de t he f oll o wi n g: 
1.  Pr o vi de a preli mi nar y assess me nt of t he a ntit u m or acti vit y of mar get u xi ma b i n c o m bi nati o n wit h 
pe m br oliz u ma b i n patie nts wit h rela pse d/refract or y u nresect a ble l ocall y a d va nce d or metastatic 
H E R 2 + G EJ or gastric ca ncer  ( G C) p ost -trast uz u ma b 
2.  F urt her c haracterize t he safet y of mar get u xi ma b at t he M T D ( or M A D) i n c o m bi nati o n wit h 
pe m br oliz u ma b; a n d  
3.  F urt her e val uate t he P K, P D, a n d i m m u n o ge nicit y of mar get u xi ma b i n c o m bi nati o n wit h 
pe m br oliz u ma b.  
 
C o h ort  E x p a nsi o n P h ase - G astric C a ncer  O nly ( P art C):  
T he g oals f or t h e e x pa nsi o n p orti o n of t he st u d y i ncl u de t he f oll o wi n g:  
1.  Pr o vi de a preli mi nar y assess me nt of t he a ntit u m or acti vit y of mar get u xi ma b i n c o m bi nati o n wit h 
pe m br oliz u ma b i n patie nts wit h rela pse d/ refract or y u nresect a ble l ocall y a d va nce d or metastatic 
H E R 2 + (3 + b y i m m u n o hist oc he mistr y [ I H C 3 +]) G C  o nl y (as defi ne d i n AJ C C Ca ncer Sta gi n g 
Ma n ual, 8 t h E diti o n) p ost -trast uz u ma b 
2.  F urt her c haracterize t he safet y of mar get u xi ma b at t he M T D ( or M A D) i n c o m bi nati o n wit h 
pe m br oliz u ma b; a n d  
3.  F urt her e val uate t he P K, P D, a n d i m m u n o ge nicit y of mar get u xi ma b i n c o m bi nati o n wit h 
pe m br oliz u ma b.  
 
Effic acy F oll o w -u p Peri o d:  
F oll o wi n g t he fi nal d ose of st u d y dr u g ( pe m br oliz u ma b or mar get u xi ma b, w hic he ver is last), eac h patie nt 
will be f oll o we d f or b ot h P F S a n d O S d uri n g a n  Effic ac y F oll o w u p Peri o d . D uri n g t his ti me, patie nts will 
u n der g o disease assess me nts a n d be f oll o we d at 1 2 -wee k i nt er vals f or m o nit ori n g of P F S  a n d o verall 
s ur vi val.  
C o nfi d e nti al
P a g e   
1 8   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
D ose Li miti n g T o xicit y:  
F or t he p ur p oses of safet y ma na ge me nt a n d defi ni n g D L Ts (li mite d t o C ycle 1 of t he D ose Escalati o n P hase 
[ P art A]), t he c o m bi nati o n of mar get u xi ma b a n d pe m br oliz u ma b will be treate d as o ne e ntit y d uri n g C ycle 1 
of t he D ose Esc al ati o n P h ase ( P art A) (i.e., t he D L T E v al u ati o n Peri o d ). If a D L T is c o nsi dere d relate d t o 
o ne of t he st u d y dr u gs d uri n g t his peri o d, a d mi nistrati o n of b ot h a ge nts will be st o p pe d. O ne e xce pti o n t o t his 
r ule will be i n t he circ u msta nc e i n w hic h a D L T occ urs d uri n g or i m me diatel y f oll o wi n g t he first 
pe m br oliz u ma b i nf usi o n a n d bef ore t he first mar get u xi ma b a d mi nistrati o n. I n t his case, t he t o xicit y will be 
attri b ute d t o pe m br oliz u ma b al o ne a n d will n ot c o u nt as a D L T of t he c o m bi nati o n of st u d y dr u gs a n d t he 
patie nt will be re place d b y a n ot h er patie nt i n t he d ose c o h ort.  
I n ge neral, f or patie nts w h o e x perie nce a n a d verse e ve nt ( A E) t hat ma y meet t he criteria f or a D L T, 
s u bse q ue nt a d mi nistrati o n of t he st u d y dr u gs s h o ul d be hel d pe n di n g ma na ge me nt a n d/ or res ol uti o n of t he 
e ve nt a n d assess me nt  of attri b uti o n t o t he st u d y dr u gs. Criteria f or s u bse q ue nt c o nti n uati o n of t hera p y are 
o utli ne d bel o w. N o i ntra -patie nt d ose re d ucti o ns of eit her mar get u xi ma b or pe m br oliz u ma b are all o we d 
d uri n g t he st u d y.  
Defi niti o ns  
D ose li miti n g t o xicities will be base d o n treat me nt -e mer ge nt, dr u g -relate d A Es ( or cli nicall y si g nifica nt 
la b orat or y a b n or malities) occ urri n g d uri n g t he D L T E v al u ati o n Peri o d  ( defi ne d as t he ti me f oll o wi n g 
a d mi nistrati o n of t he first d ose of pe m br oliz u ma b t o t he da y of t he sec o n d pla n ne d a d mi nistrati o n of 
pe m br oliz u ma b [i.e., 2 1 da ys f oll o wi n g first d ose of pe m br oliz u ma b –  e n d of C ycle 1]). T he se verit y of A Es 
will be gra de d acc or di n g t o t he Nati o nal Ca ncer I nstit ute C o m m o n T er mi n ol o g y Criteria f or A d verse E ve nts 
v 4. 0 3 ( N CI C T C A E v 4. 0 3).  
D ose  li miti n g t o xicities are defi ne d se paratel y f or he mat ol o gic a n d n o n-he mat ol o gic e ve nts as f oll o ws.  
He m at ol o gic D ose Li miti n g T oxicity  
He mat ol o gic D L T will be defi ne d as f oll o ws:  
  Gra de 4 ne utr o pe nia lasti n g > 5 da ys  
  ≥ Gra de 3 fe brile ne utr o pe nia lasti n g > 4 8 h o urs or a n y ≥ Gra de 3 fe brile ne utr o pe nia ass o ciate d 
wit h he m o d y na mic c o m pr o mise or o bj ecti ve e vi de nce of i nfecti o n  
  Gra de 4 t hr o m b oc yt o pe nia, irr es pecti ve of d urati o n  
  Gra de 3 t hr o m b oc yt o pe nia ass ociate d wit h cli nicall y si g nific a nt blee di n g  
  ≥ Gra de 3 he m ol ysis  
 
T he f oll o wi n g e ve nts will be s pecificall y e xcl u de d  fr o m t he defi niti o n of he mat ol o gic D L T: 
  ≥ Gra de 3 l y m p h o pe nia  
  Gra de 3 a ne mia t hat is n ot ass ociate d wit h ot her cli nicall y si g nifica nt c o m plicati o ns  
 
N o n -He m at ol o gic D ose Li miti n g T oxicity  
N o n -he patic n o n -he mat ol o gic D L T will be defi ne d as a n y ≥ Gra de 3 n o n -he mat ol o gic e ve nt wit h t he 
f oll o wi n g e xce pti o ns: 
  Gra de 3 electr ol yte a b n or malit y t hat lasts less t ha n 7 2 h o urs, is n ot ot her wise ass ociate d wit h 
cli nical c o m plicati o ns, a n d res p o n ds t o me dical i nter ve nti o n  
C o nfi d e nti al
P a g e   
1 9   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
  Gra de 3 fe ver t hat lasts < 7 2 h o urs a n d is n ot ass ociate d wit h he m o d y na mic c o m pr o mise  
  Gra de 3 na usea or v o miti n g t hat lasts < 7 2 h o urs a n d res p o n ds t o me dical i nter ve nti o n  
  Gra de 3 or 4 a m ylase a n d/ or li pase ele vati o n t hat is n ot ass ociat e d wit h eit her cli nical or 
ra di o gra p hic e vi de nce s u g gesti ve of pa ncreatitis 
  Gra de 3 diarr hea t hat lasts < 4 8 h o urs a n d res p o n ds t o me dic al i nter ve nti o n  
  Gra de 3 gastr oi ntesti nal A Es of c o nsti pati o n, a b d o mi nal pai n, cra m pi n g, d ys pe psia or d ys p ha gia 
t hat res ol ves t o ≤ Gra de 1 wit hi n 1 4 da ys wit h me dical t hera p y 
  Gra de 3 fati g ue t hat lasts < 7 da ys  
  Gra de 3 i nf usi o n -relate d reacti o n or c yt o ki ne release s y n dr o me t hat lasts < 1 2 h o urs a n d 
res p o n ds t o me dical i nter ve nti o n. 
  Gra de 3 or 4 e n d ocri n o pat h y t hat is a de q ua tel y c o ntr olle d wit h h or m o ne s u p ple me ntati o n 
  Gra de 3 s ki n t o xicit y t hat res ol ves t o ≤ Gra de 2 wit hi n 1 4 da ys of i nitiati o n of oral 
c ortic oster oi ds  
  Gra de 3 i nfla m mat or y reacti o n (e. g., wit h ass ociate d pai n, s welli n g) attri b ute d t o a l ocal 
a ntit u m or res p o ns e (e. g.,  i nfla m mat or y reacti o n at sites of metastatic disease, l y m p h n o des, etc.) 
t hat res ol ves t o ≤ Gra de 2 wit hi n 7 da ys wit h me dical i nter ve nti o n.  
 
N ote: T he f oll o wi n g Gra de 2 or greater n o n -he mat ol o gic A E ma y als o be c o nsi dere d as D L T:  
  Gra de 2 A Es t hat  are pr ol o n ge d i n or di natel y, base d u p o n t he me dical j u d g me nt of t he 
i n vesti gat or, a n d/ or lea d t o per ma ne nt disc o nti n uati o n of st u d y dr u g(s) d ue t o patie nt 
i nt olera nce. 
  A n y ≥ Gra de 2 dr u g -relate d A E t hat res ults i n > 7-da y treat me nt dela y w o ul d be c o nsi der e d a 
D L T.  
  A n y he patic la b orat or y a b n or malities meeti n g all t hree H y’s la w criteria ( descri be d wit hi n 
he patic n o n -he mat ol o gic D L Ts).  
  A n y Gra de 2 e ye pai n or re d ucti o n i n vis ual ac uit y t hat d oes n ot res p o n d t o t o pical t hera p y a n d 
d oes n ot i m pr o ve t o Gra de 1 wit hi n 1 4 da ys of t he i nitiati o n of t o pical t hera p y, or t hat re q uires 
s yste mic treat me nt. 
 
He p atic N o n -He m at ol o gic D ose Li miti n g T oxicity  
  A n y ele vati o n of o ne or m ore tra nsa mi nases > 8 × t he i nstit uti o nal u p per li mit of n or mal ( U L N) 
irres pecti ve of d urati o n  
  A n y Gra de 3 ele vati o n of o ne or m ore tra nsa mi nases > 5. 0 –  8. 0 × U L N t hat d oes n ot res ol ve t o 
Gra de  2 (i.e., >  2. 5 –  5. 0 × U L N) wit hi n 7 da ys a n d Gra de 1 (i.e., >  U L N –  2. 5 × U L N) wit hi n 
1 4 da ys. I n a d diti o n, ster oi ds m ust be ta pere d t o ≤ 1 0  m g of  pre d nis o ne or e q ui vale nt per da y, b y 
Da y 1 4. Please see  Secti o n  6. 5. 2. 2  f or f urt her ma na ge me nt g ui deli nes. 
  A Gra de 3 ele vati o n of t otal bilir u bi n t hat is > 5 × U L N, irres pecti ve of d urati o n.  
  A n y Gra de 3 ele vati o n of t otal bilir u bi n >  3. 0 -5. 0 × U L N t hat d oes n ot res ol ve t o Gra de 2 (i.e., 
>  1. 5 -3. 0  ×  U L N) wit hi n 7 da ys a n d Gra de 1 (i.e., >  U L N -1. 5 × U L N) wit hi n 1 4 da ys. I n 
a d diti o n, ster oi ds m ust be ta pere d t o ≤ 1 0 m g of pre d nis o ne or e q ui vale nt per da y, b y Da y 1 4. 
Please see  Secti o n  6. 5. 2. 2  f or f urt her ma na ge me nt g ui deli nes. 
  A n y e ve nt meeti n g t he criteria f or H y’s la w as f oll o ws (all t hree feat ures): 
o  
As partate a mi n otra nsferase ( A S T) a n d/ or ala ni ne a mi n otra nsferase ( A L T) > 3 × U L N.  
C o nfi d e nti al
P a g e   
2 0   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
o  
C o nc urre nt ele vati o n of t otal bilir u bi n > 2 × U L N wit h o ut i nitial e vi de nce of c h olestasis 
(e. g., ele vate d ser u m al kali ne p h os p hatase [ A L K -P]).  
o  
N o alter nati ve eti ol o g y ca n be i de ntifie d.  
D ose Esc al ati o n R ules  
T he D ose Esc al ati o n P h ase  ( P art A) of t his trial will pr ocee d usi n g a c o n ve nti o nal 3  +  3 a p pr oac h, a n d will 
be gi n wit h e nr oll me nt of 3 patie nts at a d ose of 2 0 0 m g pe m br oliz u ma b a d mi nistere d as a n I V i nf usi o n o nce 
e ver y 3 wee ks a n d a n i nitial d ose of 1 0 m g/ k g mar get u xi ma b a d mi nistere d as a n I V i nf usi o n o nce e ver y 
3  wee ks. S uccessi ve d ose escalati o n c o h orts will be e nr olle d as o utli ne d bel o w. T he M T D or M A D will be 
deter mi ne d base d o n t he assess me nt of D L Ts d uri n g t he D L T e val uati o n peri o d. Patie nts w h o are n ot 
e val ua ble f or safet y f or t he f ull D L T e val uati o n peri o d f or reas o ns ot her t ha n st u d y dr u g -relate d t o xicit y will 
be re place d i n t he sa me d ose -l e vel c o h ort.  
  If 0 of t he first 3 patie nts treate d at a gi ve n d ose le vel e x peri e nce a dr u g -relate d D L T d uri n g t he 
D L T e val uati o n peri o d, t he d os e will be escalate d a n d 3  patie nts will be e nr olle d a n d treate d at 
t he ne xt hi g her d ose le vel.  
  If 1 of t he first 3 patie nts treate d at a gi ve n mar get u xi ma b d ose le vel e x perie nces a dr u g-r elate d 
D L T, t he n 3 a d diti o nal patie nts will be e nr olle d at t hat d ose  l e vel (t h us ma ki n g a t otal of 
6  patie nts i n t his c o h ort) t o f urt her assess t he safet y of t he c o m bi nati o n.  
  If ≥ 1 of t hese 3 a d diti o nal patie nts e nr olle d i n t he c o h ort e x perie nce a D L T (t hat is, ≥2 o ut of 6), 
it will be c o ncl u de d t hat t he M T D has bee n e xcee de d, a n d 3 patie nts will be e nr olle d a n d treate d 
at t he ne xt l o wer d ose le vel. If 0 of t he 3 a d diti o nal patie nts e x perie nces a D L T (t hat is o nl y 1 of 
6 patie nts has e x perie nce d a D L T), t he n t he d ose will be esc alate d, a n d 3 patie nts will be 
e nr olle d at t h e ne xt hi g her d ose le vel.  
  If ≥ 2  patie nts o ut of t he first 3  patie nts treate d at a gi ve n d ose le vel, or ≥ 2 of 6  patie nts tre ate d 
at a gi ve n d ose le vel, e x perie nce a dr u g -relate d D L T, t he n it will be c o ncl u de d t hat t he M T D f or 
mar get u xi ma b i n c o m bi nati o n wit h pe m br oliz u ma b has bee n e xcee de d at t hat d ose le vel, a n d all 
s u bse q ue nt patie nts will be treate d at t he ne xt l o wer d ose le vel.  
  N ote t hat i n t he circ u msta nce i n w hic h a D L T occ urs d uri n g or i m me diatel y f oll o wi n g t he first 
pe m br oliz u ma b i nf usi o n a n d bef o re t he first mar get u xi ma b a d mi nistrati o n, t he t o xicit y will be 
attri b ute d t o pe m br oliz u ma b al o ne a n d will n ot c o u nt as a D L T of t he c o m bi nati o n of st u d y 
dr u gs at t he d ose le vel u n der st u d y. I n t his case t he patie nt will be re place d b y a n ot her pati e nt i n 
t he d ose c o h ort.  
  A t otal of 6 patie nts were treat e d at t he R P 2 D pri or t o e nr olli n g i n t he C o h ort E x pa nsi o n P hase 
of t he st u d y.  
 
F oll o wi n g t hese r ules f or d ose escalati o n, t he M T D/ M A D f or t he c o m bi nati o n of mar get u xi ma b a n d 
pe m br oliz u ma b will be defi ne d as t he d ose le vel at w hic h < 3 3 % of patie nts e x perie nce a dr u g -relate d D L T 
d uri n g t he D L T e val uati o n peri o d. If n o M T D is defi ne d f or t he c o m bi nati o n of mar get u xi ma b a n d 
pe m br oli z u ma b after escalati o n t o t he ma xi m u m pr ot oc ol -s pecifie d d ose, t hat d ose le vel will be desi g nate d 
as t he M A D.  
D ose escalati o n t o t he ne xt d ose le vel is per mitte d o nl y after t he patie nts e nr olle d i n t he c urre nt d ose c o h ort 
ha ve c o m pete d t he D L T e val uati o n peri o d a n d safet y data ha ve bee n re vie we d.  
At t he discreti o n of t he S p o ns or, d ose escalati o n ma y be st o p pe d bef ore a n M T D is reac he d. I n t his case, t he 
M A D ma y be c h ose n base d o n a n assess me nt of P K, p har mac o d y na mics, bi o mar ker, safet y, a n d res p o nse 
data. A n M T D d oes n ot ha ve t o be reac he d t o e x pa n d a d ose c o h ort if t he a vaila ble data de m o nstrate t hat a 
l o wer d ose le vel ma y pr o vi de a ntit u m or acti vit y w hile mi ni mizi n g p ote ntial ris k. 
C o nfi d e nti al
P a g e   
2 1   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
As n ote d a b o ve, a t otal of 6 patie nts were treate d at t he rec o m me n de d p hase  2 d ose ( R P 2 D) pri or t o e nr olli n g 
i n t he C o h ort E x pa nsi o n P hase of t he st u d y.  
R ules f or Tre at me nt Disc o nti n u ati o n:  
P atie nts w h o t olerate treat me nt wit h pe m br oliz u ma b  a n d mar get u xi ma b ma y c o nti n ue t o recei ve a d diti o nal 
treat me nt wit h t he st u d y dr u gs as s pecifie d a b o ve u ntil a n y o ne of t he f oll o wi n g c o n diti o ns are met:  
  After d oc u me ntati o n of a c o nfir me d c o m plete res p o nse (c C R), t he c o m bi nati o n of 
mar get u xi ma b a n d pe m br oliz u ma b are c o nti n ue d f or o ne m ore treat me nt c ycle.  
  P atie nt meets criteria f or ir P D ( A p pe n di x 8 ) 
  Occ urre nce of dr u g -relate d D L T  
  T he S p o ns or, i n vesti gat or, or Re g ulat or y A ge nc y ter mi nates t he st u d y  
  Wit h dra wal of patie nt d ue t o a n A E or seri o us a d verse e ve nt ( S A E)  
  Wit h dra wal of patie nt c o nse nt  
  C o m pleti o n of pr ot oc ol defi ne d t hera p y  
  I n vesti gat or discreti o n 
  Pre g na nc y  
  Deat h  
  T w o years of pe m br oliz u ma b a n d mar get u xi ma b c o m bi nati o n treat me nt  
St u d y P o p ul ati o n:  
T he patie nt p o p ulati o n t o be e nr olle d i n t his st u d y will c o nsist of a d ult patie nts wit h rela pse d/refract or y 
u nresecta ble l ocall y a d va nce d or metastatic H E R 2 + G EJ or gastric ca ncer  ( G C).  
T he n u m ber of patie nts e nr oll e d i n t he D ose Escalati o n P h ase ( Part A) ca n n ot be precisel y deter mi ne d i n 
a d va nce a n d c o ul d ra n ge u p t o 1 2 patie nts de pe n di n g o n res ults d uri n g t he c o urse of t he trial a n d t he n u m ber 
of mar get u xi ma b d oses e x pl ore d. T his patie nt n u m ber d oes n ot ta ke i nt o acc o u nt patie nt r e place me nt f or 
n o n -e val ua ble patie nts.  
T he C o h ort E x pa nsi o n P hase s of t he trial will e nr oll u p t o  8 5 patie nts . 
T he first e x pa nsi o n c o h ort ( P art B) i ncl u des 3 0  patie nts i n N ort h A merica a n d 3 0  patie nts  i n Asia  wit h 
rela pse d/refract or y unresecta ble l ocall y a d va nce d or metastatic H E R 2 + G EJ or G C . 
P art C will e nr oll  u p t o 2 5  patie nts i n N ort h A merica n a n d/ or Asia wit h rela pse d/refract or y u nresecta ble 
l ocall y a d va nce d or metastatic H E R 2 + (I H C 3 + ) G C  (as defi ne d bel o w u n der “I ncl usi o n Criteria”). 
I ncl usi o n/ E xcl usi o n Criteri a:  
T o be eli gi ble f or st u d y partici pati o n, patie nts m ust meet all t he i ncl usi o n criteria. N o e xce pti o ns will be 
gra nte d b y t he S p o ns or. P atie nts will be e xcl u de d fr o m t he st u d y if t he y meet a n y e xcl usi o n criteria.  
I ncl usi o n Criteri a: 
Ge neral  
1.  A bilit y  t o pr o vi de i nf or me d c o nse nt a n d d oc u me ntati o n of i nf or me d c o nse nt pri or t o i nitiati o n of 
a n y st u d y-relate d tests or pr oce d ures t hat are n ot part of sta n dar d of care f or t he patie nt’s 
C o nfi d e nti al
P a g e   
2 2   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
disease. P atie nts m ust als o be willi n g a n d a ble t o c o m pl y wit h st u d y pr o ce d ures, i ncl u di n g t he 
ac q uisiti o n of s pecifie d researc h s peci me ns.  
2.  A ge ≥ 1 8 years ol d ( mi ni m u m a ge de pe n de nt u p o n l ocal re g ulati o ns).  
3.  P atie nts ma y be male or fe mal e.  
4.  Si xt y  patie nts  i n P art B : Ha ve hist ol o gicall y pr o ve n u nresect a ble l ocall y a d va nce d or metastatic 
H E R 2 + gastr oes o p ha geal j u ncti o n ( G EJ) or gastric ca ncer ( G C) , deter mi ne d as 3 + b y I H C or 2 + 
b y I H C a n d i n sit u h y bri dizati o n–  (I S H-) a m plifie d  (≥2. 0)  (as per C olle ge of A merica n 
P at h ol o gists/ A merica n S ociet y of Cli nical O nc ol o g y  2 0 1 6  G ui deli nes)  i n t he m ost rece nt t u m or 
bi o ps y.   
T we nt y -fi ve patie nts  i n P art C (G C o nl y ): As of A me n d me nt  2, u p t o 2 5  a d diti o nal patie nts  wit h  
hist ol o gicall y  pr o ve n u nresect a ble l ocall y a d va nce d or metastatic H E R 2 + G C  (as defi ne d i n 
AJ C C Ca ncer Sta gi n g Ma n ual, 8 t h E diti o n)  deter mi ne d as 3 + b y I H C (as per C olle ge of 
A merica n P at h ol o gists/ A meri ca n S ociet y of Cli nical O nc ol o g y 2 0 1 6 G ui deli nes) i n t he m ost 
rece nt tu m or bi o ps y.  
5.  Ha ve recei ve d pri or treat me nt wit h trast uz u ma b . 
6.  Ha ve recei ve d treat me nt wit h o ne li ne of c yt ot o xic c he m ot hera p y i n t he metastatic setti n g  w hic h 
i ncl u des trast uz u ma b. Pri or a dj u va nt t hera p y t hat res ulte d i n rela pse wit hi n 6 m o nt hs of 
c o m pleti o n of t hera p y will be c o nsi dere d a li ne of treat me nt f or metastatic disease. Eli gi ble 
patie nts m ust ha ve d oc u me nte d pr o gressi o n  o n /after t he m ost rece nt li ne of t hera p y. Patie nts  
w h o disc o nti n ue trast uz u ma b f or ot her reas o ns (i.e., fi na ncial) are eli gi ble if t he y ha ve 
d oc u me nte d pr o gressi o n o n/after trast uz u ma b wit h o ut recei vi n g alter nate treat me nt.  
a. 
I n P arts B a n d C , o nl y o ne pri or li ne of treat me nt t hat i ncl u d es trast uz u ma b is all o we d.  
7.  Res ol uti o n of all c he m ot hera p y or ra diati o n -relate d t o xicities t o ≤ Gra de 1 ( wit h e xce pti o n of 
≤ Gra de 2 al o pecia, sta ble se ns or y ne ur o pat h y, or sta ble electr ol yte dist ur ba nces t hat are 
ma na ge d b y s u p ple me ntati o n).  
8.  Easter n C o o perati ve O nc ol o g y Gr o u p ( E C O G) perf or ma nce stat us of 0 or 1 ( A p pe n di x  6 ) 
9.  Life e x pecta nc y ≥ 1 2 wee ks.  
1 0.  Meas ura ble disease as per R E CI S T 1. 1 criteria ( A p pe n di x  7 ) a n d d oc u me nte d b y c o m p ute d 
t o m o gra p h y ( C T) a n d/ or ma g netic res o na nce i ma gi n g ( M RI). Patie nts wit h e val ua ble dise ase 
o nl y will n ot be e nr olle d o n t his st u d y. N ote: Lesi o ns t o be use d as meas ura ble disease f or t he 
p ur p ose of res p o nse assess me nt m ust eit her a) n ot re si de i n a fiel d t hat has bee n s u bj ecte d t o 
pri or ra di ot hera p y, or b) ha ve de m o nstrate d clear e vi de nce of ra di o gra p hic pr o gressi o n si nce t he 
c o m pleti o n of pri or ra di ot hera p y a n d pri or t o st u d y e nr oll me nt.  
1 1.  P atie nts s h o ul d ha ve a f or mali n-fi xe d, paraffi n e m be d de d t u m or s peci me n or u nstai ne d sli des 
i de ntifie d a n d a vaila ble f or a nal ysis, t o e na ble deter mi nati o n of t he e x pressi o n of H E R2 a n d 
pr o gra m me d deat h li ga n d 1 ( P D -L 1) wit hi n t u m or s peci me ns usi n g I H C stai ni n g.   
La b orat or y Feat ures  
1 2.  Acce pta ble la b orat or y para meters as f oll o ws:  
a. 
Platelet c o u nt  1 0 0 × 1 0 3/ µ L wit h o ut tra nsf usi o n wit hi n 2 wee ks pri or t o t he i nitiati o n 
of st u d y dr u g.  
b.  A bs ol ute ne utr o p hil c o u nt ( A N C)  1. 5 × 1 0 3/ µ L i n t he a bse nce of a n y gr o wt h fact or 
s u p p ort wit hi n 2 wee ks pri or t o t he i nitiati o n of st u d y dr u g.  
c. 
He m o gl o bi n ( H g b)  9 g/ d L  
d.  A L T/ A S T  3. 0 × U L N; f or patie nts wit h he patic metastases, A L T a n d A S T ≤ 5 × 
U L N  
C o nfi d e nti al
P a g e   
2 3   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
e. 
T o tal bilir u bi n  1. 5 × U L N, e xce pt patie nts wit h Gil bert’s s y n dr o me, w h o ma y e nr oll 
if t he c o nj u gate d bilir u bi n is wit hi n n or mal li mits. 
f. 
Creati ni ne < 2 m g/ d L, or a calc ulate d or meas ure d creati ni ne cleara nce >  5 0 m L/ mi n.  
Re pr o d ucti ve Feat ures  
1 3.  Fe male patie nt s of c hil d beari n g p ote ntial ( n ot s ur gicall y sterilize d a n d bet wee n me narc he a n d 1 
year p ost me n o pa use) m ust ha ve a ne gati ve uri ne pre g na nc y test perf or me d wit hi n 7 2  h o urs pri or 
t o t he i nitiati o n of st u d y dr u g a d mi nistrati o n. F urt her, fe mal e patie nts of c hild beari n g p ote ntial 
m ust a gree t o use hi g hl y effecti ve c o ntrace pti ve meas ures fr o m t he ti me of c o nse nt t hr o u g h 1 2 0 
da ys after disc o nti n uati o n of st u d y dr u g a d mi nistrati o n.  
F or C a n a di a n p atie nts o nl y : Fe male patie nts of c hil d beari n g p ote ntial m ust ha ve a ne gati ve 
pre g na nc y test pri or t o eac h c ycle of pe m br oliz u ma b.  
a. Hi g hl y effecti ve met h o ds of c o ntrace pti o n i ncl u de h or m o nal c o ntrace pti ves, 
i ntra uteri ne de vice or s yste m, vasect o m y, or t u bal li gati o n. If a hi g hl y effecti ve met h o d 
is n ot ac hie va ble t he n a “ d o u ble barrier” met h o d is a n effecti ve alter nati ve i n w hic h t he 
male part ner m ust use a c o n d o m wit h s per mici de a n d t he fe male part ner m ust use a 
dia p hra g m or cer vical ca p c o nc urre ntl y.  
1 4.  Male patie nts wit h part ners of c hil d beari n g p ote ntial m ust use barrier c o ntrace pti o n. I n a d diti o n, 
male patie nts s h o ul d als o ha ve t heir part ners use a n ot her met h o d of c o ntrace pti o n fr o m t he ti me 
of c o nse nt t hr o u g h 1 2 0 da ys  after disc o nti n uati o n of st u d y dr u g a d mi nistrati o n.  
1 5.  Is n ot pre g na nt or breastfee di n g or e x pecti n g t o c o ncei ve or fat her c hil dre n wit hi n t he pr oj ecte d 
d urati o n of t he trial, starti n g wit h t he prescree ni n g or scree ni n g visit t hr o u g h 1 2 0 da ys  after t he 
last d ose of trial treat me nt. 
T u m or Bi o ps y  
1 6.  At least 2 0 of t he 6 0 patie nts e nr olle d i n t he C o h ort E x pa nsi o n P hase  (Part B ) u n der  t he Ori gi nal 
Pr ot oc ol a n d Pr ot oc ol A me n d me nt  1 m ust ha ve o ne lesi o n c o nsi dere d t o be p ote ntiall y 
accessi ble t o bi o ps y a n d be willi n g t o pr o vi de c o nse nt f or bi o ps y sa m ples. A n atte m pt at a t u m or 
bi o ps y of l ocall y accessi ble lesi o ns will be ma de f or at least 2 0  of t he 6 0  patie nts. T u m or lesi o ns 
use d f or bi o ps y s h o ul d n ot be lesi o ns use d as R E CI S T tar get lesi o ns u nless t here are n o ot her 
lesi o ns s uita ble f or bi o ps y. If a R E CI S T tar get lesi o n is use d f or bi o ps y, t he lesi o n m ust b e 
≥ 2  c m i n l o n gest dia meter. T u m or bi o psies s h o ul d o nl y be o btai ne d fr o m lesi o ns t hat are felt t o 
be accessi ble wit h acce pta ble cli nical ris k i n t he j u d g me nt of t he i n vesti gat or  a n d s h o ul d n ot be 
lesi o ns use d as R E CI S T tar get lesi o ns, u nless t here are n o ot her lesi o ns s uita ble f or bi o ps y. If a 
R E CI S T tar get lesi o n is use d f or bi o ps y, t he lesi o n m ust be ≥ 2  c m i n l o n gest dia meter. Lesi o ns 
t o be bi o psie d s h o ul d n ot ha ve bee n pre vi o usl y irra diate d, u nless t he lesi o n has gr o w n i n si ze 
be gi n ni n g at least 1 4 da ys si nc e t he last ra diati o n d ose. N ote t hat m ulti ple lesi o ns ma y be use d t o 
o btai n t he bi o ps y sa m ple.   
  T he 2 5 patie nts e nr olle d i nt o Part C will n ot be re q uire d t o ha ve pre - a n d o n-treat me nt 
bi o psies.   
  Dia g n ostic  bi o ps y sa m ple perf or me d as sta n dar d of care will be c ollecte d  fr o m all 
patie nts o n st u d y . Patie nts e nr olle d o n t his st u d y will be re q uire d t o ha ve a n i de ntifie d 
arc hi val t u m or s peci me n.  
Pre vi o us C hec k p oi nt I n hi bit or T hera p y  
1 7.  P atie nts w h o ha ve pre vi o usl y r ecei ve d a n i m m u ne c hec k p oi nt i n hi bit or (e. g., pr o gra m me d -deat h 
li ga n d 1 a nti b o d y [a nti-P D -L 1], pr o gra m me d cell deat h pr otei n 1 a nti b o d y [a nti -P D -1], 
c yt ot o xic T -l y m p h oc yte-ass ociate d pr otei n 4 a nti b o d y [a nti -C T L A -4]) pri or t o e nr oll me nt m ust 
ha ve t o xicitie s relate d t o t he c hec k p oi nt i n hi bit or res ol ve d t o ≤ Gra de 1 or baseli ne ( pri or t o t he 
c hec k p oi nt i n hi bit or) t o be eli gi ble f or e nr oll me nt.  
C o nfi d e nti al
P a g e   
2 4   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
Excl usi o n Criteri a:  
1.  P atie nts wit h s y m pt o matic ce ntral ner v o us s yste m ( C N S) metastases m ust ha ve bee n treate d, be 
as ym pt o matic, a n d meet t he f oll o wi n g at t he ti me of e nr oll me nt:  
a. 
N o c o nc urre nt treat me nt f or t he C N S disease (e. g., s ur ger y, ra diati o n, c ortic oster oi ds ≥ 
1 0 m g pre d nis o ne/ da y or e q ui vale nt)  
b.  N o pr o gressi o n of C N S metastases o n M RI or C T f or at least 2 1 da ys after last da y of 
pri or t hera p y f or t he C N S met astases  
c. 
N o c o nc urre nt le pt o me ni n geal disease or c or d c o m pressi o n  
2.  P atie nts w h o e x perie nce d t he f oll o wi n g i m m u ne c hec k p oi nt i n hi bit or -relate d A Es (i.e., t he 
f oll o wi n g A Es ma ke t he patie nt i neli gi ble des pite t he A E res ol vi n g t o ≤ Gra de 1 or baseli ne): 
a. 
≥ Gra de 3 oc ular A E  
b.  C ha n ges i n li ver f u ncti o n tests t hat met t he criteria f or H y’s La w ( > 3 × U L N of eit her 
A L T/ A S T wit h c o nc urre nt >  2 × U L N of t otal bilir u bi n a n d wit h o ut alter nate eti ol o g y) 
c. 
≥ Gra de 3 ne ur ol o gic t o xicit y  
d.  ≥ Gra de 3 c olitis or p ne u m o nitis  
3.  P atie nts wit h a n y hist or y of k n o w n or s us pecte d a ut oi m m u ne disease wit h t he s pecific 
e xce pti o ns of vitili g o, res ol ve d c hil d h o o d at o pic der matitis , ps oriasis n ot re q uiri n g s yste mi c 
treat me nt ( wit hi n t he past 2 ye ars), a n d patie nts wit h a hist or y of a ut oi m m u ne disease t hat are 
n o w cli nicall y sta ble wit h re place me nt t hera p y a n d b y la b orat or y testi n g.  
a. 
P atie nts wit h hist or y of ps oriatic art hritis are e x cl u de d.  
4.  Hist or y of pri or all o ge neic b o ne marr o w, ste m -cell or s oli d or ga n tra ns pla ntati o n.  
5.  Treat me nt wit h a n y s yste mic a nti -ne o plastic t hera p y, or i n vesti gati o nal t hera p y wit hi n t he 3 
wee ks pri or t o t he i nitiati o n of st u d y dr u g a d mi nistrati o n. A dj u va nt h o r m o nal t hera p y f or 
treat me nt of pr ostate or breast ca ncer is all o we d.  
6.  Treat me nt wit h ra diati o n t hera p y wit hi n 3 wee ks pri or t o t he i nitiati o n of st u d y dr u g 
a d mi nistrati o n.  
7.  Treat me nt wit h c ortic oster oi ds ( ≥ 1 0 m g per da y pre d nis o ne or e q ui vale nt) or ot her i m m u ne 
s u p pressi ve dr u gs wit hi n t he 1 4 da ys pri or t o t he i nitiati o n of st u d y dr u g a d mi nistrati o n. Ster oi ds 
f or t o pical, o p ht hal mic, i n hale d or nasal a d mi nistrati o n are all o we d. 
8.  Hist or y of cli nicall y  si g nifica nt car di o vasc ular disease i ncl u di n g b ut n ot li mite d t o:  
a. 
M y ocar dial i nfarcti o n or u nsta ble a n gi na wit hi n t he 6 m o nt hs pri or t o t he i nitiati o n of 
st u d y dr u g.  
b.  Str o ke or tra nsie nt isc he mic attac k wit hi n 6 m o nt hs pri or t o t he i nitiati o n of st u d y 
dr u g.  
c. 
Cli nicall y  si g nifica nt car diac arr h yt h mias. 
d.  U nc o ntr olle d h y perte nsi o n: s yst olic bl o o d press ure ( S B P) > 1 8 0 m m H g, diast olic bl o o d 
press ure ( D B P) > 1 0 0 m m H g.  
e. 
C o n gesti ve heart fail ure ( Ne w Y or k Heart Ass ociati o n [ N Y H A] class III -I V). 
f. 
P ericar ditis or cli nicall y si g nifica nt pericar dial eff usi o n.  
g.  M y ocar ditis.  
C o nfi d e nti al
P a g e   
2 5   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
h.  Left ve ntricle ej ecti o n fracti o n ( L V E F) < 5 0 % b y ec h ocar di o gra m or m ulti -gate d 
ac q uisiti o n ( M U G A) sca n.  
9.  Cli nicall y  si g nifica nt p ul m o nar y c o m pr o mise, i ncl u di n g a re q uire me nt f or s u p ple me ntal o x y ge n 
use t o mai ntai n a de q uate o x y g e nati o n.  
1 0.  Has a hist or y of ( n o n -i nfecti o us) p ne u m o nitis t hat re q uire d ster oi ds or has c urre nt p ne u m o nitis.  
1 1.  Cli nicall y  si g nifica nt gastr oi nt esti nal dis or ders i ncl u di n g: 
a. 
A n y hist or y of gastr oi ntesti nal perf orati o n u nless t he affecte d area has bee n dee me d b y 
t he i n vesti gat or t o n o l o n ger be a ris k f or perf orati o n. 
b.  Hist or y of cli nicall y si g nifica nt gastr oi ntesti nal blee di n g wit hi n 4 wee ks pri or t o t he 
i nitiati o n of st u d y dr u g. 
c. 
Hist or y of ac ute pa ncreatitis wit hi n 4 wee ks pri or t o t he i nitiati o n of st u d y dr u g.  
d.  Di vertic ulitis t hat is cli nicall y si g nifica nt i n t he o pi ni o n of t he i n vesti gat or base d o n t he 
e xte nt or se verit y of k n o w n disease a n d/ or t he occ urre nce of cli nicall y  si g nifica nt 
disease flares wit hi n 4 wee ks pri or t o t he i nitiati o n of st u d y dr u g a d mi nistrati o n.  
1 2.  E vi de nce of acti ve viral, ba cterial, or s yste mic f u n gal i nfecti o n re q uiri n g pare nteral treat me nt 
wit hi n 7 da ys pri or t o t he i nitiati o n of st u d y dr u g. Patie nts re q uiri n g a n y s yste mic a nti viral, 
a ntif u n gal, or a nti bacterial t hera p y f or acti ve i nfecti o n m ust ha ve c o m plete d treat me nt n o l ess 
t ha n o ne wee k pri or t o t he i nitiati o n of st u d y dr u g.  
1 3.  K n o w n p ositi ve testi n g f or h u ma n i m m u n o deficie nc y vir us or hist or y of ac q uire d i m m u ne 
deficie nc y s y n dr o me.  
1 4.  K n o w n hist or y of he patitis B or he patitis C i nfecti o n or k n o w n p ositi ve test f or he patitis  B 
s urface a nti ge n, he patitis B c ore a nti ge n, or he patitis C p ol y merase c hai n reacti o n ( P C R).  
1 5.  H ist or y of a n ot her mali g na nc y or a c o nc urre nt mali g na nc y. E xce pti o ns i ncl u de patie nts w h o 
ha ve bee n disease free f or t w o years, or s uccessf ull y treate d f or n o n -me la n o ma s ki n ca ncer, 
l ocalize d pr ostate ca ncer ( Gleas o n Sc ore < 6) or carci n o ma i n sit u, f or e xa m ple cer vical ca ncer i n 
sit u, are eli gi ble.  
1 6.  Hist or y of tra u ma or maj or s ur ger y wit hi n 4 wee ks pri or t o t he i nitiati o n of st u d y dr u g 
a d mi nistrati o n.  
1 7.  A n y seri o us u n derl yi n g me dic al or ps yc hiatric c o n diti o n t hat w o ul d i m pair t he a bilit y of t he 
patie nt t o recei ve or t olerate t he pla n ne d treat me nt at t he i n vesti gati o nal site.  
1 8.  K n o w n h y perse nsiti vit y t o rec o m bi na nt pr otei ns, p ol ys or bat e 8 0 or a n y e xci pie nt c o ntai ne d i n  
t he dr u g or ve hicle f or m ulati o n f or mar get u xi ma b or pe m br oliz u ma b (Secti o n  6. 1 ). 
1 9.  Vacci nati o n wit h a n y li ve vir us vacci ne wit hi n 4 wee ks pri or t o t he i nitiati o n of st u d y dr u g 
a d mi nistrati o n. I nacti vate d a n n ual i nfl ue nza vacci nati o n is all o we d.  
2 0.  T he fe male patie nt w h o is pre g na nt or breastfee di n g, or e x pecti n g t o c o ncei ve, A N D t he male 
patie nt w h o is e x pecti n g t o fat her c hil dre n wit hi n t he pr oj ecte d d u rati o n of t he trial, starti n g wit h 
t he scree ni n g visit t hr o u g h 1 2 0 da ys  after t he last d ose of tri al treat me nt.  
2 1.  De me ntia or altere d me ntal stat us t hat w o ul d precl u de u n dersta n di n g a n d re n deri n g of i nf or me d 
c o nse nt.  
2 2.  E m pl o yees of Macr o Ge nics, I nc., a n d Merc k  & C o., I nc., u nless a p pr o ve d b y i nstit uti o nal 
re vie w b oar d (I R B) a n d pri nci pal i n vesti gat or. 
2 3.  Pris o ners or ot her i n di vi d uals w h o are i n v ol u ntaril y detai ne d.  
2 4.  A n y iss ue t hat i n t he o pi ni o n of t he i n vesti gat or, w o ul d c o ntr ai n dicate t he patie nt’s partici p ati o n  
i n t he st u d y or c o nf o u n d t he res ults of t he st u d y. 
C o nfi d e nti al
P a g e   
2 6   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
St u d y Dr u gs:  
M ar get u xi m a b:  Mar get u xi ma b is a sterile, clear -t o-sli g htl y-o palesce nt, c ol orless -t o-pale -yell o w or 
pale -br o w n, preser vati ve -free s ol uti o n f or I V a d mi nistrati o n. S o me visi ble, tra nsl uce nt, protei nace o us, 
mar get u xi ma b particles ma y be prese nt. Mar get u xi ma b is s u p plie d i n si n gle -use, 1 0 -m L cl ear glass vials wit h 
Fl ur o T ec ®  c oate d gra y b ut yl r u b ber ser u m st o p pers a n d al u mi n u m seals wit h plastic o verseals. Eac h vial 
c o ntai ns 2 5 0 m g mar get u xi ma b ( 2 5  m g/ m L) i n 1 0 m L of s ol uti o n. T he pr o d uct is f or m ulat e d i n a b uffer 
c o ntai ni n g 1. 1 m g/ m L s o di u m p h os p hate m o n o basic, m o n o h y drate, 0. 5 8 m g/ m L s o di u m p h os p hate di basic, 
he pta h y drate, 2. 9 m g/ m L s o di u m c hl ori de, 1 1 m g/ m L L -ar gi ni ne h y dr oc hl ori de, 3 0 m g/ m L s ucr ose, a n d 
0. 1  m g/ m L P ol ys or bate 8 0, i n Sterile Water f or I nj ecti o n, p H 6. 1.  
Mar get u xi ma b will be a d mi nistere d as a 1 2 0 -mi n ute ( 2 -h o ur) I V i nf usi o n after pe m br oliz u ma b 
a d mi nistrati o n. A sterile, l o w pr otei n bi n di n g p ol yet hers ulf o ne ( P E S) 0. 2 micr o n filtere d a d mi nistrati o n set 
m ust be use d f or I V a d mi nistr ati o n of mar get u xi ma b.  
Pe m br oliz u m a b:  P e m br oliz u ma b is s u p plie d as  l y o p hilize d p o w der i n a si n gle-use vial f or rec o nstit uti o n , or 
as s ol uti o n f or i nf usi o n i n a si n gle-use vial . 
P e m br oliz u ma b l y o p hilize d p o w der is a sterile, preser vati ve -free, w hite t o off-w hite l y o p hilize d p o w der i n 
si n gle-use vials. Eac h vial is rec o nstit ute d wit h 2. 3 m L Sterile Water f or I nj ecti o n, U S P a n d dil ute d f or I V 
i nf usi o n. Eac h 2 m L of rec o nstit ute d s ol uti o n c o ntai ns 5 0 m g of pem br oliz u ma b a n d is f or m ulate d i n L -
histi di ne ( 3. 1 m g), p ol ys or bate 8 0 ( 0. 4 m g), a n d s ucr ose ( 1 4 0 m g). Ma y c o ntai n h y dr oc hl oric aci d/s o di u m 
h y dr o xi de t o a dj ust p H t o 5. 5.  
P e m br oliz u ma b S ol uti o n f or I nf usi o n is a sterile, n o n -p yr o ge nic a q ue o us s ol uti o n s u p pl ie d i n si n gle-use 
T y pe I glass vial c o ntai ni n g 1 0 0 m g/ 4 m L of pe m br oliz u ma b. T he pr o d uct is a preser vati ve -free, late x free 
s ol uti o n w hic h is esse ntiall y free of e xtra ne o us partic ulates.  
P e m br oliz u ma b will be a d mi nistere d b y I V i nf usi o n o ver 3 0 mi n utes t hr o u g h a n I V li ne c o ntai ni n g a sterile, 
n o n -p yr o ge nic, l o w -pr otei n bi n di n g 0. 2 micr o n t o 5 micr o n i n -li ne or a d d-o n filter.  
D ur ati o n of Tre at me nt a n d St u d y D ur ati o n:  
Mar get u xi ma b a n d pe m br oliz u ma b  will be a d mi nistere d i n c o m bi nati o n o nce e ver y 3 wee ks f or u p t o 
2  years. Disease stat us will be e val uate d e ver y t w o c ycles (e ver y 6 wee ks) f or t he first si x ( 6) m o nt hs a n d 
t he n e ver y t wel ve ( 1 2) wee ks t hereafter usi n g C T a n d/ or M RI as a p pr o priate f or t he sites of disease, 
acc o m pa nie d b y p h ysical e xa mi nati o n.   Alt h o u g h res p o nse assess me nt will be perf or me d acc or di n g t o b ot h 
c o n ve nti o nal a n d i m m u ne -relate d res p o nse criteria (ir R C) (A p pe n di x 7  a n d A p pe n di x 8 , res pecti vel y), 
patie nts will be ma na ge d acc or di n g t o ir R C pri nci ples. T his a p pr oac h all o ws f or t he li mite d treat me nt of 
patie nts be y o n d t he i nitial ra di o gra p hic d oc u me ntati o n of disease pr o gressi o n, ass u mi n g t hat t he i n vesti gat or 
feels t hat t he patie nts are t olerati n g t hera p y a de q uatel y. 
P atie nts w h o recei ve treat me nt a n d w h o ac hie ve a n o bj ecti ve res p o nse stat us of sta ble dise ase ( S D), 
u nc o nfir me d partial res p o nse ( u P R), c o nfir me d partial res p o nse (c P R), u nc o nfir me d c o m pl ete res p o nse 
( u C R), c o nfir me d c o m plete res p o nse (c C R), or u nc o nfir me d pr o gressi ve disease ( u P D) acc or di n g t o 
i m m u ne-relate d res p o nse criteria (ir R C) at t he Wee k 6 ra di o gra p hic disease assess me nt will be eli gi ble t o 
recei ve s u bse q ue nt c ycles of tr eat me nt, ass u mi n g t hat t he y re mai n cli nical sta ble a n d ha ve n ot e x perie nce d 
D L Ts t hat necessitate per ma ne nt disc o nti n uati o n of st u d y dr u gs. Ra di o gra p hic disease assess me nts will 
o cc ur e ver y 6 wee ks (i.e., f oll o wi n g 2 c ycles of treat me nt [s pecificall y pri or t o C ycles 3, 5, 7 etc.]). Patie nts 
w h o ha ve e x perie nce d P D as e vi de nce d b y ≥ 2 0 % i ncrease i n t he di me nsi o ns of tar get lesi o ns or t he 
occ urre nce of ne w lesi o ns ma y c o nti n ue t hera p y at t he discr eti o n of t he i n vesti gat or pe n di n g c o nfir mati o n of 
t he P D at t he ne xt pla n ne d t u m or assess me nt a n d satisfacti o n of criteria f or ir P D. S u bse q ue nt c ycles of 
t hera p y after a n i nitial d oc u me ntati o n of P D s h o ul d be a d mi nistere d t o patie nts w h o ha ve d e m o nstrate d 
C o nfi d e nti al
P a g e   
2 7   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
acce pta ble t olera nce t o treat me nt, w h o re mai n ot her wise cli nicall y sta ble, a n d w h o, i n t he assess me nt of t he 
i n vesti gat or, ma y deri ve cli nic al be nefit fr o m t he c o nti n uati o n of treat me nt. 
It is e x pecte d t hat e nr oll me nt of P art A  of t he st u d y w ill occ ur o ver a p pr o xi matel y 6 m o nt hs, a n d e nr oll me nt 
of P arts B –  C  will ta ke a p pr o xi matel y 9 –  1 8  m o nt hs.  
T he t otal ti me f or c o n d uct of t he trial is e x pecte d t o be a p pr o xi matel y 6 0  m o nt hs. T hese esti mates of t he 
ti mi n g f or st u d y c o n d uct ma y var y fr o m t hat o bser ve d i n t he act ual c o n d uct of t he trial.  
Tre at me nt Sc he d ule ( Pr oce d ure):  see Ti me a n d E ve nts ( A p pe n di x  1 , a n d A p pe n di x  2 ). 
Criteri a f or E v al u ati o n:  
Safet y Assess me nts:  
  T he safet y assess me nt will be base d o n t he e val uati o n of treat me nt -e mer ge nt A Es t hat occ ur 
fr o m t he ti me of i nitiati o n of a d mi nistrati o n of either st u d y dr u g t hr o u g h t he E n d of Treat me nt 
Visit , 2 8 da ys after t he last d ose of st u d y dr u g , or t he i nitiati o n of a n ot her a nti-ca ncer treat me nt  
( w hic he ver is later) a n d will be deter mi ne d base d o n si g ns, s y m pt o ms, p h ysical e xa mi nati o n 
fi n di n gs a n d/ or la b orat or y test res ults fr o m e nr olle d patie nts as a p pr o priate 
  A Es a n d seri o us a d verse e ve nts ( S A Es) will be c ollecte d fr o m t he ti me t he patie nt recei ves t he 
first d ose of st u d y dr u g u ntil t he E n d of Treat me nt Visit, 2 8 da ys after t he last d ose of st u d y 
dr u g , or t he i nitiati o n of a n ot her a ntica ncer treat me nt  ( w hic he ver is later). Pr ot oc ol-relate d A Es 
a n d S A Es will be c ollecte d fr o m t he ti me t he patie nt has c o nse nte d t o st u d y partici pati o n.  
  A Es re p orte d bet wee n t he ti me t he patie nt si g ne d t he i nf or me d c o nse nt a n d t he a d mi nistrati o n of 
t he first d ose of st u d y dr u g will be ca pt ure d as me dical hist or y. 
  S A Es c o nsi dere d relate d t o st u d y dr u g ma y be re p orte d at a n y ti me, e ve n after t he patie nt’s fi nal 
visit.  
  Pr o gressi o n of t he u n derl yi n g ne o plas m res ulti n g i n h os pitali zati o n or deat h (e. g., patie nt 
h os pitalize d f or or dies fr o m P D o nl y, wit h o ut a n y ot her S A E) will be d oc u me nte d as a n 
a ntit u m or acti vit y o utc o me a n d n ot as a n S A E. If a n S A E occ urs i n a patie nt a n d it is u ncle ar 
w het her t he e ve nt is relate d t o P D, t he S A E s h o ul d be re p orte d. 
  T he re p orti n g of la b orat or y/ vit al si g ns a b n or malities as b ot h la b orat or y fi n di n gs a n d A Es s h o ul d 
be a v oi de d. T he y s h o ul d n ot be re p orte d as A Es u nless a n y o ne of t he f oll o wi n g are met:  
o  
A n y criteri o n f or a n S A E is f ulfille d  
o  
T he la b orat or y/ vital si g ns a b n or malit y ca uses t he patie nt t o disc o nti n ue fr o m t he st u d y 
treat me nt 
o  
T he la b orat or y/ vital si g ns a b n or malit y ca uses t he patie nt t o i nterr u pt t he st u d y 
treat me nt 
o  
T he la b orat or y/ vital si g ns a b n or malit y re q uires i nter ve nti o n  
o  
T he la b ora t or y/ vital si g ns are dee me d cli nicall y si g nifica nt, base d o n me dical 
j u d g me nt.  
Efficac y Assess me nts : 
T u m or assess me nts will be o btai ne d at scree ni n g usi n g C T a n d/ or M RI sca ns at ti me i nter vals as s pecifie d i n 
A p pe n di x  1  ( Ti me a n d E ve nts T a ble: D ose Escalati o n) a n d A p pe n di x  2  ( Ti me a n d E ve nts Sc he d ule: C o h ort  
E x pa nsi o n). Ra di o gra p hic disease assess me nts will occ ur e ver y 6 wee ks (i.e., f oll o wi n g 2 c ycles of treat me nt 
[ C ycles 3, 5, etc.]) f or t he first 2 4 wee ks a n d t he n e ver y 1 2 wee ks t hereafter u ntil d oc u me nte d pr o gressi o n, 
i nitiati o n of alter nati ve a nti-ca ncer t hera p y, l ost t o f oll o w -u p, wit h dra wal of i nf or me d c o nse nt, deat h, or e n d 
of st u d y.   Treat me nt will c o nti n ue u ntil patie nts ha ve c o m plete d st u d y t hera p y a n d re q uire d f oll o w -u p, 
C o nfi d e nti al
P a g e   
2 8   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
e x perie nce d disease pr o gressi o n acc or di n g t o  ir R C, or ha ve bee n wit h dra w n fr o m t he st u d y. At eac h o n-
treat me nt t u m or assess me nt ti me p oi nt, t he o bj ecti ve res p o nse stat us will be deter mi ne d.  
F or patie nts w h o de m o nstrate acce pta ble t olera bilit y of treat me nt wit h pe m br oliz u ma b a n d mar get u xi ma b 
a n d ac hie ve a n o bj ecti ve res p o nse assess me nt of ir C R, ir P R or ir S D, or u nc o nfir me d cli nic all y sta ble ir P D, 
t hera p y ma y be c o nti n ue d (see Secti o n  4. 4  a n d S ecti o n 5. 3 ). 
F or patie nts w h o are ot her wise cli nicall y sta ble, b ut ha ve met c o n ve nti o nal criteria f or P D, t hera p y ma y be 
c o nti n ue d at t he discreti o n of t he i n vesti gat or pe n di n g c o nfir mati o n of pr o gressi o n at t he ne xt sc he d ule d 
t u m or assess me nt. T his a p pr oac h all o ws f or li mite d treat me nt of patie nts be y o n d t he i nitial ra di o gra p hic 
d oc u me ntati o n of disease pr o gressi o n, ass u mi n g t hat patie nts are t olerati n g t hera p y a de q uat el y, t hat patie nts 
re mai n ot her wise cli nicall y sta ble des pite t his i nitial ra di o gra p hic e vi de nce of disease pr o gr essi o n a n d t hat 
t he i n vesti gat or feels t he patie nt ma y still deri ve be nefit fr o m c o nti n uati o n of t hera p y. Treat me nt of patie nts 
acc or di n g t o ir R C pri nci ples is s u p p orte d b y well -d oc u me nte d e vi de nce t hat i n s o me patie nts treate d wit h 
T   cell directe d, i m m u ne -m o d ulat or y a ge nts, t heir t u m ors ca n e v ol ve t o a n o bj ecti ve res p o nse after a n i nitial 
peri o d c haracterize d b y eit her a p pare nt ra di o gra p hic gr o wt h of tar get lesi o ns or t he de vel o p me nt of ne w 
tar get lesi o ns t hat w o ul d ot her wise meet t he criteria f or disease pr o gressi o n usi n g c o n ve nti o nal res p o nse 
criteria ( A p pe n di x  7 ). I n t he c o nte xt of t he statistical a nal ysis f or t his trial, o bj ecti ve res p o nse deter mi nati o n 
a n d t he assess me nt of best o verall res p o nse ( B O R) will be defi ne d usi n g b ot h  c o n ve nti o nal R E CI S T  1. 1  
(A p pe n di x  7 ) as well as a n a da ptati o n of t hese criteria, desi g nate d as i m m u ne-relate d res p o nse criteria 
(ir R C) (A p pe n di x  8 ). P atie nt ma na ge me nt decisi o ns, h o we ver, will be ma de s olel y base d o n t he i m m u ne-
relate d res p o nse criteria (A p pe n di x  8 ). 
F or patie nts i n w h o m pr o gressi o n is c o nfir me d at t he ne xt sc he d ule d t u m or assess me nt, t he criteria f or ir P D 
will ha ve bee n met, a n d treat me nt wit h mar get u xi ma b a n d pe m br oliz u ma b s h o ul d be disc o nti n ue d. T he 
patie nt s h o ul d be re m o ve d fr o m st u d y partici pati o n  after c o m pleti o n of pr ot oc ol s pecifie d f oll o w -u p (see 
Secti o n  8. 3 , A p pe n di x  1  a n d A p pe n di x  2 ). F or patie nts w h o e x perie nce a n o bj ecti ve res p o nse of i m m u ne-
relate d c o m plete res p o nse (ir C R) or i m m u ne-relate d partial res p o nse (ir P R), res p o nses will be c o nsi dere d 
u nc o nfir me d u ntil t he re s p o nse has bee n d oc u me nte d b y a s u bse q ue nt c o nfir mat or y sca n o btai ne d n o less 
t ha n 4 wee ks after t he i nitial sca n de m o nstrati n g a n o bj ecti ve res p o nse. 
E ffic ac y Assess me nts: 
O bjective Res p o nse a n d Res p o nse D ur ati o n  
T ar get a n d n o n -tar get lesi o ns will be desi g nate d a n d e val uat e d usi n g b ot h c o n ve nti o nal R E CI S T 1. 1 criteria 
(A p pe n di x  7 ) a n d ir R C (A p pe n di x  8 ) f or t he p ur p oses of st atistical a nal ysis. O bj ecti ve res p o nses will be 
cate g orize d as C o m plete Res p o nse ( C R), Partial Res p o nse ( P R), Sta ble Disease ( S D), or Pr o gressi ve Disease 
( P D) f or c o n ve nti o nal R E CI S T 1. 1 criteria a n d ir C R, ir P R, ir S D, a n d ir P D f or t he i m m u ne -relate d res p o nse 
criteria. Deter mi nati o n of t he o bj e cti ve res p o nse rate will be calc ulate d base d o n t he pr o p orti o n of res p o nse 
e val ua ble patie nts ac hie vi n g C R o r P R usi n g t he res pecti ve criteria, w he n s uc h res p o nses are c o nfir me d b y a 
s u bse q ue nt sca n o btai ne d at le ast 2 8 da ys after t he i nitial d oc u me ntati o n  of o bj ecti ve res p o nse. Res p o nse 
e val ua ble patie nts will i ncl u de t h ose patie nts w h o ha ve meas ura ble  disease a n d ha ve ha d a baseli ne t u m or 
assess me nt a n d recei ve d o ne d ose of eit her mar get u xi ma b or pe m br oliz u ma b (see A p pe n di x  1  a n d 
A p pe n di x  2 ). O bj ecti ve res p o nses t hat are n ot s u bse q ue ntl y d oc u me nte d wit h a c o nfir mat or y C T or M RI 
sca n (e. g., u nc o nfir me d res p o nses) will n ot be i ncl u de d as a n o bj ecti ve res p o nse f or t he p ur p ose of 
calc ulati n g o verall o bj ecti ve res p o nse rates. Res p o nse d urati o n will be calc ulate d fr o m t he ti me of i nitial 
res p o nse ( C R or P R) d oc u me ntati o n (i n patie nts w h o ha ve a s u bse q ue nt c o nfir mati o n of o bj ecti ve res p o nse) 
t o t he ti me of pr o gressi ve dise ase or deat h, w hic he ver occ urs first. A patie nt’s res p o nse d urati o n will be 
ce ns ore d if at t he ti me of last a ntit u m or assess me nt res p o nse is o n g oi n g.  
Pr o gressi o n -free s urviv al ( P F S) 
P F S will be calc ulate d as t he ti me fr o m t he first d ose of st u d y dr u g u ntil d oc u me nte d disease pr o gressi o n or 
deat h fr o m a n y ca use. ( A p pe n di x  5 ). A patie nt’s P F S will be ce ns ore d if at t he ti me of last assess me nt f or 
C o nfi d e nti al
P a g e   
2 9   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
pr o gressi o n, t he p atie nt re mai ns pr o gressi o n free. P F S will be deter mi ne d usi n g c o n ve nti o nal R E CI S T  1. 1. I n 
a d diti o n, P F S rate at 3 a n d 6 m o nt hs will be e val uate d.  
Over all s urviv al ( O S)  
O S will be calc ulate d as t he ti me fr o m t he first d ose of st u d y dr u g u ntil deat h d ue t o a n y c a use. A patie nt’s 
O S will be ce ns ore d if at t he ti me of last c o ntact, t he patie nt re mai ns ali ve. I n a d diti o n, O S rate at 1 a n d 2 
years will be e val uate d.  
P h ar m ac o ki netic Assess me nts:  
Ser u m c o nce ntrati o ns of mar get u xi ma b will be m o nit ore d usi n g a q ua n titati ve sa n d wic h e nz y me-li n ke d 
i m m u n os or be nt assa y ( E LI S A). Si n gle a n d m ulti ple d ose P K para meters f or mar get u xi ma b (e. g., C ma x , Tma x , 
A U C ta u, A U Ci nf, Ctr o u g h, C L, Vss, a n d Thalf) will be deri ve d fr o m mar get u xi ma b ser u m c o nc e ntrati o n vers us 
ti me data. P o p ulati o n P K a nal yses ma y be c o n d ucte d usi n g data fr o m t his st u d y al o ne or c o m bi ne d wit h data 
fr o m ot her st u dies. 
I m m u n o ge nicit y Assess me nts: 
T he ge nerati o n of a nti -dr u g a nti b o dies ( A D A) directe d a gai nst mar get u xi ma b will be assa ye d usi n g E LI S A. 
Sa m ples p osi ti ve f or A D A will be e val uate d f or ne utralizi n g acti vit y. 
P h ar m ac o d y n a mics/ Bi o m ar kers:  
T ests t o be perf or me d ma y i ncl u de t he f oll o wi n g:  
  Deter mi nati o n of Fc rece pt or ge n ot y pes f or C D 1 6 A, C D 3 2 A  a n d C D 3 2 B  
  C haracterizati o n of alterati o ns i n ser u m c yt o ki ne le ve ls i ncl u di n g, b ut n ot li mite d t o, i nterle u ki n 
(I L) I L-2, I L -6, I L -1 0, I F N -γ a n d T N F-α.  
  E n u merati o n of l y m p h oc yte s u bsets, nat ural killer ( N K) cells a n d ot her acti vati o n mar kers a n d 
acti vati o n stat us o ver ti me via m ulti -para meter fl o w c yt o metr y fl o w c yt o me tr y; e val uati o n of t he 
T -re g p o p ulati o n o ver ti me 
  Deter mi nati o n of t he p ote ntiati o n of H E R 2 s pecific a da pti ve h u m oral a n d cell ular i m m u ne 
res p o nses: Plas ma sa m ples a nal yze d b y E LI S A t o meas ure e n d o ge n o us a nti-H E R 2 I g G le vels; 
peri p heral bl o o d m o n o n uclear c ell ( P B M C) sa m ples a nal yze d b y E LI S p ot t o meas ure H E R 2 -
s pecific T-cell acti vit y  
  Deter mi nati o n of P D -L 1 e x pressi o n will be e x pl ore d via I H C stai ni n g of arc hi val t u m or bi o ps y 
s peci me ns ( u nless fres h t u m or sa m ple s u b mitte d a n d use d t o deter mi ne P D -L 1 e x pressi o n a n d 
n o arc hi ve d sa m ple o btai ne d)  
Li mite d t o C o h ort Ex p a nsi o n P h ase s ( P arts B-C ) o nly  ( u nless ot her wise n ote d):  
  Deter mi nati o n of m utati o nal b ur de n ( o n ct D N A deter mi ne d b y G uar da nt 3 6 0 assa y), as well as 
mis matc h re pair stat us b y micr osatellite i nsta bilit y (fr o m pat h ol o g y re p orts, w he n a vaila bl e). 
  Deter mi nati o n of P D -L 1 t u m or cell me m bra n o us e x pressi o n a n d T cell i nfiltrati o n (i ncl u di n g b ut 
n ot li mite d t o C D 4 + a n d C D 8 + T cells) i nt o t he t u m or be d via I H C stai ni n g of paire d pre - a n d 
o n -treat me nt tu m or bi o ps y s pe ci me ns.  
  P art B o nl y: Deter mi nati o n of H E R 2 t u m or cell me m bra n o us e x pressi o n via I H C stai ni n g of pre -
treat me nt a n d / or o n -treat me nt t u m or bi o ps y s peci me ns.  
  Deter mi nati o n of ge ne e x pressi o n si g nat ures  (i.e., na n ostri n g tec h n ol o g y)  i n tiss ues, w hic h ma y 
be i n dicati ve of i m m u n ot hera p y res p o nses ass ociate d wit h t he a ge nts o n trial.  
C o nfi d e nti al
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Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
A n al ysis P o p ul ati o ns:  
T w o ge neral p o p ulati o ns will be use d f or t he p ur p oses of dat a a nal ysis - t he Safet y P o p ulati o n a n d t he 
Res p o nse E val ua ble P o p ulati o n as defi ne d bel o w:  
  S afet y P o p ul ati o n:  All patie nts w h o recei ve d at least o ne d ose of eit her mar get u xi ma b or 
pe m br oliz u ma b. T his p o p ulati o n will be use d f or safet y a nal ysis a n d f or a nal ysis of P F S a n d O S. 
P atie nts w h o recei ve at least o ne d ose of mar get u xi ma b will be i ncl u de d i n P K, P D, a n d 
i m m u n o ge nicit y a nal yses. 
  Res p o nse E v al u a ble P o p ul ati o n:  All patie nts w h o ha ve baseli ne meas ura ble disease a n d 
recei ve d at least o ne d ose of eit her mar get u xi ma b or pe m br oliz u ma b. T his p o p ulati o n will be 
use d f or a nal ysis of O R R.  
St at istic al M et h o ds: 
Res p o nse will be cate g orize d as C R, P R, S D, or P D a n d e val uate d usi n g R E CI S T 1. 1 criteria a n d as ir C R, 
ir P R, ir S D, or ir P D usi n g t he ir R C. T he O R R will be t he pr o p orti o n of patie nts i n t he res p o nse e val ua ble 
p o p ulati o n ac hie vi n g C R or P R w he n s uc h res p o nses are c o nfir me d at least 2 8 da ys after t he i nitial 
o bser vati o n of a n o bj ecti ve res p o nse. A t w o -si de d 9 5 % e xact bi n o mial c o nfi de nce i nter val will be calc ulate d 
ar o u n d t he O R R f or eac h e x pa nsi o n re gi o n a n d als o b y t u m or t y pe.  
Res p o nse d urati o n will be calc ulate d f or res p o n ders as t he ti me fr o m i nitial res p o nse ( C R or P R) t o t he ti me 
of P D or deat h. Ka pla n -Meier met h o ds will be use d t o esti mate res p o nse d urati o n o ver ti me a n d t he me dia n 
res p o nse d urati o n. Res p o n ders w h o c o m plete t he st u d y wit ho ut d oc u me nte d P D will be ce ns ore d at t he date 
of t heir last t u m or assess me nt.  
P F S will be calc ulate d as t he ti me fr o m t he i nitial i nf usi o n of pe m br oliz u ma b or mar get u xi ma b u ntil 
d oc u me nte d disease pr o gressi o n or deat h fr o m a n y ca use. Patie nts wit h n o P F S e ve nt ( disease pr o gressi o n or 
deat h fr o m a n y ca use) will be ce ns ore d at t he date of t heir last t u m or assess me nt. I n a d diti o n, P F S rates will 
be calc ulate d at 3 a n d 6 -m o nt h ti me p oi nts fr o m t he first d ose of st u d y dr u g. Ka pla n -Meier met h o ds will be 
use d t o esti mate P F S o ver ti me a n d t he me dia n d urati o n of P F S. T he met h o d of Br o o k me yer a n d Cr o wle y  (9 ) 
will be use d t o c o nstr uct 9 5 % CIs ar o u n d P F S esti mates of t he me dia n a n d ot her q uartiles f or eac h e x pa nsi o n 
re gi o n a n d als o b y t u m or t y pe . 
I nc o m plete a n d missi n g data c a n c o m plicate i nter pretati o n of P F S. A p pe n di x  5  descri bes t he ha n dli n g of 
t hese data f or t he P F S a nal ysis.  
O verall s ur vi val is defi ne d as t he ti me fr o m t he i nitial i nf usi o n of pe m br oliz u ma b or mar get u xi ma b t o deat h 
fr o m a n y ca use. P atie nts w h o are ali ve at last c o ntact will be ce ns ore d at t he date t hat t he patie nt was last 
k n o w n t o be ali ve. Ka pla n -Meier met h o ds will be use d t o esti mate t he o verall s ur vi val f u ncti o n. I n a d diti o n, 
O S rate will be calc ulate d at 1 year a n d 2 -year ti me p oi nts fr om t he first d ose of st u d y dr u g.  
I n P art B , after 1 5 patie nts we re e nr olle d i n eac h re gi o n u n der t he Ori gi nal Pr ot oc ol a n d Pr ot oc ol 
A me n d me nt 1 a n d after eac h patie nt has at least o ne p ost -baseli ne t u m or assess me nt, a f utilit y r ule was  
a p plie d a n d e nr oll me nt i n t hat re gi o n was  c o nti n ue d. T he e nr oll me nt c o ul d ha ve bee n  st o p pe d if t here was  n o 
m ore t ha n o ne res p o nse. O ne res p o nse o ut of 1 5  patie nts will ha ve 8 0 % c o nfi de nce t o r ule o ut t he res p o nse 
rate of 2 0 % or hi g her (t he u p per li mit of o ne-si de d 8 0 % CI for res p o nse rate < 2 0 %).  
C o nfi d e nti al
P a g e   
3 1   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
2    
B A C K G R O U N D I N F O R M A TI O N   
2. 1    
Dise ase B ac k gr o u n d   
2. 1. 1    
G astr oes o p h a ge al J u ncti o n C a ncer a n d G astric C a ncer   
Alt h o u g h t he i nci de nce of gastr oes o p ha geal j u nct i o n ca ncer ( G EJ) a n d gastric ca ncer ( G C) has 
bee n decli ni n g i n rece nt deca d es, it re mai ns a gl o bal healt h pr o ble m. It is a disease ass ociate d 
wit h hi g h m ortalit y a n d p o or pr o g n osis, as it is ofte n dia g n ose d at a n a d va nce d sta ge  (1 5 , 5 2 ). If 
i de ntifie d at a n earl y sta ge, s ur ger y is t he pri mar y treat me nt f or patie nts wit h G C, wit h a 5-year 
s ur vi val of 3 6 % i n patie nts wit h o pera ble diseas e w h o als o recei ve peri o perati ve c he m ot hera p y 
(1 6 ). Fi ve-year s ur vi val a m o n g patie nts wit h a d v a nce d or metast atic  G C , h o we ver, has bee n 
re p orte d t o ra n ge bet w ee n 5-2 0 %, wit h me dia n o verall s ur vi val  ( O S) rates of less t ha n 1 year 
(6 9 ). 
Gl o ball y, G C  is t he fift h m ost c o m m o n mali g na nc y, wit h half t he t otal occ urri n g i n Easter n Asia. 
It is t he t hir d lea di n g ca use of ca n cer deat h w orl d wi de, wit h t he hi g hest esti mate d m ortalit y rat es 
occ urri n g i n East er n Asia ( htt p:// gl o b oc a n.i arc.fr/ P a ges/f act _s heets _c a ncer. as p x ). I n t he 
U nite d States ( U S), it is esti mate d t hat o ver 2 4, 5 0 0 pe o ple will be dia g n ose d wit h G C  a n d 1 0, 7 2 0 
i n di vi d uals will die fr o m t his disease i n 2 0 1 5 (6 9 ). F or patie nts wit h a d va nce d -sta ge G C, 
treat me nt t y pi call y c o nsists of a fl u or o p yri mi di ne-base d c o m bi nati o n c he m ot hera p y a n d is 
ass ociate d wit h a me di a n o verall s ur vi val of 7 -1 0 m o nt hs (5 2 , 7 8 ). The i ntr o d ucti o n of tar get e d 
treat me nts f or G C  has i m pr o ve d o verall s ur vi val rates f or s pecific p o p ulati o ns. I n t he To G A trial 
(3 ), trast uz u ma b, a m o n o cl o nal a nti b o d y a gai nst H E R 2, i n c o m bi nati o n wit h c he m ot hera p y, 
i ncreas e d me dia n o verall s ur vi val b y a p pr o xi matel y 3. 5 m o nt hs a n d is n o w use d f or t he first-li ne 
treat me nt of H E R 2 + a d v a nce d gastric or G EJ. I n patie nts wit h pre vi o usl y treate d disease, 
ra m ucir u ma b, a V E G F R-2 a nti b o d y, a d mi nistere d as si n gle a ge nt or i n c o m bi nati o n wit h 
paclita xel, de m o nstrate d i ncreas es i n me dia n o verall s ur vi val of 1. 4 m o nt hs a n d 2. 2 m o nt hs, 
res pecti vel y (2 6 , 8 1 ). Alt h o u g h ne wer t hera pies ha ve i m pr o ve d s ur vi val f or a d va nce d cases of 
G EJ a n d G C s, t here re mai ns a si g nifica nt me di cal nee d f or c o nti n ue d i m pr o ve me nt i n t hera pies 
f or t his disease. 
2. 1. 2    
H E R 2 + G astr oes o p h a ge al J u ncti o n C a ncer or G astric C a ncer   
H E R 2 p ositi vit y has b ee n o bser ve d i n 7 –  3 5 % of G C  t u m ors (3 ). T he To G A trial esta blis he d 
H E R 2 as a vali date d tar get i n patie nts wit h G EJ or G C  a n d de m o nstrate d t hat patie nts wit h 
o vere x pressi o n of H E R 2 be nefitte d fr o m recei vi n g trast uz u ma b i n a d diti o n t o sta n dar d 
(fr o ntli ne) fl u or o p yri mi di ne/cis plati n c he m ot hera p y. Me dia n o verall s ur vi val ( O S) a n d 
pr o gressi o n -free s ur vi val ( P F S) i n t he c he m ot hera p y pl us trast uzu ma b -treate d patie nts were 
1 3. 8  m o nt hs a n d 6. 7 m o nt hs, res pecti vel y, c o m pare d t o 1 1. 1 m o nt hs a n d 5. 5  m o nt hs , 
res pecti vel y, i n patie nts treate d wit h c h e m ot hera p y al o n e. A n e x pl orat or y a nal ysis c o n d ucte d i n 
patie nts w h ose t u m ors ha d hi g h H E R 2 e x pressi o n (as defi ne d b y H E R 2 3 + or 2 + p ositi ve b y 
i m m u n o hist oc he mistr y (I H C) wit h a m plifie d b y fl u oresce nce i n sit u h y bri dizati o n [ FI S H]), 
de m o nstrate d a me di a n O S of 1 6 m o nt hs f or patie nts treate d wit h c he m ot hera p y pl us 
trast uz u ma b vs. 1 1. 8 m o nt hs f or patie nts treate d wit h c he m ot hera p y al o ne. T hese res ults ha ve 
C o nfi d e nti al
P a g e   
3 2   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
f or me d t he basis f or usi n g trast uz u ma b as sta n dar d of care f or fr o ntli ne H E R 2 + G EJ or G C  
patie nts .  
Treat me nt of patie nts wit h a d va nce d H E R 2 + gastric or G EJ ca ncer w h o ha ve pr o gress e d after  
fr o ntli ne fl u or o p yri mi di ne/cis plati n c he m ot hera p y pl us trast uz u ma b is n ot well defi ne d. 
H o we ver, si n gle -a ge nt ta x a ne or iri n oteca n t hera p y is fre q ue ntl y e m pl o ye d  (1 , 1 3 , 3 3 , 3 7 , 4 4 ). 
Res p o nse rates res ulti n g fr o m t he use of wee kl y paclita xel i n t his patie nt p o p ulati o n ra n ge d  fr o m 
1 6 % t o 2 4 %, w hile me di a n P F S ra n ge d  fr o m a p pr o xi matel y 2. 1 t o 2. 6  m o nt hs a n d me dia n O S 
fr o m a p pr o xi matel y 5. 0 t o 7. 8 m o nt hs (3 3 , 4 1 , 4 4 , 8 1 ). Iri n oteca n pr o d uce d si milar res ults i n a 
si milar patie nt p o p ulati o n (4 1 ). Rece ntl y, t he R AI N B O W st u d y de m o nstrat e d a n i m pr o ve me nt i n 
o verall s ur vi val t o 9. 6 m o nt hs wit h t he a d diti o n of ra m ucir u ma b i n c o m bi nati o n wit h paclita xel 
i n sec o n d-li ne setti n g f or G EJ or G C  (8 1 ).  
A d diti o nal a nti -H E R 2 t hera pies ha ve bee n a n d are bei n g teste d i n t he sec o n d -li ne treat me nt of 
patie nts wit h a d va nce d G EJ or gastric ca ncers o vere x pressi n g H E R 2. Alt h o u g h t he Ty T A N trial 
faile d t o de m o nstrate a statisticall y si g nifica nt i m pr o ve ment i n s ur vi val f or  t he c o m bi nati o n 
of  paclita xel pl us la pati ni b  (6 3 ), t he p oi nt esti mates f or s ur vi val fa v ore d t he c o m bi nati o n 
( O S =  1 1. 0 m o nt hs) vs. t he paclita xel al o ne ar m ( O S = 8. 9 m o nt hs), s u g gesti n g t hat a m or e 
p ote nt a nti -H E R 2 t hera p y mi g ht be usef ul i n t his setti n g. I n a d diti o n, a lar ge m ulti nati o nal trial is 
u n der wa y i n v ol vi n g t he sec o n d-li ne treat me nt of patie nts wit h gastric or G EJ ca ncer c o m pari n g 
t he a nti-H E R 2 dr u g c o nj u gat e a d o -trast uz u ma b e mta nsi ne t o ta xa ne al o ne. A sec o n d trial 
e x a mi nes t he acti vit y of t he c o m bi nati o n of ca pecita bi ne pl us a d o -trast uz u ma b e mta nsi ne i n 
patie nts wit h a d va nce d H E R 2 + gastric or gastr oes o p ha geal ca ncer wit h o ut re gar d t o pri or 
treat me nt. A p pl yi n g t he para di g m de vel o p e d i n t he treat me nt of H E R 2 -o vere x pressi n g metastatic 
breast ca ncer (2 7 , 3 8 ), it ma y b e reas o na ble t o c o nti n ue a nti-H E R 2 t hera p y f oll o wi n g diseas e 
pr o gressi o n w hil e m o vi n g t o a n ot her bac k b o ne c he m ot hera p y re gi me n. H o we ver, n o s p ecific 
a nti-H E R 2 treat me nt is c urre ntl y part of t h e sta n dar d treat me nt al g orit h m f or H E R 2 
o vere x pressi n g gastric or G EJ ca ncers after trast uz u ma b. Rece nt literat ure s u g gests t hat 
pr o gressi o n p ost -trast uz u ma b a n d fail ure of ot her H E R 2 tar gete d a ge nts is d ue t o l oss of H E R 2 
o vere x pressi o n (1 8 , 3 9 , 6 5 ). F urt her m ore, t here is hi g h heter o ge neit y of H E R 2 e x pressi o n i n 
gastri c a n d G EJ ca ncers (3 1 , 8 4 ) i n dicati n g a nee d f or tests wit h hi g her s pecificit y (6 6 ). G uar da nt 
3 6 0 is a di gi tal se q ue n ci n g pa n el f or q ua ntitati ve a nal ysis of cell-free circ ul ati n g t u m or D N A 
wit h hi g h s pecifi cit y, w hi c h ca n b e use d t o m o nit or H E R 2 ge ne a m plificati o n le vel 
l o n git u di nall y as well as o verall t u m or m utati o nal b ur de n (4 5 ). T he N E X T-2 trial has s h o w n n o n -
i nferi orit y t o tiss ue bi o ps y a n d a d va nta ge of real-ti me pre dicti ve treat me nt i n refract or y t u m ors 
(4 6 ). Alt h o u g h a lar ge b o d y of literat ure s u p p orts t he n oti o n t hat trast uz u ma b acts b y alterati o n of 
si g nali n g fr o m t he H E R 2 o nc opr otei n a n d res ulti n g s u bse q ue nt gr o wt h i n hi biti o n a n d/ or 
a p o pt osis  (3 5 , 8 5 ) t here is a gr o wi n g realizati o n t hat a n i m p orta nt mec ha nis m of trast uz u ma b’s 
acti o n is t he me diati o n of a nti b o d y de pe n de nt cell ular c yt ot o xicit y ( A D C C). Cl y nes et al. (1 4 ) 
de m o nstrate d t hat t he t u m or i n hi biti o n effects of  trast uz u ma b o n h u ma n t u m or xe n o graft m o dels 
were d e pe n de nt u p o n e x pressi o n i n t he m o use of rece pt ors f or t he Fc p orti o n of t he a nti -H E R 2 
m o n ocl o nal a nti b o d y . T his o bser vati o n was f oll o we d b y t he de m o nstrati o n b y M us oli n o et al. 
(5 1 ) of pr ol o n ge d P F S f or patie nts wit h metastatic breast ca ncer treate d wit h trast uz u ma b i n hi g h 
affi nit y vs. l o w affi nit y carriers of alleles of t h e ge ne f or t he acti vati n g Fc rece pt or C D 1 6 A.  
C o nfi d e nti al
P a g e   
3 3   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
2. 2    
B ac k gr o u n d o n P D -1   
2. 2. 1    
P D -1   
T he i m p orta nce of i ntact i m m u ne s ur veilla nce i n c o ntr olli n g o ut gr o wt h of ne o plastic 
tra nsf or mati o n has bee n k n o w n f or deca des (1 9 ). Acc u m ulati n g evi de nce s h o ws a c orrelati o n 
bet wee n t u m or -i nfiltrati n g l y m p h oc ytes ( TI Ls) i n ca ncer tiss ue a n d fa v ora ble pr o g n osis i n 
vari o us mali g n a ncies (6 , 8 , 2 2 , 2 9 , 4 8 , 5 5 , 5 6 , 6 2 , 6 4 , 6 8 , 7 5 , 7 7 ). I n partic ular, t he pres e nce of 
C D 8 + T cells a n d t he rati o of C D 8 + effect or T cells/ F o x P 3 + re g ulat or y T cells  ( T-re gs) c orrelates 
wit h i m pr o ve d pr o g n osis a n d l o n g -ter m s ur vi val i n ma n y s oli d mali g na nci es, s uc h as o varia n, 
c ol orectal, a n d pa ncreati c ca n cer s; he pat ocell ular carci n o ma; mali g na nt mela n o ma; a n d re nal cell 
carci n o ma (1 2 , 2 0 , 4 3 , 4 7 , 5 5 , 5 8 , 8 6 ). T u m or -i nfiltrati n g l y m p h o c ytes ca n be e x pa n de d e x vi v o 
a n d rei nf use d, i n d uci n g d ura ble o bjecti ve t u m or res p o nses i n ca ncers s uc h as mela n o ma  (2 1 , 3 0 , 
3 6 ).   
Pr o gra m me d deat h pr ot ei n -1 ( P D -1) is a n i m m u ne -m o d ulat or y rece pt or e x presse d o n acti vate d 
T -cells. The  p h ysi ol o gical r ole of P D -1 is t o li mit t he i nfla m mat or y res p o ns e t o i nfecti o n a n d 
pre ve nt a ut oi m m u nit y b y li miti n g t he acti vit y of T cells i n t he peri p her y  (5 , 2 5 , 4 2 ). T he basis f or 
t his p h ysi ol o g y is t hat t he li ga n ds f or P D-1, na m el y pr o gra m me d deat h -li ga n d 1 ( P D-L 1) ( B 7 -
H 1) a n d pr o gra m me d deat h -li ga n d 2 ( P D-L 2) ( B 7 -D C), are u p -re g ulate d o n ma n y cell t y pes —  
he mat o p oietic, e n d ot heli al a n d e pit helial —  i n res p o nse t o pr o-i nfla m mat or y c yt o ki nes, n ota bl y 
i nterfer o n ga m ma. I n a d diti o n, PD -L 2 is u p -re g ulate d o n de n dritic cells a n d macr o p ha ges i n 
res p o nse t o differe nt pr o-i nfla m mat or y c yt o ki nes s uc h as i nterle u ki n (I L) I L-4 (6 7 , 8 0 ). 
Ca ncer cells, t o a v oi d a ntit u m or res p o nse, c o -o pt t he n or mal p h ysi ol o g y of t he P D -1 pat h wa y 
use d t o pre ve nt c ollat eral n or mal tiss ue da ma ge t h at w o ul d occ ur i n a n u nc hec ke d i nfla m mat or y 
i m m u ne res p o nse. E x pressi o n of P D-L 1 as a n a da pti ve res p o nse t o a ntit u m or i m m u nit y li kel y 
occ urs beca use t his li ga n d is i n d uce d o n m ost e pit helial ca ncers i n res p o ns e t o i nterfer o n -ga m ma, 
si milarl y t o e pit helial a n d str o mal cells i n n or mal tiss ues (7 6 ). I n a d diti o n, P D-1 is hi g hl y 
e x presse d o n i n d uce d re g ulat or y T-cells ( T-re gs), a n d P D-1: P D -L 1 i nteracti o ns a p pear t o 
pr o m ote t he i n d ucti o n, c o n versi o n a n d mai nte na nce of T-re gs, s u g gesti n g a n a d diti o nal 
mec ha nis m f or i m m u n os u p pressi o n i n a t u m or  micr oe n vir o n me nt ri c h i n P D -1 li ga n ds (2 , 2 4 ). 
Bl oc ka d e of ne gati ve re g ulat or y si g nals t o T cells, s uc h as C T L A -4 a n d P D -1/ P D -L 1, is a n area 
of acti ve i n vesti gati o n i n gastri c ca n cer. E x pressi o n of P D -L 1 o n gastric t u m ors has bee n 
d oc u me nte d i n a n u m ber of st u dies  (1 0 , 8 3 ). C ollecti vel y, t hese st u dies i ncl u de d 7 2 5 patie nts a n d 
de m o nstrate d e x pressi o n wit h a n a vera ge fre q ue nc y of 4 3 %, ra n gi n g fr o m 4 2 % t o 6 7 %, 
s u g gesti n g t hat t he P D-L 1 pat h wa y is acti ve i n t his setti n g a n d t hat bl oc ka de of P D -L 1 ac ti vit y 
c o ul d ha ve t hera pe utic b e nefit. C o m plete res p o ns es i n gastric ca ncer ha ve bee n a nec d otall y 
re p orte d wit h a nti-c yt oto x ic T l y m p h o c yt e a nti ge n 4 ( C T L A-4) a n d a nti -P D -1/ P D -L 1 a nti b o dies 
(5 9 , 7 4 ). I n dee d, t he rece nt re p ort de m o nstrati n g a n i m pr o ve me nt i n s ur vi val a m o n g hea vil y pre-
treate d a d v a nce d metastatic gastri c a n d G EJ ca ncers t hat were treat e d wit h m o n ot hera p h y 
pe m br oliz u ma b cli nicall y vali dat es t he a p pr oac h  of i n hi biti n g t his pat h wa y. I n t his st u d y, t he 
K E Y N O T E -0 1 2 st u d y, 3 9 a d va nce d metastatic gastric or G EJ ca ncer patie nts t hat were 
refract or y t o sta n dar d treat me nts were treate d wit h m o n ot hera p y pe m br oli z u ma b. A n o bjecti ve 
C o nfi d e nti al
P a g e   
3 4   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
res p o nse rate ( O R R) of 2 2. 2 % was n ote d, al o n g wit h a 1. 9 -m o nt h me dia n pr o gressi o n -free 
s ur vi val a n d a n 1 1. 4-m o nt h me dia n o verall s ur vi val (4 ). 
2. 3    
St u d y A ge nt B ac k gr o u n d   
2. 3. 1    
M ar get u xi m a b   
Mar get u xi ma b  (5 4 ) is deri ve d fr o m 4 D 5, t he m uri ne prec urs or t o t he h u ma nize d t hera pe utic 
a nti b o d y, trast uz u ma b. C hi meric 4 D 5 (c h 4 D 5) is ge nerat e d b y f usi n g t he m o use li g ht c hai n ( L C) 
a n d heav y c hai n ( H C) c o m ple me ntarit y -deter mi ni n g re gi o n ( C D R) a n d fra me w or k se q ue nces of 
4 D 5 t o a h u ma n i m m u n o gl o b uli n (I g) G 1 bac k b o ne. Mar get u xi ma b is ge nerate d fr o m c h 4 D 5 b y 
re m o val of a n N-gl yc os ylati o n site i n t he L C varia ble re gi o n ( m o dificati o n of o ne a mi n o aci d 
resi d ue) a n d b y o pti mizati o n of t he Fc d o mai n ( m o dificati o n of fi ve a mi n o aci d resi d ues). 
Mar get u xi ma b bi n ds t he H E R 2 o nc o pr otei n wit h affi nit y si milar t o t hat of trast uz u ma b, a n d 
preser ves t he direct a nti -pr oliferati ve pr o perties of trast uz u ma b. T h e o pti mize d Fc d o mai n of 
mar get u xi ma b, h o we ver, c o nfers e n ha nce d bi n di n g t o t he acti vati n g l o w -affi nit y a n d hi g h 
affi nit y Fc rece pt ors, C D 1 6 A. I n partic ular, bi n di n g t o t he l o wer -affi nit y is of or m of C D 1 6 A 
( C D 1 6 A-1 5 8 F) is e n ha n ce d i n a pr o p orti o nall y greate r fas hi o n t ha n bi n di n g t o t he hi g her-affi nit y 
is of or m ( C D 1 6 A-1 5 8 V). I n a d diti o n, t he o pti mize d Fc d o mai n of mar get u xi ma b e x hi bits re d uce d 
bi n di n g t o t he i n hi bit or y rece pt or, C D 3 2 B, a feat ure e x pecte d t o f urt her e n ha nce t he cell -directe d 
c yt ot o xic pr o pertie s of m ar get u xi ma b. I n precli nical m o dels, mar get u xi ma b e x hi bits e n ha nce d 
a nti-t u m or acti vit y c o m p are d t o a trast uz u ma b s urr o gate a gai nst H E R 2-e x pressi n g t u m or cell 
li nes i n i n vitr o A D C C assa ys a n d i n h u ma n t u m or xe n o graft m o dels i n h u ma n C D 1 6 A + 
tra ns ge nic mice.  
2. 3. 1. 1    
M ar get u xi m a b Cli nic al E x perie nce   
Mar get u xi ma b has bee n, or is c urre ntl y bei n g e val uate d i n t hree ot her cli nical st u dies, 
C P -M G A H 2 2 -0 1  (st u d y cl ose d, C S R fi nal), C P-M G A H 2 2 -0 2  ( C S R pre parati o n o n g oi n g) a n d 
C P -M G A H 2 2 -0 4  (st u d y is o n g oi n g) .  
St u d y C P -M G A H 2 2 -0 1 is a P hase 1, o pe n -l a bel, si n gle-ar m, m ultice nter d ose -escalati o n st u d y t o 
defi ne t he t o xicit y pr ofile, ma xi m u m t olerate d d ose ( M T D), i m m u n o ge nicit y, p har mac o ki net ic 
( P K), a n d p ote ntial a nti-t u m or acti vit y of mar get u xi ma b i n patie nts wit h refract or y H E R 2 + 
breast ca ncers, H E R 2 + gastric or G EJ ca ncers, a n d patie nts wit h ot her carci n o mas t hat 
o vere x press H E R 2 f or w h o m n o sta n dar d t hera p y is a vaila ble. T he st u d y e val uat e d 2 re gi me ns of 
mar get u xi ma b (a d mi nistere d via i ntra v e n o us [I V] i nf usi o n): t hree of e ver y f o ur -wee k d osi n g 
( 0. 1 –  6. 0  m g/ k g) a n d e v er y 3 -wee k d osi n g ( 1 0. 0, 1 5. 0, a n d 1 8. 0 m g/ k g). T he C S R f or t his st u d y 
has bee n c o m plet e d.  
St u d y C P -M G A H 2 2 -0 2 is a si n gle -ar m, o pe n-la bel, P hase 2 st u d y of mar get u xi ma b i n patie nts 
wit h rela pse d or refract or y breast ca ncer w h ose t u m ors e x press H E R 2 at a 2 + le vel b y I H C a n d 
lac k e vi de nce of H E R 2  ge ne a m plificati o n b y FI S H or e x press H E R 2 at a 1 + le vel b y I H C a n d 
ha ve a v al ue of  > 1 0. 5 b y H E R mar k ® testi n g. T he ori gi nal mar get u xi ma b d ose a n d sc he d ul e 
e val uate d was 6. 0 m g/ k g via I V i nf usi o n wee kl y o n Da ys 1, 8, a n d 1 5 of a 2 8 -da y c ycl e. T he 
st u d y pr ot oc ol w as s u bse q ue ntl y a m e n de d t o e val uate mar get u xi ma b at a d ose a n d sc he d ul e of 
C o nfi d e nti al
P a g e   
3 5   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
1 5  m g/ k g via I V i nf usi o n e ver y 3 wee ks, c o nsiste nt t o t hat bei n g e val uate d i n t he C P -M G A H 2 2 -
0 1 st u d y. T his st u d y is cl ose d, a n d t he C S R is bei n g c o m plet e d.  
St u d y C P -M G A H 2 2 -0 4 is a P hase 3, ra n d o mize d, o pe n -la bel, c o ntr olle d st u d y c o m p ari n g 
mar get u xi ma b t o t rast uz u ma b, eac h i n c o m bi nati o n wit h c he m ot hera p y, f or t he treat me nt of 
patie nts wit h a d va nce d H E R 2 + breast ca ncer w h o ha ve recei ve d pri or treat me nt wit h 
trast uz u ma b, pert uz u ma b, a n d a d o-trast uz u ma b e mta nsi ne i n t he ne oa dj u v a nt, a dj u va nt, or 
metastatic set ti n gs a n d h a ve recei ve d at least o ne, a n d n o m ore t ha n t hree, li nes of t hera p y i n t he 
metastatic setti n g. Patie nts m ust ha ve pr o gresse d o n or f oll o wi n g t he m ost rece nt t hera p y. 
Eli gi ble patie nts will be assi g ne d t o c he m ot hera p y of t he i n vesti gat or’s c h oi ce  t o be c h os e n fr o m 
ca pecita bi ne, eri b uli n, ge mcita bi ne, or vi n orel bi ne. St u d y treat me nts (st u d y dr u gs a n d 
c he m ot hera pi es) t o be a d mi nistere d d uri n g t his st u d y are s u m marize d i n t he f oll o wi n g ta ble . 
A ge nt  
St arti n g D ose  
Sc he d ule  
M o de of 
A d mi nistr ati o n  
C he m ot her a p y  
  Ca pecita bi ne    
1 0 0 0 m g/ m 2 BI D    
BI D f or 1 4 da ys i n a 2 1 -da y c ycle    
Oral  
  Eri b uli n  
1. 4 m g/ m 2    
Da y 1 a n d 8 of a 2 1 -da y c ycle  
I V 
  Ge mcita bi ne    
1 0 0 0 m g/ m 2    
Da y 1 a n d 8 of a 2 1 -da y c ycle  
I V 
  Vi n orel bi ne    
2 5 -3 0 m g/ m 2    
Da y 1 a n d 8 of a 2 1 -da y c ycle  
I V 
St u d y Dr u gs  
  Trast uz u ma b  
8 m g/ k g l oa di n g d ose 
t he n 6 m g/ k g 
E ver y 2 1 da ys  
I V 
  Mar get u xi ma b  
1 5 m g/ k g  
E ver y 2 1 da ys  
I V 
BI D = t wice dail y; I V = i ntra ve n o us  
 
