UCDCC#272: A Phase I/II Study of Intralesional IL-2, Hypofractionated Radiotherapy, and Pembrolizumab in Patients Refractory to Standard-of-Care PD-1/PD-L1 Checkpoint Blockade
Phase: PHASE1
Conditions: Non Small Cell Lung Cancer, Metastatic Melanoma, Metastatic Renal Cell Carcinoma, Head and Neck Squamous Cell Carcinoma
Sponsor: Megan Daly, MD

I L- 2 / Pe m br oliz u m a b 
M er c k O T S P # 5 5 5 7 1 
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2 
Versi o n 0 6/ 1 1/ 2 0 2 4 
A P H A S E 1/11 S T U D Y O F I N T R A L E SI O N A L I L- 2, H Y P O F R A C TI O N A T E D 
R A DI O T H E R A P Y, A N D P E M B R O LI Z U M A B I N P A TI E N T S R E F R A C T O R Y T O 
S T A N D A R D- O F- C A R E P D- 1/ P D- Ll C H E C K P OI N T B L O C K A D E 
I nstit uti o n al St u dy #: 
U C D C C#272, Merck O T S P #55571 
I n vesti g ati o n al Pr o d uct/ M o d alit y: I nterle u ki n- 2, Pe mbrolizu mab 
Pri nci p al I n vesti g at or(s): 
C o-I n vesti g at ors: 
U C Davis C o m pre he nsi ve C a ncer Ce nter 
C o nfi de nti al 
Alta Monjazeb, M D, Ph D 
Depa1t ment of Ra diati o n Oncology 
U ni versit y of Calif or nia, Davis 
School of Medicine 
4501 X Street 
Sacra mento, C A 95817 
Megan Daly, M D 
Depa1t ment of Ra diati o n Oncology 
U ni versit y of Calif or nia, Davis 
School of Medicine 
4501 X Street 
Sacra mento, C A 95817 
E manual Maverakis, M D 
Depa1t ment of De1 matology 
U C Davis C o m pre he nsi ve Cancer Center 
4501 X Street 
Sacra mento, C A 95817 
Robe1t J. Canter, M D 
Depa1t ment of Surgical Oncology 
U C Davis C o m pre he nsi ve Cancer Center 
4501 X Street 
Sacra mento, C A 95817 
J o nat ha n Riess, M D, MS 
U C Davis C o m pre he nsi ve Cancer Center 
4501 X Street 
Sacra mento, C A 95817 
P a ge 1 of 9 2 

I L-2 / Pe m br oliz u m a b  
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2  
Merc k O T S P # 5 5 5 7 1  
Versi o n  0 6 /1 1 /2 0 2 4  
U C D a vis C o m pre he nsi ve C a ncer Ce nter  
C o nfi de nti al  
P a ge 2  of 9 2  
St atistici a n:  
S usa n Ste wart, P h. D.  
Di visi o n of Bi ostatistics, Me d Sci 1 -C  
U ni versit y of Calif or nia, Da vis  
O ne S hiel ds A ve n ue  
Da vis, C A 9 5 6 1 6  
I N D #: 
E xe m pt  
S p o ns or: 
U C Da vis C o m pre he nsi ve Ca ncer Ce nter  
Cli nic al Tri als. g o v I D  
N C T 0 3 4 7 4 4 9 7  
Versi o n:  
J u ne 1 1, 2 0 2 4 
Se pte m ber 7 , 2 0 2 2  
Fe br uar y 2 6 , 2 0 2 0 
Ma y 2 0, 2 0 1 9  
N o ve m ber 2, 2 0 1 8  
J ul y 1 0, 2 0 1 8 
Ja n uar y 1 2, 2 0 1 8 
Dece m ber 7, 2 0 1 7  
Ori gi nal / J u ne 1 5, 2 0 1 7  

I L-2 / Pe m br oliz u m a b  
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2  
Merc k O T S P # 5 5 5 7 1  
Versi o n  0 6 /1 1 /2 0 2 4  
U C D a vis C o m pre he nsi ve C a ncer Ce nter  
C o nfi de nti al  
P a ge 3  of 9 2  
P R O T O C O L SI G N A T U R E P A G E  
Pr ot oc ol N u m ber: U C D C C # 2 7 2  
Pr ot oc ol Title: A P has e I/II St u d y of I ntralesi o nal I L -2, H y p ofracti o nate d Ra di ot hera p y, a n d 
Pe m br oliz u ma b i n Patie nts Refract or y t o Sta n dar d -of -Care P D -1/ P D -L 1 C h ec k p oi nt Bl oc ka de 
I h a ve rea d t his pr ot oc ol a n d a gree t hat it c o ntai ns all necessar y details f or carr yi n g o ut t his 
st u d y. I will c o n d uct t he st u d y as o utli ne d herei n a n d will c o m plete t he st u d y wit hi n t he ti me 
desi g nate d, i n acc or da n ce wit h all sti p ulati o ns of t he pr ot oc ol a n d i n acc or da nce wit h G o o d 
Cli nical Practices, l ocal r e g ulat or y re q uir e me nts, a n d t he Declarati o n of Helsi n ki.  
I will pr o vi de c o pies of t he pr ot oc ol a n d all perti ne nt i nf or mati o n t o all i n di vi d uals res p o nsi ble t o 
me w h o assist i n t he c o n d uct of t his st u d y. I will disc uss t his material wit h t he m t o e ns ure t hat 
t he y are f ull y i nf or me d re gar di n g t he st u d y a g e nt(s) a n d t he c o n d u ct of t he st u d y.  
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I n v esti gat or Na me ( pri nt) 
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I n v esti gat or Si g nat ure  
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Date  

I L-2 / Pe m br oliz u m a b  
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2  
Merc k O T S P # 5 5 5 7 1  
Versi o n  0 6 /1 1 /2 0 2 4  
U C D a vis C o m pre he nsi ve C a ncer Ce nter  
C o nfi de nti al  
P a ge 4  of 9 2  
LI S T O F A B B R E VI A TI O N S A N D T E R M S  
A E 
A d verse e v e nt  
A E SI  
A d verse e v e nt of s pecial i nterest  
A L K  
A na plastic l y m p h o ma ki nase  
A L T 
Ala ni ne a mi n otra nsferase/ser u m gl uta mic p yr u vic tra nsa mi nase/ S G P T  
a P T T  
acti vate d partial t hr o m b o plasti n ti me  
A S C O  
A merica n S ociet y of Cli nical O nc ol o g y  
A S T 
As partate a mi n otra nsferase/ser u m gl uta mic o xal oacetic tra nsa mi nase/ S G O T  
C N S 
Ce ntral ner v o us s yste m  
C R  
C o m plete res p o nse  
C T  
C o m p ute d T o m o gra p h y  
C R F 
Case Re p ort/ Rec or d F or m  
C R P  
C -reacti ve pr otei n
C T C A E 
C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts
C T V  
Cli nical tar get v ol u me
D C R  
Disease c o ntr ol rate
D F S  
D isease-free s ur vi val
D Lc o 
diff usi n g ca pacit y of t he l u n g f or car b o n m o n o xi de
D L T 
D ose li miti n g t o xicit y
D S M B  
Data a n d Safet y M o nit ori n g B oar d
D V H  
D ose v ol u me hist 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 G F R  
E pi der mal gr o wt h fact or rece pt or
F A C S  
Fl u oresce nce -acti vate d cell s orti n g
F D A  
U. S. 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
F N A  
Fi ne nee dle as pirati o n
G G O  
Gr o u n d glass o pacities
G T V  
Gr oss t u m or v ol u me
H C V 
H e p atitis C vir us
HI V  
h u ma n i m m u n o deficie n c y Vir us
Hr 
H o ur
H Bs A g  
He p atitis B s urface a nti ge n
H D -I L-2 
H i g h d ose i nterle u ki n-2
i. v.
I ntra v e n o us(l y)
I C H
I nter nati o nal C o nfere n ce o n Har m o nizati o n
I E C
I n de p e n de nt Et hics C o m mittee
I H C
I m m u n o hist oc h e mical
I D O
I n d ola mi ne 2, 3 Di o x y ge nase
I L-2
I nterle u ki n-2
I M P
In vesti gati o nal me dici nal pr o d uct
I N D
I n vesti gati o nal Ne w Dr u g
I N R
i nter nati o nal n or malize d rati o
I R B
I nstit uti o nal Re vie w B oar d
I U
I nter nati o nal u nit
ir A E
i m m u ne-relate d a d verse e ve nt
ir R E CI S T
I m m u ne Relate d R E CI S T (ir R E CI S T)

I L-2 / Pe m br oliz u m a b  
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2  
Merc k O T S P # 5 5 5 7 1  
Versi o n  0 6 /1 1 /2 0 2 4  
U C D a vis C o m pre he nsi ve C a ncer Ce nter  
C o nfi de nti al  
P a ge 5  of 9 2  
I T V 
I nter nal tar get v ol u me 
L D  
L o n gest dia meter  
L D H  
Lactate de h y dr o ge nase  
L V E F  
left v e ntric ular ejecti o n fracti o n  
L F Ts  
Li ver f u ncti o n tests  
Me S H  
Me dical S u bject Hea di n gs  
M M  
M etastatic mela n o ma   
m R C C  
Metastatic re n al cell carci n o ma  
m H N S C C  
Metastatic hea d a n d nec k s q ua m o us cell carci n o ma  
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  
N C C N  
Nati o nal C o m pre h e nsi ve Ca ncer Net w or k  
N S C L C  
N o n s mall cell l u n g ca ncer 
O R R  
O bjecti ve res p o nse rate  
O S  
O verall s ur vi val  
P B M C  
peri p heral bl o o d m o n o n uclear cell  
P D  
P r o gressi ve disease 
P D -1  
Pr o gra m me d deat h -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 
PI C O S  
P o p ulati o n, I nter ve nti o n, C o ntr ol, O utc o me, St u d y Desi g n  
P R  
P artial res p o nse  
P T V  
Pla n ni n g treat me nt v ol u me   
Q Tc F  
Fri d ericia -c orrecte d Q T  
R C C  
Re n al cell carci n o ma  
R E B  
Researc h Et hics B oar d  
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 N A  
Ri b o n ucleic aci d  
R T  
Ra di ot hera p y  
S A E  
Seri o us A d verse E ve nt  
S A R  
S tere otactic a blati ve ra di ot hera p y 
S D  
Sta ble disease  
SI T C  
S ociet y f or I m m u n ot hera p y of Ca ncer  
T 3  
Tri -i o d ot h yr o ni ne 
T 4  
T h yr o xi ne  
Tar get lesi o n  
Lesi o ns o utsi de of t he treat me nt fiel d w hic h are f oll o we d f or res p o nse assess me nt  
T C R  
T cell rece pt or 
TI L  
T u m or -i nfiltrati n g l y m p h oc yte 
T L T  
Treat me nt li miti n g t o xicit y  
T M E  
T u m or Micr oe n vir o n me nt  
T N F  
T u m or necr osis fact or  
Treat me nt lesi o n  
Lesi o n treate d wit h ra di ot hera p y a n d i ntralesi o nal I L -2 t hera p y  
T S H  
T h yr oi d -sti m ulati n g h or m o ne 
S O P  
Sta n dar d O perati n g Pr o ce d ure  
U C D C C C  
U C Da vis C o m pre h e nsi ve Ca ncer Ce nter  
U L N  
U p per li mit of n or mal  

I L-2 / Pe m br oliz u m a b  
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2  
Merc k O T S P # 5 5 5 7 1  
Versi o n  0 6 /1 1 /2 0 2 4  
U C D a vis C o m pre he nsi ve C a ncer Ce nter  
C o nfi de nti al  
P a ge 6  of 9 2  
T A B L E O F C O N T E N T S  
A P H A S E I/II S T U D Y O F I N T R A L E SI O N A L I L -2, H Y P O F R A C TI O N A T E D R A DI O T H E R A P Y, 
A N D P E M B R O LI Z U M A B I N P A TI E N T S R E F R A C T O R Y T O S T A N D A R D -O F -C A R E 
P D -1/ P D -L 1 C H E C K P OI N T B L O C K A D E  .................................................................................... 1  
P R O T O C O L SI G N A T U R E P A G E  .............................................................................................................. 3  
LI S T O F A B B R E VI A TI O N S A N D T E R M S  ............................................................................................... 4  
T A B L E O F C O N T E N T S  .............................................................................................................................. 6  
LI S T O F T A B L E S  ........................................................................................................................................ 8  
LI S T O F FI G U R E S  ...................................................................................................................................... 8  
LI S T O F A P P E N DI C E S  ............................................................................................................................... 8  
1. 0  
T RI A L S U M M A R Y  ........................................................................................................................ 9  
2. 0  
T RI A L D E SI G N  ............................................................................................................................ 1 0  
3. 0  
O BJ E C TI V E S  ................................................................................................................................ 1 1  
Pri mar y O bjecti ve  ............................................................................................................. 1 1  
Sec o n dar y O bjecti ves  ....................................................................................................... 1 1  
Tra nslati o nal O bjecti ves  ................................................................................................... 1 1  
4. 0  
B A C K G R O U N D  ........................................................................................................................... 1 1  
A d va nce d Sta ge N o n -S mall Cell L u n g Ca ncer ................................................................. 1 1  
Metastatic Mela n o ma  ........................................................................................................ 1 2  
Metastatic Re nal Cell Carci n o ma  ..................................................................................... 1 2  
Metastatic Hea d a n d Nec k S C C  ........................................................................................ 1 2  
I m m u ne C hec k p oi nt I n hi bit ors ......................................................................................... 1 2  
Hi g h D ose S yste mic I nterle u ki n -2  .................................................................................... 1 5  
H D -I L-2 a n d Ra di ot hera p y  ............................................................................................... 1 7  
I ntralesi o nal I L-2  .............................................................................................................. 1 7  
I ntralesi o nal I nterle u ki n-2 i n C o m bi nati o n wit h Ra di ot hera p y or C hec k p oi nt 
Bl oc ka de T hera p y.  ............................................................................................................ 2 1  
I ntralesi o nal I L-2 + R T i n patie nts refract or y t o P D -1/ P D -L 1 c hec k p oi nt bl oc ka de  ....... 2 2  
Bi o mar kers  ........................................................................................................................ 2 2  
5. 0  
M E T H O D O L O G Y  ........................................................................................................................ 2 4  
E ntr y Criteria  .................................................................................................................... 2 4  
Trial Treat me nts  ................................................................................................................ 2 7  
M o nit ori n g  ........................................................................................................................ 3 1  
D ose Selecti o n/ M o dificati o n  ............................................................................................ 3 2  
C o nc o mita nt T hera p y  ....................................................................................................... 3 8  
Resc ue Me dicati o n & S u p p orti ve Care  ............................................................................. 4 0  
Diet/ Acti vit y  ..................................................................................................................... 4 2  
S u bject Wit h dra wal/ Disc o nti n uati o n Criteria  ................................................................... 4 3  
S u bject Re place me nt Strate g y  .......................................................................................... 4 6  
Cli nical Criteria f or Earl y Trial Ter mi nati o n  .................................................................... 4 6  
D urati o n of F oll o w U p  ...................................................................................................... 4 6  
6. 0  
S T U D Y A S S E S S M E N T S A N D M O NI T O RI N G  ......................................................................... 4 8  
St u d y Cale n dar  .................................................................................................................. 4 8  
7. 0  
T RI A L P R O C E D U R E S  ................................................................................................................. 5 0  
Res p o nse Assess me nt  ....................................................................................................... 5 0  
Trial Pr oce d ures  ................................................................................................................ 5 3  

I L-2 / Pe m br oliz u m a b  
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2  
Merc k O T S P # 5 5 5 7 1  
Versi o n  0 6 /1 1 /2 0 2 4  
U C D a vis C o m pre he nsi ve C a ncer Ce nter  
C o nfi de nti al  
P a ge 7  of 9 2  
Assessi n g a n d Rec or di n g A d verse E ve nts  ........................................................................ 5 8  
8. 0  
C O R R E L A TI V E S CI E N C E ( T R A N S L A TI O N A L R E S E A R C H)  ............................................... 6 3  
Rati o nale  ........................................................................................................................... 6 3  
St u d y Desi g n a n d Met h o d ol o g y ........................................................................................ 6 4  
Res p o nsi bilities f or Tra nslati o nal Researc h  ...................................................................... 6 7  
All St u d y Varia bles  ........................................................................................................... 6 8  
9. 0  
D A T A A N D S T A TI S TI C A L A N A L Y SI S P L A N  ........................................................................ 6 9  
Sa m ple Size ....................................................................................................................... 6 9  
Statistical A nal ysis Pla n  .................................................................................................... 6 9  
Safet y  ................................................................................................................................ 6 9  
Efficac y  ............................................................................................................................. 7 0  
S u bject C o urse  .................................................................................................................. 7 0  
C orrelati ve La b orat or y Mar kers  ....................................................................................... 7 0  
1 0. 0  
L A B E LI N G, P A C K A GI N G, S T O R A G E, A N D R E T U R N O F C LI NI C A L S U P P LI E S  ............. 7 1  
I ntralesi o nal I L-2  .............................................................................................................. 7 1  
Pe m br oliz u ma b  ................................................................................................................. 7 1  
1 1. 0  
E T HI C A L C O N SI D E R A TI O N S A N D A D MI NI S T R A TI V E P R O C E D U R E S  ........................... 7 4  
Et hics a n d G o o d Cli nical Practice  .................................................................................... 7 4  
I nstit uti o nal Re vie w B oar d ............................................................................................... 7 4  
I nf or me d C o nse nt ............................................................................................................. 7 4  
Patie nt C o nfi de ntialit y  ...................................................................................................... 7 5  
Pr ot oc ol C o m plia nce a n d De viati o ns  ................................................................................ 7 5  
O nsite A u dits  .................................................................................................................... 7 5  
Pre mat ure Cl os ure of t he St u d y  ........................................................................................ 7 5  
Rec or d Rete nti o n  .............................................................................................................. 7 5  
Q ualit y Ass ura nce  ............................................................................................................. 7 6  
1 2. 0  
O V E R SI G H T A N D M O NI T O RI N G ............................................................................................. 7 6  
Data a n d Safet y M o nit ori n g  .............................................................................................. 7 6  
I n vesti gat or M o nit ori n g G ui deli nes .................................................................................. 7 6  
1 3. 0  
R E F E R E N C E S  .............................................................................................................................. 7 7  
1 4. 0  
A P P E N DI C E S  ............................................................................................................................... 8 2  

I L-2 / Pe m br oliz u m a b  
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2  
Merc k O T S P # 5 5 5 7 1  
Versi o n  0 6 /1 1 /2 0 2 4  
U C D a vis C o m pre he nsi ve C a ncer Ce nter  
C o nfi de nti al  
P a ge 8  of 9 2  
LI S T O F T A B L E S 
Ta ble 1. C o m m o n A d verse E ve nts wit h I ntralesi o nal I L -2 i n ≥ 1 0 % of Patie nts  ....................................... 2 0  
Ta ble 2. A de q uate Or ga n F u ncti o n La b orat or y Val ues  .............................................................................. 2 4  
Ta ble 3. Treat me nt Pla n  .............................................................................................................................. 2 9  
Ta ble 4. P hase I D ose Escalati o n a n d De -Escalati o n R ules  ........................................................................ 3 3  
Ta ble 5. P hase I I ntralesi o nal I L -2 D osi n g  ................................................................................................. 3 3  
Ta ble 6. P hase II I ntralesi o nal I L -2 d osi n g (i ntra -patie nt d ose escalati o n)  ................................................ 3 4  
Ta ble 7. A d verse E ve nt Ma na ge me nt  ......................................................................................................... 3 5  
Ta ble 8. Listi n g of t he Bl o o d Press ure G oals  ............................................................................................. 3 5  
Ta ble 9. D ose M o dificati o n G ui deli nes f or Dr u g -Relate d A d verse E ve nts  ................................................ 3 6  
Ta ble 1 0. I nf usi o n Reacti o n Treat me nt G ui deli nes  .................................................................................... 4 1  
Ta ble 1 1. I ma gi n g a n d Treat me nt after First Ra di ol o gic E vi de nce of Pr o gressi ve Disease  ....................... 4 5  
Ta ble 1 2. Best O verall Res p o nse E val uati o n  .............................................................................................. 5 2  
Ta ble 1 3. La b orat or y Tests  ......................................................................................................................... 5 6  
Ta ble 1 4. St u d y Varia bles a n d Meas ure me nts  ............................................................................................ 6 8  
Ta ble 1 5. Pe m br oliz u ma b Dr u g I nf or mati o n  .............................................................................................. 7 2  
LI S T O F FI G U R E S  
Fi g ure 1. I L -2 base d i m m u n ot hera p y i n d uces c o m plete re gressi o n of m uri ne 3 L L l u n g ca ncers  .............. 1 6  
Fi g ure 2. Li mite d Gra de 1 -2 T o xicit y Ass ociate d wit h I ntralesi o nal I L -2  ................................................. 1 8  
Fi g ure 3 . U C Da vis E x perie nce: I ntralesi o nal I L-2 T o xicit y  ...................................................................... 1 9  
Fi g ure 4. Ra di ot hera p y + I ntralesi o nal I L -2 i n a m uri ne mela n o ma m o del  ................................................ 2 1  
Fi g ure 5. C o m plete re gressi o n o bser ve d i n irra diate d/i njecte d metastatic mela n o ma lesi o ns  .................... 2 1  
Fi g ure 6: P hase II D ose M o dificati o n Sc he ma of I L -2  ............................................................................... 3 3  
LI S T O F A P P E N DI C E S  
A p pe n di x 1: E C O G Perf or ma nce Stat us Scale  ........................................................................................... 8 2  
A p pe n di x 2: Data C ollecti o n  ...................................................................................................................... 8 3  
A p pe n di x 3: M olec ular C orrelati ve Sa m ple Ha n dli n g ................................................................................ 8 4  
A p pe n di x 4: I m m u ne -Relate d Res p o nse Criteria (ir R C)  ............................................................................ 8 6  
A p pe n di x 5: C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts V 4. 0 ( C T C A E)  .................................... 8 9  
A p pe n di x 6. Ris k Stratificati o n of Trials  .................................................................................................... 9 0  

I L-2 / Pe m br oliz u m a b  
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2  
Merc k O T S P # 5 5 5 7 1  
Versi o n  0 6 /1 1 /2 0 2 4  
U C D a vis C o m pre he nsi ve C a ncer Ce nter  
C o nfi de nti al  
P a ge 9  of 9 2  
1. 0  
T RI A L S U M M A R Y  
A b bre vi ate d Title  
A P hase I/II St u d y of I ntralesi o nal I L -2, H y p ofracti o nate d Ra di ot hera p y, 
a n d Pe m br oliz u ma b i n Patie nts Refract or y t o Sta n dar d -of -Care P D -1/ P D -
L 1 C hec k p oi nt Bl oc ka de  
Tri al P h ase  
I/II 
Cli nic al I n dic ati o n  
A d va n ce d s oli d mali g na nc y or l y m p h o ma. wit h pr o gressi o n o n P D -1/ L 1 
c h ec k p oi nt i n hi biti o n . 
Tri al T y pe  
I nter ve nti o nal 
R o ute of a d mi nistr ati o n  
Pe m br oliz u ma b: i ntra ve n o us 
I L-2 : i ntrat u m oral i njecti o n 
Ra diati o n: e xter nal bea m  
Tri al Bli n di n g  
U n bli n de d, o pe n -la bel 
Tre at m e nt Gr o u ps 
P hase I d ose escalati o n of c o m bi nati o n pe m br oliz u ma b, i ntralesi o nal I L -2, 
a n d ra diati o n i n  A d va nce d s oli d mali g na nc y or l y m p h o ma. 
P hase II d ose e x pa nsi o n  at M T D, w hic h will i nc or p orate a o ne -sta ge 
bi n o mial  desi g n t o assess efficac y a n d safet y . 
N u m ber of tri al s u bjects  
2 5  ma xi m u m  
Esti m ate d e nr oll m e nt peri o d  
2 8 -3 6  m o nt hs
Esti m ate d d ur ati o n of tri al  
4  years  
D ur ati o n of P artici p ati o n  
2 8 -3 6 m o nt hs

I L- 2 / Pe m br oliz u m a b 
M erc k O T S P # 5 5 5 7 1 
2. 0 
T RI A L D E SI G N 
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2 
Versi o n 0 6/ 1 1/ 2 0 2 4 
Patie nts wit h a d va nce d s oli d mali g na ncies or l y m p h o ma wit h pr o gressi o n on pri or P D- 1/ L 1 
bl oc ka de will be e m olle d. A t otal ma xi m u m of 25 patie nts will be e m olle d. 
Pri m ar y O bjecti ve: A bs c o p al r es p o ns e r at e, O R R, D C R, P F S 
Sec o n d ar y O bjecti ve: M a xi m u m t ol er at e d d os e ( M T D), s af et y, a n d t o xi cit y 
C oll ater al O bjecti ves: I m m u n o p h e n ot y p e s eri al t u m or bi o psi es a n d bl o o d s a m pl es 
Bl o o d dra w, bi o ps y, 
cli nical e val uati o n• 
Cli nical 
eval uati o n• 
Cli nical 
Cli nical 
e val uati o n• 
l  
Scree ni n g 
• L a bs
• C T sca n< 
• Bl o o d dra w 
• Tiss ue bi o ps y
p 
R T 
I L- 2 
I L- 2 
Cli nical e val uati o n• 
J C T sca nc & la bs b 
p 
C o nti n ue to 
Pr o gressi o n 
• Pe m br oliz u m b 
• C T sca n<,
cli nical eval•, 
a n d la bsb q3 
R T 
I ntr alesi o n al I L- 2 
Pe m br oliz u m a b 
2 0 0 m g q 3 w e e k s 
8 G y x 3 
( c o m pl et e d i n w e e k 1 o f C y cl e 2) 
+
4 d os es i nj e ct e d i nt o R T tr e at m e nt l esi o n
+ 
( c o m pl et e d i n C y cl e 2 aft er c o m pl eti o n o f R T)
P h ase I: I L- 2 D ose Fi n di ni: 
3 + 3 Desi g n: ( 3- 6 p atie nt d ose le vel, 6- 1 8 p atie nts t ot al) 
Treat me nt 1 
Treat me nt 2 
Treat me nt 3 
Treat me nt 4 
d ose 
d ose 
d ose 
d ose 
D ose L e v el -1 
1 X 10 6 1lJ 
1 X 10 6 1lJ 
l x 1 06 I U 
1 X 10 6 1lJ 
D ose L e v el 1 
3 x 1 0 6 IU 
3 x 1 0 6 IU 
3 x 1 0 6 IU 
3 X 10 6 1lJ 
D ose L e v el 2 
3 x 1 0 6 IU 
7 x 1 0 6 I U 
7 x 1 0 6 I U 
7 X 10 6 1lJ 
D ose L e v el 3 
3 x 1 0 6 I U 
7 x 1 0 6 I U 
15 x 10 6 I U 
15 x 10 6 I U 
P h ase II: I L- 2 D ose E x p a nsi o n 
Bi n o mi al o ne- St a ge Desi g n ( 1 8 a d diti o n al p atie nts; 
a n al yze d wit h p atie nts fr o m MI D) 
•
P 0 = 0. 0 5 , pl = 0.2 0, rl = 0, n l = l 0, r T ot = 3, n T ot = 2 1,
a = O. l, p o w er = 0. 8
•
R es p o ns e will b e ass ess e d a c c or di n g t o ir R E CI S T
a n d will b e e v al u at e d at t he n o n-tre at me nt l esi o ns
( a bs c o p al r es p o ns e)
C T = co mp ute d t o m o gra p hy, D C R = disease c o ntr ol rate, M T D = ma xi m u m t olerate d d ose, O R R = o bjecti ve res p o nse rate, 
P F S = pr o gressi o n free s ur vi val, R T =ra di ot hera py, P = pe m br oliz u ma b, 
a. 
Patie nts will be cli nicall y e val uate d pri or to eac h c ycle of pe m br oliz u ma b f or t he first 3 c ycles a n d w e e kl y dt ui n g 
i ntralesi o nal I L- 2 i njecti o ns, a n d t hereafter e ver y 3 c ycles u ntil off treat me nt. 
b. 
La b orat or y e val uati o n will occ ur pre-treat me nt at e v e, y c ycle.
c.
F or res p o nse assess me nt, patie nt will ha ve C T i ma gi n g pre-treat me nt a n d after e ver y t hree c ycles of pe m br oliz u ma b. 
U C Davis C o m pre he nsi ve C a ncer Ce nter 
C o nfi de nti al 
P a ge 10 of 9 2 

I L-2 / Pe m br oliz u m a b  
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2  
Merc k O T S P # 5 5 5 7 1  
Versi o n  0 6 /1 1 /2 0 2 4  
U C D a vis C o m pre he nsi ve C a ncer Ce nter  
C o nfi de nti al  
P a ge 1 1  of 9 2  
3. 0  
O B J E C TI V E S  
Pri m ar y  O bjecti ve  
1.
T o deter mi ne if t his re gi me n c o n verts patie nts wit h resista nce t o P D -1/ P D -L 1 c hec k p oi nt
bl oc ka de i nt o res p o n d ers as deter mi ne d b y a bsc o p al res p o nse rate ( d efi ne d as res p o nse
rate at lesi o ns n ot treate d wit h R T + I L-2) usi n g i m m u ne relate d R E CI S T (ir R E CI S T)
2.
T o deter mi ne t he o bjecti ve res p o nse rate ( O R R), disease c o ntr ol rate ( D C R), a n d
pr o gressi o n free s ur vi val ( P F S) usi n g R E CI S T 1. 1 ( Res p o nse E val uati o n Criteria f or
S oli d T u m ors)
Sec o n d ar y O bjecti ves  
1.
P hase 1: T o deter mi ne t h e ma xi m u m t olerate d d os e ( M T D) of i ntralesi o nal I L -2 t hat ca n
be a d mi nistere d wit h h y p ofracti o nat e d ra di ot hera p y ( R T) a n d pe m br oliz u m a b
2.
P hase 2: T o c haracterize t he safet y pr ofile a n d t o xicit y of i ntralesi o nal I L -2, R T, a n d
pe m br oliz u ma b usi n g C T C A E v 4. 0 3 ( C o m m o n T o xicit y Criteria f or A d verse E ve nts
versi o n 4. 0 3).
Tr a nsl ati o n al O bjecti ve s 
1.
T o a nal yz e s erial bl o o d s a m ples f or s yste mic  c yt o ki ne / c he m o ki ne le vels, a n d t o q ua ntif y
t he n u m ber, f u ncti o n, T -cell di versit y, a n d ge n e e x pressi o n of cir c ulati n g i m m u ne cell
s u bsets.
2.
T o e val uate s erial t u m or tiss ue bi o psies f or t u m or i nfiltrati n g i m m u ne cell s u bsets , T -cell
di versit y,  e x pressi o n of i m m u ne pr otei ns i ncl u di n g I D O a n d P D -L 1, g e ne e x pressi o n
si g nat ures, a n d m utati o nal l oa d.
3.
T o c orre l ate i m m u ne para meters fr o m tra nslati o nal o bjecti ves 1 a n d 2  wit h cli nical
o utc o mes t o disc o v er mec ha nis ms of resista nce a n d bi o mar kers of res p o nse.
4. 0  
B A C K G R O U N D  
A d v a nce d St a ge N o n -S m all Cell L u n g C a ncer  
L u n g ca ncer is t he lea di n g ca use of ca n cer deat hs w orl d wi de beca use t he m aj orit y of patie nts 
prese nt wit h i nc ura bl e, metastatic disease. I n rece nt years, o ur i ncreas e d u n dersta n di n g of t he 
m olec ular bi ol o g y of l u n g ca ncer has le d t o t he d e vel o p me nt of m ore  efficaci o us t hera pies f or 
patie nts wit h a d va nce d st a ge n o n -s mall c ell l u n g ca ncer ( N S C L C).  As a res ult, o verall s ur vi val 
has i ncrease d b y se v eral m o nt hs a n d s u bsets of patie nts w h ose t u m ors har b or a n E G F R m utati o n 
or A L K ge n e f usi o n e nj o y pr ol o n ge d s ur vi v al be y o n d t w o years wit h tar g ete d t yr osi ne ki nase 
i n hi bit ors. N o net heless, t here re mai ns a great nee d t o disc o ver a n d de v el o p n o vel a ge nts t hat will 
i m pr o ve s ur vi val f or t he maj orit y of o ur patie nts.  

I L-2 / Pe m br oliz u m a b  
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2  
Merc k O T S P # 5 5 5 7 1  
Versi o n  0 6 /1 1 /2 0 2 4  
U C D a vis C o m pre he nsi ve C a ncer Ce nter  
C o nfi de nti al  
P a ge 1 2  of 9 2  
Met ast atic Mel a n o m a  
It w as rec o g nize d earl y o n t hat i ncreas e d t u m or-i nfiltrati n g l y m p h oc ytes best o we d i m pr o ve d 
s ur vi val f or patie nts wit h mela n o ma[1 ]. T o d a y it is clear t hat mela n o ma is a n i m m u n o ge nic 
mali g na nc y wit h well -defi ne d t u m or a nti ge ns. T h e a d ve nt of i m m u n ot hera p y has re v ol uti o nize d 
t he ma na ge me nt of m etastatic mela n o ma ( m M), a n d i m m u ne c hec k p oi nt i n hi bit ors s uc h as 
P D -1/ P D -L 1 bl oc ka de h a ve bee n ass ociate d wit h e n ha nce d T -cell res p o nses, i ncreas e d t u m or 
killi n g, a n d i m pr o ve d patie nt s ur vi val [2 , 3 ]. H o we ver, des pite t h e pr o misi n g e vi de nce f or 
d ura ble cli nical r es p o nses, t he maj orit y of patie nts still fail t o res p o n d t o i m m u n ot hera p y. T h us, 
t he de vel o p me nt of m ulti dr u g treat me nt r e gi me nts t o i m pr o ve res p o nsi ve ness is of para m o u nt 
i m p orta nce. 
Met ast atic Re n al Cell C arci n o m a  
Re nal cell carci n o ma ( R C C) ofte n d oes n ot prese nt u ntil disease is l ocall y a d va nce d a n d 
u nresect a ble or metast atic, a n d e v e n t he n treat me nt o pti o ns are ofte n li mite d b y t he de vel o p me nt 
of resista nce t o ra diati o n a n d c he m ot hera p y. T he l ac k of si g nifica nt efficac y wit h c he m ot hera p y, 
wit h t he rec o g niti o n t hat R C C is a n i m m u n ores p o nsi ve t u m or, has le d researc h t o f o c us o n 
i m m u n o m o d ulati o n as a wa y t o f oster a ntit u m or acti vit y  [4 ]. R C C is t y picall y c haracterize d b y 
hi g h le vels of t u m or i nfiltrati n g i m m u ne cells, i ncl u di n g l y m p h oc ytes, macr o p ha ges a n d 
de n dritic cells, b ut i m m u ne d ysf u ncti o n is a clear dri vi n g fact or be hi n d R C C t u m or gr o wt h [5 ]. 
T he mec ha nis ms t hat ca use t u m or esca p e i ncl u de s u p pressi o n of effect or cells or i m m u ne cell 
d ysf u ncti o n w hic h c o ul d be me diate d b y i m m u n os u p pressi ve fact ors of t he t u m or 
micr oe n vir o n me nt. Rece nt a d va nces i n c a ncer i m m u n ot hera p y ha ve b e nefite d patie nts wit h 
metastatic R C C , b ut as wit h ot her hist ol o gies, res p o nse rates are l o w a n d resista nce is c o m m o n.  
Met ast atic He a d a n d Nec k S C C  
Hea d a n d n ec k s q u a m o us cell carci n o mas ( H N S C C) are a g gressi ve mali g n a ncies  a n d dista nt 
metastases at pr ese ntati o n or rec urre n ce is c o m m o n.  T he mai nsta y of treat me nt f or metastatic 
disease is plati n u m d o u blets a n d t he E G F R i n hi bit or, cet u xi ma b. T he m e dia n s ur vi val f or 
metastatic H N S C C re mai ns less t ha n 1  year.  I m m u n ot hera pe utic a p pr oac hes a p pear pr o misi n g 
gi ve n p atie nts wit h H N S C C ha ve bee n s h o w n t o m o u nt a nti b o d y res p o nses t o a nti ge ns t hat are 
e x presse d o n t h e t u m or tiss ue . H o we ver, trials of i m m u n ot hera pe utic a p pr oac hes f or treat me nt of 
H N S C C ha ve la g ge d si g nifica ntl y c o m pare d t o ot her s oli d mali g na ncies t h at ha ve de m o nstr ate d 
a d va nta ges of c o m bi nat orial i m m u n ot hera pe utic a n d ra diati o n or c h e m o re gi me ns.  
I m m u ne C hec k p oi nt I n hi bit ors 
A ne w treat me nt a p pr o ac h t hat tar gets t he i m m u ne s yste m has ge nerate d c o nsi dera ble 
e nt h usias m. Pr o gra m deat h -1 ( P D -1) pr otei n is a c o -T -cell re g ulat or y rece pt or t hat me diates 
i m m u n os u p pressi o n b y bi n di n g t o t he P D-L 1 li ga n d f o u n d o n t u m or cells a n d str o mal  cells. 
Precli nical data h as de m o nstrate d t hat i n hi biti o n of t his rece pt or -li ga n d i nteracti o n lea ds t o a n 
e n ha nce d T -cell res p o ns e a n d i ncrease d t u m or killi n g. Pe m br oliz u ma b is a h u ma nize d a nti b o d y 
t hat tar gets t he pr o gra m me d cell deat h 1 ( P D-1) rece pt or.  T h era p e utic bl oc ka de of P D -1 or 