A p pr o xi matel y 5 3 0 p atie nts will partici pate i n t his st u d y.  
As of 3 0  Se pte m ber 2 0 1 7 , 2 7 6  patie nts  ha ve bee n  treate d i n trials i n vesti gati n g mar get u xi ma b, 
i ncl u di n g 2 7 4  patie nts treate d i n 4  Macr o Ge nics -s p o ns ore d cli nical st u dies  a n d 2  patie nt s bei n g 
treate d i n a n o n-Macr o Ge nics -s p o ns ore d ex pa n de d access pr o gra m ( E A P) trial as f oll o ws: 
 C P -M G A H 2 2 -0 1: n = 6 6 patie nts e nr olle d a n d treate d  
 C P -M G A H 2 2 -0 2: n = 2 5 patie nts e nr olle d a n d treate d  
 C P -M G A H 2 2 -0 4: n = 1 1 9 patie nts e nr olle d a n d treate d wit h mar get u xi ma b. 
( N ote: data re mai n bli n de d t o t he S p o ns or; t heref ore, t he safet y s u m maries prese nte d 
herei n i ncl u de  d ata fr o m patie nts treate d wit h t he c o m parat or a ge nt, trast uz u ma b.)  
 C P -M G A H 2 2 -0 5: n = 6 4 patie nts e nr olle d a n d treate d  
 E A P: n = 2 patie nt e nr oll e d a n d treate d ( n o n -M acr o Ge nics -s p o ns ore d trial) 
 
C o nfi d e nti al
P a g e   
3 6   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
Mar get u xi ma b has bee n t olera ble, a n d t h e o verall safet y pr of ile has re m ai ne d u nc ha n ge d wit h n o 
occ urre nce of c o n cer ni n g safet y si g nals. Refer t o t he m ar get u xi m a b in vesti g at or ’s b r oc h ure 
f or details o n its safet y pr ofile. 
2. 3. 2    
Pe m br oliz u m a b B ac k gr o u n d a n d Cli nic al Tri als   
T hera p e utic st u dies i n m o use m o dels ha ve s h o w n t hat a d mi nistrati o n of a nti b o dies bl oc ki n g 
P D -1/ P D -L 1 i nteracti o n e n ha nces i nfiltrati o n of t u m or -s pecific C D 8 + T cells a n d ulti matel y 
lea ds t o t u m or rejecti o n, eit her as a m o n ot hera p y or i n c o m bi nati o n wit h ot her treat me nt 
m o dalities  (7 , 1 7 , 3 2 , 5 7 , 7 0 , 7 1 , 7 9 ). A nti-m o use P D -1 or a nti -m o use P D -L 1 a nti b o dies ha ve 
de m o nstrate d a ntit u m or res p o nses i n m o dels of s q ua m o us cell carci n o ma , pa ncreatic carci n o ma, 
mela n o ma, ac ute m yel oi d le u ke mia a n d c ol orectal carci n o ma (1 7 , 5 3 , 5 7 , 7 1 , 8 7 ). I n s uc h 
st u dies, t u m or i nfiltrati o n b y C D 8 + T cells a n d i ncrease d I F N-γ, gra nz y me B a n d perf ori n 
e x pressi o n were o bser ve d, i n dicati n g t hat t he mec ha nis m u n derl yi n g t he a ntit u m or acti vit y of 
P D -1 c hec k p oi nt i n hi biti o n i n v ol ve d l ocal i nfiltrati o n a n d acti v ati o n of effect or T cell f u ncti o n i n 
vi v o (1 7 ). E x peri me nts ha ve c o nfir me d t he i n vi v o efficac y of a nti-m o use P D -1 a nti b o d y as a 
m o n ot hera p y, as well as i n c o m bi nati o n wit h c he m ot hera p y, i n s y n ge neic m o use t u m or m o dels.  
Pe m br oliz u ma b is a p ote nt  h u ma nize d i m m u n o gl o b uli n G 4 (I g G 4) m o n ocl o nal a nti b o d y wit h 
hi g h s pecificit y of bi n di n g t o t he P D -1 rece pt or, t h us i n hi biti n g  its i nteracti o n wit h P D -L 1 a n d 
P D -L 2 . Bas e d o n precli nical i n vitr o data, pe m br oliz u ma b has hi g h affi nit y a n d p ote nt rece pt or 
bl oc ki n g acti vit y f or P D -1. Pe m br oliz u ma b has a n acce pta ble precli nical safet y pr ofile a n d is i n 
cli nical de vel o p me nt as a n i ntra ve n o us (I V) i m m u n ot hera p y f or a d va nce d mali g na ncies. 
Ke ytr u da ®  ( pe m br oliz u ma b) is i n dicate d f or t he treat me nt of patie nts acr oss a n u m ber of 
i n dicati o ns. F or m ore d etails o n s pecific i n dicati o ns refer t o t he pe m br oliz u ma b I n vesti gat or’s 
Br oc h ure.  
Pe m br oliz u ma b has de m o nstrate d i nitial cli nical efficac y i n si n gle ar m m o n ot hera p y trials i n 
patie nts wit h N S C L C, h ea d a n d nec k s q ua m o us cell carci n o ma, ur ot helial ca ncer, G C , tri ple 
ne gati ve breast ca n cer, a n d H o d g ki n ’s Ly m p h o ma as deter mi ne d b y res p o nse rate. O n g oi n g 
cli nical trials are b ei n g c o n d ucte d i n t hese t u m or t y pes as well as a n u m ber of ot her a d va nce d 
s oli d t u m or i n dicati o ns a n d he mat ol o gic mali g na ncies. F or st u d y details, please refer t o t he 
pe m br oliz u ma b I B.  
Pe m br oliz u ma b is c urre ntl y i n dicate d f or t he treat me nt of patie nts wit h rec urre nt l ocall y 
a d va nce d or metastatic gastric or gastr oes o p ha geal j u ncti o n ( G EJ) a de n ocarci n o ma w h ose 
t u m ors e x press P D-L 1 (C o m bi ne d P ositi ve sc ore [C P S ] ≥1 ) as deter mi ne d b y a n F D A -a p pr o ve d 
test, wit h disease pr o gressi o n o n or after t w o or m ore pri or li nes of t hera p y, i ncl u di n g 
fl u or o p yri mi di ne- a n d pl ati n u m -c o ntai ni n g c he m ot hera p y a n d, if a p pr o priate, H E R 2/ ne u -tar gete d 
t hera p y. T his i n dicati o n is a p pr o ve d u n der accelerate d a p pr o val base d o n t u m or res p o nse rate a n d 
d ura bil it y of res p o nse. T he rec o m me n de d d ose of pe m br oliz u ma b is 2 0 0 m g a d mi nistere d as a n 
i ntra ve n o us i nf usi o n o ver 3 0 mi n utes e ver y 3 wee ks u ntil disease pr o gressi o n, u nacce pta ble 
t o xicit y, or u p t o 2 4 m o nt hs i n patie nts wit h o ut disease pr o gressi o n ( please refer t o t he 
K E Y T R U D A ®  [ pe m br oliz u ma b] pac ka ge i ns ert). 
St u d y K E Y N O T E -0 5 9 was a m ultice nter, n o n -ra n d o mize d, o pe n-la bel m ulti-c o h ort trial t hat 
e nr olle d 2 5 9 patie nts wit h gastri c or G EJ a de n ocarci n o ma w h o pr o gresse d o n at least 2  pri or 
C o nfi d e nti al
P a g e   
3 7   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
s yste mic treat me nts f or a d va nce d disease. Pre vi o us treat me nt m ust ha ve i ncl u de d a 
fl u or o p yri mi di ne a n d plati n u m d o u blet. H E R 2/ ne u p ositi ve patie nts m ust ha ve pre vi o usl y 
recei v e d treat me nt wit h a p pr o ve d H E R 2/ ne u-tar gete d t hera p y. 
T he maj or efficac y o utc o me meas ures were O R R acc or d i n g t o R E CI S T 1. 1, as assesse d b y 
bli n de d i n de pe n de nt ce ntral re vie w, a n d d urati o n of res p o nse.  
A m o n g t he 2 5 9 patie nts wit h G C  e nr olle d i n St u d y K E Y N O T E -0 5 9, t h e me dia n d urati o n of 
e x p os ure t o pe m br oliz u ma b  was 2. 1 m o nt hs (ra n ge: 1 da y t o 2 1. 4  m o nt hs). Pat ie nts wit h 
a ut oi m m u ne disease or a me dical c o n diti o n t hat re q uire d i m m u n os u p pressi o n or wit h cli nical 
e vi de nce of ascites b y p h ysical e x a m i nati o n were i neli gi ble. A d verse reacti o ns occ urri n g i n 
patie nts wit h G C  were si milar t o t h ose occ urri n g i n patie nts w it h mela n o ma or n o n -s mall cell 
l u n g ca ncer (N S C L C ). 
A m o n g t he 2 5 9 patie nts, 5 5 % ( n = 1 4 3) ha d t u m ors t hat e x presse d P D -L 1 (I H C 2 2 C 3 p har m D x 
Kit) wit h a c o m bi ne d p ositi ve sc ore ( C P S) of greater t ha n or e q ual t o 1 a n d micr osatellite sta ble 
( M S S) t u m or stat us or u n deter mi ne d M SI or M M R stat us. Me dia n a ge was 6 4 years; 7 7 % were 
male ; 8 2 % were W hite a n d 1 1 % Asia n ; 8 5 % ha d M 1 disease ; a n d 7 % ha d M 0 disease. Fift y-o ne 
perce nt h a d 2 a n d 4 9 % h a d 3 or m ore pri or li nes of t hera p y i n t he rec urre nt or metastatic setti n g . 
F or t he 1 4 3 p atie nts, t he O R R was 1 3. 3 % ( 9 5 % CI: 8. 2, 2 0. 0); 1. 4 % ha d a c o m plete res p o nse 
a n d 1 1. 9 % ha d a partial res p o nse. A m o n g t he 1 9 res p o n di n g patie nts, t he d urati o n of res p o ns e 
ra n ge d fr o m 2. 8 + t o 1 9. 4 + m o nt hs, wit h 1 1 patie nts ( 5 8 %) ha vi n g res p o nses of 6 m o nt hs or 
l o n ger a n d 5 patie nts ( 2 6 %) ha vi n g res p o ns es of 1 2 m o nt hs or l o n ger. 
A m o n g t he 2 5 9 patie nts e nr olle d i n K E Y N O T E -0 5 9, 7 ( 3 %) ha d t u m ors t hat were deter mi ne d t o 
be M SI -H. A n o bj ecti ve res p o nse was o bser ve d i n 4 patie nts, i ncl u di n g 1 c o m plet e res p o nse. T he 
d urati o n of res p o ns e ra n ge d fr o m 5. 3 + t o 1 4. 1 + m o nt hs.  
2. 3. 2. 1    
S afet y   
Safet y d ata are a vaila ble f or a t otal of 2 4 6 1 patie nts wit h mela n o ma or N S C L C i n 8 
Merc k -s p o ns ore d cli nical trials as a vaila ble i n t he i n vesti gat or ’s br oc h ure date d Ma y 2 0 1 6. 
I n t he pe m br oliz u ma b m o n ot hera p y trials, i n ge neral, t he m ost c o m m o nl y re p orte d A Es i ncl u de d 
fati g u e, diarr hea, d ecreas e d a p petite, na us ea, d ys p n oea, a n d a nae mia. T he i nci de nce of 
dr u g -relat e d A Es ( D R A Es) ra n ge d fr o m 3 9. 8 % t o 8 0. 0 %. T he i nci de nce of Gra de 3-5 D R A Es 
acr oss st u dies ra n ge d fr o m 6. 8 % t o 1 2. 0 %. T he m ost c o m m o nl y re p orte d Gra de 3 -5 D R A Es 
were a nae mia, ala ni ne a mi n otra nsferas e i ncrease d, as partate a mi n otra n sferase i ncreas ed, a n d 
c olitis. 
I n t he pe m br oliz u ma b m o n ot hera p y trials, m ost patie nts w h o e x perie nce d a n a d verse e ve nt ( A E ) 
c o nti n ue d i n t he st u d y, wit h t he i nci de nce of A Es l ea di n g t o disc o nti n uati o n ra n gi n g fr o m 4. 2 % 
t o 1 2. 3 %. T he maj orit y of A Es lea di n g t o disc o nti n uati o n were n ot c o nsi d ere d dr u g relate d. 
Disc o nti n uati o ns d ue t o a D R A E were i nfre q ue nt a n d ra n ge d fr o m 0 % t o 4. 5 %. T he m ost 
c o m m o nl y re p orte d D R A E lea di n g t o disc o nti n uati o n was p ne u m o nitis. Refer t o t he 
C o nfi d e nti al
P a g e   
3 8   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
pe m br oliz u ma b i n vesti gat or ’s br oc h ure [ See K E Y T R U D A
®  ( pe m br oliz u m a b) i n vesti g at or’s 
br oc h ure ] f or f urt h er det ails o n its safet y pr ofile. 
2. 4    
R ati o n ale f or C o m bi ni n g M ar get u xi m a b a n d Pe m br oliz u m a b   
Des pite c urre nt treat me nt o pti o ns f or p atie nts wit h G EJ or  G C , s u bsta ntial u n met me dical nee d 
re mai ns f or p atie nts wit h a d va nce d disease. T his st u d y e val uates a n o vel c o m bi nati o n of 
i m m u n ot hera pies i n patie nts wit h a d va nce d ca ncer a n d is desi g ne d t o i n vesti gate w het her 
c o m bi ne d a d mi nistrati o n o f mar get u xi ma b a n d pe m br oliz u ma b ma y res ult i n e n ha nce d a ntit u m or 
acti vit y.  
T he bl oc ka de of i n di vi d ual i m m u ne c hec k p oi nt i n hi bit ors has de m o nstrate d a ntit u m or acti vit y i n 
a variet y of ca n cers a n d has n o w bee n vali date d i n G EJ a n d gastric ca ncer (5 0 ). N o net heless, 
t he vast maj orit y of t u m ors a m o n g t h ese patie nts e ve nt uall y pr o gress, esca pi n g i m m u ne detecti o n 
a n d destr ucti o n.  T heref ore, strate gies t hat c o m bi ne i m m u ne c hec k p oi nt bl oc ka de t hr o u g h 
n o n -re d u n da nt i m m u ne c hec k p oi nts a n d/ or ot her mec ha nis ms are bei n g acti vel y i n vesti gate d a n d 
are be gi n ni n g t o de m o nstrate e v e n greater p ote ntial a ntit u m or acti vit y t ha n m o n ot hera p y -bas e d  
treat me nts (7 3 ). 
T he si m ulta ne o us bl oc ka de of H E R 2 wit h mar get u xi ma b a n d P D -1 wit h pe m br oliz u ma b 
re pres e nts a n attracti ve o p p ort u nit y t o p ote ntiall y e n ha nce a n d f oc us t he i m m u ne s yste m a gai nst 
H E R 2 o vere x pressi n g ca ncer cells t o me diate a ntit u m or effects m ore pr o n o u nce d t ha n bl oc ki n g 
eit her si n gl e tar get al o ne. Asi de fr o m c o or di natel y tar geti n g t he disti nct f u ncti o ns me diate d b y 
H E R 2 a n d P D -1  a xis wit h c o m bi ne d a d mi nistrati o n of mar get u xi ma b a n d pe m br oliz u ma b, 
a d diti o nal li nes of e vi de nce s u g gest t hat t hese a ge nts ma y be c o m bi ne d t o m ore effecti vel y 
e n ha nce t he a ntit u m or res p o nse c o m pare d t o bl oc ki n g eit h er tar get al o ne. Mar get u xi ma b is a n 
Fc -o pti mize d m o n ocl o nal a nti b o d y m o difie d t o i ncreas e Fc -rece pt or-me diate d effect or acti vit y, 
a n d t h us ma y e n ha nce p ote ntial A D C C i m m u ne attac k o n H E R 2 -e x pressi n g t u m or cells. 
E n ha nce d A D C C acti vit y ma y res ult i n i ncreas e d t u m or a nti ge n prese nt ati o n a n d a n i m pr o ve d 
a da pti ve i m m u ne res p o ns e (5 4 ). C o m bi ni n g t he t w o disti nct mec ha nis ms of acti o n of e n ha n ce d 
A D C C a n d release of t he P D -1 c hec k p oi nt i n hi biti o n a gai nst T-effect or cells ma y pr o vi d e 
i ncreas e d a nti-t u m or acti vit y c o m pare d t o t hat o bs er ve d wit h bl oc ki n g eit her tar get al o ne. I n 
c o ncl usi o n, treati n g patie nts wit h t w o a ge nts t hat ma y ha ve m o n ot hera p y a nti -t u m or acti vit y is 
a n effecti ve rati o nale f or c o m bi ni n g mar get u xi ma b a n d pe m br oliz u ma b, es peciall y gi ve n t heir 
c o m ple me ntar y mec ha nis ms of acti o n. F urt her m ore, p ossi ble c o or di nat e d e n ga ge me nt of b ot h 
i n nate a n d a d a pti ve i m m u nit y als o ser ves as scie ntific rati o nale f or c o m bi ni n g t hese a ge nts.  
2. 5    
R ati o n ale f or D ose Selecti o n   
2. 5. 1    
D ose Esc al ati o n P h ase ( P art A)  
2. 5. 1. 1    
Pe m br oliz u m a b   
T he d ose of pe m br oliz u ma b a d mi nistere d d uri n g t he st u d y will be 2 0 0 m g gi ve n o nce e ver y 
3  wee ks via 3 0 -mi n ute I V i nf usi o n.  I n St u d y K E Y N O T E-0 0 1 ( K N 0 0 1), t w o ra n d o mi ze d c o h ort 
e val uati o ns of mela n o ma patie nts recei vi n g pe m br oliz u ma b at a d ose of 2 m g/ k g vers us 
C o nfi d e nti al
P a g e   
3 9   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
1 0  m g/ k g Q 3 W ha ve b ee n c o m plete d, w hile o ne ra n d o mize d c o h ort e val uati o n of 1 0 m g/ k g 
Q 3 W vers us 1 0 m g/ k g Q 2 W is o n g oi n g. T he cli ni cal efficac y a n d safet y data d e m o nstrate a l ac k 
of cli nicall y i m p orta nt differe nces i n efficac y res p o nse or safet y pr ofile at t hese d oses. F or 
e x a m ple, a n o bser ve d o bj ecti ve res p o ns e rat e ( O R R) of 2 6 % ( 2 1/ 8 1) a n d 2 6 % ( 2 5/ 7 9) was 
o bser ve d a m o n g a d va nce d mela n o ma patie nts w h o ha d recei ve d pri or i pili m u ma b treate d wit h 
pe m br oliz u ma b 2 m g/ k g a n d 1 0 m g/ k g, res pecti vel y. T he pr o p orti o n of patie nts wit h dr u g -relate d 
A E, Gra d e 3 -5 dr u g -relat e d A E, seri o us dr u g-relate d A E, deat h or disc o nti n uati o n d ue t o a n A E 
was c o m para ble bet w ee n gr o u ps or l o wer i n t he 1 0 m g/ k g gr o u p (6 1 ). 
Per t he K E Y T R U D A ®  ( pe m b r oliz u m a b) i n vesti g at or’s br oc h ure, P K data a nal ysis of 
pe m br oliz u ma b a d mi nistere d Q 2 W a n d Q 3 W s h o we d sl o w s yst e mic cleara nce, li mite d v ol u me 
of distri b uti o n, a n d a l o n g half -life. P har mac o d y na mic data (I L -2 release assa y) s u g geste d t hat 
peri p heral tar get e n ga ge me nt is d ura ble ( > 2 1 da ys), t h us s u p p orti n g a Q 3 W d osi n g sc he d ule.  
A p o p ulati o n P K a nal ysis has bee n perf or me d usi n g ser u m c o nce ntrati o n ti me data fr o m 
4 7 6  patie nts. Wit hi n t he res ulti n g p o p ulati o n P K m o del, cleara nce a n d v ol u me para meters of 
pe m br oliz u ma b were f o u n d t o be de pe n de nt o n b o d y wei g ht. T he relati o ns hi p bet wee n cl eara nce 
a n d b o d y wei g ht, wit h a n all o metric e x p o ne nt of 0. 5 9, is wit hi n t he ra n ge o bser ve d f or ot her 
a nti b o dies a n d w o ul d s u p p ort b ot h b o d y wei g ht n or malize d d osi n g or a fi xe d d ose acr oss all 
b o d y wei g hts. Pe m br oliz u ma b has bee n f o u n d t o ha ve a wi de t h era pe utic ra n ge base d o n t he 
mela n o ma i n dicati o n. T he differe nces i n e x p os ure f or a 2 0 0 m g fi xe d d ose re gi me n rel ati ve t o a 
2 m g/ k g Q 3 W b o d y wei g ht -base d  re gi me n are a nti ci pate d t o re mai n well wit hi n t he esta blis he d 
e x p os ure mar gi ns of 0. 5 –  5. 0 f or pe m br oliz u ma b i n t he mela n o ma i n dicati o n. T he e x p os ure 
mar gi ns are b ase d o n t he n oti o n of si milar efficac y a n d safet y i n mela n o ma at 1 0 m g/ k g Q 3 W 
vers us t he d ose re gi me n of 2  m g/ k g Q 3 W (i.e. , 5 -f ol d hi g her d ose a n d e x p os ure). T he p o p ulati o n 
P K e val uati o n re veale d t hat t here was n o si g nifi ca nt i m pact of t u m or b ur de n o n e x p os ure. I n 
a d diti o n, e x p os ure was si milar bet wee n t he n o n -s mall cell l u n g ca ncer ( N S C L C) a n d mela n o ma 
i n dicati o ns. T heref ore, t h ere are n o a ntici pate d c ha n ges i n e x p os ure bet wee n differe nt i n dicati o n 
setti n gs. 
I n c o ncl usi o n, t he a b o v e data i n dicates t hat t he 2 0 0 m g Q 3 W fi xe d d ose re gi me n pla n ne d t o be 
use d i n t his trial is li kel y si milar, wit h re gar d t o efficac y a n d t olera bilit y, t o t he 1 0 m g/ k g Q 2 W 
d ose re gi me n use d i n K N 0 1 2, a n d s u p p orts its use i n t his st u d y. N o d ose re d ucti o n is all o we d f or 
pe m br oliz u ma b i n t his st u d y. A 2 0 0 m g Q 3 W pe m br oliz u ma b fi x e d d ose re gi me n is c urre ntl y 
e m pl o ye d i n se v eral o n g oi n g pe m br oliz u ma b st u dies ( N C T 0 2 4 9 4 5 8 3, N C T 0 2 3 3 5 4 1 1, a n d 
N C T 0 2 3 7 0 4 9 8).  
2. 5. 1. 2    
M ar get u xi m a b   
T he d ose f or m ar get u xi ma b i n t he D ose Escalati o n P hase  ( Part A) will be gi n at 1 0 m g/ k g I V 
( 1 2 0-mi n ute i nf usi o n), wit h a pr o p ose d escalati o n t o 1 5 m g/ k g, gi v e n o n a o nce e ver y 3 -wee ks 
sc he d ule. T here will be a d ose de-es calati o n t o 6 m g/ k g mar get u xi ma b if t he starti n g d os e of 
1 0  m g/ k g i n c o m bi nati o n wit h pe m br oliz u ma b is f o u n d t o e xcee d t he M T D.  
T he i nitial mar get u xi ma b d ose pr o p ose d, 1 0 m g/ k g, is base d o n t h e P K a n d safet y pr ofile of 
mar get u xi ma b fr o m t he t w o o n g oi n g cli nical st u dies.  
C o nfi d e nti al
P a g e   
4 0   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
Cli nical P K were e v al uat e d i n t he P hase 1 st u d y. A t w o -c o m p art me nt m o del wit h parall el li near 
a n d Mic haelis -Me nt e n eli mi nati o n a de q uatel y des cri be d t he o bser ve d (i nteri m) data. M o del 
para meters were ge n erall y i n a gree me nt wit h t h os e c o m m o nl y e x pecte d f or a m o n ocl o nal 
a nti b o d y. Si n gle d ose e x p os ure was pre dicte d t o b e a p pr o xi matel y d ose pr o p orti o nal at d oses 
>  3  m g/ k g w he n d ose d wee kl y f or 3 wee ks i n 4 -wee k c ycl es a n d ≥ 1 5  m g/ k g w he n d ose d e ver y 
3  wee ks. T he ter mi nal half -life was esti mate d at 1 2. 7 da ys.  
Ta ble  1  
M ar get u xi m a b P h ar m ac o ki netics at Ste a d y St ate –  6 m g/ k g , 
1 0  m g/ k g, 1 5 m g/ k g, 1 8 m g/ k g –  C P -M G A H 2 2 -0 1   
P ar a meter  
 ( u nit) 
 
M ar get u xi m a b D ose a n d Sc he d ule  
6 m g/ k g Q W  a 
N = 1 9  
1 0 m g/ k g Q 3 W  b  
N = 6  
1 5 m g/ k g Q 3 W  b  
N = 6  
1 8 m g/ k g Q 3 W  b  
N = 6  
C tr o u g h 
 ( µ g/ m L) 
Mea n  
( S D) 
7 3. 0  
( 3 8. 2) 
4 2. 3  
( 2 5. 5) 
6 9. 9  
( 4 2. 9) 
8 6. 1  
( 4 7. 9) 
 
Me dia n  
( 9 5 % CI) 
6 6. 9  
( 2 0. 5 - 1 6 9)  
3 7  
( 6. 8 6 –  1 0 1)  
6 1  
( 1 5. 8 - 1 8 0)  
7 7. 6  
( 2 0. 8 - 2 0 7)  
C ma x  
 ( µ g/ m L) 
Mea n  
( S D) 
2 1 7  
( 5 8. 1) 
2 3 6  
( 1 6. 8) 
3 6 0  
( 9 3. 9) 
4 2 9  
( 1 0 3) 
 
Me dia n  
( S D) 
2 1 1  
( 1 2 5 - 3 5 5)  
2 2 7  
( 1 3 6 –  3 8 0)  
3 4 5  
( 2 2 2 - 5 9 0)  
4 1 7  
( 2 6 3 - 6 6 0)  
A U C  
 ( µ g/ m L * h) 
Mea n  
( S D) 
8 4 7 0 0  
( 3 0 0 0 0) 
4 9 5 0 0  
( 1 6 5 0 0) 
7 2 2 0 0  
( 2 7 2 0 0) 
8 7 5 0 0  
( 3 0 3 0 0) 
 
Me dia n  
( 9 5 % CI) 
8 0 5 0 0  
( 4 0 7 0 0 - 1 5 8 0 0)  
4 3 1 0 0  
( 2 0 4 0 0 –  8 4 4 0 0)  
6 6 8 0 0  
( 3 5 3 0 0 - 1 3 9 0 0 0)  
8 2 2 0 0  
( 4 3 6 0 0 - 1 6 0 0 0 0)  
a  
D ose d o nce wee kl y ( Q W) f or 3 wee ks i n 4 -wee k ( 2 8 -da y) c ycles  
b   D ose d o nce e ver y 3 wee ks i n 3 -wee k ( 2 1 -da y) c ycles.  
 
Stea d y state e x p os ure esti mates are s h o w n i n Ta ble  1  f or mar get u xi ma b w he n d ose d at 
6. 0  m g/ k g wee k l y f or 3 of e ver y 4 wee ks ( n = 1 9), 1 0 m g/ k g e ver y 3 wee ks ( n = 6), 1 5. 0 m g/ k g 
e ver y 3 wee ks ( n = 6), a n d 1 8. 0  m g/ k g e ver y 3  wee ks ( n = 6) i n St u d y C P -M G A H 2 2 -0 1.  At stea d y 
state, t hese d oses a n d re gi me ns are esti mate d t o ha ve si milar e x p os ure. Ser u m tr o u g h 
c o nce ntrati o ns (C tr o u g h) f or t he 6 m g/ k g, 1 5 m g/ k g, a n d 1 8 m g/ k g d oses are nearl y i de ntical, are at 
or a b o ve t h ose re p orte d f or trast uz u ma b i n patie nts wit h breast ca ncer  (2 8 ) a n d are a b o ve t hat 
re q uire d f or i n hi biti o n of H E R 2 si g nali n g as de m o nstrate d f or trast uz u ma b (11 ). Si milarl y, area 
u n der t he c o n ce ntrati o n -ti me c ur ve ( A U C) val ues are als o v er y si milar. 
T here are n o o b vi o us differe nces i n t he safet y pr ofil es of eac h m ar get u xi ma b d ose e val uate d t o 
date t hat s u g gest a d ose -t o xicit y rel ati o ns hi p. ( Det ails of t he n u m ber a n d ki n d of A Es re p orte d 
b ot h i n a g gre gate a n d b y d ose are a vaila ble i n t he mar get u xi ma b I B). T he fre q ue nc y, t y pe, a n d 
se verit y of A Es o bser v e d di d n ot differ a n d alt h o u g h t he ma xi m u m ser u m c o nce ntrati o n ( C ma x ) 
differs f or t hese t hree d os e gr o u ps i n a d ose -relate d ma n ner, n o o b vi o us differe nce i n t he safet y 
pr ofile was o bser ve d b et wee n patie nts treate d at 6. 0 m g/ k g (t he l o west C ma x ), 1 5. 0 m g/ k g, a n d 
1 8. 0 m g/ k g (t he hi g hest C ma x ). N o i ncreas e i n A Es was n ote d wit h pr ol o n ge d e x p os ure, a n d n o ne 
of t hese patie nts ha ve bee n disc o nti n ue d fr o m treat me nt beca us e of t o xicit y. Base d o n t he P K a n d 
C o nfi d e nti al
P a g e   
4 1   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
safet y data a vaila ble t o d ate, 1 0 m g/ k g mar get u xi ma b a d mi nistere d e ver y 3 wee ks is a reas o na bl e 
starti n g d ose f or t his st u d y. 
T he d oses a n d sc h e d ule of mar get u xi ma b selecte d f or e val u ati o n i n t he D ose Escalati o n P hase  
( Part A) of t his st u d y, 1 0 m g/ k g a n d 1 5 m g/ k g gi ve n e ver y 3  wee ks, is b ase d o n t he o bser ve d 
safet y a n d efficac y pr ofil e of mar get u xi ma b at all d oses teste d t o date a n d t he pre dicta bl e P K 
c haracteristics i n t he o n g oi n g P hase 1 st u d y. As n ote d, t he t o p d ose f or t his st u d y ( 1 5. 0  m g/ k g) is 
als o t he d ose bei n g st u die d i n t he P hase 3 ra n d o mize d H E R 2 + brea st ca ncer st u d y ( C P -
M G A H 2 2 -0 4).  
2. 5. 2    
C o h ort E x p a nsi o n P h ase  ( H E R 2 + G E J/ G C a n d H E R 2 + 
G C -I H C 3 +) ( P arts B –  C )  
T he rec o m me n de d p has e 2 d ose (R P 2 D ) of mar get u xi ma b as deter mi ne d d uri n g t he D ose  
Escalati o n P hase  ( Part A) ( 1 5 m g/ k g Q 3 W ) is use d i n c o m bi nati o n wit h t he fi x e d d ose ( 2 0 0 m g) 
of pe m br oliz u ma b d uri n g t he C o h ort  E x pa nsi o n P hase s ( Parts B –  C ). 
C o nfi d e nti al
P a g e   
4 2   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
3    
S T U D Y P U R P O S E A N D O B J E C TI V E S   
T his st u d y is a n o pe n -la bel, d ose escalati o n, P hase 1 b/ 2 st u d y desi g ne d t o c haract erize t he safet y, 
t olera bilit y, P K, p har mac o d y na mics ( P D), i m m u n o ge ni cit y, a n d preli mi nar y a ntit u m or acti vit y of 
mar get u xi ma b a d mi nistere d I V o n ce e v er y 3 wee ks i n c o m bi nati o n wit h 2 0 0 m g pe m br oliz u ma b 
a d mi nistere d I V o n ce e v er y 3 wee ks i n patie nts wit h rela pse d /refract or y u nresecta ble l o call y 
a d va nce d or metastatic H E R 2 + G EJ or  G C . 
3. 1    
Pri m ar y O bjecti ves   
T he pri mar y o bjecti ves of t his st u d y are:  
 To c haracterize t he safet y, t olera bilit y, D L T, a n d M T D or M A D (if n o M T D is defi ne d) 
of mar get u xi ma b w he n a d mi nistere d I V e ver y 3 wee ks i n c o m bi nati o n wit h 2 0 0 m g 
pe m br oliz u ma b a d mi nistere d I V e ver y 3 wee ks t o patie nts wit h rela pse d/refract or y 
a d va nce d H E R 2 + G EJ or  G C . 
 To i n vesti gate t h e preli mi nar y  a nti-t u m or acti vit y, as meas ure d b y o bjecti ve res p o nse 
rate ( O R R) a n d res p o nse d urati o n, of mar get u xi ma b a d mi nistere d I V e ver y 3 wee ks i n 
c o m bi nati o n wit h pe m br oliz u ma b a d mi nistere d I V e ver y 3 wee ks usi n g b ot h 
c o n ve nti o nal Res p o nse E val uati o n Criteria i n S oli d T u m ors ( R E CI S T) 1. 1 (A p pe n di x  
7 ) a n d i m m u ne -rel ate d res p o nse criteria (ir R C) (A p pe n di x  8 ), i n patie nts t hat ha ve 
faile d first-li ne trast uz u ma b-c o ntai ni n g re gi me ns.  
 
3. 2    
Sec o n d ar y O bjecti ves   
Sec o n dar y o bject i ves of t his st u d y are: 
 To i n vesti gate t h e preli mi nar y effect o n O S a n d P F S of mar get u xi ma b a d mi nistere d I V 
e ver y 3 wee ks i n c o m bi n ati o n wit h pe m br oliz u ma b a d mi nistere d I V e ver y 3 wee ks  
 To c haracterize t he P D acti vit y of mar get u xi ma b a d mi nistere d I V e ver y 3 wee ks i n 
c o m bi nati o n wit h pe m br oliz u ma b a d mi nistere d I V e ver y 3 wee ks.  
 To c haracterize t he P K a n d i m m u n o ge nicit y of mar get u xi ma b a d mi nistere d I V e ver y 
3  wee ks i n c o m bi nati o n wit h pe m b r oliz u ma b a d mi nistere d I V e ver y 3 wee ks. 
 
3. 3    
E x pl or at or y O bjecti ves   
 To e x pl ore t he relati o ns hi ps bet wee n P K, P D, patie nt safet y a n d a ntit u m or acti vit y of 
mar get u xi ma b w he n a d mi niste re d i n c o m bi nati o n wit h pe m br oliz u ma b. 
 To i n vesti gate t h e i m m u ne -re g ul at or y acti vit y of mar get u xi ma b i n c o m bi nati o n wit h 
pe m br oliz u ma b b y a nal ysis of peri p heral bl o o d sa m ples f or p ote ntiati o n of H E R 2 
s pecific a d a pti ve h u m oral a n d cell ular i m m u ne res p o nses.  
C o nfi d e nti al
P a g e   
4 3   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
 To deter mi ne t he relati o ns hi ps bet wee n me m bra n o us e x pressi o n of P D -L 1 o n t u m or 
cells, i m m u ne cell i nfiltrati o n wit hi n bi o ps y s p eci me ns (i ncl u di n g b ut n ot li mite d t o 
C D 4 + a n d C D 8 + T cells), P D -L 1 e x pressi o n o n t he i m m u ne cell i nfiltrate, a n d cli nical 
res p onse via I H C stai ni n g of paire d pre - a n d o n-treat me nt t u m or bi o ps y s p eci me ns. 
 To deter mi ne t he relati o ns hi p of allelic variati o n i n C D 1 6 A, C D 3 2 A  a n d C D 3 2 B  t o 
a nti-t u m or acti vit y. 
 Deter mi nati o n of m utati o nal b ur de n ( o n ct D N A deter mi ne d b y G uar da nt 3 6 0 assa y) , 
as well as mis matc h re p air stat us b y micr osat ellite i nsta bilit y (fr o m pat h ol o g y re p orts, 
w he n a vaila bl e).  
 To deter mi ne of ge ne e x pressi o n si g nat ures i n tiss ues, w hic h ma y be i n dicati ve of 
i m m u n ot hera p y res p o nses ass ociate d wit h t he a ge nts o n trial. 
 To va li date ct D N A E R B B 2,  deter mi ne d b y circ ulati n g t u m or D N A G uar da nt 3 6 0 assa y 
a m plificati o n as a s urr o gate of H E R 2 e x pressi o n i n patie nts wit h  G C ; t o be perfor me d 
at G uar da nt La b orat ories.  
 
T he res ults of e x pl orat or y o bjecti ves ma y n ot be i ncl u de d i n t he Cli nical St u d y Re p ort or fi nal 
data ta bles a n d listi n gs u nless t he y re prese nt mea ni n gf ul fi n di n gs.  
 
C o nfi d e nti al
P a g e   
4 4   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
4    
T RI A L D E SI G N   
4. 1    
O ver all St u d y Desi g n a n d Pl a n   
4. 1. 1    
Ge ner al St u d y Desi g n   
T his st u d y is a P hase 1 b/ 2, o pe n -la bel, d ose escal ati o n a n d c o h ort e x pa nsi o n st u d y desi g ne d t o 
c haracterize t he safet y, t olera bilit y, P K, P D, i m m u n o ge ni cit y, a n d preli mi nar y a ntit u m or acti vit y 
of mar get u xi ma b a d mi nistere d I V e ver y 3 wee ks i n c o m bi nati o n wit h pe m br oliz u ma b 
a d mi nistere d I V e ver y 3 wee ks i n patie nts wit h  rel a pse d/refract or y, u nresecta ble l ocall y 
ad va nce d or metastatic H E R 2 + G EJ or  G C . 
T he st u d y c o nsists of a D ose Esc al ati o n P h ase  ( P art A) t o deter mi ne t h e M T D or M A D (if n o 
M T D is defi ne d) of escalati n g d oses of mar get u xi ma b a d mi nistere d i n c o m bi nati o n wit h a fi xe d 
d ose of 2 0 0 m g p e m br oliz u ma b, f oll o we d b y a C o h ort E x p a nsi o n P h ase  ( P arts B –  C ) t o 
f urt her defi ne t he safet y a n d i nitial efficac y of t he c o m bi nati o n wit h t he mar get u xi ma b d ose 
esta blis he d i n t he first p hase . As of Pr ot oc ol A me n d me nt 2, u p t o 2 5 a d diti o nal patie nts wit h G C  
o nl y will be a d d e d t o C o h ort E x pa nsi o n P hase  ( Part C). See Secti o n  4. 1. 3 . 
B ot h mar get u xi ma b a n d pe m br oliz u ma b will be a d mi nistere d o nce e ver y 3 wee ks ( o ne c ycl e). 
B ot h a ge nts will be a d mi nistere d o n t he sa me da y, wit h pe m br oliz u ma b a d mi nistere d first, 
f oll o we d b y mar get u xi ma b. Eac h c ycle of t hera p y is defi ne d as 3 wee ks, i n w hic h mar get u xi ma b 
a n d pe m br oliz u ma b will be gi v e n o n Da y 1. T u m or assess me nts will be perf or me d e ver y 6  wee ks 
(i.e., f oll o wi n g 2 c ycles of treat me nt [ pri or t o d osi n g f or C ycles 3, 5, 7, etc.]) f or t he first 
6  m o nt hs o n treat me nt; t hereafter, t u m or assess me nts will be perf or me d e ver y 1 2 wee ks.    
Ass u mi n g t he patie nt re mai ns cli nicall y sta ble, has n ot e x perie nce d i m m u ne -rel ate d pr o gressi ve 
disease (ir P D), a n d d oes n ot e x perie nce u nacce pt a ble t o xic it y t hat necessitates per ma ne nt 
disc o nti n uati o n of b ot h st u d y dr u gs, tr eat me nt wit h t he c o m bi nati o n treat m e nt ma y c o nti n ue f or 
u p t o 2  years ( Secti o n  4. 4  a n d Secti o n  5. 3 ). C o m bi nati o n t hera p y wit h pe m br oliz u ma b a n d 
mar get u xi ma b will be disc o nti n ue d after 2 years.  
F or patie nts w h o are ot her wise cli nicall y sta ble b ut ha ve met c o n ve nti o nal criteria f or P D, 
t hera p y ma y be c o nti n ue d at t he discreti o n of t he i n vesti gat or pe n di n g c o nfir mati o n of 
pr o gressi o n at t he ne xt sc he d ule d t u m or assess me nt. T his a p pr oac h all o ws f or li mite d treat me nt 
of patie nts be y o n d t he i nitial ra di o gra p hic d oc u me ntati o n of disease pr o gressi o n, ass u mi n g t hat 
patie nts are t olerati n g t h era p y a de q u atel y, t h at patie nts re mai n ot her wis e cli nicall y sta ble des pite 
t his i nitial ra di o gra p hic e vi de nce of disease pr o gressi o n, a n d t hat t he i n vesti gat or feels t he patie nt 
ma y still deri ve b e nefit fr o m c o nt i n uati o n of t hera p y. 
F or patie nts i n w h o m pr o gressi o n is c o nfir me d at t he ne xt sc he d ule d t u m or assess me nt, t he 
criteria f or ir P D will ha ve bee n met, a n d treat me nt wit h mar get u xi ma b a n d pe m br oliz u ma b 
s h o ul d be disc o nti n ue d. T he patie nt s h o ul d be re m o ve d fr om st u d y partici pati o n after c o m pleti o n 
of pr ot oc ol s pecifi e d f oll o w -u p (see Secti o n  8. 3  a n d A p pe n di x 1  a n d A p pe n di x 2 ). 
C o nfi d e nti al
P a g e   
4 5   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
Effic ac y F oll o w -u p Peri o d : F oll o wi n g  t he last d ose of c o m bi nati o n t hera p y, all patie nts will be 
f oll o we d f or P F S a n d O S f or u p t o 2 years or u ntil 3 m o nt hs after t he last patie nt c o m pletes or 
disc o nti n ues st u d y treat me nt .  
4. 1. 2    
D ose Esc al ati o n P h ase  ( P art A)  
T he g o al of t he D ose Esc al ati o n P h ase  ( P art A) is t o i nitiall y c haracterize t he safet y a n d 
t olera bilit y of mar getu xi ma b a n d pe m br oliz u ma b a d mi nistere d i n c o m bi nati o n, a n d m ore 
s pecificall y t o descri be t he D L Ts f or eac h d os e le vel st u die d a n d t o defi ne t he M T D or M A D (if 
n o M T D is defi ne d) base d o n t he fre q u e nc y of t he occ urre nce of D L Ts i n eac h c o h ort d uri n g t h e 
D L T E v al u ati o n Peri o d . 
F or t he p ur p os es of g ui di n g decisi o ns re gar di n g d ose escal ati o n, t he D L T E v al u ati o n Peri o d  is 
defi ne d as t he ti me f oll o wi n g a d mi nistrati o n of t h e first d ose of pe m br oliz u ma b u p t o t he da y of 
t he sec on d pla n ne d a d mi nistrat i o n of pe m br oliz u ma b (i.e., 2 1 da ys f oll o wi n g first d ose of 
pe m br oliz u ma b - e n d of C ycle 1). D L Ts are defi ne d i n Secti o n  4. 2  a n d D ose Escalati o n R ules 
descri be d i n  Secti o n  4. 3 . 
Mar get u xi ma b will be e val uate d i n t w o se q ue ntial escalati n g d oses, 1 0 m g/ k g a n d 1 5 m g/ k g, i n 
c o m bi nati o n wit h 2 0 0 m g pe m br oliz u ma b i n c o h orts of 3 t o 6 patie nts eac h. If it is deter mi ne d 
t hat t he M T D is e xcee de d i n t he first d ose c o h ort, a d ose de-escal ati o n c o h ort t o e val uate a l o wer 
d ose of mar get u xi ma b ( 6 m g/ k g) i n c o m bi nati o n wit h 2 0 0 m g pe m br oliz u ma b will be e nr olle d.  
T he d ose esca lati o n sc he ma is o utli ne d bel o w: 
Ta ble  2  
M ar get u xi m a b D ose Es c al ati o n C o h orts   
C o h ort  
M ar get u xi m a b D ose  
Pe m br oliz u m a b D ose  
C o h ort -1  a 
6 m g/ k g  
2 0 0 m g  
C o h ort 1  b  
1 0 m g/ k g  
2 0 0 m g  
C o h ort 2  
1 5 m g/ k g  
2 0 0 m g  
a  
T o be e val uate d o nl y if t he starti n g d ose is deter mi ne d t o e xcee d t he M T D.  
b   Starti n g d ose le vel  
 
A n i nter me diate d ose of mar get u xi ma b ma y be e x pl ore d d uri n g t he d ose es calati o n p orti o n of t he 
st u d y, b ase d o n re vie w of t he c u m ulati ve safet y, efficac y, a n d/ or P K dat a o n t he res pecti ve ar ms 
a n d base d u p o n a gree me nt bet wee n t he i n vesti gat ors a n d t he S p o ns or. T he Re g ulat or y A ge ncies 
a n d I nstit uti o na l Re vie w B oar ds (I R Bs)/I n de pe n de nt Et hics C o m mittees (I E Cs) will be n otifie d 
of a n y a d diti o nal d ose le vel t o be e val uate d.  
4. 1. 3    
C o h ort E x p a nsi o n P h ase   
4. 1. 3. 1    
C o h ort E x p a nsi o n P h ase ( P art B )  
D uri n g Part B  of t he C o h ort E x pa nsi o n P hase , 6 0  patie nts ( 3 0 eac h i n N ort h A merica a n d Asia) 
wit h rela pse d/refract or y u nresect a ble l ocall y a d va nce d or metast atic H E R 2 + G EJ or G C  will be 
C o nfi d e nti al
P a g e   
4 6   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
e nr olle d u n der t h e Ori gi n al Pr ot oc ol a n d Pr ot oc ol A me n d me nt  1 t o recei ve mar get u xi ma b at t he 
R P 2 D  esta blis he d fr o m t he D ose Esc al ati o n P h ase  ( P art A) of t he st u d y  ( 1 5 m g/ k g) i n 
c o m bi nati o n wit h 2 0 0  m g pe m br oliz u ma b . T he g oals f or t his p orti o n of t he st u d y will be t o:  
1.  Pr o vi de a preli mi nar y ass ess me nt of t he a ntit u m or acti vit y of mar get u xi ma b i n 
c o m bi nati o n wit h pe m br oliz u ma b i n patie nts wit h rela pse d/refract or y u nres ecta ble 
l ocall y a d va nce d or metastatic H E R 2 + G EJ or G C . 
2.  F urt her c haracterize t he safet y of mar get u xi ma b i n c o m bi nati o n wit h pe m br oliz u ma b 
at t he M T D ( or M A D); a n d  
3.  F urt her e val uat e t he P K, P D, a n d i m m u n o ge nicit y of mar get u xi ma b i n c o m bi nati o n 
wit h pe m br oliz u ma b.  
 
4. 1. 3. 2    
C o h ort E x p a nsi o n P h ase ( P art C )  
D uri n g Part C  of t he C o h ort E x pa nsi o n P hase , u p t o  2 5  pat ients i n N ort h A merica a n d/ or Asia 
wit h u nresecta bl e l ocall y a d va nce d or metastatic H E R 2 + (I H C  3 + ) G C  will be e nr olle d u n der 
Pr ot oc ol A me n d me nt  2 (as f urt her d escri be d i n Secti o n  5. 1 ) t o recei ve t he s a me re gi me n of 
mar get u xi ma b i n c o m bi nati o n wit h pe m br oliz u ma b as descri be d a b o ve. T he g oal f or t his p orti o n 
of t he st u d y will be t o:  
1.  Pr o vi de a preli mi nar y ass ess me nt of t he antit u m or  acti vit y of mar get u xi ma b i n 
c o m bi nati o n wit h pe m br oli z u ma b i n patie nts wit h rela pse d/refract or y u nres ecta ble 
l ocall y a d va nce d or metastatic H E R 2 3 + (I H C 3 +) GC  o nl y  (as d efi ne d i n AJ C C 
Ca ncer Sta gi n g Ma n ual, 8 t h E diti o n ) p ost-trast uz u ma b 
2.  F urt her c h aracterize t he safet y of mar get u xi ma b at t he M T D ( or M A D) i n c o m bi nati o n 
wit h pe m br oliz u ma b; a n d  
3.  F urt her e val uat e t he P K, P D, a n d i m m u n o ge nicit y of mar get u xi ma b i n c o m bi nati o n 
wit h pe m br oliz u ma b.  
 
4. 1. 4    
Effic ac y F oll o w -u p Peri o d   
F oll o wi n g a patie nt’s fi nal d ose of st u d y dr u g ( pe m br oliz u ma b or mar get u xi ma b, w hic he ver is 
last), eac h p atie nt will be f oll o we d  d uri n g t he Effic ac y F oll o w u p Peri o d . T he Effic ac y F oll o w 
u p Peri o d  will e n d 3 m o nt hs after t he last patie nt c o m pletes or disc o nti n ues treat me nt. D uri n g 
t his ti me, patie nts will be f oll o we d at 1 2 -wee k  i nter vals f or m o nit ori n g of pr o gressi o n -free 
s ur vi val a n d o verall s ur vi val. Disease assess me nts s h o ul d be d o ne at office f oll o w -u p visits if 
patie nts are a greea ble.    
Pri or t o data base l oc k f or fi nal O S a nal ysis, s ur vi val data will be re q ueste d f or all patie nts still i n 
Effic ac y F oll o w -u p Peri o d , re gar dless of t h e i nter val si nce t he pri or assess me nt.  
C o nfi d e nti al
P a g e   
4 7   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
4. 2    
D ose Li miti n g To xicit y   
F or t he p ur p os es of safet y ma na ge me nt a n d defi ni n g D L Ts, t he c o m bi nati o n of mar get u xi ma b 
a n d pe m br oliz u ma b will be treate d as o ne e ntit y d uri n g C ycle 1 of  t he D ose Esc al ati o n P h ase  
( P a rt A) (i.e., t he D L T E v al u ati o n Peri o d ). If a D L T c o nsi dere d relate d t o o ne of t he st u d y 
dr u gs o cc urs d uri n g t his peri o d, a d mi nistrati o n of b ot h a ge nts will be st o p pe d. O ne e xce pti o n t o 
t his r ule will be i n t he circ u msta nce i n w hic h a D L T occ urs d uri n g or i m me diatel y f oll o wi n g t he 
first pe m br oliz u ma b i nf usi o n a n d bef ore t he first mar get u xi ma b a d mi nistrati o n. I n t his case, t h e 
t o xicit y will be attri b ute d t o pe m br oliz u ma b al o ne a n d will n ot c o u nt as a D L T of t he 
c o m bi nati o n of st u d y dr u gs, a n d t h e patie nt will be re place d b y a n ot h er patie nt i n t he d ose 
c o h ort. 
I n ge neral, f or p atie nts w h o e x perie nce a n A E t hat ma y meet t he criteria f or a D L T at a n y ti me 
d uri n g t he c o urse of t he st u d y, s u bs e q ue nt a d mi nistrati o n of t he st u d y dr u gs s h o ul d be hel d 
pe n di n g ma na ge me nt a n d/ or res ol uti o n of t he e ve nt a n d assess me nt of attri b uti o n t o t he st u d y 
dr u gs. Criteria f or s u bs e q ue nt c o nti n uati o n of t hera p y are o utli ne d bel o w. N o i ntra -patie nt d ose 
re d ucti o ns of eit her mar get u xi ma b or pe m br oliz u ma b are all o we d d uri n g t he st u d y. 
4. 2. 1    
Defi niti o ns   
D ose li miti n g t o xicities will be base d o n treat me nt -e mer ge nt dr u g-relate d A Es ( or cli nicall y 
si g nifica nt la b orat or y a b n or malities) occ urri n g d uri n g t he D L T E v al u ati o n Peri o d  ( defi ne d as 
t he ti me f oll o wi n g a d mi nistrati o n of t he first d ose of pe m br oliz u ma b u p t o t he da y of t he s ec o n d 
pla n ne d a d mi nistrati o n of pe m br oliz u ma b [i.e., 2 1 da ys f oll o wi n g first d ose of pe m br oliz u ma b –  
e n d of C ycle 1] ). T he s e v erit y of A Es will be gra de d acc or di n g t o t he Nati o nal Ca ncer I nstit ute 
( N CI) C o m m o n Ter mi n ol o g y Criteria f or A d vers e E ve nts ( C T C A E) versi o n 4. 0 3. 
D ose li miti n g t o xicities are defi ne d se paratel y f or he mat ol o gic a n d n o n -he mat o l o gic e ve nts as 
o utli n e d bel o w. 
4. 2. 2    
He m at ol o gic D ose Li miti n g To xicit y   
He mat ol o gi c D L T will b e defi ne d as f oll o ws:  
 Gra de 4 n e utr o pe nia l asti n g > 5 da ys  
 ≥ Gra de 3 fe brile n e utr o pe nia lasti n g > 4 8 h o urs or a n y ≥ Gra de 3 fe brile ne utr o pe nia 
ass ociate d wit h he m o d y n a mic c o m pr o mise or o bjecti ve e vi de nce of i nfecti o n  
 Gra de 4 t hr o m b o c yt o p e nia, irres pecti ve of d urati o n  
 Gra de 3 t hr o m b o c yt o p e nia ass ociate d wit h cli nicall y si g nifi ca nt blee di n g  
 ≥ Gra de 3 h e m ol ysis  
 
C o nfi d e nti al
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Mar get u xi ma b  
Macr o Ge nics, I nc.  
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A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
T he  f oll o wi n g e ve nts will be s pecificall y e xcl u de d  fr o m t he defi niti o n of he mat ol o gic D L T: 
 ≥ Gra de 3 l y m p h o pe nia  
 Gra de 3 a ne mia t hat is n ot ass ociate d wit h ot her cli nicall y si g nifica nt c o m plicati o ns  
 
4. 2. 3    
N o n -He m at ol o gic D ose Li miti n g To xicit y   
N o n -he patic n o n -he mat ol o gic D L T will be defi ne d as a n y ≥ Gra de 3 n o n -he mat ol o gic e ve nt wit h 
t he f oll o wi n g e xce pti o ns: 
 Gra de 3 electr ol yte a b n or malit y t hat lasts less t ha n 7 2 h o u rs, is n ot ot her wise 
ass ociate d wit h cli nical c o m plicati o ns, a n d res p o n ds t o me dical i nter ve nti o n  
 Gra de 3 fe ver t hat lasts < 7 2 h o urs a n d is n ot ass ociate d wit h he m o d y na mi c 
c o m pr o mise 
 Gra de 3 n a usea or v o miti n g t hat lasts < 7 2 h o urs a n d res p o n ds t o me dical  i nter ve nti o n 
 Gra de 3 or 4 a m ylase a n d/ or li pase ele vati o n t hat is n ot ass ociate d wit h eit her cli nical 
or ra di o gra p hi c e vi de nce s u g gesti ve of pa ncreatitis  
 Gra de 3 diarr hea t hat lasts < 4 8 h o urs a n d res p o n ds t o me dical i nter ve nti o n  
 Gra de 3 gastr oi ntesti nal A Es of c o nsti pati o n, a b d o mi nal pai n, cra m pi n g, d ys pe psia or 
d ys p ha gi a t hat res ol ves t o ≤ Gra de 1 wit hi n 1 4 da ys wit h me dical t hera p y  
 Gra de 3 fati g ue t hat lasts < 7 da ys  
 Gra de 3 i nf usi o n -relate d reacti o n or c yt o ki ne rel ease s y n dr o me t hat lasts < 1 2 h o urs 
a n d res p o n ds t o me dical i nter ve nti o n.  
 Gra de 3 or 4 e n d ocri n o pat h y t hat is a de q uatel y c o ntr olle d wit h h or m o ne 
s u p ple me ntati o n 
 Gra de 3 s ki n t o xicit y t hat res ol ves t o ≤ Gra de 2 wit hi n 1 4 da ys of i ni tiati o n of oral 
c ortic oster oi ds  
 Gra de 3 i nfl a m mat or y reacti o n  (e. g., wit h ass oci ate d pai n, s welli n g) attri b ute d t o a 
l ocal a ntit u m or res p o nse (e. g., i nfla m mat or y reacti o n at sites of metastatic disease, 
l y m p h n o des, etc.) t hat res ol ves t o ≤ Gra de 2 wit hi n 7 da ys wit h me dical i nter ve nti o n  
 
N ote: T he f oll o wi n g Gra de 2  or greater n o n -he mat ol o gic A E ma y als o be c o nsi dere d as D L T:  
 Gra de 2 A Es t hat are pr ol o n ge d i n or di natel y, base d u p o n t he me dical j u d g me nt of t he 
i n vesti gat or, a n d/ or lea d t o per ma ne nt disc o nti n uati o n of st u d y dr u g(s) d ue t o patie nt 
i nt olera nce. 
 A n y ≥ Gra d e 2 dr u g-relat e d A E t hat res ults i n > 7-da y treat me nt dela y w o ul d be 
c o nsi dere d a D L T.  
C o nfi d e nti al
P a g e   
4 9   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
 A n y h e patic la b orat or y a b n or malities meeti n g all t hree H y ’s la w criteria ( descri be d 
wit hi n  Secti o n  4. 2. 4  bel o w).  
 A n y Gra d e 2 e ye p ai n or re d ucti o n i n vis ual ac uit y t hat d oes n ot res p o n d t o t o pical 
t hera p y a n d d o es n ot i m pr o ve t o Gra de 1 wit hi n 1 4 da ys of t he i nitiati o n of t o pical 
t hera p y, or t hat re q uires s yste mic treat me nt. 
 
4. 2. 4    
He p atic N o n -He m at ol o gic D ose Li miti n g To xicit y   
 A n y Gra d e 3 ele vati o n of o ne or m ore Pleas e see S ecti o n  6. 5. 2. 2  f or f urt her 
ma na ge me nt g ui deli nes.  
 A Gra de 3 el e vati o n of t otal bilir u bi n.  Please see  Secti o n  6. 5. 2. 2  f or f urt her 
ma na ge me nt g ui deli nes.  
 A n y e ve nt meeti n g t he criteria f or H y ’s la w as f oll o ws (all t hree feat ures): 
o  A s partate a mi n otra nsferase (A S T) a n d/ or ala ni ne a mi n otra nsferase ( A L T) > 3 
× U L N.  
o  C o nc urre nt ele v ati o n of t otal bilir u bi n > 2 × U L N wit h o ut i nitial e vi de nce of 
c h olestasis (e. g., el e vate d ser u m al kali ne p h os p hat ase  [ A L K-P])  
o  N o alter nati ve eti ol o g y ca n be i de ntifie d.  
 
4. 3    
D ose Esc al ati o n R ules   
T he D ose Esc al ati o n P h ase  ( P art A) of t his trial will pr ocee d usi n g a c o n ve nti o nal 3  +  3 
a p pr oac h, a n d will be gi n wit h e nr oll me nt of 3 patie nts at a d ose of 2 0 0 m g pe m br oliz u ma b 
a d mi nistere d as a n I V i nf usi o n o nce e ver y 3 wee ks a n d a n i nitial d ose of 1 0  m g/ k g 
mar get u xi ma b a d mi nistere d as a n I V i nf usi o n o nce e ver y 3 wee ks. S uccessi ve d ose escalati o n 
c o h orts will be e nr olle d as o utli ne d bel o w. T he M T D or M A D will be det er mi ne d base d o n t he 
assess me nt of D L Ts d uri n g t he D L T E val uati o n Peri o d. Patie nts w h o are n ot e val ua ble f or safet y 
f or t he full D L T e v al uati o n peri o d f or reas o ns ot her t ha n st u d y dr u g -relate d t o xicit y will be 
re place d i n t he sa me d ose-le vel c o h ort. 
 If 0 of t he first 3 p atie nts treate d at a gi ve n d ose le vel e x perie nce a dr u g-rel ate d D L T 
d uri n g t he D L T e val u ati o n peri o d, t he d ose  will be escalate d a n d 3 patie nts will be 
e nr olle d a n d treate d at t h e ne xt hi g her d ose l e vel.  
 If 1 of t he first 3 p atie nts treate d at a gi ve n mar get u xi ma b d ose le vel e x perie nces a 
dr u g -relat e d D L T, t h e n 3 a d diti o nal patie nts will be e nr olle d at t hat d os e le vel (t h us 
ma ki n g a t otal of 6 patie nts i n t his c o h ort) t o f urt her assess t he safet y of t he 
c o m bi nati o n.  
C o nfi d e nti al
P a g e   
5 0   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
 If ≥ 1 of t hese 3 a d diti o nal patie nts e nr olle d i n t he c o h ort e x perie nce a D L T (t hat is, 
≥ 2 o ut of 6), it will be c o ncl u de d t hat t he M T D has bee n e xcee de d, a n d 3 patie nts will 
be e nr olle d a n d treate d at t he ne xt l o wer d ose le vel.  If 0 of t he 3 a d diti o nal patie nts 
e x perie nces a D L T (t hat is o nl y 1 of 6 patie nts has e x perie nce d a D L T), t he n t he d ose 
will be escalate d, a n d 3 p atie nts will be e nr olle d at t he  ne xt hi g her d ose le vel.   
 If ≥ 2 patie nts o ut of t he first 3 patie nts treate d at a gi v e n d ose le vel, or ≥ 2 of 6 
patie nts treate d at a gi ve n d ose le vel, e x perie nce a dr u g -relate d D L T, t h e n it will be 
c o ncl u de d t hat t he M T D f or mar get u xi ma b i n c o m bi nati o n w it h pe m br oliz u ma b has 
bee n e x cee d e d at t hat d os e le vel, a n d all s u bse q ue nt patie nts will be treat e d at t he ne xt 
l o wer d ose le vel. 
 N ote t hat i n t he circ u mst a nce i n w hic h a D L T occ urs d uri n g or i m me diatel y f oll o wi n g 
t he first pe m br oliz u ma b i nf usi o n a n d bef ore t he first mar get u xi ma b a d mi nistrati o n, t he 
t o xicit y will be attri b ute d t o pe m br oliz u ma b al o ne a n d will n ot c o u nt as a D L T of t he 
c o m bi nati o n of st u d y dr u gs at t he d os e le vel u n der st u d y. I n t his case t he patie nt will 
be re place d b y a n ot h er patie nt i n t he  d ose c o h ort.  
 A t otal of 6 patie nts were treate d at t he R P 2 D pri or t o e nr olli n g i n t he C o h ort  
E x pa nsi o n P hase s of t he st u d y.  
 
F oll o wi n g t hese r ules f or d ose escal ati o n, t he M T D/ M A D f or t he c o m bi nati o n of mar get u xi ma b 
a n d pe m br oliz u ma b will be defi ne d as t h e d ose le vel at w hic h < 3 3 % of patie nts e x perie nce a 
dr u g -relat e d D L T d uri n g t he D L T e val u ati o n peri o d. If n o M T D is defi ne d f or t he c o m bi nati o n of 
mar get u xi ma b a n d pe m br oliz u ma b after escalati o n t o t he ma xi m u m pr ot oc ol -s pecifie d d ose, t h at 
d ose le vel  will  be desi g n ate d as t he M A D.  
D ose escalati o n t o t he ne xt d ose le vel is per mitte d o nl y after t he patie nts e nr olle d i n t he c urre nt 
d ose c o h ort ha v e c o m pet e d t he D L T e val uati o n peri o d a n d safet y data ha ve bee n re vi e we d.  
At t he discreti o n of t he S p o ns or, d ose es calati o n ma y be st o p pe d bef ore a n M T D is reac he d. I n 
t his case, t he M A D ma y be c h ose n bas e d o n a n assess me nt of P K, P D, bi o mar ker, safet y, a n d 
res p o nse data. A n M T D d oes n ot ha ve t o be reac he d t o e x pa n d a d ose c o h ort if t he a vaila ble data 
de m o nstrate t hat a l o w er d ose le vel ma y pr o vi de a ntit u m or acti vit y w hile mi ni mizi n g p ote ntial 
ris k. 
4. 4    
R ules f or Tre at me nt Disc o nti n u ati o n   
Patie nts w h o t olerate treat me nt wit h pe m br oliz u ma b a n d mar g et u xi ma b ma y c o nti n ue t o recei ve 
a d diti o nal treat me nt wit h t he st u d y dr u gs as s pecifie d i n t he pr ot oc ol (see S ecti o n  4. 1. 1 ), u ntil 
a n y o n e of t he f oll o wi n g c o n diti o ns are met: 
 After d oc u m e ntati o n of a c o nfir me d c o m plet e res p o nse (c C R), t he c o m bi nati o n of 
mar get u xi ma b a n d pe m br oliz u ma b is c o nti n ue d f or o ne m ore treat me nt c ycle.  
 Patie nt meets criteria f or i m m u ne -relate d disease pr o gressi o n (ir P D) (A p pe n di x  8 ) 
 Occ urre nce of dr u g -rel ate d D L T 
C o nfi d e nti al
P a g e   
5 1   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
 T he S p o ns or, i n vesti gat or, or re g ulat or y a ge nc y t er mi nates t he st u d y  
 Wit h dra wal of patie nt d u e t o a n A E or S A E  
 Wit h dra wal of patie nt c o nse nt  
 C o m pleti o n of pr ot oc ol defi ne d t hera p y  
 I n v esti gat or discreti o n 
 Pre g n a nc y  
 Deat h  
 T w o years of pe m br oliz u ma b a n d mar get u xi ma b c o m bi nati o n treat me nt  
 
4. 5    
G ui deli nes f or D ose M o dific ati o ns   
N o i ntra -patie nt d ose escalati o n will be all o we d.  N o d ose re d ucti o ns will be all o we d. I nf usi o n 
rate re d ucti o n is all o we d d uri n g re-c h alle n ge f or patie nts e x perie nci n g a n i nf usi o n reacti o n 
(Secti o n  6. 5. 1 ). Patie nts w h o e x perie nce a D L T t h at is c o nsi dere d relate d t o eit her st u d y dr u g 
s h o ul d be wit h dra w n fr o m f urt her pe m br oliz u ma b or mar get u xi ma b a d mi nistrati o n b ut will be 
foll o we d -u p f or safet y p ur p oses.  
4. 5. 1    
D ose Del a ys   
Patie nts w h o e x perie nce t o xicit y t hat is p ote ntiall y d ose -li miti n g s h o ul d have st u d y dr u g hel d 
pe n di n g assess me nt, ma na ge me nt, a n d res ol uti o n of t he t o xicit y.  S pecific g ui da nce f or t he 
ma na ge me nt of k n o w n t o xicities ass ociate d wit h pe m br oliz u ma b a n d mar get u xi ma b treat me nt, 
i ncl u di n g i nf usi o n-relate d reacti o ns, i m m u ne-relate d a d vers e e ve nts (ir A Es), a n d car di ot o xicities 
of s pecial i nterest is pr o vi de d i n  Secti o n  6. 5 . F or patie nts i n w h o m t he t o xicit y is assess e d t o be 
u nrelate d t o st u d y dr u g or f or w h o m t he t o xicit y d oes n ot meet t he criteria f or D L T or meet 
criteria f or t he k n o w n t o xicities, t hera p y ma y be re -i nstit ute d at t he sa me d ose a n d sc he d ul e t hat 
was a d mi nistere d pri or t o t he e ve nt, pres u mi n g t he t o xicit y has res ol ve d t o ≤ Gra de 1 i n se verit y. 
Rei nstit uti o n of t hera p y s hall be c o n d ucte d as f oll o ws:  
 F or patie nts i n w h o m t he t o xicit y is assesse d t o be relate d t o st u d y dr u g, d ose dela ys of 
u p t o 1 4 da ys are all o we d (see e xce pti o n f or car di ot o xicities of s pecial i nterest 
descri be d i n  Secti o n  6. 5. 3 ). T his ma y i n cl u de u p t o o ne misse d d ose. H o we ver, t he 
pr oce d ures at t he ori gi nal sc he d ule d misse d visit s h o ul d be perf or me d as s o o n as 
p ossi ble a n d res u me d as Da y 1 of ne xt c ycle wit h treat me nt rei nstit u ted after rec o ver y 
fr o m t o xicit y. 
 F or patie nts i n w h o m t he t o xicit y is assesse d t o be relate d t o st u d y dr u g, d ose dela ys 
>  1 4  da ys will res ult i n disc o nti n uati o n of treat me nt (see e xce pti o n f or car di ot o xicities 
of s pecial i nterest descri be d i n  Secti o n  6. 5. 3 ). 
 
C o nfi d e nti al
P a g e   
5 2   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
4. 6    
R ati o n ale f or St u d y Desi g n   
As descri be d i n  Secti o n  2. 4 , t here is a str o n g rati o nale t o e val uate t h e a ntit u m or acti vit y of t he 
mar get u xi ma b a n d pe m br oliz u ma b c o m bi nati o n i n H E R 2 + G EJ a n d G C . T he st u d y is desi g ne d 
t o deter mi ne t he M T D or M A D (if n o M T D is defi ne d) of t he c o m bi nati o n i n t he D ose 
Escalati o n P hase  ( Part A) of t he st u d y. T he D L T E val uati o n peri o d occ urs wit hi n t he first 3 -wee k 
treat me nt c ycl e; patie nts w h o d o n ot e x perie nce a D L T or ot her u nacce pta ble t o xicit y, or 
cli nicall y si g nifica nt pr o gressi ve diseas e ( P D) (i.e., i m m u ne-relate d pr o gressi ve disease [ir P D]), 
will t he n be all o we d t o c o nti n ue recei vi n g c o m bi nati o n mar get u xi ma b a n d pe m br oliz u ma b f or u p 
t o t w o years. O nce an  M A D or M T D is de fi ne d, patie nts will be e nr olle d i nt o a C o h ort 
E x pa nsi o n P hase . In  t his p orti o n of t he st u d y, t he c o m bi nati o n of mar get u xi ma b a n d 
pe m br oliz u ma b will be e val uate d i n u p t o 8 5  e val ua ble patie nts  (6 0  patie nts wit h 
rela pse d/refract or y u nres ecta ble l ocall y a d va nce d or metastatic H E R 2 + G EJ or G C  e nr olle d i n 
Part B [3 0 eac h i n N ort h A merica a n d Asia ], a n d 2 5  patie nts i n N ort h A merica a n d/ or Asia wit h 
u nresect a ble l ocall y a d v a nce d or metast atic H E R 2 + (I H C  3 + ) G C  e nr olle d i n Part C, usi n g t he 
M A D or M T D deter mi ne d i n t he D ose Escalati o n P hase  ( Part A). 
4. 7    
St u d y D ur ati o n   
Mar get u xi ma b a n d pe m br oliz u ma b will be a d mi nistere d i n c o m bi nati o n o n ce e ver y 3 wee ks f or 
u p t o 2 years.  It is e x pect e d t hat e nr oll me nt of Part A  of t he st u d y will occ ur o ver a p pr o xi matel y 
6 m o nt hs a n d t hat e nr oll me nt of Parts B - C  of t he st u d y will ta ke a p pr o xi matel y 9 -1 8  m o nt hs.  
T he t otal ti me f or c o n d uct of t he trial is e x pecte d t o be a p pr o xi matel y 6 0  m o nt hs. T hese 
esti mates of t he ti mi n g f or st u d y c o n d uct ma y var y fr o m t hat o bser ve d i n t he act ual c o n d uct of 
t he trial. 
4. 7. 1    
P atie nt Accr u al   
T he n u m ber of patie nts e nr olle d i n t he D ose Esc al ati o n P h ase ( P art A) ca n n ot be precisel y 
deter mi ne d i n a d va n ce a n d c o ul d ra n ge u p t o 1 2 p atie nts de pe n di n g o n res ults i n t he c o urse of 
t he trial a n d t he n u m ber of mar get u xi ma b d oses e x pl ore d. T his patie nt n u m ber d oes n ot ta ke i nt o 
acc o u nt patie nt re place m e nt f or n o n -e val ua ble patie nts.  
T he C o h ort E x p a nsi o n P h ase s ( P a rts B –  C ) of t he trial will e nr oll u p t o  8 5  patie nts . T his 
i ncl u des 3 0 patie nts i n N ort h A merica a n d 3 0 patie nts i n Asia wit h rela pse d/refract ory 
u nresect a ble l ocall y a d v a nce d or metast atic H E R 2 + G EJ or  G C  (Part B ), a n d 2 5  a d diti o nal 
patie nts i n N ort h A merica  a n d/ or Asia wit h u nresecta ble l ocall y a d va nce d or metastatic H E R 2 + 
(I H C 3 + ) G C  (Part C ). 
4. 7. 2    
Defi niti o n of E n d of Tri al   
T he e n d of st u d y will occ ur after t he last patie nt c o m pletes t he Effic ac y F oll o w U p Peri o d  (see 
Secti o n 4. 1. 4 ) a n d t he data c ollecti o n pr ocess is c o m plete (ti me of st u d y data base l oc k) .
C o nfi d e nti al
P a g e   
5 3   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
5    
S E L E C TI O N A N D WI T H D R A W A L O F P A TI E N T S   
I n cl usi o n a n d e x cl usi o n criteria are desi g ne d t o pr o perl y defi ne t h e tar get p o p ulati o n f or st u d y 
partici pati o n a n d t o i de ntif y t h ose patie nts w h o ma y n ot b e a p pr o priate ca n di dates f or st u d y 
partici pati o n base d o n s p ecific c o -m or bi dities or ot her cli nic o pat h ol o gic feat ures of t heir diseas e. 
Patie nts m ust meet all t he i ncl usi o n criteria; patie nts will be e xcl u de d fr o m t he st u d y if t he y meet 
a n y e x cl usi o n criteria. N o e x ce pti o ns t o t hese criteria will be gra nte d b y t h e S p o ns or.  
5. 1    
I ncl usi o n Criteri a  
Ge neral : 
1.  A bilit y t o pr o vi d e i nf or m e d c o nse nt a n d d oc u me ntati o n of i nf or me d c o ns e nt pri or t o 
i nitiati o n of a n y st u d y-relate d tests or pr oce d ures t hat are n ot part of sta n dar d-of -care 
f or t he patie nt’s disease. Patie nts m ust als o be willi n g a n d a ble t o c o m pl y wit h st u d y 
pr oce d ures, i ncl u di n g t h e ac q uisiti o n of s pecifie d researc h s peci me ns.  
2.  A ge ≥ 1 8 years ol d  ( mi ni m u m a ge de pe n de nt u p o n l ocal re g ulati o ns).  
3.  Patie nts ma y be mal e or fe male . 
4.  Si xt y p a tie nts i n P art B : Ha ve h ist ol o gicall y pr o ve n u nresecta ble l ocall y a d va nce d 
or metastatic H E R 2 + gastr oes o p ha geal j u ncti o n ( G EJ) or gastric ca ncer ( G C)  
deter mi ne d as 3 + b y I H C or  2 + b y I H C a n d  i n sit u h y bri dizati o n–  (I S H-) a m plifie d 
( ≥2. 0) (as p er C olle ge of A merica n Pat h ol o gists/ A merica n S ociet y of Cli nical 
O nc ol o g y 2 0 1 6 G ui deli nes)  i n m ost rece nt t u m or bi o ps y. 
T we nt y -fi ve p atie nts  i n P art C (G C  o nl y ): As of A me n d me nt  2, u p t o  2 5  a d diti o nal 
patie nts  will ha ve hist ol o gicall y  pr o ve n u nresect a ble l ocall y a d va nce d or metastatic 
H E R 2 + G C  (as defi ne d i n AJ C C Ca ncer Sta gi n g Ma n ual, 8t h  E diti o n) deter mi ne d as 3 + 
b y I H C (as per C olle ge of A merica n Pat h ol o gists/ A merica n S ociet y of Cli nical O nc ol o g y 
2 0 1 6 G ui deli nes) i n t he m ost rece nt t u m or bi o ps y.  
5.  Ha ve recei v e d pri or treat me nt wit h trast uz u ma b.  
6.  Ha ve recei v e d treat me nt wit h o ne li ne of c yt ot o xic c he m o t hera p y i n t he m etastatic 
setti n g, w hic h i ncl u des tr ast uz u ma b . Pri or a dj u va nt  t hera p y t hat res ulte d i n rela pse 
wit hi n 6 m o nt hs of c o m pleti o n of t hera p y will be c o nsi dere d a li ne of treat me nt f or 
metastatic disease.  Eli gi ble patie nts m ust ha ve d oc u me nte d pr o gress i o n o n / after t he 
m ost rece nt li ne of t hera p y.  Patie nts  w h o disc o nti n ue trast uz u ma b f or ot her reas o ns 
(e. g., fi na n cial) are eli gi ble if t he y ha ve doc u me nte d pr o gressi o n o n/after trast uz u ma b 
wit h o ut  recei vi n g alter nate treat me nt. 
 I n Parts B a n d C,  o nl y o ne pri or li ne of treat me nt t hat i ncl u des trast uz u ma b is 
all o we d.  
7.  Res ol uti o n of all c he m ot hera p y or ra diati o n -relate d t o xicities t o ≤ Gra de 1 ( wit h 
e x ce pti o n of ≤ Gra de 2 al o pecia, sta ble se ns or y ne ur o pat h y, or sta ble el ectr ol yte 
dist ur ba nces t hat are ma na ge d b y s u p ple me ntati o n).  
C o nfi d e nti al
P a g e   
5 4   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
8.  Easter n C o o perati ve O nc ol o g y Gr o u p ( E C O G) perf or ma nce stat us of 0 or 1 
(A p pe n di x  6 ). 
9.  Life e x pecta nc y ≥ 1 2 wee ks.  
1 0.  Meas ura ble dis ease as per Res p o nse E val uati o n Criteria i n S oli d T u m ors ( R E CI S T ) 
1. 1 ( A p pe n di x  7 ) a n d d oc u me nte d b y c o m p ute d t o m o gra p h y ( C T) a n d/ or ma g netic 
res o na nce i ma gi n g ( M RI). Patie nts wit h e val ua ble disease o nl y will n ot be e nr olle d 
o n t his st u d y. N ot e: Lesi o ns t o be use d as meas u ra ble disease f or t he p ur p ose of 
res p o nse ass ess me nt m ust eit her a) n ot resi de i n a fiel d t hat has bee n s u bjecte d t o 
pri or ra di ot hera p y,  or  b) ha ve de m o nstrat e d clear e vi de nce of ra di o gra p hic 
pr o gressi o n si nce t he c o m pleti o n of pri or ra di ot hera p y a n d pri or  t o st u d y e nr oll me nt. 
1 1.  Patie nts s h o ul d ha ve a f or mali n-fi xe d, paraffi n e m be d de d t u m or s peci me n or 
u nstai ne d sli des i de ntifie d a n d a vaila ble f or a nal ysis, t o e na ble deter mi nati o n of t he 
e x pressi o n  of H E R 2 a n d P D -L 1 wit hi n t u m or s peci me ns usi n g I H C stai ni n g.  
 
La b orat or y Feat ures : 
1 2.  Acce pt a ble la b orat or y para meters as f oll o ws:  
a. Platelet c o u nt  1 0 0 × 1 0 3/µ L wit h o ut tra nsf usi o n wit hi n 2 wee ks pri or t o t he 
i nitiati o n of st u d y dr u g. 
b.  A bs ol ute ne utr o p hil c o u nt ( A N C)  1. 5 × 1 0 3/ µ L i n t he a bse nce of a n y 
gr o wt h fact or s u p p ort wit hi n 2 wee ks pri or t o t he i nitiati o n of st u d y dr u g. 
c. He m o gl o bi n ( H g b)  9 g/ d L.  
d.  A L T/ A S T  3. 0 × U L N; f or patie nts wit h he patic metastases, A L T a n d A S T ≤ 
5 × U L N.  
e. Total bilir u bi n  1. 5 × U L N, e xce pt patie nts wit h Gil bert ’s s y n dr o me, w h o 
ma y e nr oll if t he c o nj u gate d bilir u bi n is wit hi n n or mal li mits.  
f. Creati ni ne < 2 m g/ d L, or a calc ulate d or meas ure d creati ni ne cleara nce >  5 0 
m L/ mi n.  
 
Re pr o d ucti ve Feat ures : 
1 3.  Fe male p atie nts of c hil d b ea ri n g p ote ntial ( n ot s ur gicall y sterilize d a n d bet wee n 
me narc h e a n d 1 year p ost me n o pa use) m ust ha ve a ne gati ve uri ne pre g na nc y test 
perf or me d wit hi n 7 2 h o urs pri or t o t he i nitiati o n of st u d y dr u g a d mi nistrati o n. 
F urt her, fe male p atie nts of c hil d beari n g p ote ntial m ust a gree t o use hi g hl y effecti ve  
c o ntrace pti ve meas ures fr o m t he ti me of c o nse nt t hr o u g h 1 2 0 da ys after 
disc o nti n uati o n of st u d y dr u g a d mi nistrati o n . 
F or C a n a di a n p atie nts o nl y:  Fe male patie nts of c hil d beari n g p ote ntial m ust ha ve a 
ne gati ve pre g n a n c y test pri or t o e ver y c ycle of pe m br o liz u ma b. 
C o nfi d e nti al
P a g e   
5 5   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
 Hi g hl y effecti ve met h o ds of c o ntrace pti o n i ncl u de h or m o nal c o ntrace pti ves, 
i ntra uteri ne de vice or s yste m, vasect o m y, or t u bal li gati o n. If a hi g hl y effecti ve 
met h o d is n ot ac hie va ble t he n a “d o u ble barrier ” m e t h o d is a n effecti ve 
alter nati ve i n w hic h t he male part ner m ust use a c o n d o m wit h s per mici de a n d 
t he fe male p art ner m ust use a dia p hra gm or cer vical ca p c o nc urre ntl y.  
1 4.  Male patie nts wit h part ners of c hil d beari n g p ot e ntial m ust use barrier c o ntrace pti o n. 
I n a d diti o n, male patie nts s h o ul d als o ha ve t heir part ners use a n ot h er met h o d of 
c o ntrace pti o n fr o m t he ti me of c o nse nt t hr o u g h 1 2 0 da ys after disc o nti n uati o n of 
st u d y dr u g a d mi nistrati o n. 
1 5.  Is n ot pre g na nt  or breastf ee di n g, or e x pecti n g t o c o ncei ve or fat her c hil dre n wit hi n t he 
pr ojecte d d urati o n of t he trial, starti n g wit h t he prescree ni n g or scree ni n g visit 
t hr o u g h 1 2 0 d a ys after t he last d ose of trial treat me nt.  
 
T u m or Bi o ps y  
1 6.  At least 2 0 of t he 6 0 p ati e nts e nr olle d i n t he C o h ort E x pa nsi o n P hase  (Part B ) u n der 
t he Ori gi n al Pr ot oc ol a n d Pr ot oc ol A me n d me nt 1 m ust ha ve o ne lesi o n c o nsi dere d t o 
be p ote ntiall y accessi ble  t o bi o ps y a n d be willi n g t o pr o vi de c o nse nt f or bi o ps y 
sa m ples. A n atte m pt at a t u m or bi o ps y of l ocall y accessi ble lesi o ns will be ma de  f or 
at least 2 0 of t he 6 0  patie nts . T u m or lesi o ns use d f or bi o ps y s h o ul d n ot be lesi o ns 
use d as R E CI S T tar get lesi o ns u nless t here are n o ot her lesi o ns s uita ble f or bi o ps y. If 
a R E CI S T tar get lesi o n is use d f or bi o ps y , t he lesi o n m ust be ≥ 2  c m i n l o n gest 
dia met er. T u m or bi o psies s h o ul d o nl y be o btai ne d fr o m lesi o ns t hat are felt t o be 
accessi ble wit h acce pta bl e cli nical ris k i n t he j u d g me nt of t he i n vesti gat or.  
 T he 2 5 patie nts e nr olle d i nt o Part C will n ot be re q uire d t o ha ve pre - a n d 
o n -treat me nt bi o psies. 
 Dia g n ostic bi o ps y sa m pl e perf or me d as sta n dar d of care will be c ollect e d 
fr o m all patie nts o n st u d y.  
 
Pre vi o us C hec k p oi nt I n hi bit or T hera p y  
1 7.  Patie nts w h o ha ve pre vi o usl y recei ve d a n i m m u ne c hec k p oi nt i n hi bit or (e. g., a nti -P D -
L 1, a nti -P D -1 a nti -C T L A -4) pri or t o e nr oll me nt m ust ha ve t o xicities relate d t o t he 
c hec k p oi nt i n hi bit or res ol ve d t o ≤ Gra de 1 or baseli ne ( pri or t o t he c hec k p oi nt 
i n hi bit or) t o be eli gi ble f or e nr oll me nt. 
 
5. 2    
E xcl usi o n Criteri a   
1.  Patie nts wit h s y m pt o mati c ce ntral ner v o us s yste m ( C N S) metastases m ust ha ve bee n 
treate d, be as y m pt o matic, a n d meet t he f oll o wi n g at t he ti me of e nr oll me nt: 
C o nfi d e nti al
P a g e   
5 6   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
a. N o c o nc urre nt treat m e nt f or t he C N S disease (e. g. s ur ger y, ra diati o n, 
c ortic oster oi ds ≥ 1 0 m g pre d nis o ne/ da y or e q ui vale nt).  
b.  N o pr o gressi o n of C N S metastases o n M RI or C T f or at least 2 1 da ys after last 
da y of pri or t hera p y f or t he C N S metastases.  
c. N o c o nc urre nt le pt o me ni n ge al disease or c or d c o m pressi o n.  
 
2.  Patie nts w h o e x perie nce d t he f oll o wi n g i m m u ne c hec k p oi nt i n hi bit or -relate d A Es 
(i.e., t he f oll o wi n g A Es ma ke t he patie nt i neli gi ble des pite t he A E res ol vi n g t o ≤ 
Gra de 1 or baseli ne):  
a. ≥ Gra de 3 o c ular A E.   
b.  C ha n ges i n li ver f u ncti o n tests t hat met t he criteria f or H y’s La w ( > 3 × U L N 
of eit her A L T/ A S T wit h c o nc urre nt > 2 × U L N of t otal bilir u bi n a n d wit h o ut 
alter nate eti ol o g y).  
c. ≥ Gra de 3 n e ur ol o gic t o xicit y.  
d.  ≥ Gra de 3 c olitis or p ne u m o nitis.  
 
3.  Patie nts wit h a n y hist or y of k n o w n  or s us pect e d a ut oi m m u ne disease wit h t he s pecific 
e x ce pti o ns of vitili g o, res ol ve d c hil d h o o d at o pic der matitis, ps oriasis n ot re q uiri n g 
s yste mic treat me nt ( wit hi n t he past 2 years) a n d patie nts wit h a hist or y of 
a ut oi m m u ne disease t hat are n o w cli nicall y st a ble wit h re place m e nt t hera p y a n d b y 
la b orat or y testi n g. 
a. Patie nts wit h hist or y of ps oriatic art hritis are e xcl u de d.  
 
4.  Hist or y of pri or all o ge nei c b o ne marr o w, ste m -cell or s oli d or ga n tra ns pla nt ati o n.  
5.  Treat me nt wit h a n y s yste mic a nti -ne o plastic t hera p y, or i n vesti gati o nal t hera p y wit hi n 
t he 3  wee ks pri or t o t he i nitiati o n of st u d y dr u g a d mi nistrati o n.  A dj u va nt h or m o nal 
t hera p y f or treat me nt of pr ostate or breast ca ncer is all o we d. 
6.  Treat me nt wit h ra di ati o n t hera p y wit hi n 3  wee ks pri or t o t he i nitiati o n of st u d y dr u g 
a d mi nistrati o n.  
7.  Treat me nt wit h c ortic ost er oi ds ( ≥ 1 0 m g per da y pre d nis o ne or e q ui vale nt) or ot her 
i m m u ne s u p pressi ve dr u gs wit hi n t he 1 4 da ys pri or t o t he i nitiati o n of st u d y dr u g 
a d mi nistrat i o n. Ster oi ds f or t o pical, o p ht hal mic, i n hale d or nas al a d mi nistrati o n are 
all o we d.  
8.  Hist or y of cli nicall y si g nifica nt car di o vasc ular disease i ncl u di n g b ut n ot li mite d t o:  
a. M y ocar dial i nfarcti o n or u nsta ble a n gi na wit hi n t he 6 m o nt hs pri or t o t he 
i nitiati o n of st u d y dr u g.  
b.  Str o ke or tra nsie nt isc he mic attac k wit hi n 6 m o nt hs pri or t o t he i nitiati o n of 
st u d y dr u g. 
c. Cli nicall y  si g nifica nt car diac arr h yt h mias. 
C o nfi d e nti al
P a g e   
5 7   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
d.  U nc o ntr olle d h y perte nsi o n: s yst olic bl o o d press ure ( S B P) > 1 8 0 m m H g, 
diast olic bl o o d press ure ( D B P) > 1 0 0 m m H g.  
e. C o n gesti ve heart fail ure ( Ne w Y or k Heart Ass ociati o n [ N Y H A] class III -I V). 
f. Pericar ditis or cli nicall y si g nifica nt p ericar dial eff usi o n.  
g.  M y ocar ditis.  
h.  Left ve ntricle ejecti o n fracti o n ( L V E F) < 5 0 % b y ec h ocar di o gra m or m ulti -
gat e d ac q uisiti o n ( M U G A) sca n.  
 
9.  Cli nicall y  si g nifica nt p ul m o nar y c o m pr o mise, i ncl u di n g a re q uire me nt f or 
s u p ple me ntal o x y ge n use t o mai ntai n a de q uate o x y ge nati o n. 
1 0.  Has a hist or y of ( n o n -i nfecti o us) p ne u m o nitis t hat re q uire d ster oi ds or has c urre nt 
p ne u m o nitis . 
1 1.  Cli nicall y  si g nifica nt gastr oi ntesti nal dis or ders i ncl u di n g: 
a. A n y hist or y of gastr oi ntesti nal perf orati o n u nless t he affecte d area has b ee n 
dee me d b y t he i n vesti gat or t o n o l o n ger be a ris k f or perf orati o n. 
b.  Hist or y of cli nicall y si g nifica nt gastr oi ntesti nal blee di n g wit hi n 4 wee ks pri or 
t o t he i nitiati o n of st u d y dr u g. 
c. Hist or y of ac ute pa ncreatitis wit hi n 4 wee ks pri or t o t he i nitiati o n of st u d y 
dr u g.  
d.  Di vertic ulitis t hat is cli nicall y si g nifica nt i n t he o pi ni o n of t he i n vesti gat or 
base d o n t he e xte nt or se verit y of k n o w n diseas e a n d/ or t he occ urre nce of 
cli nicall y si g nifica nt disease flares wit hi n 4 wee ks pri or t o t he i nitiati o n of 
st u d y dr u g a d mi nistrati o n. 
 
1 2.  E vi de nce of acti ve viral, bacterial, or s yst e mic f u n gal i nfecti o n re q uiri n g pare nteral 
treat me nt wit hi n 7 da ys pri or t o t he i nitiati o n of st u d y dr u g. Patie nts re q uiri n g a n y 
s yste mic a nti viral, a ntif u n gal, or a nti bacterial t hera p y f or acti ve i nfecti o n m ust ha ve 
c o m plete d treat me nt n o l ess t ha n o ne wee k pri or t o t he i nitiati o n of st u d y dr u g.  
1 3.  K n o w n p ositi ve testi n g f or h u ma n i m m u n o deficie nc y vir us or hist or y of ac q uire d 
i m m u ne deficie nc y s y n dr o me. 
1 4.  K n o w n hist or y of he patitis B or he patitis C i nfecti o n or k n o w n p ositi ve test f or 
he patitis B s urface a nti ge n, he patitis B c ore a nti ge n, or he patitis C p ol y m erase c hai n 
reacti o n ( P C R). 
1 5.  H ist or y of a n ot her mali g na nc y or a c o nc urre nt mali g na nc y. E xce pti o ns i ncl u de 
patie nts w h o ha ve bee n disease free f or t w o years, or s uccessf ull y treate d f or n o n -
mela n o ma s ki n ca ncer, l ocalize d pr ostate ca ncer ( Gleas o n Sc ore < 6) or carci n o ma  i n 
sit u, f or e x a m ple cer vical ca ncer i n sit u, are eli gi bl e. 
1 6.  Hist or y of tra u ma or maj or s ur ger y wit hi n 4 wee ks pri or t o t he i nitiati o n of st u d y dr u g 
a d mi nistrati o n.  
C o nfi d e nti al
P a g e   
5 8   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
1 7.  A n y s eri o us u n derl yi n g me dical or ps yc hiatri c c o n diti o n t hat w o ul d i m pair t he a bilit y 
of t he patie nt t o recei v e or t olerate t he pla n ne d treat me nt at t he i n vesti gati o nal site.  
1 8.  K n o w n h y p erse nsiti vit y t o rec o m bi na nt pr otei ns, p ol ys or bat e 8 0 or a n y e xci pie nt 
c o ntai ne d i n t he dr u g or ve hicle f or m ulati o n f or mar get u xi ma b  or pe m br oliz u ma b 
(Secti o n  6. 1 ). 
1 9.  Vacci n ati o n wit h a n y li v e vir us vacci ne wit hi n 4 wee ks pri or t o t he i nitiati o n of st u d y 
dr u g a d mi nistrati o n. I n acti vate d a n n ual i nfl ue nza vacci nati o n is all o we d.  
2 0.  T he  fe mal e patie nt w h o is pre g na nt or breastfee di n g, or e x pecti n g t o c o ncei ve, A N D 
t he male patie nt w h o is e x pecti n g t o fat her c hil dre n wit hi n t he pr ojecte d d urati o n of 
t he trial, starti n g wit h t he scree ni n g visit t hr o u g h 1 2 0 da ys after t he last d ose of trial 
treat me nt. 
2 1.  De me ntia or altere d me nt al stat us t hat w o ul d precl u de u n dersta n di n g a n d re n deri n g of 
i nf or me d c o nse nt. 
2 2.  E m pl o yees of Macr o Ge nics, I nc. , a n d Merc k & C o., I nc ., u nless a p pr o ve d b y 
i nstit uti o nal I R B a n d pri nci pal i n vesti gat or. 
2 3.  Pris o ners or ot her i n di vi d uals w h o are i n v ol u ntaril y det ai ne d. 
2 4.  A n y iss ue t hat i n t he o pi ni o n of t he i n vesti gat or, w o ul d c o ntrai n dicate t he patie nt’s 
partici pati o n i n t he st u d y or c o nf o u n d t he res ults of t he st u d y.  
 