I L-2 / Pe m br oliz u m a b  
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2  
Merc k O T S P # 5 5 5 7 1  
Versi o n  0 6 /1 1 /2 0 2 4  
U C D a vis C o m pre he nsi ve C a ncer Ce nter  
C o nfi de nti al  
P a ge 1 3  of 9 2  
P D -L 1 wit h m o n ocl o nal a nti b o dies has bee n s h o w n t o lea d t o t u m or re gressi o ns i n patie nts wit h 
se veral ca ncer t y pes. 
I n a p hase I trial of a nti-P D -1 bl oc ka d e i n 3 9 p atie nts wit h a d va nce d N S C L C, mela n o ma, R C C, 
c ol orectal ca ncer, or castrate -resista nt pr ostate ca n cer, bl oc ki n g t he P D-1 i m m u ne c hec k p oi nt 
wit h i nter mitte nt a nti b o d y d osi n g was s h o w n t o be well -t olerate d a n d ass o ciate d wit h e vi de n ce 
of a ntit u m or acti vit y (s ustai ne d mea n occ u pa nc y of > 7 0 % of P D -1 m olec ul es o n circ ulati n g 
T  cells ≥2 m o nt hs f oll o wi n g i nf usi o n) [6 ]. I n a lat er p hase I trial i n patie nts wit h t hese 
hist ol o gies, o bjecti ve res p o nses (c o m plete or p arti al res p o nses) were o bser ve d i n t h ose wit h 
n o n -s mall-cell l u n g ca n cer, mela n o ma, or re n al -cell ca ncer  [7 ]. 
I n n o ns q u a m o us hist ol o g y t he P hase III o p e n-la bel, ra n d o mize d C hec k M ate -0 5 7 trial e val uati n g  
pre vi o usl y treate d p atie nts w as st o p pe d earl y as t h e st u d y met its e n d p oi nt of o verall s ur vi val 
fa v ori n g ni v ol u ma b [8 ]. T he me dia n o verall s ur vi val was 1 2. 2 m o nt hs i n t he ni v ol u ma b ar m vs 
9. 4 m o nt hs i n t he d oceta xel ar m ( H R = 0. 7 3 [ 9 6 % CI: 0. 5 9 -0. 8 9], p = 0. 0 0 1 5).  T here was n ot a 
statisticall y si g nifica nt differe nce i n pr o gressi o n-free s ur vi val i n t he t w o ar ms. H o we ver, a n 
o verall res p o ns e rate of 1 9 % ( 9 5 % CI 1 5 -2 4) was n ote d i n t he ni v ol u ma b ar m ( N = 2 9 2) vs 1 2 % 
( 9 5 % CI 9-1 7) i n t he d o ceta xel ar m ( N = 2 9 0). M e dia n d ura ti o n of res p o ns e i n t his trial was 1 7. 2 
m o nt hs (ra n ge of 1. 8 m o nt hs t o > 2 2. 6 m o nt hs) i n t he ni v ol u ma b ar m vs 5. 6 m o nt hs ( > 1. 2 m o nt hs 
t o > 1 5. 2 m o nt hs). I n t h e ni v ol u ma b ar m, 7 % ha d treat me nt-relate d S A Es wit h 5 % Gra de 3-4 
A Es, w hile i n t he d oceta xel ar m 2 0 % treat me nt -relate d S A Es were re p orte d wit h 1 8 % Gra de 3-4 
A Es.  Re gar di n g treat me nt -relate d A Es of s peci al i nterest, h y p ot h yr oi dis m occ urre d i n 7 % of 
patie nts i n t he ni v ol u ma b, t h o u g h t here were n o Gra de 3 -4 e n d ocri n o p at hies. Diarr hea was 
o bser ve d i n 8 % of p atie nts wit h ni v ol u ma b, wit h 1 Gra de 3/ 4 t o xicit y; diarr hea wa s n ote d at 2 3 % 
i n t he d oceta xel ar m wit h 1 Gra de 3/ 4  t o xicit y. Tra nsa mi nitis was n ote d i n 3 % of patie nts i n t he 
ni v ol u ma b ar m v 1 % i n t he d oceta x el ar m. P ne u m o nitis was o bser ve d i n 3 % of ni v ol u ma b -
treate d patie nts, wit h 1 % Gra de 3/ 4 t o xicit y; < 1 % of patie nts i n t he d oceta xel ar m e x perie nce d 
p ne u m o nitis. S ki n ras hes were o bs er ve d wit h a ras h i n 9 % of ni v ol u ma b -treate d patie nts, pr urit us 
i n 8 %, a n d er yt he m a i n 1 %. I n d ocet a xel-tr eate d patie nts, ras h was re p orte d i n 3 % of patie nts, 
pr urit us i n 1 %, er yt he ma i n 4 %.  
Rece ntl y, K E Y N O T E -0 1 0 ra n d o mize d 1 0 3 4 patie nts wit h a n y t u m or hist ol o g y t o 
pe m br oliz u ma b 2 m g/ k g ( N = 3 4 5), pe m br oliz u m a b 1 0 m g/ k g ( N = 3 4 6) or d oceta xel 7 5 m g/ m 2 
( N = 3 4 3) [9 ]. T he m e dia n o verall s ur vi val f or p e m br oliz u ma b 2 m g/ k g vers us d oceta xel w as 1 0. 4 
m o nt hs vers us 8. 5 m o nt hs, res pecti vel y ( H R 0. 7 1 9 5 % CI . 5 8 -. 8 8; p < 0. 0 0 0 8). F or 
pe m br oliz u ma b  1 0 m g/ k g t he me dia n o verall s ur vi val was 1 2. 7 m o nt hs c o m pare d t o 8. 5 m o nt hs 
f or d ocet a xel ( H R 0. 6 1, 9 5 % CI . 4 9-. 7 5; p < 0. 0 0 0 1. T here w as n o statistical differe n ce i n P F S 
bet wee n t he gr o u ps.  O bjecti ve res p o nse rates were 1 8 % f or b ot h t he pe m br oliz u ma b gr o u ps  a n d 
9 % f or d oceta xel ( p = 0. 0 0 0 5 f or pe m br oliz u ma b 2 m g/ k g a n d p = 0. 0 0 0 2 f or pe m br oliz u ma b 1 0 
m g/ k g.  Gra de 3 -5 a d vers e e ve nts oc c urre d i n 1 3 %, 1 6 % a n d 3 5 % of patie nts i n t he 
pe m br oliz u ma b 2 m g/ k g, 1 0 m g/ k g a n d d oceta xel ar ms.  A d verse e ve nts of s pecial i nterests a n y 
gra de, i ncl u de d h y p ot h yr oi dis m 8 %, 8 % a n d < 1 %, p ne u m o nitis 5 %, 4 % a n d 6 %, a n d 
h y pert h yr oi dis m 4 %, 6 % a n d 1 %, res p ecti vel y.  All ot her s pecial i nterest A Es were less t h a n 1 %. 
Gra de 3 or greater s pecial i nterest A Es were o nl y p ne u m o nitis ( 2 %) a n d s ki n  reacti o n ( 2 %) wit h 
pe m br oliz u ma b.  
Base d o n t his data t hat c o nfir ms t he safet y a n d efficac y of P D -1 i n hi bit ors f or t he treat me nt of 
patie nts w h o ha ve faile d first li ne t hera p y t hese a g e nts were F D A a p pr o ve d i n 2 0 1 5.  As of 2 0 1 6, 

I L-2 / Pe m br oliz u m a b  
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2  
Merc k O T S P # 5 5 5 7 1  
Versi o n  0 6 /1 1 /2 0 2 4  
U C D a vis C o m pre he nsi ve C a ncer Ce nter  
C o nfi de nti al  
P a ge 1 4  of 9 2  
pe m br oliz u ma b is  a p pr o ve d i n patie nts wit h u nre secta ble or metastatic m ela n o ma; patie nts wit h 
metastatic N S C L C w h ose t u m ors e x press P D -L 1 a n d de m o nstrate  dise ase pr o gressi o n o n or after 
plati n u m -c o ntai ni n g c he m ot hera p y; a n d patie nts r ec urre nt or metastatic H N S C C wit h disease 
pr o gressi o n o n or after pl ati n u m -c o ntai ni n g c he m ot hera p y. Gi ve n t hat a p pr o xi matel y 2 0 % of 
patie nts be nefit fr o m t hes e i m m u ne c hec k p oi nt i n hi bit ors, c o m bi nati o n strate gies t o i ncrease t he 
n u m ber of res p o n d ers m ust be n o w be p urs ue d.  
C hec k p oi nt I n hi bit ors i n A d v a nce d N S C L C 
T he first re p ort of pr o misi n g efficac y f or i m m u ne c hec k p oi nt i n hi bit ors i n l u n g ca ncer was s ee n 
i n a p hase I trial of ni v ol u ma b (a f ull y h u ma nize d I g G 4 P D-1 bl oc ki n g a nti b o d y) ( 2).  I n t he 
s u bset of hea vil y pretr eat e d N S C L C patie nts, 2 2 of 1 2 9 patie nts ( 1 7 %) ac hi e ve d a n o bjecti ve 
res p o nse rate ( O R R). Res p o nses were d ura ble. T he me dia n pr o gressi o n free s ur vi val ( P F S) f or 
t he l u n g ca ncer patie nts was 2. 3 m o nt hs wit h a me dia n o verall s ur vi val ( O S) was 9. 6 m o nt hs [7 , 
1 0 ] was  see n acr oss all hist ol o gical s u bt y pes.
S u bse q ue ntl y, t here has b ee n 3 ra n d o mize d trials wit h a P D -1 a ge nt eit her ni v ol u ma b or 
pe m br oliz u ma b t hat ha ve s h o w n a n o verall s ur vi val be nefit f or t h ese a g e nts. Efficac y was hi g her 
i n patie nts w h ose t u m or e x presse d P D-L 1 b y i m m u n o hist oc he mistr y b ut res p o nses were see n i n 
patie nts wit h t u m ors t hat di d n ot e x pressi o n of P D -L 1. T he first st u d y , C hec k mate-0 1 7,  was 
c o n d ucte d i n patie nts wit h s q ua m o us cell t u m or hist ol o g y.  A t otal of 2 2 7 patie nts recei ve d 
ni v ol u ma b ( 3 m g/ k g I V e ver y 2 wee ks) or d o ceta x el ( 7 5 m g/ m 2 I V e ver y 3 wee ks) [1 1 ] . A 4 1 % 
re d ucti o n i n ris k of death ( H R: 0. 5 9, 9 5 % CI: 0. 4 4 -0. 7 9) was o bser ve d wit h ni v ol u ma b, wit h t he  
me dia n  o verall s ur vi val i n t he ni v ol u ma b ar m was 9. 2 m o nt hs ( 9 5 % c o nfi d e nce i nter val [ CI], 7. 3 
t o 1 3. 3) c o m pare d  t o 6 m o nt hs ( 9 5 % CI, 5. 1 t o 7. 3) i n t he d oceta xel ar m. T he c o nfir me d 
o bjecti ve res p o nse rate w as si g nifica ntl y hi g her wit h ni v ol u ma b t ha n wit h d oceta xel ( 2 0 % [ 9 5 % 
CI, 1 4 t o 2 8] vs 9 % [ 9 5 % CI, 5 t o 1 5]; p = 0. 0 0 8).   
C hec k p oi nt I n hi bit ors  i n Met ast atic Mel a n o m a 
Pe m br oliz u ma b was first e val uate d i n t he lar ge p h ase 1 K E Y N O T E -0 0 1 st u d y i n w hic h 4 1 1 
patie nts wit h a d va nce d m ela n o ma were f oll o w e d f or 1 8 m o nt hs a n d f o u n d t o ha ve a res p o nse 
rate of 3 4 %, w hic h w as mai ntai ne d i n 8 1 % of t h ose patie nts[1 2 ]. Me dia n O S was 2 5. 9 m o nt hs. 
T he K E Y N O T E -0 0 2 st u d y of pe m br oliz u ma b vs. c he m ot hera p y c o nfir me d s ur vi val be nefit i n 
patie nts w h o ha d disease pr o gressi o n d uri n g/after i pili m u ma b t hera p y [1 3 ].  
Later, i n a ra n d o mize d p hase 3 st u d y of pe m br oli z u ma b vs. i pili m u ma b ( K E Y N O T E -0 0 6), t w o 
re gi me ns of pe m br oliz u ma b i m pr o ve d b ot h P F S a n d O S i n patie nts wit h a d va nce d 
mela n o ma [1 4 ].  
Rece ntl y, i n a n o pe n-l a bel p hase I b cli nical trial of 6 5 5 patie nts wit h a d va nce d mela n o ma, 
pe m br oliz u ma b was ass ociate d wit h a n o verall o bjecti ve res p o ns e rat e of 3 3 %, 1 2 -m o nt h P F S 
rate of 3 5 %, a n d me dia n O S of 2 3 m o nt hs. Gra de 3 or 4 treat me nt-relate d A Es occ urre d i n 1 4 %  
[1 5 ]. 
I n a n ot her rece nt p hase I b st u d y, K E Y N O T E-0 0 1  e xa mi ne d t he use of pe m br oliz u ma b o nce 
e ver y 2 wee ks or o n ce e v er y 3 wee ks , or 2 m g/ k g o nce e v er y 3 wee ks, i n 6 5 5 patie nts wit h 
a d va nce d mela n o ma. Of 4 5 1 patie nts wit h e val ua ble P D -L 1 e x pressi o n, 7 6 % ha d P D -L 1 -p ositi ve 

I L-2 / Pe m br oliz u m a b  
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2  
Merc k O T S P # 5 5 5 7 1  
Versi o n  0 6 /1 1 /2 0 2 4  
U C D a vis C o m pre he nsi ve C a ncer Ce nter  
C o nfi de nti al  
P a ge 1 5  of 9 2  
t u m ors. P D -L 1 e x pressi o n i n pretreat me nt t u m or bi o ps y sa m ples was c orrel ate d w it h res p o nse 
rate, a n d l o n ger P F S a n d O S [hazar d rati o, 0. 7 6; 9 5 % CI, 0. 6 9 t o 0. 8 3]) [1 6 ]. 
C hec k p oi nt I n hi bit ors  i n Met ast atic Re n al Cell C arci n o m a 
Hist oricall y, hi g h -d ose I L -2 a n d i nterfer o n - α 2 B ha ve bee n via ble i m m u n ot hera pe utic o pti o ns f or 
s u bsets of patie nts wit h R C C[1 7 ]. M ore rece ntl y, p ote ntial f or P D -1 base d t hera pies has b ee n 
s h o w n, h o we ver e vi de nce is still earl y f or use of pe m br oliz u ma b i n m R C C. I n a P hase I st u d y of 
3 3 R C C patie nts treate d wit h ni v ol u ma b, o bjecti ve res p o nses were see n i n 2 4 % of patie nts 
treate d wit h 1 m g/ k g a n d 3 1 % of patie nts treate d wit h 1 0 m g/ k g a n d s h o w n t o be d ura ble 
res p o nses[7 ]. 
Pe m br oliz u ma b is c urre ntl y bei n g teste d wit h a xiti ni b a n d t h us far has b ee n s h o w n t o be well -
t olerate d at sta n dar d d oses a n d e x hi bite d s u bsta ntial a ntit u m or acti vit y i n a s mall pil ot c o h ort of 
1 1 treat me nt -naï v e patie nts wit h a d va nce d R C C [1 8 ]. A d diti o nal patie nts are bei n g e nr olle d t o 
c o nfir m t he P hase II d ose  a n d f urt her e val uat e safet y a n d a ntit u m or acti vit y of t his c o m bi nat orial 
a p pr oac h . 
C hec k p oi nt I n hi bit ors  i n Met ast atic H e a d a n d Nec k S q u a m o us Cell C arci n o m a 
In a p hase 1 b K E Y N O T E 0 1 2 st u d y of patie nts wit h rec urre nt or metastati c hea d a n d nec k 
ca ncer, pe m br oliz u ma b was s h o w n t o be well-t ol erate d a n d de m o nstrate d a ntit u m or acti vit y[1 9 ]. 
It a c hie ve d a res p o nse rat e of 2 0 % i n patie nts wit h P D-L 1 e x pressi o n i n t he first p hase of t he 
st u d y. T he e x pa nsi o n c o h ort i ncl u de d 1 3 2 patie nts w h o were u nselect e d f or P D -L 1 e x pressi o n 
a n d recei ve d a fi xe d d ose of pe m br oliz u ma b ( 2 0 0 m g/ 3 wee ks), a n d t u m o r s hri n ka ge was 
re p orte d i n 5 7 % of patie nts. After data fr o m t he K E Y N O T E 0 1 2 st u d y s h o we d a n o bje cti ve 
res p o nse rate ( O R R) of 1 6 % ( 9 5 % CI: 1 1, 2 2), a c o m plete res p o nse rate of 5 % , wit h res p o nses of 
si x m o nt hs or l o n ger o bser ve d i n 8 2 % ( n = 2 3/ 2 8) of t he res p o n di n g patie nts, t he F D A accelerate d 
a p pr o val f or t his i n dicati o n f or pe m br o liz u ma b.  
Hi g h D ose S yste mic I nterle u ki n -2  
Hi g h d ose I L -2 ( H D -I L-2) is a c yt o ki ne pr o d uce d e n d o ge n o usl y b y acti vat e d T cells a n d is 
effecti ve i n t he treat me nt of a vari et y of mali g na ncies beca use it has b ot h i m m u ne -m o d ulati n g 
a n d a ntit u m or pr o perties [2 0 ]. T his t hera p y has pr o ve n effecti ve i n t he ma na ge me nt of b ot h 
metastatic mela n o ma ( M M) a n d metastatic re nal cell carci n o ma ( m R C C) wit h t he a bilit y t o 
i n d uce d ura ble l o n g ter m res p o nses i n a mi n orit y of patie nts.  
H D -I L-2 is ass ociate d wit h si g nifica n t t o xicit y w hic h has li mite d its use. Si g nifica nt 
car di o p ul m o nar y t o xicit y has bee n re p orte d wit h gra de 3/ 4 h y p ote nsi o n re q uiri n g vas o press or 
s u p p ort i n u p t o 8 1 % of patie nts a n d res ulti n g i n s u bse q ue nt e n d-or ga n d ysf u ncti o n ca usi n g 
tra nsie nt: re nal f ail ure, h e patic d ysf u ncti o n, meta b olic deran ge m e nts a n d gastr oi ntesti nal t o xicit y  
[2 1 , 2 2 ]. Relate d t o xicities t y picall y res ol ve wit hi n 2-3 da ys aft er wit h dra wal of I L -2  [2 3 ]. 
I nitiall y, H D-I L-2 w as ass ociate d wit h m ortalit y rates of u p t o 4 %, a n d w hile t hese rat es ha ve 
decrease d as cli nicia ns h a ve gai ne d e x peri e nce a n d de vel o pe d pr ot oc ols f or I L -2 use, I L -2 
t hera p y ca n still ca use si g nifica nt d ose-, deli ver y- a nd sc he d ule - de pe n d e nt m or bi dit y . I n a n 
eff ort t o r e d uce tr eat me nt t o xicit y wit h hi g h d ose s yste mic t hera p y st u dies h a ve e x a mi ne d t he 

I L- 2 / Pe m br oliz u m a b 
M erc k O T S P # 5 5 5 7 1 
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2 
Versi o n 0 6/ 1 1/ 2 0 2 4 
efficac y ofl o w- d os e s yste mic I L- 2 b ut f o u n d hi g h- d ose re gi me ns t o be s u peri or [24, 2 5]. H D-I L-
2 gi ve n as an I V b ol us is m ore t o xic t ha n w he n gi ve n as a l o w d ose b ol us or s u bc uta ne o usl y [ 2 0, 
2 1, 2 3, 2 5, 2 6]. I n or der t o ha. mess t he cli nical be nefits of I L- 2, less t o xic met h o ds of deli ve 1 y 
nee de d to be de vel o pe d. 
4. 6. 1 
H D-I L- 2 i n A d v a n c e d N S C L C 
T here is little cli nical data testi n g s yste mic H D-I L- 2 f or t he treat me nt of l u n g ca ncer b ut 
precli nical data fr o m a m uri ne m o del has s h o w n t hat H D-I L- 2 al o ne is a n effecti ve treat me nt f or 
p ul m o n ai y metastases wit h t he a bilit y to ac hie ve a d ura ble C R i n 5 0 % oft est s peci me ns[ 2 7]. O ur 
gr o u p has de m o nstrate d t hat H D-I L- 2 use d in a c o m bi nat orial a p pr oac h ca n ca use c o m plete 
re gressi o n of m o use 3 L L l u n g ca ncers ( Fi g ure 1). 
Fi g ur e 1. I L- 2 b as e d i m m u n ot h er a p y i n d uc es c o m pl et e r e gr essi o n of m uri n e 3 L L l u n g 
c a nc ers 
W TI T 
5000 
4S O O 
4 0 0 0 
3S O O 
1 3 0 0 0 .. 
N 
i;;; 2 5 0 0 
L o o o 
lS O O 
1 0 0 0 
soo 
0 •. 
0 
10 
l S 
2 0 
2S 
3 0 
3S 
D ays 
4. 6. 2 
H D-I L- 2 i n M et ast ati c M el a n o m a 
sooo 
4S O O 
4 0 0 0 
3S O O 
l 3 0 0 0 .. 
N 
i;;; 2 S O O 
L o o o 
lS O O 
1000 
soo 
0 
0 
W T P B S /rl g G 
w 
u 
w 
u  
�  
� 
D ays 
I n a H D-I L- 2 trial of 6 8 4 patie nts wit h m M t he o verall res p o nse rate was 13 % wit h s ur vi val 
be y o n d 4 yeai·s [ 2 8]. I m p orta ntl y, ma n y of t he patie nts res p o n di n g to t his t hera p y re mai n disease 
free f or pr ol o n ge d peri o ds a n d are a p pare ntl y c ure d. Pr o misi n gl y, a rece nt retr os pecti ve a nal ysis 
of 170 patie nts wit h m M a n d 192 patie nts wit h m R C C treate d wit h H D I L- 2 in bet wee n t he years 
of 2 0 0 5 - 2 0 1 2 re p o 1te d a n i m pr o ve d me dia n o verall s ur vi val c o m pai·e d to t he hist orical 
e x perie nce. T he m O S f or m R C C was 41 m o nt hs a n d f or m M 19.6 m o nt hs [ 2 9]. 
4. 6. 3 
H D-I L- 2 i n M et ast ati c R e n al C ell C a r ci n o m a 
As i n mela n o ma, hi g h- d ose I L- 2 has de m o nstrate d a n a bilit y to i n d uce d ura ble res p o nses in 
select patie nts wit h R C C. A p hase II cli nical trial assessi n g H D-I L- 2 in 2 5 5 patie nts wit h m R C C 
a n d s h o we d a n o verall o bjecti ve res p o nse rate of 14 %, wit h 5 % C R, 9 % P R, a n d an esti mate d 
O S of 16.5 m o nt hs [ 3 0]. H o we ver, treat me nt was ass ociate d wit h se vere ac ute t o xicities, a n d 4 % 
U C Davis C o m pre he nsi ve C a ncer Ce nter 
C o nfi de nti al 
P a ge 16 of 9 2 

I L-2 / Pe m br oliz u m a b  
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2  
Merc k O T S P # 5 5 5 7 1  
Versi o n  0 6 /1 1 /2 0 2 4  
U C D a vis C o m pre he nsi ve C a ncer Ce nter  
C o nfi de nti al  
P a ge 1 7  of 9 2  
of patie nts die d of a d v ers e e ve nts j u d ge d t o be pr o ba bl y treat me nt -relate d. M ore rece ntl y, i n a  
relati vel y lar ge c o h ort of H D-I L-2 p atie nts, a n o verall o bjecti ve res p o ns e rate of  1 5. 9 % was 
s h o w n, wit h a me dia n O S of 3 5. 5 m o nt hs ( 2 2. 2 -3 8. 6 m o nt hs), c orr o b orati n g hist orical re p orts  
[3 1 ].  
N o net heless its use is li mite d b y t he si g nifica nt si de effect pr ofile t hat has le d t o restricti o ns i n 
a d o pti o n of its wi des prea d usa ge,  hi g h de gree of e x pertise re q uir e d i n patie nt selecti o n a n d H D -
I L-2 a d mi nistrati o n (i nte nsi ve care t y pe of setti n g).  
H D -I L-2 i n Met ast atic He a d a n d Nec k S q u a m o us Cell C arci n o m a 
I L-2 a n d i nterfer o n were t he first c yt o ki nes use d i n treati n g H N S C C [3 2 ]. T he use of I L -2 i n 
H N S C C has bee n li mite d t o l ocal -re gi o nal or i ntralesi o nal i njecti o n. L ocal I L-2 base d t hera pies 
ha ve bee n ass ociat e d wit h fa v ora bl e l ocal a n d s yst e mic acti vati o n of t he i m m u ne s yste m. See 
Secti o n 4. 8. 4  bel o w . 
H D -I L-2 a n d R a di ot her a p y  
Tra diti o nall y, i o nizi n g ra diati o n t hera p y ( R T) was belie ve d t o act as a n i m m u n os u p pressa nt, 
e xerti n g its c yt ot o xic mit otic effects o n prese nt t u m or cells t hr o u g h D N A da ma ge  [3 3 , 3 4 ]. 
H o we ver, a gr o wi n g b o d y of e vi de nce de m o nstrat es t hat ra diati o n i n d uces i m m u n o m o d ulat or y 
effects, c ha n gi n g t he t u m or micr oe n vir o n me nt a n d u pre g ulati n g t he i nfla m mat or y casca de. 
T u m ors t hat are e x p ose d t o R T release a nti ge ns w hic h s u bse q ue ntl y acti vat e t h e i n nate a n d 
a da pti ve h ost i m m u ne res p o nse  [3 3 -3 5 ]. T o t his e n d, ra diati o n c o m bi ne d wit h s pecific c yt o ki nes 
e n ha nces t he a nti -t u m or effects of ra di ati o n [3 6 ]. Xia n et al. s h o we d a c o m bi nati o n of I L-2 a n d 
I L-1 2 ge ne t h era p y a n d ra diati o n ge nerates p ote nt a nti -t u m or i m m u ne res p o nses a gai nst hea d a n d 
nec k ca ncer  i n a n ort h ot o pic m uri ne m o del [3 6 ]. 
I n h u ma ns, pr o misi n g earl y e vi de nce e xists for c o m bi ni n g H D -I L-2 a n d R T i n m M, R C C a n d 
ot her s oli d t u m ors  [3 7 -4 0 ]. A rece nt p hase 1 trial testi n g t he c o m bi nati o n of H D-I L-2 wit h 
h y p ofracti o nat e d R T de m o nstrate d a 6 0 % res p o nse rate c o m pare d t o r o u g hl y 1 5 % i n hist orical 
c o ntr ols of H D -I L-2 al o n e. I m p orta ntl y, n o u ne x p ecte d or a d diti ve a d verse effects of c o m bi ni n g 
hi g h d ose I L -2 wit h R T were re p orte d.  
I ntr alesi o n al I L-2  
I n a n atte m pt t o ta ke a d v a nta ge of t he r o b ust i m m u ne acti vati n g effects of I L-2 b ut a v oi d t he 
t o xicit y of hi g h d ose s yste mic I L-2 w e a n d ot hers ha ve i n vesti gate d t he us e of i ntralesi o nal I L -2 
i njecti o ns. 
I ntr alesi o n al I L-2 i n A d v a nce d N S C L C 
A n u m ber of st u dies ha v e e val uat e d l ocal I L -2 a d mi nistrati o n f or pri mar y or metastatic 
mali g na nt l u n g lesi o ns . Liss o ni et al e xa mi ne d i ntraca vitar y I L -2 tr eat me nt f or mali g na nt ple u ral 
eff usi o ns a n d de m o nstr ate d a 7 2 % res p o nse rate a n d t he o nl y t o xicit y was fe vers i n 6 % of 
patie nts  [4 1 ]. A st u d y fr o m Ital y has t este d s yste mic H D -I L-2 i n c o m bi nati o n wit h i ntralesi o nal 
I L-2 f or N S C L C [4 2 ]. T his trial re p orte d a 2 5 % res p o nse rate a n d a 6 2. 5 % disease c o ntr ol rate.  

I L-2 / Pe m br oliz u m a b  
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2  
Merc k O T S P # 5 5 5 7 1  
Versi o n  0 6 /1 1 /2 0 2 4  
U C D a vis C o m pre he nsi ve C a ncer Ce nter  
C o nfi de nti al  
P a ge 1 8  of 9 2  
N o u ne x pect e d t o xicities were o bs er ve d fr o m t he i ntralesi o nal i njecti o n of I L -2 alt h o u g h o ne  
t hir d of patie nts e x peri e n ce d p ne u m ot h ora x fr o m t he re peate d tra ns parietal i njecti o ns. O verall 
i ntralesi o nal t o xicit y rates fr o m t his trial are diffi c ult t o deter mi ne gi ve n t he use of s yste mic hi g h 
d ose I L -2. D u e t o t he ris k of p n ue m ot h ora x fr o m o ur tra ns pari etal  lesi o ns, o ur trial d oes n ot 
all o w f or t he treat me nt of l u n g lesi o ns.  
I ntr alesi o n al I L-2  i n Met ast atic Mel a n o m a 
O ne of  t he lar gest re p orts, w hic h i ncl u ded  4 8 patie nts wit h metastatic mela n o ma, i n dicates t hat 
t his a p pr oac h is hi g hl y effecti ve wit h a 7 0 % res p o nse rate of i njecte d lesi o ns a n d li mite d gra de 1-
2 t o xicit y [4 3 ]. T his st u d y i nc or p orate d a n i nitial d ose of 3 milli o n I U w hi c h was es calate d 
wit hi n eac h patie nt as t ol erate d. Treat me nts oc c urre d 3 x wee kl y f or a me dia n d urati o n of 6 
wee ks a n d t he d ose was escalate d u p t o a ma xi m u m  of 1 6 milli o n I U. T he m ost c o m m o n 
t o xicities i ncl u de d i njecti o n site reacti o n i n nearl y all patie nts, fe ver i n 5 8 % of patie nts, fati g ue 
i n 3 6 % of patie nts, a n d n a usea i n 3 4 % of patie nts. T he fe v ers were res p o nsi ve t o aceta min o p h en.  
T he t o xicities are o utli ne d i n Fi g ure 2 . 
Fi g ure 2 . Li mite d Gr a de 1 -2 T o xicit y Ass oci at e d wit h I ntr alesi o n al I L -2  
Researc h ers a t U C D a vis ha ve re p orte d a 1 0 0 % res p o nse rate usi n g i ntralesi o nal I L-2 wit h 
t o pical i m m u ne a ge nts f or i n-tra nsit mela n o ma [4 4 , 4 5 ] a n d ha ve rece ntl y p u blis he d g ui deli nes 
f or t he use of i ntr alesi o nal I L-2 t h at ha ve b ee n a d o pte d b y N C C N  [4 6 ]. I m p orta ntl y, it has bee n 
de m o nstrate d  t hat i ntralesi o nal I L-2 treat me nt is ass ociate d wit h mi ni mal t o xicit y a n d ca n be 
a d mi nistere d o n a n o ut patie nt basis. I n t he rece nt r e p ort, 6 of 1 1 patie nts de vel o pe d ri g ors wit hi n 
3 t o 6 h o urs p ost i njecti o n w hic h were self -li mite d a n d laste d 1 5-3 0 mi n utes. O ne patie nt 
de vel o pe d as y m pt o matic h y p ote nsi o n necessitati n g h ol di n g a nti h y perte nsi ve me dicati o ns o n 
s u bse q ue nt treat me nt da ys. I ntr alesi o nal I L-2 t h era p y was disc o nti n ue d i n o ne patie nt after 
se veral m o nt hs beca use of t he de vel o p me nt of l o cal urticaria at treat me nt sites. O ne patie nt wit h 
i nterstitial l u n g disease de vel o pe d s h ort ness of breat h 4 h o urs after her se ve nt h i njecti o n 
( 7 milli o n I U). Alt h o u g h s he was f o u n d t o ha v e a n or mal o x y ge n -sat ur ati o n a n d c hest x-ra y was 
u nc ha n ge d fr o m baseli ne, I L -2 was disc o nti n ue d as a preca uti o n. T his sa me patie nt re q uire d 
s ur gical de bri de m e nt of necr otic tiss ue res ulti n g fr o m i ntralesi o nal t herap y. A d verse e ve nts i n 
t he U C Da vis e x perie nce are s u m marize d bel o w wit h all t o xicities classifie d as gra d e 1 / 2 wit h 
t he e xce pti o n of gra de 3 i njecti o n site reacti o ns.  

I L- 2 / Pe m br oliz u m a b 
Merc k O T S P # 5 5 5 7 1 
Fi g ur e 3. U C Da vis E x p eri e n c e: I ntr al esi o n al I L- 2 T o xi cit y 
Gr a d e 3 I nj e cti o n 
sit e r e a cti o n 
I nj e cti o n sit e 
r e a cti o n 
A s y m pt o m ati c 
H y p ot e n si o n 
I n cr e a s e d 
D e pr e s si o n 
N a u s e a 
Ri g or s/ F e v er 
0 
2 5 
s o 
0/o 
7 5 
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2 
Versi o n 0 6/ 1 1/ 2 0 2 4 
1 0 0 
I m p o 1 1a ntl y, i ntralesi o nal I L- 2 has als o de m o nstrate d safet y a n d efficac y i n a n u m ber of ot her 
disease sites i ncl u des oral s q ua m o us cell carci n o ma [ 4 7], li ver ca ncer [48] a n d l u n g [ 4 2]. 
4. 8. 3 
I ntr al esi o n al I L- 2 i n M et ast ati c R e n al C ell C a r ci n o m a 
I ntralesi o nal I L- 2 has bee n teste d i n patie nts wit h pr o gressi ve metastatic re nal cell carci n o ma 
( R C C) i n a p hase I trial i n c o m bi nati o n wit h gra n ul oc yte macr o p ha ge c ol o n y-sti m ulati n g fact or 
( G M- C S F) a n d I F N-al p ha[ 4 9]. T he res ults were pr o misi n g: t hree of ei g ht patie nts wit h 
pr o gressi ve metastatic R C C after ne p hrect o m y ac hie ve d c o m plete re missi o n. H ula n d et al. 
i ntr o d uce d I L- 2 i n halati o n t hera p y f or 116 patie nts wit h p ul m o n ai y a n d me diasti nal metastases 
fr o m R C C w h o c o ul d n ot t olerate H D-I L- 2 [ 5 0]. Pr o gressi ve p ul m o nai y metastases res p o n de d 
dra maticall y i n 15 % of t he patie nts f or a me dia n of 15.5 m o nt hs a n d were sta bilize d i n 5 5 % of 
patie nts f or a me dia n of 6. 6 m o nt hs. T o xicit y ass ociate d wit h I L- 2 i n halati o n was l ocal a n d 
c o nsiste d mai nl y of c o u g h a n d patie nts were a ble t o be treate d o n an o ut patie nt basis. 
4. 8. 4 
I ntr al esi o n al I L- 2 i n M et ast ati c H e a d a n d N e c k S q u a m o us C ell C a r ci n o m a 
Ti mai· et al. [47] repo11ed a 4 2 % res p o nse i n t he treat me nt of oral s q ua m o us cell cai·ci n o ma a n d 
repo11 t he c o m plete a bse nce of a d verse effects wit h t his re gi me n alt h o u g h it s h o ul d be n ote d t hat 
t he d ose of i ntralesi o nal I L- 2 t he y i nc m p orate d was si g nifica ntl y l o wer t ha n t hat repo11ed f or 
mela n o ma lesi o ns. A p hase III trial s h o we d t hat patie nts wit h resecta ble S C Cs of t he oral ca vit y 
a n d or o p ha 1 y n x treate d wit h peril y m p hatic i ntralesi o nal a d mi nistrati o n of l o w- d ose I L- 2 h a d 
l o n ger disease free a n d o verall s ur vi val [ 5 1]. 
Ta ke n t o get her t hese data de m o nstrate cleai· efficac y a n d safet y f or t he use of i ntralesi o nal I L- 2 
f or t he treat me nt of mali
g n a nt lesi o ns at de n nal, s u bc uta ne o us, a n d n o n- p ul m o nai y visceral sites. 
A s u m mai y of rele va nt t o xicities fr o m i ntralesi o nal I L- 2 ca n be f o u n d i n Ta ble 1. It is i mpo11ant 
to n ote t hat m ost of t hese trials e m pl o ye d c o nc o mita nt t hera pies i ncl u di n g c o nc o mita nt 
U C D a vis C o m pre he nsi ve C a ncer Ce nter 
C o nfi de nti al 
P a ge 19 of 9 2 

I L-2 / Pe m br oliz u m a b  
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2  
Merc k O T S P # 5 5 5 7 1  
Versi o n  0 6 /1 1 /2 0 2 4  
U C D a vis C o m pre he nsi ve C a ncer Ce nter  
C o nfi de nti al  
P a ge 2 0  of 9 2  
i m m u n ot hera p y. Criticall y, of 1 8 7 patie nts treate d acr oss t hese tri als o nl y t w o ( 1. 1 %) 
e x perie n ce d gra de 3 t o xi cit y.  
T a ble 1 . C o m m o n A d verse  E ve nts wit h I ntr alesi o n al I L -2 i n ≥ 1 0 % of P atie nts  
 I L-2 D osi n g R ati o n ale  
F o ur  d oses  of i ntr alesi o n al I L -2 will be e v al uate d: -1)  1  x 1 0 6 I U; 1) 3 x 1 0 6 I U; 2) 7 x 1 0 6; 
3) 1 5 x 1 0 6 I U. T h ese d ose le vels we re selecte d base d o n t he cli nical d ata descri be d a b o ve a n d
o ur cli nical e x perie nce wit h i ntralesi o nal I L -2. O ne of  t he lar g est re p orts, w hic h i ncl u de d 4 8
patie nts wit h metastatic mela n o ma, i n dicates t hat t his a p pr oac h is hi g hl y effecti ve wit h a 7 0 %
res p o nse rate of i nject e d lesi o ns a n d li mite d gra de 1-2 t o xicit y [4 3 ]. T his st u d y i nc or p orate d a n
i nitial d ose of 3 milli o n I U w hic h was escalat e d wit hi n eac h patie nt as t olerate d. Treat me nts
occ urre d 3 x wee kl y f or a me dia n d urati o n of 6 wee ks a n d t he d ose was escalate d u p t o a
ma xi m u m  of 1 6 milli o n I U. A d diti o nall y, t he selecte d d ose le vels are i nstit uti o nal practice at  U C
Da vis ha ve bee n re p orte d i n se veral cli nical s eries  [4 4 , 4 5 ] a n d w e  ha ve rece ntl y p u blis he d  t hese
g ui deli nes f or t he use of i ntralesi o nal I L -2 t hat h a v e bee n a d o pte d b y N C C N  [4 6 ].
We will i nitiate t he trial at D ose le vel 3 a n d de -escalate t o l o wer d ose le vels as nee de d t o 
esta blis h t he M T D. We h a ve c h ose n t his a p pr oac h f or f o ur reas o ns: 1) T w o patie nts ha ve alr ea d y 
bee n treate d usi n g t his sa me treat me nt pr ot oc ol at d ose le vel 3 o n o ur pil ot trial U C D C C 2 6 9 
wit h n o e vi de nce of d os e li miti n g t o xicities. 2) T his all o ws patie nts o n trial t o be gi n treat me nt at 
t he d ose belie ve d t o be effecti ve a n d pre vi o usl y s h o w n t o be safe a n d t heref or pr o vi des t he 
greatest p ote ntial be n efit f or st u d y p artici pa nts. 3) E ve n at d ose le v el 3 t he first d ose gi ve n t o 
patie nts is 3 x 1 0 6 I U, t h us t he i ntra patie nt d ose es calati o n w hic h is t he sta n dar d a p pr oac h f or 
i ntralesi o nal I L-2 a d mi nistrati o n pr o vi des a n a d diti o nal safet y assess me nt. 4) D ose le vel 3 is o ur 
i nstit uti o nal practice w hic h has bee n a d mi nistere d t o n u mer o us patie nts off trial wit h li mite d 
t o xicities. 
N 
Sit e
Gr a d e 1/ 2
I nj e cti o n 
Sit e
Gr a d e 1/ 2 
I nj e cti o n 
P ai n
Gr a d e 1/ 2 
F e v er / 
C hill s /
Fl u -li k e 
S y m pt o m
s
Gr a d e 
1/ 2 
F ati g u e
Gr a d e 
1/ 2 
N a u s e a
Gr a d e 1/ 2 
L o c al 
I nf e cti o n
Gr a d e 1/ 2 
St o m a c h 
P ai n
Gr a d e 
1/ 2 
Di arr h e a
Gr a d e 1/ 2 
H e a d a c h e
R a d n y
2 0 0 3
2 4
D er m al, 
S Q
1 0 0 %
--
5 8 % 
4 6 % 
4 1 %
--
1 7 %
1 2 %
1 2 % 
( 4 % Gr 3)
Gr e e n
2 0 0 7
1 3
D er m al, 
S Q
1 0 0 %
--
S e v er al
p ati e nt s
--
1 5 % 
1 5 %
--
--
--
W ei d e
2 0 1 0
5 2
D er m al, 
S Q
9 8 %
7 8 % 
5 8 % 
3 6 % 
3 4 %
--
--
--
--
B o y d
2 0 1 1
3 9
D er m al, 
S Q
--
1 0 0 % 
8 5 %
-- 
-- 
--
--
--
--
S hi
2 0 1 5
1 1
D er m al, 
S Q
1 0 0 %
( 9 % Gr 3)
--
5 5 %
-- 
-- 
--
--
--
--
Ti m ar 
2 0 0 5
3 9
Or al 
m u c o s a
--
--
-- 
-- 
-- 
--
--
--
--
F erl a z z o
1 9 9 7
9 
Li v er
--
--
S e v er al 
P ati e nt s
-- 
-- 
--
--
--
--

I L-2 / Pe m br oliz u m a b  
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2  
Merc k O T S P # 5 5 5 7 1  
Versi o n  0 6 /1 1 /2 0 2 4  
U C D a vis C o m pre he nsi ve C a ncer Ce nter  
C o nfi de nti al  
P a ge 2 1  of 9 2  
I ntr alesi o n al I nterle u ki n-2 i n C o m bi n ati o n wit h R a di ot her a p y or C hec k p oi nt 
Bl oc k a de T her a p y.  
Alt h o u g h H D -I L-2 h as b ee n c o m bi ne d wit h R T t h ere is li mite d p u blis he d data e xa mi ni n g 
i ntralesi o nal I L-2 i n c o m bi nati o n wit h R T.  Preli mi nar y m o use m o del data ge nerat e d i n o ur la b 
de m o nstrates a s y ner gistic a nti -t u m or effect t o t his c o m bi nati o n si milar t o s yste mic H D -I L-2 
c o m bi nati o ns.   
Fi g ure 4 . R a di ot her a p y + I ntr alesi o n al I L -2 i n a m uri ne mel a n o m a m o del  
F urt her m ore, i n t w o patie nts wit h m etastatic mela n o ma w h o recei ve d  i ntral esi o nal I L-2 a n d 
palliati ve ra di ot hera p y w e o bser ve d c o m plete re gressi o n of irra diate d / i njecte d lesi o ns a n d l o n g 
ter m pr o gressi o n free s ur vi val wit h o ut a n y e vi de nce of u ne x p ecte d or a d diti ve t o xicit y. Ta ke n 
t o get her t hese precli nical st u dies a n d cli nical o bser vati o ns s u g gest s y ner g y bet wee n ra di ot hera p y 
a n d i ntralesi o nal I L -2.  
Fi g ure 5 . C o m plete r e g ressi o n o bser ve d i n irr a di ate d/i njecte d met ast atic mel a n o m a lesi o ns 
A rece nt re p ort at A S C O 2 0 1 5 has als o de m o nstrat e d t he safet y a n d efficac y of i ntralesi o nal I L -2 
i n c o m bi nati o n wit h i ntralesi o nal C T L A-4 c hec k p oi nt bl oc ka de.  T wel ve  p atie nts were treate d 
wit h n o d ose li miti n g t o xicities a n d a 7 5 % res p o nse rate at u ntreate d l esi o ns.  

I L-2 / Pe m br oliz u m a b  
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2  
Merc k O T S P # 5 5 5 7 1  
Versi o n  0 6 /1 1 /2 0 2 4  
U C D a vis C o m pre he nsi ve C a ncer Ce nter  
C o nfi de nti al  
P a ge 2 2  of 9 2  
I ntr alesi o n al I L-2 + R T i n p atie nts refr act or y t o P D -1/ P D -L 1 c hec k p oi nt bl oc k a de  
T he a d ve nt of c hec k p oi nt bl oc ka de  i m m u n ot hera p y has re v ol uti o nize d t he ma na ge me nt of 
metastatic ca n cer. D es pite t he pr o misi n g e vi de nce f or dee p a n d d ura ble res p o nses wit h t hese 
a ge nts t he maj orit y of patie nts fail t o res p o n d. It is h y p ot hesize d  t hat a n o vel strate g y c o m bi ni n g 
ra di ot hera p y a n d i ntralesi o nal i nterle u ki n-2 (I L -2), a si g nali n g m olec ule a n d me m ber of t he 
c yt o ki ne fa mil y i n v ol ve d i n t he acti vati o n of le u k oc ytes a n d l y m p h oc ytes, ma y o verc o me 
resista nce t o c h ec k p oi nt bl oc ka de t hera p y a nd offer si g nifica nt cli nical b e n efit t o patie nts w h o 
fail t o res p o n d t o c hec k p oi nt bl oc ka de al o ne. We are pr o p osi n g a b ol d  c o m bi nat orial 
i m m u n ot hera p y strate g y c o nsisti n g of ra di ot hera p y ( R T), i ntralesi o nal I L-2, a n d c hec k -p oi nt 
bl oc ka de f or patie nts wit h metastatic N S C L C, mela n o ma, R C C, a n d H N S C C w h o ha ve 
pr o gresse d after c hec k p oi nt i n hi biti o n. I L -2 ca n u pre g ulate P D -1 e x pressi o n a n d acti vate T -cells. 
T here is data s u p p orti n g c o m bi nati o n t hera pies wit h I L -2 a n d c h ec k p oi nt bl oc ka de, I L -2 a n d 
ra di ot hera p y, a n d c h ec k p oi nt bl oc ka de a n d ra di ot hera p y b ut cli nical d ata is li mite d a n d t he tri ple 
c o m bi nati o n has ne ver bee n teste d. I L -2 + c hec k p oi nt bl oc ka de was rece ntl y teste d i n a s mall 
cli nical trial a n d s h o we d pr o misi n g res ults b ut R T w as n ot i ncl u de d i n t his trial.  As  o utli ne d 
a b o ve R T has bee n de m o nstrate d t o i ncrease t he efficac y of b ot h I L -2 a n d c hec k p oi nt bl oc ka de. 
We belie v e t hat t he tri ple c o m bi nati o n of ra di ot hera p y + I L -2 + c h ec k p oi nt i n hi biti o n will be 
hi g hl y effecti ve as R T + I L -2 ca n s er ve hi g hl y acti vate t h e i m m u ne s yste m a n d c hec k p oi nt 
bl oc ka de ca n re v erse t h e i m m u ne s u p pressi ve pat h wa ys i n d uce d b y t u m or a n d t hera p y.   
We h y p ot hesize t h at t h e tri ple c o m bi n ati o n of r a di ot her a p y + i ntr alesi o n al I L -2 + 
Pe m br oliz u m a b will be hi g hl y effecti ve a n d c o n vert p atie nts wit h pri m ar y or sec o n d ar y 
resist a nce t o c hec k p oi nt bl oc k a de i nt o res p o n ders . We h y p ot hesize t hat t he c o m bi nati o n of 
i ntralesi o nal I L-2 wit h r a di ot hera p y will act as a n “i n -sit u” vacci ne i n d uci n g a n a nti-t u m or 
i m m u ne res p o nse a n d i ncreasi n g t u m or i nfiltrati n g l y m p h oc ytes t here b y o v erc o mi n g a maj or 
mec ha nis m of c h ec k p oi nt bl oc ka de resista nce w hile t he c o nti n uati o n of P D-1 i n hi biti o n will be 
critical f or o v erc o mi n g t u m or a n d t hera p y i n d u ce d i m m u ne s u p pressi o n.  T his trial will 
i nc or p orate r o b ust c orrel ati ve assa ys t o pr o vi de i nsi g hts i nt o mec ha nis ms of pri mar y a n d 
sec o n dar y resista nce t o c hec k p oi nt bl oc ka de a n d h o w t his t hera p y ma y o verc o me t hat resista nce.  
T his trial, alt h o u g h s mall, has t he p ote ntial t o drasticall y a d va nce b ot h o ur u n dersta n di n g a n d 
treat me nt of P D-1/ P D -L 1 c hec k p oi nt bl oc ka d e resista nt ca ncer.  W e re vie we d t he Nati o nal 
I nstit utes of Healt h Cli nical Researc h St u dies (htt ps://cli nicaltrials. g o v/ ), w hic h are o p e n a n d 
a vaila ble f or patie nt e nr oll me nt , a n d t here are n o o pe n trials l o o ki n g at t he effects of i ntralesi o nal 
I L-2 c o m bi ne d wit h r a diati o n  a n d c hec k p oi nt i n h ibiti o n . C ollecti vel y, t his pr o vi des t he basis of 
o ur pr o p osal w hic h is e xt e nsi vel y detaile d bel o w.  
Bi o m ar kers  
O ne of t he maj or s h ortc o mi n gs of i m m u n ot hera p y trials has bee n t he lac k of i n-de pt h  c orrelati ve 
st u dies t o hel p i de ntif y t he mec ha nis m of acti o n, i de ntif y bi o mar kers of res p o nse, a n d e x plai n t he 
mec ha nis ms g o ver ni n g tr eat me nt res p o nse or fail ure. T o a d dress t his, we pl a n t o perf or m i n 
de pt h i m m u n ol o gical a nal ysis of patie nt bl o o d a n d t u m or sa m ples.  T his st u d y i nc or p orates s erial 
tiss ues sa m ples pre- treat me nt, d uri n g t hera p y, a n d at pr o gressi o n. T he d esi g n of t his st u d y 
all o ws us t o c o m pare i m m u ne mec ha nis m s pre- t o p ost-t hera p y.  

I L-2 / Pe m br oliz u m a b  
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2  
Merc k O T S P # 5 5 5 7 1  
Versi o n  0 6 /1 1 /2 0 2 4  
U C D a vis C o m pre he nsi ve C a ncer Ce nter  
C o nfi de nti al  
P a ge 2 3  of 9 2  
T u m or P D -L 1 e x pressi o n has bee n li n ke d t o r es p o nse rates of P D -1 c hec k p oi nt bl oc ka de [7 ]. Pre -
cli nical data s u g gests t hat ra di ot hera p y ma y u pre g ulate i ntrat u m oral P D-L 1 e x pressi o n [5 2 ] b ut 
little is k n o w n a b o ut t he d ose res p o nse of t hese effects. A d diti o nall y,  little is k n o w n a b o ut h o w 
t he patter n of e x pressi o n (i.e., t u m or cells vs. i nfiltrati n g i m m u ne cells) affects res p o nse. Data 
prese nte d at A S C O a n d SI T C i n dicat e t hat d ur val u ma b m o n ot hera p y res p o nse rates i n N S C L C 
are 2 7 % i n P D -L 1 p ositi ve t u m ors a n d 5 % i n P D -L 1 ne gati ve t u m ors.  TI Ls a n d a T -cell i nfla me d 
p he n ot y pe ha ve b ee n li n ke d wit h res p o nse t o C T L A -4 c hec k p oi nt bl oc ka d e i n mela n o ma  [5 3 , 
5 4 ]. E xcl usi o n of T -cells i n t he t u m or micr oe n vir o n me nt has als o bee n li n k e d wit h lac k of 
res p o nse t o c h ec k p oi nt i n hi biti o n [5 5 ] wit h d o w n -re g ulati o n of C C L 4 me diate d de n dritic cell 
recr uit me nt as o n e p ote ntial mec ha nis m [5 5 ]. R T has bee n de m o nstr ate d t o i n d uce TI Ls [5 6 ] a n d 
ma y p ote ntiall y o verc o m e t his mec ha nis m of resista nce t o c hec k p oi nt bl oc ka de. O ur u n p u blis he d 
data s u g gests t hat R T ca n i n d uce C C L 4 e x pressi o n a n d i ncrease  TI Ls. Li k e wise, I L -2 ma y 
e x pa n d i ntrat u m oral T -cells hel pi n g t o circ u m ve nt t he mec ha nis ms of c h ec k p oi nt bl oc ka de 
resista nce. 
M utati o nal b ur de n a n d a nti ge nic l oa d are t h o u g ht t o re prese nt a s urr o g ate f or t u m or a nti ge nicit y 
a n d ha ve b ee n li n ke d wit h res p o nse t o c h ec k p oi nt bl oc ka de i n N S C L C  [5 7 ]. W het her m utati o nal 
l oa d is a tr ue i n dicat or of t u m or a nti ge nicit y a n d h o w t his c orrelates wit h res p o nse t o t his 
c o m bi nat orial a p pr o ac h  is u n k n o w n. 

I L-2 / Pe m br oliz u m a b  
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2  
Merc k O T S P # 5 5 5 7 1  
Versi o n  0 6 /1 1 /2 0 2 4  
U C D a vis C o m pre he nsi ve C a ncer Ce nter  
C o nfi de nti al  
P a ge 2 4  of 9 2  
5. 0  
M E T H O D O L O G Y  
E ntr y Criteri a  
Di a g n osis / C o n diti o n f or E ntr y i nt o t he Tri al 
A d va nce d  s oli d mali g na n c y or l y m p h o ma  wit h pr o gr essi o n o n P D -1/ P D -L 1 c hec k p oi nt 
bl oc ka de . 
S u bject I ncl usi o n Criteri a 
1.
A d ults ≥1 8 years of a g e wit h hist ol o gicall y pr o ve n , a d va nce d s oli d mali g na nc y or
l y m p h o ma.
2.
Cli nical a n d/ or ra di o gra p hic p r o gressi o n o n c h ec k p oi nt bl oc ka de t hera p y  (eit her after
pri or res p o nse or pri mar y refract or y) .
3.
E C O G ( Easter n C o o p erati ve O nc ol o g y Gr o u p ) perf or ma nce stat us sc ore of 0 –  1
( A p pe n di x 1)
4.
Prese nce of a ca n di date treat me nt lesi o n (s u bc ut a ne o us, m usc ular, n o dal , or ot her s oft
tiss ue lesi o ns, a n d ot her lesi o ns will als o be c o nsi dere d wit h PI a p pr o val) accessi ble a n d
safe f or ra di ot hera p y a n d serial i ntralesi o nal i njecti o ns.
5.
Prese nce of at least o n e tar get lesi o n ( disti nct fr o m treat me nt lesi o n a n d o utsi de of
treat me nt lesi o n ra diati o n fiel d) e val u a ble f or res p o nse b y irR E CI S T
6.
Life e x pecta nc y ≥ 6 m o nt hs
7.
De m o nstrate a d e q uate or ga n f u ncti o n as defi ne d i n Ta ble 2 , all scree ni n g l a bs s h o ul d be
perf or me d wit hi n 1 0 da ys of treat me nt i nitiati o n.
T a ble 2 . A de q u ate Or g a n F u ncti o n L a b or at or y V al ues
S yste m  
L a b or at or y V al ue  
He m at ol o gic al  
A bs ol ute ne utr o p hil c o u nt ( A N C)  
≥1, 5 0 0 / mc L  
Platelets  
≥1 0 0, 0 0 0 / mc L  
He m o gl o bi n  
≥9 g/ d L or ≥5. 6 m m ol/ L wit h o ut tra nsf usi o n or E P O 
de pe n de nc y ( wit hi n 7 da ys of assess me nt)  
Re n al  
Ser u m creati ni n e 
O R  
Meas ure d or calc ulate d
a creati ni ne cleara nce  
( G F R ca n als o be use d i n place of creati ni n e or Cr Cl) 
≤1. 5 X u p per li mit of n or mal ( U L N) 
O R  
≥6 0 m L/ mi n f or s u bject wit h creati ni n e le vels > 1. 5 
X i nstit uti o nal U L N  
He p atic  
Ser u m t otal bilir u bi n 
≤ 1. 5 X U L N O R  
Direct bilir u bi n ≤ U L N f or s u bjects wit h t otal 
bilir u bi n le vels > 1. 5 U L N  
A S T ( S G O T) a n d A L T ( S G P T)  
≤ 2. 5 X U L N  O R  
≤ 5 X U L N f or s u bjects wit h li v er metastases  
Al b u mi n  
> 2. 5 m g/ d L

I L-2 / Pe m br oliz u m a b  
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2  
Merc k O T S P # 5 5 5 7 1  
Versi o n  0 6 /1 1 /2 0 2 4  
U C D a vis C o m pre he nsi ve C a ncer Ce nter  
C o nfi de nti al  
P a ge 2 5  of 9 2  
C o a g ul ati o n  
I nter nati o nal N or malize d Rati o (I N R) or 
Pr ot hr o m bi n Ti me ( P T)  
Acti vate d Partial T hr o m b o plasti n Ti me (a P T T)  
≤1. 5 X U L N u nless s u bject is recei vi n g a ntic oa g ula nt 
t h era p y 
as l o n g as P T or P T T is wit hi n t hera pe utic ra n ge of 
i nte n de d use of a ntic oa g ula nts 
≤1. 5 X U L N u nless s u bject is recei vi n g a ntic oa g ula nt 
t h era p y 
as l o n g as P T or P T T is wit hi n t hera pe utic ra n ge of 
i nte n de d use of a ntic oa g ula nts 
aCreati ni n e cleara nce s h o ul d be calc ulate d per i nstit uti o nal sta n dar d.  
8.
Delete d as of A me n d me nt 0 9/ 0 7/ 2 0 2 2 .
9.
Fe male s u bject of c hil d b eari n g p ote ntial s h o ul d h a ve a n e gati ve uri ne or ser u m pre g na n c y
wit hi n 4 da ys  pri or t o recei vi n g t he first d ose of st u d y me dicati o n.  If t he uri ne test is
p ositi ve or ca n n ot be c o nfir me d as ne g ati ve, a ser u m pre g na nc y test will b e re q uir e d.
1 0. Fe male s u bjects of c hil d beari n g p ote ntial ( Secti o n 5. 7. 2 ) m ust be willi n g t o use a n
a de q uate m et h o d of c o ntr ace pti o n as o utli ne d i n Secti o n 5. 7. 2  –  C o ntrace pti o n,  f or t he
c o urse of t he st u d y t hr o u g h 1 2 0 da ys after t he last d ose of st u d y me dicati o n.
N ote: A bsti ne nce is a cce pta ble if t his is t he us ual lifest yle a n d preferre d c o ntrace pti o n f or
t he s u bject.
1 1. Male s u bjects of c hil d beari n g p ote ntial ( Secti o n 5. 7. 2 ) m ust a gree t o use a n a de q uate
met h o d of c o ntrace pti o n as o utli ne d i n Secti o n 5. 7. 2  - C o ntrace pti o n, starti n g wit h t he
first d ose of st u d y t hera p y t hr o u g h 1 2 0 da ys after t he last d ose of st u d y t hera p y.
N ote: A bsti ne nce is a cce pta ble if t his is t he us ual lifest yle a n d preferre d c o ntrace pti o n f or
t he s u bject.
1 2. Si g ne d i nf or me d c o nse nt.
1 3. A bilit y t o c o m pl y wit h t he pr ot oc ol.
1 4. S yst olic bl o o d press ure ≥8 0.
1 5. Delete d  as of A me n d me nt 0 9/ 0 7/ 2 0 2 2.
1 6. Delete d  as of A me n d me nt 0 9/ 0 7/ 2 0 2 2.
S u bject E xcl usi o n Criteri a  
1.
U nc o ntr olle d c o nc o mita nt disease .
2.
Is c urre ntl y partici pati n g a n d recei vi n g st u d y t hera p y or has partici pat e d i n a st u d y of a n
i n vesti gati o nal a ge nt a n d recei v e d st u d y t hera p y or use d a n i n vesti gati o nal de vice wit hi n
4 wee ks of t he first d ose of treat me nt.
3.
Has a dia g n osis of i m m u n o deficie nc y or is recei vi n g s yste mic ster oi d t hera p y or a n y
ot her f or m of i m m u n os u p pressi ve t hera p y wit hi n 7 da ys pri or t o t he first d ose of trial
treat me nt. Use of i n h ale d or t o pical ster oi ds or s yste mic c ortic oster oi ds < 1 0 m g/ da y  a n d
pre d nis o ne e q ui val e nt ≤1 0 m g/ d  is per mitte d.
4.
Has a k n o w n hist or y of acti ve T B  ( Bacill us T u berc ul osis)

I L-2 / Pe m br oliz u m a b  
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2  
Merc k O T S P # 5 5 5 7 1  
Versi o n  0 6 /1 1 /2 0 2 4  
U C D a vis C o m pre he nsi ve C a ncer Ce nter  
C o nfi de nti al  
P a ge 2 6  of 9 2  
5.
H y perse nsiti vit y t o pe m br oliz u ma b or a n y of its e xci pie nts.
6.
Has ha d a pri or a nti -ca ncer m o n ocl o nal a nti b o d y ( m A b)  (e xcl u di n g P D-1/ P D -L 1
i n hi bit or) wit hi n 4 wee ks pri or t o st u d y Da y 1 or w h o has n ot rec o v ere d (i. e., ≤ Gra d e 1
or at baseli ne) fr o m a d v erse e ve nts d ue t o a ge nts a d mi nistere d m ore t ha n 4 wee ks earlier.
7.
Has ha d pri or c he m ot hera p y, tar gete d s m all m olec ule t hera p y, or ra di ati o n t hera p y wit hi n
2 wee ks pri or t o st u d y D a y 1 or w h o has n ot rec o vere d (i. e., ≤ Gra d e 1 or at baseli ne)
fr o m cli nicall y si g nifica nt  a d verse e ve nts d ue t o a pre vi o usl y a d mi nistere d a ge nt.
N ote:  S u bjects wit h ≤ Gra de 2 ne ur o pat h y a n d ≤ G rade 2  a dre n al i ns uffici e nc y  are a n
e xce pti o n t o t his criteri o n a n d ma y q ualif y f or t h e st u d y.
N ote:  If s u bject r ecei ve d maj or s ur ger y, t he y m ust ha ve rec o vere d a d e q uatel y fr o m t he
t o xicit y a n d/ or c o m plicati o ns fr o m t he i nter ve nti o n pri or t o starti n g t hera p y.
8.
Has a k n o w n a d diti o nal mali g na nc y t hat is pr o gressi n g or re q uires acti ve tr eat me nt.
E xce pti o ns i ncl u de basal cell carci n o ma of t he s ki n or s q ua m o us cell carci n o ma of t he
s ki n t hat has u n der g o ne p ote ntiall y c urati ve t hera p y or i n sit u cer vical ca ncer.
9.
Has k n o w n acti ve ce ntr al ner v o us s yste m ( C N S) metastases a n d/ or carci n o mat o us
me ni n gitis.  S u bjects wit h pre vi o usl y treate d brai n metastases ma y partici pate pr o vi de d
t he y are sta bl e ( wit h o ut e vi de nce of pr o gressi o n b y i ma gi n g f or at least f o ur wee ks pri or
t o t he first d ose of trial tr eat me nt a n d a n y n e ur ol o gic s y m pt o ms ha ve ret ur ne d t o
baseli ne) , ha v e n o e vi de n ce of ne w or e nl ar gi n g brai n metastases, a n d are n ot usi n g
ster oi ds f or at least 7 d a ys pri or t o trial treat me nt. T his e xce pti o n d oes n ot i ncl u de
carci n o mat o us me ni n gitis w hic h is e xcl u de d re gar dless of cli nical sta bilit y.
1 0. Has acti ve a ut oi m m u ne disease t hat has re q uire d s yste mic treat me nt i n t he past 2 years
(i.e., wit h use of diseas e m o dif yi n g a ge nts, c ortic oster oi ds or i m m u n os u p pressi ve dr u gs).
Re place me nt t hera p y ( e. g., t h yr o xi ne, i ns uli n, or p h ysi ol o gic c ortic oster oi d re place me nt
t hera p y f or a dre nal or pit uitar y i ns ufficie nc y, etc.) is n ot c o nsi dere d a f or m of s yste mic
treat me nt.
1 1. Hist or y of se vere a ut oi m m u ne disease.
1 2. Treat me nt wit h s yste mic i m m u n osti m ulat or y a ge nts wit hi n 4 wee ks or fi ve half -li ves of
t he dr u g, w hic he v er is s h orter, pri or t o e nr oll me nt ( wit h t he e xce pti o n of c h ec k p oi nt
bl oc ka de t hera p y).
1 3. Treat me nt wit h s yste mic c ortic oster oi ds or ot her s yste mic i m m u n os u p pressi ve
me dicati o ns wit hi n past 4 wee ks or 5 half -li ves w hic he ver is s h orter. Use of i n hale d or
t o pical ster oi ds or s yste mic c ortic oster oi ds < 1 0 m g/ da y  a n d pre d nis o ne e q ui vale nt
≤1 0 m g/ d  is per mitte d.
1 4. Has a hist or y of ( n o n -i nf ecti o us) p ne u m o nitis t hat re q uire d ster oi ds or c urre nt
p ne u m o nitis.
1 5. Has a n acti ve i nfecti o n re q uiri n g s yste mic t hera p y.
1 6. Has a hist or y or c urre nt e vi de nce of a n y c o n diti o n, t hera p y, or la b orat or y a b n or malit y
t hat mi g ht c o nf o u n d t he res ults of t he trial, i nterfere wit h t he s u bject’s partici pati o n f or
t he f ull d urati o n of t he tri al, or is n ot i n t he best i nterest of t he s u bject t o partici pate, i n
t he o pi ni o n of t he treati n g i n vesti gat or.

I L-2 / Pe m br oliz u m a b  
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2  
Merc k O T S P # 5 5 5 7 1  
Versi o n  0 6 /1 1 /2 0 2 4  
U C D a vis C o m pre he nsi ve C a ncer Ce nter  
C o nfi de nti al  
P a ge 2 7  of 9 2  
1 7. Has k n o w n ps yc hiatri c or s u bsta nce a b use dis or ders t hat w o ul d i nterfere wit h c o o perati o n
wit h t he re q uire me nts of t he trial.
1 8. Is 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 ojecte d d urati o n of t he trial, starti n g wit h t he pre -scree 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.
1 9. Has a k n o w n hist or y of H u ma n I m m u n o deficie nc y Vir us ( HI V) ( HI V 1/ 2 a nti b o dies).
2 0. Has k n o w n acti ve He p atitis B (e. g., H Bs A g reacti ve) or k n o w n He patitis C (e. g., H C V
R N A [ q ualitati ve]).
2 1. Has recei ve d a li ve vacci ne wit hi n 3 0 da ys of pla n ne d start of st u d y t hera p y.
N ote:  Seas o nal i nfl ue nza vacci nes f or i njecti o n are ge nerall y i nacti vate d fl u vacci nes a n d
are all o w e d; h o we ver i ntra nasal i nfl ue n za v acci n es (e. g., Fl u -Mist ®) are li ve atte n uate d
vacci nes, a n d are n ot all o we d.
2 2. Patie nts u na ble t o t olerat e c hec k p oi nt i n hi bit or t hera p y.
2 3. U nres ol ve d Gra de 3 or  a n y gra de 4 n o n -h e mat ol o gical, treat me nt -relate d A Es attri b ute d
t o pri or P D-1/ P D -L 1 c hec k p oi nt bl oc ka de . A mi ni m u m of 2 wee ks fr o m pri or P D -1/ P D -
L 1 c hec k p oi nt bl oc ka d e t o i nitiati n g st u d y treat me nt.
Tri al Tre at me nts  
T his is a p hase I/II st u d y t hat will e val uate t he safet y a n d t o xicit y of t his c o m bi nat orial a p pr oac h.  
Eli gi ble patie nts > 1 8 years of a ge wit h hist ol o gicall y  pr o ve n a d va nce d s oli d mali g na nc y or 
l y m p h o ma w h o ha ve fail e d P D -1 / P D -L 1 c hec k p oi nt bl oc ka de t hera p y  will be e nr olle d. Patie nts 
m ust ha ve a ca n di d ate treat me nt  lesi o n accessi ble a n d safe f or ra di ot hera p y a n d serial 
i ntralesi o nal i njecti o ns as s pecifie d b y t he pr ot o c ol. T he y m ust als o ha ve  at least o ne tar get lesi o n 
( disti nct fr o m treat me nt l esi o n a n d o utsi de of treat me nt lesi o n ra diati o n fiel d) e val ua ble f or 
res p o nse b y R E CI S T. 
T his st u d y will c o nsist of a p hase I d os e escalati o n  / de-escalati o n  usi n g a sta n dar d 3 + 3 desi g n t o 
deter mi ne safet y a n d M T D of i ntralesi o nal I L -2 w hic h will be d ose escalate d i n c o nj u ncti o n wit h 
sta n dar d fi xe d d os es of R T a n d Pe m br oliz u ma b. T he st u d y will be gi n at d ose le vel 3 a n d t he 
d ose will be de -es calate d if nee d e d t o det er mi ne t he M T D. At t he M T D t h ere will be a p h ase II 
d ose e x pa nsi o n w hic h will i nc or p orate a si m o n-t w o sta ge desi g n t o assess efficac y a n d safet y. 
Patie nts will recei ve pe m br oliz u ma b a n d i ntralesi o nal I L-2 i n c o m bi nati o n wit h h y p ofracti o nate d 
ra di ot hera p y.  
•
Ra di ot hera p y will be deli vere d t o t he tr eat me nt lesi o n d uri n g t he sec o n d c y cle of t hera p y
usi n g a n  8 G y x 3 fracti o ns palliati ve re gi me n.  Fracti o ns ma y be deli vere d o n c o nsec uti ve
da ys or e ver y ot her da y b ut m ust be c o m plete d d uri n g wee k s 1 -2  of c ycle 2  a n d will n ot be
re peat e d i n f ut ure c ycles.
•
Pe m br oliz u ma b will be deli vere d at 2 0 0 m g i n t hr ee-wee k  c y cles .

I L-2 / Pe m br oliz u m a b  
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2  
Merc k O T S P # 5 5 5 7 1  
Versi o n  0 6 /1 1 /2 0 2 4  
U C D a vis C o m pre he nsi ve C a ncer Ce nter  
C o nfi de nti al  
P a ge 2 8  of 9 2  
•
A t otal of f o ur i nterle u ki n -2 treat me nts will be deli vere d i nt o t he treat me nt lesi o n b y
i ntralesi o nal i njecti o n bi wee kl y (at least 4 8 h o urs a part) starti n g 2 4-9 6  h o urs after t h e
c o m pleti o n of ra di ot hera p y a n d t o be c o m plete d d uri n g t he sec o n d o n -tri al c ycle of
Pe m br oliz u ma b.  I ntralesi o nal i njecti o ns will be perf or me d b y dir ect vis ualizati o n a n d/ or
pal pati o n of t he lesi o n or u n der ultras o u n d or C T g ui da nce as i n dicate d. I ntralesi o nal I L -2
i njecti o ns will f oll o w g ui deli nes w hic h we h a ve pre vi o usl y p u blis he d [4 6 ]. I L-2 will be
a d mi nistere d  at t hree d os e le vels: 1) 3 x 1 0 6 I U, 2) 7 x 1 06, 3) 1 5 x 1 06 I U. T he st u d y will
be gi n at d ose le vel 3 a n d t he d ose will be de -escal ate d as nee de d t o esta blis h t he M T D.
At d ose escal ati o n le vels 2 a n d 3 a n d i n t he p hase II p orti o n eac h patie nt will recei ve a 
test d ose of 3 x 1 0 6 I U f or t heir first i njecti o n pri or t o escalati o n t o hi g her d oses 
acc or di n g t o o ur p u blis he d g ui deli nes.  F or e x a m ple, at d ose le vel 3 eac h p atie nt will 
recei v e a n i nitial test d ose of 3 x 1 06 I U of I L-2, w hic h will be escal ate d t o 7 x 1 0 6 f or t he 
sec o n d treat me nt a n d t he n 1 5 x 1 0 6 I U f or t he fi nal t w o treat me nts as t olerate d. If a d ose 
le vel is n ot t olerate d t he treat me nt will be de-escalate d t o previ o us d ose le vels f or 
s u bse q ue nt treat me nts. If 3 milli o n I U I L-2 is n ot t olerate d t he d os e ca n b e de -escalate d 
t o 1 milli o n I U I L-2.  If 1 milli o n I U I L-2 is n ot t olerate d t he treat me nt will be dee me d 
i nt olera ble a n d patie nt r e m o ve d fr o m st u d y (see Fi g ure 6 ). 
Patie nts will be assesse d b y a p h ysicia n o nce d uri n g t he first wee k of ra di ot hera p y, wee kl y 
d uri n g i ntralesi o nal I L -2 i njecti o n s, a n d wit h e ver y c ycle of p e m br oliz u ma b. R o uti ne la b orat or y 
e val uati o n will occ ur pre -treat me nt. F or res p o nse assess me nt patie nt will ha ve i ma gi n g pre -
treat me nt a n d after e ver y t hree c y cles of Pe m br oli z u ma b. F or c ollateral st u dies patie nts will 
u n der g o ma n dat or y tr eat me nt lesi o n bi o psies a n d bl o o d dra ws pre -treat me nt a n d d uri n g t he 
nee dle place me nt f o r t h e fi nal I L-2 treat me nt.  
Preli mi nar y effic ac y as d eter mi ne d b y a bs c o pal res p o nse rate, O R R, D C R a n d P F S will be 
assesse d e v er y 3 c y cles . Patie nts o n acti ve treat m e nt at 1 2  m o nt hs ma y c o nti n ue t o recei ve 
pe m br oliz u ma b  b ut will re vert t o sta n dar d of care ( S O C) ma na ge me nt a n d be la bele d i n “f oll o w 
u p”.  At t his ti me o nl y P F S a n d l o n g -ter m t o xicit y data will be c ollecte d e ver y 3 m o nt hs.  
T he pri mar y e n d p oi nt  is t o deter mi ne if t his re gi m e n c o n verts p atie nts wit h resista nce t o 
P D -1/ P D -L 1 c hec k p oi nt bl oc ka de i nt o res p o n d ers as deter mi ne d b y a bsc o p al res p o nse rate 
( defi ne d as res p o nse rate at lesi o ns n ot treate d wit h R T + I L-2)  usi n g ir R E CI S T  as w ell as O R R, 
D C R, a n d P F S usi n g R E CI S T 1. 1. T he s ec o n dar y e n d p oi nt is t olera bilit y, safet y, a n d t o xicit y 
usi n g C T C A E v 4. 0 3 . C orrelati ve st u dies  i ncl u de i m m u n o p he n ot y pi n g serial t u mor bi o psies a n d 
bl o o d sa m ples.  
Tri al Pr oce d ures  
Patie nts will be recr uite d f r o m t he U C Da vis C o m pre he nsi ve Ca n cer Ce nt er ( U C D C C C).  All 
patie nts will be re gistere d at t he U C Da vis facilit y . Patie nts will be i de ntifie d  t hr o u g h t he vari o us 
cli nics at U C Da vis,  at t he U C Da vis m ulti disci pli nar y t u m or b oar ds, a n d t he U C D C C C P hase I 
cli nic. C o or di nate d recr uit me nt eff orts s pecifi call y tail ore d f or t his trial will be creat e d. W e 
c o nser vati vel y pr oj ect a 3 6 -m o nt h  accr ual peri o d.  