5. 3    
Wit h dr a w al of P atie nt fr o m t he St u d y   
If t he i n vesti gat or deci des t hat t he patie nt s h o ul d be  wit h dra w n fr o m t he st u d y or fr o m d osi n g f or 
a n y reas o n ot h er t ha n dis ease pr o gressi o n, t he S p o ns or or its desi g nee m ust be alerte d wit hi n 
2 4  h o ur s via a n I m me diat el y Re p orta ble E ve nt f or m (Secti o n  7. 9. 6 ). 
Patie nts w h o wit h dra w bef ore St u d y Da y 2 1 d uri n g t he D os e Escalati o n P hase  ( Part A) f or a 
reas o n u nrelate d t o dr u g t o xicit y ma y be c o nsi dere d t o ha ve i na de q uate data t o s u p p ort d ose 
escalati o n. I n t his cas e, re place m e nt patie nts ma y be e nr olle d i n t he sa m e d ose le vel.  
Pr oce d ures f or ha n dli n g patie nts w h o fail t o a p pear f or st u d y visits a n d c riteria re gar di n g w he n t o 
c o nsi der patie nts l ost -t o-f oll o w-u p will be defi ne d i n t he St u d y M a n ual.  
C o nfi d e nti al
P a g e   
5 9   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
5. 3. 1    
G ui deli nes f or St u d y Disc o nti n u ati o n   
Patie nts w h o are n o l o n ger o n treat me nt b ut are still f oll o we d o n t he st u d y ca n be ter mi nate d 
fr o m t he st u d y f or t he f oll o wi n g reas o ns: 
 C o m pleti o n of pr ot oc ol defi ne d f oll o w -u p peri o d.  
 U nc o ntr olle d i nterc urre nt ill ness u nrelate d t o ca ncer t hat re n ders c o nti n ui n g st u d y 
f oll o w-u p u nsafe or re g ul ar  st u d y visits i m p ossi ble. 
 T he S p o ns or, i n vesti gat or, or re g ulat or y a ge nc y t er mi nates t he st u d y.  
 T he patie nt re q u ests t o be disc o nti n ue d fr o m t he st u d y, i.e., wit h dra wal of c o nse nt.  
 N o nc o m plia nce wit h pr ot oc ol -re q uire d e val u ati o ns. 
 T he patie nt e x hi bits pr o gressi o n of disease (acc or di n g t o ir R C).  
 Deat h  
 
C o nfi d e nti al
P a g e   
6 0   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
6    
S T U D Y T R E A T M E N T S   
6. 1    
Descri pti o n of Tre at me nts a n d St u d y Dr u g a n d S u p plies   
B ot h st u d y dr u gs will be a d mi nistere d as a n o pe n -la bel I V s oluti o n, f oll o we d b y o bs er vati o n.  
U n der n o circ u msta nces is t he i n vesti gat or all o we d t o release t h ese cli nical s u p plie s f or use b y 
a n ot her p h ysicia n n ot na me d o n F or m F D A 1 5 7 2 (a n d/ or c o u ntr y or re gi o n e q ui vale nt d oc u me nt) 
or t o a d mi nister st u d y dr u g t o a patie nt w h o is n ot e nr olle d i n t his st u d y. St u d y dr u g m ust be 
dis pe nse d at a n i nstit uti o n s pecifie d o n F or m F D A 1 5 7 2 ( or e q ui vale nt d o c u me nt).  
6. 1. 1    
M ar get u xi m a b   
Mar get u xi ma b is a sterile, clear -t o-sli g htl y-o pal esce nt, c ol orless -t o-pal e -yell o w or pale -br o w n, 
preser vati ve -free s ol uti o n f or I V a d mi nistrati o n. S o me visi ble, tra nsl uce nt, pr otei nace o us, 
mar get u xi ma b particles ma y b e pres e nt. Mar get u xi ma b is s u p plie d i n si n gle -use, 1 0 -m L clear 
glass vials wit h Fl ur o Tec ®  c oat e d gra y b ut yl r u b ber ser u m st o p pers a n d al u mi n u m seals wit h 
plastic o verseals. Eac h v i al c o ntai ns 2 5 0 m g mar get u xi ma b ( 2 5 m g/ m L) i n 1 0 m L of s ol uti o n. 
T he pr o d uct is f or m ulate d i n a b uffer c o ntai ni n g 1. 1 m g/ m L s o di u m p h os p hate m o n o basic, 
m o n o h y drate, 0. 5 8 m g/ m L s o di u m p h os p hate di basic, he pta h y drat e, 2. 9 m g/ m L s o di u m c hl ori de, 
1 1 m g/ m L L -ar gi ni ne h y dr oc hl ori de, 3 0 m g/ m L s ucr ose, a n d 0. 1 m g/ m L P ol ys or bat e 8 0, i n 
Sterile Water f or I nj ecti o n, p H 6. 1.  
6. 1. 2    
Pe m br oliz u m a b   
Pe m br oliz u ma b ( mar kete d as K E Y T R U D A ®  b y M erc k & C o., I nc, W hite h o use Stati o n, NJ 
0 8 8 8 9  U. S. Lice nse N o. 0 0 0 2 ) is a h u ma nize d m o n ocl o nal a nti b o d y t h at bl oc ks t he i nteracti o n 
bet wee n P D -1 a n d its li ga n ds, P D -L 1 a n d P D -L 2. Pe m br oliz u ma b is a n I g G 4 ka p pa 
i m m u n o gl o b uli n wit h a n a p pr o xi mate m olec ular wei g ht of 1 4 9 k Da.  
Pe m br oliz u ma b is s u p plie d as  l y o p hilize d p o w der i n a si n gle-us e vial f or rec o nstit uti o n  or as 
s ol uti o n f or i nf usi o n i n si n gle-us e  vials . 
Ta ble  3  
Pe m b r oliz u m a b Pr o d uct Descri pti o ns   
Pr o d uct N a me  
D os a ge F or m  a n d Stre n gt h  
M K -3 4 7 5  
F or I nj ecti o n: 5 0 m g l y o p hiliz e d p o w der i n si n gle-d ose  
vial f or rec o nstit uti o n  
or  
I nj ecti o n: 1 0 0 m g/ 4 m L  s ol uti o n i n si n gle-use  vial  
 
Pe m br oliz u ma b l y o p hilize d p o w der is a st erile, preser vati ve -free, w hite t o off-w hite l y o p hilize d 
p o w der i n si n gl e -use vials. Eac h vial is rec o nstit ute d wit h 2. 3 m L Sterile Water f or I njecti o n, 
U S P a n d dil ute d f or I V i nf usi o n. Eac h 2 m L of rec o nstit ute d s ol uti o n c o ntai ns 5 0 m g of 
pe m br oliz u ma b a n d is f or m ulate d i n L -histi di ne ( 3. 1 m g), p ol ys or bate 8 0 ( 0. 4 m g), a n d s ucr ose 
( 1 4 0 m g). Ma y c o ntai n h y dr oc hl oric aci d/s o di u m h y dr o xi de t o a dj ust p H t o 5. 5. 
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Pe m br oliz u ma b sol uti o n f or inf usi o n is a st erile, n o n-p yr o ge nic a q ue o us s ol uti o n s u p plie d i n a 
 vial c o ntai ni n g 1 0 0 m g/ 4 m L of pe m br oliz u ma b.
 
. 
6. 2    
Dr u g Pre p ar ati o n   
6. 2. 1    
Ge ner al G ui deli nes a n d Prec a uti o ns   
T he calc ul ate d d ose of mar get u xi ma b will be a d mi nistere d base d o n t he pa tie nt’s act ual wei g ht at 
Da y 1. Si g nifica nt ( ≥ 1 0 %) c ha n ge i n b o d y wei g ht fr o m baseli ne s h o ul d pr o m pt recalc ulati o n of 
d ose.  
I nf usi o n or aller gi c reacti o ns ma y o cc ur wit h t he i nf usi o n of m o n ocl o nal a nti b o dies a n d ot her 
pr otei n -base d t hera p e utics. Preca uti o ns f or a na p h yla xis or i nf usi o n -relate d reacti o ns (i ncl u di n g 
C R S) s h o ul d be o bser ve d d uri n g b ot h mar get u xi ma b a n d pe m br oliz u ma b a d mi nistrati o n. 
S u p p orti ve meas ures ma y i ncl u de, b ut are n ot li mite d t o: e pi ne p hri ne, a nti hista mi nes, 
c ortic oster oi ds, I V fl ui ds,  vas o press ors, o x y ge n, br o nc h o dilat ors, di p he n h y dra mi ne, a n d 
aceta mi n o p he n. Please refer t o  Secti o n  6. 5. 1  f or s pecific g ui deli nes re gar di n g t he ma na ge me nt 
of i nf usi o n reacti o ns. S u p p orti ve care meas ures c o nsiste nt wit h o pti mal patie nt care will be 
pr o vi de d t hr o u g h o ut t he st u d y acc or di n g t o i nstit uti o nal sta n dar ds.  
Se parate i nf usi o n ba gs m ust be use d f or eac h i nf usi o n. Pe m br oliz u m a b is t o be a d mi nistere d 
first. 
A n eff ort s h o ul d be ma de t o be gi n t he mar get u xi ma b i nf usi o n wit hi n 3 0 mi n utes after t he 
c o m pleti o n of t he pe m br oliz u ma b i nf usi o n. It is u n d erst o o d t hat t his wi n d o w ma y n ot al wa ys be 
attai na ble, b ut is t he preferre d wi n d o w of ti me t o a d mi nister mar get u xi ma b.  
6. 2. 2    
Pe m br oliz u m a b Pre p ar ati o n   
T he P har mac y M a n ual c o ntai ns s pec ific i nstr ucti o ns f or t he pre parati o n of t he pe m br oliz u ma b 
i nf usi o n a n d a d mi nistrati o n of i nf usi o n s ol uti o n. 
6. 2. 3    
M ar get u xi m a b Pre p ar ati o n   
T he P har mac y M a n ual c o ntai ns s pecific i nstr u cti o ns f or t he pre parati o n of t he mar get u xi ma b 
i nf usi o n a n d a d mi nistrati o n of i nf usi o n s ol uti o n. 
6. 2. 4    
Pl ace b o or C o ntr ol   
T here will be n eit her place b o n or acti ve c o ntr ol dr u g f or t his  st u d y. 
6. 3    
St u d y Dr u g A d mi nistr ati o n   
N ote: D osi n g i nterr u pti o ns are per mitte d i n t he case of me dical/s ur gi cal e ve nts or l o gistical 
reas o ns (i.e. electi ve s ur ger y, u nrelate d me dical e ve nts, patie nt vacati o n, h oli da ys, etc.) n ot 
relate d t o st u d y t hera p y. 
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A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
6. 3. 1    
Pe m br oliz u m a b A d mi nistr ati o n   
T he pe m br oliz u ma b i nf usi o n s ol uti o n s h o ul d be a d mi nistere d o ver 3 0 mi n utes t hr o u g h a n I V li ne 
c o ntai ni n g a sterile, n o n -p yr o ge nic, l o w -pr otei n bi n di n g 0. 2 micr o n t o 5 micr o n i n -li ne or a d d-o n 
filter usi n g a n i nf usi o n p u m p. D o n ot c o-a d mi nister ot her dr u gs t hr o u g h t he sa me i nf usi o n li ne. 
6. 3. 2    
M ar get u xi m a b A d mi nistr ati o n   
After pe m br oliz u ma b a d mi nistrati o n, mar get u xi ma b will be a d mi nistere d as a 1 2 0 -mi n ute ( 2 -
h o ur) I V i nf usi o n usi n g a ste rile P E S 0. 2 micr o n filtere d a d mi nistrati o n set. M ar get uxi m a b 
s h o ul d n ot be a d mi nistere d as a n I V p us h or b ol us. 
Mar get u xi ma b s h o ul d n ot be mi x e d or dil ute d wit h ot her dr u gs.  
6. 4    
Selecti o n a n d Ti mi n g of D ose f or E ac h P atie nt   
Patie nts will be assi g ne d t o s uccessi ve d ose c o h orts as descri be d i n Secti o n  4. 1. 2  a n d 
Secti o n  4. 1. 3 . O n eac h treat me nt da y, pe m br oliz u ma b will be a d mi nistere d first, f oll o we d b y 
mar get u xi ma b a d mi nistrati o n wit hi n 3 0  t o 1 2 0 mi n utes f oll o wi n g c o m pleti o n of pe m br oliz u ma b 
i nf usi o n. 
6. 5    
P ote nti al A d verse E ve nts a n d S u p p orti ve C are Me as ures   
6. 5. 1    
I nf usi o n-Rel ate d Re acti o ns I ncl u di n g C yt o ki ne Rele ase S y n dr o me   
I nf usi o n reacti o ns (i ncl u di n g c yt o ki ne releas e s y n dr o me [ C R S]) ass ociate d wit h eit her 
mar get u xi ma b or pe m br oliz u ma b a d mi nistrati o n s h o ul d be ma na ge d acc or di n g t o t he sta n dar d 
practice of me dici ne. Ge neral g ui deli nes f or t he ma na ge me nt of s u c h reacti o ns are pr o vi de d i n 
t his secti o n. H o we ver, s e vere reacti o ns ma y re q uire m ore i nte nsi ve i nter ve nti o ns (e. g., ster oi ds, 
a nti-T N F  a nti b o dies, a n d/ or I L-6 i n hi bit ors).  
Patie nts s h o ul d be m o nit ore d cl osel y f or t he de vel o p me nt of i nf usi o n -relate d reacti o ns d uri n g t he 
pe m br oliz u ma b a n d mar get u xi ma b i nf usi o ns. Me dicati o ns a n d s u p p orti ve meas ures f or t he 
treat me nt of se v ere h y p erse nsiti vit y reacti o ns s h o ul d be a vaila ble f or i m me diate use f or a n 
i nf usi o n reacti o n d uri n g st u d y dr u g a d mi nistrati o n a n d ma y i ncl u de, b ut are n ot li mite d t o: 
s u bc uta ne o us ( S C) e pi ne p hri ne ( 0. 3 t o 0. 5 m L of a 1: 1 0 0 0 s ol uti o n), a nti hista mi nes (e. g., 
di p he n h y dra mi ne 2 5 t o 5 0 m g I V), c ortic oster oi ds (e. g., de xa met has o ne 2 0 m g I V p us h or 
e q ui vale nt), I V fl ui ds, vas o press ors, o x y ge n, br o nc h o dilat ors, a n d a nti p yretics. Res uscitati o n 
e q ui p me nt a n d ot her s u p plies f or t he e mer ge nc y ma na ge me nt of a n aller gi c/t o xic reacti o n m ust 
be a vaila ble. T he patie nt s h o ul d be treate d acc or di n g t o t he best a vaila ble l ocal practices a n d 
pr oce d ures. All s u p p orti v e meas ures c o nsiste nt wit h o pti mal patie nt care will be pr o vi de d 
t hr o u g h o ut t he st u d y acc or di n g t o i nstit uti o nal sta n dar ds. 
S h o ul d s y m pt o ms of fe v er or c hills de vel o p it ma y be diffic ult  t o disti n g uis h a m o n g p ote ntial 
ca uses of t he s y m pt o ms i ncl u di n g e m er gi n g i nfecti o n, or i nf usi o n reacti o n. Patie nts s h o ul d be 
e val uate d caref ull y f or t h e prese n ce of i nfecti o n, wit h t he ac q uisiti o n of c ult ures a n d/ or 
i m ple me ntati o n of e m piric a nti bi otic t hera p y as a p pr o priate bas e d o n t he assess me nt of t he 
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i n vesti gat or. Please refer t o Secti o n  6. 5. 1. 3  f or g ui da nce re gar di n g t h e ma na ge me nt of i nf usi o n 
reacti o ns. 
If a patie nt h as a Gra de 1 or 2 i nf usi o n reacti o n wit h pe m br oliz u ma b a n d t he i n vesti gat or 
c o nsi ders it pr u de nt, base d o n me dical j u d g m e nt, f or a dela y of t he patie nt ’s mar get u xi ma b dr u g 
a d mi nistrati o n at t he sc he d ule d i nf usi o n ti me, t he mar get u xi ma b d ose ma y be a d mi nistere d o n 
t he f oll o wi n g da y (t he da y after t he p e m br oliz u ma b i nf usi o n). F or Gra de 3 i nf usi o n reacti o ns 
wit h pe m br oliz u ma b t hat res ol ve c o m pletel y or t o Gra de 1 wit hi n 1 2 h o urs, t he sc he d ule d d ose 
of mar get u xi ma b ma y b e a d mi nistere d t he f oll o wi n g da y wit h pre me dicati o ns as liste d bel o w. 
6. 5. 1. 1    
Gr a di n g of I nf usi o n Re acti o ns   
I nf usi o n reacti o ns will be cate g orize d as f oll o ws: 
 Gra de 1:  mil d reacti o n; i nf usi o n i nterr u pt i o n n ot i n dicate d, i nter ve nti o n n ot i n dicate d; 
N ote: alt h o u g h i nterr u pti o n i n i nf usi o n is n ot i n dicate d, te m p orar y rate re d ucti o n 
i n dicate d bef ore res u mi n g ori gi nal rate, as p atie nt t olerates (see Secti o n 6. 5. 1. 3 ); 
 Gra de 2:  t hera p y or i nf usi o n i nterr u pti o n i n dicate d b ut res p o n ds pr o m ptl y t o 
s y m pt o matic treat me nt [e. g., a nti hista mi nes, n o n-ster oi dal a nti-i nfla m mat or y dr u gs 
( N S AI D S), narc otics, I V fl ui ds]; pr o p h ylactic me dicati o ns i n dicate d f or  2 4 h o urs;  
 Gra de 3:  pr ol o n ge d (e. g., n ot ra pi dl y res p o nsi ve t o me dicati o n a n d/ or brief 
i nterr u pti o n of i nf usi o n); rec urre nce of s y m pt o ms f oll o wi n g i nitial i m pr o ve me nt; 
h os pitalizati o n i n dicate d f or cli nical se q ue lae (e. g., re nal i m pair me nt, p ul m o nar y 
i nfiltrates); 
 Gra de 4:  life-t hreate ni n g c o nse q ue nces; press or or ve ntilat or y s u p p ort i n dicate d; 
 Gra de 5:  deat h.  
 
T he a b o ve gra di n g scal e is t he C T C A E v 4. 0 3 gra di n g scal e f or  i nf usi o n reacti o n, w hic h is nearl y 
i de ntical t o t he C T C A E v 4. 0 3 gra di n g scale f or c yt o ki ne releas e s y n dr o me a n d aller gic reacti o n, 
a n d t heref ore c o nsi dere d a p pr o priate f or gra di n g all i nf usi o n reacti o ns i n t his st u d y, irres pecti ve 
of t he u n derl yi n g mec h a nis m of t he reacti o n. T he S p o ns or ’s Me dical M o nit or or desi g nee s h o ul d 
be c o ntact e d i m me diatel y if q uesti o ns arise c o ncer ni n g t he gra de of t he reacti o n.  
6. 5. 1. 2    
Pre me dic ati o ns a n d Pr o p h yl a xis   
Pre me dicati o n s h o ul d be a d mi nistere d per i nstit uti o nal sta n dar ds a n d i n vesti gat or’s criteri o n. T he 
f oll o wi n g are s u g geste d g ui deli nes f or t he i n vesti gat or re gar di n g pr o p h ylactic pre-i nf usi o n 
meas ures t o be f oll o we d t o miti gate t he occ urre nce or se verit y of p ote ntial i nf usi o n reacti o ns.  
Pri or t o first i nf usi o n of pe m br oliz u ma b ( C ycle 1, g ui deli nes t o be f oll o we d):  
 Aceta mi n o p he n 6 5 0 -1 0 0 0 m g orall y ( P O) or i b u pr ofe n 4 0 0 m g P O  
 Di p he n h y dra mi ne 5 0 m g P O or I V or e q ui vale nt H 1 a nta g o nist  
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 Ra niti di ne 3 0 0 m g P O or I V or e q ui v ale nt H 2 a nta g o nist  
 De x a met has o ne 2 0 m g I V  
 
O nl y o ne d os e of pre -i nf usi o n pr o p h yla xis ster oi ds a d mi nistere d pri or t o pe m br oliz u ma b ma y be 
re q uire d. N o n -ster oi dal pre-me dicati o ns ma y be a d mi nistere d pri or t o t he s u bse q ue nt 
mar g et u xi ma b i nf usi o n if warr a nte d.  
If pr o p h yla xis was use d pri or t o pe m br oliz u ma b i nf usi o n, n o ster oi dal pr o p h yla xis is nee de d 
pri or t o mar get u xi ma b i nf usi o n; n o n -ster oi dal pr o p h yla xis ma y be e m pl o ye d per cli nical 
discreti o n of t he i n vesti gat or.  
F or all s u bse q ue nt a d mi nistrati o ns of pe m br oliz u ma b a n d mar get u xi ma b, patie nts w h o ha d 
i nf usi o n reacti o ns w h o were n ot a de q uatel y or o nl y m o deratel y c o ntr olle d wit h aceta mi n o p he n, 
di p he n h y dra mi ne, or ra niti di ne, I V d e xa met has o ne at d oses of 4 m g ma y be c o nsi dere d.  
6. 5. 1. 3    
M a n a ge me nt of O bser ve d I nf usi o n Re acti o ns   
T he f oll o wi n g are treat m e nt g ui deli nes ( w hic h ma y be m o difie d as nee de d b y t he i n vesti gat or 
acc or di n g t o t he b est practices of me dici ne) f or i nf usi o n reacti o ns. N ote  t h at t hese a p pl y t o b ot h 
mar get u xi ma b a n d pe m br oliz u ma b:  
 Gra de 1:  
o  Sl o w t he i nf usi o n rate b y 5 0 %.  
o  M o nit or t he patie nt f or w orse ni n g of c o n diti o n.  
o  C o nti n ue rate at 5 0 % re d ucti o n a n d i ncrease d ose rate t o t he ori gi nal rate b y 
d o u bli n g t he i nf usi o n rat e after  3 0 mi n utes, as t olerate d t o t he i nitial rate. 
C o nsi derati o n ca n be gi v e n t o be gi n ni n g all s u bse q ue nt i nf usi o ns at 5 0 % ra te 
a n d i ncreasi n g as t olerat e d.  
o  If a patie nt h as a n i nf usi o n reacti o n wit h pe m br oli z u ma b, t he mar get u xi ma b 
i nf usi o n ca n be gi ve n ( wit h out pr o p h ylactic m e dicati o ns) o n t he sa me da y if 
t he i nf usi o n reacti o n res ol ves wit hi n 3 h o urs. F or sc he d uli n g p ur p oses, t he 
mar get u xi ma b i nf usi o n ma y be gi ve n t he ne xt da y if t he reacti o n lasts greater 
t ha n 3 h o urs. 
o  If a patie nt h as a n i nf usi o n reacti o n wit h pe m br oli z u ma b, pr o p h ylactic 
prei nf usi o n me dicati o ns s h o ul d be gi ve n pri or t o all s u bse q ue nt 
pe m br oliz u ma b i nf usi o ns as writte n bel o w f or Gra de 1 i nf usi o n reacti o ns. 
o  If a patie nt h as a n i nf usi o n reacti o n wit h mar get u xi ma b, pr o p h ylactic 
prei nf usi o n me dica ti o ns s h o ul d be gi ve n pri or t o all s u bse q ue nt mar get u xi ma b 
i nf usi o ns as writte n bel o w. 
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Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
o  T he f oll o wi n g pr o p h yl actic prei nf usi o n me dicati o ns are rec o m me n de d pri or t o 
f ut ure i nf usi o ns of mar get u xi ma b a n d/ or pe m br oliz u ma b f or patie nts w h o 
e x perie nce Gra de 1 i nf usi o n reacti o ns: di p he n h y dra mi ne 5 0 m g P O or I V ( or 
e q ui vale nt) a n d/ or acet a mi n o p he n 6 5 0  m g P O at least 3 0 mi n utes bef ore 
a d diti o nal st u d y dr u g a d mi nistrati o ns.  
o  Re p ort as a n A d verse E ve nt of S pecial I nterest ( A E SI) b y c o m pleti n g  t he 
a p pr o priate e C R F pa ge.  
 
 Gra de 2:  
o  St o p t he i nf usi o n.  
o  A d mi nister di p he n h y dra mi ne h y dr oc hl ori de 2 5 -5 0 m g I V, aceta mi n o p he n 6 5 0 
m g P O f or fe ver, a n d o x y ge n a n d br o nc h o dilat ors f or mil d br o nc h os pas m.  
o  Res u me t he i nf usi o n at 5 0 % of t he pri or rate o nce t he i nf usi o n reacti o n has 
res ol ve d or decrease d t o Gra de 1. T he rate ma y t h e n be escalate d t o t he 
ori gi nal rate after 3 0 mi n utes, as t olerate d. C o nsi derati o n ca n be gi ve n t o 
be gi n ni n g all s u bse q ue nt i nf usi o ns at 5 0 % rate a n d i ncreasi n g as t olerate d.  
o  M o nit or f or w orse ni n g c o n diti o n. If s y m pt o ms rec ur, disc o nti n ue t he i nf usi o n; 
n o f urt her st u d y dr u g will be a d mi nistere d at t hat visit.  
o  If a patie nt h as a n i nf usio n reacti o n wit h pe m br oli z u ma b:  
▪ T he mar get u xi ma b  i nf usi o n ca n be a d mi nistere d o n t he sa me da y if t he 
i nf usi o n reacti o n res ol ves wit hi n 3 h o urs. T he mar get u xi ma b i nf usi o n 
ma y b e gi ve n t he ne xt da y if t he i nf usi o n rea cti o n last l o n ger t ha n 3 
h o urs.  
▪ Pre me dicati o n of di p he n h y dra mi ne h y dr oc hl ori d e 2 5 -5 0 m g I V a n d 
aceta mi n o p he n 6 5 0 m g P O s h o ul d be a d mi n istere d 3 0 mi n utes pri or t o 
t he mar get u xi ma b  d ose. If n o c ortic oster oi ds w ere gi ve n f or t he 
pe m br oliz u ma b i nf usi o n reacti o n, de xa met has o n e 2 0 m g I V ma y be 
c o nsi dere d pri or t o mar get u xi ma b a d mi nistrati o n. 
▪ Pr o p h ylactic pre -i nf usi o n me dicati o ns s h o ul d be gi ven pri or t o all 
s u bse q ue nt pe m br oliz u ma b i nf usi o ns. Patie nts w h o e x perie nce a Gra de 
2 i nf usi o n reacti o n s h o ul d be pre -m e dicate d wit h di p he n h y dra mi ne 
h y dr oc hl ori de 2 5 -5 0 m g I V a n d aceta mi n o p he n 6 5 0 m g P O f or 
s u bse q ue nt d oses of pe m br oliz u ma b. 
o  If a patie nt h as a n i nf usi o n reacti o n wit h mar get u xi ma b, pr o p h ylactic pre-
i nf usi o n me dicati o ns s h o ul d be gi ve n pri or t o all s u bse q ue nt mar get u xi ma b 
i nf usi o ns. 
C o nfi d e nti al
P a g e   
6 6   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
o  F or patie nts wit h Gra de 2 i nf usi o n reacti o ns des pit e pre me dicati o n wit h 
di p he n h y dra mi ne a n d aceta mi n o p he n, c orti c oster oi ds ( de xa met has o ne 2 0 m g 
I V) s h o ul d be c o nsi dere d f or ac ut e ma na ge me nt of t he e ve nt a n d s h o ul d be 
a d de d t o t he pre m e dicati o n re gi me n f or s u bs e q ue nt d osi n g of pe m br oliz u ma b 
a n d / or mar get u xi ma b.  
o  Re p ort as a n A d verse E ve nt of S pecial I nterest b y c o m p leti n g the a p pr o priate 
e C R F pa ge.  
 
 Gra de 3:  
o  S T O P T H E I N F U SI O N A N D DI S C O N N E C T T H E I N F U SI O N T U BI N G 
F R O M T H E P A TI E N T.  
o  T O A V OI D E X A C E R B A TI O N O F I N F U SI O N R E A C TI O N O R C R S: D O 
N O T F L U S H T H E T U BI N G –  A S PI R A T E R E SI D U A L D R U G F R O M T H E 
P O R T L U M E N.  
o  A d mi nister di p he n h y d ra mi ne h y dr oc hl ori de 2 5-5 0 m g I V, de xa met has o ne 2 0 
m g I V ( or e q ui vale nt), a n d ot her me dicati o ns/treat me nt as me dicall y 
i n dicate d. Hi g her d oses of c ortic oster oi ds (e. g. met h yl pre d nis ol o ne 2-4 m g/ k g 
I V or t he e q ui vale nt) ma y als o be c o nsi dere d f or ac ute ma nage me nt.  
o  I V fl ui ds, s u p ple me ntal o x y ge n a n d br o nc h o dilat ors s h o uld be c o nsi dere d as 
a p pr o priate.  
o  Gr a de 3 i nf usi o n re acti o n:  If t he Gra de 3 i nf usi o n reacti o n occ urs wit h 
pe m br oliz u ma b, b ot h mar get u xi ma b a n d pe m br oliz u ma b will be disc o nti n ue d 
f or t hat da y. If s y m pt o ms ha ve res ol v e d t o baseli ne wit hi n 1 2 h o urs, 
mar get u xi ma b ma y be i nf use d t he ne xt da y.  Pe m br oliz u ma b w o ul d be re -
c halle n ge d at t he ne xt sc he d ule d i nf usi o n c ycle, wit h a 5 0 % re d ucti o n of 
i nf usi o n rate. I n a d diti o n, patie nts s h o ul d be pre-m e dicate d  f or t his re-
c halle n ge a n d f or a n y s u bse q ue nt d oses of pe m br oliz u ma b wit h t he f oll o wi n g: 
di p he n h y dra mi ne h y dr oc hl ori de 2 5 -5 0 m g I V, oral aceta mi n o p he n 6 2 5 m g a n d 
de x a met has o ne 2 0 m g I V. Mar get u xi ma b d osi n g ca n be res u m e d wit h at t he 
ne xt sc he d ule d i nf usi o n  da y if t h e pe m br oliz u ma b Gra de 3 i nf usi o n reacti o n 
res ol ve d t o gra d e 1 wit hi n 1 2 h o urs. Patie nts w h o ha ve a Gra de 3 i nf usi o n 
reacti o n t hat d oes n ot res ol ve wit hi n 1 2 h o urs des pite me dical ma na ge m e nt 
s h o ul d n ot recei ve f urt her mar get u xi ma b or pe m br oliz u ma b treat ment.  
o  Patie nts w h o e x perie nce a sec o n d Gra de 3 i nf usi o n reacti o n at t he ti me of re -
c halle n ge of mar get u xi ma b or pe m br oliz u ma b (irres pecti ve of d urati o n of first 
Gra de 3 reacti o n) will per ma ne ntl y dis c o nti n ue mar get u xi ma b a n d 
pe m br oliz u ma b.  
o  Re p ort as  a n A d verse E ve nt of S pecial I nterest a n d a n I m m e diatel y Re p orta ble 
E ve nt (I R E) wit hi n 2 4 h o urs.  
o  Re p ort t he e ve nt as a S A E, if a p pr o priat e.  
 
C o nfi d e nti al
P a g e   
6 7   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
 Gra de 4:  
o  S T O P T H E I N F U SI O N A N D DI S C O N N E C T T H E I N F U SI O N T U BI N G 
F R O M T H E P A TI E N T.  
o  T O A V OI D E X A C E R B A TI O N O F I N F U SI O N R E A C TI O N O R C R S: D O 
N O T F L U S H T H E T U BI N G.  
o  A d mi nister di p he n h y dra mi ne h y dr oc hl ori de 5 0 m g I V, met h yl pre d nis ol o ne 2 -
4  m g/ k g I V ( or m ore as c o nsi dere d a p pr o priate), a n d ot her 
me dicati o ns/treat me nt as me dicall y i n dicate d (e. g., a n I L -6 rece pt or i n hi bit or 
or I L -6 i n hi bit or, a n I L -2 rece pt or i n hi bit or, a n d/ or a n a nti -T N F  a nti b o d y).  
o  Gi ve e pi ne p hri ne or br o nc h o dilat ors as i n dicate d.  
o  S u p p ort ve ntilati o n a n d bl o o d press ure as i n dicate d.  
o  Re p ort as a n A d verse E ve nt of S pecial I nterest a n d a n I R E wit hi n 2 4 h o urs.  
o  Re p ort t he e ve nt as a n S A E.  
o  Patie nts w h o ha ve a Gra de 4 i nf usi o n reacti o n will n ot recei ve f urt her 
mar get u xi ma b or pe m br oliz u ma b.  
 
 Gra de 5:  
o  Re p ort as a n I R E wit hi n 2 4 h o urs.  
o  Re p ort t he e ve nt as a n S A E.  
 
All c ha n ges i n t he i nf usi o n of eit her mar get u xi ma b  o r pe m br oliz u ma b, i ncl u di n g i nterr u pti o n of 
t he i nf usi o n a n d its d urati o n as well as re d ucti o ns i n i nf usi o n rate a n d d urati o n, m ust be rec or de d. 
6. 5. 2    
I m m u ne-Rel ate d A d verse E ve nts   
A hi g h le vel of a ware ness f or t he p ossi bilit y t h at a n A E ma y be a n i m m u ne -relate d A E (ir A E) is 
necessar y i n t he ma na ge me nt of patie nts recei vi n g pe m br oliz u ma b beca us e t he pres e ntati o ns of 
a n ir A E ca n be s u btle, a n d ot her ca us es m ust be r ule d o ut. A n ir A E ca n o cc ur at a n y p oi nt d uri n g 
treat me nt wit h pe m br oliz u ma b. It is i m perati ve t o esta blis h t he c orrect dia g n osis pr o m ptl y, 
deter mi ni n g s e verit y bas e d o n C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts ( C T C A E) 
gra di n g a n d i nitiati n g treat me nt wit h ster oi ds, if nec essar y, a n d h ol di n g f urt her pe m br oliz u ma b 
treat me nt is esse ntial (4 9 ). 
I m m u ne c hec k p oi nt bl oc ka de t hera pies ha ve bee n ass ociate d wit h se veral s y n dr o mes res ulti n g 
fr o m t he brea ki n g of i m m u n ol o gical t olera nce i n n or mal tiss ues (3 4 , 6 0 , 7 2 ). T hese s y n dr o mes 
i ncl u de b ut are n ot li mite d t o: p ne u m o nitis, c olitis, a ut oi m m u ne he patitis, art hritis, 
gl o mer ul o ne p hritis, m y o car ditis a n d car di o m y o pat h y, h y p o p h ysitis, t h yr oi ditis, or ot her 
a ut oim m u ne e n d ocri n o pat hies. T he occ urre nce of a n y of t hese s y n dr o mes dictates i nterr u pti o n 
a n d p ote ntiall y disc o nti n uati o n of st u d y dr u g a d mi nistrati o n pe n di n g f urt h er e val uati o n a n d 
re p orti n g t he m t o t he S p o ns or as A E SIs. M ost l o w-gra de i m m u ne -relate d A Es (irA Es) ca n be 
C o nfi d e nti al
P a g e   
6 8   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
ma na ge d s y m pt o maticall y. Persiste nt l o w gra de or m o derate t o xicities ma y re q uire treat me nt 
wit h c ortic oster oi ds or i n refract or y cases ot her i m m u ne s u p pressi n g a ge nts s uc h as 
m yc o p h e n olate or i nfli xi ma b. Hi g h -gra de i m m u ne -rel ate d t o xicities will, i n al m ost all cases, 
re q uire treat me nt wit h c ortic oster oi ds. 
F or t he p ur p os es of t he s afet y ma na ge me nt, n o disti ncti o n s h o ul d be ma de as t o w hic h dr u g is t he 
ca usati ve a ge nt a n d b ot h a ge nts st o p pe d (te m p oraril y hel d or disc o nti n ue d).  
Te m p orar y i nterr u pt i o ns of mar get u xi ma b  a n d/ or pe m br oliz u ma b ma y be re q uire d i n t he e ve nt of 
treat me nt-relate d i m m u ne-rel ate d t o xicit y. Ge neral g ui deli nes f or s pecific t o xicit y re gar di n g 
d osi n g a n d treat me nt are pr o vi de d bel o w. All t o xicities will be gra de d acc or di n g t o N CI C T C A E 
v 4. 0 3.  
6. 5. 2. 1    
Di arr he a or C olitis   
Diarr hea t hat de v el o ps i n patie nts w hile recei vi n g pe m br oliz u ma b ma y reflect i m m u ne reacti vit y 
a gai nst n or mal c ol o nic e pit heli u m a n d caref ul m o ni t ori n g f or p ote ntial i m m u ne relate d c olitis 
s h o ul d be i nstit ute d. Patie nts s h o ul d be m o nit ore d cl osel y f or e vi de nce of diarr hea or ot her 
c ha n ge i n b o w el ha bits as well as ot her si g ns a n d s y m pt o ms s u g gesti ve of c olitis.  Patie nts w h o 
de vel o p si g ns or s y m pt o m s i ncl u di n g a b d o mi nal pai n, bl oati n g, na us ea, v o miti n g, diarr hea or 
bl o o d i n t he st o ols s h o ul d be e val uat e d caref ull y f or p ote ntial c olitis.  
 Gra de  1 diarr hea  
o  Cl osel y m o nit or t he diarr hea u ntil res ol uti o n.  
 Gra de  2 diarr hea  
o  H ol d pe m br oliz u ma b a n d mar get u xi ma b  
o  I n crease fre q ue n c y of m o nit ori n g u ntil res ol uti o n 
o  S y m pt o matic m a na ge me nt  
▪ L o pera mi de/ di p he n o x ylate  
▪ C o nsi der l o w d ose ster oi ds, if cli nicall y i n dicat e d.  
o  C o nsi der ma na ge me nt as per Gra de 3 diarr hea wit h pr ol o n ge d Gra de 2 e ve nt 
lasti n g m ore t ha n 5 t o 7 da ys or rela pse d diarr hea.  
 Gra de  3 diarr hea  
o  H ol d pe m br oliz u ma b a n d mar get u xi ma b  
o  H os pitalize patie nt pr o m ptl y f or f urt her e val uati o n a n d ma na ge m e nt 
i ncl u di n g: 
▪ B o wel rest  
▪ S u p ple me ntal I V fl ui ds wit h cl ose m o nit ori n g of fl ui d a n d electr ol yte 
stat us. 
C o nfi d e nti al
P a g e   
6 9   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
o  M o nit ori n g of fre q ue nc y of b o wel m o ve me nts  
▪ C o nsi der i ma gi n g t o r ule o ut b o wel o bstr ucti o n or perf orati o n  
▪ C o nsi derati o n of c ol o n osc o p y as a p pr o priate  
▪ I m ple me nt ati o n of i nitial e m piric i m m u ne s u p pressi o n c o nsisti n g of I V 
c ortic oster oi ds usi n g m et h yl pre d nis ol o ne at a d osa ge of 2  m g/ k g/ da y 
di vi de d t wice dail y.  As t olerate d, patie nts ma y be c o n verte d t o oral 
c ortic oster oi ds (i.e., pre d nis o ne 2  m g/ k g/ da y di vi de d t wice dail y) a n d 
ta pere d as a p pr o priate g ui de d b y t he patie nts’ cli nical stat us.   
▪ Ta per c ortic oster oi ds as cli nical l y i n dicate d  
▪ F or patie nts wit h se vere c olitis, or t h ose w h o d o n ot res p o n d t o 
c ortic oster oi ds, a d diti o nal i m m u ne s u p pressi o n wit h a nti -T N F -α 
a nti b o dies (i.e., i nfli xi ma b) s h o ul d be c o nsi dere d earl y i n t he c o urse.   
o  C o nsi der restarti n g pe m br oliz u ma b a n d mar get u xi ma b if:  
▪ It is deter mi ne d t here is n o c olitis a n d a n alter nati ve ca use of diarr hea 
is f o u n d, a n d 
▪ Diarr hea res ol v es t o ≤ Gra de  1 wit hi n 1 4  da ys  
 Gra de 4 diarr hea   
o  Disc o nti n ue pe m br oliz u ma b a n d h ol d mar get u xi ma b  
o  Treat as f or Gra d e  3  
 
6. 5. 2. 2    
He p atic To xicit y   
6. 5. 2. 2. 1    
Ele v ati o ns i n Tr a ns a mi n ases   
Ma na ge me nt g ui deli nes f or patie nts e x perie nci n g he patic t o xicit y are as  f oll o ws: 
 Gra de 1 ele vati o ns  
o  N o s pecific t hera p y re q uire d  
 Gra de 2 ele vati o ns  
o  F or ele vati o ns i n tra nsa mi nases 3  t o 5  ×  U L N ( Gra de  2), r ule o ut viral a n d 
ot her eti ol o gies, a n d c o nsi der i m me diate oral ster oi ds s uc h as pre d nis o ne 6 0 
m g/ da y di vi de d t wice dail y,  a n d h ol d pe m br oliz u ma b a n d mar get u xi ma b.  
o  If i m pr o ve me nt t o ≤ Gra de  1 d oes n ot occ ur wit hi n 4 8  h o urs wit h oral 
ster oi ds, c o nsi der I V ster oi ds s uc h as met h yl pre d nis ol o ne at 2 m g/ k g/ da y 
di vi de d t wice dail y or oral ster oi ds s uc h as pre d nis o ne 6 0 t o 1 2 0 m g per  da y, 
di vi de d t wice dail y   
C o nfi d e nti al
P a g e   
7 0   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
o  Res u me pe m br oliz u ma b a n d mar get u xi ma b at t he ne xt sc he d ule d d ose if:  
▪ N o m ore t ha n o ne d os e of pe m br oliz u ma b a n d mar get u xi ma b was 
misse d  
o  If i m pr o ve me nt t o ≤ Gra de 1 d oes n ot occ ur wit hi n 1 4 da ys, disc o nti n ue 
pe m br oliz u ma b a n d mar g et u xi ma b.  
 Gra de 3 ele vati o ns  
o  Disc o nti n ue  pe m br oliz u ma b a n d mar get u xi ma b  
▪ I nitiate I V ster oi ds a n d,  
▪ If n o res p o ns e t o c ortic oster oi d t hera p y wit hi n 3 t o 5 da ys is o bser ve d, 
c o nsi der a d di n g i m m u ne s u p pressi o n t hera p y wit h m yc o p he n olate.  D o 
n ot use i nfli xi ma b i n t hese cases b eca use of a p ote ntial f or 
a ut oi m m u ne he patitis  (4 0 ). 
▪ M o nit or li ver f u ncti o n tests at least t wice wee kl y ( or m ore fre q ue ntl y 
as cli nicall y a p pr o priate i n t he j u d g me nt of t he i n vesti gat or) u ntil 
tra nsa mi nases ha ve ret ur ne d t o Gra de 1 or bas eli ne. 
 Gra de 4 ele vati o n   
o  Disc o nti n ue pe m br ol iz u ma b a n d mar get u xi ma b 
o  Treat as f or Gra d e 3 ele vati o n .  
 
6. 5. 2. 2. 2    
Ele v ati o ns i n Tot al Bilir u bi n   
Ma na ge me nt g ui deli nes f or patie nts e x perie nci n g ele vati o ns i n t otal bilir u bi n are as f oll o ws: 
 Gra de 1 ele vati o ns  
o  N o s pecific t hera p y re q uire d  
 Gra de 2 ele vati o ns  
o  H ol d pe m br oliz u ma b a n d mar get u xi ma b u ntil i m pr o ve me nt t o ≤ Gra de 1.  
o  C o nsi der oral ster oi ds  
o  If i m pr o ve me nt t o ≤ Gra de 1 d oes n ot occ ur wit hi n 1 4 da ys, disc o nti n ue 
pe m br oliz u ma b a n d mar get u xi ma b a n d be gi n oral ster oi ds.  
 Gra de 3 ele vati o ns  
o  Disc o nti n ue  pe m br oliz u ma b a n d mar get u xi ma b  
▪ F or ele vati o ns i n t otal bilir u bi n > 5 × U L N, per ma ne ntl y disc o nti n ue 
pe m br oliz u ma b a n d mar get u xi ma b a n d i nitiate I V ster oi ds a n d,  
C o nfi d e nti al
P a g e   
7 1   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
▪ If n o res p o ns e t o c ortic oster oi d t hera p y wit hi n 3 t o 5 da ys is o bser ve d, 
c o nsi der a d di n g i m m u ne s u p pressi o n t hera p y wit h m yc o p he n olate.  D o 
n ot use i nfli xi ma b i n t hese cases b eca use of a p ote ntial f or 
a ut oi m m u ne he patitis  (4 0 ). 
▪ M o nit or li ver f u ncti o n testi n g at least t wice wee kl y ( or m ore 
fre q ue ntl y as cli nicall y a p pr o priate i n t he j u d g me nt of t he i n vesti gat or) 
u ntil tra nsa mi nases ha ve ret ur ne d t o Gra de 1 or baseli ne.  
 Gra de 4 ele vati o ns  
o  Disc o nti n ue pe m br oliz u ma b a n d mar get u xi ma b  
o  Treat as f or Gra d e 3  ele vati o n 
 
6. 5. 2. 3    
P ne u m o nitis   
Ma na ge me nt g ui deli nes f or patie nts e x perie nci n g p ne u m o nitis, are as f oll o ws:  
 Gra de 1 p n e u m o nitis  
o  N o s pecific t hera p y re q uire d; cl ose m o nit ori n g of l u n g f u ncti o n a n d i ma gi n g  
 Gra de 2 p n e u m o nitis  
o  H ol d pe m br oliz u ma b a n d mar get u xi ma b. B e gi n c ortic oster oi ds: 1 t o 2 m g/ k g 
of oral pre d nis o n e or e q ui vale nt, per da y di vi de d t wice dail y  
▪ Ta per o ver 4 wee ks as cli nicall y i n dicat e d  
o  Res u me pe m br oliz u ma b a n d mar get u xi ma b a d mi nistrati o n at ne xt sc he d ule d 
d ose if p ne u m o nitis res ol ves t o ≤ Gra de 1 wi t hi n 3 da ys wit h or wit h o ut 
treat me nt. 
o  Per ma ne ntl y dis c o nti n ue pe m br oliz u ma b a n d mar get u xi ma b f or rec urre nt 
Gra de 2 p n e u m o nitis.  
 Gra de 3 a n d 4 p ne u m o nitis  
o  Per ma ne ntl y dis c o nti n ue pe m br oliz u ma b a n d mar get u xi ma b.  
o  H os pitalize  
o  I nitiati o n of ma xi mal s u p p orti ve care i ncl u di n g I V c ortic oster oi ds, s u g gest 
met h yl pre d nis ol o ne at 2 -4  m g/ k g/ da y di vi de d t wi ce dail y. Hi g her d oses m a y 
be use d i n c o ns ultati o n wit h t he S p o ns or ’s me dical m o nit or  
o  If n o res p o ns e t o c ortic oster oi d t hera p y is o bser ve d wit hi n 3-5 da ys, c o nsi der 
a d di n g i m m u ne s u p pressi o n t hera p y (i.e., i nfli xi ma b, etc.)  
 
6. 5. 2. 4    
Der m at ol o gic To xicit y   
Ma na ge me nt g ui deli nes f or patie nts e x perie nci n g der mat ol o gi c t o xicit y are as f oll o ws:  
C o nfi d e nti al
P a g e   
7 2   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
 Gra de 1 or 2 s ki n reacti o ns  
o  S y m pt o matic treat me nt wit h l o w -d ose t o pical c ortic oster oi ds ( beta met has o ne 
0. 1 % or h y dr oc ortis o ne 1 %) or a nti hista mi nes  ( di p he n h y dra mi ne). 
o  Persiste nt  ( 7-1 4 da ys)  Gra de 1 or 2 ras h s h o ul d be ma na ge d wit h h i g her d ose 
t o pical c ortic oster oi ds a n d/ or oral pre d nis o ne ( 1-2 m g/ k g/ da y) if t here is n ot 
i m pr o ve me nt wit h i nitial t o pical t hera pies or t h e ras h is ass ociate d wit h ot her 
der mal t o xicities s uc h as pr urit us.  
 Gra de 3 s ki n reacti o ns  
o  H ol d pe m br oliz u ma b a n d mar g et u xi ma b. I nitiate oral c ortic oster oi ds ( oral 
pre d nis o ne 1 -2 m g/ k g/ da y)  
o  Pe m br oliz u ma b a n d mar get u xi ma b c o m bi nati o n a d mi nistrati o n ma y be 
restarte d at t he ne xt sc he d ule d d osi n g if s y m pt o ms res ol ve t o ≤ Gra de 2 wit hi n 
1 4 da ys.   
o  Gra de 3 s ki n t o xicit y t hat d oe s n ot res ol ve t o ≤ Gra de 2 wit hi n 1 4 da ys of 
i nitiati o n of oral c ortic oster oi ds re q uires per ma ne nt disc o nti n uati o n of st u d y 
dr u gs.  
 Gra de 4 s ki n reacti o ns  
o  Disc o nti n ue pe m br oliz u ma b a n d mar get u xi ma b.  
o  I nitiate oral c ortic oster oi ds ( oral pre d nis o ne 1-2 m g/ k g/ d a y)  
o  C o nsi derati o n s h o ul d be gi ve n t o start I V c ortic oster oi ds ( met h yl pre d nis ol o ne 
1 -2  m g/ k g/ da y) f or Gra de 4 der mat ol o gic t o xicities wit h ta peri n g o n 
res ol uti o n t o < Gra de 2 o ver 3 0 da ys.  
 
6. 5. 2. 5    
Ne p hritis/ Re n al F ail ure   
Ma na ge me nt g ui deli nes f or patie nts e x perie nci n g ne p hritis are as f oll o ws:  
 Gra de 1 n e p hritis  
o  N o s pecific t hera p y re q uire d; cl ose m o nit ori n g of re nal f u ncti o n  
 Gra de 2 n e p hritis  
o  H ol d pe m br oliz u ma b a n d mar get u xi ma b  
o  C o nsi der ne p hr ol o g y c o ns ultati o n a n d re nal bi o ps y t o c o nfir m i nterstitial 
ne p hritis.  
o  Be gi n c ortic oster oi ds: 1 t o 2 m g/ k g of oral pre d nis o ne or e q ui vale nt, p er da y 
di vi de d t wice dail y  
▪ Ta per o ver 4 wee ks as cli nicall y i n dicat e d  
o  Res u me pe m br oliz u ma b a n d mar get u xi ma b a d mi nistrati o n at ne xt sc he d ule d 
d ose if:  
C o nfi d e nti al
P a g e   
7 3   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
▪ Ne p hritis res ol ves t o ≤ Gra de 1 wit hi n 1 4  da ys wit h or wit h o ut 
treat me nt 
 Gra de 3 a n d 4 ne p hritis  
o  Per ma ne ntl y dis c o nti n ue pe m br oliz u ma b a n d mar get u xi ma b  
o  C o nsi der h os pitalizati o n, ne p hr ol o g y c o ns ultati o n, a n d re nal bi o ps y t o c o nfir m 
i nterstitial ne p hritis 
o  Be gi n c ortic oster oi ds: 2 t o 4 m g/ k g of oral or I V pre d nis o ne or e q ui vale nt, per 
da y di vi de d t wi ce dail y  
▪ Ta per o ver 4 wee ks as cli nicall y i n dicat e d  
 
6. 5. 2. 6    
I m m u ne-Me di ate d H y p o p h ysitis   
Ma na ge me nt g ui deli nes f or patie nts e x perie nci n g h y p o p h ysitis are as f oll o ws:  
 Gra de 2 or 3 h y p o p h ysitis d oc u me nte d o n M RI  
o  H ol d pe m br oliz u ma b a n d mar get u xi ma b  
o  C o ns ult e n d ocri n ol o gi st 
o  C o nsi der h os pitalizati o n  
o  Be gi n s h ort c o urse of hi g h d ose I V c ortic oster oi ds: e. g., met h yl pre d nis ol o ne 
2 -4 m g/ k g I V ( or e q ui vale nt) di vi de d t wice dail y  
o  I nitiate h or m o nal re place me nt as i n dicate d  
o  Pe m br oliz u ma b a n d mar get u xi ma b c o m bi nati o n treat me nt ma y  be res u me d as 
all o we d b y pr ot oc ol w he n  
▪ E n d ocri n o pat h y is c o ntr olle d wit h a p pr o priate re pl ace me nt t hera p y  
▪ C ortic oster oi d d ose re d uce d t o ≤ 1 0 m g pre d nis o ne or e q ui vale nt p er 
da y  
o  Re peat brai n M RI as cli nicall y i n dicat e d  
 Gra de 4 h y p o p h ysitis  
o  Per ma ne ntl y dis c o nti n ue pe m br oliz u ma b a n d mar get u xi ma b.  
 
6. 5. 2. 7    
T h yr oi d To xicit y   
T h yr oi d dis or ders ca n occ ur at a n y ti me d uri n g treat me nt wit h pe m br oliz u ma b. M o nit or patie nts 
f or c ha n ges i n t h yr oi d f u ncti o n per pr ot oc ol a n d as i n dicate d base d o n cli nical e val u ati o n a n d f or 
cli nical si g ns a n d s y m pt o ms of t h yr oi d dis or ders.  Is olate d h y p ot h yr oi dis m ma y ge nerall y be 
ma na ge d wit h re pl ace m e nt t hera p y wit h o ut treat m e nt i nterr u pti o n a n d wit h o ut c ortic oster o i ds, 
a n d a s u g geste d treat me nt g ui deli ne f or h y pert h yr oi dis m is descri be d bel o w:  
C o nfi d e nti al
P a g e   
7 4   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
 Gra de 1 h y p ert h yr oi dis m  
o  N o s pecific t hera p y re q uire d  
 Gra de 2 h y p ert h yr oi dis m  
o  H ol d pe m br oliz u ma b a n d mar get u xi ma b  
o  C o nsi der starti n g oral c ortic oster oi d t hera p y  
o  Res u me pe m br oliz u ma b a n d mar get u xi ma b if c ortic oster oi d d ose is re d uce d 
t o ≤ 1 0  m g pre d nis o ne or e q ui vale nt per da y a n d sta ble o n h or m o ne 
re place me nt t hera p y (if necessar y). 
 Gra de 3 or 4 h y pert h yr oi dis m  
o  H ol d pe m br oliz u ma b a n d mar get u xi ma b  
o  C o nsi der h os pitalizati o n  a n d c o ns ulti n g e n d ocri n ol o gist  
▪ Be gi n I V c ortic oster oi ds s uc h as met h yl pre d nis ol o ne 2 -4 m g/ k g I V ( or 
e q ui vale nt) di vi de d t wice dail y  
o  I nitiate h or m o nal re place me nt as necess ar y 
o  Ma y c o nsi der restarti n g pe m br oliz u ma b a n d mar get u xi ma b wit h c o m plete 
res ol uti o n or sta ble o n h or m o ne re place me nt t hera p y wit hi n 1 4 da ys  
 
6. 5. 2. 8    
Ty pe 1 Di a betes Mellit us   
T he f oll o wi n g g ui d eli nes s h o ul d be f oll o we d f or dia betes mellit us (if ne w o nset, i ncl u di n g 
dia be tic ket oaci d osis [ D K A]) or ≥ Gra de 3 H y per gl yce mia, if ass ociat e d wit h ket osis ( ket o n uri a) 
or meta b olic aci d osis ( D K A).  
 F or T 1 D M  or Gr a de 3 -4  H y per gl yce mia  
 I ns uli n re place m e nt t hera p y is rec o m me n de d f or Ty pe I dia betes m ellit us a n d f or 
Gra de 3 -4 h y per gl yce mia ass ociate d wit h m eta b oli c aci d osis or ket o n uri a.  
 E val uate patie nts wit h ser u m gl uc ose a n d a m eta b olic pa nel, uri ne ket o n es, 
gl yc os ylate d h e m o gl o bi n, a n d C -pe pti de.  
 
6. 5. 2. 9    
Ot her I m m u ne -R el ate d A Es   
 I nt olera ble/ persiste nt Gra de 2  
o  H ol d pe m br oliz u ma b a n d mar get u xi ma b  
o  Base d o n t h e t y p e a n d se verit y of A E, a d mi nister c ortic oster oi ds  
o  E ns ure a de q u ate e v al uati o n t o c o nfir m eti ol o g y a n d / or e xcl u de ot her ca us es 
C o nfi d e nti al
P a g e   
7 5   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
 Gra de 3  
o  H ol d or disc o nti n ue pe m br oliz u ma b a n d mar get u xi ma b base d o n t he t y pe of 
e ve nt  
▪ Disc o nti n uati o n is re q uire d f or A Es s uc h as, b ut n ot li mite d t o, 
G uillai n -Barr é S y n dr o me a n d e nce p halitis  
▪ Rec urre n ce  of t he sa me Gra de 3 t o x icit y re q uires disc o nti n uati o n 
 Gra de 4  
o  Per ma ne ntl y dis c o nti n ue  
 
6. 5. 3    
C ar di ot o xicities of S pecific I nterest   
6. 5. 3. 1    
Decre ase d Left V e ntric ul ar E jecti o n F r acti o n  
Left ve ntric ular ejecti o n fracti o n ( L V E F) will be m o nit ore d at re g ular i nter vals d uri n g t he st u d y. 
If a decrease i n car diac f u ncti o n is s us pecte d, L V E F s h o ul d be deter mi ne d usi ng t he sa me 
met h o d as use d pri or t o treat me nt.  
S pecificall y, f or e v e nts of decrease d car diac f u ncti o n, patie nts will be disc o nti n ue d fr o m f urt her 
treat me nt if eit her of t he f oll o wi n g criteria are met: 
 ≥ 1 5 % a bs ol ute decreas e i n L V E F fr o m pre -treat me nt val ues, or  
 L V E F bel o w i nstit uti o nal n or mal li mits ( or 5 0 % if n o li mits are a vaila ble) a n d ≥ 1 0 % 
a bs ol ute decrease i n L V E F fr o m pretreat me nt val ues  
 
6. 5. 3. 2    
M y o c ar ditis   
 Gra de 1 or 2 m y o car ditis  
o  H ol d pe m br oliz u ma b a n d mar get u xi ma b  
o  Base d o n s e verit y, a d mi nister c ortic oster oi ds  
o  E ns ure a de q u ate e v al ua tio n t o c o nfir m eti ol o g y a n d/ or e xcl u de ot her ca us es  
 Gra de 3 or 4 m y o car ditis  
o  Per ma ne ntl y dis c o nti n ue pe m br oliz u ma b a n d mar get u xi ma b  
o  Base d o n s e verit y, a d mi nister c ortic oster oi ds  
o  E ns ure a de q u ate e v al ua tio n t o c o nfir m eti ol o g y a n d/ or e xcl u de ot her ca us es  
 
C o nfi d e nti al
P a g e   
7 6   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
6. 6    
Met h o d of Assi g ni n g P atie nts t o Tre at me nt Gr o u ps   
Patie nts will be assi g ne d se q ue ntiall y t o t he d os e escalati o n c o h orts a n d c o h ort e x pa nsi o n 
p orti o ns of t he st u d y.  
6. 7    
Bli n di n g   
T his is a n o pe n -la bel st u d y a n d n o bli n di n g will be e m pl o ye d. 
6. 8    
C o nc o mi t a nt T her a p y  
Mar get u xi ma b  a n d pe m br oliz u ma b are t he o nl y a nti -ca ncer dr u gs t o be a d mi nistere d r o uti nel y i n 
t his st u d y. N o c o n c o mita nt a nti-ca ncer t hera p y will be gi ve n wit h e xce p ti o n of a dj u va nt 
h or m o nal t hera p y f or treat me nt of patie nts wit h breast or pr ostat e ca ncer. All c o nc o mita nt 
me dicati o ns a n d bl o o d pr o d ucts a d mi nistere d d uri n g t he patie nt ’s partici pati o n i n t he st u d y u ntil 
t he p ost treat me nt f oll o w-u p visit m ust be rec or de d i n t he s o urce d oc u m e nt a n d o n t he electr o nic 
Case Re p ort F or m (e C R F). All c ha n ges i n i nf usi o ns, i ncl u di n g i nterr u pti o ns a n d t heir d urati o n as 
well as re d u cti o ns i n rate a n d d urati o n m ust be rec or de d.  
T he f oll o wi n g r ules c o n cer ni n g c o nc urre nt treat m e nt(s)  will a p pl y i n t his st u d y:  
 A n y ot her a nti -ne o pl astic t hera pies i ncl u di n g b ut n ot li mite d t o c he m ot hera p y or 
ot her s mall m olec ules, bi ol o gics, or ra di ot hera p y are n ot all o we d. F or patie nts w h o 
re q uire p alliati ve ra di ot h era p y (i.e., c u m ulati ve d ose less t ha n 3 0 0 0 ra ds, li mite d fiel d 
of distri b uti o n) f or reas o ns ot her t ha n disease pr o gressi o n, t hera p y wit h 
mar get u xi ma b a n d/ or pe m br oliz u ma b ma y be i nterr u pte d f or u p t o 4 wee ks. Palliati ve 
ra di ot hera p y m a y n ot be gi ve n c o nc urre ntl y wit h eit her mar get u xi ma b or 
pe m br oliz u ma b. Treat me nt wit h palliati ve t hera p y s h o ul d be i nitiate d at least 2 4 h o urs 
after recei vi n g eit her mar get u xi ma b or pe m br oliz u ma b, a n d re -i nitiati o n of 
mar get u xi ma b or pe m br oliz u ma b ca n be gi n se ve n ( 7) da ys after t he c o m pleti o n of 
palliati ve ra di ot hera p y if t here were n o c o m plicati o ns ass ociate d wit h t he 
ra di ot hera p y. Palliati ve ra di ot hera p y fiel ds als o s h o ul d n ot o verla p t u m or lesi o ns t hat 
ha ve pre vi o usl y bee n desi g nate d as tar get lesi o ns. I n t he e ve nt t hat t his is me dicall y 
necessar y f or p alliati v e p ur p oses, t he patie nt ma y c o nti n ue o n st u d y, b ut will n o 
l o n ger be e v al ua ble f or o bjecti ve res p o nse fr o m t he ti me palliati ve ra di ot hera p y is 
i nitiate d. 
 Patie nts ma y n ot recei ve ot her i n vesti gati o nal dr u gs d uri n g t he peri o d of st u d y 
partici pati o n.  
C o nfi d e nti al
P a g e   
7 7   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
 Beca use  mar get u xi ma b has t he ca pacit y t o i n d uce A D C C a n d pe m br oliz u ma b has a 
mec ha nis m of acti o n de p e n de nt u p o n t he e n ga ge me nt of T l y m p h o c ytes, t he use of 
c ortic oster oi ds s h o ul d be li mite d t o t he e xte nt p ossi ble.  C hr o nic d oses of 
c ortic oster oi ds i n e x cess of 1 0 m g dail y of pre d nis o ne or e q ui vale nt is pr o hi bite d 
ot her t ha n f or t he m a na ge me nt of dr u g -relate d a d verse e x perie nces. Ster oi ds or ot her 
i m m u ne s u p pressi o n t hera p y m a y be e m pl o ye d i n t he treat me nt of s us pecte d 
mar get u xi ma b or pe m br oliz u ma b -ass ociate d i m m u ne -i nfla m mat or y or a ut oi m m u ne 
A Es i n c o ns ultati o n wit h t he S p o ns or. N ote: i n hale d ster oi ds are all o we d f or 
ma na ge me nt of ast h ma.  
 T he use of ot her i m m u n o -s u p pressi ve a ge nts is pr o hi bite d, u nless t he y are bei n g use d 
t o treat a n a d v erse e ve nt.  
 Use of gra n ul oc yte c ol o n y sti m ulati n g fact or, gra n ul oc yte -macr o p ha ge c ol o n y 
sti m ulati n g fact or or ot her gr o wt h fact ors is pr o hi bite d. 
 Li ve vacci n es wit hi n 3 0 da ys pri or t o t he first d os e of trial treat me nt a n d w hile 
partici pati n g i n t he tri al are pr o hi bite d . E xa m ples of li ve vacci n es i ncl u de, b ut are n ot 
li mite d t o, t he f oll o wi n g: measles, m u m ps, r u bella, c hic ke n p o x, yell o w fe ver, ra bi es, 
B C G, a n d t y p h oi d ( oral) vacci ne. Seas o nal i nfl ue nza vacci nes f or i njecti o n are 
ge n erall y kille d vir us vacci nes a n d are all o we d. H o we ver, i ntra nasal i nfl ue nza 
vacci nes (e. g. Fl u - Mist ®) are li ve atte n uate d vacci nes, a n d are n ot all o we d.  
 
Patie nts ma y recei v e t he f oll o wi n g c o n c urre nt t hera p y:  
 A ntie metics, a nti diarr heals, a ntic h oli ner gics, a ntis pas m o dics, a nti p yretics, 
a nti hist a mi nes, a nal gesics, a nti bi otics a n d ot her a nti micr o bials, hista mi ne rece pt or 
a nta g o nists or pr ot o n p u m p i n hi bit ors, a n d ot her me dicati o ns i nte n de d t o treat 
s y m pt o ms or si g ns of dis ease. 
 Tra nsf usi o ns s uc h as re d bl o o d cells a n d platelets are per mitte d t o tr eat s y m pt o ms or 
si g ns of a n e mia or t hr o m b oc yt o p e nia a n d s h o ul d be d oc u me nte d o n t he c o nc o mita nt 
me dicati o n f or m. I V fl ui ds use d f or s y m pt o matic treat me nt/ h y drati o n s h o ul d als o be 
d oc u me nte d o n t he me di cati o n f or m.  
 Use of bis p h os p h o nates or rece pt or acti va t or of n uclear fact or ka p pa-B li ga n d 
( R A N K-L) i n hi bit ors is all o we d.  
 All patie nt s s h o ul d use hi g hl y effecti ve met h o ds of c o ntrace pti o n d uri n g treat me nt 
a n d f or a p eri o d of 7 m o nt hs after disc o nti n uati o n of treat me nt. Hi g hl y effecti ve birt h 
c o ntr ol i ncl u des h or m o nal c o ntrace pti ves, i ntra uteri ne de vice or s yste m, v as ect o m y, 
or t u bal li gati o n. If a hi g hl y effecti ve met h o d is n ot ac hie va ble , t he n a “d o u ble 
barrier ” met h o d is a n effecti ve alter nati ve i n w hic h t he male part ner m ust use a 
c o n d o m wit h s per mici de a n d t he fe male part ner m ust use a dia p hra g m or cer vical ca p 
c o nc urre ntl y.  
 
C o nfi d e nti al
P a g e   
7 8   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
6. 9    
Restricti o ns   
6. 9. 1    
Pri or T her a p y   
Pri or t hera p y restricti o ns are des cri be d i n t he i ncl usi o n/e xcl usi o n criteria s pecifie d i n Secti o n  5 . 
6. 9. 2    
Fl ui d a n d F o o d I nt a ke   
T here are n o re q uire m e nts f or fasti n g a n d n o restri cti o ns f or fl ui d a n d f o o d i nta ke b y t h e patie nts 
d uri n g t he st u d y, alt h o u g h it is rec o m me n de d t hat, t o t he e xte nt p ossi ble, pa tie nts ha ve a fl ui d 
i nta ke of  2 liters o n da ys ass o ciate d wit h P K sa m pli n g, a n d t hat electr ocar di o g ra ms will be 
o btai ne d pre -m eal.  
6. 9. 3    
P atie nt Acti vit y Restricti o ns   
T here are n o re stricti o ns o n patie nt acti vities a n d n o re q uire me nt f or patie nt c o nfi ne me nt d uri n g 
t he st u d y. 
6. 1 0    
Tre at me nt C o m pli a nce   
Mar get u xi ma b a n d pe m br oliz u ma b will be a d mi nistere d b y healt hca re pr ofessi o nals u n der t he 
s u per visi o n of t he i n vesti gat ors. R ec or ds of m ar get u xi ma b a n d pe m br oliz u ma b d ose calc ulati o n, 
a d mi nistrati o n, a n d d osi n g re gi me n will be acc uratel y mai ntai ne d b y site staff. T he m o nit or will 
re vie w d ose calc ul ati o n, a d mi nistrati on a n d re gi me n as well as me di cati o n acc o u nta bilit y d uri n g 
i n vesti gati o nal site visits a n d at t he c o m pleti o n of t he st u d y. 
6. 1 1    
P ac k a gi n g a n d L a beli n g   
6. 1 1. 1    
Pe m br oliz u m a b   
Pe m br oliz u ma b will be pr o vi de d b y Macr o Ge nics i n t he c o m mercial pac ka gi n g, wit h a n 
a u xiliar y l a bel i n dicatin g f or cli nical trial use o nl y.  
Pe m br oliz u ma b is s u p plie d as f oll o ws:  
 K E Y T R U D A ®  ( pe m br oli zu ma b) f or i njecti o n (l y o p hilize d p o w der): cart o n 
c o ntai ni n g o n e 5 0  m g si n gle -us e vial ( N D C 0 0 0 6 -3 0 2 9 -0 2) , or as s ol uti o n f or 
i nf usi o n i n o ne 1 0 0 m g si n gle use vial. 
 
Please see t he P har mac y Ma n ual f or det aile d i nf or mati o n a b o ut t he pac ka gi n g a n d l a beli n g of 
pe m br oliz u ma b.  
C o nfi d e nti al
P a g e   
7 9   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
6. 1 1. 2    
M ar get u xi m a b   
Mar get u xi ma b will be s u p plie d i n 2 5 0 m g/ 1 0 m L ( 2 5 m g/ m L) si n gle -us e vials. Mar get u xi ma b 
will be la belle d acc or di n g t o l ocal re g ulat or y healt h a ut h o rit y re q uire me nts. Please see t he 
P har mac y Ma n u al f or det aile d i nf or mati o n a b o ut t he pac ka gi n g of mar get u xi ma b.  
N or mal sali ne i n 2 5 0 -m L ( or ot her) I V ba gs will be o btai ne d fr o m t he i nstit uti o n ’s us ual 
c o m mercial s u p plier f or t he dil uti o n of mar get u xi ma b s o l uti o n f or I V a d mi nistrati o n. 
6. 1 2    
St or a ge a n d Acc o u nt a bilit y   
Pe m br oliz u ma b a n d mar get u xi ma b s h o ul d be st ore d as o utli ne d bel o w. To e ns ure c o m plia nce 
wit h rec o m me n de d st ora ge c o n diti o ns, te m perat ure l o gs will be mai ntai ne d. T he refri gerat or 
m ust ha ve a di gital mi n/ ma x t her m o meter or c o nti n u o us rec or di n g de vice. Vials s h o ul d be st ore d 
i n a n a p pr o priat e l oc ke d r o o m accessi ble o nl y t o t he p har mac y pers o n nel or a d ul y desi g nate d 
pers o n.  
Se e P har mac y M a n ual f or details.  
6. 1 2. 1    
Pe m br oliz u m a b   
Pe m br oliz u ma b is mar kete d as K E Y T R U D A ®  b y Merc k & C o., I nc, W hite h o use Stati o n, NJ 
0 8 8 8 9.  
Pe m br oliz u ma b m ust be st ore d u n der refri ge rati o n at 2° C t o 8° C ( 3 6° F t o 4 6° F) a n d m ust n ot be 
fr oze n. Kee p p e m br oliz u ma b i n t he ori gi nal cart o n t o pr otect fr o m li g ht d uri n g st ora ge. D o n ot 
s ha ke pe m br oliz u ma b vials. Refer t o t he P har mac y Ma n ual f or details of st ora ge c o n diti o ns.  
6. 1 2. 2    
M ar get u xi m a b   
Vials c o ntai ni n g mar get u xi ma b m ust be st ore d u n der refri gerati o n at 2° C t o 8° C ( 3 6° F t o 4 6° F) 
a n d m ust n ot be fr oze n. Kee p mar get u xi ma b i n t he ori gi n al cart o n t o pr otect fr o m li g ht d u ri n g 
st ora ge. D o n ot s ha k e mar get u xi ma b vials. Refer t o t he P har mac y Ma n ual f or a d diti o nal details.  
6. 1 2. 3    
Acc o u nti n g f or t he M ateri als   
Acc urate acc o u nti n g of all st u d y me di cati o n m ust be mai ntai ne d. T he i n v esti gat or a grees t o kee p 
a n i n ve nt or y of st u d y dr u gs usi n g t he i nstit uti o n ’s dr u g acc o u nt a bilit y l o gs or l o gs pr o vi de d b y 
Macr o Ge nics. Dr u g dis p ositi o n rec or ds m ust be ke pt i n c o m plia nce wit h a p plica ble g ui deli nes 
a n d re g ulati o ns.  
A P har mac y Ma n ual will be pr o vi de d t o t he i n vesti gat or or desi g nee. W he n t he st u d y is 
c o m plete d, c o pies of all st u d y dr u g acc o u nta bilit y rec or ds m ust be pr o vi de d t o t he S p o ns or.  
Ori gi nal dr u g acc o u nta bilit y rec or ds m ust be mai ntai ne d wit h t he rest of t he d oc u me ntati o n  f or 
i ns pecti o n b y t he st u d y m o nit ors. A d diti o nal details re gar di n g st ora ge, ha n dli n g, a n d 
acc o u nta bilit y ca n b e f o u n d i n t he P har mac y Ma n ual.  
C o nfi d e nti al
P a g e   
8 0   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
6. 1 3    
I n vesti g ati o n al Pr o d uct Dis p ositi o n at E n d of St u d y  
U p o n c o m pleti o n or ter mi nati o n of t he st u d y, all u n o pe ne d vials of st u d y me dicati o n m ust be 
ret ur ne d t o Macr o Ge nics or its re prese ntati ve, u nless t he site has recei ve d writte n aut h orizati o n 
fr o m Macr o Ge nics t o destr o y st u d y dr u g at t he site. All dr u g ret ur ns t o Macr o Ge nics or its 
re pres e ntati ve m ust be acc o m pa nie d b y t he a p pr o priate d oc u me ntati o n a n d be clearl y i d e ntifie d 
b y pr ot oc ol n u m ber a n d st u d y site n u m ber o n t he o uter m ost s hi p pi n g c o ntai ner. If Macr o Ge ni cs 
a p pr o ves t he destr ucti o n of dr u g at t he site, t he i n vesti gat or m ust e ns ure arra n ge me nts are ma de 
f or pr o per dis p osal a n d t hat a p pr o priat e rec or ds of dis p osal are d oc u me nte d a n d mai ntai ne d a n d 
c o pies pr o vi de d t o t he S p o ns o r. 
C o nfi d e nti al
P a g e   
8 1   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
7    
S T U D Y P R O C E D U R E S   
T his secti o n pr o vi des a ge neral d escri pti o n of t he pr oce d ures a n d ass ess me nts ass ociate d wit h 
t his st u d y. Ti me a n d E ve nts Sc he d ule ( A p pe n di x  1  a n d A p pe n di x  2 ) details t he sc he d ule of 
assess me nts b y st u d y da y.  
N ote: O n da ys w here m ulti ple pr oce d ures are re q uire d at t he sa me ti me p oi nt, t he P K sa m ple 
s h o ul d be c ollecte d first. 
7. 1    
I nf or me d C o nse nt  
T he i n vesti gat or is res p o nsi ble f or e ns uri n g t hat t he patie nt or his/ her le gal re pres e ntati ve 
pr o vi des i nf or me d c o ns e nt pri or t o perf or mi n g a n y st u d y rel ate d assess me nts, e val uati o ns, or 
pr oce d ures. I nf or me d c o nse nt f or t his st u d y m ust be pr o vi de d b y si g ni n g a n I nstit uti o n al 
Re vie w B o ar d (I R B)/I n d e pe n de nt Et hics C o m mittee (I E C) -a p pr o ve d i nf or me d c o nse nt 
d oc u me nt ( C o nse nt f or St u d y Partici pati o n). A c o p y of t he rele va nt si g ne d i nf or me d c o nse nt 
d oc u me nt m ust be pr o vi de d t o t he patie nt a n d t he ori gi nal mai ntai ne d acc or di n g t o 
i nstit uti o nal pr oce d ures. T he patie nt’s me dical rec or ds will i ncl u de d oc u me ntati o n of t he 
i nf or me d c o nse nt pr ocess. I nf or me d c o nse nt will be o btai ne d pri or t o a n y st u d y scree ni n g 
pr oce d ures bei n g perf or me d.  
7. 2    
Me dic al Hist or y   
A c o m plete me di cal hist or y s h o ul d be o bt ai ne d d uri n g t he scree ni n g visit. All c o nc urre nt 
me dical c o n diti o ns i n t he last 6 0 da ys a n d a n y si g nifica nt me dical c o n diti o ns (e. g., 
h os pitalizati o ns, s ur geries, pri or ca ncer hist or y) s h o ul d be c ollecte d. D uri n g t he scree ni n g 
peri o d ( pri or t o first d ose of pe m br oliz u ma b or mar get u xi ma b), a n y u nt o war d e ve nt t hat 
occ urs s h o ul d be rec or de d as me dical hist or y a n d n ot as a n A E, u nless it is d ue t o a pr ot oc ol -
relate d pr oce d ure. T hereafter (i.e.,  after t he ti me of st u d y dr u g a d mi nistrati o n), a n y u nt o war d 
e ve nt s h o ul d be c ollect e d as a n A E.  
7. 3    
Pri or a n d C o nc o mit a nt Me dic ati o ns   
All c o nc o mita nt me dicati o ns a n d  bl o o d pr o d ucts a d mi nistere d d uri n g t he patie nt ’s 
partici pati o n i n t he st u d y u ntil t he E n d of Treat me nt  ( E O T) Visit ( or 2 8 da ys after t he last 
d ose of st u d y dr u g, w hic he ver occ urs later) m ust be rec or de d i n t he s o urce d oc u me nt a n d 
o n  t he electr o nic case rep ort f or m (e C R F). To t he e xte nt p oss i ble, patie nts w h o recei ve 
a nti-ca ncer a ge nts, eit her a p pr o ve d or e x peri me ntal, after re m o val fr o m st u d y t hera p y s h o ul d 
ha ve t his i nf or mati o n rec or de d i n t he e C R F, i ncl u di n g t he na m e of t he a ge nt a n d t he d urati o n 
of e x p o s ure. 
Pri or c o urses of s yste mic ca ncer t hera p y (e. g., c he m ot hera p y, i m m u n ot hera p y, etc.) will be 
d oc u me nte d i n t he m e dical rec or ds a n d i n t he e C R F.  
C o nfi d e nti al
P a g e   
8 2   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
7. 4    
P h ysic al E x a mi n ati o n   
T he i n ves ti gat or will perf or m p h ysical e xa mi nati o n of all patie nts. P h ysical e xa mi nati o n will 
i ncl u de hei g ht ( baseli ne o nl y), wei g ht, a n d e xa mi nati o n of s ki n, H E E N T ( hea d, e yes, ears, 
n ose, a n d t hr oat), l y m p h n o des, heart, c hest, l u n gs, a b d o me n, e xtre mities, a n d ne ur ol o gic 
s yste m as s pecifie d i n A p pe n di x  1  a n d A p pe n di x  2 . I nter val p h ysical e xa ms (s y m pt o m-
directe d) n oti n g a n y c ha n ges fr o m baseli ne will be rec or de d after t he i nitial e xa m.  
Wei g ht will be meas ure d d uri n g scree ni n g, Da y 1, a n d t he n bef ore eac h d os e of 
pe m br oliz u ma b a n d/ or mar get u xi ma b.  
A n y a b n or malities f o u n d d uri n g t he p h ysical e xa ms pri or t o d osi n g s h o ul d be re p orte d o n t he 
me dical hist or y f or m. A n y a b n or malities f o u n d d uri n g p h ysical e xa ms after first d ose s h o ul d 
be rec or de d as A Es.  
7. 5    
Vit al Si g ns   
Vital si g ns i ncl u de te m perat ure, p ulse, bl o o d press ure, a n d res pirat or y rate a n d will be 
o btai ne d d uri n g e ac h treat me nt c ycl e as f oll o ws:  
 I n relati o n t o pe m br oliz u ma b i nf usi o ns on Da ys 1: Vital si g ns will be ta ke n 
i m me diatel y bef ore t he pe m br oliz u ma b i nf usi o n ( u p t o 5 mi n utes bef ore t h e 
i nf usi o n [ pre-d ose]); at 1 5  mi n utes after t he start of i nf usi o n; at 3 0 mi n utes (e n d 
of i nf usi o n), a n d at 1 h o ur after i nf usi o n c o m pleti o n if t he m ar get u xi ma b d ose has 
n ot alrea d y c o m me n ce d.  
 I n relati o n t o mar get u xi ma b i nf usi o ns o n Da ys 1: Vital si g ns will be ta ke n 
i m me diatel y bef ore mar get u xi ma b i nf usi o n ( u p t o 5 mi n utes bef ore t he i nf usi o n 
[ pre-d ose]), at 6 0  mi n utes after start of i nf usi o n, at 1 2 0 mi n utes (e n d of i nf usi o n), 
a n d at 1 h o ur after t he c o m pleti o n of i nf usi o n.  
 N O T E: F or s u bse q ue nt c ycl es after C ycle 1: T he 1 -h o ur p ost -i nf usi o n vital si g ns 
meas ure me nts f or b ot h i nf usi o ns ma y be deferre d if c o nti n ue d m o nit ori n g is n ot 
cli nicall y i n dicat e d.  
 
7. 6    
Cli nic al L a b or at or y Tests   
Bl o o d a n d uri ne sa m ples will be c ollecte d at t he ti mes s pecifie d i n  A p pe n di x  1  a n d 
A p pe n di x  2 . He mat ol o g y, c he mistr y, pre g na nc y, uri nal ysis, c oa g ulati o n ti me, a n d e n d ocri ne 
e val uati o n tests will be perf or me d l o call y. Safet y la bs s h o ul d be perf or me d a n d re vie we d 
bef ore st u d y dr u g a d mi nistrati o n.  
Please c o ns ult t he La b orat or y M a n ual f or s pecifi c directi o ns o n c ollecti o n a n d pr ocessi n g 
sa m ples. 
C o nfi d e nti al
P a g e   
8 3   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
7. 6. 1    
L a b or at or y P ar a meters   
Cli nical la b orat or y tests t o be perf or me d l ocall y will i ncl u de t he f oll o wi n g:  
Ta ble  4  
Cli nic al L a b or at or y Tests   
Pre g n a nc y test:  
Uri ne or ser u m H u ma n c h ori o nic g o na d otr o pi n 
( h C G) 
 
He m at ol o g y:  
He mat ocrit ( Hct)  
He m o gl o bi n ( H g b)  
Mea n c or p usc ular he m o gl o bi n ( M C H)  
Mea n c or p usc ular he m o gl o bi n c o nce ntrati o n 
( M C H C) 
Mea n c or p usc ular v ol u me ( M C V)  
Platelet c o u nt  
Re d bl o o d cell ( R B C) c o u nt  
W hite bl o o d cell ( W B C) c o u nt wit h differe ntial 
c o u nts  
 
Ser u m C he mistr y:  
Al b u mi n ( A L B)  
Al kali ne p h os p hatase ( A L K -P)  
Ala ni ne a mi n otra nsferase ( A L T; S G P T)  
A m ylase  
As partate a mi n otra nsferase ( A S T; S G O T)  
Bicar b o nate  
Bl o o d urea nitr o ge n ( B U N)  
Calci u m ( Ca)  
C hl ori de ( Cl)  
Creati ni ne  
Gl uc ose  
Li pase  
Ma g nesi u m  
P h os p h or us  
P otassi u m ( K)  
S o di u m ( Na)  
T otal pr otei n  
Uric aci d   
Bilir u bi n ( T otal a n d Direct)  
C o a g ul ati o n :  
Pr ot hr o m bi n ti me ( P T) 
I nter nati o nal n or malize d rati o (I N R) 
Acti vate d Partial T hr o m b o plasti n Ti me ( A P T T)  
 
E n d ocri ne tests:  
Free t h yr o xi ne ( T 4)  
T h yr oi d -sti m ulati n g h or m o ne ( T S H) 
 
Uri n al ysis :  
Bilir u bi n  
C ol or  
Gl uc ose  
Ket o nes  
Nitrite  
Occ ult bl o o d  
p H  
Pr otei n  
S pecific gra v it y 
 
 
Ot her tests ( P K, a nti -dr u g a nti b o d y [ A D A], c yt o ki nes, deter mi nati o n of le u k oc yt e s u bsets, 
e val uati o n of T cell acti v ati o n stat us, e x pressi o n of mar kers of T cells, deter mi nati o n of T  cell 
i nfiltrati o n, t u m or P D-L 1 e x pressi o n, c haracterizati o n of H E R 2 e x pressi o n, ct D N A, a n d Fc 
ge n ot y p e) will be carrie d o ut at S p o ns or -s pecifie d ce ntral la b orat ories (refer t o t he 
La b orat or y M a n ual).  
C o nfi d e nti al
P a g e   
8 4   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
7. 6. 2    
S a m ple C ollecti o n, St or a ge, a n d S hi p pi n g   
Cli nical la b orat or y testi n g des cri be d i n  Secti o n  7. 6. 1  will be perf or me d l o call y. Details o n 
l ocal a n d ce ntral la b orat or y s p eci me n c ollecti o n, st ora ge, a n d s hi p pi n g will be pr o vi de d i n 
t he La b orat or y M a n ual. 
7. 7    
T u m or Bi o ps y S peci me ns   
7. 7. 1    
S a m ples f or H E R 2 a n d P D -L 1 Testi n g   
A pat h ol o gic s peci me n or u nstai ne d sli des (secti o ne d wit hi n 3 m o nt hs of st u d y e n tr y) are 
re q ueste d w h e ne v er p ossi ble f or ce ntral H E R 2 a n d P D-L 1 testi n g. Sa m ples ca n be fr o m t he 
patie nt ’s ori gi n al bi o ps y or resecti o n or be o btai ne d fr o m s u bse q ue nt sa m pl es or 
c o nte m p ora ne o us bi o ps y. Sa m ples ca n be fr o m eit her pri mar y or metastatic tiss u e alt h o u g h 
t he latest bi o ps y is preferre d. T he res ults of ce ntral H E R 2 a n d P D-L 1 testi n g will be use d i n 
efficac y a nal yses a n d n ot f or eli gi bilit y. Eli gi bilit y will be deter mi ne d b y H E R 2 testi n g of 
patie nt ’s pat h ol o gi c s peci me n at t he l ocal i nstit uti o n. Details of sa m ple ac q uisiti o n 
re q uire me nts are pr o vi d e d i n t he La b orat or y M a n ual. 
7. 7. 1. 1    
Arc hi v al T u m or Bi o ps y S peci me ns   
Patie nts e nr olle d o n t his st u d y will be re q uire d t o ha ve a n i de n tifie d arc hi v al t u m or s peci me n. 
P araffi n -e m be d de d  bl oc k  or 1 2  u nstai ne d sli des  will be use d  f or t he det er mi nati o n of  P D -L 1 
a n d H E R 2 e x pressi o n wit hi n t u m or s peci me ns usi n g a n I H C stai ni n g assa y or b y i n -sit u 
h y bri dizati o n (f or H E R 2). If a t u m or bi o ps y is perf or me d at baseli ne wit h res ulti n g sa m ple 
a de q uate t o ma ke 1 2 sli des, t he arc hi ve d sa m ple re q uire me nt will be wai v e d , b ut it is still 
str o n gl y e n c o ura ge d t o o btai n t he arc hi ve d sa m ple s o t hat c o m paris o ns i n P D -L 1 stai ni n g ca n 
be ma de bet w ee n arc hi ve d a n d  fres h tiss ue. 
7. 7. 1. 2    
M a n d at or y B aseli ne T u m or Bi o ps y a n d O pti o n al Fres h 
P aire d T u m or Bi o ps y S peci me ns   
F o r P art B : At least 2 0 o ut of t he 6 0 patie nts (a p pr o xi matel y 1 0 fr o m eac h re gi o n [ N ort h 
A merica a n d Asia ]) e nr olle d i n t he  C o h ort E x pa nsi o n P hase  (Part B ) u n der t he Ori gi nal 
Pr ot oc ol or Pr ot oc ol A m e n d me nt 1 m ust be willi n g t o pr o vi de c o nse nt f or baseli ne a n d o n  
treat me nt bi o ps y s a m ples t o be d o ne wit hi n 7  da ys pri or t o d osi n g o n C ycle 1 Da y 1 a n d o n 
C ycle  2 Da y 1, res pecti v el y. All patie nts w h o c o nse nt f or t he bi o ps y m ust ha ve o ne lesi o n 
t hat i n t he j u d g me nt of t h e i n vesti gat or ca n s u p p ort pre- a n d o n-treat me nt bi o psies. A n 
atte m pt t o o btai n a t u m or bi o ps y of a l o call y accessi ble lesi o n pre - a n d o n-treat me nt ( C ycle 1 
Da y 1 a n d C ycle  2 Da y  1) will be re q uire d f or at l east 2 0 of t he 6 0  patie nts . T u m or lesi o ns 
use d f or bi o ps y s h o ul d be lesi o ns t hat are felt t o be accessi ble wit h acce pta ble cli nical ris k i n 
t he j u d g me nt of t he i n v esti gat or a n d s h o ul d n ot be lesi o ns use d as R E CI S T t ar get lesi o ns, 
u nless t here are n o ot her lesi o ns s uita ble f or bi o ps y. If a R E CI S T tar get lesi o n is use d f or 
bi o ps y, t he l esi o n m ust be ≥ 2  c m i n l o n gest dia m eter. Lesi o ns t o be bi o psie d s h o ul d n ot ha ve 
bee n pre vi o usl y irra diate d, u nless t he lesi o n has gr o w n i n size be gi n ni n g at least 1 4 da ys 
C o nfi d e nti al
P a g e   
8 5   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
si nce t he last ra diati o n d ose. N ote t hat m ulti ple lesi o ns ma y be us e d t o o btai n t he bi o ps y 
sa m ple. 
Lesi o ns t o be bi o psie d s h o ul d be of s uffici e nt s ize t o e na ble ac q uisiti o n of at least 2 t u m or 
bi o ps y c ores usi n g a 1 6 -ga u ge bi o ps y nee dle. E xce pti o ns t o t he ga u ge of t he nee dle ma y be 
c o nsi dere d after c o ns ultati o n wit h t he S p o ns or ’s Me dical M o nit or. T w o a d diti o nal bi o ps y 
c ores ma y b e o btai ne d t o e ns ure a de q uate sa m pli n g f or a nal ysis, if t his ca n be perf or me d 
wit h acce pt a ble cli nical ris k i n t he j u d g me nt of t h e i n vesti gat or. P u nc h bi o psies or e xcisi o nal 
bi o psies are all o we d if t hese ca n b e perf or me d wit h acce pta ble cli nical ris k i n t he j u d g me nt 
of t he i n v esti gat or. I m me diate c o nfir mati o n of t he a de q uac y of t he bi o ps y s peci me n a n d t he 
prese nce of mali g na nt cells i n t he t u m or bi o ps y is str o n gl y e nc o ura ge d.  
A d diti o nal i nstr ucti o ns f or t he ac q uisiti o n, pr ocessi n g a n d st ora ge of t u m or bi o ps y s peci me ns 
will be p r o vi de d i n t he La b Ma n ual. T he paire d t u m or bi o ps y s peci me ns will be o btai ne d t o 
e na ble i n vesti gati o n of t h e p har mac o d y na mic effects of t he c o m bi nati o n of mar get u xi ma b 
a n d pe m br oliz u ma b wit hi n t he l ocal t u m or micr oe n vir o n me nt. St u dies t o be perf or me d will 
i ncl u de assess me nt of l ocal T cell i nfiltrati o n a n d t he e x pressi o n of t u m or a p o pt osis mar kers. 
K E Y N O T E -0 1 2 st u d y s u g geste d t h at P D -L 1 stat us ma y be rele va nt t o pe m br oliz u ma b 
efficac y (4 ). 
F o r P art C : Patie nts will n ot be re q uire d  t o h a ve pre- a n d o n -treat me nt bi o psies. 
7. 8    
C ar di ac E v al u ati o ns   
7. 8. 1    
1 2 -Le a d Electr oc ar di o gr a ms   
T wel ve -lea d electr ocar di o gra ms ( E C Gs, i n tri plicate, a p pr o xi matel y 1 mi n ute a part) will be 
o btai ne d acc or di n g t o t he Ti me a n d  E ve nts ( A p pe n di x  1  a n d A p pe n di x  2 ) i n or der t o 
e val uate t he p ote ntial car diac effects of mar get u xi ma b or pri or a nti -H E R 2 treat me nt, 
i ncl u di n g Q T i nter val pr ol o n gati o n. T here are n o re q uire me nts f or fasti n g a n d n o restricti o ns 
f or fl ui d a n d f o o d i nta k e b y t he patie nts d uri n g t h e st u d y, alt h o u g h it is rec o m me n de d t hat, t o 
t he e xte nt p ossi ble, E C Gs be o btai ne d pre-meal.  H o we ver, t his ma y n ot b e p ossi ble beca us e 
of i nf us i o n ti mes a n d cli nic l o gistics. 
To acc o u nt f or i ntri nsic vari a bilit y, all E C Gs s h o ul d be o btai ne d i n tri plicate ( 3 E C Gs per 
ti me p oi nt at a p pr o xi matel y 1-mi n ute i nter vals). Ce ntral i nter pretati o n of E C Gs will be use d 
f or data a nal ysis p ur p oses. 
If a P K sa m ple c ollecti o n c oi nci des wit h meas ure me nt of E C Gs, t he P K sa mple s h o ul d 
be  c ollecte d first, a n d E C G meas ure m e nts ta ke n after t he patie nt has reste d f or a p pr o xi matel y 
5  –  1 0  mi n utes. T he pla n ne d a n d act ual ti mes of t he E C G assess me nts will be rec or de d o n t he 
e C R Fs. 
C o nfi d e nti al
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A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
D ose Esc al ati o n P h ase  ( P art A) 
 C ycle 1:  
o  Pe m br oliz u ma b i nf usi o n o n Da y 1: E C Gs will be o btai ne d i m me diatel y 
bef ore t h e pe m br oliz u ma b i nf usi o n ( u p t o 3 mi n utes bef ore t he i nf usi o n 
[ pre-d ose]) a n d a t 3 0 mi n utes (e n d of i nf usi o n).  
o  Mar get u xi ma b i nf usi o n o n Da y 1 (i nte nsi ve P K da y): E C Gs will be ta ke n 
at 1 2 0 mi n u tes (e n d of i nf usi o n) a n d at 2 4 h o urs after t he c o m pleti o n of 
i nf usi o n. 
 C ycles 2 t hr o u g h 5:  
o  Pe m br oliz u ma b i nf usi o ns o n Da y 1 of eac h c ycle: E C G will be o btai ne d 
i m me diatel y pri or t o t he first pe m br oliz u ma b i nf usi o n ( u p t o 3 mi n utes 
bef ore t h e i nf usi o n [ pre -d ose]).  
o  Mar get u xi ma b i nf usi o ns o n Da y 1 of eac h c ycle (e xce pt C ycle 3): E C G 
will be o btai ne d i m me diatel y pri or t o t he first mar get u xi ma b i nf usi o n ( u p 
t o 3 mi n utes bef ore t he i nf usi o n [ pre -d ose])  
o  Mar get u xi ma b i nf usi o n o n Da y 1 of C ycle 3 (i nte nsi ve P K da y) : E C Gs 
will be ta ke n i m me diatel y bef ore m ar get u xi ma b i nf usi o n ( u p t o 3 mi n utes 
bef ore t h e i nf usi o n [ pre -d ose]), at 1 2 0 mi n utes (e n d of i nf usi o n), a n d at 2 4 
h o urs after i nf usi o n c o m pleti o n.  
 E n d of Treat me nt Visit:  
o  E C Gs will be ta ke n at n o s pecific ti me p oi n t d uri n g  E n d of Treat me nt 
Visit.  
 
C o h ort  E x p a nsi o n P h ase  ( P arts B –  C ): 
 C ycles 1, 3, 5 a n d 7 o nl y  
o  Pe m br oliz u ma b i nf usi o ns o n Da y 1 of C ycles 1, 3, 5, a n d 7: E C G will be 
o btai ne d i m me diatel y pri or t o t he first pe m br oliz u ma b i nf usi o n ( u p t o 
3  mi n utes bef ore t he i nf usi o n [ pre-d ose]) a n d at 3 0  mi n utes (e n d of 
i nf usi o n). 
o  Mar get u xi ma b i nf usi o ns o n Da y 1 of C ycles 1, 3, 5 , a n d 7: E C G will be 
o btai ne d at 1 2 0  mi n utes (e n d of i nf usi o n) . 
 E n d of Treat me nt Visit:  
o  E C Gs will be ta ke n at n o s pecific ti me p oi nt d uri n g  E n d of Treat me nt 
Visit.  
 
C o nfi d e nti al
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A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
7. 8. 2    
M ulti g ate d Ac q uisiti o n Ve ntric ul o gr a p h y Sc a n ni n g a n d 
Ec h oc ar di o gr a p h y   
M ulti gate d ac q uisiti o n ve ntric ul o gra p h y sca n ni n g ( M U G A) sca ns or ec h ocar di o gra ms w ill be 
o btai ne d a n d a n al yze d l o call y i n all patie nts acc or di n g t o t he Ti me a n d E ve nts sc he d ules 
(A p pe n di x  1  a n d A p pe n di x  2 ). T he sa me m o dalit y s h o ul d be use d t hr o u g h o ut t he st u d y f or 
a n y gi v e n patie nt. All M U G A sca ns or ec h ocar di o gra p h y perf or me d will be e val u at e d f or t he 
c ha n ge i n L V E F fr o m b aseli ne.  
7. 9    
S afet y Assess me nts   
7. 9. 1    
Criteri a f or E v al u ati o n   
All A Es  a n d SA Es, re gar dless of ca usalit y , will be re p orte d fr o m t he ti me a si g ne d a n d date d 
I C F (see Secti o n  7. 1 ) is o btai ne d t hr o u g h 2 8  da ys f oll o wi n g t he last d ose of st u d y dr u g or t he 
E n d of Treat me nt Visit  or u ntil t he start of a s u bse q ue nt s yste mic a ntica ncer t hera p y 
( w hic he ver occ urs first). After  t he c o m pleti o n of t he 2 8 da y-peri o d or start of a s u bse q ue nt 
s yste mic a ntica ncer t hera p y, o nl y treat me nt-relate d A Es  will be re p orte d.  
 Pr ot oc ol -relate d A Es a n d S A Es will be c ollecte d fr o m t he ti me t he patie nt has 
c o nse nte d t o st u d y p artici pati o n.   
 A Es re p orte d after t he i nf or me d c o nse nt d oc u me nt is si g ne d a n d pri or t o treat me nt 
wit h st u d y dr u g s h o ul d be ca pt ure d as me dical hist or y; h o we ver, if t he 
I n v esti gat or belie ves t h e A E ma y ha ve bee n ca use d b y a pr ot oc ol pr oce d ure it will 
be re p orte d t o t he S p o ns or o r its desi g nee a n d/ or e ntere d o n t he e C R F. S A Es 
c o nsi dere d relate d t o st u d y dr u g  s h o ul d be re p orte d at a n y ti me, e ve n after t he 
patie nt ’s fi nal visit.  
 Pr o gressi o n of t he u n derl yi n g ne o plas m res ulti n g i n h os pitalizati o n or deat h (e. g., 
patie nt h os pitalize d  f or or dies fr o m P D o nl y, wit h o ut a n y ot her S A E) will be 
d oc u me nte d as a n a ntit u m or acti vit y o utc o me a n d n ot as a n S A E, u nless 
c o nsi dere d as dr u g -relate d b y t he i n vesti gat or. If a n S A E occ urs i n a patie nt a n d it 
is u nclear w h et her t he e ve nt is relate d t o P D, t he S A E s h o ul d be re p orte d.   
 T he re p orti n g of la b orat or y/ vital si g ns a b n or malities as b ot h la b orat or y fi n di n gs 
a n d A Es s h o ul d be a v oi de d. T he y s h o ul d n ot be re p orte d as A Es u nless a n y o ne of 
t he f oll o wi n g are met:  
o  A n y criteri o n f or a n S A E is f ulfille d  
o  T he la b orat or y/ vital si g ns a b n or malit y ca uses t he patie nt t o disc o nti n ue 
fr o m t he st u d y treat me nt 
o  T he la b orat or y/ vital si g ns a b n or malit y ca uses t he patie nt t o i nterr u pt t he 
st u d y treat me nt 
C o nfi d e nti al
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A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
o  T he la b orat or y/ vital si g ns a b n or malit y re q uires i nter ve nti o n  
o  T he la b orat or y/ vital si g ns are dee me d cli nicall y si g nifica nt, base d o n 
me dical j u d ge me nt .   
 
7. 9. 2    
A d verse E ve nt: Defi niti o ns   
7. 9. 2. 1    
A d verse E ve nt   
Pr o gressi o n of t he ca ncer u n der st u d y is n ot c o nsi dere d a n a d verse e ve nt u nless it is 
c o nsi dere d t o be dr u g -relate d b y t he i n vesti gat or. 
A n a d verse e ve nt is  a n y u nt o war d me dical o cc urre nce i n a patie nt or cli nical i n vesti gati o n 
patie nt a d mi nistere d a p h ar mace utical pr o d uct a n d w hic h d oes n ot necessaril y ha ve t o ha ve a 
ca usal relati o ns hi p wit h t his treat me nt. A n A E ca n t heref ore be a n y u nfa v ora ble a n d 
u ni nte n de d si g n (e. g., a n a b n or mal la b orat or y fi n di n g), s y m pt o m, o r diseas e te m p orall y 
ass ociate d wit h t he use of a me dici nal pr o d uct, w het her or n ot c o nsi dere d relate d t o t he 
me dici nal pr o d uct.  
A n a d verse e ve nt will als o be c o nsi dere d t o be a n y u nt o war d effect of a st u d y -relate d 
pr oce d ure, w hic h is c o n d ucte d after si g ne d i nf or m e d c o nse nt a n d pri or t o st u d y dr u g 
a d mi nistrati o n.  
All a d verse e ve nts will be rec or de d fr o m t he ti me t he c o nse nt f or m is si g ne d t hr o u g h 2 8  da ys 
f oll o wi n g cessati o n of treat me nt a n d at eac h e xa mi nati o n o n t he A d verse E ve nt case re p ort 
f or ms/ w or ks heets. T he re p orti n g ti mefra me f or a d verse e ve nts meeti n g a n y se ri o us criteria is 
descri be d i n S ecti o n  7. 9. 6  - N otificati o n  t o t he S p o ns or of E ve nts Re q uiri n g I m me diate 
Re p orti n g . 
7. 9. 2. 2    
A d verse Dr u g Re acti o n   
A n a d verse dr u g reacti o n ( A D R) is a n o xi o us a n d u ni nte n de d res p o nse t o t he me dici nal 
pr o d uct relat e d t o a n y d ose. As use d herei n, t he p hrase “res p o nse t o a me dici nal pr o d uct” 
mea ns t hat a ca usal rel ati o ns hi p bet wee n a me dici nal pr o d uct a n d a n A E is at least a 
reas o na bl e p ossi bilit y (i.e., t he relati o ns hi p ca n n ot be r ule d o ut). 
7. 9. 2. 3    
A d verse E ve nt of S peci al I nterest   
A n A E SI is a n e v e nt of s cie ntific a n d me dical i nterest or c o ncer n t o t he S p o ns or ’s pr o d uct or 
pr o gra m, f or w hic h o n g oi n g m o nit ori n g a n d ra pi d c o m m u nicati o n t o t he S p o ns or c o ul d be 
a p pr opriate. It m a y be a s eri o us or n o n -seri o us A E, w hic h ma y re q uire f urt h er i n vesti gati o n 
i n or der t o c haract erize a n d u n dersta n d it. 
7. 9. 2. 4    
Tre at me nt E mer ge nt A d verse E ve nt   
A n e ve nt t hat is te m p orall y ass oci ate d wit h a d mi nistrati o n of st u d y pr o d uct is defi ne d as a 
treat me nt-e mer ge nt a d verse e ve nt ( T E A E).  E ve nts meeti n g t his defi niti o n will be t h ose 
C o nfi d e nti al
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occ urri n g d uri n g or after a d mi nistrati o n of t he first d ose of st u d y dr u g. E ve nts t hat e xiste d 
bef ore t h e first a d mi nistrati o n of st u d y pr o d uct a n d t he n i ncreas e d i n se verit y d uri n g or after 
t he first a d mi nistrati o n of st u d y pr o d uct will als o b e c o nsi dere d treat me nt e mer ge nt. S uc h 
e ve nts will be ca pt ure d o n t he e C R F as ne w e ve nts, wit h t he o nset d ate as t he date of t he 
i ncreas e i n se verit y. 
7. 9. 2. 5    
Seri o us A d verse E ve nts   
A S A E is a n y a d v erse e v e nt t hat res ults i n a n y of t he f oll o wi n g o utc o mes:  
 Deat h  
 Life -t hreate ni n g (i m me di ate ris k of deat h) 
 I n p atie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n (e ve n if t he 
e ve nt is Gra d e 1)  
 Persiste nt or si g nifica nt disa bilit y or i nca pacit y  
 C o n ge nital a n o mal y/ birt h defect  
 I m p ort a nt me dical e ve nts t hat ma y n ot res ult i n deat h, be life-t hreate ni n g, or 
re q uire h os pitalizati o n ma y be c o nsi dere d S A Es w he n, base d u p o n a p pr o priate 
me dical j u d g m e nt, t he y ma y je o par dize t he patie nt a n d ma y re q uire me dical or 
s ur gi cal i nter ve nti o n t o pre ve nt o ne of t he o utc o mes liste d i n t his defi niti o n. 
E xa m ples of s uc h me dical e ve nts i ncl u de aller gic br o nc h os pas m re q uiri n g 
i nte nsi ve treat me nt i n a n e mer ge nc y r o o m or at h o me; bl o o d d yscrasias or 
c o n v ulsi o ns t hat d o n ot res ult i n i n patie nt h os pitalizati o n or t he de vel o p me nt of 
dr u g d e pe n de nc y or dr u g a b use.  
 
7. 9. 2. 6    
I m me di atel y Re p ort a ble E ve nt  
I m me diat el y re p orta ble e ve nts (I R Es) are e ve nts t hat m ust be re p orte d i m me diatel y t o 
Macr o Ge nics Pr o d uct Safet y wit hi n 2 4  h o urs of bei n g i de ntifie d. I R Es i ncl u de b ut are n ot 
li mite d t o: 
 S A Es  
 A Es lea di n g t o per ma ne nt disc o nti n uati o n of st u d y dr u g i n a n i n di vi d ual patie nt.  
 All pre g n a ncies a n d e x p os ure d uri n g breastfee di n g, fr o m t he ti me of treat me nt 
t hr o u g h 7 m o nt hs  f oll o wi n g cessati o n of st u d y treat me nt. All p re g na nt a n d/ or 
lactatin g  fe male p art ners of a male patie nt m ust be re q ueste d t o c o m plet e a 
Pre g n a nt Part ner C o nse nt F or m s o t hat pre g na nt part ner, fetal , a n d/ or ne w b or n 
i nf or mati o n ca n be c ollecte d. U p o n c o nfir mati o n of ser u m pre g na nc y testi n g, t he 
patie nt will be f oll o we d f or t he o utc o me of pre g na nc y. All li ve ne w b or ns will be 
f oll o we d si x m o nt hs after t he birt h, a n d all necess ar y i nf or mati o n will be 
c ollecte d t o assess t he effects of st u d y dr u g o n t he ne w b or n. If necessar y, t h e 
f oll o w-u p peri o d wil l be e xte n de d f or t he ne w b or n. 
C o nfi d e nti al
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 A d verse e ve nts of s pecial i nterest ( A E SI) c o nsi dere d i m me diatel y re p orta ble 
e ve nts as descri be d i n Secti o n  7. 9. 3  a n d bel o w : 
o  ≥ Gra de 3 I nf usi o n -relate d reacti o ns or C R S (see als o Secti o n  6. 5. 1 ) 
o  ir A E (see als o Secti o n  6. 5. 2 ) 
o  Car di ot o xicit y (see als o  Secti o n  6. 5. 3 ) 
 A d mi nistrati o n of a d ose si g nifica ntl y greater ( + 2 0 %) t ha n t he pla n ne d d ose of 
eit her mar get u xi ma b or pe m br oliz u ma b res ulti n g i n a n e ve nt o f cli nical 
c o nse q ue nce.  
 A n y s us pecte d tra ns missi o n of a n i nfecti o us a ge nt via st u d y dr u g ( mar get u xi ma b 
or pe m br oliz u ma b).  
 Wit h dra wal of t he patie nt fr o m st u d y dr u g a d mi nistrati o n f or a n y reas o n ot her 
t ha n disease pr o gressi o n. 
 A b n or mal li ver e nz y m es t hat me et t he criteria f or p ote ntial H y’s l a w, w hic h is 
defi ne d as A S T a n d/ or A L T t hat is greater t h a n 3 × U L N a n d t otal bilir u bi n t hat is 
greater t ha n 2  × U L N wit h o ut a n y alter nate eti ol o g y.  
 
I n t h ose cases, i n w hi c h t he I R E is c o nsi dere d relate d t o st u d y dr u g a n d t h e e ve nt is of 
s ufficie nt cli nical c o ncer n t o warra nt st u d y dr u g disc o nti n uati o n, t he st u d y dr u g ma y be 
disc o nti n ue d a n d t he pati e nt will c o nti n ue partici p ati o n i n t he st u d y f or o bs e r vati o nal safet y 
a n d a nal ysis (e x ce pt f or cases w here t he patie nt wit h dra ws c o nse nt or is wit h dra w n fr o m t he 
st u d y b y t he i n vesti gat or). At a n y ti me after c o m pl eti o n of t he st u d y, if a n i n vesti gat or 
bec o mes a ware of a S A E t hat is s us pecte d relate d t o st u d y  dr u g, t he i n vesti gat or s h o ul d 
re p ort t he e v e nt t o Macr o Ge nics Pr o d uct Safet y i m me diatel y. 
A p h ysicia n ’s assess me nt of t he e ve nt is e x pecte d t o be c o m plete d i n c o nj u n cti o n wit h 
re p orti n g a n I R E t o Macr o Ge nics Pr o d uct Safet y. 
7. 9. 3    
A d verse E ve nts of S peci al I nter est  
A E SI will i ncl u de t he f oll o wi n g:  
 All I nf usi o n reacti o ns i ncl u di n g c yt o ki ne releas e s y n dr o me. ( Gra de 3 or greater 
will be re p orte d as I R Es)  
 I m m u ne-relat e d A Es of Gra de 3 or greater s u g gesti ve of a n a ut oi m m u ne pr ocess, 
i ncl u di n g b ut n ot li mite d t o: p ne u m o nitis, c olitis, a ut oi m m u ne he patitis, art hritis, 
gl o mer ul o ne p hritis, m y ocar ditis a n d car di o m y o pat h y, h y p o p h ysitis, t h yr oi ditis, 
m y ositis, u veitis, ne ur ot o xicit y, or ot her a ut oi m m u ne e n d ocri n o pat hie s, 
pericar ditis, or m y ocar ditis  
 Left ve ntric ular d ysf u ncti o n re q uiri n g dela y or  cessati o n of mar get u xi ma b  
 A d mi nistrati o n of a n  o ver d ose , as defi ne d i n Secti o n 7. 9. 5. 2  of eit her 
mar get u xi ma b or pe m br oliz u ma b res ulti n g i n a n  e ve nt of cli nical c o nse q ue nce.  
C o nfi d e nti al
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7. 9. 4    
Perf or mi n g A d verse E ve nt Assess me nts   
Me dical e val u ati o n  a n d classificati o n of t he a d verse e ve nt m ust be perf or m e d b y t h e 
i n vesti gat or w h o is q ualifie d t o re vie w A E i nf or mati o n. T he deter mi nati o n of seri o us ness, 
se verit y a n d ca usalit y m ust be ma de acc or di n g t o t he f oll o wi n g criteria:  
Assess me nt of Seri o us ness: E ve nt seri o us ness will be deter mi ne d acc or di n g t o t he 
defi niti o n of a n S A E i n  Secti o n  7. 9. 2 . Seri o us ness ser ves as a g ui de f or defi ni n g re g ul at or y 
re p orti n g o bli gati o ns f or A Es. 
Assess me nt of Se verit y:  E ve nt severity will be assi g ne d acc or di n g t o t he i n vesti gat or ’s 
assess me nt usi n g t he C T C A E Versi o n 4. 0 3 (f or descri be d e ve nts a n d s y n dr o mes). F or e ve nts 
n ot c o ntai ne d i n C T C A E , t he i n vesti gat or m a y assi g n se verit y acc or di n g t o t he f oll o wi n g 
scale: 
 Gra de 1 = Mil d  
 Gra de 2 = M o derate A E  
 Gra de 3 = Se vere A E  
 Gra de 4 = Life -t hreat e ni n g or disa bli n g A E 
 Gra de 5 = Deat h relat e d t o A E  
 
A n y e ve nt or la b orat or y val ue j u d ge d as Gra de 4 se verit y s h o ul d be se paratel y e val uate d t o 
deter mi ne w het h er it als o meets t he seri o us criteri o n of "i m me diatel y life t hreate ni n g" (see 
Secti o n  7. 9. 2. 5 ). 
N ote: Se verit y is n ot s y n o n y m o us wit h seri o us ness. T he ter m "se vere" is ofte n use d t o 
descri be t he i nte nsit y (se verit y) of a s p ecific e ve nt. T he e ve nt itself, h o we ver, ma y be of 
relati vel y mi n or me dical si g nifica n ce (s uc h as se vere hea dac he). T his is n ot t he sa me as 
"seri o us," w hic h is bas e d o n patie nt/e ve nt o utc o me or acti o n criteria us u all y ass o ciate d wit h 
e ve nts t hat p ose a t hreat t o a patie nt's life or f u ncti o ni n g.  
Assess me nt of C a us alit y:  T he  i n vesti gat or is re q uire d t o pr o vi de a n assess me nt of ca usalit y 
or relati o ns hi p of A Es t o t he st u d y dr u g base d o n 1) te m p oral rel ati o ns hi p of t he e ve nt t o t he 
a d mi nistrati o n of st u d y dr u g; 2) w het her a n alter nati ve eti ol o g y has bee n i d e ntifie d, a n d 
3)  bi ol o gical pla usi bilit y. Ca usalit y m ust be assesse d se paratel y f or eac h dr u g. T he ca us alit y 
assess me nt cate g ories t hat will be use d f or t his st u d y are des cri be d bel o w.  
Ca usalit y assess me nts t h at are c o nsi dere d n ot rel ate d  t o st u d y dr u g:  
N o ne:  T he e ve nt is rel ate d t o a n eti ol o g y ot her t ha n t he st u d y dr u g (t he alter nati ve eti ol o g y 
s h o ul d be d oc u me nte d i n t he patie nt’s me dical rec or d). 
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U nlikely:  T he e ve nt is u nli kel y t o be relate d t o t he st u d y dr u g a n d li kel y t o be relate d t o 
fact ors ot her t ha n st u d y dr u g. 
If a n S A E is c o nsi dere d " u nli kel y" or " u nrel ate d" t o st u d y dr u g, t he i n vesti gat or s h o ul d offer 
his/ her cli nical o pi ni o n as t o w hat fact or(s), a ge nt(s), or pr ocess(es) were t he li kel y ca u sati ve 
mec ha nis m f or t he e ve nt.  
Ca usalit y assess me nts t h at are c o nsi dere d rel ate d t o st u d y dr u g: 
P ossi ble:  T here is a n ass ociati o n bet wee n t he e ve nt a n d t he a d mi nistrati o n of t he st u d y dr u g 
a n d t here is a pl a usi ble mec ha nis m f or t he e ve nt t o be relate d t o st u d y dr u g; b ut t here ma y 
als o be alter nati ve eti ol o g y, s uc h as c haracterist ics of t he patie nt’s cli nical stat us or 
u n derl yi n g disease.  
Pr o b a ble:  T here is a n ass ociati o n bet wee n t he e ve nt a n d t he a d mi nistrati o n of st u d y dr u g, a 
pla usi ble mec ha nis m f or t he e ve nt t o be relate d t o t he st u d y dr u g a n d t he e ve nt c o ul d n ot be 
reas o na bl y e x plai ne d b y k n o w n c haracteristics of t he patie nt ’s cli nical stat us or a n alter nati ve 
eti ol o g y is n ot a p pare nt.  
Defi nite:  T here is a n ass ociati o n bet wee n t he e ve nt a n d t he a d mi nistrati o n of st u d y dr u g; a 
pla usi ble mec ha nis m f or t he e ve nt t o be relate d t o t he st u d y dr u g a n d ca us e s ot her t ha n t he 
st u d y dr u g has b ee n r ule d o ut a n d/ or t he e ve nt re -a p peare d o n re -e x p os ure t o t he st u d y dr u g.  
Assess me nt of E x pecte d ness : As part of t he re g ul at or y re p orti n g re q uire m e nts, t he S p o ns or 
m ust perf or m a n ass ess me nt of e x p ecte d ness (e x pecte d/ u ne x pecte d fr o m t he pers pecti ve of 
pre vi o usl y o bs er ve d, n ot o n t he basis of w hat mi g ht be a ntici pate d fr o m t he p har mac ol o gi cal 
pr o perties of a me dici nal pr o d uct) f or A Es. A d verse reacti o ns will be c o nsi dere d u ne x pecte d 
if t he nat ure, seri o us ness, se verit y or o utc o me of t he reacti o n(s) is n ot c o nsiste nt wit h t he 
refere nce i nf or mati o n (e. g., t he A d verse Dr u g R eacti o n secti o n of t he i n vesti gat or’s br oc h ure 
[I B]) f or t he st u d y pr o d uct. 
7. 9. 5    
Re p orti n g of A d verse E ve nts t o t he S p o ns or   
T hr o u g h o ut t he st u d y, t he i n vesti gat or m ust d oc u me nt all A Es o n t he e C R F i n a ti mel y 
ma n ner.  A d verse e ve nts will be c ollecte d a n d f oll o we d fr o m t he ti me t he patie nt pr o vi des 
i nf or me d c o nse nt f or t he st u d y (see Secti o n  7. 1 ) u ntil 2 8  da ys  f oll o wi n g t he last d ose  of 
st u d y dr u g or t h e E n d of Treat me nt Visit  or u ntil t he start of a s u bs e q ue nt s yste mic a ntica ncer 
t hera p y ( w hi c he ver occ urs first). After t h e c o m pleti o n of t he 2 8 da y -peri o d or start of a 
s u bse q ue nt s yste mic a ntica ncer t hera p y, o nl y treat me nt-relate d A Es  will be re p orte d.  If a 
patie nt e x perie nces a n A E after t he i nf or me d c o ns e nt d oc u me nt is si g ne d a n d pri or t o 
treat me nt wit h st u d y dr u g, it s h o ul d be ca pt ure d as me dical hist or y; h o we ver, if t he 
i n vesti gat or belie ves t he A E ma y ha ve bee n ca use d b y a pr ot oc ol -relate d pr oce d ure it will be 
rec or de d as a n A E a n d e ntere d o nt o t he e C R F. 
To i de ntif y t he occ urre n ce of a n y ne w me dical c o m plai nts or w orse ni n g of pre vi o us 
c o m plai nts, n o n -lea di n g q uesti o ni n g s h o ul d be p ose d t o t he patie nt. 
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E ve nts relate d t o disea se pr o gressi o n/ w orse ni n g of u n derl yi n g disease (i ncl u di n g t h ose wit h a 
fatal o utc o me) will be c ollecte d as efficac y e n d p oi nts, a n d n ot d oc u me nte d as A Es/ S A Es. 
T hese e v e nts ma y n ot q u alif y f or e x pe dite d re p orti n g t o re g ulat or y a ge ncies if c o nsiste nt wit h 
e x pecte d rates of pr o gressi o n f or t he u n derl yi n g disease. H o we ver, if a n A E/ S A E occ urs i n a 
patie nt a n d it is u nclear if t he e ve nt is d ue t o pr o gressi ve disease, t he A E/ S A E s h o ul d be 
re p orte d.  
 A n y seri o us a d v erse e ve nt, or f oll o w u p t o a seri o us a d verse e v e nt, i ncl u di n g deat h d ue t o 
a n y ca use ot h er t ha n pr o gressi o n of t he ca ncer t hat occ urs t o a n y patie nt fr o m t he ti me t he 
c o nse nt is si g ne d t hr o u g h 9 0 da ys f oll o wi n g cessati o n of treat me nt, or 2 8  da ys f oll o wi n g 
cessati o n of treat me nt if t he patie nt i nitiates  ne w a ntica ncer t hera p y, w hic he ver is earlier, 
w het her or n ot relate d t o t he S p o ns or's pr o d uct, m ust be re p orte d wit hi n 2 4 h o urs t o t he 
S p o ns or.  
After 2 8  da ys  f oll o wi n g t he last d ose of st u d y dr u g a d mi nistrati o n, if a n I n vesti gat or bec o mes 
a ware of an S A E  t h at s/ he s us pects is relate d t o st u d y dr u g, t h e I n vesti gat or s h o ul d re p ort t he 
e ve nt t o t he S p o ns or.  
If a patie nt  re p orts si g ns a n d s y m pt o ms t hat re prese nt a si n gle me dical s y n dr o me, dia g n osis, 
or c o nce pt, t he s y n dr o me/ dia g n osis/c o nce pt s h o ul d be d oc u me n te d (e. g., c o u g h, r u n n y n os e, 
fe ver = U p per Res pirat or y Tract I nfecti o n) i n t he e C R F. 
T he i n vesti gat or m ust f oll o w all S A Es u ntil res ol uti o n a n d rec or d t he date of res ol uti o n. 
Res ol uti o n of a n e ve nt is defi ne d as t he ret ur n t o pre -treat me nt stat us or sta bilizati o n of t he 
c o n diti o n wit h t he e x pectati o n t hat it will re mai n c hr o nic.  
A d verse e ve nts occ urri n g after t he patie nt c o m pletes t he trial or after earl y t er mi nati o n nee d 
n ot be re p orte d u nl ess t he e ve nt is seri o us a n d t h e i n vesti gat or belie ves t hat t he e v e nt ma y 
ha ve bee n ca us e d b y t he st u d y dr u g or a pr ot oc ol pr oce d ure. All pe n di n g pre g na nc y 
o utc o mes will be re p orte d t o t he S p o ns or after c o m pleti o n of t he trial. It is t he res p o nsi bilit y 
of i n vesti gat ors or t heir desi g nees t o re p ort a n y pre g na nc y or lactat i o n i n a patie nt 
(s p o nta ne o usl y re p orte d t o t he m) t hat occ urs d uri n g t he trial or wit hi n 7 m o nt hs  of 
c o m pleti n g t he trial.  
7. 9. 5. 1    
C h a n ges i n Cli nic al L a b or at or y P ar a meters   
Safet y l a b orat or y assess me nts will be carrie d o ut l ocall y a n d e val uate d b y t he i n vesti gat or t o 
e ns ure patie nt safet y. T he i n vesti gat or is res p o nsi ble f or re vi e wi n g t he res ults of all 
la b orat or y tests as t he y b ec o me a v aila ble. La b orat or y tests will be gra ded acc or di n g t o 
C T C A E v 4. 0 3.  
La b orat or y v al ues t hat fall o utsi de of a cli nicall y acce pte d refere nce ra n ge or val ues t hat 
differ si g nifica ntl y fr o m pre vi o us val ues m ust be e val uate d b y t he i n vesti gat or f or cli nical 
si g nifica n ce. T he i n vesti gat or m a y re peat t he la b orat or y test or re q uest a d diti o nal tests t o 
verif y t he res ults of t he ori gi nal la b orat or y tests. A b n or mal la b orat or y fi n di n gs s h o ul d be 
re p orte d as a n A E if it meets a n y of t he f oll o wi n g criteria: 1) ca uses t he patie nt t o disc o nti n ue 
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fr o m st u d y treat me nt, 2) ca uses t he patie nt t o i nterr u pt t he st u d y treat me nt, or 3) re q uires 
i nter ve nti o n. 
Ge nerall y, Gra de 1 la b orat or y fi n di n gs n ee d n ot b e re p orte d as A Es u nless cli nicall y 
si g nifica nt. T he i n vesti gat or will e val uate la b orat or y fi n di n gs of ≥ Gra de 2 or  hi g her 
classificati o n t o deter mi n e t heir cli nical si g nifica nce a n d if a n A E has occ urre d. C o nsiste nt 
wit h t he C T C A E desi g nati o n of Gra de 3 e ve nts as se vere or me dicall y si g nifica nt a n d 
Gra de  4 e ve nts as life -t hreate ni n g, Gra de 3 a n d Gra de 4 la b orat or y fi ndi n gs s h o ul d be 
re p orte d as A Es or S A Es, as a p pr o priat e. Gra de 2 l a b orat or y fi n di n gs ma y be re p orte d as A Es 
if, i n t he o pi ni o n of t he i n vesti gat or, t h e e ve nt e x hi bits cli nical si g nifica nce. If cli nicall y 
rele va nt a b n or mal la b orat or y val u es are ass ociat e d wit h cli nical s y m pt o m(s), or c o nsiste nt 
wit h a dia g n osis, t he dia g n osis s h o ul d be re p orte d as t he A E (e. g., he m o gl o bi n 9 g/ d L i n a n 
a d ult fe male = a ne mia). If t hese cli nicall y rele va nt a b n or mal la b orat or y val ues d o n ot res ult 
i n a dia g n osis, t he test r es ult or fi n di n g s h o ul d be re p orte d as t he A E ass u mi n g t hat it d oes 
n ot re prese nt a la b orat or y err or. Re peat testi n g m a y be i n dicate d. S uc h la b orat or y val ues 
s h o ul d ge n erall y be rec or de d as “i ncreas e d” or “decreas e d ” (e. g., c ha n ge fr o m baseli ne 
he m o gl o bi n of 1 3  g/ d L t o 1 1  g/ d L  =  he m o gl o bi n decrease d). I n vesti gat ors are re q uire d t o 
re p ort a n y a b n or mal li ver e nz y me la b orat or y val u es meeti n g t he criteria f or p ote ntial H y’s 
La w as des cri be d i n  Secti o n  7. 9. 2. 6  f or i m me diatel y re p orta ble e ve nt). 
7. 9. 5. 2    
O ver d ose   
If a n e v e nt of cli nical c o nse q ue nce occ urs d ue t o t he o ver d ose of eit her pe m br oliz uma b or 
mar get u xi ma b, a n A E nee ds t o be re p orte d t o Macr o Ge nics wit hi n 2 4 h o urs of a ware ness. All 
A Es ass ociate d wit h a n o ver d ose s h o ul d be rec or de d i n t he e C R F  
7. 9. 5. 2. 1    
Pe m br oliz u m a b   
 
  
N o s pecific i nf or mati o n is a vaila ble o n t he treat me nt of o ver d ose of pe m br oliz u ma b. I n t h e 
e ve nt of o ver d ose, t he partici pa nt s h o ul d be o bser ve d cl osel y f or s i g ns of t o xicit y. 
A p pr o priate s u p p orti ve treat me nt s h o ul d be pr o vi d e d if cli nicall y i n dicate d.  
7. 9. 5. 2. 2    
M ar get u xi m a b   
 I n 
t he e ve nt of a n o v er d ose, t he patie nt s h o ul d be cl osel y m o nit ore d f or p ote ntial A Es.  
. 
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7. 9. 6    
N otific ati o n t o t he S p o ns or of E ve nts Re q uiri n g I m me di ate 
Re p orti n g   
I R Es, as d efi ne d i n Secti o n  7. 9. 2 , are e ve nts t hat m ust be re p orte d i m me diatel y t o 
Macr o Ge nics Pr o d uct Safet y or desi g nee wit hi n 2 4 h o urs of bei n g i de ntifie d via t he I R E 
re p orti n g f or m. 
T hr o u g h o ut t he st u d y, t he i n vesti gat or m ust i m me diatel y c o m plete a n d fa x/e mail t he 
I m me di ately Re p ort a ble Eve nt (I R E) Re p ort F or m wit hi n 2 4 h o urs of i de ntif yi n g t he e ve nt t o 
Macr o Ge nics Pr o d uct Safet y or desi g nee. T he  I R E Re p ort F or m a n d I R E Re p ort F or m 
C o m pleti o n G ui deli nes are f o u n d i n t he St u d y Pr oce d ures M a n ual. A d diti o nall y, t h e 
i nf or mati o n re gar di n g I R Es nee ds t o be e ntere d i nt o t he e C R Fs as s o o n as p ossi ble, as 
o utli ne d i n y o ur site c o ntract.  
I n case of patie nt or patie nt part ner pre g na nc y, t he Macr o Ge nics Pre g na nc y E x p os ure F or m 
m ust als o be c o m plete d per St u d y Pr oce d ures. T he i n vesti gat or m ust atte m pt t o f oll o w t he 
pre g na nc y t o ter m or ter mi nati o n i n or der t o re p ort o n o utc o me a n d healt h stat us of m ot her 
a n d c hil d. T he Pre g n a nc y E x p os ure F or m is f o u n d i n t he St u d y Pr oce d ures Ma n ual. 
7. 9. 7    
E mer ge nc y U n bli n di n g   
N ot a p plica ble. T his is a n o pe n -la bel st u d y. 
7. 1 0    
Effic ac y, I m m u n o ge nicit y, P h ar m ac o ki ne tic, a n d 
P h ar m ac o d y n a mic Assess me nts   
7. 1 0. 1    
Effic ac y Assess me nts   
7. 1 0. 1. 1    
R a di ol o gic E v al u ati o n: Tre at me nt of P atie nts Acc or di n g t o 
Pri nci ples of I m m u ne -Rel ate d Res p o nse Criteri a   
T u m or assess me nts will be o btai ne d at scree ni n g usi n g C T a n d/ or M RI sca ns at ti me i nter vals 
as s pecifie d i n t he A p pe n di x  1  a n d A p pe n di x  2  ( Ti me a n d E ve nts Ta bles). Ra di o gra p hic 
disease assess me nts will occ ur e v er y 6 wee ks (i.e., f oll o wi n g 2 c ycl es of treat me nt 
[s pecificall y pri or t o C ycles 3 , 5 , 7 , etc.]) f or t he first 2 4 wee ks a n d t h e n e ver y 1 2 wee ks 
t hereafter u ntil d oc u me nt e d pr o gressi o n, i nitiatio n of alter nati ve a nti -ca ncer t hera p y, l ost t o 
f oll o w u p, wit h dra wal of i nf or me d c o nse nt, deat h, or e n d of st u d y. Treat me nt will c o nti n ue 
u ntil patie nts ha ve c o m plete d st u d y t hera p y a n d re q uire d f oll o w -u p, e x perie nce d diseas e 
pr o gressi o n acc or di n g t o ir R C, or ha ve bee n wit h dra w n fr o m t he st u d y (see Secti o n  4. 4  a n d 
Secti o n  5. 3 ). At eac h o n-treat me nt t u m or assess m e nt ti me p oi nt, t he o bjecti ve res p o nse stat us 
will be deter mi ne d.  I n t h e c o nte xt of t he statistical a nal ysis f or t his trial, o bjecti ve res p o ns e 
deter mi nati o n a n d t he ass ess me nt of best o verall res p o nse ( B O R) will be defi ne d usi n g b ot h 
c o n ve nti o nal R E CI S T 1. 1 criteria ( A p pe n di x  7 ) as well as a n a da ptati o n of t hese criteria, 
desi g nat e d as i m m u ne -relate d res p o nse criteria (ir R C) (A p pe n di x  8 ). Patie nt ma na ge me nt 
decisi o ns, h o we ver, will be ma de s olel y bas e d o n t he i m m u ne -relate d res p o nse criteria. 
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F or patie nts w h o d e m o nstrate acce pta ble t olera bilit y of treat me nt wit h pe m br oliz u ma b a n d 
mar get u xi ma b a n d ac hie ve a n o bjecti ve res p o nse assess me nt of ir C R, ir P R or ir S D, or 
u nc o nfir me d cli nicall y  st a ble ir P D, t hera p y m a y be c o nti n ue d (see Secti o n  4. 4  a n d 
Secti o n  5. 3 ). 
F or patie nts w h o are ot her wise cli nicall y sta ble, b ut ha ve met c o n ve nti o nal criteria f or P D, 
t hera p y ma y be c o nti n ue d at t he discreti o n of t he i n vesti gat or pe n di n g c o nfir mati o n of 
pr o gressi o n at t he ne xt sc he d ule d t u m or assess me nt. T his a p pr oac h all o ws f or li mite d 
treat me nt of patie nts be y o n d t he i nitial ra di o gra p hic d oc u me ntati o n of disease pr o gressi o n, 
ass u mi n g t hat patie nts are t olerati n g t hera p y a de q uatel y, t hat patie nts re mai n ot her wise 
cli nicall y sta ble d es pite t his i nitial ra di o gra p hic e vi de nce of disease pr o gressi o n, a n d t hat t he 
i n vesti gat or feels t he p atie nt ma y still deri ve be nefit fr o m c o nti n uati o n of t hera py. Treat me nt 
of patie nts acc or di n g t o ir R C pri nci ples is s u p p orte d b y well -d oc u me nte d e vi de nce t hat i n 
s o me patie nts treate d wit h T cell directe d, i m m u ne-m o d ulat or y a ge nts, t heir t u m ors ca n 
e v ol ve t o a n o bjecti ve res p o nse after a n i nitial peri o d c haracteri ze d b y eit her a p pare nt 
ra di o gra p hic gr o wt h of tar get lesi o ns or t he de vel o p me nt of ne w tar get lesi o ns t hat w o ul d 
ot her wise meet t he criteria f or diseas e pr o gressi o n usi n g c o n ve nti o nal res p o nse criteria 
(A p pe n di x  7 ). 
F or patie nts i n w h o m pr o gressi o n is c o nfir me d at t he ne xt sc he d ule d t u m or assess me nt, t he 
criteria f or i m m u ne -rel ate d P D (ir P D) will ha ve bee n met, a n d treat me nt wit h mar get u xi ma b 
a n d pe m br oliz u ma b s h o ul d be disc o nti n ue d. T he patie nt s h o ul d be re m o ve d fr o m  st u d y 
partici pati o n after c o m pl eti o n of pr ot oc ol s pecifi e d f oll o w -u p (see Secti o n  8. 3  a n d A p pe n di x 
1  a n d A p pe n di x 2 ). F or patie nts w h o e x perie nce a n o bjecti ve res p o nse of i m m u ne-relate d 
c o m plete res p o nse (ir C R) or i m m u ne -rel ate d parti al res p o nse (ir P R), res p o nses will be 
c o nsi dere d u n c o nfir me d u ntil t he res p o nse has bee n d oc u me nte d b y a s u bse q ue nt 
c o nfir mat or y sca n o btai n e d n o less t ha n 4 wee ks after t he i nitial sca n de m o n strati n g a n 
o bjecti ve res p o ns e.  
7. 1 0. 1. 2    
O bjecti ve Res p o nse a n d Res p o nse D ur ati o n   
Tar get a n d n o n -tar get lesi o ns will be desi g nat e d a n d e val uate d usi n g b ot h c o n ve nti o nal 
R E CI S T  1. 1 criteria ( A p pe n di x  7 ) a n d ir R C (A p pe n di x  8 ) as n ote d a b o ve f or t he p ur p oses 
of statistical a nal ysis. O bjecti ve res p o nses will be cate g orize d as C R, P R, S D, or P D f or 
c o n ve nti o nal R E CI S T 1. 1 criteria a n d ir C R, ir P R, ir S D, a n d ir P D f or t he i m m u ne-relate d 
res p o nse criteria. Deter mi nati o n of t he o bjecti ve res p o nse rate will be calc ulate d base d o n t he 
pr o p orti o n of res p o nse e val ua ble patie nts ac hie vi n g C R or P R usi n g t he res pecti ve criteria, 
w he n s uc h res p o nses are c o nfir me d b y a s u bs e q ue nt  sca n o btai ne d at least 2 8 da ys after t he 
i nitial d oc u me ntati o n of o bjecti ve res p o nse. R es p o nse-e val u a ble patie nts will i ncl u de t h ose 
patie nts w h o ha ve meas ura ble  diseas e a n d ha ve ha d a baseli ne t u m or ass ess me nt a n d at 
least 1 o n -treat me nt t u m or assess me nt (see A p pe n di x  1  a n d A p pe n di x  2 ). O bjecti ve 
res p o nses t hat are n ot s u bse q ue ntl y d oc u me nte d wit h a c o nfir mat or y C T or M RI s ca n (e. g., 
u nc o nfir me d res p o nses) will n ot be i ncl u de d as a n o bjecti ve res p o nse f or t he p ur p ose of 
calc ulati n g o verall o bjecti ve res p o nse rates. Res p o nse d urati o n will be ca l c ulate d fr o m t he 
ti me of i nitial res p o nse ( C R or P R) d oc u me ntati o n (i n patie nts w h o ha ve a s u bse q ue nt 
c o nfir mati o n of o bjecti ve res p o nse) t o t he ti me of pr o gressi ve disease or deat h, w hic he ver 
occ urs first.  
C o nfi d e nti al
P a g e   
9 7   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
7. 1 0. 1. 3    
Pr o gressi o n -F ree S ur vi v al ( P F S)   
P F S will be calc ulate d as t he ti me fr o m t he date of t he first d ose of st u d y dr u g u ntil t he date 
of a n y d oc u me nte d P D or t he date of deat h fr o m a n y ca use, w hic he ver occ urs first 
(A p pe n di x  5 ). A patie nt’s P F S will be ce ns ore d if at t he ti me of last assess me nt f or 
pr o gressi o n, t he patie nt re mai ns pr o gressi o n free. P F S will be  deter mi ne d usi n g c o n ve nti o nal 
R E CI S T 1. 1 criteria. I n a d diti o n, P F S rate at 3 a n d 6 m o nt hs will be e val uate d . 
7. 1 0. 1. 4    
O ver all S ur vi v al   
O verall s ur vi val ( O S) will be calc ulate d as t he ti me fr o m t he first d ose of st u d y dr u g u ntil 
deat h d ue t o a n y ca use. A patie nt ’s O S will be ce ns ore d if at t he ti me of last c o ntact, t he 
patie nt was ali ve. I n a d diti o n, O S rate at 1  a n d 2 years will be e val uate d.  
7. 1 0. 2    
I m m u n o ge nicit y  
Bl o o d sa m ples f or t he i m m u n o ge nicit y ass ess me nts (i.e., a nti -dr u g a nti b o d y [ A D A]) of 
mar get u xi ma b will be c ollecte d at t he f oll o wi n g ti me p oi nts gi ve n i n t he ta ble bel o w.  
Ta ble  5  
I m m u no ge nicit y Bl o o d S a m pli n g Sc he d ule  (P arts A, B, a n d C )  
Ti me P oi nt    
St u d y 
D a y  
Tre at me nt 
D a y of 
C ycle  
A D A S a m pli n g Ti me    
A D A S a m ple C ollecti o n 
f or M ar get u xi m a b 
C ycle 1  
1    
1  
0 ( Pre d ose) a  
X  
C ycle 2  
2 2    
1  
0 ( Pre d ose)  b  
X  
O d d C ycles  
( 3, 5, 7, 9, 1 1 , etc.) 
4 3, 8 5, 
1 2 7, 
etc. 
1  
0 ( Pre d ose)  b  
X  
E n d of Treat me nt Visit or 
2 8 da ys after last d ose of 
st u d y dr u g c  
N A    
N A  
N A  d  
X  
a  
Pre d ose A D A sa m ple will be c ollecte d pri or t o mar get u xi ma b i nf usi o n.  
b   Pre d ose sa m ple c ollecte d pri or t o mar get u xi ma b i nf usi o n; t he start of i nf usi o n is desi g nate d as ti me = 0.  
c  
W hic he ver ti me p oi nt occ urs l ater.  
d   N ot a p plica ble; h o we ver, A D A sa m ple will be c ollecte d si m ulta ne o usl y wit h P K sa m ple.  
N O T E: Act ual start a n d e n d of  i nf usi o n ti mes a n d A D A sa m ple c ollecti o n ti mes will be rec or de d o n t he e C R Fs. 
T he a b o ve A D A sa m ple c ollecti o n s h o ul d be f oll o we d f or all patie nts e nr olle d i n D ose Esc alati o n a n d C o h ort  
E x pa nsi o n.  
 