I L-2 / Pe m br oliz u m a b  
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2  
Merc k O T S P # 5 5 5 7 1  
Versi o n  0 6 /1 1 /2 0 2 4  
U C D a vis C o m pre he nsi ve C a ncer Ce nter  
C o nfi de nti al  
P a ge 2 9  of 9 2  
 Tre at me nt Pl a n  
T a ble 3 . Tre at me nt Pl a n  
A ge nt  
D ose  
R o ute  
Fre q ue nc y  
I L-2  
D ose 1:  3 x 1 0 6   I U 
D ose 2:  7 x 1 0 6   I U 
D oses 3 & 4:  1 5 x  1 0 6 I U 
I ntrat u m oral 
• 4 t otal d oses
• S tarti n g 2 4 – 7 2  h o urs after t he c o m pleti o n of
ra di ot hera p y  a n d
• C o m plete d d uri n g C ycle 2 of pe m br oliz u ma b
• D oes n ot re peat  wit h f ut ure c ycles
Ra diati o n  
2 4 G y  
E xter nal 
bea m  
• 3 fracti o ns  of 8 G y palliatia ve re gi me n
• D eli vere d  1 2 – 9 6 h o urs a part
• M ust be c o m plete d  d uri n g wee k 1 of C ycle 2
• D oes n ot re peat wit h f ut ure c ycles .
Pe m br oliz u ma b  
2 0 0  m g 
I V 
Q 3 wee ks ( o ne c ycle) 
Eli gi ble patie nts wit h a d va nce d s oli d mali g na ncies or l y m p h o ma w h o fail t o res p o n d t o or 
pr o gress o n P D 1/ P D L 1 c hec k p oi nt bl oc ka de will be e nr olle d. Patie nts will recei v e 
pe m br oliz u ma b  a n d i ntralesi o nal I L -2 i n c o m bi nati o n wit h h y p ofracti o nate d ra di ot hera p y. 
5. 2. 2. 1  
R a di ot her a p y  
Ra di ot hera p y will be deli vere d t o t he tr eat me nt lesi o n d uri n g t he first wee k of C ycle 2 usi n g a n 
8  G y x 3 fracti o ns palliati ve re gi me n.  Fracti o ns ma y be deli vere d o n c o ns ec uti ve or e ver y ot her 
da y b ut m ust be c o m plete d d uri n g wee k 1 -2  of C ycle 2 a n d will n ot be re p eate d i n f ut ur e c ycles. 
5. 2. 2. 1. 1  
D ose S pecific ati o ns a n d Tre at me nt Deli ver y  
Ra di ot hera p y will be deli vere d as 2 4 G y o ver 3 fracti o ns.  T here s h o ul d be a mi ni m u m of 1 2 
h o urs a n d a ma xi m u m of 9 6 h o urs bet wee n treat m e nts.  All treat me nts m ust be c o m plete d wit hi n  
wee k 1 –  2  of c ycle 2 . If a patie nt ca n n ot r ecei ve a ra diati o n fracti o n it will be s ki p pe d. T he d ose 
per fracti o n is t o be pres cri be d s uc h t hat  9 5 % of t h e  pla n ni n g treat me nt v ol u me ( P T V) is 
e nc o m passe d b y t he pres cri pti o n d ose.  
5. 2. 2. 1. 2  
Tec h nic al F act ors 
O nl y p h ot o n ( x -ra y) bea ms wit h p h ot o n e ner gies 4-1 5 M V or electr o n bea ms wit h electr o n 
e ner gies of 6 -1 2 Me V will be all o we d.  
5. 2. 2. 1. 3  
L oc aliz ati o n, Si m ul ati o n, a n d I m m o biliz ati o n 
Patie nts will be p ositi o ne d i n a sta ble p ositi o n ca p a ble of all o wi n g acc urate re pr o d uci bilit y of t he 
tar get p ositi o n fr o m treat me nt t o treat me nt. Patie nt i m m o bilizati o n m ust be relia ble e n o u g h t o 
e ns ure t hat t he gr oss t u m or v ol u me ( G T V) d oes n ot de viate be y o n d t he c o nfi nes of t he P T V as 
wit h a n y s i g nifica nt pr o b a bilit y (i.e., <5 %).  Patie nts will  u n der g o a n i ma gi n g st u d y ( electr o n 
p ortal i ma gi n g, c o ne bea m c o m p ute d t o m o gra p h y or Me ga v olta ge c o m p ute d t o m o gra p h y) 

I L-2 / Pe m br oliz u m a b  
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2  
Merc k O T S P # 5 5 5 7 1  
Versi o n  0 6 /1 1 /2 0 2 4  
U C D a vis C o m pre he nsi ve C a ncer Ce nter  
C o nfi de nti al  
P a ge 3 0  of 9 2  
i m me diatel y pri or t o treat me nt t o e ns ure pr o per ali g n me nt of t he ge o metric ce nter (i.e., is oce nter) 
of t he si m ulate d fiel ds.   
5. 2. 2. 1. 4  
T ar get V ol u mes 
I m a ge Ac q uisiti o n 
C o m p ute d t o m o gra p h y will be use d f or tar g eti n g a n d treat me nt pla n ni n g. I V c o ntrast is 
e nc o ura g e d w he n its use will e n ha nce tar get deli n eati o n b ut is n ot re q uire d. A xial ac q uisiti o ns 
wit h ga ntr y 0 de grees will be re q uire d wit h s paci n g ≤3. 0 m m bet wee n sca ns i n t he re gi o n of t he 
t u m or.  
T ar get V ol u me  
T he treat me nt  lesi o n will be o utli ne d a n d desi g nat e d t he gr oss t u m or v ol u me ( G T V). N o 
a d diti o nal cli nical tar get v ol u me ( C T V) mar gi n f or micr osc o pic s prea d will be a d de d. D e pe n di n g 
o n t he sta bilit y a n d re pr o d uci bilit y of patie nt set u p a n a d diti o nal mar gi n of 0. 3 –  2 c m will be 
a d de d t o t he G T V t o c o nstit ute t he P T V.   
Or g a ns at Ris k  
All or ga ns at ris k wit hi n a xial slices c o ntai ni n g t he P T V a n d e x p ecte d t o b e wit hi n t he treat me nt 
fiel d s h o ul d be c o nt o ure d. All sta n dar d n or mal tiss ue c o nstrai nts f or 3 fracti o n ra di ot hera p y p er 
R T O G g ui deli nes s h o ul d be o bser ve d. Treat me nt h ots p ots i n ra di ose nsiti ve or ga ns s h o ul d be 
a v oi de d a n d t he d ose ca n be m o difie d t o res pect n or mal tiss ue t olera nce as o utli ne d i n secti o n 
5. 4. 2 . T he ma xi m u m p oi nt d ose t o 0. 1cc s h o ul d n ot e xcee d 2 5 G y f or s ki n  ( defi ne d as o uter m ost 
0. 5 c m ri n d o n a xial slices)  a n d maj or peri p heral n er ves  (i.e., brac hial ple x us, sacral ple x us, 
sciatic etc.). T h e ma xi m u m p oi nt d ose s h o ul d n ot e xcee d 1 8 G y t o t he s pi nal c or d.  
Tec h ni q ue a n d D ose C alc ul ati o ns 
C o nf or mal treat me nt a p pr oac hes i n cl u di n g 3 D c o nf or mal ra di ot hera p y usi n g static, prefera bl y 
n o n -c o pla nar fiel ds; i nte nsit y m o d ulate d ra di ot hera p y (I M R T), V ol u me M o d ulate d Arc t hera p y 
( V M A T), D y n a mic C o nf or mal Arc Ra diati o n T h era p y ( D C A R T), a n d helical t o m ot hera p y are 
acce pta ble. Is o d ose li nes c o veri n g t he P T V m ust be > = 9 5 %  of t he prescri b e d d ose . W he n I V 
a n d/ or oral c o ntrast are use d, c o ntrast de nsities s h o ul d be o verri d de n i n t he pla n ni n g pr ocess. 
Tiss ue de nsit y heter o ge n eit y c orrecti o n is re q uire d f or l u n g t u m ors. S u per p ositi o n/c o n v ol uti o n 
d ose al g orit h ms are preferre d.  
All ra di ot hera p y pla ns will b e ce ntrall y re vie we d b y t he pri nci p al i n vesti gat or or c o-pri nci p al 
i n vesti gat or pri or t o deli ver y of t he first fracti o n.   
5. 2. 2. 2  
Pe m br oliz u m a b  
Pe m br oliz u ma b  will be starte d d uri n g wee k 1  of C ycle 1  wit h c ycles e v er y 3 wee ks.  
5. 2. 2. 2. 1  
Ti mi n g of D ose A d mi nistr ati o n  
Pe m br oliz u ma b s h o ul d be a d mi nistere d o n Da y 1 of eac h c ycle after all pr oce d ures/ assess me nts 
ha ve bee n c o m plete d as detaile d o n t he St u d y Cale n dar  ( Secti o n 6. 0 ). Pe m br oliz u ma b  ma y be 
a d mi nistere d u p t o 3 da ys bef ore or after t he sc h e d ule d Da y 1 of eac h c ycl e.  Pe m br oliz u ma b  will 
be a d mi nistere d o n a n o ut patie nt basis.  Pe m br oliz u ma b 2 0 0 m g will be a d mi nistere d as a  

I L-2 / Pe m br oliz u m a b  
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2  
Merc k O T S P # 5 5 5 7 1  
Versi o n  0 6 /1 1 /2 0 2 4  
U C D a vis C o m pre he nsi ve C a ncer Ce nter  
C o nfi de nti al  
P a ge 3 1  of 9 2  
3 0 -mi n ute I V  i nf usi o n e v er y 3 wee ks. Sites s h o ul d ma ke e ver y eff ort t o tar g et i nf usi o n ti mi n g t o
be as cl ose t o 3 0 mi n utes as p ossi ble.  H o we ver, gi ve n t he varia bilit y of i nf usi o n p u m ps fr o m site
t o site, a wi n d o w of -5 mi n utes a n d + 1 0 mi n utes is per mitte d (i.e., i nf usi o n ti me is 3 0 mi n utes: -5
mi n/ + 1 0 mi n).
Refer t o secti o n 1 0. 2  f or s pecific 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 
fl ui d a n d a d mi nistrati o n of i nf usi o n s ol uti o n. 
5. 2. 2. 3  
I nterle u ki n-2  
I nterle u ki n-2 will be deli vere d i nt o t he treat me nt lesi o n b y i ntralesi o nal i njecti o ns starti n g 2 4 -9 6  
h o urs after t h e c o m pleti o n of ra di ot hera p y a n d t o be c o m plete d d uri n g C ycle 2 . O nce n ee dle is 
place d, i ntralesi o n al I L -2 will be a d mi nistere d b y q ualifie d pers o n nel . I ntralesi o nal I L-2 
i njecti o ns will f oll o w g ui deli nes, w hic h we h a ve pre vi o usl y p u blis he d [4 6 ]. Briefl y, eac h p atie nt 
will recei ve  a n i nitial d ose of 3 x 1 0 6 I U of I L-2, w hic h will be escal ate d t o 7 x 1 0 6 f or t he 
sec o n d treat me nt a n d t he n 1 5 x 1 0 6 I U f or t he fi nal t w o treat me nts as t olerate d. At d ose 
escalati o n le vels 2 a n d 3, eac h p atie nt will recei v e a test of 3 x 1 0 6 I U f or t heir first i njecti o n 
pri or t o escalati o n t o hi g her d oses acc or di n g t o o ur p u blis he d g ui deli nes.  If a d ose le vel is n ot 
t olerate d (i.e., gra de 3 -4 n o n -he mat ol o gic t o xicit y)  t he treat me nt will be de-escal ate d t o pre vi o us 
d ose le vels f or s u bse q u e nt treat me nts.  If t he i nitial d ose of 3 x 1 06 I U of I L-2 is n ot t olerate d t he 
d ose ca n be re d u ce d t o 1 milli o n I U.  Safet y a n d t o xicit y will be e val uate d usi n g C T C A E  v 4. 0 3 . 
A d ose li miti n g t o xicit y ( D L T) will be defi n e d as a treat me nt r elate d gra de 3 -4 t o xicit y n o n -
he mat ol o gic t o xicit y a n d will re q uire  d ose de -escalati o n. If a D L T d o es n ot res ol ve wit hi n 5 
da ys, is n ot res p o nsi ve t o ma na ge me nt, or o cc urs at t he l o west d ose le vel ( 1 milli o n I U I L -2) 
after de-es calati o n t he n t hat patie nt will be re m o v e d fr o m trial a n d t he t h era p y will be dee me d 
i nt olera ble. T hera p y will be dee me d s afe a n d t olera ble if n o greater t ha n 3 3 % of patie nts fi n d t he 
treat me nt i nt olera ble. 
M o nit ori n g  
Safet y will be e val uat e d i n t his st u d y t hr o u g h t he m o nit ori n g of all seri o us a n d n o n -seri o us A Es, 
defi ne d a n d gra de d acc or di n g t o N CI C T C A E v 4. 0 3 . Patie nts will be assesse d f or safet y 
(i ncl u di n g la b orat or y val ues) acc or di n g t o t he St u d y Cale n dar. Patie nts will be f oll o we d f or 
safet y f or 3 0 d a ys f oll o wi n g t he last d ose of st u d y treat me nt w he n p ossi ble  or u ntil recei pt of 
a n ot her a ntica ncer t hera p y, w hic he ver c o mes first.  
Patie nts w h o ha ve a n o n g oi n g st u d y treat me nt -relate d A E u p o n st u d y c o m pleti o n or at 
disc o nti n uati o n fr o m t he st u d y will be f oll o we d u ntil t he e ve nt has res ol ve d t o baseli ne gra d e, t he 
e ve nt is assesse d b y t he i n vesti gat or as sta ble, ne w a ntica ncer treat me nt is i nitiate d, t he patie nt is 
l ost t o f oll o w-u p, t he patie nt wit h dra ws c o ns e nt, or u ntil it has bee n deter mi ne d t hat st u d y 
treat me nt or partici pati o n is n ot t he ca use of t he A E. 

I L-2 / Pe m br oliz u m a b  
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2  
Merc k O T S P # 5 5 5 7 1  
Versi o n  0 6 /1 1 /2 0 2 4  
U C D a vis C o m pre he nsi ve C a ncer Ce nter  
C o nfi de nti al  
P a ge 3 2  of 9 2  
D ose Selecti o n/ M o dific ati o n  
I ntralesi o n al I L -2  
5. 4. 1. 1  
M a xi m u m T oler ate d D ose Selecti o n   
I n P has e I, fo ur  tar get d oses  of i ntralesi o nal I L -2 will be e val uate d: 
D ose Le vel -1:  
1  x 1 0 6 I U; 
D ose Le vel 1 :  
3 x 1 0 6 I U; 
D ose Le vel 2 :  
7 x 1 0 6 I U; 
D ose Le vel 3 :  
1 5 x 1 0 6 I U (starti n g d ose) 
We will i nitiate t he trial at D ose le vel 3 a n d de -escalate t o l o wer d ose le vels as nee de d t o 
esta blis h t he M T D. If d ose le vel -1  is n ot t olerate d t he st u d y will be halte d a n d m o difie d after 
disc ussi o n wit h pri nci pal i n vesti gat ors a n d st u d y s p o ns ors .  
T he M T D will be  defi n e d  i n p hase I as t he hi g hest d ose at w hic h n o m ore t ha n o ne of si x patie nt s 
de vel o ps a D L T or D ose Le vel 3 if t he M T D is n ot reac h e d. A D L T is defi ne d as  o ne of t h e 
f oll o wi n g w hic h occ urs d uri n g D L T peri o d w hic h lasts u ntil 7 da ys after last i njecti o n of I L -2 :  
•
gra de  ≥ 4 i njecti o n site react io n O R
•
gra de ≥ 3 treat me nt relat e d i m m u n ol o gic a d verse e ve nt (e x cl u di n g i njecti o n site reacti o ns)
O R
•
ot her gra d e  ≥ 3 treat me nt relate d a d v erse e ve nts t h at d o n ot res ol ve t o  gra d e  ≤ 2 wit hi n 1 4
da ys O R
•
A S T/ A L T > 3 x U L N wit h bilir u bi n > 2 ×  U L N, O R
•
p ne u m o nitis t hat re q uires h ol di n g treat me nt > 1 4 da ys

I L-2 / Pe m br oliz u m a b  
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2  
Merc k O T S P # 5 5 5 7 1  
Versi o n  0 6 /1 1 /2 0 2 4  
U C D a vis C o m pre he nsi ve C a ncer Ce nter  
C o nfi de nti al  
P a ge 3 3  of 9 2  
Ta ble 4  a n d 
Ta ble 5  descri be t he sta n dar d d osi n g r ules t h at will be f oll o we d.  At d ose le vels 2 a n d 3 eac h 
patie nt will recei ve a test d ose of 3 x 1 0 6 I U f or t h eir first i njecti o n pri or t o escalati o n t o hi g her 
d oses acc or di n g t o o ur p u blis he d g ui deli nes.  F or e xa m ple, at d ose le v el 3 eac h p atie nt will 
recei v e a n i nitial test d ose of 3 x 1 06 I U of I L-2, w hic h will be escal ate d t o 7 x 1 0 6 f or t he sec o n d 
treat me nt a n d t he n 1 5 x 1 06 I U f or t h e fi nal t w o treat me nts as t olerate d. If a d ose le vel is n ot 
t olerate d t he treat me nt will be de-escalate d t o pre vi o us d ose le vels f or s u bse q ue nt treat me nts . 
S u bjects w h o are n ot e v al ua ble f or t o xicit y will b e re place d f or D L T assess me nt. If s u bjects 
ca n n ot recei ve 7 5 % of i nte n de d d ose of st u d y treat me nt, f or reas o ns ot her t ha n t o xicit y a n d di d 
n ot e x perie nce a D L T, t he y will be re place d f or D L T assess me nt.  

I L- 2 / P e m br oli z u m a b 
M er c k O T S P # 5 5 5 7 1 
Cli ni c al St u d y Pr ot o c ol U C D C C # 2 7 2 
V ersi o n 0 6/ 1 1/ 2 0 2 4 
T a bl e 4. P h as e I D os e Es c al ati o n a n d D e- Es c al ati o n R ul es 
N u m b e r of P ati e nts wit h D L T 
Es c al ati o n D e cisi o n R ul e 
at a Gi ve n D os e L e v el 
0 o ut of 3 
E nter 3 a d diti o nal patie nts at t he ne xt d ose le vel. 
1 o ut of 3 
E nter 3 a d diti o nal patie nts at t he d ose le vel. If no a d diti o nal D L T 
e nter 3 a d diti o nal patie nts at t he ne xt d ose le vel. 
2 o ut of 3 or 6 
De-escalate t he d ose to t he ne xt l o wer le vel a n d acc me 3 patie nts. 
< 2 o ut of 6 at t he hi g hest d ose le vel 
T his is t he rec o m me n de d p hase 2 d ose. 
T a ble 5. P h ase I I ntr alesi o n al I L- 2 D osi n g 
T r e at m e nt 1 D os e 
T r e at m e nt 2 D os e 
T r e at m e nt 3 D os e 
T r e at m e nt 4 D os e 
D ose L e v el -1 
l x l 0 6 I U
1 X 10 6 I U 
I X 10 6 I U 
1 X 10 6 I U 
D ose L e v el I 
3 X 10 6 I U 
3 X 10 6 I U 
3 X 10 6 I U 
3 X 10 6 I U 
D ose L e v el 2 
3 X 10 6 I U 
7 X 10 6 I U 
7 X 10 6 I U 
7 X 10 6 I U 
D ose L e v el 3 
3 X 10 6 I U 
7 X 10 6 I U 
15 x 10 6 I U 
15 X 10 6 I U 
5. 4. 1. 2 
P h ase II D ose M o dific ati o n 
Fi g ure 6: P h ase II D ose M o dific ati o n Sc he m a of I L- 2 
pt 
D ose 
2nd 
D ose 
31-d 
D ose 
4th 
D ose 
I 
N o T L T 
Tr e at at D ose 2 01· 
M T D, w hi c h e v er is 
l o w er 
N o T L T 
T L T 
Tr e at at 
De-esc al ate t o 
D ose 3 01· M T D 
D ose 1 
N o T L T 
T L T 
N o T L T 
" 
\ I
Tr e at at 
De-esc al ate t o 
C o nti n ue at 
D ose 3 01· 
D os e 2 
D ose 1 
M T D 
D ose 1 
T L T 
De-esc al ate t o 
D ose -1 
N o T L T 
t 
T L T 
'I 
St o p tr e at m e nt-
C o nti n ue at 
Re m o ve patie nt 
D ose -1 
fr o m st u d y-
Treat me nt 
T L T 
N o T L T 
i nt olera ble 
\ I 
" 
De-esc al ate t o 
C o nti n ue at 
D ose - 1 
D ose -1 
A n y d ose le vel t hat is f o n n d to be i nt olera ble or ass ociate d wit h gra de 3- 4 t o xicit y or i nt olera ble gra de 2 A E will be 
dee me d a T L T. T L T = P hase II treat me nt li miti n g t o xicit y. 
U C D a vis C o m pre he nsi ve C a ncer Ce nter 
C o nfi de nti al 
P a ge 3 4 of 9 2 

I L-2 / Pe m br oliz u m a b  
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2  
Merc k O T S P # 5 5 5 7 1  
Versi o n  0 6 /1 1 /2 0 2 4  
U C D a vis C o m pre he nsi ve C a ncer Ce nter  
C o nfi de nti al  
P a ge 3 5  of 9 2  
T a ble 6 . P h ase II I ntr alesi o n al I L-2 d osi n g ( i ntr a-p atie nt d ose esc al ati o n)  
P 2 D ose  -1  
1 x 1 0 6 I U 
Le vel 1 (st arti n g d ose le vel)  
3 x 1 0 6 I U 
Le vel 2 ( 2 n d  d ose)  
7 x 1 0 6 I U or P has e I M T D  
Le vel 3 ( 3 r d a n d 4 t h d ose)  
1 5 x 1 0 6 I U or P has e I M T D 
 P hase II will be c o n d u cte d usi n g t he M T D . F or p hase II, a  treat me nt li miti n g t o xicit y (T L T) will 
be defi ne d as a n  I L-2 treat me nt relate d gra de 3-4 n o n -he mat ol o gic  or gra d e 4 he mat ol o gic  
t o xicit y a n d will re q uire d ose de-es calati o n. A T L T m ust res ol ve t o gra de 2 or less bef ore t he 
ne xt de -es calate d d os e is a d mi nistere d. Treat me nt i nt olera bilit y will be  meas ure d i n p hase II t o 
defi ne t he perce nta ge of patie nts t hat  ha ve t o c o m e off st u d y treat me nt or miss a n I L -2 treat me nt 
d ue t o i na bilit y t o  t olerate t he f ull c o urse of t hera p y. T his is a se parate m eas ure fr o m t he M T D 
assess me nt i n p hase  I a n d is o nl y meas ure d d uri n g p hase II . Treat me nt i nt olera bilit y will be 
defi ne d as  a T L T t hat d o es n ot res ol ve  t o gra d e 2 or less wit hi n 5  da ys, is n ot res p o nsi ve t o 
ma na ge me nt, or o cc urs at t he l o west  d ose le vel ( 1 milli o n I U I L -2) . I n t his case t he patie nt will 
be re m o ve d fr o m trial a n d t he t hera p y will be dee me d i nt olera ble f or t h at patie nt. If a d ose of I L -
2 is misse d d ue t o T L T n ot res ol vi n g t o gra de 2 or less wit hi n 5 da ys t his falls i nt o t he defi niti o n 
of treat me nt i nt olera bilit y.  If a d ose I L-2 is misse d f or ot her reas o ns t his d oes n ot q ualif y as 
treat me nt i nt olera bilit y. T he T L T peri o d b e gi ns wit h t he a d mi nistrati o n of I L -2 a n d l asts u p  t o 7 
da ys after t h e last i njecti o n of I L -2. As o utli ne d a b o ve t he i nitial d ose of i ntralesi o nal I L -2 will 
be a d mi nistere d as 3 milli o n I U test d os e. If t here are I L-2 rel ate d gra de 3 -4  n o n -he mat ol o gic  or 
gra de 4 he m at ol o gic  treat me nt relate d a d v erse effects t he d ose will be de-es calate d f or t he 
sec o n d treatme nt t o 1 milli o n I U.  If t here are gra d e 3-4 n o n -he mat ol o gic a d verse effects, or 
gra de 4 he m at ol o gic a d v erse effects at t he 1 milli o n I U d ose t he patie nt will be re m o ve d fr o m 
st u d y a n d t he t hera p y d ee me d i nt olera ble . F or a gi ve n patie nt d ose es calati o n will occ ur if t here 
are n o  I L-2 re late d gra de 3 -4  n o n -he mat ol o gic or gra de 4 he m at ol o gic  treat me nt relate d 
t o xicities. F or eac h patie nt if a d ose le vel is ass oci ate d wit h gra de 3 -4 n o n -he mat ol o gic or gra d e 
4 he m at ol o gic t o xicit y t his will be dee me d a T L T a n d  t he patie nt will be de-escal ate d t o t he 
l o wer d ose f or t he ne xt treat me nt. O nce t he d ose is decrease d t here will be n o f urt her d ose re -
escalati o n all o we d f or a n i n di vi d ual patie nt.  If a pla n ne d d ose  ca n n ot be deli vere d wit hi n t he 
prescri be d wee k  it will b e s ki p pe d.  
I ntr at u m oral I L-2 is well t olerate d per Ta ble 1  a b o ve wit h t he maj orit y of patie nts e x perie n ci n g 
mil d t o xicit y.  

I L-2 / Pe m br oliz u m a b  
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2  
Merc k O T S P # 5 5 5 7 1  
Versi o n  0 6 /1 1 /2 0 2 4  
U C D a vis C o m pre he nsi ve C a ncer Ce nter  
C o nfi de nti al  
P a ge 3 6  of 9 2  
T a ble 7 . A d verse E ve nt M a n a ge me nt  
I njecti o n site p ai n 
A d mi nister 3 2 5 -6 5 0 m g aceta mi n o p he n p o e ver y 4 -6 h o urs pr n  
Fl u -li ke s y m pt o ms 
A d mi nister 3 2 5 -6 5 0 m g aceta mi n o p he n p o e ver y 4 -6 h o urs pr n  
He a d ac he  
A d mi nister 3 2 5 -6 5 0 m g aceta mi n o p he n p o e ver y 4 -6 h o urs pr n  
N a use a/ v o miti n g  
Prescri be a ntie m etics per treati n g p h ysicia n’s rec o m me n dati o n 
Di arr h ea  
Prescri be a nti diarr heal a ge nts per treati n g p h ysicia n’s 
rec o m me n dati o n 
H y p ote nsi o n is a rare e ve nt wit h o nl y 1 patie nt fr o m t he a b o ve cli nical trials a n d case s eries 
re p orti n g it. 
T a ble 8 . L isti n g of t he B l o o d P ress ure G o als  
B aseli ne S yst olic Bl o o d Press ure  
T ar get S yst olic Bl o o d Press ure o n 
D a ys of Tre at me nt  
< 1 0 0 m m H g  
> 8 0 m m H g
1 0 0 -1 2 0 m m H g
> 8 5 m m H g
> 1 2 0 m m H g
> 9 0 m m H g
If patie nt’s B P is less t ha n 8 0 m m H g o n t he da y of treat me nt a d mi nister 1-1. 5 L of fl ui d t o meet 
t he bl o o d press ure g o als.  If B P re mai ns less t ha n 8 0 m m H g , t he patie nt ca n n ot be treate d a n d 
t he d ose will be dela ye d f or u p t o 5 da ys . T his is n ot c o nsi dere d a D L T or tr eat me nt i nt olera bilit y 
u nless t he l o w B P is d ue t o I L -2 t h era p y.  
If patie nts e x perie nce a cli nicall y si g nifica nt Gra d e 3 or greater a d verse e v e nt please c o nt act t he 
pri nci pal i n vesti gat or t o disc uss A E ma na ge me nt.  
H y p ofr acti o n ate d R a di ot her a p y  
Ra di ot hera p y is deli vere d as a sta n dar d of care p alliati ve re gi me n a n d ra di ot hera p y relate d 
t o xicities will be a d dress e d usi n g sta n dar d i nstit uti o nal practices. Wit h a palliati ve d ose of 2 4 G y 
deli vere d  i n 3 fracti o ns of 8 G y eac h we a ntici pate mi ni mal a d verse effects f or t he treat me nt of 
der mal, s u bc uta n e o us, n o dal, or li ver lesi o ns. T he d ose of ra di ot hera p y ca n be re d uce d t o n o 
l o wer t ha n 5 G y p er fracti o n at t he discreti o n of t h e treati n g ra diati o n o nc ol o gist  i n res p o nse t o 
cli nicall y si g nifica nt  treat me nt relate d t o xicit y at t he treat me nt lesi o n or pri or t o t he o nset of 
treat me nt t o res pect n or mal tiss ue t olera nces as dee me d necessar y b y t he treati n g ra di ati o n 
o nc ol o gist.  If a d ose of ra di ot hera p y is misse d it ca n be dela ye d. A n y ra di ot hera p y fracti o ns n ot 
deli vere d d uri n g t he wee k 1 -2 of c ycl e 2  of t hera p y ca n n ot be ma d e u p a n d t h ose d oses will be 
s ki p pe d. 

I L-2 / Pe m br oliz u m a b  
 
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2  
Merc k O T S P # 5 5 5 7 1  
 
Versi o n  0 6 /1 1 /2 0 2 4  
U C D a vis C o m pre he nsi ve C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a ge 4 0  of 9 2  
 Acce pt a ble C o nc o mit a nt Me dic ati o ns  
All treat me nts t hat t he i n vesti gat or c o nsi ders necessar y f or a s u bject’s welf are ma y be 
a d mi nistere d at t he discreti o n of t he i n vesti gat or i n kee pi n g wit h t he c o m m u nit y sta n dar ds of 
me dical care.  All c o n c o mita nt me dicati o n will be rec or de d i n t he me di cal rec or d i n cl u di n g all 
prescri pti o n, o ver -t he-c o u nter ( O T C), h er bal s u p ple me nts, a n d I V me dicati o ns a n d fl ui ds.  If 
c ha n ges occ ur d uri n g t he trial peri o d, d oc u me ntati o n of dr u g d osa ge, fre q u e nc y, r o ute, a n d date 
ma y als o be i ncl u de d i n t he me dical r ec or d. 
All c o nc o mita nt me dicati o ns recei v e d wit hi n 2 8 da ys bef ore t he first d ose of trial treat me nt a n d 
3 0 da ys after t h e last d ose of trial treat me nt s h o ul d be rec or de d. C o nc o mit a nt me dicati o ns 
a d mi nistere d after 3 0 da ys after t he last d ose of tri al treat me nt s h o ul d be rec or de d f or S A Es a n d 
E CIs as d efi ne d i n Secti o n 7. 3. 3. 2 . 
 Pr o hi bite d C o nc o mit a nt T her a p y  
S u bjects are pr o hi bite d fr o m recei vi n g t he f oll o wi n g t hera pies d uri n g t he S cree ni n g a n d 
Treat me nt P hase (i ncl u di n g retreat me nt f or p ost -c o m plete res p o nse rela pse) of t his trial:  
•  A nti ne o plastic s yste mic c he m ot hera p y or bi ol o gical t hera p y  
•  I m m u n ot hera p y n ot s pecifie d i n t his pr ot oc ol 
•  C he m ot hera p y n ot s pecifie d i n t his pr ot oc ol  
•  I n v esti gati o nal a ge nts ot her t ha n pe m br oliz u m a b 
•  Ra diati o n t hera p y n ot s pecifie d i n t his pr ot oc ol  
•  N ote:  Palliati ve r a diati o n t hera p y f or s y m pt o matic b ut n ot pr o gressi n g  lesi o ns ma y be 
all o we d at t he i n vesti gat or’s discreti o n  s o l o n g as u ntreate d tar get lesi o ns re mai n f or 
res p o nse ass ess me nt.  
•  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 trial.  E xa m ples of li ve vacci nes 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, varicella/z ost er, yell o w fe ver, ra bies, B C G, a n d 
t y p h oi d vacci ne.  
•  S yste mic gl uc oc ortic oi ds f or a n y p ur p os e ot her t h a n t o m o d ulate s y m pt o ms fr o m a n 
e ve nt of cli nical i nterest of s us pecte d i m m u n ol o gic eti ol o g y.  T he use of p h ysi ol o gic 
d oses of c ortic oster oi ds ma y be a p pr o ve d aft er c o ns ultati o n wit h t he S p o ns or.  
S u bjects w h o, i n t he assess me nt b y t he i n vesti gat or, re q uire t h e use of a n y of t he af ore me nti o ne d 
treat me nts f or cli nical ma na ge me nt s h o ul d be re m o ve d fr o m t he trial. S u bjects ma y recei ve ot her 
me dicati o ns t hat t he i n vesti gat or dee ms t o be me dicall y necess ar y.  
T he E xcl usi o n Criteria d escri bes ot her me dicati o ns w hic h are pr o hi bite d i n t his trial.  
T here are n o pr o hi bite d t hera pies d uri n g t he P ost -Treat me nt F oll o w -u p P hase.  

I L-2 / Pe m br oliz u m a b  
 
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2  
Merc k O T S P # 5 5 5 7 1  
 
Versi o n  0 6 /1 1 /2 0 2 4  
U C D a vis C o m pre he nsi ve C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a ge 4 1  of 9 2  
I n a d diti o n, all patie nts (i ncl u di n g t h ose w h o disc o nti n ue t he st u d y earl y) s h o ul d n ot recei ve 
ot her i m m u n osti m ulat or y a ge nts  (e. g., c yt o ki nes) f or 1 0 wee ks after t h e last d ose of I L-2  wit h t he 
e xcepti o n of c h ec k p oi nt bl oc ka de . 
 
Resc ue Me dic ati o n & S u p p orti ve C are   
 S u p p orti ve C are f or R a di ot her a p y  
Ra di ot hera p y is deli vere d as a sta n dar d of care p alliati ve re gi me n a n d ra di ot hera p y relate d 
t o xicities will be a d dress e d usi n g sta n dar d i nstit uti o nal practices. Wit h palliati ve d oses deli vere d 
i n t his trial we a ntici pate mi ni mal a d verse effects f or t he treat me nt of d er mal, s u bc uta ne o us, 
n o dal, or visceral lesi o ns.  
 
 

I L-2 / Pe m br oliz u m a b  
 
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2  
Merc k O T S P # 5 5 5 7 1  
 
Versi o n  0 6 /1 1 /2 0 2 4  
U C D a vis C o m pre he nsi ve C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a ge 4 2  of 9 2  
Ta ble 1 0  bel o w  s h o ws tr eat me nt g ui deli nes f or s u bjects w h o e x perie nce a n i nf usi o n reacti o n 
ass ociate d wit h a d mi nistrati o n of pe m br oliz u ma b ( M K -3 4 7 5).  
 
 

I L-2 / Pe m br oliz u m a b  
 
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2  
Merc k O T S P # 5 5 5 7 1  
 
Versi o n  0 6 /1 1 /2 0 2 4  
U C D a vis C o m pre he nsi ve C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a ge 4 3  of 9 2  
T a ble 1 0 . I nf usi o n Re acti o n Tre at me nt G ui deli nes 
N CI C T C A E Gr a de  
Tre at m e nt  
Pre m e dic ati o n at 
s u bse q ue nt d osi n g 
Gra de 1  
Mil d reacti o n; i nf usi o n 
i nterr u pti o n n ot i n dicate d; 
i nter ve nti o n n ot i n dicate d 
I ncrease m o nit ori n g of vital si g ns as me dicall y i n dicate d u ntil t h e s u bject 
is d ee me d me dicall y sta ble i n t he o pi ni o n of t h e i n vesti g at or. 
N o ne  
Gra de 2  
Re q uires i nf usi o n 
i nterr u pti o n 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 n es, 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 hrs  
St o p I nf usi o n a n d m o nit or s y m pt o ms.  
A d diti o nal a p pr o priate me dical t hera p y ma y i n cl u de b ut is n ot li mite d t o:  
I V fl ui ds 
A nti hista mi n es  
N S AI D S  
Aceta mi n o p he n  
Narc otics  
I ncrease m o nit ori n g of vital si g ns as me dicall y i n dicate d u ntil t h e s u bject 
is d ee me d me dicall y sta ble i n t he o pi ni o n of t h e i n vesti g at or. 
If s y m pt o ms res ol ve wit hi n o ne h o ur of st o p pi n g dr u g i nf usi o n, t he 
i nf usi o n ma y be restarte d at 5 0 % of t h e ori gi n al i nf usi o n rate (e. g., fr o m 
1 0 0 m L/ hr t o 5 0 m L/ hr).  Ot her wise,  d osi n g will be hel d u ntil s y m pt o ms 
res ol v e a n d t h e s u bject s h o ul d be pre me dicate d f or t he ne xt sc he d ule d 
d ose.  
S u bjects w h o de vel o p Gr a de 2 t o xicit y des pite a de q u ate 
pre me dic ati o n s h o ul d be per m a ne ntl y disc o nti n ue d fr o m f urt her 
tri al tre at ment a d mi nistr ati o n.  
S u bject ma y be 
pre me dicate d 1. 5 h ( ± 
3 0 mi n utes) pri or t o 
i nf usi o n of 
pe m br oliz u ma b ( M K -
3 4 7 5) wit h:  
 
Di p he n h y dra mi n e 5 0 
m g p o ( or e q ui vale nt 
d ose of a nti hista mi n e).  
 
Aceta mi n o p he n 5 0 0 -
1 0 0 0 m g p o ( or 
e q ui v ale nt d ose of 
a nti p yretic). 
Gra des 3 or 4  
Gra de 3:  
Pr ol o n ge d (i.e., n ot ra pi dl y 
res p o nsi ve t o s y m pt o matic 
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 ot h er cli nical 
se q uelae (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; press or or 
ve ntilat or y s u p p ort i n dicate d  
St o p I nf usi o n.  
A d diti o nal a p pr o priate me dical t hera p y ma y i n cl u de b ut is n ot li mite d t o:  
I V fl ui ds 
A nti hista mi n es  
N S AI D S  
Aceta mi n o p he n  
Narc otics  
O x y ge n  
Press ors  
C ortic oster oi ds  
E pi n e p hri ne  
I ncrease m o nit ori n g of vital si g ns as me dicall y i n dicate d u ntil t h e s u bject 
is dee me d me dicall y sta ble i n t he o pi ni o n of t h e i n vesti g at or.  
H os pitalizati o n ma y be i n dicate d.  
S u bject is per m a ne ntl y disc o nti n ue d fr o m f urt her tri al tre at me nt 
a d mi nistr ati o n.  
N o s u bse q ue nt d osi n g  
A p pr o priate res uscitati o n e q ui p me nt s h o ul d be a vaila ble i n t he r o o m a n d a p h ysicia n rea dil y a vaila ble d uri n g t he peri o d of dr u g a d mi nistrati o n.  
 
 
 

I L-2 / Pe m br oliz u m a b  
 
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2  
Merc k O T S P # 5 5 5 7 1  
 
Versi o n  0 6 /1 1 /2 0 2 4  
U C D a vis C o m pre he nsi ve C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a ge 4 4  of 9 2  
 
Diet/ Acti vit y  
 Diet  
S u bjects s h o ul d mai ntai n a n or mal diet u nless m o dificati o ns are re q uire d t o ma na ge a n A E s uc h 
as diarr hea, na us ea or v o miti n g.  
 C o ntr ace pti o n  
Pe m br oliz u ma b ma y ha v e a d vers e effects o n a fet us i n uter o.  F urt her m ore, it is n ot k n o w n if 
pe m br oliz u ma b has tra nsie nt a d verse effects o n t h e c o m p ositi o n of s per m.   
F or t his trial, male s u bjects will be c o nsi dere d t o b e of n o n -re pr o d ucti ve p ot e ntial if t he y ha ve 
az o os per mia ( w het her d ue t o ha vi n g ha d a v asect o m y or d ue t o a n u n derl yi n g me dical 
c o n diti o n). 
Fe male s u bjects will be c o nsi dere d of n o n -re pr o d ucti ve p ote ntial if t he y are eit her:  
( 1) P ost -me n o pa usal ( defi ne d as at least 1 2 m o nt hs wit h n o me nses wit h o ut a n alter nati ve 
me dical ca us e; i n w o me n < 4 5 years of a g e a hi g h f ollicle sti m ulati n g h or m o ne ( F S H) 
le vel i n t he p ost me n o pa usal ra n ge ma y be use d t o c o nfir m a p ost-me n o pa usal state i n 
w o me n n o t usi n g h or m o nal c o ntrace pti o n or h or m o nal re place me nt t hera p y. I n t he 
a bse nce of 1 2 m o nt hs of a me n orr hea, a si n gle F S H meas ure m e nt is i ns ufficie nt.);  
O R  
( 2) ha ve ha d a h ysterect o m y a n d/ or bilateral o o p h or ect o m y, bilateral sal pi n gect o m y or 
bilateral t u bal li gati o n/ occl usi o n, at least 6 wee ks pri or t o scree ni n g;  
O R  
( 3) has a c o n ge nital or ac q uire d c o n diti o n t hat pre v e nts c hil d beari n g.  
Fe male a n d male s u bjects of re pr o d ucti ve p ote ntial m ust a gree t o a v oi d b ec o mi n g pre g na nt or 
i m pre g nati n g a part n er, res pecti vel y, w hile recei vi n g st u d y dr u g a n d f or 1 2 0 da ys after t h e last 
d ose of st u d y dr u g b y c o m pl yi n g wit h o ne of t he f oll o wi n g:  
( 1) use ( or ha v e t heir part ner use) acce pta bl e c o ntrace pti o n d uri n g heter ose x ual acti vit y.   
Acce pt a ble met h o ds of c o ntrace pti o n are ‡:  
Si n gle met h o d ( o ne of t he f oll o wi n g is acce pta ble):  
•  i ntra uteri ne de vic e (I U D) 
•  vasect o m y of a fe male s u bject’s male part ner  
•  c o ntrace pti ve r o d i m pla nte d i nt o t he s ki n  
 
C o m bi nati o n met h o d (re q uires use of t w o of t h e f oll o wi n g):  
•  dia p hra g m wit h s per mici de (ca n n ot b e use d i n c o nj u ncti o n wit h cer vical ca p/s per mici de)  
•  cer vical ca p wit h s per mici de ( n ulli par o us w o me n o nl y)   
•  c o ntrace pti ve s p o n ge ( n ulli par o us w o me n o nl y)  

I L-2 / Pe m br oliz u m a b  
 
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2  
Merc k O T S P # 5 5 5 7 1  
 
Versi o n  0 6 /1 1 /2 0 2 4  
U C D a vis C o m pre he nsi ve C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a ge 4 5  of 9 2  
•  male c o n d o m or fe male c o n d o m (ca n n ot be use d t o get her)  
•  h or m o nal c o ntrace pti ve: oral c o ntrace pti ve pill (estr o ge n/ pr o gesti n pill or pr o gesti n -o nl y 
pill), c o ntrace pti ve s ki n p atc h, va gi nal c o ntr ace pti ve ri n g, or s u bc uta ne o us c o ntrace pti ve 
i njecti o n 
Peri o dic a bsti ne nce (e. g., cale n dar, o v ulati o n, s y m pt o -t her mal, p ost-o v ulati o n met h o ds, etc.) a n d 
wit h dra wal are n ot a cce pta ble met h o ds of c o ntrace pti o n.  
‡If a c o ntr ace pti ve met h o d liste d a b o ve is restrict e d b y l ocal re g ul ati o ns/ g ui deli nes, t he n it d oes 
n ot q ualif y as a n acce pt a ble met h o d of c o ntrace pti o n f or s u bjects partici pati n g at sites i n t his 
c o u ntr y/re gi o n.  
S u bjects s h o ul d be i nf or me d t hat ta ki n g t he st u d y me dicati o n ma y i n v ol ve u n k n o w n ris ks t o t he 
fet us ( u n b or n ba b y) if pre g na nc y w ere t o o cc ur d uri n g t he st u d y. I n or der t o partici pate i n t he 
st u d y s u bjects of c hil d beari n g p ote ntial m ust a d here t o t he c o ntr ace pti o n re q uire me nt ( descri be d 
a b o ve) fr o m t he da y of st u d y me dicati o n i nitiati o n ( or 1 4 da ys pri or t o t he i nitiati o n of st u d y 
me dicati o n f or oral c o ntrace pti o n) t hr o u g h o ut t he st u d y peri o d u p t o 1 2 0 da ys after t he last d ose 
of trial t hera p y.  If t here is an y q uesti o n t hat a s u bject of c hil d beari n g p ote ntial will n ot relia bl y 
c o m pl y wit h t he re q uire me nts f or c o ntrace pti o n, t hat s u bject s h o ul d n ot be e ntere d i nt o t he st u d y.  
 Use i n Pre g n a nc y  
If a s u bject i na d v erte ntl y bec o mes pre g na nt w hile o n treat me nt wit h pe m br oliz u ma b, t he s u bject 
will i m me diatel y be re m o ve d fr o m t he st u d y.  T he site will c o ntact t he s u bject at least m o nt hl y 
a n d d oc u me nt t he s u bject’s stat us u ntil t he pre g na nc y has bee n c o m plete d or ter mi nate d.  T he 
o utc o me of t he pre g na nc y will be re p orte d t o t he S p o ns or a n d t o Merc k wit h o ut dela y a n d wit hi n 
2 4 h o urs t o t he S p o ns or a n d wit hi n 2 w or ki n g da ys t o Merc k if t he o utc o me is a seri o us a d verse 
e x perie n ce (e. g., deat h, a b orti o n, c o n ge nital a n o m al y, or ot her disa bli n g or life -t hreat e ni n g 
c o m plicati o n t o t he m ot her or ne w b or n).   
T he st u d y i n vesti gat or will ma ke e ver y eff ort t o o btai n per missi o n t o f oll o w t he o utc o me of t he 
pre g na nc y a n d re p ort t he c o n diti o n of t he fet us or ne w b or n t o t he S p o ns or.  If a male s u bject 
i m pre g nates his fe mal e p art ner t he st u d y pers o n nel at t he site m ust be i nf or me d i m me diatel y a n d 
t he pre g na n c y re p orte d t o t he S p o ns or a n d t o Merc k a n d f oll o we d as descri be d a b o ve a n d i n 
Secti o n 7. 3. 2 . 
 Use i n N ursi n g W o me n  
It is u n k n o w n w h et her p e m br oliz u ma b is e xcret e d i n h u ma n mil k. Si nce ma n y dr u gs are e xcrete d 
i n h u ma n mil k, a n d beca use of t he p ote ntial f or seri o us a d verse reacti o ns i n t he n ursi n g i nfa nt, 
s u bjects w h o are breast-fee di n g are n ot eli gi ble f or e nr oll me nt. 
 
S u bject Wit h dr a w al/ Disc o nti n u ati o n Criteri a  
S u bjects ma y wit h dra w c o nse nt at a n y ti me f or a n y reas o n or be dr o p pe d fr o m t he trial at t he 
discreti o n of t he i n vesti g at or s h o ul d a n y u nt o war d effect occ ur.  I n a d diti o n, a s u bject ma y be 
wit h dra w n b y t he i n vesti gat or  f or a n y reas o n i ncl u di n g t he f oll o wi n g: if e nr oll me nt i nt o t he trial 

I L-2 / Pe m br oliz u m a b  
 
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2  
Merc k O T S P # 5 5 5 7 1  
 
Versi o n  0 6 /1 1 /2 0 2 4  
U C D a vis C o m pre he nsi ve C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a ge 4 6  of 9 2  
is i na p pr o priate, t he trial pla n is vi olate d, or f or a d mi nistrati ve a n d/ or ot her safet y reas o ns. 
S pecific details re g ar di n g disc o nti n uati o n or wit h dra wal are pr o vi d e d i n Secti o n 7. 2. 4  Ot her 
Pr oce d ures.  
A s u bject m ust be disc o nti n ue d fr o m t he trial  treat me nt f or a n y of t he f oll o wi n g reas o ns: 
•  T he s u bject or le g al re prese ntati ve (s uc h as a pare nt or le gal g uar dia n) wit h dra ws 
c o nse nt.  
•  C o nfir me d ra di o gra p hi c disease pr o gressi o n  per ir R E CI S T  
N ote: F or u nc o nfir me d r a di o gr a p hic dise ase pr o gressi o n, ple ase see S ecti o n 5. 8. 1  
N ote: A s u bject m ay b e gr a nte d a n exce pti o n t o c o nti n ue o n tre at me nt wit h c o nfir me d 
r a di o gr a p hic pr o gressi o n if cli nic ally st a ble or cli nic ally i m pr ove d, ple ase see Secti o n 
5. 8. 1  
•  I nterc urre nt ill ness t hat pre ve nts f urt h er a d mi nistrati o n of treat me nt 
•  U nacce pta ble a d vers e e v e nts  as descri b e d i n Secti o n 5. 4. 3  
•  I n v esti gat or’s decisi o n t o wit h dra w t he s u bject 
•  T he s u bject has c o nfir me d p ositi ve ser u m pre g na n c y test  
•  C o m plete d 1 2  m o nt hs of st u d y t hera p y 
•  A d mi nistrati ve reas o ns  
T he E n d of Treat me nt a n d F oll o w -u p visit pr oce d ures are liste d i n Secti o n 6. 0  ( Pr ot oc ol Fl o w 
C hart) a n d Secti o n 7. 2. 5  ( Visit Re q uire me nts). After t he e n d of tr eat me nt, eac h s u bject will be 
f oll o we d f or 3 0 d a ys f or a d verse e ve nt m o nit ori n g (seri o us a d verse e v e nts will be c ollecte d f or 
9 0 da ys after t h e e n d of treat me nt as d escri be d i n Secti o n 7. 3. 3. 1 ). S u bjects w h o disc o nti n ue f or 
reas o ns ot her t h a n pr o gressi ve disease will ha ve p ost-treat me nt f oll o w-u p f or disease stat us u ntil 
disease pr o gressi o n, i nitiati n g a n o n -st u d y ca n cer treat me nt, wit h dra wi n g c o nse nt or bec o mi n g 
l ost t o f oll o w-u p.  After d oc u me nte d diseas e pr o gressi o n eac h s u bject will be f oll o we d b y 
tele p h o ne f or o v erall s ur vi val u ntil deat h, wit h dra wal of c o nse nt, or t he e n d of t he st u d y, 
w hic he ver occ urs first.  
 Disc o nti n u ati o n of St u d y T her a p y D ue t o Dise ase Pr o gressi o n  
I m m u n ot hera pe utic a ge nts s uc h as pe m br oliz u ma b a n d I L-2 ma y pr o d uce a ntit u m or effects b y 
p ote ntiati n g e n d o ge n o us ca ncer -s pecific i m m u ne res p o nses. T he res p o nse patter ns see n wit h 
s uc h a n a p pr oac h ma y e xte n d be y o n d t he t y pical ti me c o urse of res p o nses s ee n wit h c yt ot o xic 
a ge nts a n d ca n ma nifest as a cli nical r es p o nse after a n i nitial i ncreas e i n t u m or b ur de n or e ve n 
t he a p peara nce of ne w lesi o ns.  
I m m u ne relate d R E CI S T will be use d f or ass ess me nt of t u m or res p o nse f or t he p ur p oses of 
ma na gi n g s u bjects o n Pr ot oc ol treat me nt a n d decisi o n ma ki n g f or disc o nti n uati o n of st u d y 
t hera p y d ue t o disease pr o gressi o n. P D s h o ul d be c o nfir me d n o earlier t h a n 4 wee ks later 
acc or di n g t o t he criteria o utli ne d i n Ta ble 1 1  bel o w . S u bjects w h o are d ee me d cli nicall y u nsta ble 
or w h o ha ve bi o ps y pr o v e n ne w metastatic l esi o ns are n ot r e q uire d t o ha ve re peat i ma gi n g f or 
c o nfir mati o n . T his decisi o n will be base d o n cli nical j u d g me nt of a s u bject's o verall cli nical 

I L-2 / Pe m br oliz u m a b  
 
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2  
Merc k O T S P # 5 5 5 7 1  
 
Versi o n  0 6 /1 1 /2 0 2 4  
U C D a vis C o m pre he nsi ve C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a ge 4 7  of 9 2  
c o n diti o n, i ncl u di n g perf or ma nce stat us, cli nical s y m pt o ms, a n d la b orat or y data . At a mi ni m u m, 
s u bjects m ust meet t he f oll o wi n g criteria f or c o nti n ue d treat me nt o n st u d y after disease 
pr o gressi o n is i de ntifie d at a t u m or assess me nt:  
W he n feasi ble, s u bjects s h o ul d n ot be disc o nti n ue d u ntil pr o gressi o n is c o nfir me d; h o we ver, t he 
decisi o n t o c o nti n ue st u d y treat me nt after t he first e vi de nce of disease pr o gressi o n is at t he 
in vesti gat or 's discreti o n base d o n t he cli nical stat us of t he s u bject. 
S u bjects ma y recei ve st u d y treat me nt w hile waiti n g f or c o nfir m ati o n of P D if t he y are cli nicall y 
sta ble as defi ne d b y t h e f oll o wi n g criteria: 
•  N o decli ne i n E C O G perf or ma nce stat us.  
•  A bse nce of ne w or w orse ni n g s y m pt o ms.  
•  A bse nce of ra pi d pr o gressi o n of disease.  
•  A bse nce of pr o gressi ve t u m or at critical a nat o mical sites (e .g ., s pi nal c or d c o m pressi o n) 
re q uiri n g ur ge nt al ter nati ve me dical i nter v e nti o n. 
T a ble 1 1 . I m a gi n g a n d Tre at me nt after First R a di ol o gic E vi de nce of Pr o gressi ve Dis e ase  
 
Cli nic all y St a ble  
Cli nic all y U nst a ble  
I m a gi n g 
Tre at m e nt  
I m a gi n g 
Tre at m e nt  
First ra di ol o gic 
e vi de n ce of P D  
Re p eat i ma gi n g at 
≥ 4 wee ks t o 
c o nfir m P D 
Ma y c o nti n ue st u d y 
treat me nt at t he 
i n vesti gat or's 
discreti o n w hile 
a waiti n g 
c o nfir mat or y sca n  
Re peat i ma gi n g at 
≥ 4 wee ks t o 
c o nfir m P D if 
p ossi ble  
Disc o nti n ue 
treat me nt 
Re p eat sca n 
c o nfir ms P D  
N o a d diti o nal 
i ma gi n g re q uire d 
Disc o nti n ue 
treat me nt 
N o a d diti o nal 
i ma gi n g re q uire d 
N/ A  
Re p eat sca n 
s h o ws S D, P R, or 
C R i. 
C o nti n ue re g ularl y 
sc h e d ule d i ma gi n g 
assess me nts e v er y 
6  wee ks  x 3 t he n 
res u me i ma gi n g 
e v er y 1 2 wee ks 
t hereafter. 
C o nti n ue st u d y 
treat me nt at t he 
i n vesti gat or's 
discreti o n  
C o nti n ue re g ularl y 
sc he d ule d i ma gi n g 
assess me nts e ver y 
6  wee ks  x 3 t he n 
res u me i ma gi n g 
e ver y 1 2 wee ks 
t hereafter. 
Ma y restart st u d y 
treat me nt if 
c o n diti o n has 
i m pr o ve d a n d/ or 
cli nicall y sta ble per 
i n vesti gat or's 
discreti o n  
i. S D, P R, C R is base d o n ne w baseli ne fr o m first e vi de nce of P D.  
 
 

I L-2 / Pe m br oliz u m a b  
 
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2  
Merc k O T S P # 5 5 5 7 1  
 
Versi o n  0 6 /1 1 /2 0 2 4  
U C D a vis C o m pre he nsi ve C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a ge 4 8  of 9 2  
 Disc o nti n u ati o n of St u d y T her a p y after C R  
Disc o nti n uati o n of treat me nt ma y be c o nsi dere d f or s u bjects w h o ha v e att ai ne d a c o nfir me d C R 
t hat ha ve bee n treat e d f or at least 2 4 wee ks wit h pe m br oliz u ma b a n d ha d at least t w o treat me nts 
wit h pe m br oliz u ma b be y o n d t he date w he n t h e i nitial C R was declare d . S u bjects w h o t he n 
e x perie n ce ra di o gra p hic disease pr o gressi o n ma y be eli gi ble f or u p t o o ne year of a d diti o nal 
treat me nt wit h pe m br oliz u ma b via t he Sec o n d C o urse P hase at t he discreti o n of t he i n vesti gat or 
if n o ca ncer treat me nt was a d mi nistere d si nce t he l ast d ose of pe m br oliz u m a b, t he s u bject meets 
t he safet y para meters liste d i n t he I ncl usi o n/ E xcl usi o n criteria, a n d t he trial is o pe n. S u bjects will 
res u me t hera p y at t he sa me d ose a n d sc h e d ule at t he ti me of i nitial disc o nti n uati o n. A d diti o nal 
details are pr o vi d e d i n Secti o n 5. 4 . 
 
S u bject Re pl ace me nt St r ate g y  
F or t he p h ase I c o m p o ne nt, a n y patie nt w h o is u ne val ua ble f or D L T will b e re place d. F or t he 
p hase II c o m p o ne nt, pati e nts m ust ha ve c o m plete d at least 3 of t he pla n ne d 4 st u d y i njecti o ns t o 
be c o nsi dere d e val u a ble.  
 
Cli nic al Criteri a f or E a rl y Tri al Ter mi n ati o n  
Earl y trial ter mi nati o n will be t he res ult of  pri nci p al i n vesti gat or discreti o n. T he f oll o wi n g  
criteria s pecifie d bel o w:  
1.  Q ualit y or q ua ntit y of dat a rec or di n g is i nacc urate or i nc o m plete  
2.  P o or a d here n ce t o pr ot oc ol a n d re g ulat or y re q uire me nts  
3.  I n ci de nce or se v erit y of a d verse dr u g reacti o n i n t his or ot her st u dies i n dicates a p ote ntial 
healt h hazar d t o s u bjects  
4.  Pla ns t o m o dif y or disc o nti n ue t he de vel o p me nt of t he st u d y dr u g  
I n t he e ve nt t hat n o patie nts are a ble t o t olerate t h e l o west d ose of I L-2 ( 3 x 1 0 6 I U), t he st u d y 
will be ter mi nate d.   
I n t he e ve nt t he D S M C d eci des t he st u d y is n ot safe f or p atie nts, t he st u d y will be ter mi nate d.  
 
D ur ati o n of F oll o w U p  
All patie nts will be f oll o we d f or 3 0  d a ys after t he last d ose of st u d y treat me nt or u ntil all 
treat me nt-relate d, cli nical l y si g nifica nt t o xicities res ol ve t o baseli ne or gra d e  ≤ 1. A d verse e ve nts 
wit h attri b uti o n of p ossi ble, pr o ba ble , or defi nite will be re p orte d f oll o wi n g g ui deli nes f or 
a d verse e ve nt r e p orti n g , a n d all S A Es will be re p orte d f or 3 0  d a ys after t he last d ose  of st u d y 
treat me nt. 
P atie nts o n acti ve treat m e nt at 1 2 m o nt hs ma y c o nti n ue t o recei ve pe m br oliz u ma b b ut will re vert 
t o S O C ma na ge me nt a n d be la bele d i n “f oll o w-u p ”.  At t his ti me o nl y P F S a n d l o n g -ter m t o xicit y 
data will be c ollecte d e ver y 3 m o nt hs as part of r o uti ne S O C ma na ge me nt.   

I L-2 / Pe m br oliz u m a b  
 
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2  
Merc k O T S P # 5 5 5 7 1  
 
Versi o n  0 6 /1 1 /2 0 2 4  
U C D a vis C o m pre he nsi ve C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a ge 4 9  of 9 2  
All patie nts will be f oll o we d e ver y 3 m o nt hs per r o uti ne S O C ma na ge me nt u ntil d oc u me nte d 
pr o gressi o n , deat h, l oss t o f oll o w u p, c o nse nt wit h dra wal, or st u d y ter mi nati o n. Patie nts w h o 
disc o nti n ue st u d y treat me nt earl y will be f oll o we d f or pr o gressi o n free s ur vi val  a n d late t o xicit y 
assess me nt  e ver y 3 m o nt hs  as part of t heir r o uti ne S O C  ma na ge me nt . 
 

I L-2 / Pe m br oliz u m a b  
 
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2  
Merc k O T S P # 5 5 5 7 1  
 
Versi o n  0 6 /1 1 /2 0 2 4  
U C D a vis C o m pre he nsi ve C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a ge 5 2  of 9 2  
7. 0  
T RI A L P R O C E D U R E S  
 
Res p o nse Assess m e nt  
 Effic ac y  
Res p o nse will be e val uat e d i n t his st u d y usi n g t he ne w i nter nati o nal criteria pr o p ose d b y t he 
re vise d Res p o nse E v al uati o n Criteria i n S oli d T u m ors ( R E CI S T) g ui deli n e ( versi o n 1. 1) [5 8 ] as 
well as ir R E CI S T criteria.  Pr o gressi o n will be e val uate d usi n g ir R E CI S T criteria.  A d diti o nall y, 
i ma gi n g will be re vie we d b y a ra di ol o gist i n c o nj u ncti o n wit h a ra diati o n o nc ol o gist t o hel p 
disti n g uis h t u m or pr o gressi o n fr o m p ost -S A R scarri n g. C ha n ges i n t he lar g est dia meter 
( u ni di me nsi o nal meas ure me nt) of t he t u m or lesi o ns a n d t he s h ortest dia met er i n t he cas e of 
mali g na nt l y m p h n o des are use d i n t he R E CI S T criteria.  
 Dise ase P ar a meters  
7. 1. 2. 1  
Me as ur a ble Dise ase  
T he  prese n ce  of  at least o ne  meas ur a ble  lesi o n.  
7. 1. 2. 2  
Me as ur a ble Lesi o ns  
Lesi o ns  t hat ca n be  acc uratel y  meas ur e d  i n at least o ne  di me nsi o n  wit h l o n gest  dia meter  ( L D) 
2 0 m m  usi n g  c o n ve nti o nal  tec h ni q ues or  1 0 m m  wit h  s piral C T  sca n.  
7. 1. 2. 3  
N o n -Me as ur a ble Lesi o ns  
All  ot her  lesi o ns, i ncl u di n g s mall lesi o ns (l o n gest dia meter  < 2 0  m m  wit h  c o n ve nti o nal  
tec h ni q ues or  < 1 0  m m  wit h  s piral C T  sca n), i.e., b o ne  lesi o ns, le pt o me ni n geal disease,  ascites, 
ple ural/ pericar dial  eff usi o n,  i nfla m mat or y breast  disease,  l y m p ha n gitis c utis/ p ul m o nis,  c ystic 
lesi o ns, a n d als o a b d o mi nal  masses  t hat are n ot  c o nfir me d a n d f oll o we d b y  i ma gi n g tec h ni q ues. 
All  meas ure me nts  s h o ul d be  ta ke n a n d rec or de d i n metric  n otati o n,  usi n g  a r uler or  cali pers. All  
baseli ne  e val u ati o ns  s h o ul d be  perf or m e d  as cl osel y  as p ossi ble  t o t he be gi n ni n g  of  treat me nt a n d 
ne ver  m or e  t ha n 4  wee ks  bef ore  t h e be gi n ni n g  of  t he treat 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.   
Cli nical  lesi o ns will  o nl y  be  c o nsi dere d  meas ura bl e  w he n  t he y are s u p erfici al (e. g., s ki n n o d ules  
a n d pal pa ble  l y m p h n o des).  F or  t he case 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 rec o m me n de d.  
 Met h o ds of Me as ure me nt  
C T a n d M RI are t he b est c urre ntl y a v aila ble a n d re pr o d uci ble met h o ds t o meas ure t ar get lesi o ns 
selecte d f or res p o ns e ass ess me nt. C o n ve nti o nal C T a n d M RI s h o ul d b e perf or me d wit h c uts of 
1 0 m m or less i n slice t hic k ness c o nti g u o usl y. S piral C T s h o ul d be per f or me d usi n g a 5 m m 

I L-2 / Pe m br oliz u m a b  
 
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2  
Merc k O T S P # 5 5 5 7 1  
 
Versi o n  0 6 /1 1 /2 0 2 4  
U C D a vis C o m pre he nsi ve C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a ge 5 3  of 9 2  
c o nti g u o us rec o nstr ucti o n al g orit h m. T his a p plies t o t u m ors of t he c hest, a b d o me n a n d pel vis. 
Hea d a n d n ec k t u m ors a n d t h ose of e xtre mities us uall y re q uire s pecific pr ot oc ols.  
Lesi o ns o n c hest X -ra y are acce pta bl e as meas ura ble lesi o ns w he n 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. H o we ver, C T is prefera ble.  
W he n t he pri mar y e n d p oi nt of t he st u d y is o bjecti ve res p o nse e val uati o n, ultras o u n d ( U S) s h o ul d 
n ot be use d t o meas ure t u m or lesi o ns. It is, h o we v er, a p ossi ble alter nati ve t o cli nical 
meas ure me nts of s u p erfi cial pal pa ble l y m p h n o des, s u bc uta ne o us lesi o ns a n d t h yr oi d n o d ules. 
U S mi g ht als o be usef ul t o c o nfir m t he c o m plete disa p peara nce of s u perfici al lesi o ns us uall y 
assesse d b y cli nical e xa mi nati o n.  
T he  utilizati o n  of  e n d osc o p y  a n d la par osc o p y f or o bjecti ve  t u m or e val uati o n  has  n ot  yet  bee n  
f ull y a n d wi del y  vali date d.  T heir  uses  i n t his s pecific c o nte xt re q uire s o p histicate d e q ui p me nt  
a n d a hi g h  le vel of  e x pertise  t hat ma y  o nl y  be  a vaila ble i n s o me ce nters. T h eref ore,  t he 
utilizati o n  of  s uc h tec h ni q ues f or o bjecti ve  t u m or res p o nse s h o ul d be  restri cte d t o vali dati o n  
p ur p oses  i n s pecializ e d ce nters.  H o we ver,  s u c h tec h ni q ues ca n b e  usef ul  i n c o nfir mi n g  c o m plete 
pat h ol o gical  res p o nse w h e n  bi o psies  are o btai n e d.   
C yt ol o g y  a n d hist ol o g y  ca n be  use d  t o differe ntiat e  bet wee n  P R  a n d C R  i n rare cases (e. g., after 
treat me nt t o differe ntiate  bet wee n  resi d ual be ni g n  lesi o ns a n d resi d ual mali g na nt  lesi o ns i n t u m or 
t y pes s uc h as ger m  cell  t u m ors).  
 Res p o nse Criteri a  
7. 1. 4. 1  
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 p eara nce of t he tar get lesi o n  
•  P arti al  Res p o nse  ( P R): At least a 3 0 % decrease i n t he s u m of t he L D of tar get lesi o ns, 
ta ki n g as refere n ce t he b aseli ne s u m L D  
•  Pr o gressi ve  Dise ase  ( P D): At least a 2 0 % i ncrease i n t he s u m of t he L D of tar get lesi o n, 
or t he a p peara n ce of o ne or m ore ne w l esi o ns  
•  St a ble Dise ase ( S D): N eit her s ufficie nt s hri n ka g e t o q ualif y f or P R n or s ufficie nt 
i ncreas e t o q ualif y f or P D, ta ki n g as refere nce t h e s mallest s u m L D si nce t he treat me nt 
starte d 
7. 1. 4. 2  
I m m u ne Rel ate d Res p o nse Criteri a (i r R E CI S T) 
A gr o wi n g b o d y of literat ure i n dicates t hat r a di o gr a p hic res p o ns es t o i m m u n ot hera p y ma y ha v e 
differe nt p atter ns a n d ki n etics t ha n w hat w o ul d be e x pecte d wit h tra diti o nal c yt ot o xic t hera pies.  
T o acc o u nt f or t hese differe nces we will als o c haracterize ra di o gra p hic o ut c o mes usi n g t he 
i m m u ne relate d res p o ns e criteria o utli ned b y W ol c h o k a n d c ollea g ues [5 9 ]. See A p pe n di x 4 . 
7. 1. 4. 3  
 E v al u ati o n of Best O ver all Res p o nse  
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 treat me nt u ntil 
disease pr o gressi o n/rec urre nce (ta ki n g as refere n ce f or P D t he s mallest meas ure me nts rec or de d 

I L-2 / Pe m br oliz u m a b  
 
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2  
Merc k O T S P # 5 5 5 7 1  
 
Versi o n  0 6 /1 1 /2 0 2 4  
U C D a vis C o m pre he nsi ve C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a ge 5 4  of 9 2  
si nce t he treat me nt starte d). I n ge neral, t he patie nt's best res p o nse assi g n me nt will de pe n d o n t he 
ac hie ve m e nt of b ot h meas ure me nt a n d c o nfir mati o n criteria.  
T a ble 1 2 . Best O ver all Res p o nse E v al u ati o n 
T ar g et Lesi o n  
Ne w Lesi o n  
O ver all Res p o nse  
C R  
N o  
C R  
P R  
N o  
P R  
S D  
N o  
S D  
P D  
Yes or N o  
P D  
 
Patie nts  wit h  a gl o bal  deteri 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 n ce of  dise ase  pr o gressi o n  at t hat ti me s h o ul d be  classifie d as ha vi n g  
“s y m pt o matic  deteri orati o n”.  E ver y  eff ort s h o ul d be  ma de  t o d oc u me nt  t he o bjecti ve  pr o gressi o n  
e ve n aft er disc o nti n uati o n  of  treat me nt.  
I n s o me circ u msta n ces  it ma y  be  diffic ult  t o disti n g uis h  resi d ual disease  fr o m n or mal  tiss ue. 
W he n  t he e v al uati o n  of  c o m plete res p o nse de p e n ds  o n  t his deter mi nati o n,  it is rec o m me n de d t hat 
t he resi d ual lesi o n be i n v esti gate d  (fi ne n ee dle  as pirate/ bi o ps y)  t o c o nfir m  t he c o m plete res p o nse 
stat us.  
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 met  f or C R  
or  P R  ( w hic he ver st at us is rec or de d first) u ntil  t he first date  t hat rec urre nce or  P D  is o bjecti vel y  
d oc u me nte d,  ta ki n g as refere n ce f or P D  t he s mallest meas ure me nts  rec or de d si nce t he treat me nt 
starte d.  
D ur ati o n of St a ble Dise ase  
S D  is meas ure d  fr o m t he start of  t he treat me nt u ntil  t he criteria f or diseas e  pr o gressi o n  are met,  
ta ki n g as refere n ce t he s mallest meas ure me nts  rec or de d si nc e t he treat me nt starte d.  
T he  cli nical rel e va nce of  t he d urati o n  of  S D  varies  f or differe nt  t u m or t y pes a n d gra des.   
T heref ore,  it is hi g hl y  rec o m me n de d t hat t he pr ot o c ol  s pecif y t he mi ni mal  ti me i nter val re q uir e d 
bet wee n  t w o me as ure m e nts  f or deter mi nati o n  of  S D.  T his  ti me i nter val s h o ul d ta ke i nt o acc o u nt  
t he e x pect e d  cli nical  be n efit  t hat s uc h a stat us ma y  bri n g  t o t he p o p ulati o n  u n der  st u d y.  
Dise ase C o ntr ol R ate ( D C R)  
D C R is defi ne d as t he perce nta g e of patie nts t hat ac hie ve a n o bjecti ve t u m or res p o nse or sta ble 
disease t o t hera p y.  
Pr o gressi o n -Free S ur vi v al ( P F S)  
P F S is defi ne d as t he d urati o n of ti me fr o m start of treat me nt t o ti me of pr o gressi o n or deat h, 
w hic he ver occ urs first.  
A bsc o p al Res p o nse R ate ( A R R)  

I L-2 / Pe m br oliz u m a b  
 
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2  
Merc k O T S P # 5 5 5 7 1  
 
Versi o n  0 6 /1 1 /2 0 2 4  
U C D a vis C o m pre he nsi ve C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a ge 5 5  of 9 2  
A R R is defi ne d as t he perce nta g e of patie nt s t hat ac hie ve a n o bjecti ve t u m or res p o nse at 
u nirra diate d lesi o ns as d efi ne d b y ir R E CI S T criteria . 
Re p orti n g of Res ults  
All  patie nts  i ncl u de d i n t he st u d y m ust  be  assesse d  f or res p o ns e t o treat me nt, e ve n if t here are 
maj or  pr ot oc ol  treat me nt de viati o ns  or  if t he y are i neli gi ble. Eac h  patie nt  will  be  assi g ne d  o ne  of  
t he f oll o wi n g cate g ori es:  1)  c o m plete res p o nse, 2)  partial  res p o nse, 3)  sta ble disease,  4)  
pr o gressi ve  dise ase,  5)  earl y deat h  fr o m mali g na nt  disease,  6)  earl y deat h  fr o m t o xicit y, 7)  earl y 
deat h  beca use  of  ot h er  ca use,  or  9)  u n k n o w n  ( n ot assessa ble, i ns uffi cie nt data).   
All  of  t he patie nts  w h o  met  t he eli gi bilit y  criteria s h o ul d be  i ncl u de d i n t he mai n  a nal ysis  of  t he 
res p o nse rate. Patie nts  i n res p o nse cate g ories  4 -9  s h o ul d be  c o nsi dere d  as faili n g t o res p o n d t o 
treat me nt ( diseas e pr o gressi o n).  T h us,  a n i nc orrect treat me nt sc he d ul e or  dr u g  a d mi nistrati o n  
d oes  n ot  res ult i n e xcl usi o n  fr o m t he a nal ysis  of  t he res p o nse rate. Precise  defi niti o ns  f or 
cate g ories 4 -9  will  be  pr ot oc ol  s pecific.  
All  c o ncl usi o ns  s h o ul d be  base d  o n  all eli gi ble patie nts.  S u ba nal yses  ma y  t he n be  perf or me d  o n  
t he basis  of  a s u bset of  p atie nts,  e xcl u di n g  t h ose f or w h o m  maj or  pr ot oc ol  de viati o ns  ha ve  bee n  
i de ntifie d (e. g., earl y deat h  d ue  t o ot her  reas o ns, earl y disc o nti n uati o n  of  tr eat me nt, maj or  
pr ot oc ol  vi olati o ns,  etc.).  H o we ver,  t hese s u ba n al yses ma y  n ot  ser ve as t he basis  f or dra wi n g  
c o ncl usi o ns  c o ncer ni n g  treat me nt efficac y,  a n d t h e reas o ns f or e x cl u di n g  patie nts  fr o m t he 
a nal ysis  s h o ul d be  clearl y  re p orte d.  
T he  9 5 %  c o nfi d e nce i nter vals s h o ul d be  pr o vi de d.  
 
Tri al Pr oce d ures  
T he St u d y Cale n dar  - Secti o n 6. 0  s u m marizes t he trial pr oce d ures t o be perf or me d at eac h visit. 
I n di vi d ual trial pr o ce d ures are des cri be d i n det ail bel o w. It ma y be necessar y t o perf or m t hese 
pr oce d ures at u nsc h e d ule d ti me p oi nts if dee me d cli nicall y necessar y b y t h e i n vesti gat or.  
F urt her m ore, a d diti o nal e val uati o ns/testi n g ma y be dee me d necessar y b y t he S p o ns or a n d/ or 
Merc k  f or reas o ns relat e d t o s u bject safet y. I n s o me cases, s uc h e val uati o n/testi n g ma y be 
p ote ntiall y se nsiti ve i n nat ure (e. g., HI V, He patitis C, etc.), a n d t h us l ocal r e g ulati o ns ma y 
re q uire t hat a d diti o nal i nf or me d c o nse nt be o bt ai ne d fr o m t he s u bject. I n t hese cas es, s uc h 
e val uati o ns/testi n g will be perf or me d i n acc or da nce wit h t h ose re g ulati o ns.  
 A d mi nistr ati ve Pr oce d ures  
7. 2. 1. 1  
I nf or me d C o nse nt 
T he I n vesti gat or m ust o btai n d oc u me nte d c o nse nt fr o m eac h p ote ntial s u bject pri or t o 
partici pati n g i n a cli nical trial.  
7. 2. 1. 2  
Ge ner al I nf or me d C o nse nt  
C o nse nt m ust be d oc u me nte d b y t he s u bject’s date d si g nat ure or b y t he s u bj ect’s le gall y 
acce pta ble re pres e ntati ve’s date d si g nat ure o n a c o nse nt f or m al o n g wit h t he date d si g nat ure of 
t he pers o n c o n d u cti n g t he c o nse nt disc ussi o n.  

I L-2 / Pe m br oliz u m a b  
 
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2  
Merc k O T S P # 5 5 5 7 1  
 
Versi o n  0 6 /1 1 /2 0 2 4  
U C D a vis C o m pre he nsi ve C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a ge 5 6  of 9 2  
A c o p y of t he si g ne d a n d date d c o nse nt f or m s h o ul d be gi ve n t o t he s u bject bef ore p artici pati o n 
i n t he trial. 
T he i nitial i nf or me d c o ns e nt f or m, a n y s u bse q u e nt re vise d writte n i nf or m e d c o nse nt f or m a n d 
a n y writte n i nf or mati o n pr o vi de d t o t he s u bject m ust recei ve t h e I R B/ E R C’s a p pr o val/fa v ora ble 
o pi ni o n i n a d va nce of us e.  T he s u bject or his/ her le gall y acce pta ble re prese ntati ve s h o ul d be 
i nf or me d i n a ti mel y ma n ner if ne w i nf or mati o n bec o mes a vaila ble t h at ma y be rele va nt t o t he 
s u bject’s willi n g ness t o c o nti n ue partici pati o n i n t he trial. T he c o m m u nicati o n of t his 
i nf or mati o n will be pr o vi de d a n d d oc u me nt e d via a re vise d c o nse nt f or m or a d de n d u m t o t he 
ori gi nal c o nse nt f or m t hat ca pt ures t he s u bject’s d ate d si g nat ure or b y t h e s u bject’s le gall y 
acce pta ble re pres e ntati ve’s date d si g nat ure.  
S pecifics a b o ut a trial a n d t he trial p o p ulati o n will be a d de d t o t he c o nse nt f or m te m plate at t he 
pr ot oc ol le vel.   
T he i nf or me d c o ns e nt will a d here t o I R B/ E R C re q uire me nts, a p plica ble la ws a n d re g ulati o ns a n d 
S p o ns or re q uire me nts.  
7. 2. 1. 3  
I ncl usi o n/ E xcl usi o n Criteri a 
All i ncl usi o n a n d e xcl usi o n criteria will be re vie we d b y t he i n vesti gat or or q ualifie d desi g nee t o 
e ns ure t hat t he s u bject q ualifies f or t he trial.  
7. 2. 1. 4  
Me dic al Hist or y  
A me dical hist or y will be o btai ne d b y t he i n vesti gat or or q ualifie d d esi g nee.  Me dical hist or y will 
i ncl u de all acti ve c o n diti o ns, a n d a n y c o n diti o n dia g n ose d wit hi n t he pri or 1 0 years t hat are 
c o nsi dere d t o be cli nicall y si g nifica nt b y t he I n vesti gat or.  Details re gar di n g t he disease f or w hic h 
t he s u bject has e nr olle d i n t his st u d y will be rec or de d se paratel y a n d n ot liste d as me dical 
hist or y.   
7. 2. 1. 5  
Pri or a n d C o nc o mit a nt Me dic ati o ns Re vie w  
7. 2. 1. 5. 1  
Pri or Me dic ati o ns  
T he i n vesti gat or or q ualifie d desi g nee will re vi e w pri or me dicati o n use, i ncl u di n g a n y pr ot oc ol -
s pecifie d w as h o ut re q uir e me nt, a n d rec or d pri or me dicati o n ta ke n b y t he s u bject wit hi n 2 8 da ys 
bef ore starti n g t he trial.  Treat me nt f or t he diseas e f or w hic h t he s u bject has e nr olle d i n t his st u d y 
will be rec or de d se paratel y a n d n ot liste d as a pri or me dicati o n.  
7. 2. 1. 5. 2  
C o nc o mit a nt Me dic ati o ns  
T he i n vesti gat or or q ualifie d desi g nee will rec or d me dicati o n, if a n y, ta ke n b y t he s u bject d uri n g 
t he trial. All me dicati o ns relate d t o r e p orta ble S A Es a n d E CIs s h o ul d be rec or de d as defi ne d i n 
Secti o n 7. 3 . 
7. 2. 1. 6  
Pri or Tre at me nt Det ails  
T he i n vesti gat or or q ualifie d desi g nee will re vi e w all pri or ca n cer treat me nts i ncl u di n g s yste mic 
treat me nts, ra diati o n, a n d s ur geries.  

I L-2 / Pe m br oliz u m a b  
 
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2  
Merc k O T S P # 5 5 5 7 1  
 
Versi o n  0 6 /1 1 /2 0 2 4  
U C D a vis C o m pre he nsi ve C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a ge 5 7  of 9 2  
7. 2. 1. 6. 1  
S u bse q ue nt A nti -C a ncer T her a p y St at us  
T he i n vesti gat or or q ualifie d desi g nee will re vi e w all ne w a nti -ne o plastic t h era p y i nitiate d aft er 
t he last d ose of trial treat me nt. If a s u bject i nitiates a ne w a nti-ca ncer t hera p y wit hi n 3 0 da ys 
after t he l ast d ose of trial treat me nt, t he 3 0 -d a y  Safet y F oll o w -u p visit m ust occ ur bef ore t h e first 
d ose of t he ne w t h era p y.  O nce ne w a nti -ca ncer t hera p y has bee n i nitiate d t he s u bject will m o ve 
i nt o s ur vi val f oll o w-u p.  
 Cli nic al Pr oce d ures/ Assess m e nts  
7. 2. 2. 1  
A d verse E ve nt ( A E) M o nit ori n g  
T he i n vesti gat or or q ualifie d desi g nee will assess eac h s u bject t o e v al uate f or p ote ntial ne w or 
w orse ni n g A Es as s pe cifi e d i n t he Trial Fl o w C hart a n d m ore fre q ue ntl y if cli nicall y i n dicate d.  
A d verse e x perie n ces will be gra de d a n d rec or de d t hr o u g h o ut t he st u d y a n d d uri n g t he f oll o w -u p 
peri o d acc or di n g t o N CI C T C A E Versi o n 4. 0 (see A p pe n di x 5 ). T o xicities will be c haracterize d 
i n ter ms re gar di n g seri o us ness, ca usalit y, t o xicit y gra di n g, a n d acti o n ta ke n wit h re gar d t o trial 
treat me nt.  
Please refer t o secti o n 7. 3  f or detaile d i nf or mati o n re gar di n g t he assess me nt a n d rec or di n g of 
A Es.   
7. 2. 2. 2  
F ull P h ysic al E x a m  
T he i n vesti gat or or q ualifie d desi g nee will perf or m a c o m plete p h ysical e xa m d uri n g t he 
scree ni n g p eri o d. Cli nicall y si g nifica nt a b n or mal fi n di n gs s h o ul d be rec or de d as me dical hist or y.  
A f ull p h ysical e xa m s h o ul d be perf or m e d d uri n g scree ni n g . 
7. 2. 2. 3  
Directe d P h ysic al E x a m  
F or c y cles t hat d o n ot re q uire a f ull p h ysical e xa m per t he Trial Fl o w C hart, t he i n vesti gat or or 
q ualifie d desi g nee will perf or m a direct e d p h ysical e xa m as cli nicall y i n dicate d pri or t o trial 
treat me nt a d mi nistrati o n.  
7. 2. 2. 4  
Vit al Si g ns  
T he i n vesti gat or or q ualifie d desi g nee will ta ke vit al si g ns at scree ni n g, pri or t o t he 
a d mi nistrati o n of eac h d ose of trial treat me nt a n d at treat me nt disc o nti n uati o n as s pecifie d i n t he 
Trial Fl o w C hart ( Secti o n 6. 0 ). Vital si g ns s h o ul d i ncl u de te m perat ure, p ulse, res pirat or y rate, 
wei g ht,  a n d bl o o d press ure. Hei g ht will be meas ure d at scree ni n g o nl y.  
7. 2. 2. 5  
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 Sc ale  
T he i n vesti gat or or q ualifie d desi g nee will assess E C O G stat us (see A p pe n di x 1 ) at scree ni n g, 
pri or t o t he a d mi nistrati o n of eac h d os e of trial tr eat me nt a n d disc o nti n uati o n of trial treat me nt as 
s pecifie d i n t he Tri al Fl o w C hart.  