7. 1 0. 3    
P h ar m ac o ki netics   
Ser u m c o nce ntrati o ns of mar get u xi ma b will be m o nit ore d usi n g a q ua ntitati ve sa n d wic h 
E LI S A. Si n gle a n d m ulti ple d ose P K para m eters f or mar get u xi ma b (e. g., C ma x , Tma x , A U Cta u, 
A U C i nf, Ctr o u g h, C L, Vss, a n d Thalf) will be deri ve d fr o m mar get u xi ma b ser u m c o nce ntrati o n 
vers us ti me data.  P o p ulati o n P K a nal ys es ma y be c o n d ucte d usi n g data fr o m t his st u d y al o n e 
or c o m bi ne d wit h data fr o m ot her st u dies.  
C o nfi d e nti al
P a g e   
9 8   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
Bl o o d sa m ples f or mar get u xi ma b P K will be c ollecte d at t he f oll o wi n g ti me p oi nts gi ve n i n 
t he ta ble bel o w. Bl o o d sa m ples will be c ollecte d fr o m t he ar m c o ntral ateral t o t he site of I V 
i nf usi o n. If a n i n d welli n g cat heter is use d, t h e fl ui d i n t he cat heter will be re m o ve d a n d 
discar de d pri or  t o t he c ollecti o n of bl o o d sa m ple f or A D A or P K ass ess me nt. 
Ta ble  6  
P h ar m a c o ki netics Bl o o d S a m pli n g Sc he d ule f or M ar get u xi m a b   
T u m or 
Assess me nt 
C ycle  
Tre at me nt 
D a y of 
C ycle  
Pe m br oliz u m a b 
/ M ar get u xi m a b 
D ose N u m ber  a , b  
P K S a m pli n g 
Ti me After t he e n d 
of I nf usi o n ( hr)  
P K S a m ple C ollecti o n f or 
M ar get u xi m a b  
D ose 
Esc al ati o n  
C o h ort  
E x p a nsi o n  
I nitial ( 1st)   
1  
1  
0 ( Pre d ose)  c   
X  
X  
 
 
E OI  d  
X  
X  
 
 
5  g    
X  
X  
2  
 
2 4  g  
X  
N A  
8  
 
N A  h  
X  
N A  
2 n d 
1  
2  
0 ( Pre d ose)  e   
X  
X  
 
 
E OI  d  
X  
X  
3 r d 
1  
3  
0 ( Pre d ose)  e   
X  
X  
 
 
E OI  d  
X  
X  
2  
 
2 4  g  
X  
N A  
5 t h & 7 t h 
C ycle  
1  
 
0 ( Pre d ose)  e   
X  
X  
 
 
E OI  d  
X  
X  
E O T V    
N A  f 
E O T V ( 2 8 da ys 
after t he last d ose 
of st u d y dr u g)  
N A  f 
X  
X  
a 
P e m br oliz u ma b d ose a n d mar get u xi ma b d ose a d mi nistere d as 0. 5 h o ur ( 3 0 mi n) a n d 2 -h o ur ( 1 2 0 mi n) i nf usi o ns, 
res pecti vel y. 
b  
Mar get u xi ma b ma y be a d mi nistere d t he da y f oll o wi n g pe m br oliz u ma b a d mi nistrati o n f or safet y re as o ns or sc he d uli n g 
p ur p oses.  
c 
Pre d ose P K sa m ple o n St u d y Da y 1 ( T reat me nt Da y 1 of I nitial [ 1 st] C ycle) will be c ollecte d pri or t o mar get u xi ma b 
i nf usi o n; A D A sa m ple f or t his ti me p oi nt will be c ollecte d pri or t o mar get u xi ma b i nf usi o n. 
d  
E OI = e n d of mar get u xi ma b i nf usi o n; sa m ple will be c ollecte d wit hi n 5 mi n t o t he e n d of  i nf usi o n. 
e 
All ot her pre d ose P K sa m ples will be c ollecte d pri or t o mar get u xi ma b i nf usi o n si m ulta ne o usl y wit h A D A s a m ple.  
f 
N ot a p plica ble as t his is f or t he e n d of treat me nt visit ( E O T V); h o we ver, P K sa m ple will be c ollecte d si m ulta ne o usl y 
wit h A D A sa m ple.  
g  
T hese ti mes ar e n ote d fr o m mar get u xi ma b e n d of i nf usi o n. If t here are dela ys i n mar get u xi ma b i nf usi o n, t hese ti me 
p oi nts will be at 5, a n d 2 4 h o urs p ost e n d of mar get u xi ma b i nf usi o n, res pecti vel y.  
h  
N o s pecific ti me p oi nt is ma n date d f or e x pa nsi o n C ycle 1 Da y  8 P K bl o o d dra w. B ut ti me of dra w s h o ul d be n ote d o n 
t he C R F. 
N O T E: Act ual start a n d e n d of i nf usi o n ti mes a n d P K sa m ple c ollecti o n ti mes will be rec or de d o n t he C R Fs.  
 
7. 1 0. 4    
P h ar m ac o d y n a mics/ Bi o m ar kers   
Pr oce d ures f or t he ac q uisiti o n, ha n dli n g a n d pr ocessi n g of p har mac o d y na mic bi o mar ker 
s peci me ns will be pr o vi d e d i n t he La b orat or y Ma n ual. 
Tests t o be perf or me d ma y i ncl u de t h e f oll o wi n g:  
 Deter mi nati o n of Fc rece pt or ge n ot y pes f or C D 1 6 A,  C D 3 2 A  a n d C D 3 2 B  
C o nfi d e nti al
P a g e   
9 9   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
 C haracterizati o n of alterati o ns i n ser u m c yt o ki ne l e vels t o i ncl u de, b ut n ot li mite d 
t o, I L-2, I L -6, I L -1 0, I F N -γ, a n d T N F-α   
 E n u merati o n of l y m p h o c yt e s u bsets, N K cells a n d ot her acti vati o n mar kers a n d 
acti vati o n stat us o ver ti me via m ult i-para meter fl o w c yt o m etr y; e val uati o n of t he 
T -re g p o p ulati o n o ver ti me 
 Deter mi nati o n of t he p ote ntiati o n of H E R 2 s pecific a da pti ve h u m oral a n d cell ular 
i m m u ne res p o nses: Plas ma sa m ples a nal yz e d b y E LI S A t o meas ure e n d o ge n o us 
a nti-H E R 2 I g G le vels; P B M C sa m ples a nal yz e d b y E LI S p ot t o meas ure H E R 2 -
s pecific T-cell acti vit y 
 Deter mi nati o n of P D -L 1 e x pressi o n will be e x pl ore d via I H C stai ni n g of arc hi val 
t u m or bi o ps y s peci me ns ( u nless fres h t u m or sa m ple s u b mitte d a n d use d t o 
deter mi ne P D -L 1 e x pressi o n a n d n o arc hi ve d sa m ple o btai ne d)  
Li mite d t o C o h ort Ex p a nsi o n P h ase  ( P arts B-C ) o nly  ( u nl ess ot her wise n ote d):  
 Deter mi nati o n of m utati o nal b ur de n  ( G ura da nt 3 6 0 assa y), as well as mis matc h 
re pair stat us b y micr osatellite i nsta bilit y (fr o m pat h ol o g y re p orts, w he n a vaila ble). 
 Deter mi nati o n of P D -L 1 t u m or cell me m bra n o us e x pressi o n a n d T cell i nfiltrati o n 
(i ncl u di n g b ut n ot li mite d t o C D 4 + a n d C D 8 + T cells) i nt o t he t u m or be d via I H C 
stai ni n g of paire d pre- a n d o n-treat me nt t u m or bi o ps y s peci me ns.  
 Part B  o nl y: Deter mi nati o n of H E R 2 t u m or cell me m bra n o us e x pressi o n via I H C 
stai ni n g of pre-treat me nt a n d o n-treat me nt t u m or bi o ps y s peci me ns. 
 Deter mi nati o n of ge n e e x pressi o n si g nat ures i n tiss ues  (i.e., b y na n ostri n g 
tec h n ol o g y), w hic h ma y b e i n dicati ve of i m m u n ot hera p y res p o nses ass o ciate d 
wit h t he a ge nts o n trial.  
 
7. 1 1    
Ot her St u d y Pr oce d ures   
7. 1 1. 1    
Ce ntr al L a b or at or y E v al u ati o ns   
Macr o Ge nics or its desi g nee will pr o vi de bl o o d sa m pli n g s u p plies s uc h as p ol y pr o p yle ne 
tra ns p ort t u bes, la bels, a n d l o g s heets. Ser u m t u bes s h o ul d be la bele d wit h t he patie nt’s 
n u m ber, date, a n d ti me of sa m pli n g. T he i n vesti gat or will mai ntai n a l o g wit h t he sa me data.  
S peci me ns m ust be a p pr o priatel y pre pare d, di vi de d if a p pr o priate, fr oze n, a n d s hi p pe d ( w hile 
ofte n retai ni n g certai n re plicate sa m ples at t he site) acc or di n g t o t he i nstr ucti o ns i n t he 
La b orat or y M a n ual.  
7. 1 1. 2    
S a m ple  Rete nti o n a n d F urt her Testi n g   
Sa m ples ac q uire d f or pr ot oc ol s pecifie d ass a ys will be retai ne d f or st u d y p ur p oses 
(a nal ysis/re-a nal ysis) u p t o 2 years after last a p pr o val of a ma r keti n g a p plicati o n i n a n I C H 
re gi o n a n d u ntil t here are n o pe n di n g or c o nte m plate d mar keti n g a p plicati o ns i n a n I C H 
re gi o n or u ntil at least 2 years ha v e ela pse d si nce f or mal disc o nti n uati o n of cli nical 
C o nfi d e nti al
P a g e   
1 0 0   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
de vel o p me nt of t he i n vesti gati o nal pr o d uct. If pati e nts c o nse nt t o t he use of t heir st u d y 
sa m ples f or n o n-st u d y researc h p ur p oses, t hese s a m ples ma y als o b e use d f or e x pl orat or y 
testi n g (i ncl u di n g assa y d e vel o p me nt/ o pti mizati o n) a n d ma y be retai ne d u p t o 1 5 years fr o m 
t he e n d of st u d y. 
7. 1 2    
A p pr o pri ate ness of M e as ure me nts   
R o uti ne la b orat or y e val u ati o ns i ncl u di n g he mat ol o g y, c he mistr y, c oa g ulati o n, a n d uri nal ysis 
will be carri e d o ut i n l ocal i nstit uti o nal la b orat ories. A d diti o nal l ocal safet y la b orat or y 
assess me nts ma y be use d t o s u p ple me nt t he pr ot oc ol -prescri be d assess me nts a n d ma y be 
use d t o el uci date certai n A Es.  
Ser u m c o nce ntrati o ns of mar get u xi ma b will be m o nit ore d usi n g a n E LI S A base d assa y. 
Sta n dar d bri d gi n g E LI S As will be carrie d o ut i n t he S p o ns or ’s desi g nate d ce ntral la b orat or y 
t o c haracterize t he i m m u n o ge ni cit y of mar get u xi ma b. A nal ysis of P K data will be carri e d o ut 
usi n g i n d ustr y sta n dar d s oft ware.  P o p ulati o n P K m o deli n g ma y be perf or me d a n d a n 
a p pr o priate m o d el a n d m o d el para meters ma y be descri be d. 
7. 1 2. 1    
R ati o n ale f or Use of I m m u ne Res p o nse Criteri a   
Patie nts will be ma na ge d acc or di n g t o ir R C pri nci ples. T his a p pr oac h all o ws f or li mite d 
treat me nt of patie nts be y o n d t he i nitial ra di o gra p hic d oc u me ntati o n of disease pr o gressi o n, 
ass u mi n g t hat patie nts are t olerati n g t hera p y a de q uatel y, t hat patie nts re mai n ot her wise 
cli nicall y sta ble d es pite t his i nitial ra di o gra p hic e vi de nce of disease pr o gressi o n a n d t hat  t he 
i n vesti gat or c o nsi ders t hat t he patie nt ma y still deri ve be nefit fr o m c o nti n uati o n of t hera p y. 
Treat me nt of patie nts acc or di n g t o ir R C pri nci ples is s u p p orte d b y well -d oc u me nte d e vi de nce 
t hat i n s o me patie nts treate d wit h T cell directe d, i m m u ne-m o d ul at or y a ge nts, t heir t u m ors 
ca n e v ol ve t o a n o bjecti v e res p o nse after a n i nitial peri o d c haract erize d b y eit her gr o wt h of 
tar get lesi o ns or t he d e vel o p me nt of ne w tar get lesi o ns t hat w o ul d ot her wise meet t he criteria 
f or disease pr o gressi o n usi n g c o n v e nti o n al res p o nse criteria  (A p pe n di x  8 ). F urt her details 
re gar di n g t he a p plicati o n of t his a p pr oac h are descri be d i n Secti o n  7. 1 0. 1 . 
C o nfi d e nti al
P a g e   
1 0 1   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
8    
S T U D Y A C TI VI TI E S   
A ta ble of st u d y acti vities i ncl u di n g scree ni n g, o n -st u d y a n d e n d-of st u d y visits is prese nte d 
i n A p pe n di x  1  a n d A p pe n di x 2 , Ti me a n d E ve nts Ta bles. 
Bl o o d v ol u mes re q uire d f or vari o us la b orat or y tests are s h o w n i n  A p pe n di x 3  (D ose 
Escalati o n P has e [ Part A]) a n d A p pe n di x 4  (C o h ort  E x pa nsi o n P hase  [ Parts B– C ]). 
8. 1    
Scree ni n g Peri o d   
At t he scree ni n g visit, patie nts will e nter t he st u d y u p o n si g ni n g t he i nf or me d c o nse nt 
d oc u me nt.  N o scree ni n g acti vities o utsi de of us ual sta n dar d of care s h o ul d be perf or me d 
p ri or t o o btai ni n g i nf or m e d c o nse nt fr o m t he patie nt. O nl y t h ose patie nts w h o meet all 
i ncl usi o n/e x cl usi o n criteria s pecifie d i n Secti o n  5  w ill be e ntere d i nt o t his st u d y. 
8. 2    
Re gistr ati o n   
Eac h patie nt m ust be re gistere d wit h Macr o Ge nics pri or t o e nr oll me nt. T he f oll o wi n g 
i nf or mati o n s h o ul d be pr o vi de d d uri n g re gistrati o n: 
 Date of birt h  
 Date of  si g ne d i nf or me d c o nse nt 
 Pla n ne d date of first p e m br oliz u ma b a n d mar get u xi ma b a d mi nistrati o n  
 Eli gi bilit y  c o nfir m ati o n d oc u me nts  
 
T he i nstr ucti o ns f or t he re gistrati o n pr ocess are pr o vi de d i n t he St u d y Ma n ual.  
8. 3    
E n d of Tre at me nt Visit   
A list of e val uati o ns t o b e perf or me d f or t h e E n d of Treat me nt visit is pr o vi de d i n  A p pe n di x 
1  a n d A p pe n di x 2 . Criteria f or tri g geri n g t he E n d of Treat me nt visit are s p ecifie d i n 
Secti o n  5. 3 . T he E n d of Treat me nt Visit s h o ul d be perf or me d after t he patie nt has met 
off -treat me nt criteria a n d E n d of St u d y s h o ul d be n ote d after patie nt has bee n f oll o we d f or at 
least 2 8 da ys after t he last d ose of st u d y dr u g de pe n di n g o n a bilit y t o f oll o w t he patie nt a n d 
d urati o n a n d se verit y of o n g oi n g A Es.  It is rec o g nize d t hat certai n patie nts (s uc h as t h ose 
e x perie nci n g pr o gressi o n of disease) ma y be  care d f or i n facilities ot her t ha n t he partici pati n g 
i n vesti gati o nal site, ma y pr ocee d t o recei ve ot her ca ncer t hera p y, a n d/ or m a y elect n ot t o 
ret ur n t o t he i n vesti gati o nal site. T heref ore, t his visit is c o nsi dere d o pti o nal, b ut s h o ul d be 
carri e d o ut w hene v er p ossi ble.  
C o nfi d e nti al
P a g e   
1 0 2   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
9    
P L A N N E D S T A TI S TI C A L M E T H O D S   
9. 1    
Ge ner al C o nsi der ati o ns   
T his P hase 1 b/ 2a st u d y is pri maril y o bser vati o nal a n d, t h us, t he maj orit y of t he statistical 
s u m maries will be descri pti ve. S u m mar y statistics will c o nsist of a bs ol ute a n d relati ve 
fre q ue n cies of eac h cate g or y of discret e varia bl es a n d of mea ns, sta n dar d de viati o ns, 
me dia n s, mi ni m u ms a n d ma xi m u ms f or c o nti n u o us varia bles. 
Safet y a n d efficac y s u m maries will be pr o vi de d f or eac h d os e le vel c o h ort d uri n g d ose 
escalati o n a n d f or all d os e le vel c o h orts c o m bi ne d, as well as f or e x pa nsi o n part . Res p o nse 
rates ma y be calc ulat e d f or s pecific disease s u b-gr o u ps, if a p pr o priate.  
Baseli ne will be c o nsi dere d t he cl osest val ue o bt ai ne d pri or t o first d ose. Data t hat are 
re p orte d as missi n g will be treate d as missi n g i n all data s u m maries. I nc o m plete dates will be 
i m p ute d a n d defi ne d i n t he Statistical A nal ysis Pla n. I n descri pti ve s u m maries f or safet y, 
o bser vati o ns t hat are s p uri o us (e xtre me relati ve t o t he maj orit y of t he data) will n ot be altere d 
or re m o ve d fr o m t he s u m mar y.  
9. 2    
Deter mi n ati o n of S a m ple Size   
T he n u m ber of patie nts e nr olle d i n t he D ose Escalati o n P hase  ( Part A) ca n n ot be precisel y 
deter mi ne d i n a d va n ce a n d c o ul d ra n ge u p t o 1 2 p atie nts base d o n 3 + 3 desi g n a p plie d t o 
2  d ose le vels. T his patie nt n u m ber d oes n ot ta ke i nt o acc o u nt patie nt re place me nt f or n o n -
e val ua ble p atie nts.  
T he  C o h ort E x pa nsi o n P hase s of t he trial will e nr oll u p t o 8 5  patie nts .  
T he first e x pa nsi o n c o h ort ( Part B) i ncl u des 3 0 patie nts i n N ort h A merica a n d 3 0 patie nts i n 
Asia wit h rela p se d/refract or y u nresect a ble l ocall y a d va nce d or metastatic H E R 2 + G EJ or 
G C .  
Part C will e nr oll u p t o 2 5 patie nts i n N ort h A merica n a n d/ or Asia wit h rela pse d/refract or y 
u nresect a ble l ocall y a d v a nce d or metast atic H E R 2 + (I H C 3 +) ge ne a m plificati o n G C .  
T he sa m ple size f or eac h part i n t he C o h o rt E x pa nsi o n P hase is pri maril y base d o n pr o vi di n g 
preli mi nar y esti mati o n of res p o nses. T he f oll o wi n g ta ble pr o vi des t he 2 -si d e d 
9 5 %  c o nfi de n ce i nter val ( CI) f or a n u m ber of p ot e ntial res p o nse rat es  u n der vari o us sa m ple 
sizes. 
C o nfi d e nti al
P a g e   
1 0 3   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
Ta ble  7  
Res p o nse R ates a n d 9 5 % C o nfi de nce I nter v als   
S a m ple Size    
N u m ber of Res p o nses    
Res p o nse R ate ( %)  
9 5 % C o nfi de nce 
I nter v al ( %) 
3 0  
1  
3. 3  
0 –  1 7  
3 0  
5  
1 6. 7  
5. 6 –  3 4. 7  
3 0  
1 0  
3 3. 3  
1 7. 3 –  5 2. 8  
3 0  
1 5  
5 0. 0  
3 1. 3 - 6 8. 7  
3 0  
2 0  
6 6. 7  
4 7. 2 –  8 2. 7  
2 5  
1  
4  
0 –  2 0. 4  
2 5  
3  
1 2  
2. 5 –  3 1. 2  
2 5  
6  
2 4  
9. 4 –  4 5. 1  
2 5  
9  
3 6  
1 8. 0 –  5 7. 5  
 
After 1 5 patie nts we re e nr olle d i n eac h re gi o n i n Part B a n d after eac h patie nt ha d  at least o ne 
p ost -baseli ne t u m or assess me nt,  a f utilit y r ule was  a p plie d a n d e nr oll me nt i n t hat re gi o n w as 
c o nti n ue d. T he e nr oll me nt c o ul d ha ve be e n st o p pe d if t here was  n o m ore t ha n o ne res p o ns e. 
O ne res p o ns e o ut of 1 5 patie nts will ha ve greater t ha n 8 0 % c o nfi de nce t o r ule o ut t he 
res p o nse rate of 2 0 % or hi g her (t he u p per li mit of o ne-si de d 8 0 % CI f or res p o nse rate 
<  2 0 %).  
9. 2. 1    
A n al ysis P o p ul ati o ns   
T w o p o p ulati o ns wil l be use d f or data a nal ysis, t he S afet y P o p ul ati o n  a n d t he Res p o nse 
E v al u a ble P o p ul ati o n , as defi ne d bel o w: 
 S afet y P o p ul ati o n : All patie nts w h o recei ve d at least o ne d ose of eit her 
mar get u xi ma b or pe m br oliz u ma b. T his p o p ulati o n will be use d f or safet y a nal ysis 
a n d f or a n al ysis of P F S a n d O S.  Patie nts w h o recei ve at least o ne d ose of 
mar get u xi ma b will be i ncl u de d i n P K, P D, a n d i m m u n o ge nicit y a nal ys es . 
 Res p o nse E v al u a ble P o p ul ati o n:  All patie nts w h o ha ve baseli ne m eas ura ble 
disease a n d recei ve d o ne d ose of eit her mar get u xi ma b or pe m br oliz u ma b.  T his 
p o p ulati o n will be use d f or a nal ysis of O R R.  
 
Patie nts w h o wit h dra w bef ore recei vi n g all pr ot oc ol -s pecifie d treat me nt bef ore c o m pleti o n of 
t he D L T e val u ati o n peri o d f or a reas o n u nrelate d t o dr u g t o xicit y will be c o nsi dere d t o ha ve 
i na de q uate data t o s u p p ort d ose escal ati o n. I n t his case, re place me nt patie nts ma y be e nr olle d 
at t he sa me d ose le vel a n d sc he d ule as n ecess ar y t o c o m plete t he c o h ort.  
C o nfi d e nti al
P a g e   
1 0 4   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
9. 3    
De m o gr a p hics a n d B aseli ne C h ar acteristics   
Patie nt dis p ositi o n, de m o gra p hics, baseli ne c haracteristics, disease hist or y, me dical hist or y, 
c o nc o mita nt me dicati o ns, a n d st u d y  dr u g e x p os ure data will be s u m marize d usi n g descri pti ve 
statistics. 
9. 4    
S afet y E n d p oi nt(s)   
9. 4. 1    
A d verse E ve nts   
A d verse e ve nts will be c o de d t o t he Me dical Dicti o nar y f or Re g ul at or y Acti vities ( Me d D R A) 
dicti o nar y.  O nl y treat me nt -e mer ge nt A Es, as d efi ne d i n  Secti o n  7. 9. 2 , will be s u m marize d i n 
ta bles. E ve nts pri or t o treat me nt (e. g., d ue t o st u d y -relate d pr oce d ure) will be liste d i n a n 
a p pe n di x t o t he fi nal st u d y re p ort.  
T he f oll o wi n g t a bles of a d verse e v e nt data will be creat e d t o s u m marize t he n u m ber a n d 
perce nt of patie nts w h o e x perie nce at least o ne e ve nt of eac h of t he f oll o wi n g t y pes:  
 A n y T E A Es  
 Treat me nt relate d T E A Es  
 T E A Es wit h C T C A E Gra de se verit y Gra de  3  
 Treat me nt  relate d T E A Es b y C T C A E Gra de se verit y Gra de  3  
 T E A Es relate d t o eac h i n di vi d ual st u d y dr u g  
 A n y  S A E s (t his ma y be a listi n g if t here are fe w e ve nts) 
 Treat me nt  relate d S A Es 
 S A Es relate d t o eac h i n di vi d ual st u d y dr u g 
 Fatal A Es (t his ma y be a listi n g if t here are fe w e ve nts)  
 A E SIs  
 I R Es 
 T E A Es t hat res ult i n st u d y disc o nti n uati o n 
 T E A Es w hic h lea d t o i nt err u pti o n  of eac h i n di vi d ual st u d y dr u g  
 T E A Es t hat lea d t o wit h dra wal of eac h i n di vi d ual st u d y dr u g 
 
A ll of t hese ta bles will dis pla y t he n u m ber a n d perce nt of patie nts t hat e x perie nce t he gi v e n 
eve nt a n d will dis pla y e v e nts b y Me d D R A S yste m Or ga n Class ( S O C) a n d Preferre d Ter m. 
E ve nts will be dis pla ye d al p ha beticall y f or S O C a n d Preferre d Ter m. A n o verall s u m mar y of 
A Es will dis pla y t he n u m ber a n d perce nt of patie nt/ patie nts w h o e x perie nce at leas t o ne e ve nt 
of eac h of t he a b o v e A E t y p es.  
C o nfi d e nti al
P a g e   
1 0 5   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
9. 4. 2    
L a b or at or y Val ues   
S u m maries of la b orat or y val ues will dis pla y des cri pti ve statistics f or n u mericall y q ua ntifie d 
la bs. S u m maries will be  gr o u pe d b y la b pa nel (e. g., he mat ol o g y, bl o o d c he mistr y, a n d 
uri nal ysis) a n d will be dis pla ye d b y visit f or eac h la b para meter.  
A list of re peate d la bs i ncl u di n g ori gi nal val ues a n d re peat v al ues will be i ncl u de d. 
Gra p hs of mea n val ues o ver ti me ma y als o be ge nerate d.  
9. 4. 3    
Ot her S afet y E n d p oi nts   
E C Gs will be c ollecte d a n d a nal yze d f or e vi d e nce of car diac t o xicit y, es p eciall y pr ol o n gati o n 
of Q T i nter val.  Vital si g ns will be s u m marize d wit h descri pti ve statistics at eac h visit a n d 
ti me p oi nt w here t he y are c ollecte d. 
9. 5    
Effic ac y E n d p oi nts   
Res p o nse will be cate g orize d as C R, P R, S D, or P D a n d e val u ate d usi n g R E CI S T  1. 1 criteria 
(A p pe n di x  7 ) a n d as ir C R, ir P R, ir S D, or ir P D usi n g t he ir R C ( A p pe n di x 8 ). T he O R R will 
be t he pr o p orti o n of patie nts i n t he res p o nse e val u a ble p o p ulati o n ac hie vi n g C R or P R w he n 
s uc h res p o nses are c o nfir me d at least 2 8 da ys after t he i nitial o bser vati o n of a n o bjecti ve 
res p o nse. A t w o-si d e d 9 5 % e x act bi n o mial c o nfi de nce i nterval will be cal c ulate d ar o u n d t he 
O R R f or eac h e x pa nsi o n re gi o n a n d als o b y t u m or t y pe . 
Res p o nse d urati o n will be calc ul ate d f or res p o n ders as t he ti me fr o m i nitial res p o nse ( C R or 
P R) t o t he ti me of P D or deat h.  Ka pla n -Meier m et h o ds will be use d t o esti ma te res p o nse 
d urati o n o ver ti me a n d t h e me dia n res p o ns e d urati o n.  Res p o n ders w h o c o m plete t he st u d y 
wit h o ut d oc u me nte d P D will be ce ns ore d at t he date of t heir last t u m or assess me nt.  
P F S will be calc ulate d as t he ti me fr o m t he i nitial i nf usi o n of pe m br oliz u ma b or 
mar get u xi ma b u ntil d oc u me nte d disease pr o gressi o n or deat h fr o m a n y ca use.  Patie nts wit h 
n o P F S e ve nt ( n o diseas e pr o gressi o n or deat h fr o m a n y ca use) will be ce ns ore d at t he dat e of 
t heir last t u m or assess me nt. I n a d diti o n, P F S rat es will be calc ulate d at 3 a n d 6 -m o nt h ti me 
p oi nts fr o m t he first d ose of st u d y dr u g. Ka pla n -M eier met h o ds will be use d t o esti mate P F S 
o ver ti me a n d t he me dia n d urati o n of P F S.  T he met h o d of Br o o k me yer a n d Cr o wle y (9 ) wi ll 
be use d t o c o nstr uct 9 5 % CIs ar o u n d P F S esti mates of t he me dia n a n d ot her q uartiles f or 
eac h e x pa nsi o n re gi o n a n d als o b y t u m or t y pe . 
I n c o m plete a n d missi n g data ca n c o m plicate i nter pretati o n of P F S. A p pe n di x  5  descri bes t he 
ha n dli n g of t hes e data f or t he P F S a nal ysis.  
O verall s ur vi val is defi ne d as t he ti me fr o m t he i nitial i nf usi o n of pe m br oliz u ma b or 
mar get u xi ma b t o deat h fr o m a n y ca use.  Patie n ts w h o are ali ve at last c o ntact will be ce ns ore d 
at t he date t hat t he patie nt was last k n o w n t o be ali ve. Ka pla n -M eier met h o ds will be use d t o 
esti mate t he o verall s ur vi val f u ncti o n.  I n a d diti o n, O S rate will be cal c ulate d at 1 year a n d 2-
year ti me p oi nts  fr o m t he first d ose of st u d y dr u g. 
C o nfi d e nti al
P a g e   
1 0 6   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
9. 6    
Ot her Assess me nts or A n al yses   
P h ar m ac o ki netic A n al ysis:  S u m mar y statistics will be ta b ulate d f or P K para meters b y 
mar get u xi ma b  d ose. Ge o metric  mea ns a n d perce nt c oefficie nts of variati o n will be re p orte d 
f or Cma x , A U Cta u, a n d Ctr o u g h; arit h metic mea ns a n d sta n dar d de viati o ns will be re p orte d f or 
ter mi nal half-life ( Thalf), C L, a n d Vss; a n d me dia ns, mi ni m u m, a n d ma xi m u m will be re p orte d 
f or Tma x . Se parate scatter pl ots of C ma x  a n d A U C will be pr o vi de d vers us d ose t o assess d ose 
de pe n de n c y. P o p ulati o n P K a nal ys es ma y be c o n d ucte d usi n g data fr o m t his st u d y al o ne or 
c o m bi ne d wit h data fr o m ot her st u dies . 
I m m u n o ge nicit y A n al ysis: T he pr o p orti o n of pa tie nts w h o are ne gati ve f or mar get u xi ma b 
A D A at baseli ne a n d b ec o me p ositi ve i n t his assa y, t he pr o p orti o n of patie nts w h o are 
ne gati ve at baseli ne a n d re mai n ne gati ve, a n d t h ose w h o ha ve p ositi ve A D A at baseli ne t hat 
i ncreas es or decreases i n titer o ver the c o urse of treat me nt will be s u m marize d.  
P h ar m ac o d y n a mi c A n al ysis:  S u m mar y statistics f or p har mac o d y na mics p ara meters s uc h 
as, b ut n ot li mite d t o, t h ose liste d u n der secti o n, “P har mac o d y na mics/ Bi o mar kers/ T u m or 
Bi o ps y ” (Secti o n  7. 1 0. 4 ) a n d c orres p o n di n g c ha n ges fr o m baseli ne, will be s u m marize d 
a n d/ or ma y als o be prese nte d gra p hicall y as will p ossi ble ass ociati o ns bet wee n c ha n ges i n 
p har mac o d y n a mics meas ures of i nterest a n d mar get u xi ma b d os e a n d e x p os ure ma y be 
e x pl ore d. 
C o nfi d e nti al
P a g e   
1 0 7   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
1 0    
Q U A LI T Y C O N T R O L A N D A S S U R A N C E   
Q ualit y re vie w acti vities will be u n derta ke n t o e ns ure acc urate, c o m plete, a n d relia ble data. 
Macr o Ge nics, I nc. a n d/ or its re prese ntati ves will d o t he f oll o wi n g:  
 Pr o vi de i nstr ucti o nal material t o t he st u d y sites, as a p pr o priate.  
 S p o ns or a start -u p trai ni n g sessi o n (I n vesti gat or Meeti n g or S t u d y I nitiati o n Visit) 
t o i nstr uct t he i n vesti gat ors a n d st u d y c o or di nat ors. T his sessi o n will gi ve 
i nstr ucti o n o n t he pr ot oc ol, t he c o m pleti o n of t he e C R Fs, a n d st u d y pr oce d ures. 
 Ma ke peri o dic visits t o t he st u d y site t o m o nit or pr ot oc ol c o m plia nce a n d ge neral 
G o o d Cli nical Practice G C P c o m plia nce.  
 Be a v aila ble f or c o ns ultati o n a n d sta y i n c o ntact wit h t he st u d y site pers o n nel b y 
mail, e -mail, tele p h o ne, a n d/ or fa x.  
 Re vie w a n d e v al uate e C R F data a n d us e sta n dar d c o m p uter c hec ks t o detect a n d 
q uer y err ors i n data c ollecti o n.  
 C o n d uct a q ualit y re vie w of t he data bas e.  
 
1 0. 1    
M o nit ori n g, A u diti n g a n d I ns pecti o ns   
To e ns ure t he safet y of partici pa nts i n t he st u d y, c o m plia nce wit h a p plica bl e r e g ulati o ns, a n d 
e ns ure acc urate, c o m plet e, a n d relia bl e data, t he i n vesti gat or will kee p rec or ds of la b orat or y 
tests, cli nical n otes, a n d patie nt me dical rec or ds i n t he patie nt files as s o urce d oc u me nts f or 
t he st u d y (refer t o Secti o n  11. 5  f or a d diti o nal i nf or mati o n o n s o urce d oc u m e nts). 
Macr o Ge nics, I nc. or its desi g nee will m o nit or t he st u d y o n a re g ular basis t hr o u g h o ut t he 
st u d y peri o d acc or di n g t o t he st u d y m o nit ori n g pl a n. T he i n vesti gat or will all ocate a de q uate 
ti me f or s uc h m o nit ori n g acti vities. T he st u d y m o nit or peri o dicall y will c o n d uct a cr oss -
c hec k of a sa m ple of t he patie nt data rec or de d o n e C R Fs a gai nst s o urce d oc u me nts at t he 
st u d y site. T he i n vesti gat or will als o e ns ure t hat t h e m o nit or is gi ve n access t o all t he a b o ve 
n ote d st u d y -relate d d o c u me nts, s o urce d oc u me nts (re gar dless of me dia) a n d st u d y-relate d 
facilities (e. g., i n vesti gati o nal p har mac y, et c.), a n d has a de q uat e s pace t o c o n duct t he 
m o nit ori n g visit.  Q ueries will be raise d f or a n y dat u m t hat is u nclear or is c o ntra dict or y wit h 
t he s o urce d o c u me nts. T he i n vesti gat or a n d site pers o n nel m ust a d dress all q ueries i n a ti mel y 
ma n ner.  
Partici pati o n as a n i n vesti gat or i n t his st u d y i m plies acce pta nce of t he p ote ntial f or i ns pecti o n 
b y t he st u d y S p o ns or/ Re prese ntati ves, U S or n o n -U S g o ver n me nt re g ulat or y a ut h orities, 
I R B/I E C a n d a p plica ble c o m plia nce a n d q ualit y ass ura nce offices. T he i n v esti gat or will 
per mit st u d y -relate d a u dits a n d i ns pecti o ns a n d will pr o vi de access t o all st u d y-relate d 
d oc u me nts (e. g., s o urce d oc u me nts, re g ulat or y d oc u me nts, data c ollecti o n i nstr u me nts, st u d y 
data etc.).  T he i n vesti gat or will e ns ure t he ca pa bilit y f or i ns pecti o ns of a p plica ble st u d y -
relate d facilities (e. g., p h ar mac y, dia g n ostic la b orat or y, et c.). 
C o nfi d e nti al
P a g e   
1 0 8   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
1 0. 2    
D at a C ollecti o n a n d M a n a ge me nt   
A n electr o nic d ata ca pt ure s yste m will be use d i n t his trial. Ot her data ass ess me nts, s uc h as 
ce ntral la b orat or y ass a ys, i m m u n oc he mistr y, a n d E C G data, will be ma na ge d b y ce ntral 
ve n d ors f or tra nsfer t o Macr o Ge nics, I nc. or re prese ntati ve f or use i n t he st u d y a nal ysis 
data base.  
T he i n vesti gat or is res p o nsi ble f or mai ntai ni n g acc urate, c o m plete, a n d u p -t o-date rec or ds f or 
eac h p atie nt. T he i n vesti gat or is als o res p o nsi ble f or mai ntai ni n g a n y s o urce d oc u me ntati o n 
relate d t o t he st u d y, i ncl u di n g a n y fil ms, traci n gs, or ot her me dia c o ntai ni n g dat a pertai ni n g 
t o t his pr ot oc ol. 
T he a n o n y mit y of partici pati n g patie nts m ust be mai ntai ne d. F or data c oll ecti o n, a n d 
ma na ge me nt p ur p os es, patie nts are t o be i de ntifie d b y a patie nt n u m ber o nl y. D oc u me nts t hat 
i de ntif y t he patie nt be y o n d patie nt n u m ber will n ot be s u b mitte d t o t he S p o ns or (e. g., t he 
si g ne d i nf or me d c o nse nt d oc u me nt; patie nt i nitials) a n d m ust be mai ntai ne d i n strict 
c o nfi de nce b y t he i n vesti gat or, e x ce pt t o t he e xte nt t o all o w a u diti n g b y t he re g ulat or y 
a ut h orities, st u d y m o nit or, or S p o ns or re prese ntati ves.  
Site pers o n nel rec or d all data f or eac h pa tie nt t hr o u g h el ectr o nic case re p ort f or ms (e C R Fs) 
usi n g a n Electr o nic Data Ca pt ure ( E D C) s yste m pr o vi de d a n d a p pr o ve d b y t he S p o ns or. 
Refer t o t he St u d y P r oce d ures Ma n ual f or a d diti o nal i nf or mati o n re gar di n g e C R Fs, if a n y 
t hat will be use d as s o urce d oc u me ntati o n. Sites m ust c o m plete e C R Fs f or eac h patie nt i n a 
ti mel y ma n ner s h ortl y after eac h patie nt visit. As t he pers o n ulti matel y res p o nsi ble f or t he 
acc urac y of all e C R F dat a, t he i n vesti gat or m ust si g n t he i n vesti gat or ’s State me nt i n eac h 
patie nt ‘s e C RF.  
T he E D C s yst e m a ut o maticall y ge n erat es q ueries res ulti n g fr o m t he c o m p uter c hec ks 
e m be d de d i nt o t he s yste m t o e ns ure data acc urac y, q ualit y, c o nsiste nc y, a n d c o m plete ness.  
Ma n ual q ueries res ulti n g fr o m re vie w b y m o nit ors, me dical c o ders, a n d Data Ma na ge m e nt 
staff are als o ge n erate d fr o m wit hi n t he E D C s yst e m, w here t he y are trac ke d. Sites res ol ve 
t he q ueries a n d c orrect t h e e ntere d data acc or di n gl y. E ver y c ha n ge t o d ata is ca pt ure d i n t he 
E D C s yste m a u dit trail. A d verse e ve nts a n d me di cal hist or y are c o d e d usi n g Me d D R A, 
w hereas c o nc o mita nt me dicati o ns are c o de d usi n g t he W H O Dr u g Dicti o nar y. U p o n 
c o m pleti o n of t he st u d y, or after reac hi n g a pre -s p ecifie d p oi nt i n t he st u d y, Data 
Ma na ge me nt will l oc k t h e data bas e a n d ge nerate t he S A S datasets necessar y f or  a nal ysis a n d 
re p orti n g. U p o n c o m pleti o n of t he st u d y, eac h site will be pr o vi de d wit h a c o m pact dis k 
c o ntai ni n g t he e C R Fs f or eac h of t heir patie nts.  
C o nfi d e nti al
P a g e   
1 0 9   
of   
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Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
1 1    
A D MI NI S T R A TI V E C O N SI D E R A TI O N S   
1 1. 1    
I nstit uti o n al Re vie w B o ar d (I R B) or I n de pe n de nt Et hics 
C o m mittee (I E C) A p pr o v al   
T he i n vesti gat or s h o ul d pr o vi de t he S p o ns or wit h a state me nt of c o m plia nce fr o m t h e 
I R B/I E C i n dicati n g c o m plia nce wit h t he a p plica ble re g ulati o ns i n t he re gi o n a n d I C H. A n y 
d oc u me nts t hat t he I R B/I E C ma y nee d t o f ulfill its res p o nsi bilities, s uc h as t he pr ot oc ol a n d 
a n y a me n d me nts, I B, a n d i nf or mati o n c o ncer ni n g patie nt recr uit me nt, pa y me nt or 
c o m pe nsati o n pr oce d ures, or i nf or mati o n fr o m t he S p o ns or will be s u b mitte d t o t he I R B/I E C. 
T he I R B/I E C ’s writte n u nc o n diti o nal a p pr o val of t he st u d y pr ot oc ol a n d t he i nf or me d 
c o nse nt f or ms (I C Fs) will be i n t he p ossessi o n of t he i n vesti gat or a n d t h e S p o ns or bef ore t he 
st u d y dr u g is i nitiate d at t he i n vesti gat or’s site. T he i n vesti gat or will tra ns mit t he I R B/I E C’s 
u nc o n diti o nal a p pr o val st ate me nt t o t he S p o ns or. T his a p pr o val m ust i ncl u de t he date of 
re vie w, a n d refer t o t he st u d y b y pr ot oc ol title an d/ or st u d y n u m ber a n d versi o n n u m ber a n d 
refer t o t he I C Fs b y v ersi o n n u m ber or date. If t he I R B/I E C or i nstit uti o n uses its o w n u ni q ue 
n u m ber f or t he pr ot oc ol i nstea d of t he S p o ns or ’s n u m ber, t hat u ni q ue n u m ber s h o ul d be 
n ote d o n t he a p pr o val state me nt. If a p pr o val of t he I C Fs is sta m pe d o n t he f or ms (i nstea d of 
d oc u me nte d i n t he I R B/I E C a p pr o val state me nt) t he date of a p pr o val a n d/ or e x pirati o n m ust 
be i ncl u de d.  
Pr ot oc ol m o dificati o ns or c ha n ges ma y n ot be i niti ate d wit h o ut a p pr o val fr o m t he S p o ns or 
a n d pri or writte n I R B/I E C a p pr o val ( w he n re q uire d), e xce pt w he n necess ar y t o eli mi nate 
i m me diate hazar ds t o t he patie nts. S uc h m o dificati o ns will be s u b mitte d t o t he I R B/I E C; 
writte n verificati o n t hat t he m o dificati o n was s u b mitte d s h o ul d be o btai ne d.  
T he i n ve sti gat or m ust, w here re q uire d b y l ocal re g ulati o ns, s u b mit t o t he I R B/I E C:  
 T he pr ot oc ol a n d t he in vesti gat or ’s b r oc h ure (I B) a n d a n y a me n d me nts or 
u p dates.  
 T he i nf or me d c o ns e nt f or m(s) a n d a n y a me n d me nts or c ha n ges.  
 A n y d o c u me nts gi ve n t o patie nts or p ote n tial patie nts (e. g., recr uit me nt materials, 
diar y car ds) a n d t he pl a n f or distri b uti o n/ use.  
 Re visi o ns of ot her d oc u me nts ori gi nall y s u b mitte d f or re vie w or f or n otificati o n.  
 Seri o us a n d/ or u ne x pecte d A Es occ urri n g d uri n g t he st u d y.  
 Ne w i nf or mati o n t hat ma y  a d versel y affect t he safet y of patie nts or c o n d uct of t he 
st u d y. 
 At mi ni m u m, a n a n n ual u p date a n d/ or re q uest f or re -a p pr o val of st u d y, u nl ess 
ot her wise s pecifie d b y I R B/I E C.  
 Pr ot oc ol vi olati o ns or de viati o ns  
 N otificati o n w he n t he st u d y has b ee n c o m plete d.  
C o nfi d e nti al
P a g e   
1 1 0   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
 Pr o of of i n de m nit y/lia bilit y i ns ura nce.  
 Ot her d oc u me nts re q uire d b y t he I R B/I E C  
 