I L-2 / Pe m br oliz u m a b  
 
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2  
Merc k O T S P # 5 5 5 7 1  
 
Versi o n  0 6 /1 1 /2 0 2 4  
U C D a vis C o m pre he nsi ve C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a ge 5 8  of 9 2  
 L a b or at or y Pr oce d ures/ Assess me nts  
Details re gar di n g s pecifi c la b orat or y pr oce d ures/assess me nts t o be perf or m e d i n t his trial are 
pr o vi de d bel o w . La b orat or y tests f or he mat ol o g y, c he mistr y, uri nal ysis, a n d ot hers are s p ecifie d 
i n Ta ble 1 3 . 
T a ble 1 3 . L a b or at or y Tests 
He m at ol o g y  
C he mistr y  
Uri n al ysis  
Ot her  
He mat o crit  
Al b u mi n  
 
Ser u m β -h u ma n c h ori o nic 
g o na d otr o pi n †  
He m o gl o bi n  
Al kali ne p h os p hatase  
 
 ( β-h C G) †  
Platelet c o u nt  
Ala ni n e a mi n otra nsferase ( A L T)  
 
P T (I N R)  
W B C (t otal a n d 
differe ntial)  
As partate a mi n otra nsferase ( A S T)  
 
a P T T  
Re d Bl o o d Cell C o u nt  
Lactate de h y dr o ge nase ( L D H)  
 
T otal t hrii o d ot h yr o ni n e ( T 3)  
A bs ol ute Ne utr o p hil C o u nt  Car b o n Di o xi d e ‡  
 
Free t yr o xi n e ( T 4)  
A bs ol ute L y m p h oc yte 
C o u nt  
( C O2 or bi oc ar b o n ate)  
Uri ne pre g na nc y test †  
T h yr oi d sti m ulati n g h or m o ne 
( T S H) 
 
Uric Aci d  
 
 
 
Calci u m  
 
 
 
C hl ori de  
 
Bl o o d f or c orrelati v e st u dies  
 
Gl u c ose  
 
  
 
P h os p h or us  
 
  
 
P otassi u m   
 
  
 
S o di u m  
 
  
 
Ma g nesi u m  
 
  
 
T otal Bilir u bi n  
 
  
 
Direct Bilir u bi n (If t ot al bilir u bi n is 
elev ate d a b ove t h e u p per li mit of 
n or m al)  
 
 
 
T otal pr otei n  
 
 
 
Bl o o d Urea Nitr o ge n  
 
 
†  
Perf or m o n w o me n of c hil d beari n g p ote ntial o nl y. If uri n e pre g na nc y res ults ca n n ot be c o nfir me d as n e gati ve, a ser u m 
pre g na nc y test will be re q uire d.   
‡  
If c o nsi dere d sta n dar d of care i n y o ur re gi o n. 
 
La b orat or y tests f or scree ni n g or e ntr y i nt o t he Sec o n d C o urse P hase s h o ul d be perf or me d wit hi n 
1 0 da ys pri or t o t he first d ose of treat me nt.  After C ycle 1, pre -d os e la b orat or y pr oce d ures ca n be 
c o n d ucte d u p t o 4 da ys  pri or t o d osi n g.  Res ults m ust be re vie we d b y t he i n vesti gat or or q ualifie d 
desi g nee a n d f o u n d t o be acce pta ble pri or t o eac h d ose of trial treat me nt.  
 
 

I L-2 / Pe m br oliz u m a b  
 
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2  
Merc k O T S P # 5 5 5 7 1  
 
Versi o n  0 6 /1 1 /2 0 2 4  
U C D a vis C o m pre he nsi ve C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a ge 5 9  of 9 2  
 Ot her Pr oce d ures  
7. 2. 4. 1  
Wit h dr a w al/ Disc o nti n u ati o n  
W he n a s u bject disc o nti n ues/ wit h dra ws pri or t o tri al c o m pleti o n, all a p plica ble acti vities 
sc he d ule d f or t h e fi nal tri al visit s h o ul d be perf or me d at t he ti me of disc o nti n uati o n.  A n y a d verse 
e ve nts t hat are pres e nt at t he ti me of disc o nti n uati o n/ wit h dra wal s h o ul d be f oll o we d i n 
acc or da nce wit h t he safet y re q uire me nts o utli ne d i n Secti o n 7. 3  - Assessi n g a n d Rec or di n g 
A d verse E v e nts.  S u bjects w h o a) attai n a C R or b) c o m plete 1 2  m o nt hs of treat me nt wit h 
pe m br oliz u ma b ma y disc o nti n ue treat me nt wit h t he o pti o n of restarti n g treat me nt if t he y meet 
t he criteria s p ecifie d i n S ecti o n 5. 8 . After disc o nti n ui n g treat me nt f oll o wi n g assess me nt of C R, 
t hese s u bjects s h o ul d ret ur n t o t he site f or a Safet y F oll o w-u p Visit ( descri be d i n Secti o n 5. 1 1 ) 
a n d t he n pr ocee d t o t he F oll o w -U p Peri o d of t he st u d y ( descri be d i n Secti o n 5. 1 1 ). 
 Visit Re q uire me nts  
Visit re q uire me n ts are o utli ne d i n Secti o n 6. 0 . S pecific pr oce d ure -rel ate d details are pr o vi d e d 
a bo ve . 
7. 2. 5. 1  
Scree ni n g  
Scree ni n g s h o ul d be c o m plete d wit hi n 2 8 da ys of Da y 1 . 
7. 2. 5. 2  
Tre at me nt peri o d  
See st u d y cale n dar f or treat me nt peri o d details.  
7. 2. 5. 3  
P ost Tre at me nt Visits  
7. 2. 5. 3. 1  
S afet y F oll o w -u p Visit  
T he ma n dat or y Safet y F oll o w -U p Visit s h o ul d be c o n d ucte d a p pr o xi matel y 3 0 da ys after t h e last 
d ose of trial treat me nt or bef ore t h e i nitiati o n of a ne w a nti -ca ncer treat me nt, w hic he ver c o mes 
first. All A Es t hat occ ur pri or t o t he Safet y F oll o w -U p Visit s h o ul d be rec or de d.  S u bjects wit h a 
treat me nt relat e d A E of Gra de > 1 will be f oll o w e d u ntil t he res ol uti o n of t he A E t o Gra d e 0 -1 or 
u ntil t he be gi n ni n g of a ne w a nti -ne o plastic t h era p y, w hic he ver occ urs first.  S A Es t hat occ ur 
wit hi n 9 0 da ys of t he e n d of tr eat me nt or b ef ore i nitiati o n of a ne w a nti -ca n cer treat me nt s h o ul d 
als o be f oll o we d a n d rec or de d.  S u bjects w h o are eli gi ble f or retr eat me nt wit h pe m br oliz u ma b (as 
descri be d i n Secti o n  5. 8 ) ma y ha ve u p t o t w o safet y f oll o w-u p visits, o ne after t he Treat me nt 
Peri o d a n d o ne after t he Sec o n d C o urse P hase.  
7. 2. 5. 4  
F oll o w -u p Visits  
S u bjects w h o disc o nti n ue trial treat me nt f or a reas o n ot her t ha n disease pr o gressi o n will m o ve 
i nt o t he F oll o w-U p P has e a n d s h o ul d be ass esse d e ver y 6 wee ks  b y ra di ol o gic i ma gi n g t o 
m o nit or disease stat us  or per sta n dar d of care . After 1 year, t h e i ma gi n g ti me p oi nt will occ ur 
e ver y 9 wee ks  or per sta n dar d of care . E ver y eff ort s h o ul d be ma de i n t he f oll o w u p p hase t o 
c ollect i nf or mati o n re g ar di n g disease stat us u ntil t he start of ne w a nti -ne o pl astic t hera p y, disease 
pr o gressi o n, deat h, e n d of t he st u d y or if t he s u bject be gi ns retreat me nt wit h pe m br oliz u ma b as 

I L-2 / Pe m br oliz u m a b  
 
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2  
Merc k O T S P # 5 5 5 7 1  
 
Versi o n  0 6 /1 1 /2 0 2 4  
U C D a vis C o m pre he nsi ve C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a ge 6 0  of 9 2  
detaile d i n Secti o n 5. 8 . I nf or mati o n re gar di n g p ost-st u d y a nti-ne o plastic treat me nt will be 
c ollecte d if ne w treat me nt is i nitiate d.  
S u bjects w h o are eli gi ble t o recei ve retr eat me nt wit h pe m br oliz u ma b acc or di n g t o t he criteria i n 
Secti o n 5. 8  will m o ve fr o m t he f oll o w -u p p hase t o t he Sec o n d C o urse P has e w he n t he y 
e x perie n ce dise ase pr o gressi o n.   
7. 2. 5. 4. 1  
S ur vi v al F oll o w -u p  
O nce a s u bject e x perie nces c o nfir me d disease pr o gressi o n or starts a n e w a nti -ca ncer t hera p y, t he 
s u bject m o ves i nt o t he s ur vi val f oll o w-u p p hase a n d s h o ul d be f oll o we d e v er y 1 2 wee ks t o assess 
f or s ur vi val stat us u ntil deat h, wit h dra wal of c o ns e nt, or t he e n d of t h e st u d y, w hic he ver occ urs 
first. 
 
Assessi n g a n d Rec or di n g A d verse E ve nts  
A n a d vers e e ve nt is defi ne d as a n y u nt o w ar d me di cal occ urre n ce i n a patie nt or cli nical 
i n vesti gati o n s u bject a d mi nistere d a p har m ace utical pr o d uct a n d w hic h d oes n ot necessaril y ha v e 
t o ha ve a ca usal r elati o ns hi p wit h t his treat me nt. A n a d verse e ve nt ca n t heref ore be a n y 
u nfa v ora bl e a n d u ni nte n d e d si g n (i ncl u di n g a n a b n or mal la b orat or y fi n di n g, f or e xa m ple), 
s y m pt o m, or disease te m p orall y ass ociate d wit h t he use of a m e dici nal pr o d uct or pr ot oc ol -
s pecifie d pr oce d ure, w het her or n ot c o nsi dere d rel ate d t o t he me dici nal pr o d uct or pr ot oc ol -
s pecifie d pr oce d ure. A n y w orse ni n g (i.e., a n y cli nicall y si g nifica nt a d verse c ha n ge i n fre q ue n c y 
a n d/ or i nte nsit y) of a pree xisti n g c o n diti o n t hat is te m p orall y ass ociate d wit h t he use of t he st u d y 
i nter ve nti o n, is als o a n a d verse e v e nt. 
C ha n ges res ulti n g fr o m n or mal gr o wt h a n d de v el o p me nt t hat d o n ot var y si g nifica ntl y i n 
fre q ue n c y or se v erit y fr o m e x pecte d le v els are n ot t o be c o nsi dere d a d verse e ve nts. E xa m ples of 
t his ma y i ncl u de, b ut are n ot li mite d t o, teet hi n g, t y pical cr yi n g i n i nfa nts a n d c hil dre n a n d o nset 
of me nses or me n o p a use occ urri n g at a p h ysi ol o gicall y a p pr o pri ate ti me.  
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 v e nt.  
All a d verse e ve nts t hat o cc ur after t he c o nse nt f or m is si g ne d b ut bef ore treat me nt 
all ocati o n/ra n d o mizati o n m ust be re p orte d b y t he i n vesti gat or if t he y ca us e t he s u bject t o be 
e xcl u de d fr o m t he trial, or are t h e res ult of a pr ot o c ol -s pecifie d i nter ve nti on, i ncl u di n g b ut n ot 
li mite d t o was h o ut or disc o nti n uati o n of us ual t hera p y, diet, place b o treat m e nt or a pr oce d ure. 
Fr o m t he ti me of treat me nt all ocati o n  t hr o u g h 3 0 da ys f oll o wi n g cessati o n of treat me nt, all 
a d verse e ve nts m ust be re p orte d b y t he i n vesti gat or. S uc h e ve nts will be rec or de d at eac h 
e xa mi nati o n o n t he A d verse E ve nt c ase re p ort f or ms/ w or ks heets.   
 Defi niti o n of a n O ver d ose f or t his Pr ot oc ol a n d Re p orti n g of O ver d ose t o t he 
S p o ns or a n d t o Merc k  
F or p ur p os es of t his trial, a n o ver d ose of pe m br oli z u ma b will be defi ne d as a n y d ose of 1, 0 0 0 m g 
or great er ( ≥5 ti mes t he i n dicate d d ose).  N o s pecific i nf or mati o n is a vaila bl e 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 s u bject s h o ul d be o bser ve d cl osel y f or 
si 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 de d if cli nicall y i n dicate d.  

I L-2 / Pe m br oliz u m a b  
 
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2  
Merc k O T S P # 5 5 5 7 1  
 
Versi o n  0 6 /1 1 /2 0 2 4  
U C D a vis C o m pre he nsi ve C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a ge 6 1  of 9 2  
If a n a d v erse e ve nt(s) is ass ociate d wit h (“res ults fr o m”) t he o ver d ose of a st u d y i nter ve nti o n, t he 
a d verse e ve nt(s) is re p ort e d as a seri o us a d verse e ve nt, e ve n if n o ot her seri o us ness criteria are 
met.  
If a d ose of st u d y i nter ve nti o n meeti n g t he pr ot oc ol defi niti o n of o ver d ose is ta ke n wit h o ut a n y 
ass ociate d cli nical s y m pt o ms or a b n or mal la b orat or y res ults, t he o ver d ose is re p orte d as a n o n -
seri o us E ve nt of Cli nical I nterest ( E CI), usi n g t he ter mi n ol o g y “acci de ntal or i nte nti o nal 
o ver d ose wit h o ut a d verse effect.”  
All re p orts of o ver d ose wit h a n d wit h o ut a n a d verse e ve nt m ust be re p orte d wit hi n 2 4 h o urs t o 
t he S p o ns or a n d wit hi n 2 w or ki n g da ys h o urs t o Merc k Gl o bal Safet y. ( Att n: W orl d wi de Pr o d uct 
Safet y; F A X 2 1 5 9 9 3 -1 2 2 0)  
 Re p orti n g of Pre g n a nc y a n d L act ati o n t o t he S p o ns or a n d t o Merc k  
Alt h o u g h pre g na nc y a n d lactati o n are n ot c o nsi dere d a d verse e v e nts, 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 n a nc y or lactati o n i n a s u bject (s p o nta ne o usl y 
re p orte d t o t he m) t hat o cc urs d uri n g t he trial. 
Pre g na ncies a n d lactati o ns t hat occ ur after t he c o nse nt f or m is si g ne d b ut bef ore tr eat me nt 
all ocati o n/ra n d o mizati o n m ust be re p orte d b y t he i n vesti gat or if t he y ca us e t he s u bject t o be 
e xcl u de d fr o m t he trial, or are t h e res ult of a pr ot o c ol -s pecifie d i nter ve nti o n, i ncl u di n g b ut n ot 
li mite d t o was h o ut or disc o nti n uati o n of us ual t hera p y, diet, place b o treat m e nt or a pr oce d ure.  
Pre g na ncies a n d lactati o ns t hat occ ur fr o m t he ti me of treat me nt all ocati o n/ra n d o mizati o n 
t hr o u g h 1 2 0 da ys f oll o wi n g cessati o n of S p o ns or’s pr o d uct, or 3 0 da ys f oll o wi n g cessati o n of 
treat me nt if t he s u bject i nitiates ne w a ntica n cer t hera p y, w hic he v er is earlier, m ust be re p orte d b y 
t he i n vesti gat or. All re p orte d pre g n a ncies m ust be f oll o we d t o t he c o m pleti o n/ter mi nati o n of t he 
pre g na nc y.  Pre g na n c y o utc o mes of s p o nta ne o us a b orti o n, misse d a b orti o n, be ni g n h y dati dif or m 
m ole, bli g hte d o v u m, fetal deat h, i ntra uteri n e deat h, miscarria ge a n d still birt h m ust be re p orte d 
as seri o us e ve nts (I m p ort a nt Me dical E ve nts). If t he pre g na n c y c o nti n ues t o ter m, t he o utc o me 
( healt h of i nfa nt) m ust als o be re p orte d. 
S uc h e ve nts m ust be re p orte d wit hi n 2 4 h o urs t o t he S p o ns or a n d wit hi n 2 w or ki n g da ys t o 
Merc k Gl o bal Safet y  ( Att n: W orl d wi de Pr o d uct Safet y; F A X 2 1 5 9 9 3-1 2 2 0) . 
 I m me di ate Re p orti n g of A d verse E ve nts t o t he S p o ns or a n d t o Merc k  
7. 3. 3. 1  
Seri o us A d ve rse E ve nts 
A seri o us a d verse e v e nt is a n y a d vers e e ve nt occ urri n g at a n y d ose or d uri n g a n y use of 
pe m br oliz u ma b  t hat: 
•  Res ults i n deat h;  
•  Is life t hreat e ni n g; 
•  Res ults i n persiste nt or si g nifica nt disa bilit y/i nca pacit y;  
•  Res ults i n or pr ol o n gs a n e xisti n g i n patie nt h os pitalizati o n;  
•  Is a c o n ge nital a n o mal y/ birt h defect; 

I L-2 / Pe m br oliz u m a b  
 
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2  
Merc k O T S P # 5 5 5 7 1  
 
Versi o n  0 6 /1 1 /2 0 2 4  
U C D a vis C o m pre he nsi ve C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a ge 6 2  of 9 2  
•  Is a n ot her i m p orta nt me dical e ve nt  
N ote: I n a d diti o n t o t he a b o ve criteri a, a d verse e v e nts meeti n g eit her of t he bel o w criteri a, 
alt h o u g h n ot seri o us per I C H defi niti o n, are re p ort a ble t o Merc k i n t he s a me ti mefra me as S A Es 
t o meet certai n l ocal re q uire me nts. T heref ore, t hes e e ve nts are c o nsi dere d s eri o us b y Merc k f or 
c ollecti o n p ur p oses.  
•  Is a ne w ca ncer (t h at is n ot a c o n diti o n of t he st u d y); 
•  Is ass ociate d wit h a n o v er d ose. 
 
F or t he ti me peri o d be gi n ni n g w he n t he c o nse nt f or m is si g ne d u ntil treat me nt 
all ocati o n/ra n d o mizati o n, 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 ve nt, 
i ncl u di n g deat h d ue t o a n y ca use ot her t ha n pr o gressi o n of t he ca ncer u n der st u d y t hat occ urs t o 
a n y s u bject m ust be re p orte d wit hi n 2 4 h o urs t o t he S p o ns or a n d wit hi n 2 w or ki n g da ys t o Merc k 
Gl o bal Safet y if it ca uses t he s u bject t o be e xcl u d e d fr o m t he trial, or is t he res ult of a pr ot oc ol -
s pecifie d i nter ve nti o n, i ncl u di n g b ut n ot li mite d t o was h o ut or disc o nti n uati o n of us ual t hera p y, 
diet, place b o treat me nt , or a pr oce d ure.  
F or t he ti me peri o d be gi n ni n g at treat me nt all ocati o n/ra n d o mizati o n t hr o u g h 3 0  da ys f oll o wi n g 
cessati o n of treat me nt,  w hic he ver is earlier, a n y seri o us a d verse e ve nt, or f oll o w u p t o a seri o us 
a d verse e ve nt, i ncl u di n g deat h d ue t o a n y ca use ot her t ha n pr o gressi o n of t he ca n cer u n der st u d y , 
w het her or n ot relate d t o t he st u d y i nter ve nti o n, m ust be re p orte d wit hi n 2 4 h o urs t o t he S p o ns or 
a n d wit hi n 2 w or ki n g da ys t o Merc k Gl o bal Safet y.  
A d diti o nall y, a n y seri o us a d verse e ve nt, c o nsi dere d b y a n i n vesti gat or w h o is a q ualifie d 
p h ysicia n t o be relat e d t o st u d y i nter ve nti o n t hat is br o u g ht t o t he atte nti o n of t he i n vesti gat or at 
a n y ti me f oll o wi n g c o nse nt t hr o u g h t he e n d of t he s pecifie d safet y f oll o w -u p peri o d s pecifie d i n 
t he para gra p h a b o v e, or at a n y ti me o utsi de of t he ti me peri o d s pecifie d i n t h e pre vi o us para gra p h 
also m ust be re p orte d i m me diatel y t o t he S p o ns or a n d t o Merc k Gl o b al Safet y.  
All s u bjects wit h seri o us a d verse e ve nts m ust be f oll o we d u p f or o utc o me.   
S A E re p orts a n d a n y ot her rele v a nt s afet y i nf or m ati o n are t o be f or w ar de d t o t he Merc k 
Gl o b al S afet y f acsi mile n u m ber:  + 1 -2 1 5 -9 9 3 -1 2 2 0 . 
 
7. 3. 3. 2  
E ve nts of Cli nic al I nterest  
Selecte d n o n -seri o us a n d seri o us a d verse e v e nts are als o k n o w n as E v e nts of Cli nical I nterest 
( E CI) a n d m ust be re p ort e d wit hi n 2 4 h o urs t o t he S p o ns or a n d wit hi n 2 w or ki n g da ys t o Merc k 
Gl o bal Safet y. ( Att n: W orl d wi de Pr o d uct Safet y; F A X 2 1 5 9 9 3 -1 2 2 0).  
F or t he ti me peri o d be gi n ni n g w he n t he c o nse nt f or m is si g ne d u ntil treat me nt 
all ocati o n/ra n d o mizati o n, a n y E CI, or f oll o w u p t o a n E CI, t hat occ urs t o a n y s u bject m ust be 
re p orte d wit hi n 2 4 h o urs t o t he S p o ns or a n d wit hi n 2 w or ki n g da ys t o Merc k Gl o bal Safet y if it 
ca uses t he s u bje ct t o be e xcl u de d fr o m t he trial, or is t he res ult of a pr ot oc ol -s pecifie d 
i nter ve nti o n, i ncl u di n g b ut n ot li mite d t o was h o ut or disc o nti n uati o n of us ual t hera p y, diet, 
place b o treat me nt or a pr oce d ure.  

I L-2 / Pe m br oliz u m a b  
 
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2  
Merc k O T S P # 5 5 5 7 1  
 
Versi o n  0 6 /1 1 /2 0 2 4  
U C D a vis C o m pre he nsi ve C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a ge 6 3  of 9 2  
F or t he ti me peri o d be gi n ni n g at treat me nt all ocati o n/ra n d o mizati o n t hr o u g h 9 0 da ys f oll o wi n g 
cessati o n of treat me nt, or 3 0 da ys f oll o wi n g cessati o n of treat me nt if t he s u bject i nitiates ne w 
a ntica ncer t hera p y, w hic he ver is earlier, a n y E CI, or f oll o w u p t o a n E CI, w het her or n ot relate d 
t o st u d y i nter ve nti o n, m ust be re p orte d wit hi n 2 4 h o urs t o t he S p o ns or a n d wit hi n 2 4 h o urs t o 
Merc k Gl o bal Safet y.  
E ve nts of cli nical i nterest f or t his trial i ncl u de:  
1.  A n o ver d ose of st u d y i nter ve nti o n, as defi n e d i n Secti o n 7. 3. 1  - Defi niti o n of a n O ver d ose f or 
t his Pr ot oc ol a n d Re p orti n g of O ver d ose t o t he S p o ns or, t hat is n ot ass ociate d wit h cli nical 
s y m pt o ms or a b n or mal la b orat or y res ults.  
2.  A n ele vate d A S T or A L T la b val ue t hat is greater t ha n or e q ual t o 3 X t he u p per li mit of 
n or mal a n d a n el e vate d t otal bilir u bi n la b val ue t hat is greater t h a n or e q u al t o 2 X t he u p per li mit 
of n or mal a n d, at t he s a me ti me, a n al kali ne p h os p hatase la b val u e t hat is less t ha n 2 X t he u p per 
li mit of n or mal, as deter mi ne d b y wa y of pr ot oc ol-s pecifie d la b orat or y testi n g or u nsc he d ule d 
la b orat or y testi n g. * 
* N ote:  T hese criteria are base d u p o n a v aila ble re g ulat or y g ui da nce d o c u me nts. T he p ur p ose of 
t he criteria is t o s pecif y a t hres h ol d of a b n or mal h e patic tests t hat ma y re q uire a n a d diti o nal 
e val uati o n f or a n u n derl yi n g eti ol o g y.  
7. 3. 3. 3  
Pr ot oc ol -S pecifi c E xce pti o ns t o Seri o us A d verse E ve nt Re p orti n g  
Efficac y e n d p oi nts as o utli ne d i n t his secti o n will n ot be re p orte d t o Merc k, u nless t here is 
e vi de nce s u g g esti n g a ca usal relati o ns hi p bet wee n t he dr u g a n d t he e v e nt. A n y s uc h e ve nt will be 
s u b mitte d t o t he S p o ns or wit hi n 2 4 h o urs a n d t o Merc k Gl o bal Safet y wit hi n 2 w or ki n g da ys 
eit her b y ele ctr o nic or pa per me dia.  
S pecificall y, t he s us pect e d/act ual e ve nts c o v ere d i n t his e xce pti o n i ncl u de a n y e ve nt t hat is 
disease pr o gressi o n of t h e ca n cer u n der st u d y.  
T he S p o ns or will m o nit or u n bli n de d a g gre g ate d efficac y e n d p oi nt e ve nts a n d safet y data t o 
e ns ure t he safet y of t he s u bjects i n t he trial. A n y s us pecte d e n d p oi nt w hic h u p o n re vie w is n ot 
pr o gressi o n of t he ca ncer u n der st u d y will be f or war de d t o Merc k Gl o ba l S afet y as a S A E wit hi n 
2 w or ki n g da ys of det er mi nati o n t hat t he e ve nt is n ot pr o gressi o n of t he ca ncer u n der st u d y  
H os pitalizati o n relate d t o c o n ve nie nce (e. g.,  tra ns p ortati o n iss ues, etc.) will n ot be c o nsi dere d a 
S A E.  
 E v al u ati n g A d verse E ve nts  
A n i n vesti gat or w h o is a q ualifie d p h ysicia n will e val uate all a d verse e v e nts acc or di n g t o t he 
N CI C o m m o n Ter mi n ol o g y f or A d verse E ve nts ( C T C A E), versi o n 4. 0. A n y a d verse e ve nt w hic h 
c ha n ges C T C A E gra de o ver t he c o urse of a gi ve n e pis o de will ha ve eac h c ha n ge of gra de 
rec or de d o n t he a d v erse e ve nt case re p ort f or ms/ w or ks heets. 
All a d verse e ve nts re g ar dless of C T C A E gra de m ust als o be e val uate d f or s eri o us ness.  

I L-2 / Pe m br oliz u m a b  
 
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2  
Merc k O T S P # 5 5 5 7 1  
 
Versi o n  0 6 /1 1 /2 0 2 4  
U C D a vis C o m pre he nsi ve C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a ge 6 4  of 9 2  
 S p o ns or Res p o nsi bilit y f or Re p orti n g A d verse E ve nts  
All A d verse E v e nts will be re p ort e d t o re g ulat or y a ut h orities, I R B/I E Cs a n d i n vesti gat ors i n 
acc or da nce wit h all a p plica ble gl o bal la ws a n d re g ulati o ns.  
7. 3. 5. 1  
S afet y Re p orti n g Re q uire me nts f or I N D E xe m pt St u dies  
F or I n v esti gat or S p o ns ore d I N D E x e m pt St u dies t here are s o me re p orti n g re q uire me nts f or t h e 
F D A i n a cc or da nce wit h t he g ui da nce set f ort h i n 2 1 C F R 3 1 4. 8 0.  
7. 3. 5. 2  
Re p orti n g t o t he I R B  
B ot h seri o us a n d n o n -seri o us a d verse e ve nts will be re p ort e d i n acc or da n ce wit h U C D I R B 
A d mi nistrati o n a n d U C D C o m pre he nsi ve Ca ncer Ce nter’s Office of Cli nical Researc h ( O C R) 
p olicies.  T he U C Da vis I R B ca n be reac he d at ( 9 1 6) 7 0 3 -9 1 5 1.  
Partici pati n g site(s) will re p ort a d verse e v e nts per i nstit uti o n’s I R B g ui deli nes.   
 

I L-2 / Pe m br oliz u m a b  
 
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2  
Merc k O T S P # 5 5 5 7 1  
 
Versi o n  0 6 /1 1 /2 0 2 4  
U C D a vis C o m pre he nsi ve C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a ge 6 5  of 9 2  
8. 0  
C O R R E L A TI V E S CI E N C E  ( Tr a nsl ati o n al Rese arc h)  
 
R ati o n ale  
O ne of t he maj or s h ortc o mi n gs of i m m u n ot hera p y trials has bee n t he lac k of i n-de pt h  c orrelati ve 
st u dies t o hel p i de ntif y t he mec ha nis m of acti o n a n d resista nce, i de ntif y bi o mar kers of res p o nse, 
a n d pr o vi de a f o u n dati o n f or f urt her i m pr o vi n g t hese a p pr oac h es.  T o a d dress t his, we pla n t o 
perf or m i n de pt h i m m u n ol o gical a nal ysis of ma n dat or y serial patie nt bl o o d a n d t u m or sa m ples.  
T u m or bi o psies will be o btai ne d pre -tr eat me nt a n d d uri n g  t he fi nal i ntralesi o nal nee dle 
place me nt f or I L -2 d eli ver y . Bl o o d sa m ples w ill be o btai ne d pre-treat me nt, after t he fi n al d ose 
o n i ntralesi o nal I L -2 a n d at t he first res p o nse assess me nt ti me p oi nt  at 6 wee ks . We will e val u ate 
i m m u n ol o gic c ha n ges s yste micall y a n d i n t he t u m or micr oe n vir o n me nt wit hi n patie nt’s pre t o 
p ost t hera p y a n d acr oss t he c o h ort of p atie nts t o i de ntif y pre dicti ve bi o mar kers a n d el u ci date t he 
mec ha nistic i m m u n ol o gic effects of t hera p y a n d t hera p y resista nce. We will e xa mi ne p utati ve 
bi o mar kers of res p o nse t o c hec k p oi nt i m m u n ot hera p y s uc h as P D -L 1 e x pressi o n, m u tati o nal 
l oa d, a n d TI Ls.  
 Tr a nsl ati o n al Rese arc h H y p ot hesis  
T hese st u dies will als o e val uate o ur t w o mec ha nistic h y p ot heses: 1) We h y p ot hesize t hat t he 
tri ple c o m bi nati o n of ra di ot hera p y + i ntral esi o nal I L-2 + a n d pe m br oliz u m a b will c o n vert 
patie nts wit h pri mar y or sec o n dar y resista nce t o P D -1/ P D -L 1 bl oc ka d e i nt o res p o n ders b y 
i n d uci n g a n a nti-t u m or i m m u ne res p o nse a n d o v erc o mi n g t he lac k of a pre-e xiste nt a nti -t u m or 
i m m u ne res p o nse (e. g., d ue t o a p o orl y i m m u n o ge nic t u m or or T -cell e xcl usi o n fr o m t he t u m or).  
2) We h y p ot hesize t hat t he e xiste nce of ot her d o mi na n t m o des of i m m u ne s u p pressi o n will li mit 
res p o nse t o t hera p y. We will e xa mi ne h y p ot hesis 1 b y e val uati n g TI Ls, T cell acti vati o n, T C R 
di versit y, a n d c yt o ki nes /c he m o ki nes i ncl u di n g C C L 4. We will e xa mi ne h y p ot hesis 2 b y 
e val uati n g i m m u n os u p pressi ve cell s u bsets, i m m u n os u p pressi ve m olec ules, a n d e nz y mes. 
C orrelati ve st u dies will i ncl u de (i n or der of pri orit y):  
 T r a nsl ati o n al Rese arc h O bjecti ves  
Bl o o d  
•  F A C S f or q ua ntificati o n, i m m u n o p he n ot y pi n g, a n d f u ncti o nal assess me nt of P B M Cs a n d 
i m m u n os u p pressi ve cell s u bsets 
•  q P C R ( q ua ntitati ve p ol y merase c hai n reacti o n) e val uati o n of  i m m u ne ge n e si g nat ures 
i ncl u di n g: c yt o ki nes, T-cell acti vati o n mar kers, i m m u n os u p pressi ve e nz y m es a n d 
m olec ules (I D O [i n d olea mi ne -p yrr ole 2, 3 -di o x y g e nase], ar gi nas e, C T L A -4, P D -1/ P D -L 1, 
Ti m -3, L A G 3), macr o p ha ge p olarizati o n, etc.  
•   L u mi ne x e val uati o n of plas ma f or s yste mic c yt o ki ne / c he m o ki ne si g nat ures  
•  T -cell rece pt or ( T C R) dee p se q ue nci n g t o det er mi ne cl o nal e x p a nsi o n of T -cells i n t he 
s yste mic circ ulati o n  

I L-2 / Pe m br oliz u m a b  
 
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2  
Merc k O T S P # 5 5 5 7 1  
 
Versi o n  0 6 /1 1 /2 0 2 4  
U C D a vis C o m pre he nsi ve C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a ge 6 6  of 9 2  
•  W h ole e x o me se q u e nci n g of baseli ne P B M Cs as a n or mal tiss ue c o ntr ol f or t u m or w h ole 
e x o me se q ue n ci n g   
•  Ot her st u dies as dee me d feasi ble a n d i nf or mati ve b y t he pri nci pal i n vesti gat ors  
Tiss ue   
•  M ulti -ple xe d I H C / I F t o deter mi ne t he e x pressi o n of P D-1, P D -L 1, C D 8, C D 4, C D 3,  
I D O, F O X P 3, C D 6 8 a n d ot hers. A ut o mate d i nteracti o n a nal ysis t o deter mi ne e x pressi o n 
patter ns a n d cell -cell i nteracti o ns i n t he T M E.  
•  q P C R e val uati o n of  t he t u m or micr oe n vir o n me nt ge ne si g nat ures i ncl u di n g: c yt o ki nes, T-
cell acti vati o n mar k ers, i m m u n os u p pressi ve e nz y mes a n d m olec ules (I D O, ar gi nase, 
C T L A 4, P D -1/ P D -L 1), macr o p ha g e p olarizati o n, etc. q P C R ma y als o be use d i n a 
directe d ma n n er t o c o nfir m res ults of R N Ase q.  
•  T -cell rece pt or ( T C R) dee p se q ue nci n g t o det er mi ne cl o nal e x p a nsi o n of T -cells i n t he 
T M E.  
•  W h ole e x o me se q u e nci n g of baseli ne t u m or sa m ples t o deter mi ne m utati o nal l oa d.  
•  R N Ase q t o e xa mi ne c h a n ges i n ge ne e x pressi o n pr ofiles pre - a n d p ost -treat me nt. 
R N Ase q will als o be use d t o c o nfir m e x pressi o n of p utati ve t u m or m utati o ns i de ntifie d 
b y w h ole e x o me se q u e nci n g.  
•  Ot her st u dies as dee me d feasi ble a n d i nf or mati ve b y t he pri nci pal i n vesti gat ors  
 
St u d y Desi g n a n d Met h o d ol o g y  
Details of c orrelati ve st u d y sa m ple c ollecti o n, pre parati o n, a n d st ora g e are o utli ne d i n  

I L-2 / Pe m br oliz u m a b  
 
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2  
Merc k O T S P # 5 5 5 7 1  
 
Versi o n  0 6 /1 1 /2 0 2 4  
U C D a vis C o m pre he nsi ve C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a ge 6 7  of 9 2  
A p pe n di x 3 . F or tra nslati o nal st u dies t u m or tiss ue will be o btai ne d pre - a n d p ost - treat me nt a n d 
peri p heral bl o o d will be o btai ne d pre -tr eat me nt a n d at t w o ti me p oi nts p ost-treat me nt fr o m eac h 
patie nt. T h us , a t otal ma xi m u m of 9 2 fres h t u m or bi o psies a n d 1 3 8 bl o o d sa m ples will be 
o btai ne d f or t his st u d y. We ha v e e xte nsi ve e x pertise i n all of t he tec h ni q ues descri be d at t he U C 
Da vis La b orat or y of T u m or I m m u n ol o g y  a n d i m m u ne m o nit ori n g c ore .  
 F A C S a n al ysis of P B M Cs  
T o e xa mi ne treat me nt i n d uce d c h a n ges i n t he q ua ntit y  a n d p he n ot y pe of circ ulati n g i m m u ne 
cells P B M Cs will be a nal yze d b y fl o w c yt o metr y pre -treat me nt a n d at t w o ti me p oi nts p ost-
treat me nt. Bl o o d sa m ples will be se parat e d i nt o P B M Cs a n d plas ma a n d st ore d at -8 0 f or batc he d 
a nal ysis.  P B M Cs will be stai ne d f or F A C S a nal ysis usi n g well c haracterize d a nti b o dies a gai nst 
mar kers i ncl u di n g C D 4 5 R A , C D 3, C D 4, C D 8, C D 6 2 L, F O X P 3,  C D 2 5, I C O S, C D 1 2 7, P D 1, 
P D L 1, Ti m -3, L A G 3, C D 5 6, C D 1 4, C D 1 5, C D 1 6, C D 1c, C D 1 1 b, C D 3 0 3, a n d  C D 8 3. Cell ular 
f u ncti o n will be assesse d b y stai ni n g f or i ntracell ul ar c yt o ki nes a n d pr oliferati o n usi n g a nti b o dies 
a gai nst  Gra n z y me B, I nterfer o n ga m ma, t u m or necr osis fact or ( T N F) al p ha,  a n d Ki-6 7.  Res ults 
will be a nal yze d usi n g a B D F ortessa m ulti -c ol or fl o w c yt o meter a n d Fl o wj o s oft ware.   
 Pl as m a  c yt o ki ne / c he m o ki ne si g n at ures  
T o e xa mi ne treat me nt i n d uce d c h a n ges i n s yste mic c yt o ki nes / c he m o ki nes plas ma pr otei ns will 
be e xa mi ne d pre -tr eat me nt a n d at t w o ti me p oi nts p ost-treat me nt. Mar kers s uc h as I L -2, I L -6, I L -
1 0, I L -1 2 p 7 0, G M -C S F ( gra n ul oc yte -m acr o p ha ge c ol o n y -sti m ulati n g fact or), T N F al p ha, I F N 
(i nterfer o n) ga m ma, C X C L 1 0 ( C-X -C m otif c he m o ki ne 1 0), R A N T E S (re g ulate d o n acti vati o n, 
n or mal T cell e x presse d a n d secrete d), MI P 1 ( Macr o p ha ge I nfla m mat or y Pr otei n) al p ha, MI P 1 
beta a n d ot hers will be e val uate d usi n g t he Bi o -Ra d h u ma n 2 7 -ple x pa n el a n d T G F -beta will be 
e valuate d usi n g t he Bi o -Ra d T G F -b eta 3 -ple x pa nel.  T hese m ulti -ple xe d s us pe nsi o n arra ys will 
be a nal yz e d usi n g a Bi o -Ple x 2 0 0 s yste m a n d Bi o -Ple x Ma na ger s oft ware.  
 T C Rse q  
T o e xa mi ne treat me nt i n d uce d c h a n ges i n T -cell di versit y a n d cl o nal e x p a nsi o n a n d t o 
u n dersta n d h o w T -cell cl o nes i n t he T M E relate t o circ ulati n g  T -cells T C Rse q will be perf or me d 
o n P B M Cs a n d t u m or tiss ue pre - a n d p ost -treat me nt. F or T C R dee p se q u e n ci n g t otal R N A will 
be re verse tr a nscri be d usi n g S M A R T Scri be re verse tra nscri ptas e ( Cl o ntec h ), a ge ne s p ecific 
oli g o n ucle oti de, a n d a te m plate s witc hi n g oli g o t o f or m a u ni versal 5 ’-a d a pter. T his all o ws us t o 
a m plif y t he e ntire di versit y of T C R -beta varia bl e c ha i ns usi n g j ust a pair of pri mers, s pecific t o 
t he te m plate s witc h oli g os  o n t he 5 ’-e n d a n d t o t he c o nsta nt ge ne se g m e nts o n t he 3 ’-e n d. 
S u bse q ue nt li brar y a m plificati o n is d o ne usi n g Netera X T i n de x kit. Se q ue nci n g is perf or me d o n 
t he Ill u mi na Mi Se q a n d Hi Se q platf or ms. C D R 3 se q ue nces are e xtracte d fr o m ra w se q u e nce data 
a n d eac h se q ue n ce rea d is referre d t o a partic ular V a n d J fa mil y e m pl o yi n g B L A S T al g orit h m. 
After cl usteri n g i n di vi d ual cl o nes (se q u e nce rea ds wit h i de ntical V, J a n d C D R 3), virt ual C D R 3 
le n gt h s pectrat y pi n g f or eac h of t h e V a n d J g e ne fa milies is dis pla ye d base d o n t he relati ve 
a m o u nt of eac h cl o nal se q ue nce w hi c h c orres p o n ds t o t he act ual a b u n da n ce of t he T cell cl o n e.  