1 1. 2    
Et hic al C o n d uct of t he St u d y   
T he i n vesti gati o nal st u d y will be c o n d ucte d acc or di n g t o t he Pr otec ti o n of H u ma n Patie nts 
( 2 1 C F R [ C o de of Fe deral Re g ulati o ns] 5 0), I nstit uti o nal Re vie w B oar ds ( 2 1 C F R 5 6), 
O bli gati o ns of Cli nical i n vesti gat ors ( 2 1 C F R 3 1 2. 6 0  3 1 2. 6 9), t he c urre nt I C H G ui d eli ne 
f or G o o d Cli nical Practice (I C H E 6), a n d all ot her a p plica ble re g ulati o ns. 
T he pr ot oc ol a n d t he i nf or me d c o nse nt d oc u me nt will be re vie we d a n d a p pr o ve d b y t he 
I R B/I E C of eac h partici p ati n g ce nter bef ore st u d y i nitiati o n. Seri o us a d verse e ve nts, 
re gar dless of ca us alit y, will be re p orte d t o t he S p o ns or/ desi g nee a n d t o t he I R B/I E C, if 
re q uire d b y l ocal re g ulati o ns. T he i n vesti gat or will kee p t he I R B/I E C i nf or me d re gar di n g t h e 
pr o gress of t he st u d y.  
1 1. 3    
P atie nt I nf or m ati o n a n d C o nse nt   
It is t he res p o nsi bilit y of t he i n vesti gat or t o o btai n a n d d oc u me nt writte n i nf or me d c o nse nt 
fr o m t he patie nt. I nf or me d c o nse nt, i n c o m plia nce wit h t he pri nci ples of i nf or me d c o nse nt i n 
I C H E 6 a n d all a p plica bl e l ocal re g ul ati o ns, s h o ul d be o btai ne d bef ore a n y pr ot oc ol-s pecifi e d 
pr oce d ures or i nter v e nti o ns are c o n d ucte d. T he S p o ns or reser ves t he ri g ht t o dela y i nitiati o n 
of t he st u d y at a site w here I C Fs d o n ot meet t he sta n dar ds of a p plica ble l ocal re g ulati o ns or 
I C H E 6. 
I nf or mati o n s h o ul d be gi ve n t o t he patie nt i n b ot h oral a n d writte n f or m, a n d patie nts m ust be 
gi ve n a m ple o p p ort u nit y t o i n q uire a b o ut details of t he st u d y.  
T he c o nse nt f or m  ge nerate d b y t he i n vesti gat or m ust be a p pr o ve d b y t he I R B/I E C.  T he 
i n vesti gat or will pr o vi de t he S p o ns or wit h a c o p y of t he I RB/I E C -a p pr o ve d c o nse nt f or ms 
a n d a c o p y of t he I R B/I E C ’s writte n a p pr o val bef ore t he start of t h e st u d y.  
C o nse nt f or ms m ust be writte n (a n d a p pr o priatel y tra nslate d i n t he patie nt ’s nati ve la n g ua ge 
or la n g u a ge i n w hic h t h e patie nt has fl ue nc y) s o as t o be  u n derst o o d b y t he pr os pecti ve 
patie nt. I nf or me d c o nse nt will be d oc u me nte d b y t he use of a writte n c o nse nt f or m a p pr o ve d 
b y t he I R B/I E C.  T he f or m m ust be si g ne d a n d date d b y t h e patie nt, a n d b y t he pers o n w h o 
c o n d ucte d t he disc ussi o n of t he i nf or me d c o ns e nt.  
All versi o ns of eac h patie nt ’s si g ne d I C F m ust be ke pt o n file b y t h e i n vesti gat or f or p ossi ble 
i ns pecti o n b y re g ulat or y a ut h orities a n d/ or a ut h ori ze d Macr o Ge ni cs’ re pres e ntati ves 
m o nit ori n g a n d re g ulat or y c o m plia nce pers o ns. T he patie nt s h o ul d recei ve  a c o p y of t he 
si g ne d a n d date d writte n I C F a n d a n y ot h er writte n i nf or mati o n pr o vi de d t o t he patie nts.  
C o nfi d e nti al
P a g e   
1 1 1   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
1 1. 4    
P atie nt C o nfi de nti alit y   
To mai ntai n c o nfi de ntialit y of patie nts, all la b or at or y s p eci me ns, e val uati o n f or ms, re p orts, 
a n d ot her rec or ds will be i de ntifie d b y a c o de d n u m ber.  Cli nical i nf or mati o n will n ot be 
releas e d wit h o ut writte n per missi o n of t he patie nt, e xce pt as necess ar y f or m o nit ori n g b y t h e 
rele va nt re g ulat or y a ut h orities, t he S p o ns or of t he cli nical trial, or t he S p o ns or ’s 
re pres e ntati ve. T he i n vesti gat or m ust als o c o m pl y wit h all l ocal a p plica ble pri vac y 
re g ulati o ns (e. g., U S H ealt h I ns ura nce P orta bilit y a n d Acc o u nta bilit y Act of 1 9 9 6 [ HI P A A]), 
o n pr otecti o n of i n di vi d uals wit h re gar d t o pers o nal data.  
1 1. 5    
C ase Re p ort F or ms a n d St u d y Rec or ds   
S o urce data i n a cli nical trial are t h e ori gi nal rec or ds or certifie d c o pies w here cli nical 
o bser vati o ns ar e first rec or de d, w hic h ma y i ncl u de, b ut are n ot li mite d t o, t he patie nt ’s 
me dical file, ori gi nal la b orat or y re p orts, hist ol o g y, a n d pat h ol o g y re p orts (as a p plica ble).  T he 
i n vesti gat or is res p o nsi ble f or mai ntai ni n g a de q uate a n d acc urat e me dical rec or ds fro m w hic h 
acc urate i nf or mati o n will be e ntere d o nt o C R Fs desi g ne d t o ca pt ure all o bser vati o ns a n d 
ot her data perti ne nt t o t he cli nical i n vesti gati o n. Data s h o ul d be rec or de d o n s o urce 
d oc u me nts a n d e ntere d o nt o e C R Fs. Electr o nic C R Fs s h o ul d be fille d o ut c o m pletel y b y t h e 
i n vesti gat or or his/ her desi g nee. Pri or t o e C R F dat a base l oc k, t he i n v esti gat or will verif y t he 
c o m plete ness a n d acc urac y of t he data a n d i n dicat e t hat he/s he has d o n e s o b y pr o vi di n g a n 
electr o nic si g nat ure o n t h e a p pr o priate e C R F. T he i n v esti gat or will ret ai n a c o p y of all s o urce 
d oc u me nts.  
1 1. 6    
Access t o S o urce D oc u me nt ati o n   
T he i n vesti gat or a n d st u d y ce nter will per mit t he S p o ns or, its re prese nt ati ves, I R B/I E C, a n d 
all rele va nt re g ulat or y a ge ncies access t o all ori gi n al s o urce data a n d d oc u me nts re gar dless of 
me dia, f or st u d y m o nit ori n g a u dits a n d i ns pecti o ns.  
T he i n vesti gat or ma y be s u bjecte d t o a fiel d a u dit b y Macr o Ge nics, I nc. ( or desi g nee) a n d/ or 
re g ulat or y i ns pect ors i n or der t o vali date t he partici pati o n of patie nts i n t he st u d y a n d t o 
verif y t he dat a re p orte d o n t he e C R Fs o n file at M acr o Ge nics, I nc. M acr o Ge nics or 
re pres e ntati ves s h o ul d be n otifie d i m me diatel y of a n y a u dits sc he d ule d b y a n y re g ulat or y 
a ut h orities. C o pies of a u dit re p orts, fi n di n gs a n d/ or c orres p o n de nce fr o m re g ul at or y 
a ut h orities f or a u dits c o n d ucte d o n a Macr o Ge nics -s p o ns ore d st u d y s h o ul d be pr o m ptl y 
f or war de d t o Macr o Ge ni cs or re prese ntati ves. 
1 1. 7    
Rete nti o n of D at a   
Per I C H g ui deli nes, all esse ntial d oc u me nts, i ncl u di n g e C R Fs, s o urce d oc u me nts (re gar dless 
of me dia), si g ne d I C Fs, a n d la b orat or y test res ults, s h o ul d be retai ne d b y t h e i n vesti gat or f or 
at least 2 years afte r last a p pr o val of a mar keti n g a p plicati o n i n a n I C H re gi o n a n d u ntil t here 
are n o pe n di n g or c o nte m plate d mar keti n g a p plicati o ns i n a n I C H re gi o n or u ntil at least 
2  years ha v e ela pse d si nce f or mal disc o nti n uati o n of cli nical de vel o p me nt of t he 
i n vesti gati o nal pr o d u ct. T here ma y be ot her circ u msta nces f or w hic h Macr o Ge nics, I nc. is 
re q uire d t o mai ntai n st u d y rec or ds f or l o n ger peri o ds (e. g., a p plica bl e l ocal re g ulati o ns); 
C o nfi d e nti al
P a g e   
1 1 2   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
t heref ore, Macr o Ge ni cs, I n c or re pres e ntati ves. s h o ul d be c o ntacte d bef ore st u d y rec or ds are 
re m o ve d fr o m t he c o ntr ol of t he i n vesti gati o nal sit e f or a n y reas o n. T he i n v esti gat or m ust  
o btai n writte n per missi o n fr o m Macr o Ge nics, I nc or re prese ntati ves pri or t o destr ucti o n of 
st u d y d oc u me nts. 
1 1. 8    
Fi n a nci al Discl os ure   
T he i n vesti gat or a n d s u b -i n vesti gat ors will be re q uire d t o discl ose a n y a p pli ca ble fi na ncial 
arra n ge me nt as defi ne d i n U S or l ocal re g ulati o n (i.e. 2 1 C F R 5 4). T he f oll o wi n g i nf or m ati o n 
will be c ollecte d: a n y si g nifica nt pa y me nts of ot her s orts fr o m Macr o Ge nics, I nc. or a n y 
allia nce part ner, s uc h as a gra nt t o f u n d o n g oi n g researc h, c o m pe nsati o n i n t he f or m of 
e q ui p me nt, retai ner f or o n g oi n g c o ns ultati o n or h o n oraria; a n y pr o prietar y i nterest i n 
mar get u xi ma b ; a n d a n y si g nifica nt e q uit y i nterest i n Macr o Ge ni cs, I nc., as defi ne d i n 2 1 
C F R 5 4.  I n v esti gat ors are o bli ge d t o u p d ate t he S p o ns or or re prese ntati ves wit h a n y c ha n ges 
i n re p orte d i nf or m ati o n u p t o 1 year f oll o wi n g t he e n d of t he st u d y (as d efi ne d i n 
Sect i o n 4. 7. 2 ). 
I n c o nsi derati o n of p artici pati o n i n t he st u d y, Macr o Ge nics, I nc. will pa y t he i n vesti gat or or 
n o mi nate d pa yee t h e s u ms set o ut i n t he pa y me nt s c he d ule attac he d t o t he i n vesti gat or 
a gree m e nt.  
Fi na ncial discl os ur e i nf or mati o n will be d oc u me nte d i n writi n g a n d si g ne d a n d date d b y t he 
i n vesti gat or. T his i nf or m ati o n will be c ollecte d pri or t o t hat i n vesti gat or ta ki n g part i n t he 
researc h. 
1 1. 9    
P u b lic ati o n a n d Discl os ure P olic y  
Data c ollecte d i n t his cli nical st u d y bel o n g t o t he st u d y S p o ns or w hic h will f or m ulate a 
p olic y o n t he use of st u d y dat a.  T his p olic y will be c o dif ie d i n t he Cli nical Trial A gree me nt. 
T his i ncl u des a ut h ors hi p iss ues: sc he d uli n g a n d pri oritizi n g a nal ys es f or re p orts, p u blicati o ns, 
a n d prese nt ati o ns; a n d de vel o pi n g a re vie w a n d a p pr o val pr ocess.  
1 1. 1 0    
Disc o nti n u ati o n of t he St u d y or St u d y Sites   
1 1. 1 0. 1    
Disc o nti n u ati o n of St u d y Sites   
Partici pati o n ma y b e disc o nti n ue d if Macr o Ge nics, I nc., t he i n vesti gat or, a re g ul a t or y 
a ut h orit y, or t he I R B/I E C of t he st u d y sites dee ms it necessar y f or a n y reas o n.  
1 1. 1 0. 2    
Disc o nti n u ati o n of t he St u d y   
T he st u d y ma y b e disc o nti n ue d b y a re g ulat or y a ut h orit y or at  t he discreti o n of t he S p o ns or.  
T he i n vesti gat or mai ntai ns t he ri g ht t o disc o nti n ue his/ her partici pati o n i n t he st u d y s h o ul d 
his/ her cli nical j u d g me nt s o dictate.  T he i n vesti gat or will n otif y t he I R B/I E C of a n y st u d y 
disc o nti n uati o n.  St u d y rec or ds m ust be re tai ne d as n ote d a b o ve. 
C o nfi d e nti al
P a g e   
1 1 3   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
1 1. 1 1    
I de ntific ati o n of t he C o or di n ati n g Pri nci p al I n vesti g at or  
A C o or di nati n g Pri nci pal I n v esti gat or will be a p p oi nte d b y t he S p o ns or Me dical M o nit or 
pri or t o t he e n d of t he st u d y. 
As part of his or her res p o nsi bilities, t he C o or di nati n g Pri nci pal I n vesti gat or will re vie w t he 
fi nal C S R. A gree me nt wit h t he fi nal C S R will be d oc u me nte d b y t he dat e d si g nat ure of t he 
C o or di nati n g Pri nci pal I n vesti gat or.  
C o nfi d e nti al
P a g e   
1 1 4   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
1 2    
R E F E R E N C E LI S T   
N ote:  Ne wly a d de d liter at ure refere nces are i n c ol ore d text. Previ o usly cite d s u b mitte d 
liter at ure refere n ces are i n bl ack text.  
1.  Aj a ni J A, Ils o n D H, D a u g hert y K,  P az d ur R, L y nc h P M, a n d Kelse n D P , Acti vit y of 
ta x ol i n patie nts wit h s q ua m o us cell carci n o ma a n d a de n ocarci n o ma of t he es o p ha g us. J. 
Natl. Ca ncer I nst, 1 9 9 4. 8 6( 1 4): p. 1 0 8 6 -1 0 9 1.  
2.  A m ar n at h S, M a n g us C W, W a n g J C, Wei F, H e A, K a p o or V, et al. , T he P D L 1-P D 1 
a xis c o n verts h u ma n T H 1 cells i nt o re g ulat or y T cells. Sci. Tra nsl. Me d, 2 0 1 1. 3( 1 1 1): p. 
1 1 1ra 1 2 0.  
3.  B a n g Y J, V a n C E, Fe yereisl o v a A, C h u n g H C, S he n L, S a w a ki A, et al. , Trast uz u ma b 
i n c o m bi nati o n wit h c he m ot hera p y vers us c he m ot hera p y al o ne f or treat me nt of H E R 2 -
p ositi ve a d va nce d gastric or gastr o -oes o p h a geal j u ncti o n ca ncer ( T o G A): a p hase 3, 
o pe n -la bel, ra n d o mise d c o ntr olle d trial. La ncet, 2 0 1 0. 3 7 6( 9 7 4 2): p. 6 8 7-6 9 7.  
4.  B a n g Y J, C h u n g H C, S h a n k ar a n V, Ge v a R, C ate n acci D V T, G u pt a S, et al. , 
Relati o ns hi p be t wee n P D-L 1 e x pressi o n a n d cli nical o utc o mes i n patie nts wit h a d va nce d 
gastri c ca n cer treate d wit h t he a nti -P D -1 m o n ocl o nal a nti b o d y pe m br oliz u ma b ( M K -
3 4 7 5) i n K E Y N O T E -0 1 2. J Cli n O nc ol, 2 0 1 5. 3 3.  
5.  B ar ber D L, W herr y E J, M as o p ust D, Z h u B, Allis o n J P, S h ar pe  A H, et al. , Rest ori n g 
f u ncti o n i n e x ha uste d C D 8 T cells d uri n g c hr o nic viral i nfecti o n. Nat ure, 2 0 0 6. 
4 3 9( 7 0 7 7): p. 6 8 2 -6 8 7.  
6.  Bell ati F, Visc o nti V, N a p olet a n o C, A nt o nilli M, Fr ati L, P a nici P B, et al. , 
I m m u n ol o g y of g y nec ol o gic ne o plas ms: a nal ysis of t he pr o g n ostic si g nifi ca nce of t he 
i m m u ne stat us. C urr. Ca ncer Dr u g Tar gets, 2 0 0 9. 9( 4): p. 5 4 1-5 6 5.  
7.  Bl a n k C, Br o w n I, Peters o n A C, S pi ott o M, I w ai Y, H o nj o T, et al. , P D-L 1/ B 7 H -1 
i n hi bits t he effect or p hase of t u m or rejecti o n b y T cell rece pt or ( T C R) tra ns genic C D 8 + T 
cells. Ca ncer R es, 2 0 0 4. 6 4( 3): p. 1 1 4 0 -1 1 4 5.  
8.  Bre m nes R M, Al -S hi bli K, D o n ne m T, Sirer a R, Al -S a a d S, A n derse n S, et al. , T he 
r ole of t u m or-i nfiltrati n g i m m u ne cells a n d c hr o nic i nfla m mati o n at t he t u m or site o n 
ca ncer de v el o p me nt, pr o gressi o n, a n d pr o g n osis: e m p hasis o n n o n -s mall cell l u n g ca ncer. 
J T h orac O nc ol, 2 0 1 1. 6( 4): p. 8 2 4-8 3 3.  
9.  Br o o k me y er R a n d Cr o wle y J , A C o nfi de nce I nt er val f or t h e Me dia n S ur vi val Ti me. 
Bi o metrics, 1 9 8 2. 3 8: p. 2 9 -4 1.  
1 0.  Br o w n J A, D orf m a n D M, M a F R, S ulli v a n E L, M u n oz O , W o o d C R, et al., Bl oc ka de 
of pr o gra m me d d eat h -1 li ga n ds o n d e n dritic cells e n ha nces T cell acti vati o n a n d c yt o ki ne 
pr o d ucti o n. J. I m m u n ol, 2 0 0 3. 1 7 0( 3): p. 1 2 5 7 -1 2 6 6.  
C o nfi d e nti al
P a g e   
1 1 5   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
1 1.  C arter P, Prest a L, G o r m a n C M, Ri d g w a y J B, He n ner D, W o n g W L, et al. , 
H u ma nizati o n of a n a nti -p 1 8 5 H E R 2 a nti b o d y f or h u ma n ca ncer t hera p y. Pr oc Natl Aca d 
Sci U S A, 1 9 9 2. 8 9( 1 0): p. 4 2 8 5 -9.  
1 2.  C h a n g W J, D u Y, Z h a o X, M a L Y, a n d C a o G W , I nfla m mati o n-rel ate d fact ors 
pre dicti n g pr o g n osis of gastric ca ncer. W orl d J. Gastr oe nter ol, 2 0 1 4. 2 0( 1 6): p. 4 5 8 6 -
4 5 9 6.  
1 3.  C h u n J H, Ki m H K, Lee J S, C h oi J Y, Lee H G, Y o o n S M, et al. , Wee kl y iri n oteca n i n 
patie nts wit h metastatic gastric ca ncer faili n g cis plati n -base d c he m ot hera p y. J p n. J. Cli n. 
O nc ol, 2 0 0 4. 3 4( 1): p. 8 -1 3.  
1 4.  Cl y nes R A, T o wers T L, Prest a L G, a n d R a vetc h J V , I n hi bit or y Fc rece pt ors m o d ulate 
i n vi v o c yt o xicit y a gai nst t u m or tar gets. Nat. Me d, 2 0 0 0. 6( 4): p. 4 4 3-4 4 6.  
1 5.  Cre w K D a n d Ne u g ut AI , E pi de mi ol o g y of gastric ca ncer. W orl d J. Gastr oe nter ol, 
2 0 0 6. 1 2( 3): p. 3 5 4 -3 6 2.  
1 6.  C u n ni n g h a m D, All u m W H, Ste n ni n g S P, T h o m ps o n J N, v a n de Vel de C J, Nic ols o n 
M, et al. , Peri o perati ve c he m ot hera p y vers us s ur ger y al o ne f or resecta ble 
gastr o es o p ha geal ca n cer. N. E n gl. J Me d, 2 0 0 6. 3 5 5( 1): p. 1 1 -2 0.  
1 7.  C urr a n M A, M o nt al v o W, Y a git a H, a n d Allis o n J P , P D-1 a n d C T L A -4 c o m bi nati o n 
bl o c ka de e x pa n ds i nfiltrati n g T cells a n d re d uces re g ul at or y T a n d m yel oi d cells wit hi n 
B 1 6 mela n o ma t u m ors. Pr oc. Natl. Aca d. Sci. U. S. A, 2 0 1 0. 1 0 7( 9): p. 4 2 7 5 -4 2 8 0.  
1 8.  De nli n ger C, M a q ue d a D, W at ki ns D, S y m S, Be n dell J, P ar k S, et al. , Ra n d o mize d 
p hase 2 st u d y of paclita xel ( P T X), trast uz u ma b ( T) wit h or wit h o ut M M -1 1 1 i n H E R 2 
e x pressi n g gastr o es o p ha geal ca ncers ( G E C). 2 0 1 6.  
1 9.  Disis M L , I m m u ne Re g ulati o n of Ca ncer. J Cli n O nc ol, 2 0 1 0. 2 8( 2 9): p. 4 5 3 1-4 5 3 8.  
2 0.  D u dle y M E, W u n derlic h J R, R o b bi ns P F, Y a n g J C, H w u P, Sc h w artze ntr u ber D J, 
et al., Ca ncer re gressi o n a n d a ut oi m m u nit y i n patie nts after cl o nal re p o p ul ati o n wit h 
a ntit u m or l y m p h o c ytes. Scie nce, 2 0 0 2. 2 9 8( 5 5 9 4): p. 8 5 0 -8 5 4.  
2 1.  D u dle y M E, W u n derlic h J R, Y a n g J C, S herr y R M, T o p ali a n S L, Restif o N P, et al. , 
A d o pti ve cell tra nsfer t hera p y f oll o wi n g n o n -m yel oa blati ve b ut l y m p h o de pleti n g 
c he m ot hera p y f or t he treat me nt of patie nts wit h refract or y m etastatic mela n o ma. J Cli n 
O nc ol, 2 0 0 5. 2 3( 1 0): p. 2 3 4 6 -5 7.  
2 2.  D u n n G P, D u n n I F, a n d C urr y W T , F oc us o n TI Ls: Pr o g n ostic si g nifica nce of t u m or 
i nfiltrati n g l y m p h o c yt es i n h u ma n gli o ma. Ca ncer I m m u n, 2 0 0 7. 7: p. 1 2. 
2 3.  Eise n h a uer E A, T her asse P, B o g aerts J, Sc h w artz L H, S ar ge nt D, F or d R, et al. , 
Ne w res p o nse e v al uati o n criteria i n s oli d t u m o urs: re vise d R E CI S T g ui deli ne ( versi o n 
1. 1), i n E ur J Ca ncer. 2 0 0 9. p. 2 2 8-2 4 7.  
C o nfi d e nti al
P a g e   
1 1 6   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
2 4.  Fr a ncis c o L M, S ali n as V H, Br o w n K E, V a n g uri V K, Free m a n G J, K u c hr o o V K, et 
al. , P D-L 1 re g ulates t he de vel o p me nt, mai nte na nce, a n d f u ncti o n of i n d uce d re g ulat or y T 
cells. J E x p Me d, 2 0 0 9. 2 0 6( 1 3): p. 3 0 1 5 -3 0 2 9.  
2 5.  Free m a n G J,  L o n g A J, I w ai Y, B o ur q ue K, C her n o v a T, Nis hi m ur a H, et al. , 
E n ga ge me nt of t he P D -1 i m m u n oi n hi bit or y rece pt or b y a n o vel B 7 fa mil y me m ber lea ds 
t o ne gati ve re g ulati o n of l y m p h oc yte acti vati o n. J. E x p. Me d, 2 0 0 0. 1 9 2( 7): p. 1 0 2 7-
1 0 3 4.  
2 6.  F uc hs C S, T o m ase k J, Y o n g C J, D u mitr u F, P ass al ac q u a R, G os w a mi C, et al. , 
Ra m ucir u ma b m o n ot hera p y f or pre vi o usl y treate d a d va nce d gastric or gastr o -
oes o p ha geal j u ncti o n a d e n ocarci n o ma ( R E G A R D): a n i nter nati o nal, ra n d o mise d, 
m ultice ntre, place b o -c o ntr olle d, p hase 3 trial. La nc et, 2 0 1 4. 3 8 3( 9 9 1 1): p. 3 1 -3 9.  
2 7.  v o n Mi n c k witz G, d u B ois A, Sc h mi dt M, M a ass N, C ufer T, de J o n g h F E, et al. , 
Trast uz u ma b be y o n d pr o gressi o n i n h u ma n e pi der mal gr o wt h fact or rece pt or 2 -p ositi ve 
a d va nce d breast ca n cer: a ger ma n breast gr o u p 2 6/ breast i nter na ti o nal gr o u p 0 3-0 5 st u d y. 
J. Cli n. O nc ol, 2 0 0 9. 2 7( 1 2): p. 1 9 9 9-2 0 0 6.  
2 8.  Ge ne ntec h , Herce pti n (trast uz u ma b) prescri bi n g i nf or mati o n. Ge ne nt ec h pa m p hlet, 
2 0 1 5.  
2 9.  G o o de n M J, de B oc k G H, Leffers N, D ae me n T, a n d Nij m a n H W , T he pr o g n ostic 
i nfl ue nce of t u m o ur-i nfiltrati n g l y m p h oc ytes i n ca ncer: a s yste matic re vie w wit h meta-
a nal ysis. Br. J. Ca ncer, 2 0 1 1. 1 0 5( 1): p. 9 3 -1 0 3.  
3 0.  Gree n w al d R J, Free m a n G J, a n d S h ar pe A H , T he B 7 fa mil y re visite d. A n n u. Re v 
I m m u n ol, 2 0 0 5. 2 3: p. 5 1 5-5 4 8.  
3 1.  H aff ner I, L u ber B, M aier D, Kretzsc h m a r A K, v o n Wei kerst h al L, A hl b or n M, et 
al. , Ce ntral vali dati o n of H E R 2 stat us t o deter mi ne heter o ge neit y of mar ker e x pressi o n i n 
H E R 2 -p ositi ve gastri c ca ncer ( G C). A bstract, 2 0 1 7.  
3 2.  Hir a n o F, K a ne k o K, T a m ur a H, D o n g H, W a n g S, Ic hi k a w a M, et al. , Bl oc ka de of 
B 7 -H 1 a n d P D -1 b y m o n ocl o nal a nti b o dies p ote ntiates ca ncer t hera pe utic i m m u nit y. 
Ca ncer Res, 2 0 0 5. 6 5( 3): p. 1 0 8 9 -1 0 9 6.  
3 3.  Hir o n a k a S, Ze n d a S, B o k u N, F u k ut o mi A, Y os hi n o T, a n d O n oz a w a Y , Wee kl y 
paclita xel as sec o n d -li ne c he m ot hera p y f or a d va nce d or rec urre nt gastric ca ncer. Gastric. 
Ca ncer, 2 0 0 6. 9( 1): p. 1 4 -1 8.  
3 4.  H o di F S, O' D a y S J, Mc Der m ott D F, We ber R W, S os m a n J A, H a a ne n J B, et al. , 
I m pr o ve d s ur vi val wit h i pili m u ma b i n patie nts wit h metastatic mela n o ma. N. E n gl. J. 
Me d, 2 0 1 0. 3 6 3( 8): p. 7 1 1 -7 2 3.  
3 5.  H u dis C A , Trast uz u ma b--mec h a nis m of acti o n a n d use i n cli nical practice. N. E n gl. J 
Me d, 2 0 0 7. 3 5 7( 1): p. 3 9 -5 1.  
C o nfi d e nti al
P a g e   
1 1 7   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
3 6.  H u n der N N, W alle n H, C a o J, He n dric ks D W, Reill y J Z, R o d m yre R, et al. , 
Treat me nt of metastatic mela n o ma wit h a ut ol o g o us C D 4 + T cells a gai nst N Y -E S O -1.  N 
E n gl J Me d, 2 0 0 8. 3 5 8( 2 5): p. 2 6 9 8 -7 0 3.  
3 7.  Ils o n D H, W a dlei g h R G, Leic h m a n L P, a n d Kelse n D P, Paclita xel gi ve n b y a wee kl y 
1 -h i nf usi o n i n a d va nce d es o p ha geal ca ncer. A n n. O nc ol, 2 0 0 7. 1 8( 5): p. 8 9 8 -9 0 2.  
3 8.  J a h a nze b M , C o nti n ui n g trast uz u ma b be y o n d pr o gressi on. J. Cli n. O nc ol, 2 0 0 9. 2 7( 1 2): 
p. 1 9 3 5 -1 9 3 7.  
3 9.  J a nji gi a n Y Y, S a nc hez -Ve g a F, T u v y Y, B o u vier N, Ric hes J, M ar g olis M, et al. , 
E mer ge nce of R T K/ R A S/ PI 3 K pat h wa y alterati o ns i n trast uz u ma b -refract or y H E R 2-
p ositi ve es o p ha g o gastric ( E G) t u m ors. A bstract, 2 0 1 6.  
4 0.  J a nsse n Bi otec h , Re mica de (i nfli xi ma b) Prescri bi n g I nf or mati o n, Re vise d N o ve m ber 
2 0 1 3. J a nsse n Bi otec h Pa m p hlet, 2 0 1 3.  
4 1.  K a n g J H, Lee SI, Li m d H, P ar k K W, O h S Y, K w o n H C, et al. , Sal va ge c he m ot hera p y 
f or pretreate d gastric ca n cer: a ra n d o mize d p hase III trial c o m p ari n g c he m ot hera p y pl us 
best s u p p orti ve care wit h best s u p p orti ve care al o n e. J. Cli n. O nc ol, 2 0 1 2. 3 0( 1 3): p. 
1 5 1 3 -1 5 1 8.  
4 2.  Keir M E, B utte M J, Free m a n G J, a n d S h ar pe A H , P D-1 a n d its li ga n ds i n t olera nce 
a n d i m m u nit y. A n n u. Re v. I m m u n ol, 2 0 0 8. 2 6: p. 6 7 7 -7 0 4.  
4 3.  Ki m S T, Je o n g H, W o o O H, Se o J H, Ki m A, Lee E S, et al. , T u m or-i nfiltrati n g 
l y m p h oc ytes, t u m or c h aracteristics, a n d rec urre nce i n patie nts wit h earl y breast ca ncer. 
A m. J. Cli n. O nc ol, 2 0 1 3. 3 6( 3): p. 2 2 4 -2 3 1.  
4 4.  K o der a Y, It o S, M oc hiz u ki Y, F ujit a ke S , K os hi k a w a K, K a n y a m a Y, et al., A p hase 
II st u d y of wee kl y p aclita x el as sec o n d-li ne c he m ot hera p y f or a d va nce d gastric Ca ncer 
( C C O G 0 3 0 2 st u d y). A nti ca ncer Res, 2 0 0 7. 2 7( 4 C): p. 2 6 6 7-2 6 7 1.  
4 5.  L a n m a n R B, M orti mer S A, Zill O A, Se bis a n o vic D, L o pez R, Bl a u S, e t al., 
A nal ytical a n d Cli nical Vali dati o n of a Di gital Se q ue nci n g Pa nel f or Q ua ntitati ve, Hi g hl y 
Acc urate E val u ati o n of Cell -Free Circ ulati n g T u m or D N A. P L o S O ne, 2 0 1 5. 1 0( 1 0): p. 
e 0 1 4 0 7 1 2. 
4 6.  Lee J, Ki m S, Ki m K, K a n g W K, T al as az A, a n d P ar k K , Cell-free D N A se q ue nci n g-
g ui de d t hera p y i n a pr os pecti ve cli nical trial: N E X T -2 trial — A feasi bilit y a nal ysis. 
A bstract, 2 0 1 6.  
4 7.  M at h ai A M, K a p a di a M J, Ale x a n der J, Ker n oc h a n L E, S w a ns o n P E, a n d Ye h M M , 
R ole of F o x p 3 -p ositi ve t u m or -i nfiltrati n g l y m p h o c yt es i n t he hist ol o gic feat ures a n d 
cli nical o utc o mes of he p at ocell ular carci n o ma. A m. J. S ur g. Pat h ol, 2 0 1 2. 3 6( 7): p. 9 8 0 -
9 8 6.  
C o nfi d e nti al
P a g e   
1 1 8   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
4 8.  Mei Z, Li u Y, Li u C, C ui A, Li a n g Z, W a n g G, et al. , T u m o ur-i nfiltrati n g 
i nfla m mati o n a n d pr o g n osis i n c ol orectal ca ncer: s yste matic re vie w a n d meta-a nal ysis. 
Br. J. Ca ncer, 2 0 1 4. 1 1 0( 6): p. 1 5 9 5 -1 6 0 5.  
4 9.  Merc k , K E Y T R U D A ( pe m br oliz u ma b) Prescri bi n g I nf or mati o n. Merc k pa m p hlet, 2 0 1 5. 
5 0.  M ur o K, B a n g Y J, S h a n k ar a n V, Ge v a R, C ate n acci D V, G u pt a S, et al. , 
Relati o ns hi p bet wee n P D -L 1 e x pressi o n a n d cli nical o utc o mes i n patie nts ( Pts) wit h 
a d va nce d gastric ca ncer treate d wit h t he a nti -P D -1 m o n ocl o nal a nti b o d y pe m br oliz u ma b 
( Pe m br o; M K-3 4 7 5) i n K E Y N O T E -0 1 2. J Cli n O nc ol, 2 0 1 5. 3 3.  
5 1.  M us oli n o A, N al di N, B ortesi B, Pezz u ol o D, C a pelletti M, Miss ale G, et al. , 
I m m un o gl o b uli n G fra g me nt C rece pt or p ol y m or p his ms a n d cli nical efficac y of 
trast uz u ma b-base d t hera p y i n patie nts wit h H E R -2/ ne u -p ositi ve metastatic breast ca ncer. 
J Cli n O nc ol, 2 0 0 8. 2 6( 1 1): p. 1 7 8 9-1 7 9 6.  
5 2.  N C C N , Cli nical Practice G ui deli nes i n O nc ol o g y ( N C C N G ui deli nes): Gastric Ca ncer. 
Nati o nal C o m pre he nsi ve Ca ncer Net w or k ( N C C N), 2 0 1 5( Versi o n 3. 2 0 1 5).  
5 3.  N o mi T, S h o M, A k a h ori T, H a m a d a K, K u b o A, K a ne hir o H, et al. , Cli nical 
si g nifica n ce a n d t hera p e utic p ote ntial of t he pr o gra m me d deat h-1 li ga n d/ pr o gra m me d 
dea t h-1 pat h w a y i n h u ma n pa ncreatic ca ncer. Cli n. Ca ncer Res, 2 0 0 7. 1 3( 7): p. 2 1 5 1 -
2 1 5 7.  
5 4.  N or dstr o m J L, G orl at o v S, Z h a n g W, Y a n g Y, H u a n g L, B ur ke S, et al. , A nti-t u m or 
acti vit y a n d t o xic o ki netics a nal ysis of M G A H 2 2, a n a nti -H E R 2 m o n ocl o nal a nti b o d y 
wit h e n ha nce d Fc -ga m m a rece pt or bi n di n g pr o perties. Breast. Ca ncer Res, 2 0 1 1. 1 3( 6): p. 
R 1 2 3.  
5 5.  N os h o K, B a b a Y, T a n a k a N, S hi m a K, H a y as hi M, Me yer h ar dt J A, et al. , T u m o ur-
i nfiltrati n g T-cell s u bsets, m olec ular c ha n ges i n c ol orectal ca ncer, a n d pr o g n osis: c o h ort 
st ud y a n d literat ure re vie w. J. Pat h ol, 2 0 1 0. 2 2 2( 4): p. 3 5 0 -3 6 6.  
5 6.  O ble D A, L oe we R, Y u P, a n d Mi h m M C, Jr. , F oc us o n TI Ls: pr o g n osti c si g nifica nce 
of t u m or i nfiltrati n g l y m p h oc yt es i n h u ma n mela n o ma. Ca ncer I m m u n, 2 0 0 9. 9: p. 3.  
5 7.  Pil o n -T h o m as S, M a c k a y A, V o hr a N, a n d M ule J J , Bl oc ka de of pr o gra m me d deat h 
li ga n d 1 e n h a nces t he t hera pe utic efficac y of c o m bi nati o n i m m u n ot hera p y a gai nst 
mela n o ma. J. I m m u n ol, 2 0 1 0. 1 8 4( 7): p. 3 4 4 2 -3 4 4 9.  
5 8.  Prest o n C C, M a urer M J, O ber g A L, Vissc her D W, K alli K R, H art m a n n L C, et al. , 
T h e rati os of C D 8 + T cells t o C D 4 + C D 2 5 + F O X P 3 + a n d F O X P 3 - T Cells C orrelate wit h 
P o or Cli nical O utc o me i n H u ma n Ser o us O varia n Ca ncer. P L o S. O N E, 2 0 1 3. 8( 1 1): p. 
e 8 0 0 6 3. 
5 9.  R al p h C, El k or d E, B urt D J, O' D w yer J F, A usti n E B, Ster n P L, et al. , M o d ulati o n of 
l y m p hoc yte re g ulati o n f or ca ncer t hera p y: a p hase II trial of tre m eli m u ma b i n a d va nce d 
gastri c a n d es o p h a geal a de n ocarci n o ma. Cli n. Ca ncer Res, 2 0 1 0. 1 6( 5): p. 1 6 6 2 -1 6 7 2.  
C o nfi d e nti al
P a g e   
1 1 9   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
6 0.  R o bert C, T h o m as L, B o n d are n k o I, O' D a y S, J W M D, G ar be C, et al. , I pili m u ma b 
pl us dacar ba zi ne f or pre vi o usl y u ntreat e d metastatic mela n o ma. N. E n gl. J. Me d, 2 0 1 1. 
3 6 4( 2 6): p. 2 5 1 7 -2 5 2 6.  
6 1.  R o bert C, Ri b as A, W ol c h o k J D, H o di F S, H a mi d O, Keff or d R, et al. , A nti-
pr o gra m me d -d eat h -rece pt or-1 treat me nt wit h pe m br oliz u ma b i n i pili m u ma b -refract or y 
a d vance d mela n o ma: a ra n d o mise d d ose -c o m paris o n c o h ort of a p hase 1 tri al. La ncet, 
2 0 1 4. 3 8 4( 9 9 4 8): p. 1 1 0 9 -1 1 1 7.  
6 2.  S al g a d o R, De n kert C, De m ari a S, Sirt ai ne N, Kl a usc he n F, Pr u neri G, et al. , T he 
e val uati o n of t u m or -i nfiltrati n g l y m p h oc ytes ( TI Ls) i n breast ca ncer: rec o m me n dati o ns 
b y a n I nter n ati o nal TI Ls W or ki n g Gr o u p 2 0 1 4. A n n. O nc ol, 2 0 1 5. 2 6( 2): p. 2 5 9 -2 7 1.  
6 3.  S at o h T, X u R H, C h u n g H C, S u n G P, D oi T, X u J M, et al. , La pati ni b pl us paclita xel 
vers us paclita xel al o ne i n t he sec o n d -li ne treat me nt of H E R 2-a m plifie d a d va nce d gastric 
ca ncer i n Asia n p o p ulati o ns: T y T A N --a ra n d o mize d, p hase III st u d y. J. Cli n. O nc ol, 
2 0 1 4. 3 2( 1 9): p. 2 0 3 9 -2 0 4 9.  
6 4.  Sc hrei ber R D, Ol d L J, a n d S m yt h M J , Ca ncer i m m u n oe diti n g: i nte grati n g i m m u nit y's 
r oles i n ca ncer s u p pressi o n a n d pr o m oti o n. Science, 2 0 1 1. 3 3 1( 6 0 2 4): p. 1 5 6 5 -1 5 7 0.  
6 5.  Se o S, R y u M H, A h n J, P ar k Y, P ar k S R, R y o o B Y, et al. , L oss of H E R 2 p ositi vit y 
after a nti -H E R 2 c he m ot h era p y i n H E R 2 -p ositi ve gastri c ca ncer patie nts: Res ults of 
G A S Tric ca n cer H E R 2 reassess me nt st u d y 3 ( G A S T H E R 3). A bstr act, 2 0 1 7. 
6 6.  S hi H Z, W a n g Y N, H u a n g X H, Z h a n g K C, Xi H Q, C ui J X, et al. , Ser u m H E R 2 as a 
pre dicti ve bi o mar k er f or tiss ue H E R 2 stat us a n d pr o g n osis i n patie nts wit h gastri c ca ncer. 
W orl d J Gastr oe nter ol, 2 0 1 7. 2 3( 1 0): p. 1 8 3 6 -1 8 4 2.  
6 7.  S hi n E C, Pr otzer U, U nter g a sser A, Fei nst o ne S M, Rice C M, H assels c h wert D, et al., 
Li ver -directe d ga m ma i nt erfer o n ge ne deli ver y i n c hr o nic he patitis C. J Vir ol, 2 0 0 5. 
7 9( 2 1): p. 1 3 4 1 2 -1 3 4 2 0.  
6 8.  S hir a be K, M ot o m ur a T, M ut o J, T os hi m a T, M at o n o R, M a n o Y, et al. , T u m or-
i nfiltrati n g l y m ph o c yt es a n d he pat ocell ular carci n o ma: pat h ol o g y a n d cli nical 
ma na ge me nt. I nt. J. Cli n. O nc ol, 2 0 1 0. 1 5( 6): p. 5 5 2 -5 5 8.  
6 9.  Sie gel R L, Miller K D, a n d Je m al A , Ca ncer statistics, 2 0 1 5. C A Ca ncer J. Cli n, 2 0 1 5. 
6 5( 1): p. 5 -2 9.  
7 0.  S pr a n ger S, K o blis h H K, H ort o n B, Sc herle P A, Ne wt o n R, a n d G aje ws ki T F , 
Mec ha nis m of t u m or rej ecti o n wit h d o u blets of C T L A -4, P D -1/ P D -L 1, or I D O bl oc ka de 
i n v ol ves rest ore d I L-2 pr o d ucti o n a n d pr oliferati o n of C D 8( +) T cells directl y wit hi n t he 
t u m or micr oe n vir o n me nt. J. I m m u n ot her. Ca ncer, 2 0 1 4. 2: p. 3.  
7 1.  Str o me S E, D o n g H, T a m ur a H, V oss S G, Flies D B, T a m a d a K, et al. , B 7-H 1 
bl oc ka de a u g m e nts a d o pti ve T -cell i m m u n ot hera p y f or s q ua m o us cell carci n o ma. Ca ncer 
Res, 2 0 0 3. 6 3( 1 9): p. 6 5 0 1 -6 5 0 5.  
C o nfi d e nti al
P a g e   
1 2 0   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
7 2.  S u n Y, W a n g Y, Z h a o J, G u M, Gisc o m be R, L ef vert A K,  et al., B 7-H 3 a n d B 7 -H 4 
e x pressi o n i n n o n -s mall-cell l u n g ca ncer. L u n g C a ncer, 2 0 0 6. 5 3( 2): p. 1 4 3 -1 5 1.  
7 3.  Sz n ol M, Kl u ger H M, C all a h a n M K, P ost o w M A, G or d o n R A, Se g al N H, et al. , 
S ur vi val, res p o nse d urati o n, a n d acti vit y b y B R A F m utati o n ( M T) stat us of ni v o l u ma b 
( NI V O, a nti-P D -1, B M S -9 3 6 5 5 8, O N O -4 5 3 8) a n d i pili m u ma b (I PI) c o nc urre nt t hera p y 
i n a d va nce d m ela n o ma ( M E L). J Cli n O nc ol, 2 0 1 4. 3 2( 5s). 
7 4.  T a ber ner o J, P o w derl y J D, H a mi d O, G or d o n M S, Fis her G A, Br aite h F S, et al. , 
Cli nical acti vit y, safet y, a n d bi o mar kers of M P D L 3 2 8 0 A, a n e n gi neere d P D -1 a nti b o d y 
i n patie nts wit h l ocall y a d va nce d or metastatic C R C, gastric ca ncer ( G C), S C C H N, or 
ot her t u m ors. J Cli n O nc ol, 2 0 1 3. 3 1.  
7 5.  T al m a d ge J E , I m m u ne cell i nfiltrati o n of pri mar y a n d metastatic lesi o ns: mec ha nis ms 
a n d cli nical i m pact. Se mi n Ca ncer Bi ol, 2 0 1 1. 2 1( 2): p. 1 3 1 -1 3 8.  
7 6.  T o p ali a n S L, Dr a ke C G, a n d P ar d oll D M , Tar geti n g t he P D-1/ B 7 -H 1( P D -L 1) pat h wa y 
t o acti vate a nti-t u m or i m m u nit y. C urr. O pi n. I m m u n ol, 2 0 1 2. 2 4( 2): p. 2 0 7-2 1 2.  
7 7.  U p p al uri R, D u n n G P, a n d Le wis J S, J r., F oc us o n TI Ls: pr o g n ostic si g nifica nce of 
t u m or i nfiltrati n g l y m p h o c yt es i n hea d a n d nec k ca ncers. Ca ncer I m m u n, 2 0 0 8. 8: p. 1 6. 
7 8.  W a g ner A D, Gr ot he W, H aerti n g J, Kle ber G, Gr ot he y A, a n d Flei g W E , 
C he m ot hera p y i n a d va n ce d gastric ca ncer: a s yste matic r e vie w a n d meta-a nal ysis bas e d 
o n a g gre gat e data. J Cli n O nc ol, 2 0 0 6. 2 4( 1 8): p. 2 9 0 3 -2 9 0 9.  
7 9.  We ber J , I m m u ne c h ec k p oi nt pr otei ns: a ne w t hera pe utic para di g m f or ca ncer--
precli nical bac k gr o u n d: C T L A -4 a n d P D -1 bl oc ka de. Se mi n O nc ol, 2 0 1 0. 3 7( 5): p. 4 3 0 -
4 3 9.  
8 0.  Wil ke C M, Wei S, W a n g L, Kr ycze k I, K a o J, a n d Z o u W , D ual bi ol o gical effects of 
t he c yt o ki n es i nterle u ki n-1 0 a n d i nterfer o n -ga m ma. Ca ncer I m m u n ol. I m m u n ot her, 2 0 1 1. 
6 0( 1 1): p. 1 5 2 9 -1 5 4 1.  
8 1.  Wil ke H, M ur o K, V a n C E, O h S C, B o d o k y G, S hi m a d a Y, et al. , Ra m u ciru ma b pl us 
paclita xel vers us place b o pl us paclita xel i n patie nts wit h pre vi o usl y treate d a d va nce d 
gastri c or gastr o -oes o p ha geal j u ncti o n a de n ocarci n o ma ( R AI N B O W): a d o u ble -bli n d, 
ra n d o mise d p hase 3 tri al. La n cet O nc ol, 2 0 1 4. 1 5( 1 1): p. 1 2 2 4-1 2 3 5.  
8 2.  W olc h o k J D, H o os A, O' D a y S, We ber J S, H a mi d O, Le b be C, et al. , G ui deli nes f or 
t he e val uati o n of i m m u ne t hera p y acti vit y i n s oli d t u m ors: i m m u ne-relate d res p o nse 
criteria. Cli n. Ca ncer Res, 2 0 0 9. 1 5( 2 3): p. 7 4 1 2 -7 4 2 0.  
8 3.  W u Y Y, Li n C W, C he n g K S, Li n C, W a n g Y M, Li n I T, et al., I ncrease d pr o gra m me d 
deat h -li ga n d-1 e x pressi o n i n h u ma n gastri c e pit helial cells i n Helic o bacter p yl ori 
i nfecti o n. Cli n. E x p. I m m u n ol, 2 0 1 0. 1 6 1( 3): p. 5 5 1-5 5 9.  
C o nfi d e nti al
P a g e   
1 2 1   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
8 4.  Y a gi S, W a k ats u ki T, Y a m a m ot o N, C hi n K, T a k a h ari D, O g ur a M, et al. , Cli nical 
si g nifica n ce of i ntrat u m oral H E R 2 heter o ge neit y (I H H) usi n g e n d osc o pi c bi o ps y 
s peci me ns i n patie nts wit h H E R 2-p ositi ve gastri c ca ncer ( G C) w h o recei ve d T -ma b -
base d c he m ot hera p y. . J Cli n O nc ol, 2 0 1 7. 8 1( 8 1).  
8 5.  Y a kes F M, C hi nr at a n al a b W, Ritter C A, Ki n g W, Seeli g  S, a n d Arte a g a C L , 
Herce pti n -i n d uce d i n hi biti o n of p h os p hati d yli n osit ol-3 ki nase a n d A kt Is re q uire d f or 
a nti b o d y-me di ate d effects o n p 2 7, c ycli n D 1, a n d a ntit u m or acti o n. Ca ncer Res, 2 0 0 2. 
6 2( 1 4): p. 4 1 3 2 -4 1 4 1.  
8 6.  Y o o n H H, Orr oc k J M, F oster N R, S ar ge nt D J, S m yr k T C, a n d Si nicr o pe F A , 
Pr o g n ostic i m pact of F o x P 3 + re g ulat or y T cells i n relati o n t o C D 8 + T l y m p h oc yt e 
de nsit y i n h u ma n c ol o n carci n o mas. P L o S. O N E, 2 0 1 2. 7( 8): p. e 4 2 2 7 4.  
8 7.  Z h a n g L, G aje ws ki T F, a n d Kli ne J , P D-1/ P D -L 1 i nteracti o ns i n hi bit a ntit u m or 
i mm u ne res p o nses i n a m uri ne ac ute m yel oi d le u ke mia m o del. Bl o o d, 2 0 0 9. 1 1 4( 8): p. 
1 5 4 5 -1 5 5 2.  
 
C o nfi d e nti al
P a g e   
1 2 2   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
C o nt acts  
 
   
   
   
   
   
 
 
   
 
T ele p h o ne, Electr o nic C o ntact, or office 
visit  
 
   
   
   
   
   
   
 
 
x  
1   Visits occ ur ± 3 da ys of a sc he d ule d visit, wit h e xce pti o n of C ycle 1 Da y 1 a n d u nless ot her wise n ote d.  
2   P e m br oliz u ma b m ust be a d mi nistere d first. A n eff ort s h o ul d be ma de t o be gi n t he mar get u xi ma b i nf usi o n bet wee n 3 0 mi n utes t o 6 0  mi n utes aft er t he 
c o m pleti o n of t he pe m br oliz u ma b i nf usi o n. It is u n derst o o d t hat t his wi n d o w ma y n ot al wa ys be attai na ble, b ut it is t he pr efe rre d wi n d o w of ti me t o a d mi nister 
mar get u xi ma b. Mar get u xi ma b ma y be a d mi nistere d t he ne xt da y f or safet y reas o ns or sc he d uli n g p ur p oses. T he start a n d st o p ti me of eac h pe m br oliz u ma b 
a n d mar get u xi ma b i nf usi o n m ust be d oc u me nte d.  
3   T o be o btai ne d bef ore re gistrati o n ( n o ti me c o nstrai nt).  
4   Ti mi n g of E C Gs i n relati o n t o pe m br oliz u ma b:  
  C ycle 1 - E C Gs will be o btai ne d i m me diatel y bef ore t he pe m br oliz u ma b i nf usi o n ( u p t o 3 mi n utes bef ore t he i nf usi o n [ pre -d ose]) a n d at 3 0 mi n utes 
(e n d of i nf usi o n) o n Da y 1.  
  C ycles 2 t hr o u g h 5 - E C G will be o btai ne d i m me diatel y pri or t o t he first pe m br oliz u ma b i nf usi o n ( u p t o 3 mi n utes bef ore t he i nf usi o n [ pre -d ose]) 
o n Da y 1 of eac h c ycle.  
  E C Gs are o btai ne d t hr o u g h C ycle 7 a n d t hereafter n ot a gai n u ntil t he E n d of Treat me nt Visit.  
Ti mi n g of E C Gs i n relati o n t o mar get u xi ma b:   
  C ycle 1 - O n Da y 1 (i nte nsi ve P K da y) E C Gs will be ta ke n at 1 2 0 mi n utes (e n d of i nf us i o n) a n d at 2 4 h o urs after t he c o m pleti o n of i nf usi o n.  
  C ycles 2 t hr o u g h 5 –  E C Gs will be o btai ne d i m me diatel y pri or t o t he first mar get u xi ma b i nf usi o n ( u p t o 3 mi n utes bef ore t he i nf usi o n [ pre -d ose]) 
o n Da y 1 of eac h c ycle. O n D a y 1 of C ycle 3 (i nte nsi ve P K da y), E C Gs will be ta ke n i m me diatel y bef ore mar get u xi ma b i nf usi o n ( u p t o 3 mi n utes 
bef ore t he i nf usi o n [ pre -d ose]) a n d at 1 2 0 mi n utes (e n d of i nf usi o n), a n d at 2 4 h o urs after i nf usi o n c o m pleti o n.  
  E n d of Treat me nt at n o s pecifi c ti me  
5   M U G A or ec h ocar di o gr a p h y t o be perf or me d at Scree ni n g; C ycle 3 Da y 1; C ycle 5 Da y 1, a n d o n Da y 1 of eac h 4 t h c ycle t hereafter (e g, C ycles 9, 1 3, 1 7) 
w hile o n treat me nt; a n d at t he E n d of Treat me nt visit. C ycle 1 Da y 1 M U G A or ec h o n ot re q uire d if t he Scree ni n g M U G A sca n or ec h o was perf or me d wit hi n 
4 wee ks of patie nt ra n d o mizati o n. M U G A or ec h o e val uati o ns ma y be perf or me d u p t o 7 da ys pri or t o t he sc he d ule d st u d y visit.  
6   F or w o me n of c hil d beari n g p ote ntial, t o be o btai ne d wit hi n 7 2 h o urs pri or t o i nitial d ose of pe m br oliz u ma b. F or C a n a di a n p atie nts o nl y:  Fe male patie nts of 
c hil d beari n g p ote ntial m ust ha ve a ne gati ve pre g na nc y test pri or t o e ver y c ycle of pe m br oliz u ma b.   
7   I ncl u des hei g ht ( baseli ne o nl y) a n d wei g ht. N ote t hat f ull p h ysical e xa ms t o be d o ne o n Scree ni n g Da y ( bas eli ne) a n d at t he E O T V. All ot her p h ysical e xa ms 
will be directe d p h ysical e xa ms base d o n patie nt s y m pt o ms, t u m or l ocati o n a n d as cli nicall y i n dicate d.  
8   Sa m ple will be c ollecte d pri or t o pe m br oliz u ma b i nf usi o n; C B C wit h differe ntial, platelet c o u nt, C he mis tr y pa nel, Fr ee T 4 a n d T S H, P T a n d a P T T, a n d 
Uri nal ysis ma y occ ur u p t o 7 2 h o urs i n a d va nce of t he Da y 1 i nf usi o n da y of eac h treat me nt c ycle.  
9   Bl o o d f or H E R 2 -s pecific i m m u ne res p o nse t o be dra w n pre-pe m br oliz u ma b i nf usi o n o n C ycle 1 Da y 1; C ycle 4  Da y 1; a n d at E n d of Treat me nt Visit. ct D N A 
testi n g perf or me d retr os pecti vel y f or patie nts w h o c o nse nte d t o f ut ure use testi n g.  
1 0  Bl o o d f or fl o w c yt o metr y assa ys t o be dra w n o n Da y 1 at pre -pe m br oliz u ma b i nf usi o n a n d 5 h o urs p ost Mar get u xi ma b E OI, o n Da y  2 a n d Da y  8 f or C ycle 1 
o nl y; s u bse q ue ntl y t o be dra w n Da y 1 of eac h c ycle pre -pe m br oliz u ma b i nf usi o n u p t o a n d i ncl u di n g C ycle 6, a n d lastl y at E n d of Treat me nt Visit.  
1 1  Fc rece pt or ge n ot y pi n g t o be dra w n o nl y o nce o n Da y 1 of C ycle 1 pre -pe m br oliz u ma b i nf usi o n.  
C o nfi d e nti al
P a g e   
1 2 5   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
1 2  Sa m ples will be a nal yze d b y t he l ocal la b orat or y.  
1 3  I ncl u des A L B, A L K-P, A L T, A S T, a m ylase, bicar b o nate, B U N, Ca, Cl, creati ni ne, gl uc ose, li pase, ma g nesi u m, p h os p h or us, K, Na, t otal a n d direct b ilir u bi n, 
t otal pr otei n, a n d uric aci d. 
1 4  F or c yt o ki ne sa m ples: F or  D ose Escalati o n: Da y 1 sa m ple will be c ollecte d pre -pe m br oliz u ma b i nf usi o n, pre -mar get u xi ma b i nf usi o n a n d wit h t he 5 h o ur after 
e n d of mar get u xi ma b i nf usi o n P K sa m ple, a n d wit h t he mar get u xi ma b P K sa m ple o n Da y 2. A d diti o nal sa m ples s h o ul d be o btai ne d s electi vel y at a d diti o nal 
ti me p oi nts i n patie nts w h o e x perie nce si g ns a n d s y m pt o ms of c yt o ki ne release at t he ti me of t he a d verse e ve nt, wit h t he g oal t o o btai n a c yt o ki ne sa m ple 
i m me diatel y at t he ti me of o nset of a d verse e ve nt. M ulti ple c yt o ki ne sa m ples can be dra w n f or a n y s pecific a d verse e ve nt t hat is s us pecte d t o be d ue t o c yt o ki ne 
release, as cli nicall y i n dicate d; s pecific date a n d ti mes of bl o o d dra ws m ust be rec or de d. Se parate c yt o ki ne sa m ples s h o ul d b e dra w n f or eac h a d verse e ve nt 
s us pecte d of c yt o ki ne release, wit h s pecific date a n d ti me of dra w t o be rec or de d. 
1 5  Vital si g ns i ncl u de te m perat ur e, p ulse, bl o o d press ure, a n d res pirat or y rate a n d are o btai ne d as f oll o ws:  
  I n relati o n t o pe m br oliz u ma b i nf usi o ns o n Da ys 1: Vital si g ns will be ta ke n i m me diatel y bef ore t he pe m br oliz u ma b i nf usi o n ( u p t o 5 mi n utes bef ore 
t he i nf usi o n [ pre-d ose]); at 1 5 mi n utes after t he start of i nf usi o n; at 3 0 mi n utes (e n d of i nf usi o n), a n d at 1 h o ur after i nf usi o n if t he mar ge t u xi ma b 
d ose has n ot alrea d y c o m me nc e d.  
  I n relati o n t o mar get u xi ma b i nf usi o ns o n Da ys 1: Vital si g ns will be ta ke n i m me diatel y bef ore mar get u xi ma b i nf usi o n ( u p t o 5 mi n utes bef ore t he 
i nf usi o n [ pre-d ose]), at 6 0 mi n utes after start of i nf usi o n, at 1 2 0 mi n utes (e n d of i nf usi o n), a n d at 1 h o ur after t he c o m p leti o n of i nf usi o n. 
  N ote: F or s u bse q ue nt c ycles after c ycle 1; t he 1 -h o ur p ost -i nf usi o n vital si g ns meas ure me nts ma y be deferre d if c o nti n ui n g m o nit ori n g is n ot cli nicall y 
i n dicate d.  
1 6  Ra di o gra p hic disease assess me nts will occ ur e ver y 6 wee ks (i.e., f oll o wi n g 2 c ycles of tr eat me nt) f or t he first 2 4 wee ks a n d t he n e ver y 1 2 wee ks t hereafter 
u ntil d oc u me nte d pr o gressi o n, i nitiati o n of alter nati ve a nti -c a ncer t hera p y, l ost t o f oll o w u p, wit h dra wal of i nf or me d c o nse nt, deat h, or e n d of st u d y. T o be 
perf or me d wit h i n 3 da ys pri or t o d osi n g o n Da y 1 of e ver y ot her c ycle f or t he first 2 4 wee ks (s pecificall y pri or t o C ycles 3, 5, 7 a n d 9) an d t he n e ver y 4 t h c ycle 
t hereafter ( pri or t o C ycles 1 3, 1 7, 2 1, etc.).  
1 7  Scree ni n g brai n sca ns s h o ul d be perf or me d o n all patie nts w h o ha ve pre vi o us hist or y of C N S metastasis or as cli nicall y i n dicate d. Re peat brai ns sca ns will 
o nl y be perf or me d if t he Scree ni n g brai n sca n was p ositi ve or as cli nicall y i n dicate d.  
1 8  P har mac o ki netic sa m pli n g t o be perf or me d acc or di n g t o T a ble  6 . 
1 9  S ee T a ble  5  f or A D A sa m ple da ys a n d ti mes. 
 
C o nfi d e nti al
P a g e   
1 2 6   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
E v al u ati o n/ Pr oce d ure  1 
Scree ni n g    
C ycle 1    
C ycle 2    
C ycle 3    
C ycle 4 - 3 5    
E n d of Tre at me nt 
Visit  
 
F oll o w -U p 
Visits  
D a y -2 8 t o 0    
D a y 1    
D a y 1    
D a y 1    
D a y 1  
A D A bl o o d sa m ple (a nti -mar get u xi ma b 
a nti b o dies) 1 9  
 
X    
x    
x  
x 1 9 
X  
 
C o nt acts  
 
   
   
   
 
 
 
T ele p h o ne, Electr o nic C o ntact, or office 
visit  
 
   
   
 
 
 
x  
1   Visits occ ur ± 3 da ys of sc he d ule d visit, wit h e xce pti o n of C ycle 1 Da y 1 a n d u nless ot her wise n ote d.  
2   P e m br oliz u ma b m ust be a d mi nistere d first. A n eff ort s h o ul d be ma de t o be gi n t he mar get u xi ma b i nf usi o n bet wee n 3 0 mi n utes t o 6 0  mi n utes aft er t he 
c o m pleti o n of t he pe m br oliz u ma b i nf usi o n. It is u n derst o o d t hat t his wi n d o w ma y n ot al wa ys be attai na ble, b ut i t is t he pr eferre d wi n d o w of ti me t o a d mi nister 
mar get u xi ma b. Mar get u xi ma b ma y be a d mi nistere d t he ne xt da y f or safet y reas o ns or sc he d uli n g p ur p oses. T he start a n d st o p ti m e of eac h pe m br oliz u ma b 
a n d mar get u xi ma b i nf usi o n m ust be d oc u me nte d.   
3   T o be o btai ne d bef ore re gistrati o n ( n o ti me c o nstrai nt).  
4   Ti mi n g of E C Gs i n rel ati o n t o pe m br oliz u m a b:  
E x p a nsi o n  
  C ycles 1, 3, 5, a n d 7  E C Gs will be o btai ne d bef ore pe m br oliz u ma b i nf usi o n ( u p t o 3 mi n ut es bef ore t he i nf usi o n [ pre -d ose]  a n d at 3 0 mi n utes (e n d 
of i nf usi o n)  o n Da y 1  
  E n d of Treat me nt E C Gs will be o btai ne d at n o s pecific ti me.  
Ti mi n g of E C Gs i n rel ati o n t o m ar get u xi m a b:  
E x p a nsi o n  
  C ycles 1, 3, 5, 7  E C Gs will be o btai ne d at 1 2 0 mi n utes (e n d of i nf usi o n) o n Da y 1 of eac h c ycle .  
E n d of Treat me nt E C Gs will b e o btai ne d at n o s pecific ti me.  
5   M U G A or ec h ocar di o gra p h y t o be perf or me d o n Da y 1 ( or 3 t o 4 pri or t o Da y 1) of e ver y ot her c ycle f or 6 m o nt hs; t hereafter, t hese assess me nts ma y be 
perf or me d e ver y 4 c ycles.  
6   F or w o me n of c hil d beari n g p ote ntial, t o be o btai ne d wit hi n 7 2 h o urs pri or t o i nitial d ose of pe m br oliz u ma b. F or C a n a di a n p atie nts o nl y:  Fe male patie nts of 
c hil d beari n g p ote ntial m ust ha ve a ne gati ve pre g na nc y test pri or t o e ver y c ycle of pe m br oliz u ma b.   
7   I ncl u des hei g ht ( baseli ne o nl y) a n d wei g ht. N ote t hat f ull p h ysical e xa ms t o be d o ne o n Scree ni n g Da y ( baseli ne) a n d at t he E O T V. All ot her p h y sical e xa ms 
will be directe d p h ysical e xa ms base d o n patie nt s y m pt o ms, t u m or l ocati o n a n d as cli nicall y i n dicate d.  
8   Sa m ple will be c ollecte d pri or t o pe m br oliz u ma b i nf usi o n; C B C wit h differe ntial, platelet c o u nt, C he mistr y pa nel, Fr ee T 4 a n d T S H, P T a n d a P T T, a n d 
Uri nal ysis ma y occ ur u p t o 7 2 h o urs i n a d va nce of t he Da y 1 i nf usi o n da y of eac h treat me nt c ycle.  
9   Bl o o d f or H E R 2 -s pecific i m m u ne res p o nse t o be dra w n pre-pe m br oliz u ma b i nf usi o n o n C ycle 1, Da y 1; C ycle 4, Da y 1; a n d at E n d of Treat me nt Visit.  
1 0  Bl o o d f or Fl o w C yt o metr y assa ys t o be dra w n o n Da y 1 at pre -pe m br oliz u ma b i nf usi o n f or C ycle 1 t o C ycle 6, i ncl usi ve, a n d lastl y at E n d of Treat me nt Visit.  
1 1  Fc rece pt or ge n ot y pi n g t o be dra w n o nl y o nce o n Da y 1 of C ycle 1 pre -pe m br oliz u ma b i nf usi o n.  
C o nfi d e nti al
P a g e   
1 2 9   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
1 2  Sa m ples will be a nal yze d b y t he l ocal la b orat or y.  
1 3  I ncl u des A L B, A L K-P, A L T, A S T, a m ylase, bicar b o nate, B U N, Ca, Cl, creati ni ne, gl uc ose, li pase, ma g nesi u m, p h os p h or us, K, Na, t otal pr otei n, uric aci d, 
t otal a n d direct bilir u bi n. 
1 4  F or C yt o ki ne sa m ples: Sa m pl es ca n be o btai ne d selecti vel y at a d diti o nal ti me p oi nts i n patie nts w h o e x perie nce a n a d verse e ve n wit h si g ns a n d s y m pt o ms of 
c yt o ki ne release, wit h t he g oal t o o btai n a c yt o ki ne sa m ple i m me diatel y at t he ti me of o nset of a d vers e e ve nt. M ulti ple c yt o ki ne sa m ples ca n be dra w n f or a n y 
s pecific a d verse e ve nt t hat is s us pecte d t o be d ue t o c yt o ki ne release, as cli nicall y i n dicate d; s pecific date a n d ti mes of b l o o d dra ws m ust be rec or de d. Se parate 
c yt o ki ne sa m ples s h o ul d be dra w n f or eac h a d verse e ve nt s us pecte d of c yt o ki ne release, wit h s pecific date a n d ti me of dra w t o be rec or de d.  
1 5  Vital si g ns i ncl u de te m perat ur e, p ulse, bl o o d press ure, a n d res pirat or y rate a n d are o btai ne d as f oll o ws:  
  I n relati o n t o pe m br oliz u ma b i nf usi o ns o n Da ys 1: Vital si g ns will be ta ke n i m me diatel y bef ore t he pe m br oliz u ma b i nf usi o n ( u p t o 5 mi n utes bef ore 
t he i nf usi o n [ pre-d ose]); at 1 5 mi n utes after t he start of i nf usi o n; at 3 0 mi n utes (e n d of i nf usi o n), a n d at 1 h o ur after i nf usi o n if t he mar ge t u xi ma b 
d ose h as n ot alrea d y c o m me nc e d.  
  I n relati o n t o mar get u xi ma b i nf usi o ns o n Da ys 1: Vital si g ns will be ta ke n i m me diatel y bef ore mar get u xi ma b i nf usi o n ( u p t o 5 mi n utes bef ore t he 
i nf usi o n [ pre-d ose]), at 6 0 mi n utes after start of i nf usi o n, at 1 2 0 mi n utes (e n d of i nf usi o n), a n d at 1  h o ur after t he c o m pleti o n of i nf usi o n.  
  N ote: F or s u bse q ue nt c ycles after C ycle 1; t he 1 -h o ur p ost -i nf usi o n vital si g ns meas ure me nts ma y be deferre d if c o nti n ui n g m o nit ori n g is n ot cli nicall y 
i n dicate d.  
1 6  Ra di o gra p hic disease assess me nts w ill occ ur e ver y 6 wee ks (i.e., f oll o wi n g 2 c ycles of tr eat me nt) f or t he first 2 4 wee ks a n d t he n e ver y 1 2 wee ks t hereafter 
u ntil d oc u me nte d pr o gressi o n, i nitiati o n of alter nati ve a nti -c a ncer t hera p y, l ost t o f oll o w u p, wit h dra wal of i nf or me d c o nse nt, deat h,  or e n d of st u d y. T o be 
perf or me d wit hi n 3 da ys pri or t o d osi n g o n Da y 1 of e ver y ot her c ycle f or t he first 2 4 wee ks (s pecificall y pri or t o C ycles 3,  5, 7 , a n d 9) a n d t he n e ver y 4 t h c ycle 
( pri or t o C ycles 1 3, 1 7, 2 1, etc.). D isease assess me nt will be d o ne at office  f oll o w-u p visits  u ntil e n d of st u d y  if patie nt a grees. 
1 7  Scree ni n g brai n sca ns s h o ul d be perf or me d o n all patie nts w h o ha ve pre vi o us hist or y of C N S metastasis or as cli nicall y i n dica te d. Re peat brai ns sca ns will 
o nl y be perf or me d if t he Scree ni n g brai n sca n was p ositi ve or as cli nicall y i n dicate d.  
1 8  P har mac o ki netic sa m pli n g t o be perf or me d i n acc or d a nce wit h T a ble  6 ; P K s h o ul d be c ollecte d at C ycles 1, 2, 3, 5, 7, a n d E O T. E O T s h o ul d be n ote d “ P K 
teste d usi n g ali q u ot of A D A c ollecti o n.” 
1 9  See T a ble  5  f or A D A sa m ple da ys a n d ti mes; A D A sa m ple s h o ul d be c ollecte d at C ycles 1, 2, 3, 5, 7, 9, 1 1  a n d e ver y o d d c ycle t hereafter (i ncl u di n g E O T or 
2 8 da ys after last d ose of st u d y dr u g ).  
2 0  P art B: T o be perf or me d f or at least 2 0 of 6 0 patie nts e nr olle d  i n t he C o h ort E x pa nsi o n P hase u n der t he Ori gi nal Prot oc ol or Pr ot oc ol A me n d me nt  1  wit hi n 
3  da ys pri or t o d osi n g o n C ycl e 1 Da y 1 a n d o n C ycle 2 Da y 1.  
 
C o nfi d e nti al
P a g e   
1 3 0   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
A p pe n di x 5    
Ce ns ori n g R ules f or P F S   
Sit u ati o n  
D ate  
O utc o me  
N o baseli ne t u m or assess me nts    
D ate of first d ose  
Ce ns ore d  
Deat h pri or t o first sc he d ule d 
t u m or assess me nt 
Date of deat h  
Pr o gresse d  
N o p ost baseli ne t u m or 
assess me nts i n a bse nce of deat h 
pri or t o first sc he d ule d t u m or 
assess me nt  
Date of first d ose  
Ce ns ore d  
D oc u me nte d disease pr o gressi o n    
Date of disease pr o gressi o n  
Pr o gresse d  
I nitiati o n of alter nati ve a nti-
ca ncer treat me nts i n a bse nce of 
pr o gressi o n  
D ate of last t u m or assess me nt pri or 
t o i nitiati o n of s uc h treat me nt 
Ce ns ore d  
Deat h or pr o gressi o n 
i m me diatel y after missi n g t w o or 
m ore c o nsec uti ve sc he d ule d 
t u m or assess me nts 
Date of last t u m or assess me nt pri or 
t o misse d assess me nts 
Ce ns ore d  
 
 
 
C o nfi d e nti al
P a g e   
1 3 3   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
A p pe n di x 6    
E aster n C o o per ati ve O nc ol o g y Gr o u p ( E C O G) 
Perf or m a nce St at u s  
Gr a de  
Descri pti o n  
0  
F ull y acti ve, a ble t o carr y o n all pre -disease perf or ma nce wit h o ut restricti o n.  
1  
Restricte d i n p h ysicall y stre n u o us acti vit y, b ut a m b ulat or y a n d a ble t o carr y o ut w or k of 
a li g ht or se de ntar y nat ure (e. g., li g ht h o use w or k or office w or k)  
2  
A m b ulat or y a n d ca pa ble of all self -care, b ut u na ble t o carr y o ut a n y w or k acti vities. U p 
a n d a b o ut m ore t ha n 5 0 % of wa ki n g h o urs.  
3  
Ca pa ble of o nl y li mite d self -c are, c o nfi ne d t o be d or c hair m ore t ha n 5 0 % of wa ki n g 
h o urs.  
4    
C o m pletel y disa ble d. Ca n n ot carr y -o n a n y self -care. T otall y c o nfi ne d t o be d or c hair.  
5  
Dea d  
 
 
 
C o nfi d e nti al
P a g e   
1 3 4   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
A p pe n di x 7    
R E CI S T 1. 1 G ui deli nes   
( A da pte d fr o m Eise n ha u er  2 0 0 9  (2 3 ) 
All patie nts wi ll be re q uire d t o ha ve at least 1 meas ura ble lesi o n t o be c o nsi dere d as h a vi n g 
meas urea ble diseas e at b aseli ne f or t he deter mi nati o n of eli gi bilit y f or t his st u d y.  
Meas ure a ble lesi o ns are defi ne d bel o w. 
M E A S U R A BI LI T Y O F T U M O R A T B A S E LI N E   
D E FI NI TI O N S  
At baseli ne, t u m or lesi o ns/l y m p h n o d es will be cat e g orize d meas ura bl e or n o n -meas ura bl e as 
f oll o ws: 
Me as ur a ble  
Tu m or lesi o ns : M ust be acc urat el y m eas ure d i n at least o ne di me nsi o n (l o n gest dia meter i n 
t he pla ne of meas ure me nt is t o be rec or de d) wit h a mi ni m u m  size of: 
 1 0 m m b y C T sca n ( C T s ca n slice t hic k ness n o greater t ha n 5 m m).  
 1 0 m m cali per meas ure m e nt b y cli nical e xa m (lesi o ns w hic h ca n n ot be acc uratel y 
meas ure d wit h cali pers s h o ul d be rec or de d as n o n -meas urea ble).  
 2 0 m m b y c hest X -ra y. 
 
M ali g n a nt ly m p h n o des : To be c o nsi dere d pat h ol o gicall y e nlar ge d a n d meas urea ble, a l y m p h 
n o de m ust be ≥ 1 5 m m i n s h ort a xis w he n assesse d b y C T sca n ( C T sca n slice t hic k ness 
rec o m me n de d t o b e n o greater t ha n 5 m m). At bas eli ne a n d i n f oll o w-u p, o nl y t he s h ort a xis 
will be meas ure d a n d f oll o we d. See als o n otes bel o w o n ‘Baseli ne d oc u me ntati o n of tar get 
a n d n o n-tar get lesi o ns’ f or i nf or mati o n o n l y m p h n o de meas ure me nt. 
N o n -me as ur a ble  
All ot her lesi o ns, i ncl u di n g s mall lesi o ns (l o n gest dia meter < 1 0 m m or pat h ol o gical l y m p h 
n o des wit h ≥ 1 0 t o < 1 5 m m s h ort a xis) as well as tr ul y n o n -meas ura bl e lesi o ns. Lesi o ns 
c o nsi dere d tr ul y n o n -m eas urea ble i ncl u d e: le pt o me ni n geal diseas e, ascites, ple ural or 
pericar dial eff usi o n, i nfla m mat or y breast diseas e, l y m p ha n gitic i n v ol ve me nt of s ki n or l u n g, 
a b d o mi nal masses/a b d o mi nal or ga n o me gal y i de ntifie d b y p h ysical e xa m t hat is n ot 
meas urea bl e b y re pr o d uci ble i ma gi n g tec h ni q ues.  
S peci al c o nsi der ati o ns re g ar di n g lesi o n me as ur a bilit y  
B o ne lesi o ns, c ystic lesi o ns, a n d lesi o ns pre vi o usl y treate d wit h l ocal t hera p y re q uire 
partic ular c o m me nt:  
C o nfi d e nti al
P a g e   
1 3 5   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
B o ne lesi o ns:  
 B o ne sca n, P E T sca n or plai n fil ms are n ot c o nsi d ere d a de q uate i ma gi n g 
tec h ni q ues t o meas ure b o ne lesi o ns. H o we ver, t hese tec h ni q ues ca n be us e d t o 
c o nfir m t he pres e nce or disa p peara nce of b o ne lesi o ns.  
 Lyti c b o ne lesi o ns or mi x e d l ytic -bl astic lesi o ns, wit h i de ntifia ble s oft tiss ue 
c o m p o ne nts,  t hat ca n be e val uate d b y cr oss secti o nal i ma gi n g tec h ni q ues s uc h as 
C T or M RI ca n be c o nsi dere d as m eas ura ble lesi o ns if t he s oft tiss ue c o m p o ne nt 
meets t he defi niti o n of meas ura bilit y descri be d a b o ve.  
 Blastic b o ne lesi o ns are n o n -meas ura bl e.  
 
C ystic lesi o ns:  
 Lesi o ns t hat meet t he crit eria f or ra di o gra p hicall y defi ne d si m ple c ysts s h o ul d n ot 
be c o nsi dere d as mali g na nt lesi o ns ( neit her meas urea ble n or n o n -meas ura bl e) 
si nce t he y are, b y defi 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 metast ases ca n be c o nsi dere d as 
meas ura ble l esi o ns, if t he y meet t he defi niti o n of meas ura bilit y descri be d a b o ve. 
H o we ver, if n o n -c ystic lesi o ns are pres e nt i n t he sa me patie nt, t hese are preferre d 
f or selecti o n as t ar get lesi o ns. 
 
Lesi o ns wit h pri or l ocal treat me nt: 
 T u m or lesi o ns sit uate d i n a pre vi o usl y irra di ate d area, or i n a n area s u bjecte d t o 
ot her l oc o -re gi o nal t hera p y, are n ot c o nsi dere d meas ura bl e u nless t here has bee n 
de m o nstrate d pr o gressi o n i n t he lesi o n pri or t o st u d y e nr oll me nt.  
 