I L-2 / Pe m br oliz u m a b  
 
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2  
Merc k O T S P # 5 5 5 7 1  
 
Versi o n  0 6 /1 1 /2 0 2 4  
U C D a vis C o m pre he nsi ve C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a ge 6 8  of 9 2  
 q P C R  
E x pressi o n le vels of i m m u ne ge nes of i nterest will be assa ye d pre -a n d p ost -treat me nt wit hi n 
P B M Cs a n d t u m or tiss ue. q P C R will als o be use d t o c o nfir m fi n di n gs of i nterest fr o m R N As e q. 
q P C R will be perf or me d usi n g t he Ste p O ne Pl us real ti me P C R s yste m ( Life tec h n ol o gies) wit h 
pri mers of i nterest t o e x a mi ne i m m u ne ge ne si g nat ures of c he m o ki nes, c yt o ki nes, c hec k p oi nt 
m olec ules, a n d ot hers.  We will e xa mi ne  ge n es i ncl u di n g , C C L 4, T y pe I I F Ns, T-cell mar k ers,  
I D O, ar gi n ase, i N O S (i n d uci ble Nitric o xi de s y nt hases), C T L A -4, P D -1, P D -L 1 a n d ot hers . 
 M ulti -ple x I H C/I F  
I m m u ne mar kers a n d TI L S will be a nal yze d i n t u m or tiss ue pre- a n d p ost - treat me nt. A secti o n 
of tiss ue will be f or mali n fi xe d a n d paraffi n e m be d de d f or m ulti ple x I H C or I F stai ni n g a n d 
a ut o mate d a nal ysis i n c olla b orati o n wit h Dr. K urt Sc hal per, direct or of t he Yale tra nslati o nal 
i m m u n o-o nc ol o g y la b o rat or y as pre vi o usl y descri be d [6 0 , 6 1 ]. We will stai n f or mar kers 
i ncl u di n g c yt o kerati n, C D 3, C D 4, C D 8, C D 2 0, F o x P 3, I D O, P D 1, P D-L 1, Ki 6 7, Gra nz y m e B, 
I F N a n d ot hers.  
 W h ole e x o me se q ue nci n g  
Ge n o mic D N A will be e xtracte d fr o m baseli ne P B M C a n d t u m or tiss ue sa m ples t o deter mi ne t he 
m utati o nal l oa d of t u m or tiss ues. W h ole e x o me se q ue nci n g will be perf or m e d at t he U C Da vis 
ge n o mics c ore. E x o m e ca pt ure, se q u e nci n g a n d varia nt calli n g: Fr oze n matc he d t u m or a n d 
n or mal tiss ue sa m ples will be use d t o e xtract at least 2 µ g of hi g h q ualit y i n p ut g D N A. A 
fl u or o metric-b ase d a p pr oac h will be use d f or acc urate D N A q ua ntificati o n. D N A q ualit y will be 
assesse d a n d m ust ha v e a 2 6 0/ 2 8 0 n m a bs or ba nce rati o of 1. 8 -2.  E xtracte d D N A will be 
fra g me nte d usi n g a C o v aris S 2 S yste m i n a 1 3 0 μl v ol u me (ai m: 4 0 0  b p fra g me nts, setti n gs: d ut y 
c ycle: 1 0 %, i nte nsit y: 4, c ycles per b urst: 2 0 0, ti me: 5 5s). Size selecti o n, e nric h me nt P C R a n d 
li brar y pre p arati o n will b e perf or me d f ollo wi n g m a n ufact urers pr ot o c ols. Se q ue nci n g of 
barc o de d li braries of 1 5 0 b p paire d e n ds will be perf or me d o n a Hi Se q 4 0 0 0 platf or m i n t he U C -
Da vis se q ue nci n g facilit y t o a n a vera ge c o v era ge of 1 0 0 X. A bi oi nf or matic pi peli ne will be 
i m ple me nte d t o i de ntif y p utati ve n o n -s y n o n y m o us pr otei n c o di n g varia nts. T he pr ocess starts b y 
pre -pr ocessi n g se q ue n ci n g rea ds t o re m o v e se q ue n ci n g a da pt ors a n d l o w q u alit y se q ue nces usi n g 
Tri m m o matic s oft ware p ac ka g e ( V 0. 3 6) [6 2 ]. L o n g rea ds ( > 3 6 b p) will be ke pt a n d or p ha ns 
fr o m eit her paire d e n ds will be p o ole d i n a si n gle file. Hi g h q ualit y rea ds will t he n be ali g ne d t o 
t he h u ma n refere n ce g e n o me. D u plicate rea ds are e xcl u de d usi n g t he Mar k D u plicates  m o d ule of 
t he Picar d s oft ware ( v 2. 2. 4)[2 0 ]. G A T K s oft ware pac ka g e all o ws a d diti o nal ste ps of rea d 
reali g n me nt t o mi ni mize ma p pi n g artifacts ar o u n d i n dels f oll o we d b y base q ualit y recali brati o n 
t o a dj ust f or p ossi ble s yste matic tec h nical err ors of se q ue nci n g q ualit y sc ori n g[6 3 ]. Varia nt 
calli n g will be d o ne usi n g f o ur i n de pe n d e nt varia nt callers; G A T K Ha pl ot y pe Caller ( v 3. 5) [6 3 ], 
Free Ba yes ( v 1. 2) [6 4 ], S A Mt o ols m pile u p [6 5 ], a n d Var Sca n [6 6 ]. Differe nt callers a p pl y 
differe nt al g orit h ms f or v aria nt detecti o n e. g., ba y esia n statistics a n d l ocal de n o v o reass e m bl y. 
A n e nse m ble mac hi n e le ar ni n g pi peli ne will be us e d t o i nc or p orat e res ults fr o m m ulti ple m o dels 
[6 7 ]. Varia nts will be a n n otate d usi n g t he Varia nt A n n otati o n I nte grat or t o ol of U C S C ge n o me 
br o wser [2 4 ]. P utati ve ne o -a nti ge ns will be cat al o ge d b y deter mi ni n g t he n o n -s y n o n y m o us 
m utati o ns prese nt i n t he t u m or tiss ue b ut a bse nt fr o m t he p aire d P B M Cs  a n d t heir prese n ce i n 

I L-2 / Pe m br oliz u m a b  
 
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2  
Merc k O T S P # 5 5 5 7 1  
 
Versi o n  0 6 /1 1 /2 0 2 4  
U C D a vis C o m pre he nsi ve C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a ge 6 9  of 9 2  
pre dicte d pr ot ei n c o di n g se q ue nce.  A d diti o nall y, i n dels, c o p y n u m ber variati o ns a n d str uct ural 
rearra n ge m e nts will be catal o ge d.  
 R N A se q ue nci n g  
T u m or tiss ue pre - a n d p ost -treat me nt will u n der g o ge ne e x pressi o n a nal ysis usi n g ne xt 
ge nerati o n se q u e nci n g. R N A -se q a n al ysis: m R N A, li braries will be pre p are d usi n g t he Tr u Se q 
Stra n de d m R N A Sa m ple Pre p Kit (Ill u mi na).  I n brief, p ol y A c o ntai ni n g m R N A m olec ules will 
be p urifie d fr o m 2 u g of t otal R N A ( RI N > 7) fr o m t he fr oze n sa m ples usi n g  p ol y -T oli g os 
attac he d t o ma g netic b ea ds. m R N A will t he n be fra g me nte d t o ~ 3 0 0 b p d uri n g t he p ol y A el uti o n 
ste p. First stra n d c D N A will be s y nt hesize d usi n g S u per Scri pt II re verse tr a nscri ptase 
(I n vitr o ge n) a n d ra n d o m pri mers. After sec o n d stra n d s y nt hesis, c D N A will u n der g o 3’e n d 
a de n ylati o n f oll o we d b y li gati o n of t he i n de xi n g a da pters. A da pt er -li gate d D N A will be e nri c he d 
usi n g 1 5 c ycl es of P C R. All p urificati o n a n d size selecti o n ste ps will be perf or me d usi n g 
A M P ure X P S P RI bea ds ( Bec k ma n C o ulter Ge n o mics). Li braries will be v ali date d usi n g t he 
Bi oa nal yzer Hi g h Se nsiti vit y D N A Kit ( A gile nt Tec h n ol o gies) a n d  q u a ntifie d o n t he Ec o Real -
Ti me P C R I nstr u me nt (Ill u mi na) usi n g K A P A Ill u mi na Li brar y Q ua ntifi cati o n Kits ( K A P A 
Bi oscie nces) acc or di n g t o t he sta n dar d ma n ufact urer’s pr ot oc ols. Paire d -e n d cl uster ge nerati o n 
a n d se q ue nci n g of 2 x 1 0 1 c ycles will be perf or me d f or all li braries o n t he I ll u mi na Hi-Se q 2 0 0 0 
platf or m. S h ort rea d se q u e nces will be o ut p ut i n F A S T Q f or mat wit h c orres p o n di n g base q ualit y 
sc ores. T he ra w d ata will be i nitiall y filtere d f or rea ds c o ntai ni n g a m bi g u o us base calls, w hic h 
di d n ot meet t he Ill u mi na c hastit y filter base d o n q ualit y meas ures. Q ualit y c o ntr ol of t he 
re mai ni n g se q ue n ces fr o m eac h se q u e nce d li brar y will be assesse d usi n g FastQ C t o c hec k f or 
a da pters, a n d distri b uti o n of base q ualit y. T he rea ds will t he n be filtere d f or l o w q ualit y rea ds, 
c o nta mi nati n g 5’ a d a pters, a n d tri m me d f or 3’ a d a pters. T he pre -pr ocesse d rea ds will be ali g ne d 
usi n g B W A [6 8 ] t o t he h g 1 9 h u ma n refere n ce ge n o me C uffli n ks [6 9 ], t he n will be use d f or 
e x pressi o n esti mati o n wit h b ot h bias c orrecti o n a n d m ulti -rea d c orrecti o n p ara meters e na bl e d. 
Fi nal Q C metrics are c oll ecte d wit h Picar d’s C ollect R na Se q Metrics 
(htt p:// br oa di nstit ute. git h u b.i o/ picar d ), R Se Q C [7 0 ], a n d i nter nall y de v el o pe d scri pts. R N A-se q 
data will be a nal y ze d f or s o matic varia nt c o nfir mati o n a n d f or e x pressi o n of s o maticall y altere d 
tra nscri pts. A d diti o nall y , c ha n ges i n ge n e e x pressi o n pr ofiles pre- a n d p ost - treat me nt will be 
c haracteri ze d.  
 
Res p o nsi bilities f or Tr a nsl ati o n al Rese arc h  
All tra nslati o nal researc h st u dies descri be d a b o v e will be perf or me d b y t h e i n vesti gat or at t he U C 
Da vis La b orat or y of ca ncer I m m u n ol o g y a n d H u m a n I m m u ne M o nit ori n g C ore or i n c o nj u ncti o n 
wit h c olla b orati n g i ntra m ural or e xtr a m ural la b orat ories. Dr. Dal y a n d Dr. M o njaze b will o versee 
all of t he st u dies, data a n al ysis, a n d data i nter pretati o n. Statistical A nal ysis will be perf or me d b y 
Dr. S usa n L. Ste wart.  
Merc k will be res p o nsi ble f or f u n di n g t he researc h as o utli ne d i n t he researc h b u d get a n d 
c o ntract. Merc k will als o be res p o nsi ble f or P D -L 1 stai ni n g, o utsi de of t he m ulti ple xe d assa y 
descri be d a b o ve, usi n g t he I H C 2 2 C 3 p har m D x assa y.   
 
 

I L-2 / Pe m br oliz u m a b  
 
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2  
Merc k O T S P # 5 5 5 7 1  
 
Versi o n  0 6 /1 1 /2 0 2 4  
U C D a vis C o m pre he nsi ve C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a ge 7 0  of 9 2  
 
All St u d y V ari a bles  
T he pa nel of st u d y e n d p oi nts a n d h o w t he y will be meas ure d are d escri be d i n t he bel o w ta ble . 
T a ble 1 4 . St u d y V ari a bles a n d Me as ure me nts 
E n d p oi nt  
V ari a ble  
Me as ure me nt  
C o m me nt  
Pri mar y - P hase 1  
A R R  
ir R E CI S T 
O bjecti ve res p o nse at u nirra diate d sites, t he 
e n d p oi nt f or meas uri n g res p o nses f or t he 
S i m o n t w o-sta ge p hase 2 st u d y 
Pri mar y - P hase 1  
O R R  
R E CI S T a n d ir R E CI S T  
 
Pri mar y - P hase 1  
D C R  
R E CI S T a n d ir R E CI S T  
 
Pri mar y –  P hase 1  
P F S  
R E CI S T a n d ir R E CI S T  
 
Sec o n dar y - P hase 1  
M T D  
C T C A E V 4. 0 3  
T h e ma xi m u m d ose at w hic h < 2 of 6 patie nts 
e x perie nce d a D L T  
Sec o n dar y - P hase 1  
D L T  
C T C A E V 4. 0 3  
O utli n e d i n secti o n 5. 4 . A D L T is defi n e d as 
>  gra de 4 i njecti o n site reacti o n O R >  gra de  3 
treat me nt relate d i m m u n ol o gic a d verse e ve nt 
(e xcl udi n g i njecti o n site reacti o ns) O R ot h er >  
gra de 3 treat me nt relate d a d verse e ve nts t hat 
d o n ot res ol v e t o <  gra de 2 wit hi n 1 4 da ys of 
o nset d uri n g t h e 3 0 da y D L T peri o d O R 
Gra de 3 diarr hea, A S T/ A L T > 3 x U L N wit h 
bilir u bi n > 2 X U L N, or p ne u m o nitis t hat 
re q uires h ol di n g treat me nt > 1 4 da ys.  
Sec o n dar y - P hase 2  
Safet y  
C T C A E V 4. 0 3  
 
Tra nslati o nal  
P B M C I m m u n o p he n ot y pe  F A C S  
Bl o o d  
Tra nslati o nal  
P B M C ge ne e x pressi o n  
q P C R  
Bl o o d  
Tra nslati o nal  
S yste mic C yt o ki ne 
Si g nat ure  
L u mi n e x  
Ser u m  
Tra nslati o nal  
Tiss ue I m m u ne Mar kers  
I H C / I F 
Tiss ue  
Tra nslati o nal  
T u m or ge ne e x pressi o n  
q P C R  
Tiss ue  
Tra nslati o nal  
M utati o nal l oa d  
W h ole e x o me se q ue nci n g / 
R N A se q ue nci n g  
Bl o o d a n d Tiss ue  
Tra nslati o nal  
T cell rece pt or di v ersit y  
T C R dee p se q ue nci n g 
Bl o o d a n d Tiss ue  
 
 
 

I L-2 / Pe m br oliz u m a b  
 
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2  
Merc k O T S P # 5 5 5 7 1  
 
Versi o n  0 6 /1 1 /2 0 2 4  
U C D a vis C o m pre he nsi ve C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a ge 7 1  of 9 2  
9. 0  
D A T A A N D S T A TI S TI C A L A N A L Y SI S P L A N  
 
S a m ple Size  
T his is a p hase I/II st u d y t hat will e nr oll patie nts wit h a n a d va nce d s oli d mali g na nc y, or 
l y m p h o ma t o deter mi ne if t his re gi me n c o n verts patie nts wit h resista nce t o P D -1/ P D -L 1 
bl oc ka de i nt o res p o n d ers as deter mi ne d b y a bsc o p al res p o nse rate ( d efi ne d as res p o nse rate at 
lesi o ns n ot treate d wit h R T + I L-2)  usi n g ir R E CI S T as well as O R R, D C R, a n d P F S usi n g 
R E CI S T 1. 1.  
T he p hase I d ose es calati o n will e m pl o y a sta n dar d 3 + 3 desi g n wit h a g oal of deter mi ni n g t he 
M T D t hr o u g h D L T asse ss me nt. Wit h t hree d ose escalati o n le vels t his ar m will recr uit u p t o 1 8 
patie nts.  
T he P hase II d os e e x p a nsi o n will e m pl o y a bi n o mial o ne sta ge  desi g n w hi c h will all o w us t o 
e val uate if t his t hera p y ca n c o n vert t h ose resista nt t o P D -1/ P D -L 1 bl oc ka d e i nt o res p o n ders  
Res p o nse will be assesse d acc or di n g t o R E CI S T a n d will be e val uate d at t he n o n -treat me nt 
lesi o ns (a bsc o pal r es p o ns e). I n or der t o mi ni mize t he re q uir e d patie nt n u m b ers,  t he 3  patie nts 
e nr olle d at t he M T D will be i ncl u de d i n t he p hase II efficac y e val u ati o n.  We ha ve c h ose n a 
t hres h ol d of 5 % res p o nse as n ot w ort h y of f urt h er e val uati o n ( p 0) a n d a t hr es h ol d of 2 0 % as 
w ort h y of f urt her e v al uati o n i n a lar ger trial ( p 1).   T he trial will e nr oll a t otal of 2 1  patie nt s 
i ncl u di n g t he t hree patie nts treate d at t he M T D i n t he p hase I ( nt ot) a n d m ust ha ve greater t ha n  3 
res p o n ders (rt ot) f or t his re gi me n t o be dee me d w ort h y of f urt her e val uati o n. T his desi g n 
pr o vi des a t y pe I err or rat e of 0. 1  a n d p o wer of 0. 8 2 . T his trial desi g n will e nr oll a t otal 
ma xi m u m of 2 5  e val ua bl e patie nts   
 
St atistic al A n al ysis Pl a n  
Descri pti ve statistics will be use d. All data will be s u m marize d b y d ose c o h ort, d ose e x pa nsi o n 
a n d o verall s u bject p o p ulati o n.  
 
S afet y  
T he a d verse e v e nts o bser ve d will be s u m marize d as fre q u e nc y, pr o p orti o n of patie nts, a n d e x act 
9 5 % c o nfi de n ce i nter val f or pr o p orti o n, cate g orize d b y t y pe ( or ga n affect e d or la b orat or y 
deter mi nati o n), se verit y b y C T C A E v 4 . 0 3 a n d na dir or ma xi m u m val ues f or t he la b orat or y 
meas ures), ti me of o ns et ( i.e., c o urse n u m ber), d urati o n, a n d re versi bilit y or o utc o me. Ta bles will 
be create d t o s u m mariz e t hese t o xicities b y d ose a n d c o urse.  T h e sec o n d ar y e n d p oi nt is safet y 
a n d t o xicit y. A treat me nt li miti n g t o xicit y (T L T) will be defi ne d as a treat me nt relate d gra de 3 -4 
n o n -he mat ol o gic t o xicit y a n d will re q uire d ose d e -escalati o n. If a  T L T d oes n ot res ol ve wit hi n 5 
da ys, is n ot res p o nsi ve t o ma na ge me nt, or o cc urs at t he l o west d ose le vel ( 1 milli o n I U I L -2) 
after de-es calati o n t he n t hat patie nt will be re m o v e d fr o m trial a n d t he t h era p y will be dee me d 
i nt olera ble. T hera p y will be dee me d s afe a n d t olera ble if n o greater t ha n 3 3 % of patie nts fi n d t he 
treat me nt i nt olera ble. 

I L-2 / Pe m br oliz u m a b  
 
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2  
Merc k O T S P # 5 5 5 7 1  
 
Versi o n  0 6 /1 1 /2 0 2 4  
U C D a vis C o m pre he nsi ve C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a ge 7 2  of 9 2  
 
Effic ac y  
As a n e x pl orat or y e n d p oi nt, all res p o nses will be re p orte d usi n g R E CI S T 1. 1 defi niti o ns [5 8 ]. 
Beca use of t h e p ote ntial heter o ge n eit y of t he patie nts, all res ults will be c o nsi dere d preli mi nar y 
a n d h y p ot hesis ge nerati n g f or f ut ure st u dies. Res p o nse rate a m o n g will be s u m marize d b y e x act 
bi n o mial c o nfi de nce i nter vals.  Disease free s ur vi v al will be s u m marize d wit h Ka pla n -Meier pl ots 
t o descri be t he o utc o m e of patie nts treate d o n t his pr ot oc ol. T he me dia n D F S ti me will be 
esti mate d usi n g sta n dar d life ta ble met h o ds.  
 
S u bject  C o urse  
I nf or mati o n re g ar di n g t h e s u bject’s c o urse s uc h as c o m pleti n g t he st u d y treat me nt, d ose dela ys, 
pre mat ure disc o nti n uati o n a n d maj or pr ot oc ol vi ol ati o n will be ca pt ure d i n electr o nic C R Fs . 
 
C orrel ati v e L a b or at or y M ar kers  
C orrelati ve bi o mar k er e n d p oi nts are e x pl orat or y a n d h y p ot hesis ge nerati n g.  Descri pti ve statistics 
will be a p plie d t o c haract erize differe nces wit hi n a gi ve n patie nt pre -tr eat m e nt t o p ost-treat me nt 
a n d acr oss t he c o h ort of patie nts. C ha n ges i n t he c orrel ati ve e n d p oi nts will be e val uat e d usi n g a 
t w o-taile d paire d st u de nt’s T-test. T o pr o vi de a preli mi nar y esti mate of t he pre dicti ve or 
pr o g n ostic val ue of t he v ari o us c orrelati ve e n d p oi nts f or D F S we will be usi n g m ulti ple 
re gressi o n a n al ysis wit h or di nal cate gor y f or res p o nse ( ge neralize d li near m o dels) or ti me t o 
e ve nt ( pr o p orti o nal h azar ds s ur vi val a nal ysis) as t he o utc o me.  W e will c o m p ute descri pti ve 
statistics ( mea n, sta n dar d de viati o n, me dia n, mi ni m u m, a n d ma xi m u m) f or m utati o nal l oa d a n d 
t he i m m u ne-relate d v aria bles (e. g., TI Ls, Tre gs, C D 8/ Tre g rati o, P D L -1, I D O, C T L A -4, P D -1, 
a n d i m m u ne ge ne si g nat ures) b y t u m or t y pe a n d i n t he sa m ple as a w h ol e.  We will assess t he 
ass ociati o n bet wee n m utati o nal l oa d , eac h i m m u n e -rel ate d vari a ble, a n d cli nical o utc o mes b y  
c o m p uti n g Pears o n or S pear ma n c orrelati o n c oeffi cie nts wit h 9 5 % c o nfi de n ce i nter vals, as well 
as usi n g gra p hical met h o ds t o deter mi ne w het her t he ass ociati o ns are ge n erall y li near or w het her 
a n ot her f u ncti o nal f or m fits t he data better.  We will ha ve at least 8 0 % p o wer t o detect a m o derat e 
c orrel ati o n of 0. 4  at t he 0. 0 5 le vel ( 2 -si de d). We m a y  als o de vel o p m ulti ple re gressi o n m o dels t o 
f urt her e x pl ore t he relati o ns hi p bet wee n cli nical o utc o mes a n d c orrelati ve mar kers. 
 
 

I L-2 / Pe m br oliz u m a b  
 
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2  
Merc k O T S P # 5 5 5 7 1  
 
Versi o n  0 6 /1 1 /2 0 2 4  
U C D a vis C o m pre he nsi ve C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a ge 7 3  of 9 2  
1 0. 0  
L A B E LI N G, P A C K A GI N G, S T O R A G E , A N D R E T U R N O F C LI NI C A L 
S U P P LI E S  
 
I ntr alesi o n al I L-2  
 F or m ul ati o n, Pre p ar ati o n, P ac k a gi n g a n d H a n dli n g  
I ntr alesi o nal I L-2 (als o r eferre d t o as Pr ole u ki n ® or al desle u ki n) is  a sterile, w hite t o off -w hite, 
preser vati ve -free, l y o p hilize d p o w der.I L-2 vials s h o ul d be st ore d i n a refri g erat or at 2 -8 ° C, 
pr otecte d fr o m li g ht a n d st ore d i n cart o n. E ac h vial c o ntai ns 2 2 milli o n i nter na ti o nal u nits ( 1. 3 
m g). Rec o nstit ute eac h vi al wit h 1. 2 m L sterile water f or i njecti o n (s W FI). D o n ot s ha ke. D o n ot 
rec o nstit ute wit h 0. 9 % N a Cl or bacteri ostatic water f or i njecti o n. Res ulta nt c o nce ntr ati o n is 1 8 
milli o n i nter nati o nal u n its/ m L ( 1. 1 m g/ m L). I L-2 ma y be f urt her dil ute d i n D 5 W f or fi nal 
c o nce ntr ati o n of 3 0 -7 0 m c g/ m L.  A v oi d bacteri ostatic water f or i njecti o n a n d N S f or 
rec o nstit uti o n or dil uti o n. 
 A d mi nistr ati o n  
T he fi nal dil ute d d ose will be deli vere d t o t he treat me nt lesi o n t hr o u g h i ntralesi o nal nee dle 
place me nt. N ee dle place me nt will be perf or me d b y pal pati o n or usi n g ultras o u n d or c o m p ute d 
t o m o gra p h y g ui da nce as i n dicate d. 4 i ntralesi o nal i njecti o ns will be a dmi nistere d o ver a 2 -w ee k  
peri o d wit h t w o treat me nts eac h wee k a n d i n di vi d ual treat me nts will be a mi ni m u m of 4 8 h o urs 
a part.  
 Dis p os al a n d Destr ucti o n  
Dr u g s u p pl y will eit her be dis p ose d of at t he st u d y site acc or di n g t o t he st u d y site’s i nstit uti o nal 
sta n dar d o perati n g pr oce d ure. Acc urat e rec or ds of all i n vesti gati o nal pr o d uct recei ve d at, 
dis pe nse d fr o m, r et ur ne d t o, a n d dis p ose d of b y t he st u d y site s h o ul d be rec or de d o n t he dr u g 
acc o u nta bilit y f or m. 
 S u p plier  
I ntr alesi o nal I L-2 will be s u p plie d b y t he st u d y .  
 
Pe m br oliz u m a b   
T he i n vesti gat or s hall ta k e res p o nsi bilit y f or a n d s hall ta ke all ste ps t o mai ntai n a p pr o priate 
rec or ds a n d e ns ur e a p pr o priate s u p pl y, st ora ge, h a n dli n g, distri b uti o n a n d usa ge of 
i n vesti gati o nal pr o d uct i n acc or da nce wit h t he pr ot oc ol a n d a n y a p plica ble l a ws a n d re g ulati o ns. 
Ta ble 1 5  
Pe m br ol iz uma b (als o referre d t o as Ke ytr u d a ® a n d M K -3 4 7 5 ) will be pr o vi de d b y Merc k as 
s u m marize d i n Ta ble 1 5 .  Ta ble 1 5  Pe m br oliz u ma b  will be a d mi nistere d usi n g a d ose of 2 0 0  m g  
Q 3 W.   
 

I L-2 / Pe m br oliz u m a b  
 
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2  
Merc k O T S P # 5 5 5 7 1  
 
Versi o n  0 6 /1 1 /2 0 2 4  
U C D a vis C o m pre he nsi ve C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a ge 7 4  of 9 2  
T a ble 1 5 . Pe m br oliz u m a b Dr u g  Inf or m ati o n  
 
Pr o d uct N a me & P ote nc y  
D os a ge F or m  
Pe m br oliz u ma b 1 0 0 m g/ 4 m L (si n gle use vial)  
S ol uti o n f or I njecti o n  
 
 P ac k a gi n g a n d L a beli n g I nf or m ati o n  
Cli nical s u p plies will be affi xe d wit h a cli nical la b el i n acc or da nce wit h re g ulat or y re q uire m e nts.  
F or c o m plete d etails o n dr u g pre parati o n, a d mi nistrati o n, st ora ge c o n diti o ns, cli nical 
p har mac ol o g y, p har mac o ki netics, a n d k n o w n preca uti o ns a n d a d verse reacti o ns please see t he 
pe m br oliz u ma b  I B a n d or t he pac k a ge i nsert.  
 Pre p ar ati o n a n d A d mi nistr ati o n  
T he s ol uti o n s h o ul d be vis uall y i ns pecte d f or partic ulate matter a n d disc ol orati o n pri or t o 
a d mi nistrati o n. Pe m br oliz u ma b  s ol uti o n is clear t o sli g htl y o palesce nt, c ol orless t o sli g htl y 
yell o w. Discar d t he vi al if visi ble particles are o bs er ve d. Wit h dra w t he re q uire d v ol u me of 
pe m br oliz u ma b   fr o m t he vial(s) of pe m br oliz u ma b a n d tra nsfer t o a n i ntra ve n o us (I V) b a g 
c o ntai ni n g 0. 9 % S o di u m C hl ori de I nje cti o n, U S P or 5 % De xtr os e I njecti o n, U S P. Mi x dil ute d 
s ol uti o n b y ge ntle i n versi o n. T he fi nal c o nce ntrati o n of t he dil ute d s ol uti o n s h o ul d be bet wee n 
1  m g/ m L t o 1 0 m g/ m L. Discar d u n use d p orti o n of t he vial.  
A d mi nister  pe m br oliz u ma b I V i nf usi o n o ver 3 0 mi n utes e ver y 3 wee ks  t hr o u g h a n i ntra ve n o us 
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 o n ot i nf use ot her me dicati o ns t hr o u g h t he sa me i nf usi o n li ne.   
 Cli nic al S u p plies Discl os ure  
T his trial is o pe n -la bel; t heref ore, t he s u bject, t he trial site pers o n nel, t he S p o ns or-I n vesti gat or 
a n d/ or desi g nee are n ot bli n de d t o treat me nt. Dr u g i de ntit y ( na me, stre n gt h) is i ncl u de d i n t he 
la bel te xt; ra n d o m c o de/ discl os ure e n vel o pes or lists are n ot pr o vi de d. 
 St or a ge a n d H a n dli n g Re q uire me nts  
Pe m br oliz u ma b vials m ust be st ore d i n t he refri gerat or at 2 o t o 8oC ( 3 6° F t o 4 6° F). 
Pe m br oliz u ma b i njecti o n s ol uti o n s h o ul d be st ore d i n ori gi nal cart o n t o pr otect fr o m li g ht; d o n ot 
freeze or s h a ke vials.  
T he pr o d uct d oes n ot c o ntai n a preser vati ve, P e m br oliz u ma b s h o ul d be use d i m me diatel y  after 
pre parati o n. Pe m br oliz u ma b  s ol uti o ns dil ute d f or i nf usi o n i n N S or D 5 W ma y be st ore d at r o o m 
te m perat ur e f or n o m or e t ha n 6 h o urs fr o m t he ti me of rec o nstit uti o n or dil uti o n. T his i ncl u des 
r o o m te m perat ur e st ora g e of t he rec o nstit ute d vials, st ora ge of t he i nf usi o n s ol uti o n i n t he I V 
ba g, a n d t he d urati o n of i nf usi o n. Alter na ti vel y, pe m br oliz u ma b i nf usi o n s ol uti o ns ma y be st ore d 
u n der refri gerati o n at 2 t o 8 oC ( 3 6 t o  4 6 oF) f or n o m ore t ha n 2 4 h o urs fr o m t he ti me 
rec o nstit uti o n or dil uti o n a n d pr otecte d fr o m li g ht. T he i nf usi o n s h o ul d n ot be fr oze n.  

I L-2 / Pe m br oliz u m a b  
 
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2  
Merc k O T S P # 5 5 5 7 1  
 
Versi o n  0 6 /1 1 /2 0 2 4  
U C D a vis C o m pre he nsi ve C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a ge 7 5  of 9 2  
Cli nical s u p plies m ust be st ore d i n a sec ure, li mite d -access l ocati o n u n der t he st ora ge c o n diti o ns 
s pecifie d o n t he la b el. Recei pt a n d dis pe nsi n g of trial me dicati o n m ust be rec or de d b y a n 
a ut h orize d pers o n at t he trial site.  Cli nical s u p plies ma y n ot be use d f or a n y p ur p ose ot her t ha n 
t hat state d i n t he pr ot oc ol. 
 Dr u g Dis p os al a n d Acc o u nt a bilit y  
T he i n vesti gat or  a n d t he assi g ne d p har macist or desi g nee are res p o nsi ble f or dr u g acc o u nta bilit y . 
Dr u g s u p pl y will be dis p ose d of acc or di n g t o i nstit uti o nal sta n dar d o perati n g pr oce d ures a n d 
p olicies. Acc urate rec or ds of all i n vesti gati o nal pr o d uct recei ve d at a n d dis pe nse d fr o m t he st u d y 
site s h o ul d be rec or de d o n t he dr u g acc o u nta bilit y rec or d.  
 
 S u p plier  
Pe m br oliz u ma b  will be s u p plie d b y t he st u d y.  
 
 
 

I L-2 / Pe m br oliz u m a b  
 
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2  
Merc k O T S P # 5 5 5 7 1  
 
Versi o n  0 6 /1 1 /2 0 2 4  
U C D a vis C o m pre he nsi ve C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a ge 7 6  of 9 2  
1 1. 0  
E T HI C A L C O N SI D E R A TI O N S A N D A D MI NI S T R A TI V E P R O C E D U R E S  
 
Et hics a n d G o o d Cli nic al Pr actice  
T his st u d y m ust be carrie d o ut i n c o m plia nce wit h t he pr ot oc ol a n d G o o d Cli nical Practice, as 
descri be d i n:  
1.  
Inter nati o nal C o u ncil f or Har m o nisati o n  (I C H) Har m o nize d Tri partite G ui deli nes f or 
G o o d Cli nical Practice 1 9 9 6.  
2.  
Directi ve 9 1/ 5 0 7/ E E C, T he R ules G o ver ni n g Me dici nal Pr o d ucts i n t he E ur o pea n 
C o m m u nit y.  
3.  
U S 2 1 C o de of Fe d eral R e g ulati o ns deali n g wit h cli nical st u dies (i ncl u di n g parts 5 0 
a n d 5 6 c o ncer ni n g i nf or me d c o nse nt a n d I R B re g ulati o ns).  
4.  
Declarati o n of Helsi n ki, c o ncer ni n g me di cal res earc h i n h u ma ns ( Rec o m m e n dati o ns 
G ui di n g P h ysicia ns i n Bi o me dical Researc h I n v ol vi n g H u ma n S u bjects, Helsi n ki 
1 9 6 4, a me n de d T o k y o 1 9 7 5, Ve nice 1 9 8 3, H o n g K o n g 1 9 8 9, S o merset West 1 9 9 6).  
 
T he i n vesti gat or a grees, w he n si g ni n g t he pr ot oc ol, t o a d here t o t he i nstr ucti o ns a n d pr oce d ures 
descri be d i n it a n d t here b y t o a d here t o t he pri nci ples of G o o d Cli nical Practice t hat it c o nf or ms t o.  
 
I nstit uti o n al Re vie w B o ar d 
T he pr ot oc ol, t he pr o p os e d i nf or me d c o ns e nt f or m, a n d all patie nt -faci n g d oc u me nts m ust be 
re vie we d a n d a p pr o ve d b y a pr o perl y c o nstit ute d I nstit uti o nal Re vie w B oar d bef ore a n y res earc h 
i n v ol vi n g h u ma n s u bjects has bee n c o n d u cte d. Pri or t o o btai ni n g I R B a ppr o val, t he pr ot oc ol 
m ust be a p pr o ve d b y t he U C Da vis C o m pre he nsi v e Ca ncer Ce nter Scie ntifi c Re vie w C o m mittee 
( S R C).  
 
I nf or me d C o nse nt 
T he i n vesti gat or m ust e x plai n t o eac h s u bject ( or l e gall y a ut h orize d re prese ntati ve) t he nat ure of 
t he st u d y, its p ur p ose, t he pr oce d ures i n v ol ve d, t he e x pecte d d urati o n, t he p ote ntial ris ks a n d 
be nefits i n v ol ve d a n d a n y disc o mf ort it ma y e ntail. Eac h s u bj ect m ust be i nf or me d t hat 
partici pati o n i n t he st u d y is v ol u ntar y a n d t hat he/s he ma y wit h dra w fr o m t he st u d y at a n y ti me 
a n d t hat wit h dra wal of c o nse nt will n ot affect his/ h er s u bse q ue nt me dical treat me nt or 
relati o ns hi p wit h t he treati n g p h ysicia n. 
T his i nf or me d c o nse nt s h o ul d be gi ve n b y mea ns of a sta n dar d writte n stat e me nt, writte n i n n o n -
tec h nical la n g ua g e. T he s u bject s h o ul d rea d a n d c o nsi der t he state me nt bef ore si g ni n g a n d dati n g 
it a n d s h o ul d be gi ve n a c o p y of t he si g ne d d oc u m e nt. If t he s u bject ca n n ot rea d or si g n t he 
d oc u me nts, oral pres e ntati o n ma y be ma de or si g n at ure gi ve n b y t he s u bject’s le gall y a p p oi nte d 
re pres e ntati ve, if wit ness e d b y a pers o n n ot i n v ol v e d i n t he st u d y, me nti o ni n g t hat t he patie nt 
c o ul d n ot rea d or si g n t he d oc u me nts . N o patie nt ca n e nter t he st u d y b ef ore his/ her i nf or me d 
c o nse nt has bee n o btai ne d.  