S P E CI FI C A TI O N S B Y M E T H O D S O F M E A S U R E M E N T S  
Me as ure me nt of lesi o ns  
All meas ure me nts s h o ul d be rec or de d i n metric n otati o n, usi n g cali pers if cli nicall y ass esse d. 
All baseli ne e val uati o ns s h o ul d be perf or me d as cl ose as p ossi ble t o t he treat me nt start a n d 
ne ver m ore t ha n 4 wee ks bef ore t h e be gi n ni n g of t he treat me nt.  
Met h o d of assess me nt  
T he sa me met h o d of assess me nt a n d t he sa me tec h ni q ue s h o ul d be use d t o c haract erize eac h 
i de ntifie d a n d re p orte d lesi o n at baseli ne a n d d uri n g f oll o w-u p. I ma gi n g bas e d e val uati o n 
s h o ul d alwa ys b e d o ne rat her t ha n cli nical e xa mi nati o n u nless t he lesi o n(s) bei n g f oll o we d 
ca n n ot be i ma ge d b ut are assessa ble b y cli nical e xa m.  
C o nfi d e nti al
P a g e   
1 3 6   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
Cli nic al lesi o ns: Cli nical lesi o ns will o nl y be c o nsi dere d meas ura ble w he n t he y are 
s u perficial a n d ≥ 1 0 m m dia meter as assesse d usi n g cali pers (e. g. s ki n n o d ules). F or t he cas e 
of s ki n lesi o ns, d oc u me ntati o n b y c ol or p h ot o gra p h y i ncl u di n g a r uler t o esti mate t he size of 
t he lesi o n is s u g geste d. As n ote d a b o ve, w he n lesi o ns ca n be e val uate d b y b ot h cli nical e xa m 
a n d i ma gi n g, i ma gi n g e v al uati o n s h o ul d be u n derta ke n si nce it is m ore o bjecti ve a n d ma y 
als o be re vie we d at t he e n d of t he st u d y.  
C hest X -r ay: C hest C T is preferre d o ver c hest X -ra y, partic ularl y w he n pr o gressi o n is a n 
i m p orta nt e n d p oi nt, si nce C T is m ore se nsiti ve tha n X -ra y, partic ul arl y i n i de ntif yi n g ne w 
lesi o ns. H o we ver, l esi o ns o n c hest X-ra y ma y be c o nsi dere d meas ura ble if t he y are clearl y 
defi ne d a n d s urr o u n de d b y aerat e d l u n g.  
C T, M RI:  C T is t he best c urre ntl y a vaila ble a n d re pr o d uci ble met h o d t o meas ure les i o ns 
selecte d f or res p o ns e ass ess me nt. T his g ui deli ne has defi ne d meas ura bilit y of lesi o ns o n C T 
sca n base d o n t h e ass u m pti o n t hat C T slice t hic k ness is 5 m m or less. W he n C T sca ns ha ve 
slice t hic k ness greater t h a n 5 m m, t he mi ni m u m size f or a meas ura ble lesi o n s h o ul d be t wice 
t he slice t hic k ness. M RI is als o acce pta ble i n certai n sit uati o ns (e. g. f or b o d y sca ns).  
Ultr as o u n d:  Ultras o u n d is n ot usef ul i n assess me nt of lesi o n size a n d s h o ul d n ot be use d as a 
met h o d of meas ure m e nt. Ultras o u n d e xa mi nati o ns ca n n ot be re pr o d uce d i n t heir e ntiret y f or 
i n de pe n de nt re vi e w at a l ater date a n d, beca use t h e y are o perat or de pe n de nt, it ca n n ot be 
g uara ntee d t hat t he sa me tec h ni q ue a n d meas ure m e nts will be ta ke n fr o m o ne assess me nt t o 
t he ne xt. If ne w lesi o ns are i de ntifie d b y ultras o u n d i n t he c o urse of t he st u d y, c o nfir mati o n 
b y C T or M RI is a d vise d. If t here is c o ncer n a b o ut ra diati o n e x p os ure at C T, M RI ma y be 
use d i nstea d of C T i n sel ecte d i nsta nces.  
E n d osc o py, l a p ar os c o py:  T he utilizati o n of t hese tec h ni q ues f or o bj ecti ve t u m or e val uati o n is 
n ot a d vise d.  
Tu m or m arkers:  T u m or mar kers al o ne  ca n n ot be use d t o assess o bjective  t u m or res p o nse. 
T U M O R R E S P O N S E E V A L U A TI O N   
A S S E S S M E N T O F O V E R A L L T U M O R B U R D E N A N D M E A S U R A B L E DI S E A S E  
To assess o bjecti ve res p o nse or f ut ure pr o gressi o n, it is necessar y t o esti mate t he over all 
t u m or b ur de n at b aseli ne a n d use t his as a c o m parat or f or s u bse q ue nt meas ure me nts. O nl y 
patie nts wit h meas ura ble disease at baseli ne s h o ul d be i ncl u de d. Meas ura bl e disease is 
defi ne d b y t he prese nce of at least o ne meas ura bl e lesi o n (as detaile d a b o ve).  
B A S E LI N E D O C U M E N T A TI O N O F ‘T A R G E T ’ A N D ‘N O N -T A R G E T ’ L E SI O N S  
W here m ore t ha n o ne meas ura ble lesi o n is pres e nt at baseli ne all lesi o ns u p t o a ma xi m u m of 
fi ve lesi o ns t otal (a n d a ma xi m u m of t w o lesi o ns per or ga n) re pres e ntati ve of all i n v ol ve d 
or ga ns s h o ul d be i de ntifi e d as t ar get lesi o ns a n d will be rec or de d a n d meas ure d at baseli ne. 
F or e x a m ple, i n i nsta nces w here p atie nts ha ve o nl y o ne or t w o or ga n sites i n v ol ve d, a 
ma xi m u m of t w o a n d f o ur lesi o ns res pecti vel y will be rec or de d). Tar get lesi o ns s h o ul d be 
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selecte d o n t he b asis of t heir size (lesi o ns wit h t he l o n gest dia meter), be re prese ntati ve of all 
i n v ol ve d or ga ns, b ut i n a d diti o n s h o ul d be t h ose t hat le n d t he msel ves t o re pr o d uci ble 
re pe ate d me as ure me nts. It ma y be t h e cas e t hat, o n occasi o n, t he lar gest lesi o n d oes n ot le n d 
itself t o re pr o d uci ble meas ure me nt i n w hic h circ u msta nce t he ne xt lar gest l esi o ns w hic h ca n 
be meas ure d re pr o d uci bl y s h o ul d be sel ecte d.  
Ly m p h n o des  merit s peci al me nti o n si nce t he y are n or mal a nat o mical str uct ures w hic h ma y 
be visi ble b y i ma gi n g e v e n if n ot i n v ol ve d b y t u m or. As n ot e d a b o ve, pat h ol o gical n o d es 
w hic h are d efi ne d as meas ura ble a n d ma y be i de ntifie d as tar get lesi o ns m ust meet criteri o n 
of a s h ort a xis of ≥ 1 5 m m b y C T sca n. O nl y t he s h ort a xis of t hese n o des will c o ntri b ute t o 
t he baseli ne s u m. T he s h ort a xis of t he n o de is t he dia meter n or mall y use d b y ra di ol o gists t o 
j u d ge if a n o de is i n v ol ve d b y s oli d t u m or. N o dal size is n or mall y re p orte d as t w o di me nsi o ns 
i n t he pla ne i n w hic h t he i ma ge is o btai ne d (f or C T sca n t his is al m ost al wa ys t he a xial pla ne; 
f or M RI t he pla ne of ac q uisiti o n ma y be a xial, sa g gital or c or o nal). T he s m aller of t hese 
meas ures is t he s h ort a xis. F or e x a m ple, a n a b d o mi nal n o de w hic h is re p orte d as bei n g 
2 0  m m x  3 0  m m has a s h ort a xis of 2 0 m m a n d q ualifies as a mali g na nt, meas ura ble n o de. I n 
t his e x a m ple, 2 0 m m s h o ul d be rec or de d as t he n o de meas ure me nt. All ot her pat h ol o gical 
n o des (t h ose wit h s h ort a xis ≥ 1 0 m m b ut < 1 5 m m) s h o ul d be c o nsi dere d n o n -tar get lesi o ns. 
N o des t hat ha ve a s h ort a xis < 1 0 m m are c o nsi dere d n o n -pa t h ol o gical a n d s h o ul d n ot be 
rec or de d or f oll o we d. 
A s u m of t he di a meters (l o n gest f or n o n-n o dal lesi o ns, s h ort a xis f or n o dal lesi o ns) f or all 
tar get lesi o ns will be cal c ulate d a n d re p orte d as t h e b aseli ne s u m di a meters.  If l y m p h n o d es 
are t o be i ncl u d e d i n t he s u m, t he n as n ote d a b o ve, o nl y t he s h ort a xis is a d de d i nt o t he s u m. 
T he baseli ne s u m dia met ers will be use d as refere nce t o f urt her c haracterize a n y o bjecti ve 
t u m or re gressi o n i n t he meas ura ble di me nsi o n of t he disease. 
All ot her lesi o ns ( or sites of disease) i ncl u di n g pat h ol o gical l y m p h n o des s h o ul d be i de ntifie d 
as n o n -t ar get lesi o ns a n d s h o ul d als o be rec or de d at baseli ne. Meas ure me nts are n ot re q uire d 
a n d t hese lesi o ns s h o ul d be f oll o we d as ‘pres e nt ’, ‘a bse nt’, or i n rare cas es ‘u ne q ui v ocal 
pr o g ressi o n. I n a d diti o n, it is p ossi ble t o rec or d m ulti ple n o n-tar get lesi o ns i n v ol vi n g t he 
sa me or ga n as a si n gle ite m o n t he case rec or d f or m (e. g. ‘m ulti ple e nlar ge d pel vic l y m p h 
n o des ’ or ‘m ulti ple li ver metastases ’). 
R E S P O N S E C RI T E RI A  
T his secti o n pr o vi des t he defi niti o ns of t he criteria use d t o deter mi ne o bjecti ve t u m or 
res p o nse f or tar get lesi o ns. 
E v al u ati o n of t ar get lesi o ns  
C o m plete Res p o nse ( C R) : Disa p peara nce of all tar get lesi o ns. A n y pat h ol o gical l y m p h n o des 
( w het her t ar get or n o n-tar get) m ust ha ve re d ucti o n i n s h ort a xis t o < 1 0 m m. 
P arti al Res p o nse ( P R) : at least a 3 0 % decrease i n t he s u m of dia meters of t ar get lesi o ns, 
ta ki n g as refere n ce t he baseli ne s u m dia meters.  
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Pr o gressive Dise ase ( P D) : at least a 2 0 % i ncreas e i n t he s u m of dia meters of tar get lesi o ns, 
ta ki n g as refere n ce t he s m allest s u m o n st u dy (t his i ncl u des t he baseli ne s u m if t hat is t he 
s mallest o n st u d y). I n a d diti o n t o t he relati ve i ncrease of 2 0 %, t he s u m m ust als o de m o nstrate 
a n a bs ol ute i ncrease of at least 5 m m. ( N ote:  t he a p peara nce of o ne or m ore ne w lesi o ns is 
als o c o nsi dere d pr o gressi o n).  
St a ble Dise ase ( S D) : N eit her s uffici e nt s hri n ka ge t o q ualif y f or P R n or s ufficie nt i ncrease t o 
q ualif y f or P D, ta ki n g as refere nce t he s mallest s u m dia meters w hile o n st u d y.  
S peci al n o tes o n t he assess me nt of t ar get lesi o ns 
Ly m p h n o des.  Ly m p h n o des i de ntifie d as tar get lesi o ns s h o ul d al wa ys ha ve t he act ual s h ort 
a xis meas ure me nt rec or de d ( meas ure d i n t he sa me a nat o mical pla ne as t he baseli ne 
e x a mi nati o n), e ve n if t he n o des re gress t o be l o w 1 0 m m o n st u d y. T his mea ns t hat w he n 
l y m p h n o des are i ncl u de d as tar get lesi o ns, t he ‘s u m’ of lesi o ns ma y n ot b e zer o e ve n if 
c o m plete res p o nse criteria are m et, si nce a n or mal l y m p h n o de is defi n e d as ha vi n g a s h ort 
a xis of < 1 0 m m. I n or der t o q ualif y  f or C R, eac h n o de m ust ac hie ve a s h ort a xis < 1 0 m m. F or 
P R, S D a n d P D, t he act ual s h ort a xis meas ure me nt of t he n o des is t o be i ncl u de d i n t he s u m 
of tar get lesi o ns.  
Tar get lesi o ns t h at bec o me ‘t o o s m all t o me as ure’. W hile o n st u d y, all lesi o ns ( n o dal a n d  
n o n -n o dal) rec or de d at b aseli ne s h o ul d ha ve t heir act ual meas ure me nts rec or de d at eac h 
s u bse q ue nt e val uati o n, e ve n w he n ver y s mall (e. g. 2 m m). H o we ver, s o m eti mes lesi o ns or 
l y m p h n o des w hic h are rec or de d as tar get lesi o ns at baseli ne bec o me s o fai nt o n CT sca n t hat 
t he ra di ol o gist ma y n ot feel c o mf orta ble assi g ni n g a n e xact meas ure a n d ma y re p ort t he m as 
bei n g ‘t o o s mall t o meas ure’. W he n t his occ urs it is i m p orta nt t hat a val ue be rec or de d o n t he 
case re p ort f or m. If it is t he o pi ni o n of t he ra di ol o gist t hat t he lesi o n has li kel y disa p peare d, 
t he meas ure m e nt s h o ul d be rec or de d as 0 m m. If t he lesi o n is belie ve d t o b e prese nt a n d is 
fai ntl y see n b ut t o o s mall t o meas ure, a defa ult val ue of 5 m m s h o ul d be assi g ne d (N ote:  It is 
less li kel y t hat t his r ule will be use d f or l y m p h n o des si nce t he y us uall y ha ve a defi na ble size 
w he n n or mal a n d are fre q ue ntl y s urr o u n de d b y fat s uc h as i n t he retr o perit o ne u m; h o we ver, if 
a l y m p h n o de is belie ve d t o be prese nt a n d is fai ntl y see n b ut t o o s mall t o meas ure, a defa ult 
v al ue of 5 m m s h o ul d be assi g ne d i n t his circ u msta nce as well). T his defa ult val ue is deri ve d 
fr o m t he 5 m m C T slice t hic k ness ( b ut s h o ul d n ot be c ha n ge d wit h var yi n g C T slice 
t hic k ness). T he meas ure me nt of t hese lesi o ns is p ote ntiall y n o n-re pr o d uci ble, t heref ore 
pr o vi di n g t his defa ult val ue will pre ve nt false res p o nses or pr o gressi o ns base d u p o n 
meas ure me nt err or. H o we ver, if t he ra di ol o gist is a ble t o pr o vi de a n act ual meas ure, t hat 
s h o ul d be rec or de d, e v e n if it is bel o w 5 m m. 
Lesi o ns t h at s plit or c o ales ce o n tre at me nt.  W he n n o n -n o dal lesi o ns ‘fra g me nt’, t he l o n gest 
dia meters of t he fra g me nte d p orti o ns s h o ul d be a d de d t o get her t o calc ulate t he tar get lesi o n 
s u m. Si milarl y, as lesi o ns c oalesce, a pla ne bet wee n t he m ma y be mai ntai ne d t hat w o ul d ai d 
i n o btaini n g ma xi mal dia meter meas ure me nts of eac h i n di vi d ual lesi o ns. If t he lesi o ns ha ve 
tr ul y c oalesce d s uc h t hat t he y are n o l o n ger se para ble, t he vect or of t he l o n gest dia meter i n 
t his i nsta nce s h o ul d be t he ma xi mal l o n gest dia meter f or t he ‘c oal esce d lesi o n ’. 
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E v al u ati o n of n o n -t ar get lesi o ns 
T his secti o n pr o vi des t he defi niti o ns of t he criteria use d t o deter mi ne t he t u m or res p o nse f or 
t he gr o u p of n o n-tar get lesi o ns. W hile s o me n o n-tar get lesi o ns ma y act u all y be meas urea ble, 
t he y n ee d n ot be meas ure d a n d i nstea d s h o ul d be assesse d o nl y q u alit atively  at t he ti me 
p oi nts s pecifie d i n t he pr ot oc ol.  
C o m plete Res p o nse ( C R):  Disa p peara nce of all n o n -tar get lesi o ns. All l y m p h n o des m ust be 
n o n -pat h ol o gical i n size ( < 1 0 m m s h ort a xis).  
N o n -C R/ N o n -P D : Persiste nce of o ne or m ore n o n -tar get lesi o ns(s). 
Pr o gressive Dise ase ( P D) : U ne q uiv oc al pr o gressi o n  (see c o m me nts bel o w) of e xisti n g n o n-
tar get lesi o ns. (N ote:  t he a p peara nce of o ne or m ore ne w lesi o ns is als o c o nsi dere d 
pr o gressi o n).  
S pecial n otes o n assess m e nt of pr o gress i o n of n o n-tar get disease 
T he c o nce pt of pr o gressi o n of n o n -tar get disease re q uires a d diti o nal e x pla nati o n as f oll o ws: 
W h e n a p atie nt als o h as me as ur a ble dise ase . I n t his setti n g, t o ac hie ve ‘u ne q ui v ocal 
pr o gressi o n; o n t he basis of t he n o n -tar get disease, t here m ust be a n o verall le vel of 
s u bsta ntial w orse ni n g i n n o n-tar get disease s uc h t hat, e ve n i n pres e nce of S D or P R i n tar get 
disease, t he o verall t u m or b ur de n has i n crease d s ufficie ntl y t o merit disc o nti n uati o n of 
t hera p y. A m o dest ‘i ncrease’ i n t he size of o ne or m ore n o n -tar get lesi o ns is us uall y n ot 
s ufficie nt t o q ualit y f or u ne q ui v ocal pr o gressi o n stat us. T he desi g nati o n of o verall 
pr o gressi o n s olely o n t he basis of c ha n ge i n n o n -tar get disease i n t he face of S D or P R of 
tar get diseas e will t heref ore be e xtre mel y rare.  
W h e n t he p atie nt h as o nly n o n -me as ur a ble dise ase.  T he sa m e ge neral c o nce pts a p pl y here as 
n ote d a b o ve, h o wever , i n t his i nsta nce t here is n o meas ura ble disease assess me nt t o fact or 
i nt o t he i nter pretati o n of a n i ncrease i n n o n-meas ura b le diseas e b ur de n. Beca use w ors e ni n g 
i n n o n-tar get diseas e ca n n ot be easil y q ua ntifie d ( b y defi niti o n: if all lesi o ns are tr ul y n o n-
meas ura ble) a usef ul test t hat ca n be a p plie d w he n assessi n g patie nts f or u ne q ui v ocal 
pr o gressi o n is t o c o nsi der if t he i ncr ease i n o verall disease b ur de n base d o n t he c ha n ge i n 
n o n -meas ura bl e disease is c o m para ble i n ma g nit u de t o t he i ncrease t hat w o ul d be re q uire d t o 
declare P D f or meas ura bl e disease: i.e. a n i ncrease i n t u m or b ur de n re prese nti n g a n 
a d diti o nal 7 3 % i ncrease i n  ‘v ol u me ’ ( w hic h is e q ui vale nt t o a 2 0 % i ncrease dia meter i n a 
meas ura ble l esi o n). E xa m ples i ncl u de a n i ncreas e i n a ple ural eff usi o n fr o m ‘trace’ t o ‘lar ge’, 
a n i ncrease i n l y m p h a n gitic disease fr o m l ocalize d t o wi des prea d, or ma y be descri be d i n 
pr ot oc ol s as ‘s ufficie nt t o re q uire a c ha n ge i n t hera p y’. If ‘u ne q ui v ocal pr o gressi o n ’ is see n, 
t he patie nt s h o ul d be c o nsi dere d t o ha ve ha d o verall P D at t hat p oi nt. W hile it w o ul d be i deal 
t o ha ve o bjecti ve criteria t o a p pl y t o n o n-meas ura ble disease, t he ver y n at ure of t hat disease 
ma kes it i m p ossi ble t o d o s o; t heref ore, t he i ncreas e m ust be s u bsta ntial.  
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Ne w Lesi o ns  
T he a p peara n ce of ne w mali g na nt lesi o ns de n otes disease pr o gressi o n. T here are n o s pecific 
criteria f or t he i de ntificati o n of ne w ra di o gra p hic lesi o ns; h o we ver, t he fi n di n g of a ne w 
lesi o n s h o ul d be u ne q ui v ocal: i.e. n ot attri b uta ble t o differe nces i n sca n ni n g tec h ni q ue, 
c ha n ge i n i ma gi n g m o dalit y or fi n di n gs t h o u g ht t o re pres e nt s o met hi n g ot h er t ha n t u m or (f or 
e x a m ple, s o me ‘ne w ’ b o ne lesi o ns ma y be  si m pl y heali n g or flare of pre-e xisti n g lesi o ns). 
T his is partic ularl y i m p orta nt w he n t he patie nt ’s b aseli ne lesi o ns s h o w partial or c o m plete 
res p o nse. F or e x a m ple, n ecr osis of a li ver lesi o n ma y be re p orte d o n a C T sca n re p ort as a 
‘ne w ’ c ystic lesi o n, w hic h it is n ot.  
A lesi o n i de ntifie d o n a f oll o w -u p st u d y i n a n a nat o mical l ocati o n t hat was n ot  sca n ne d at 
baseli ne is c o nsi dere d a n e w lesi o n a n d will i n dicate disease pr o gressi o n. A n e xa m ple of t his 
is t he patie nt w h o has visceral disease at b aseli ne a n d w hile o n st u d y has a C T or M RI brai n 
or dere d w hic h re v eals m etastases. T he patie nt ’s brai n metastases are c o nsi dere d t o be 
e vi de nce of P D e ve n if he/s he di d n ot ha ve brai n i ma gi n g at b aseli ne.  
If a ne w lesi o n is e q ui v ocal, f or e xa m ple beca use of its s mall size, c o nti n ue d t hera p y a n d 
f oll o w-u p e val uati o n will clarif y if it re prese nts tr ul y ne w dis ease. If re peat sca ns c o nfir m 
t here is defi nitel y a n e w l esi o n, t he n pr o gressi o n s h o ul d be declare d usi n g t he date of t he 
i nitial sca n.  
E V A L U A TI O N O F B E S T O V E R A L L  R E S P O N S E  
T he best o verall res p o nse is t he best res p o nse rec or de d fr o m t he start of t he st u d y treat me nt 
u ntil t he e n d of treat me nt ta ki n g i nt o acc o u nt a n y re q uire me nt f or c o nfir mati o n. T he patie nt ’s 
best o verall res p o ns e assi g n me nt will de pe n d o n t h e fi n di n gs of b ot h tar get a n d n o n -tar get 
disease a n d will als o ta ke i nt o c o nsi derati o n t he a p peara nce of ne w lesi o ns.  
Ti me p oi nt res p o nse  
It is ass u me d t hat at eac h pr ot oc ol s pecifie d ti me p oi nt, a res p o nse ass ess me nt occ urs. 
Ta ble  A -1  o n t he ne xt pa ge pr o vi des a s u m mar y of t he o verall res p o nse stat us calc ulati o n at 
eac h ti me p oi nt f or p atie nts w h o ha ve meas urea bl e disease at baseli ne.  
Missi n g assess me nts a n d i ne v al u a ble desi g n ati o n 
W he n n o i ma gi n g/ meas ure me nt is d o ne at all at a partic ular ti me p oi nt, t he patie nt is n ot 
e val ua ble ( N E) at t hat ti me p oi nt. If o nl y a s u bset of lesi o n meas ure m e nts are ma de at a n 
assess me nt, us uall y t he case is als o c o nsi dere d N E a t t hat ti me p oi nt, u nless a c o n vi nci n g 
ar g u me nt ca n be ma de t hat t he c o ntri b uti o n of t he i n di vi d ual missi n g lesi o n(s) w o ul d n ot 
c ha n ge t he assi g n e d ti me p oi nt res p o nse. T his w o ul d be m ost li kel y t o h a p pe n i n t he case of 
P D. F or e x a m ple, if a patie nt ha d a baseli ne s u m of 5 0 m m wit h t hree meas ure d lesi o ns a n d 
at f oll o w-u p o nl y t w o l esi o ns were ass esse d, b ut t h ose ga ve a s u m of 8 0 m m, t he patie nt will 
ha ve ac hie ve d P D stat us, re gar dless of t he c o ntri b uti o n of t he missi n g lesi o n.  
C o nfi d e nti al
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Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
Best o ver all res p o nse: all ti me p oi nts  
T he best over all res p o ns e  is deter mi ne d o nce all t he data f or t he patie nt is k n o w n. 
Ta ble  A -1    
Ti me p oi nt res p o nse: p atie nts wit h t ar get ( +/ - n o n -t ar get) 
dise ase                          
Tar get lesi o ns    
N o n -t ar get lesi o ns   
Ne w lesi o ns    
O ver all res p o nse  
C R  
C R  
N o  
C R  
C R  
N o n -C R/ n o n -P D  
N o  
P R  
C R  
N ot e val uate d  
N o  
P R  
P R  
N o n -P D or n ot all 
e val uate d  
N o  
P R  
S D  
N o n -P D or n ot all 
e val uate d  
N o  
S D  
N ot all e val uate d  
N o n -P D  
N o  
N E  
P D  
A n y  
Yes or N o  
P D  
A n y  
P D  
Yes or N o  
P D  
A n y  
A n y  
Yes  
P D  
C R = c o m plete res p o nse, P R = partial res p o nse, S D = sta ble disease, P D = pr o gressi ve disease, a n d N E = 
i ne val ua ble. 
 
Best res p o nse det er mi n ati o n i n tri als w here c o nfir m ati o n of c o m plete or p arti al res p o nse I S 
re q uire d: C o m plete or p artial res p o nses ma y be cl ai me d o nl y if t he o bj ecti ve res p o nse is 
c o nfir me d o n a f oll o w -u p sca n o btai ne d n o less t ha n 4 wee ks after t he i nitial sca n 
de m o nstrati n g a n o bjecti ve res p o nse. I n t his circ u msta nce, t he best o verall res p o nse ca n be 
inter prete d as i n Ta ble  A -2 . 
C o nfi d e nti al
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A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
Ta ble  A -2    
Best o ver all res p o nse w he n c o nfir m ati o n of C R a n d P R re q uire d                          
O ver all res p o nse  
First ti me p oi nt  
O ver all res p o nse  
S u bse q ue nt ti me p oi nt  
 
B E S T o ver all res p o nse  
C R  
C R  
C R  
C R  
P R  
S D, P D or P R  a 
C R  
S D  
S D  
C R  
P D  
S D  
C R  
N E  
S D  
P R  
C R  
P R  
P R  
P R  
P R  
P R  
S D  
S D  
P R  
P D  
S D pr o vi de d mi ni m u m criteri a f or S D d urati o n met, 
ot her wise, P D  
P R  
N E  
S D pr o vi de d mi ni m u m criteri a f or S D d urati o n met, 
ot her wise, N E  
N E  
N E  
N E  
C R = c o m plete res p o nse, P R = partial res p o nse, S D = sta ble disease, P D = pr o gressi ve disease, a n d N E = 
i ne val ua ble. 
a  
If a C R is tr uly met at first ti me p oi nt, t he n a n y disease see n at a s u bse q ue nt ti me p oi nt, e ve n disease 
meeti n g P R criteria relati ve t o baseli ne, ma kes t he disease P D at t hat p oi nt (si nce disease m ust ha ve 
rea p peare d after C R). Best res p o nse w o ul d de pe n d o n w het her mi ni mu m d urati o n f or S D was met. 
H o we ver, s o meti mes ‘ C R’ ma y be clai me d w he n s u bse q ue nt sca ns s u g gest s mall lesi o ns were li kel y still 
prese nt a n d i n fact t he patie nt ha d P R, n ot C R at t he first ti me p oi nt. U n der t hese circ u msta nces, t he 
ori gi nal C R s h o ul d be c h a n ge d t o P R a n d t he best res p o nse is P R.  
 
S peci al n otes o n res p o nse assess me nt  
W he n n o dal disease is i ncl u de d i n t he s u m of tar get lesi o ns a n d t he n o des decrease t o 
‘n or mal ’ size ( < 1 0 m m), t he y ma y still ha ve a meas ure me nt re p orte d o n sca ns . T his 
meas ure me nt s h o ul d be rec or de d e ve n t h o u g h t he n o des are n or mal i n or der n ot t o o verstate 
pr o gressi o n s h o ul d it be base d o n i ncrease i n size of t he n o des. As n ote d earlier, t his mea ns 
t hat patie nts wit h C R ma y n ot ha ve a t otal s u m of ‘zer o’ o n t he ca s e re p ort f or m ( C R F). 
Patie nts wit h a gl o bal det eri orati o n of healt h stat us re q uiri n g disc o nti n uati o n of treat me nt 
wit h o ut o bjecti ve e vi de nce of disease pr o gressi o n at t hat ti me s h o ul d be re p orte d as 
‘s y m pt o matic det eri orati o n”. E ver y eff ort s h o ul d be ma de  t o d oc u me nt o bj ecti ve pr o gressi o n 
e ve n after disc o nti n uati o n of treat me nt. S y m pt o m atic deteri orati o n is n ot  a descri pt or of a n 
o bjecti ve res p o nse: it is a reas o n f or st o p pi n g st u d y t hera p y. T he o bjecti ve res p o nse stat us of 
s uc h patie nts is t o be deter mi ned b y e val u ati o n of tar get a n d n o n -tar get disease as s h o w n i n 
Ta ble  A -1  a n d Ta ble  A -2 . 
F or e q ui v o cal fi n di n gs of pr o gressi o n (e. g. ver y s mall a n d u ncertai n n e w lesi o ns; c ystic 
c ha n ges or necr osis i n e xisti n g lesi o ns), treat me nt ma y c o nti n ue u ntil t he ne xt sc he d ule d 
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A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
assess me nt. If at t he n e xt sc he d ule d ass ess me nt, pr o gressi o n is c o nfir me d, t he date of 
pr o gressi o n s h o ul d be t h e earlier date w he n pr o gressi o n was s us pecte d.  
C O N FI R M A TI O N/ D U R A TI O N O F R E S P O N S E  
C o nfir m ati o n  
O bjecti ve res p o ns es s h o ul d be c o nfir me d b y C T a n d/ or M RI sca ns o btai ne d n o less t ha n 4  
wee ks after t he ori gi n al sca n.  
D ur ati o n of o ver all res p o nse  
T he d urati o n of o verall res p o nse is meas ure d fr o m t he ti me meas ure me nt criteria are first met 
f or C R/ P R ( w hic he ver is first rec or de d) u ntil t he first date t hat rec urre nt or pr o gressi ve 
disease is  o bjecti vel y d oc u me nte d (ta ki n g as refere nce f or pr o gressi ve dis ease t he s mallest 
meas ure me nts rec or de d o n st u d y). T he d urati o n of o verall c o m plete res p o ns e is meas ure d 
fr o m t he ti me meas ure me nt criteria are first met f or C R u ntil t he first date t hat rec urre nt 
disease is o bjecti vel y d oc u me nte d.  
D ur ati o n of st a ble dise ase  
Sta ble disease is meas ure d fr o m t he start of t he treat me nt u ntil t he criteria f or pr o gressi o n are 
met, ta ki n g as refere n ce t he s m allest s u m o n st u dy (if t he baseli ne s u m is t he s mallest, t his is 
t he refere n ce f or cal c ulati o n of P D). 
C o nfi d e nti al
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A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
A p pe n di x 8    
I m m u ne-Rel ate d R E CI S T G ui deli nes   
[A da pte d fr o m Wolc h o k 2 0 0 9  (8 2 )] 
All patie nts will b e re q uire d t o ha ve at least 1 meas ura ble lesi o n t o be c o nsi dere d as h a vi n g 
meas urea ble diseas e at b aseli ne f or t he deter mi nati o n of eli gi bilit y f or t his st u d y. 
Meas urea ble lesi o ns are defi ne d bel o w.  
M E A S U R A BI LI T Y O F T U M O R A T B A S E LI N E   
D E FI NI TI O N S  
At baseli ne, t u m or lesi o ns/l y m p h n o d es will be cat e g orize d meas ura bl e or n o n -meas ura bl e as 
f oll o ws: 
Me as ur a ble  
Tu m or lesi o ns : M ust be acc urat el y m eas ure d i n at least o ne di me nsi o n (l o n gest dia meter i n 
t he pla ne of meas ure me nt is t o be rec or de d) wit h a mi ni m u m  size of: 
 1 0 m m b y C T sca n ( C T s ca n slice t hic k ness n o greater t ha n 5 m m).  
 1 0 m m cali per meas ure m e nt b y cli nical e xa m (lesi o ns w hic h ca n n ot be acc uratel y 
meas ure d wit h cali pers s h o ul d be rec or de d as n o n -meas urea ble).  
 2 0 m m b y c hest X -ra y. 
 
M ali g n a nt ly m p h n o des : To be c o nsi dere d pat h ol o gicall y e nlar ge d a n d meas urea ble, a l y m p h 
n o de m ust be ≥ 1 5 m m i n s h ort a xis w he n assesse d b y C T sca n ( C T sca n slice t hic k ness n o 
greater t ha n 5 m m). At  b aseli ne a n d i n f oll o w -u p, o nl y t he s h ort a xis will be meas ure d a n d 
f oll o we d. See als o n otes bel o w o n ‘Baseli ne d oc u me ntati o n of tar get a n d n o n -tar get lesi o ns’ 
f or i nf or mati o n o n l y m p h n o de meas ure me nt. 
N o n -me as ur a ble  
All ot her lesi o ns, i ncl u di n g s mall lesi o ns (l o n gest dia meter < 1 0 m m or pat h ol o gical l y m p h 
n o des wit h ≥ 1 0 t o < 1 5  m m s h ort a xis) as well as tr ul y n o n -meas ura bl e lesi o ns. Lesi o ns 
c o nsi dere d tr ul y n o n -m eas urea ble i ncl u d e: le pt o me ni n geal diseas e, ascites, ple ural or 
pericar dial eff usi o n, i nfla m mat or y breast diseas e, l y m p ha n gitic i n v ol ve me nt of s ki n or l u n g, 
a b d o mi nal masses/a b d o mi nal or ga n o me gal y i de ntifie d b y p h ysical e xa m t hat is n ot 
meas urea ble b y re pr o d uci ble i ma gi n g tec h ni q ues.  
S peci al c o nsi der ati o ns re g ar di n g lesi o n me as ur a bilit y  
B o ne les i o ns, c ystic lesi o ns, a n d lesi o ns pre vi o usl y treate d wit h l ocal t hera p y re q uire 
partic ular c o m me nt:  
C o nfi d e nti al
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A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
B o ne lesi o ns:  
 B o ne sca n, P E T sca n or plai n fil ms are n ot c o nsi d ere d a de q uate i ma gi n g 
tec h ni q ues t o meas ure b o ne lesi o ns. H o we ver, t hese tec h ni q ues ca n be us e d t o 
c o nfir m t he pres e nce or disa p peara nce of b o ne lesi o ns.  
 Lyti c b o ne lesi o ns or mi x e d l ytic -bl astic lesi o ns, wit h i de ntifia ble s oft tiss ue 
c o m p o ne nts, t hat ca n be e val uate d b y cr oss secti o nal i ma gi n g tec h ni q ues s uc h as 
C T or M RI ca n be c o nsi dere d as m e as ura ble lesi o ns if t he s oft tiss ue c o m p o ne nt 
meets t he defi niti o n of meas ura bilit y descri be d a b o ve.  
 Blastic b o ne lesi o ns are n o n -meas ura bl e.  
 
C ystic lesi o ns:  
 Lesi o ns t hat meet t he crit eria f or ra di o gra p hicall y defi ne d si m ple c ysts s h o ul d n ot 
be c o nsi dere d  as mali g na nt lesi o ns ( neit her meas urea ble n or n o n -meas ura bl e) 
si nce t he y are, b y defi 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 metast ases ca n be c o nsi dere d as 
meas ura ble l esi o ns, if t he y meet t he defi niti o n of meas ura bilit y descri be d a b o ve. 
H o we ver, if n o n -c ystic lesi o ns are pres e nt i n t he sa me patie nt, t hese are preferre d 
f or selecti o n as t ar get lesi o ns. 
 
Lesi o ns wit h pri or l ocal treat me nt:  
 T u m or lesi o ns sit uate d i n a pre vi o usl y irra di ate d area, or i n a n area s u bjecte d t o 
ot her l o c o-re gi o nal t hera p y, are n ot c o nsi dere d meas ura bl e u nless t here has bee n 
de m o nstrate d pr o gressi o n i n t he lesi o n pri or t o st u d y e nr oll me nt.  
 
S P E CI FI C A TI O N S B Y M E T H O D S O F M E A S U R E M E N T S  
Me as ure me nt of lesi o ns  
All meas ure me nts s h o ul d be rec or de d i n metric n otat i o n, usi n g cali pers if cli nicall y ass esse d. 
All baseli ne e val uati o ns s h o ul d be perf or me d as cl ose as p ossi ble t o t he treat me nt start a n d 
ne ver m o re t h a n 4 wee ks bef ore t he be gi n ni n g of t he tre at me nt . 
Met h o d of assess me nt  
T he sa me met h o d of assess me nt a n d t he sa me tec h ni q ue s h o ul d be use d t o c haract erize eac h 
i de ntifie d a n d re p orte d lesi o n at baseli ne a n d d uri n g f oll o w-u p. I ma gi n g bas e d e val uati o n 
s h o ul d al wa ys b e d o ne rat her t ha n cli nical e xa mi nati o n u nless t he lesi o ns(s) bei n g f oll o we d 
ca n n ot be i ma ge d b ut  are assessa ble b y cli nical e xa m.  
C o nfi d e nti al
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A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
Cli nic al lesi o ns: Cli nical lesi o ns will o nl y be c o nsi dere d meas ura ble w he n t he y are 
s u perficial a n d ≥ 1 0 m m dia meter as assesse d usi n g cali pers (e. g. s ki n n o d ules). F or t he cas e 
of s ki n lesi o ns, d oc u me ntati o n b y c ol or p h ot o gra p h y i ncl u di n g a r uler t o esti mate t he size of 
t he lesi o n is s u g geste d. As n ote d a b o ve, w he n lesi o ns ca n be e val uate d b y b ot h cli nical e xa m 
a n d i ma gi n g, i ma gi n g e v al uati o n s h o ul d be u n derta ke n si nce it is m ore o bjecti ve a n d ma y 
als o be re vie we d at t he e n d of t he st u d y.  
C hest X -r ay: C hest C T is preferre d o ver c hest X -ra y, partic ularl y w he n pr o gressi o n is a n 
i m p orta nt e n d p oi nt, si nce C T is m ore se nsiti ve t ha n X-ra y, partic ul arl y i n i de ntif yi n g ne w 
lesi o ns. H o we ver, l esi o ns o n c hest X-ra y ma y be c o nsi dere d meas ura ble if t he y are clearl y 
defi ne d a n d s urr o u n de d b y aerat e d l u n g.  
C T, M RI:  C T is t he best c urre ntl y a vaila ble a n d re pr o d uci ble met h o d t o meas ure lesi o ns 
selecte d f or res p o ns e ass ess me nt. T his g ui deli ne has defi ne d meas ura bilit y of lesi o ns o n C T 
sca n base d o n t h e ass u m pti o n t hat C T slice t hic k ness is 5 m m or less. W he n C T sca ns ha ve 
slice t hic k ness greater t h a n 5 m m, t he mi ni m u m size f or a meas ura ble lesi o n s h o ul d be t wice 
t he slice t hic k ness. M RI is als o acce pta ble i n certai n sit uati o ns (e. g. f or b o d y sca ns). 
Ultr as o u n d:  Ultras o u n d is n ot usef ul i n assess me nt of lesi o n size a n d s h o ul d n ot be use d as a 
met h o d of meas ure m e nt. Ultras o u n d e xa mi nati o ns ca n n ot be re pr o d uce d i n t heir e ntiret y f or 
i n de pe n de nt re vi e w at a l ater date a n d, beca use t h e y are o perator de pe n de nt, it ca n n ot be 
g uara ntee d t hat t he sa me tec h ni q ue a n d meas ure m e nts will be ta ke n fr o m o ne assess me nt t o 
t he ne xt. If ne w lesi o ns are i de ntifie d b y ultras o u n d i n t he c o urse of t he st u d y, c o nfir mati o n 
b y C T or M RI is a d vise d. If t here is c o ncer n a b o ut ra diati o n e x p os ure at C T, M RI ma y b e 
use d i nstea d of C T i n sel ecte d i nsta nces.  
E n d osc o py, l a p ar os c o py:  T he utilizati o n of t hese tec h ni q ues f or o bjecti ve t u m or e val uati o n is 
n ot a d vise d.  
Tu m or m arkers:  T u m or mar kers will n ot be use d t o assess o bjective  t u m or res p o nse. 
T U M O R R E S P O N S E E V A L U A TI O N   
A S S E S S M E N T O F O V E R A L L T U M O R B U R D E N A N D M E A S U R A B L E DI S E A S E  
To assess o bjecti ve res p o nse or f ut ure pr o gressi o n, it is necessar y t o esti mate t he over all 
t u m or b ur de n at b aseli ne a n d use t his as a c o m parat or f or s u bse q ue nt meas ure me nts. O nl y 
patie nts wit h meas ura ble disease at baseli ne s h o ul d be i ncl u de d. Meas ura bl e disease is 
defi ne d b y t he prese nce of at least o ne meas ura bl e lesi o n (as detaile d a b o ve).  
B A S E LI N E D O C U M E N T A TI O N O F ‘T A R G E T ’ A N D ‘N O N -T A R G E T ’ L E SI O N S  
W here m ore t ha n o ne meas ura ble lesi o n is pres e nt at baseli ne all lesi o ns u p t o a ma xi m u m of 
fi ve lesi o ns t otal (a n d a ma xi m u m of t w o lesi o ns per or ga n) re pres e ntati ve of all i n v ol ve d 
or ga ns s h o ul d be i de ntifi e d as t ar get lesi o ns a n d will be rec or de d a n d meas ure d at baseli ne. 
F or e x a m ple, i n i nsta nces w here p atie nts ha ve o nl y o ne or t w o or ga n sites i n v ol ve d, a 
ma xi m u m of t w o a n d f o ur lesi o ns res pecti vel y will be rec or de d). Tar get lesi o ns s h o ul d be 
C o nfi d e nti al
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selecte d o n t he b asis of t heir size (lesi o ns wit h t he l o n gest dia meter), be re prese ntati ve of all 
i n v ol ve d or ga ns, b ut i n a d diti o n s h o ul d be t h ose t hat le n d t he msel ves t o re pr o d uci ble 
re pe ate d me as ure me nts. It ma y be t h e cas e t hat, o n occasi o n, t he lar gest lesi o n d oes n ot le n d 
itself t o re pr o d uci ble meas ure me nt i n w hic h circ u msta nce t he ne xt lar gest l esi o ns w hic h ca n 
be meas ure d re pr o d uci bl y s h o ul d be sel ecte d.  
Ly m p h n o des  merit s peci al me nti o n si nce t he y are n or mal a nat o mical str uct ures w hic h ma y 
be visi ble b y i ma gi n g e v e n if n ot i n v ol ve d b y t u m or. As n ot e d pre vi o usl y, pat h ol o gical n o des 
w hic h are d efi ne d as meas ura ble a n d ma y be i de ntifie d as tar get lesi o ns m ust meet criteri o n 
of a s h ort a xis of ≥ 1 5 m m b y C T sca n. O nl y t he s h ort a xis of t hese n o des will c o ntri b ute t o 
t he baseli ne s u m. T he s h ort a xis of t he n o de is t he dia meter n or mall y use d b y ra di ol o gists t o 
j u d ge if a n o de is i n v ol ve d b y s oli d t u m or. N o dal size is n or mall y re p orte d as t w o di me nsi o ns 
i n t he pla ne i n w hic h t he i ma ge is o btai ne d (f or C T sca n t his is al m ost al wa ys t he a xial pla ne; 
f or M RI t he pla ne of ac q uisiti o n ma y be a xial, sa g gital or c or o nal). T he s m aller of t hese 
meas ures is t he s h ort a xis. F or e x a m ple, a n a b d o mi nal n o de w hic h is re p orte d as bei n g 2 0 
m m x 3 0 m m has a s h ort a xis of 2 0 m m a n d q ualifies as a mali g na nt, meas ura ble n o de. I n t his 
e x a m ple, 2 0 m m s h o ul d be rec or de d as t he n o de meas ure me nt. All ot her pat h ol o gical n o des 
(t h ose wit h s h ort a xis ≥ 1 0 m m b ut < 1 5 m m) s h o ul d be c o nsi dere d n o n -tar get lesi o ns. N o des 
t hat ha ve a s h ort a xis < 1 0 m m are c o nsi dere d n o n -pat h ol o gical a n d s h o ul d n ot be rec or de d 
or f oll o we d.  
A s u m of t he di a meters (l o n gest f or n o n-n o dal lesi o ns, s h ort a xis f or n o dal lesi o ns) f or all 
tar get lesi o ns will be cal c ulate d a n d re p orte d as t h e b aseli ne s u m di a meters.  If l y m p h n o d es 
are t o be i ncl u d e d i n t he s u m, t he n as n ote d a b o ve, o nl y t he s h ort a xis is a d de d i nt o t he s u m. 
T he baseli ne s u m dia met ers will be use d as refere nce t o f urt her c haracterize a n y o bjecti ve 
t u m or re gressi o n i n t he meas ura ble di me nsi o n of t he disease.  
All ot her lesi o ns ( or s ites of disease) i ncl u di n g pat h ol o gical l y m p h n o des s h o ul d be i de ntifie d 
as n o n -t ar get lesi o ns a n d s h o ul d als o be rec or de d at baseli ne. Meas ure me nts are n ot re q uire d 
a n d t hese lesi o ns s h o ul d be f oll o we d as ‘pres e nt ’, ‘a bse nt’, or i n rare cas es ‘u ne q ui v ocal  
pr o gressi o n ’. I n a d diti o n, it is p ossi ble t o rec or d m ulti ple n o n-tar get lesi o ns i n v ol vi n g t he 
sa me or ga n as a si n gle ite m o n t he case rec or d f or m (e. g. ‘m ulti ple e nlar ge d pel vic l y m p h 
n o des ’ or ‘m ulti ple li ver metastases ’). 
R E S P O N S E C RI T E RI A  
T his secti o n pr o vi des t he defi niti o ns of t he criteria use d t o deter mi ne o bjecti ve t u m or 
res p o nse f or tar get lesi o ns b y i m m u ne-relate d res p o nse criteria. 
E v al u ati o n of t ar get lesi o ns  
I m m u ne-Rel ate d C o m plete Res p o nse (ir C R) : Disa p peara nce of all tar get lesi o ns. A n y 
pat h o l o gical l y m p h n o des ( w het her tar get or n o n-t ar get) m ust ha ve re d ucti o n i n s h ort a xis t o 
< 1 0 m m.  
I m m u ne-Rel ate d P arti al Res p o nse (ir P R) : at least a 3 0 % decrease i n t he s u m of dia meters of 
tar get lesi o ns, ta ki n g as reference t he baseli ne s u m dia meters.  
C o nfi d e nti al
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Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
I m m u ne-rel ate d Pr o gressive Dise ase (ir P D): at least a 2 0 % i ncrease i n t he s u m of dia meters 
of tar get lesi o ns, ta ki n g as refere nce t he s m allest s u m o n st u dy (t his i ncl u des t he baseli ne s u m 
if t hat is t he s mallest o n st u d y). I n a d diti o n t o t he relati ve i ncrease of 2 0 %, t he s u m m ust als o 
de m o nstrate a n a bs ol ute i ncreas e of at least 5 m m.  
U nli ke c o n ve nti o nal R E CI S T criteria, t he a p peara nce of ne w meas ura ble lesi o ns d oes n ot 
a ut o maticall y d e n ote disease pr o gressi o n u n der i m m u ne -relate d res p o nse criteria. Rat her t he 
d i me nsi o ns of ne w meas ura ble lesi o ns are a d de d t o o verall s u m of t u m or dia meters f or 
deter mi nati o n of o bjecti v e res p o nse stat us. Patie nts will n ot be c o nsi dere d as ha vi n g 
pr o gressi o n u nless t he ne w o verall s u m of dia meters has i ncrease d b y >  2 0 % fr o m t he 
s mallest s u m of t u m or dia meters ac hie ve d w hile o n st u d y.  
I m m u ne-Rel ate d St a ble Dise ase (ir S D) : Neit her s ufficie nt s hri n ka ge t o q ualif y f or P R n or 
s ufficie nt i ncrease t o q u alif y f or P D, ta ki n g as refere nce t h e s mallest s u m dia meters w hile o n 
st u d y. 
S peci al n otes o n t he assess me nt of t ar get lesi o ns  
Ly m p h n o des.  Ly m p h n o des i de ntifie d as tar get lesi o ns s h o ul d al wa ys ha ve t he act ual s h ort 
a xis meas ure me nt rec or de d ( meas ure d i n t he sa me a nat o mical pla ne as t he baseli ne 
e x a mi nati o n), e ve n if t he n o des re gress t o b el o w 1 0 m m o n st u d y. T his mea ns t hat w he n 
l y m p h n o des are i ncl u de d as tar get lesi o ns, t he ‘s u m’ of lesi o ns ma y n ot b e zer o e ve n if 
c o m plete res p o nse criteria are m et, si nce a n or mal l y m p h n o de is defi n e d as ha vi n g a s h ort 
a xis of < 1 0 m m. I n or der t o q ualif y f or ir C R, eac h n o de m ust ac hie ve a s h ort a xis < 1 0 m m. 
F or ir P R, ir S D a n d ir P D, t he act ual s h ort a xis meas ure me nt of t he n o des is t o be i ncl u de d i n 
t he s u m of tar get lesi o ns. 
Tar get lesi o ns t h at bec o me ‘t o o s m all t o me as ure. W hile o n st u d y, all lesi o ns ( n o dal a n d n o n -
n o dal) rec or de d at baseli ne s h o ul d ha ve t heir act u al meas ure m e nts rec or de d at eac h 
s u bse q ue nt e val uati o n, e ve n w he n ver y s mall (e. g. 2 m m). H o we ver, s o m eti mes lesi o ns or 
l y m p h n o des w hic h are rec or de d as tar get lesi o ns at baseli ne bec o me s o fai nt o n C T sca n t hat 
t he ra di ol o gist ma y n ot feel c o mf orta ble assi g ni n g a n e xact meas ure a n d ma y re p ort t he m as 
bei n g ‘t o o s mall t o meas ure’. W he n t his occ urs it is i m p orta nt t hat a val ue be rec or de d o n t he 
case re p ort f or m. If it is t he o pi ni o n of t he ra di ol o gist t hat t he lesi o n has li kel y disa p peare d, 
t he meas ure m e nt s h o ul d be rec or de d as 0 m m. If t he lesi o n is belie ve d t o b e prese nt a n d is 
fai ntl y see n b ut t o o s mall t o meas ure, a defa ult val ue of 5 m m s h o ul d be assi g ne d (N ote:  It is 
less li kel y t hat t his r ule will be use d f or l y m p h n o des si nce t he y us uall y ha ve a defi na ble size 
w he n n or mal a n d are fre q ue ntl y s urr o u n de d b y fat s uc h as i n t he retr o perit o ne u m; h o we ver, if 
a l y m p h n o de is belie ve d t o be prese nt a n d is fai ntl y see n b ut t o o s mall t o meas ure, a d efa ult 
val ue of 5 m m s h o ul d be assi g ne d i n t his circ u msta nce as well). T his defa ult val ue is deri ve d 
fr o m t he 5 m m C T slice t hic k ness ( b ut s h o ul d n ot be c ha n ge d wit h var yi n g C T slice 
t hic k ness). T he meas ure me nt of t hese lesi o ns is p ote ntiall y n o n-re pr o d ucible, t heref ore 
pr o vi di n g t his defa ult val ue will pre ve nt false res p o nses or pr o gressi o ns base d u p o n 
meas ure me nt err or. H o we ver, if t he ra di ol o gist is a ble t o pr o vi de a n act ual meas ure, t hat 
s h o ul d be rec or de d, e v e n if it is bel o w 5 m m. 
C o nfi d e nti al
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of   
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Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
Lesi o ns t h at s plit o r c o alesce o n tre at me nt. W he n n o n -n o dal lesi o ns ‘fra g me nt’, t he l o n gest 
dia meters of t he fra g me nte d p orti o ns s h o ul d be a d de d t o get her t o calc ulate t he tar get lesi o n 
s u m. Si milarl y, as lesi o ns c oalesce, a pla ne bet wee n t he m ma y be mai ntai ne d t hat w o ul d ai d 
i n o btai ni n g ma xi mal dia meter meas ure me nts of eac h i n di vi d ual lesi o ns. If t he lesi o ns ha ve 
tr ul y c oalesce d s uc h t hat t he y are n o l o n ger se para ble, t he vect or of t he l o n gest dia meter i n 
t his i nsta nce s h o ul d be t he ma xi mal l o n gest dia meter f or t he ‘c oal esce d lesi o n’. 
E v al u ati o n of n o n -t ar get lesi o ns 
T his secti o n pr o vi des t he defi niti o ns of t he criteria use d t o deter mi ne t he t u m or res p o nse f or 
t he gr o u p of n o n-tar get lesi o ns. W hile s o me n o n-tar get lesi o ns ma y act u all y be meas urea ble, 
t he y n ee d n ot be meas ure d a n d i nstea d s h o ul d be assesse d o nl y q u alit atively  at t he ti me 
p oi nts s pecifie d i n t he pr ot oc ol.  
I m m u ne-Relate d C o m plete Res p o nse (ir C R): Disa p peara nce of all n o n -tar get lesi o ns. All 
l y m p h n o des m ust be n o n-pat h ol o gical i n size ( < 1 0 m m s h ort a xis).  
N o n -C R/ N o n -P D: Persiste nce of o ne or m ore n o n -t ar get lesi o ns(s). 
I m m u ne-Relate d Pr o gressi ve Disease (ir P D): U nli ke c o n ve nti o nal R E CI S T 1. 1, ne w 
meas ura ble l esi o ns or i ncreases i n t he size of n o n -t ar get lesi o ns d o n ot defi n e P D i n is olati o n 
i n t he i m m u ne-relate d resp o nse criteria. Rat h er, i m m u ne -relate d P D is est a blis he d if t he s u m 
of dia meters is ≥ 2 0 % of t he na dir of t he s u m of dia meters f or a gi ve n patie nt.  
Ne w Lesi o ns  
T he a p peara n ce of ne w mali g na nt lesi o ns al o ne d oes n ot de n ote disease pr o gressi o n. I nstea d, 
t he dia meter of n e w lesi o ns is a d de d t o t he s u m of dia meters f or tar get a n d n o n-tar get lesi o ns.  
E V A L U A TI O N O F B E S T O V E R A L L R E S P O N S E  
T he best o verall res p o nse is t he best res p o nse rec or de d fr o m t he start of t he st u d y treat me nt 
u ntil t he e n d of treat me nt ta ki n g i nt o acc o u nt a n y re q uire me nt f or c o nfir mati o n. T he patie nt ’s 
best o verall res p o ns e assi g n me nt will de pe n d o n t h e fi n di n gs of b ot h tar get a n d n o n -tar get 
disea se. 
Ti me p oi nt res p o nse  
It is ass u me d t hat at eac h pr ot oc ol s pecifie d ti me p oi nt, a res p o nse ass ess me nt occ urs. F or 
patie nts e x perie nci n g ir C R or ir P R, a c o nfir mat or y sca n o btai ne d n o less t ha n 4 wee ks after 
t he ori gi nal s ca n is re q uire d t o c o nfir m t he o bjecti ve res p o nse. F or patie nts e x perie nci n g 
ir P D, b ut w h o de m o nstrate acce pta ble t olera bilit y of treat me nt as e val uate d b y t he 
i n vesti gat or, a c o nfir m at or y s ca n o btai ne d n o l ess t ha n 4 wee ks after t he ori gi nal sca n is 
re q uire d f or t he c o nfir mati o n of ir P D. 
C o nfi d e nti al
P a g e   
1 5 0   
of   
1 5 4

Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
 
I m m u ne-Rel ate d C o m plete Res p o nse (ir C R):  C o m plete disa p peara nce of all tar get a n d 
n o n -tar get lesi o ns a n d n o ne w lesi o ns. T he s h ort a xis of all l y m p h n o des m ust be ≤ 1 0  m m.  
I m m u ne-Rel ate d P a rti al Res p o nse (ir P R):  T he s u m of dia meters has decrease d ≥ 3 0 % 
fr o m t he baseli ne, b ut d o es n ot meet t he criteria f or ir C R. 
I m m u ne-Rel ate d St a ble Dise ase (ir S D): T he pati e nt d oes n ot meet criteria f or ir C R, ir P R or 
ir P D. 
I m m u ne-Rel ate d Pr o gressi ve Dise ase (ir P D):  T he s u m of dia meters f or tar get lesi o ns a n d 
ne w meas urea b le l esi o ns has i ncrease d b y ≥ 2 0 % fr o m t he na dir s u m of dia meters  
Missi n g assess me nts a n d i ne v al u a ble desi g n ati o n  
W he n n o i ma gi n g/ meas ure me nt is d o ne at all at a partic ular ti me p oi nt, t he patie nt is n ot 
e val ua ble ( N E) at t hat ti me p oi nt. If o nl y a s u bset  of lesi o n meas ure m e nts are ma de at a n 
assess me nt, us uall y t he case is als o c o nsi dere d N E at t hat ti me p oi nt, u nless a c o n vi nci n g 
ar g u me nt ca n be ma de t hat t he c o ntri b uti o n of t he i n di vi d ual missi n g lesi o n(s) w o ul d n ot 
c ha n ge t h e assi g n e d ti me p oi nt res p o n se. 
Best o ver all res p o nse: all ti me p oi nts  
T he best over all res p o ns e  is deter mi ne d o nce all t he data f or t he patie nt is k n o w n.  
C o m plete or partial res p o nses ma y be clai me d o nl y if t he o bjecti ve res p o nse is c o nfir me d o n 
a f oll o w-u p sca n o btai ne d n o less t h a n 4 wee ks after t he i nitial sca n de m o nstrati n g a n 
o bjecti ve res p o nse. A bse nt t his s u bse q ue nt ra di o gra p hic c o nfir mati o n, ir C R or ir P R 
desi g nati o ns will be c o nsi dere d as u n c o nfir me d res p o nses.  
C o nfi d e nti al
P a g e   
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of   
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Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
S peci al n otes o n res p o nse assess me nt  
W he n n o dal disease is i ncl u de d i n t he s u m of tar get lesi o ns a n d t he n o des decrease t o 
‘n or mal ’ size ( < 1 0 m m), t he y ma y still ha ve a meas ure me nt re p orte d o n sca ns T his 
meas ure me nt s h o ul d be rec or de d e ve n t h o u g h t he n o des are n or mal i n or der n ot t o o verstate 
pr o gressi o n s h o ul d it be b ase d o n i ncrease i n size of t he n o des. As n ote d earlier, t his mea ns 
t hat patie nts wit h ir C R ma y n ot h a ve a t otal s u m of ‘zer o’ o n t he case re p ort f or m ( C R F).  
Patie nts wit h a gl o bal det eri orati o n of healt h stat us re q uiri n g disc o nti n uati o n of treat me nt 
wit h o ut o bjecti ve e vi de nce of disease pr o gressi o n at t hat ti me s h o ul d be re p orte d as 
‘s y m pt o matic det eri orati o n”. E ver y eff ort s h o ul d be ma de t o d oc u me nt o bj ecti ve pr o gressi o n 
e ve n after disc o nti n uati o n of treat me nt. S y m pt o m atic deteri orati o n is n ot  a descri pt o r of a n 
o bjecti ve res p o nse: it is a reas o n f or st o p pi n g st u d y t hera p y. T he o bjecti ve res p o nse stat us of 
s uc h patie nts is t o be deter mi ne d b y e val u ati o n of tar get a n d n o n-tar get disease as s h o w n i n 
Ta ble  1 . 
C O N FI R M A TI O N/ D U R A TI O N O F R E S P O N S E  
C o nfir m ati o n  
O bjecti ve res p o ns es s h o ul d be c o nfir me d b y C T a n d/ or M RI sca ns o btai ne d n o less t ha n 4 
wee ks after t he ori gi n al sca n.  
D ur ati o n of o ver all res p o nse  
T he d urati o n of o verall res p o nse is meas ure fr o m t he ti me meas ure me nt criteria are first met 
f or ir C R/ir P R ( w hic he ver is first rec or de d) u ntil t he first date t hat rec urre nt or pr o gressi ve 
disease is o bjecti vel y d oc u me nte d (ta ki n g as refere nce f or pr o gressi ve d is ease t he s mallest 
meas ure me nts rec or de d o n st u d y). T he d urati o n of o verall c o m plete res p o ns e is meas ure d 
fr o m t he ti me meas ure me nt criteria are first met f or ir C R u ntil t he first date t hat rec urre nt 
disease is o bjecti vel y d oc u me nte d.  
D ur ati o n of st a ble d ise ase 
Sta ble disease is meas ure d fr o m t he start of t he treat me nt u ntil t he criteria f or pr o gressi o n are 
met, ta ki n g as refere n ce t he s m allest s u m o n st u dy (if t he baseli ne s u m is t he s mallest, t his is 
t he refere n ce f or cal c ulati o n of ir P D). 
 
 
C o nfi d e nti al
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Mar get u xi ma b  
Macr o Ge nics, I nc.  
Cli nical Trial Pr ot oc ol: C P -M G A H 2 2 -0 5  
A me n d me nt 6, 2 9 J u ne 2 0 2 0  
 
 
 
 
 
A p pe n di x 9    
Pri nci p al I n vesti g at or’s A gree me nt  
St u d y Title:  
A P hase 1 b/ 2, O pe n La bel, D ose Escalati o n St u d y of 
Mar get u xi ma b i n C o m bi nati o n wit h Pe m br oliz u ma b i n Patie nts 
wit h  Rela pse d/ Refract or y A d va n ce d H E R 2 + Gastr oes o p ha geal 
J u ncti o n or Gastric Ca ncer  
St u d y N u m ber:    
C P -M G A H 2 2 -0 5  
 
I h a ve rea d t he pr ot oc ol descri be d a b o ve. 
I h a ve f ull y disc usse d t he o bjecti ves of t his trial a n d t he c o nte nts of t his pr ot oc ol wit h t he 
S p o ns or ’s re pres e ntati ve. 
I u n d ersta n d t hat t he i nf or mati o n i n t his pr ot oc ol is c o nfi de ntial a n d s h o ul d n ot be discl ose d, 
ot her t ha n t o t h ose directl y i n v ol ve d i n t he e xec uti o n of t he et hical re vie w of t he st u d y, 
wit h o ut writte n a ut h orizati o n fr o m Macr o Ge nics, I nc. It is, h o we ver, per missi b le t o pr o vi de 
i nf or mati o n t o a patie nt i n or der t o o btai n c o nse nt.  
I a gree t o c o n d uct t his trial acc or di n g t o t his pr ot o c ol a n d t o c o m pl y wit h its re q uire me nts, 
s u bject t o et hical a n d safet y c o nsi derati o ns a n d g ui deli nes, a n d t o c o n d uct t he trial i n 
acc or da nce wit h I C H g ui deli nes o n G C P a n d wit h t he a p plica ble re g ulat or y re q uire me nts.  
I u n d ersta n d t hat t he S p o ns or ma y deci de t o s us pe n d or pre mat urel y t er mi n ate t he trial at a n y 
ti me f or w hate ver reas o n; s uc h a decisi o n will be c o m m u nicate d t o me i n writi n g. 
C o n versel y, s h o ul d I deci de t o wit h dra w fr o m e xec uti o n of t he trial, I will c o m m u nicate m y 
i nte nti o n i m me diatel y i n writi n g t o t he S p o ns or. 
 
Si g ne d:  
 
D ate:    
 
 
PI N a me ( pri nte d): 
 
PI Affili ati o n:  
 
PI A d dress:  
 
PI P h o ne N u m ber:  
 
 
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C P- M G A H 2 2- 0 5 Pr ot oc ol A me n d me nt 6 ( 2 9-J u n- 2 0 2 0)
T his is t he electr o nic si g nat ure pa ge f or t he a b o ve refere nce d d oc u me nt.
User Tas k: e Si g nat ories A p pr o val
arc h A p pr o val (I nte n de d or Desi g nee)
2 9-J u n- 2 0 2 0 1 9: 2 7: 2 9 G M T + 0 0 0 0
User Tas k: e Si g nat ories A p pr o val
Data Ma na ge me nt/ Statistics A p pr o val
(I nte n de d or Desi g nee)
2 9-J u n- 2 0 2 0 2 0: 1 5: 1 0 G M T + 0 0 0 0
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