I L-2 / Pe m br oliz u m a b  
 
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2  
Merc k O T S P # 5 5 5 7 1  
 
Versi o n  0 6 /1 1 /2 0 2 4  
U C D a vis C o m pre he nsi ve C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a ge 7 7  of 9 2  
T he i nf or me d c o ns e nt f or m is c o nsi dere d t o be part of t he pr ot oc ol a n d m ust be s u b mitte d b y t he 
i n vesti gat or wit h it f or I R B a p pr o val.  
 
P atie nt C o nfi de nti alit y  
I n or der t o mai ntai n patie nt pri vac y, all st u d y re p orts a n d c o m m u nicati o ns will i de ntif y t he 
patie nt b y i nitials a n d t he assi g ne d patie nt n u m ber.  Me dical rec or ds of p atie nts will be 
mai ntai ne d i n strict c o nfi de nce acc or di n g t o le gal re q uire me nts.  T h e patie nt’s c o nfi de ntialit y will 
be mai ntai ne d a n d will n ot be ma de p u blicl y a vail a ble t o t he e xte nt per mitte d b y t he a p plica bl e 
la ws a n d re g ul ati o ns.  
 
Pr ot oc ol C o m pli a nce a n d De vi ati o ns  
T he i n vesti gat or will c o n d uct t he st u d y i n c o m plia nce wit h t he pr ot oc ol gi v e n a p pr o val/fa v ora bl e 
o pi ni o n b y t he I R B a n d t he a p pr o pri ate re g ul at or y a ut h orit y(ies).  C ha n ges t o t he pr ot oc ol will 
re q uire a p pr o val fr o m Merc k  a n d writte n I R B a p pr o val/fa v ora ble o pi ni o n pri or t o 
i m ple me ntati o n, e xce pt w he n t he m o dificati o n is nee de d t o eli mi nate a n i m me diate hazar d(s) t o 
patie nts.  T he I R B ma y pr o vi de, if a p plica ble re g ul at or y a ut h orit y(ies) per mit, e x pe dite d re vie w 
a n d a p pr o val/fa v ora bl e o pi ni o n f or mi n or c ha n ge(s) i n o n g oi n g st u dies t hat ha ve t he a p pr o val 
/fa v ora ble o pi ni o n of t he I R B. T he i n vesti gat or will s u b mit  all pr ot oc ol m o dificati o ns t o Merc k 
a n d t he re g ulat or y a ut h orit y(ies) i n acc or da nce wit h t he g o ver ni n g re g ul ati o ns.  
All pr ot oc ol de viati o ns will be re p orte d i n acc or da nce wit h U C D I R B A d mi nistrati o n a n d U C D 
Ca ncer Ce nter O C R  p olicies a n d t he partici pati n g site’s I R B p olicies. A n y de part ures fr o m t he 
pr ot oc ol m ust be f ull y d oc u me nte d i n t he s o urce d oc u me nts.  
 
O nsite A u dits  
Re g ulat or y a ut h orities or the I R B  ma y re q uest a ccess t o all s o urce d oc u m e nts, data ca pt ur e 
rec or ds, a n d ot her st u d y d oc u me ntati o n f or o n-sit e a u dit or i ns pecti o n. Direct access t o t hese 
d oc u me nts m ust be g uara ntee d b y t he i n vesti gat or, w h o m ust pr o vi de s u p p ort at all ti mes f or 
t hese acti vities. 
 
Pre m at ure Cl os ure of t he St u d y  
T his st u d y ma y be pre mat urel y ter mi nate d, if i n t h e o pi ni o n of t he i n vesti gat or or Merc k , t h ere is 
s ufficie nt reas o na ble ca use. Writte n n otificati o n d oc u me nti n g t he reas o n f or st u d y ter mi nati o n 
will be p r o vi de d t o t he i n vesti gat or or Merc k b y t he ter mi nati n g part y.   
 
Rec or d R ete nti o n  
T he i n vesti gat or will mai ntai n all st u d y rec or ds acc or di n g t o I C H -G C P a n d a p plica ble re g ulat or y 
re q uire me nt(s). 

I L-2 / Pe m br oliz u m a b  
 
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2  
Merc k O T S P # 5 5 5 7 1  
 
Versi o n  0 6 /1 1 /2 0 2 4  
U C D a vis C o m pre he nsi ve C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a ge 7 8  of 9 2  
 
Q u alit y Ass ur a nce  
Q ualit y ass ura nce a u dits of select patie nts a n d s o urce d oc u m e nts ma y be  c o n d ucte d b y t he 
Q ualit y Ass ura nce a n d/ or Data Safet y  C o m mittees as o utline d i n t he U C Da vis Ca ncer Ce nter 
Data a n d Safet y M o nit ori n g pla n.  Q ualit y c o ntr ol will be mai ntai ne d b y t he O C R Q ualit y 
Ass ura nce tea m a cc or di n g t o O C R p olic y . 
1 2. 0  
O V E R SI G H T A N D M O NI T O RI N G   
 
D at a a n d S afet y M o nit o ri n g  
I n a d diti o n t o t he re q uire me nts f or a d verse e v e nt r e p orti n g as o utli ne d i n Secti o n 7. 3 , t his 
pr ot oc ol is als o s u bject t o t he U C Da vis C o m pre he nsi ve Ca ncer Ce nt er’s ( U C D C C C) Data a n d 
Safet y M o nit ori n g Pla n. T he U C D C C C is c o m mitte d t o p urs ui n g hi g h -q ualit y patie nt -orie nte d 
cli nical researc h a n d has esta blis he d mec ha nis ms t o e ns ure b ot h scie ntific ri g or a n d patie nt 
safet y i n t he c o n d u ct of cli nical researc h st u dies. T he U C DC C C relies o n a m ulti -tiere d 
c o m mittee s yste m t hat re vie ws a n d m o nit ors all ca ncer cli nical trials a n d e ns ures t he safet y of its 
partici pa nts, i n c o m plia nce wit h i nstit uti o nal a n d fe deral re q uire m e nts o n a d verse e v e nt ( A E)  
re p orti n g, verifi cati o n of data acc urac y, a n d a d here nce t o pr ot oc ol eli gi bilit y re q uire me nts, 
treat me nt g ui deli nes, a n d relate d matters. T his trial has bee n assi g ne d hi g h ris k le vel per t he Data 
a n d Safet y M o nit ori n g Pla n ( D S M P) versi o n J ul y 1, 2 0 2 0, Ta ble 3 Ris k Stratificati o n of Trials, 
w hic h defi nes t he fre q u e nc y at w hic h t his trial will be a u dite d, m o nit ore d, a n d re vie we d b y t he 
Data a n d Safet y M o nit ori n g C o m mittee ( D S M C) (see A p pe n di x  6).  
 
I n vesti g at or M o nit ori n g G ui deli nes 
I n v esti gat ors will c o n d uct c o nti n u o us re vie w of patie nt safet y w hile o n st u d y treat me nt. 

I L-2 / Pe m br oliz u m a b  
 
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2  
Merc k O T S P # 5 5 5 7 1  
 
Versi o n  0 6 /1 1 /2 0 2 4  
U C D a vis C o m pre he nsi ve C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a ge 7 9  of 9 2  
1 3. 0  
R E F E R E N C E S  
1.  
Cle me nte, C. G., et al., Pr o g n ostic v al ue of t u m or i nfiltr ati n g ly m p h ocytes i n t he vertic al 
gr o wt h p h ase of pri m ary c ut a ne o us mel a n o m a.  Ca ncer, 1 9 9 6. 7 7 ( 7): p. 1 3 0 3-1 0.  
2.  
F o urca de, J., et al., < div x ml ns =" htt p:// w w w. w 3. or g/ 1 9 9 9/x ht ml" > C D 8 <s u p > + </s u p > T 
Cells S pecific f or T u m or A nti ge ns C a n Be Re n der e d Dysf u ncti o n al by t he T u m or 
Micr oe nvir o n m e nt t hr o u g h U pre g ul ati o n of t he I n hi bit ory Rece pt ors B T L A a n d P D -
1 </ div >.  Ca ncer Researc h, 2 0 1 2. 7 2 ( 4): p. 8 8 7-8 9 6.  
3.  
I wai, Y., et al., I nv olv e m e nt of P D-L 1 o n t u m or cells i n t he esc a pe fr o m h ost i m m u ne 
syste m a n d t u m or i m m u n ot her a py by P D-L 1 bl ock a de.  Pr oc Natl Aca d Sci U S A, 2 0 0 2. 
9 9 ( 1 9): p. 1 2 2 9 3-7.  
4.  
C o p pi n, C., et al., I m m u n ot her a py f or a dv a nce d r e n al cell c a ncer. C oc hra n e Data base S yst 
Re v, 2 0 0 5( 1): p. C d 0 0 1 4 2 5.  
5.  
S ha btai, M., et al., I ncre ase d ex pressi o n of activ ati o n m arkers i n re n al cell c arci n o m a 
i nfiltr ati n g ly m p h ocytes. J Ur ol, 2 0 0 2. 1 6 8 ( 5): p. 2 2 1 6-9.  
6.  
Bra h mer, J. R., et al., P h ase I st u dy of si n gle-a ge nt a nti -pr o gr a m me d de at h -1 ( M D X -1 1 0 6) 
i n refr act ory s oli d t u m ors: s afety, cli nic al activity, p h ar m ac o dy n a mics, a n d i m m u n ol o gic 
c orrel ates. J Cli n O nc ol, 2 0 1 0. 2 8 ( 1 9): p. 3 1 6 7-7 5.  
7.  
T o palia n, S. L., et al., S afety, Activity, a n d I m m u ne C orrel ates of A nti – P D -1 A nti b o dy i n 
C a ncer.  N E n gl J Me d, 2 0 1 2. 3 6 6 ( 2 6): p. 2 4 4 3-5 4.  
8.  
B or g haei, H., et al., Niv ol u m a b vers us D ocet axel i n A dv a nce d N o ns q u a m o us N o n -S m all -
Cell L u n g C a ncer.  N E n gl J Me d, 2 0 1 5. 3 7 3 ( 1 7): p. 1 6 2 7-3 9.  
9.  
Her bst, R. S., et al., Pe m br oliz u m a b vers us d ocet axel f or previ o usly tre ate d, P D -L 1 -
p ositive, a dv a nce d n o n -s m all-cell l u n g c a ncer ( K E Y N O T E -0 1 0): a r a n d o mise d c o ntr olle d 
tri al. La ncet, 2 0 1 6. 3 8 7 ( 1 0 0 2 7): p. 1 5 4 0-5 0.  
1 0.  Bra h mer, J. R., et al., S ur viv al a n d l o n g -ter m f oll o w-u p of t he p h ase I tri al of niv ol u m a b 
( A nti-P D -1; B M S -9 3 6 5 5 8; O N O -4 5 3 8) i n p atie nts ( pts) wit h previ o usly tre ate d a dv a nce d 
n o n -s m all cell l u n g c a ncer ( N S C L C). J Cli n O nc ol, 2 0 1 3. 3 1 ( 1 5 S; a bstr 8 0 3 0). 
1 1.  Bra h mer, J., et al., Niv ol u m a b vers us D ocet axel i n A dv a nce d S q u a m o us -Cell N o n -S m all -
Cell L u n g C a ncer.  N E n gl J Me d, 2 0 1 5. 3 7 3 ( 2): p. 1 2 3-3 5.  
1 2.  R o bert, C., et al., A nti -pr o gr a m me d -de at h -rece pt or-1 tre at me nt wit h pe m br oliz u m a b i n 
i pili m u m a b-refr act ory a dv a nce d mel a n o m a: a r a n d o mise d d ose-c o m p aris o n c o h ort of a 
p h ase 1 tri al.  T he La ncet. 3 8 4 ( 9 9 4 8): p. 1 1 0 9-1 1 1 7.  
1 3.  Ri bas, A., et al., Pe m br oliz u m a b vers us i nvesti g at or -c h oice c he m ot her a p y f or i pili m u m a b -
refr act ory mel a n o m a ( K E Y N O T E-0 0 2): a r a n d o mise d, c o ntr olle d, p h ase 2 tri al.  T he 
La ncet O n c ol o g y. 1 6 ( 8): p. 9 0 8-9 1 8.  
1 4.  R o bert, C., et al., Pe m br oliz u m a b vers us I pili m u m a b i n A dv a nce d Mel a n o m a.  N E n gl J 
Me d, 2 0 1 5. 3 7 2 ( 2 6): p. 2 5 2 1-3 2.  
1 5.  Ri bas, A., et al., Ass oci ati o n of pe m br oliz u m a b wit h t u m or res p o nse a n d s urviv al a m o n g 
p atie nts wit h a dv a nce d mel a n o m a.  J A M A, 2 0 1 6. 3 1 5 ( 1 5): p. 1 6 0 0-1 6 0 9.  

I L-2 / Pe m br oliz u m a b  
 
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2  
Merc k O T S P # 5 5 5 7 1  
 
Versi o n  0 6 /1 1 /2 0 2 4  
U C D a vis C o m pre he nsi ve C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a ge 8 0  of 9 2  
1 6.  Da u d AI, et al., Pr o gr a m me d De at h -Li g a n d 1 Ex pressi o n a n d Res p o nse t o t he A nti -
Pr o gr a m me d De at h 1 A nti b o dy Pe m br oliz u m a b i n Mel a n o m a.  
. J Cli n O nc ol, 2 0 1 6 Dec. 3 4 ( 3 4): p. 4 1 0 2-4 1 0 9.  
1 7.  Ga n ga d har, T. C. a n d A. K. S. Sala ma, Cli nic al a p plic ati o ns of P D -1 -b ase d t her a py: a f oc us 
o n pe m br oliz u m a b ( M K -3 4 7 5) i n t he m a n a ge me nt of mel a n o m a a n d ot her t u m or ty pes.  
O nc o Tar gets T her, 2 0 1 5. 8 : p. 9 2 9-3 7.  
1 8.  At ki ns, M. B., et al., P h ase I b d ose -fi n di n g st u dy of axiti ni b pl us pe m br oliz u m a b i n 
tre at me nt-n aïve p atie nts wit h a dv a nce d re n al cell c arci n o m a.  J I m m u n ot her Ca ncer, 2 0 1 5. 
3 ( S u p pl 2): p. P 3 5 3. d oi: 1 0. 1 1 8 6/ 2 0 5 1-1 4 2 6 -3 -S 2 -P 3 5 3.  
1 9.  Sei wert, T. Y., et al., S afety a n d cli nic al activity of pe m br oliz u m a b f or tre at me nt of 
rec urre nt or met ast atic s q u a m o us cell c arci n o m a of t he he a d a n d neck ( K E Y N O T E -0 1 2): 
a n o pe n -l a bel, m ultice ntr e, p h ase 1 b tri al. T he La ncet O nc ol o g y. 1 7 ( 7): p. 9 5 6-9 6 5.  
2 0.  At ki ns, M. B., et al., R a n d o mize d p h ase II tri al of hi g h -d ose i nterle uki n -2 eit her al o ne or i n 
c o m bi n ati o n wit h i nterfer o n alf a-2 b i n a dv a nce d r e n al cell c arci n o m a.  J Cli n O nc ol, 1 9 9 3. 
1 1 ( 4): p. 6 6 1-7 0.  
2 1.  Ka m m ula, U. S., D. E. W hite, a n d S. A. R ose n ber g, Tre n ds i n t he s afety of hi g h d ose b ol us 
i nterle uki n-2 a d mi nistr ati o n i n p atie nts wit h met ast atic c a ncer.  Ca ncer, 1 9 9 8. 8 3 . 
2 2.  Sc h wartze ntr u ber, D., I nt erle uki n-2: Cli nic al a p plic ati o ns - pri nci ples of a d mi nistr ati o n 
a n d m a n a ge me nt of si de effects , i n Pri nci ples a n d Pr actice of t he Bi ol o gic T her a py of 
C a ncer . 2 0 0 0, Li p pi nc ott, Willia ms & Wil ki ns: P hila del p hia. 
2 3.  Ya n g, J. C. a n d S. A. R ose n ber g, A n o n g oi n g pr os pective r a n d o mize d c o m p aris o n of 
i nterle uki n-2 re gi me ns f or t he tre at me nt of met ast atic re n al cell c a ncer.  Ca ncer J Sci A m, 
1 9 9 7. 3 S u p pl 1 : p. S 7 9-8 4.  
2 4.  Ya n g, J. C., et al., R a n d o mize d st u dy of hi g h -d ose a n d l o w -d ose i nterle uki n -2 i n p atie nts 
wit h met ast atic re n al c a ncer.  J Cli n O nc ol, 2 0 0 3. 2 1 ( 1 6): p. 3 1 2 7-3 2.  
2 5.  At ki ns, M. B., et al., Hi g h -d ose rec o m bi n a nt i nterle uki n 2 t her a py f or p atie nts wit h 
met ast atic mel a n o m a: a n alysis of 2 7 0 p atie nts tre ate d bet wee n 1 9 8 5 a n d 1 9 9 3.  J Cli n 
O nc ol, 1 9 9 9. 1 7 . 
2 6.  F yfe, G., et al., Res ults of tre at me nt of 2 5 5 p atie nts wit h met ast atic re n al cell c arci n o m a 
w h o receive d hi g h -d os e r ec o m bi n a nt i nterle uki n -2 t her a py.  J Cli n O nc ol, 1 9 9 5. 1 3 . 
2 7.  R ose n ber g, S. A., et al., R e gressi o n of est a blis he d p ul m o n ary met ast ases a n d s u bc ut a ne o us 
t u m or me di ate d by t he syste mic a d mi nistr ati o n of hi g h-d ose rec o m bi n a nt i nterle uki n 2.  J 
E x p Me d, 1 9 8 5. 1 6 1 ( 5): p. 1 1 6 9-8 8.  
2 8.  S mit h, F. O., et al., Tre at me nt of met ast atic mel a n o m a usi n g i nterle uki n -2 al o ne or i n 
c o nj u ncti o n wit h v acci nes.  Cli n Ca ncer Res, 2 0 0 8. 1 4 ( 1 7): p. 5 6 1 0-8.  
2 9.  Al va, A., et al., C o nte m p or ary ex perie nce wit h hi g h -d ose i nterle uki n -2 t her a py a n d i m p act 
o n s urviv al i n p atie nts wit h met ast atic mel a n o m a a n d met ast atic re n al cell c arci n o m a.  
Ca ncer I m m u n ol o g y, I m m u n ot hera p y, 2 0 1 6. 6 5 ( 1 2): p. 1 5 3 3-1 5 4 4.  

I L-2 / Pe m br oliz u m a b  
 
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2  
Merc k O T S P # 5 5 5 7 1  
 
Versi o n  0 6 /1 1 /2 0 2 4  
U C D a vis C o m pre he nsi ve C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a ge 8 1  of 9 2  
3 0.  F yfe, G., et al., Res ults of tre at me nt of 2 5 5 p atie nts wit h met ast atic re n al cell c arci n o m a 
w h o receive d hi g h -d os e r ec o m bi n a nt i nterle uki n -2 t her a py.  J Cli n O nc ol, 1 9 9 5. 1 3 ( 3): p. 
6 8 8 -9 6.  
3 1.  Ha nzl y, M., et al., Hi g h -d ose I nterle uki n -2 T her a py f or Met ast atic Re n al Cell C arci n o m a: 
A C o nte m p or ary Ex perie nce.  Ur ol o g y, 2 0 1 4. 8 3 ( 5): p. 1 1 2 9-1 1 3 4.  
3 2.  F or ni, G., et al., Perily m p h atic i njecti o ns of cyt oki nes: a ne w t o ol i n active c a ncer 
i m m u n ot her a py. Ex p eri m e nt al r ati o n ale a n d cli nic al fi n di n gs. A n n Ist S u per Sa nita, 1 9 9 0. 
2 6 ( 3-4): p. 3 9 7 -4 0 9.  
3 3.  De maria, S., et al., C o m bi ni n g r a di ot her a py a n d i m m u n ot her a py: a revive d p art ners hi p.  I nt 
J Ra diat O nc ol Bi ol P h ys, 2 0 0 5. 6 3 ( 3): p. 6 5 5-6 6.  
3 4.  Le v y, A., et al., R a di ati o n t her a py a n d i m m u n ot h er a py: i m plic ati o ns f or a c o m bi ne d 
c a ncer tre at m e nt.  Crit Re v O nc ol He mat ol, 2 0 1 3. 8 5 ( 3): p. 2 7 8-8 7.  
3 5.  Halla ha n, D. E., et al., I ncre ase d t u m or necr osis f a ct or al p h a m R N A after cell ul ar ex p os ure 
t o i o nizi n g r a di ati o n. Pr oc Natl Aca d Sci U S A, 1 9 8 9. 8 6 ( 2 4): p. 1 0 1 0 4-7.  
3 6.  Xia n, J., et al., C o m bi n ati o n n o nvir al m uri ne i nterle uki n 2 a n d i nterle uki n 1 2 ge ne t her a py 
a n d r a di ot her a py f or he a d a n d neck s q u a m o us cell c arci n o m a.  Arc h Ot olar y n g ol Hea d 
Nec k S ur g, 2 0 0 5. 1 3 1 ( 1 2): p. 1 0 7 9-8 5.  
3 7.  Se u n g, S. K., et al., P h ase 1 st u dy of stere ot actic b o dy r a di ot her a py a n d i nterle uki n -2 --
t u m or a n d i m m u n ol o gic al res p o nses. Sci Tra nsl Me d, 2 0 1 2. 4 ( 1 3 7): p. 1 3 7r a 7 4. 
3 8.  Saf wat, A., et al., A p h ase II tri al of l o w -d ose t ot al b o dy irr a di ati o n a n d s u bc ut a ne o us 
i nterle uki n-2 i n met ast atic mel a n o m a.  Ra di ot her O nc ol, 2 0 0 5. 7 7 ( 2): p. 1 4 3-7.  
3 9.  S u n g, K. W., et al., T a n de m hi g h -d ose c he m ot her a py a n d a ut ol o g o us ste m cell 
tr a ns pl a nt ati o n i n p atie nts wit h hi g h-risk ne ur o bl ast o m a: res ults of S M C N B-2 0 0 4 st u dy.  
B o ne Marr o w Tra ns pla nt, 2 0 1 3. 4 8 ( 1): p. 6 8-7 3.  
4 0.  Sasa ki, R., et al., A n gi os arc o m a tre ate d wit h r a di ot her a py: i m p act of t u m or ty pe a n d size 
o n o utc o me.  I nt J Ra diat O nc ol Bi ol P h ys, 2 0 0 2. 5 2 ( 4): p. 1 0 3 2-4 0.  
4 1.  Liss o ni, P., et al., Pr o gress re p ort o n t he p alli ative t her a py of 1 0 0 p atie nts wit h ne o pl astic 
eff usi o ns by i ntr ac avit ary l o w -d ose i nterle uki n -2.  O nc ol o g y, 2 0 0 1. 6 0 ( 4): p. 3 0 8-1 2.  
4 2.  Sc u deletti, M., et al., I m m u n ot her a py wit h i ntr alesi o n al a n d syste mic i nterle uki n-2 of 
p atie nts wit h n o n -s m all-cell l u n g c a ncer.  Ca ncer I m m u n ol I m m u n ot her, 1 9 9 3. 3 7 ( 2): p. 
1 1 9 -2 4.  
4 3.  Wei de, B., et al., Hi g h res p o nse r ate after i ntr at u m or al tre at me nt wit h i nterle uki n -2: 
res ults fr o m a p h ase 2 st u dy i n 5 1 p atie nts wit h met ast asize d mel a n o m a. Ca ncer, 2 0 1 0. 
1 1 6 ( 1 7): p. 4 1 3 9-4 6.  
4 4.  S hi, V. Y., et al., 1 0 0 % C o m plete res p o nse r ate i n p atie nts wit h c ut a ne o us met ast atic 
mel a n o m a tre ate d wit h i ntr alesi o n al i nterle uki n (I L) -2, i mi q ui m o d, a n d t o pic al reti n oi d 
c o m bi n ati o n t her a py: res ults of a c ase series.  J A m Aca d Der mat ol, 2 0 1 5. 7 3 ( 4): p. 6 4 5-5 4.  

I L-2 / Pe m br oliz u m a b  
 
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2  
Merc k O T S P # 5 5 5 7 1  
 
Versi o n  0 6 /1 1 /2 0 2 4  
U C D a vis C o m pre he nsi ve C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a ge 8 2  of 9 2  
4 5.  Garcia, M. S., et al., C o m plete re gressi o n of s u bc ut a ne o us a n d c ut a ne o us met ast atic 
mel a n o m a wit h hi g h -d ose i ntr alesi o n al i nterle uki n 2 i n c o m bi n ati o n wit h t o pic al 
i mi q ui m o d a n d reti n oi d cre a m. Mela n o ma Res, 2 0 1 1. 2 1 ( 3): p. 2 3 5-4 3.  
4 6.  Patel, F., et al., D et aile d pr ot oc ol f or a d mi nistr ati o n of i ntr alesi o n al I L -2 f or t he tre at me nt 
of St a ge IIIc a n d I V M 1 a met ast atic mel a n o m a b as e d o n c urre nt N C C N g ui deli nes.  
Der mat ol O nli ne J, 2 0 1 4. 2 0 ( 1 1). 
4 7.  Ti mar, J., et al., Ne o a dj u v a nt i m m u n ot her a py of or al s q u a m o us cell c arci n o m a m o d ul ates 
i ntr at u m or al C D 4/ C D 8 r ati o a n d t u m or micr oe nvir o n me nt: a m ultice nter p h ase II cli nic al 
tri al. J Cli n O nc ol, 2 0 0 5. 2 3 ( 1 5): p. 3 4 2 1-3 2.  
4 8.  Ferlazz o, G., et al., I ntr al esi o n al s o n o gr a p hic ally g ui de d i njecti o ns of ly m p h oki ne-
activ ate d killer cells a n d rec o m bi n a nt i nterle uki n -2 f or t he tre at me nt of liver t u m ors: a 
pil ot st u dy.  J I m m u n ot her, 1 9 9 7. 2 0 ( 2): p. 1 5 8-6 3.  
4 9.  de Gast, G. C., et al., P h ase I tri al of c o m bi ne d i m m u n ot her a py wit h s u bc ut a ne o us 
gr a n ul ocyte m acr o p h a g e c ol o ny -sti m ul ati n g f act or, l o w-d ose i nterle uki n 2, a n d i nterfer o n 
al p h a i n pr o gressive met ast atic mel a n o m a a n d re n al cell c arci n o m a.  Cli n Ca ncer Res, 
2 0 0 0. 6 ( 4): p. 1 2 6 7 -7 2.  
5 0.  H ula n d, E., et al., I n h ale d i nterle uki n-2 t her a py i n p ul m o n ary met ast atic re n al cell 
c arci n o m a: six ye ars of ex perie nce.  Ca ncer J Sci A m, 1 9 9 7. 3 S u p pl 1 : p. S 9 8-1 0 5.  
5 1.  De Stefa ni, A., et al., I m pr ove d s urviv al wit h perily m p h atic i nterle uki n 2 i n p atie nts wit h 
resect a ble s q u a m o us cell c arci n o m a of t he or al c a vity a n d or o p h ary nx.  Ca n cer, 2 0 0 2. 
9 5 ( 1): p. 9 0-7.  
5 2.  D o ve di, S.J., et al., Ac q uire d resist a nce t o fr acti o n ate d r a di ot her a py c a n be overc o me by 
c o nc urre nt P D -L 1 bl oc k a de.  Ca ncer Researc h, 2 0 1 4. 7 4 ( 1 9): p. 5 4 5 8-6 8.  
5 3.  Gaje ws ki, T. F., J. L o u a h e d, a n d V. G. Bric h ar d, Ge ne si g n at ure i n mel a n o m a ass oci ate d 
wit h cli nic al activity: a p ote nti al cl ue t o u nl ock c a ncer i m m u n ot her a py.  C a ncer J, 2 0 1 0. 
1 6 ( 4): p. 3 9 9-4 0 3.  
5 4.  Harli n, H., et al., C he m o ki ne ex pr essi o n i n mel a n o m a met ast ases ass oci ate d wit h C D 8 + T -
cell recr uit me nt.  Ca ncer Res, 2 0 0 9. 6 9 ( 7): p. 3 0 7 7-8 5.  
5 5.  S pra n ger, S., R. Ba o, a n d T. F. Gaj e ws ki, Mel a n o m a -i ntri nsic bet a-c ate ni n si g n alli n g 
preve nts a nti -t u m o ur i m m u nity. Nat ure, 2 0 1 5. 5 2 3 ( 7 5 5 9): p. 2 3 1-5.  
5 6.  Kl u g, F., et al., L o w -D os e Irr a di ati o n Pr o gr a ms M acr o p h a ge Differe nti ati o n t o a n 
i N O S( +)/ M 1 P he n oty pe t h at Orc hestr ates Effective T Cell I m m u n ot her a py, i n C a ncer Cell . 
2 0 1 3. p. 5 8 9 -6 0 2.  
5 7.  Riz vi, N. A., et al., C a ncer i m m u n ol o gy. M ut ati o n al l a n dsc a pe deter mi nes se nsitivity t o 
P D -1 bl ock a d e i n n o n -s m all cell l u n g c a ncer. Scie nce, 2 0 1 5. 3 4 8 ( 6 2 3 0): p. 1 2 4-8.  
5 8.  Eise n ha uer, E. A., et al., Ne w res p o nse ev al u ati o n criteri a i n s oli d t u m o urs: revise d 
R E CI S T g ui deli ne (versi o n 1. 1).  E ur J Ca ncer, 2 0 0 9. 4 5 ( 2): p. 2 2 8-4 7.  
5 9.  W olc h o k, J. D., et al., G ui deli nes f or t he ev al u ati o n of i m m u ne t her a py activity i n s oli d 
t u m ors: i m m u ne-rel ate d res p o nse criteri a. Cli n Ca ncer R es, 2 0 0 9. 1 5 ( 2 3): p. 7 4 1 2-2 0.  

I L-2 / Pe m br oliz u m a b  
 
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2  
Merc k O T S P # 5 5 5 7 1  
 
Versi o n  0 6 /1 1 /2 0 2 4  
U C D a vis C o m pre he nsi ve C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a ge 8 3  of 9 2  
6 0.  Sc hal per, K. A., et al., O bjective me as ure me nt a n d cli nic al si g nific a nce of TI Ls i n n o n -
s m all cell l u n g c a ncer. J Natl Ca ncer I nst, 2 0 1 5. 1 0 7 ( 3). 
6 1.  Sc hal per, K. A., et al., I n sit u t u m or P D-L 1 m R N A ex pressi o n is ass oci ate d wit h i ncre ase d 
TI Ls a n d better o utc o me i n bre ast c arci n o m as.  Cli n Ca ncer Res, 2 0 1 4. 2 0 ( 1 0): p. 2 7 7 3-8 2.  
6 2.  B ol ger, A. M., M. L o hse, a n d B. Usa del, Tri m m o m atic: a flexi ble tri m mer f or Ill u mi n a 
se q ue nce d at a. Bi oi nf or matics, 2 0 1 4. 3 0 ( 1 5): p. 2 1 1 4-2 0.  
6 3.  Mc Ke n na, A., et al., T he Ge n o me A n al ysis T o olkit: a M a p Re d uce fr a me w ork f or a n alyzi n g 
next -ge n er ati o n D N A se q ue nci n g d at a.  Ge n o me R es, 2 0 1 0. 2 0 ( 9): p. 1 2 9 7-3 0 3.  
6 4.  Garris o n, E. a n d G. Mart h H a pl oty pe -b ase d v ari a nt detecti o n fr o m s h ort -re a d se q ue nci n g. 
Ar Xi v e -pri nts, 2 0 1 2. 1 2 0 7 . 
6 5.  Li, H., et al., T he Se q ue n ce Ali g n me nt/ M a p f or m at a n d S A Mt o ols.  Bi oi nf or matics, 2 0 0 9. 
2 5 ( 1 6): p. 2 0 7 8-9.  
6 6.  K o b ol dt, D. C., et al., V ar Sc a n: v ari a nt detecti o n i n m assively p ar allel se q u e nci n g of 
i n divi d u al a n d p o ole d s a m ples. Bi oi nf or matics, 2 0 0 9. 2 5 ( 1 7): p. 2 2 8 3-5.  
6 7.  C H A P M A N, B. A n a ut o m ate d e nse m bl e met h o d f or c o m bi ni n g a n d ev al u ati n g ge n o mic 
v ari a nts fr o m m ulti ple c allers . 2 0 1 3; A vaila ble fr o m: htt p:// bc b.i o/ 2 0 1 3/ 0 2/ 0 6/a n -
a ut o mate d-e ns e m ble -met h o d -f or-c o m bi ni n g -a n d-e val uati n g -ge n o mic -v aria nts -fr o m-
m ulti ple -callers/. 
6 8.  Li, H. a n d R. D ur bi n, F ast a n d acc ur ate s h ort re a d ali g n me nt wit h B urr o ws -W heeler 
tr a nsf or m. Bi oi nf or matics, 2 0 0 9. 2 5 ( 1 4): p. 1 7 5 4-6 0.  
6 9.  Tra p nell, C., et al., Differ e nti al ge ne a n d tr a nscri pt ex pressi o n a n alysis of R N A -se q 
ex peri me nts wit h T o p H at a n d C uffli nks.  Nat Pr ot oc, 2 0 1 2. 7 ( 3): p. 5 6 2-7 8.  
7 0.  Wa n g, L., S. Wa n g, a n d W. Li, R Se Q C: q u ality c o ntr ol of R N A -se q ex peri me nts.  
Bi oi nf or matics, 2 0 1 2. 2 8 ( 1 6): p. 2 1 8 4-5.  
  
 

I L-2 / Pe m br oliz u m a b  
 
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2  
Merc k O T S P # 5 5 5 7 1  
 
Versi o n  0 6 /1 1 /2 0 2 4  
U C D a vis C o m pre he nsi ve C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a ge 8 4  of 9 2  
1 4. 0  
A P P E N DI C E S  
A p pe n di x 1 : E C O G Perf or m a nce St at us Sc ale 
K ar n ofs k y St at us  
K ar n ofs k y 
Gr a de * *  
E C O G 
Gr a de  
E C O G St at us * *  
N or mal, n o c o m plai nts  
1 0 0  
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  
A ble t o carr y o n n or mal acti vities. 
Mi n or si g ns or s y m pt o ms of disease  
9 0  
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, office w or k  
N or mal acti vit y wit h eff or t 
8 0  
Care f or self. U na ble t o carr y o n 
n or mal acti vit y or t o d o acti ve w or k  
7 0  
2  
A m b ulat or y a n d ca pa ble of all selfcare 
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  
Re q uires occasi o nal assista nce, b ut 
a ble t o care f or m ost of his nee ds  
6 0  
Re q uires c o nsi dera ble assista nce a n d 
fre q ue nt me dical care 
5 0  
3  
Ca pa ble of o nl y li mite d selfcare, 
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  
Disa ble d. Re q uires s pecial care a n d 
assista nce  
 
4 0  
Se verel y disa ble d. H os pitalizati o n 
i n dicate d t h o u g h deat h n o ni m mi ne nt 
3 0  
4  
C o m pletel y disa ble d. Ca n n ot carr y o n 
a n y selfcare. T otall y c o nfi ne d t o be d or 
c hair  
Ver y sic k. H os pitalizati o n necessar y. 
Acti ve s u p p orti ve treat me nt necessar y  
2 0  
M ori b u n d  
1 0  
Dea d  
0  
5  
Dea d  
* K P S will be use d i n t his st u d y. E C O G stat us is liste d f or refere nce.  
* * O ke n, M. M., Creec h, R. H., T or me y, D. C., H ort o n, J., Da vis, T. E., Mc Fa d de n, E. T., Car b o ne, P. P.:  T o xicit y A n d Res p o nse 
Criteria Of T h e Easter n C o o perati ve O nc ol o g y Gr o u p. A m J Cli n O nc ol 5: 6 4 9 -6 5 5, 1 9 8 2.  

I L-2 / Pe m br oliz u m a b  
 
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2  
Merc k O T S P # 5 5 5 7 1  
 
Versi o n  0 6 /1 1 /2 0 2 4  
U C D a vis C o m pre he nsi ve C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a ge 8 5  of 9 2  
A p pe n di x 2 : D at a C ollecti o n  
All data will be c ollecte d usi n g U C Da vis data c ollecti o n f or ms.  A n y a n d all s o urce 
d oc u me ntati o n s hall be mai ntai ne d .  
 
 

I L-2 / Pe m br oliz u m a b  
 
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2  
Merc k O T S P # 5 5 5 7 1  
 
Versi o n  0 6 /1 1 /2 0 2 4  
U C D a vis C o m pre he nsi ve C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a ge 8 6  of 9 2  
A p pe n di x 3 : M olec ul ar C orrel ati v e S a m ple H a n dli n g  
S peci m e n S u b missi o n f or C orrel ati ve St u dies :  
Patie nts m ust be offere d partici pati o n i n t hese m olec ular c orrelati ve st u dies. Wit h t he patie nt's 
c o nse nt, tiss ue a n d bl o o d s peci me ns will be s u b mitte d as o utli ne d bel o w. Sa m ples will be de -
i de ntifie d a n d c o de d wit h a ne w patie nt I D n u m ber t o pr otect patie nt’s i de ntit y. 
S peci m e n C ollecti o n, St or a ge, S hi p pi n g a n d S u b missi o n Re q uire me nts  
It is re q uire d t hat paraffi n-e m be d de d tiss ue bl oc ks or sli des fr o m ti me of dia g n osis ( or 
s u bse q ue nt, b ut pri or t o t hera p y) as well as bl o o d s peci me ns, as o utli ne d bel o w, be s u b mitte d f or 
e x pressi o n of rele va nt m olec ular tar gets.  
•  Arc hi v al t u m or s peci me ns : If a vaila ble, 1 - 2 paraffi n -e m be d de d tiss ue bl oc ks 
c o ntai ni n g f or mali n -fi xe d t u m or or nee dle as pirat e sli des fr o m ti me of dia g n osis ( or 
s u bse q ue nt, b ut pri or t o t hera p y) s h o ul d b e s u b mitte d f or e v al uati o n of e x pressi o n of P D -
L 1 a n d ot her rele va nt m olec u les. Paraffi n bl oc ks ma y be pr ocesse d acc or di n g t o sta n dar d 
i nstit uti o nal pr ot oc ols. If bl oc ks are u n a vaila ble, 1 6 u nstai ne d sli des are acce pta ble 
alter nati ves.  
•  Fres h t u m or bi o ps y: All s peci m e ns m ust be l a bele d wit h pr ot oc ol n u m ber, p atie nt 
re gistr ati o n n u m ber, a n d d ate of s peci m e n c ollecti o n.  Tiss ue p orti o ns will be use d f or 
(i n or der of pri orit y): 
1.  
Fi xe d i n f or mali n f or t he pre parati o n of F F P E bl oc ks  
2.  
Place d i n 1 ml R N A later a n d s na p fr o ze n wit h li q ui d nitr o ge n a n d st ore d at -7 0 t o -
8 0° C f or f ut ure R N A e xtracti o n a n d q P C R a n d i m m u n oc hi p a nal ysis,  
3.  
S na p fr oze n wit h li q ui d nitr o ge n a n d st ore d at -7 0 t o -8 0° C f or f ut ure D N A 
e xtracti o n  
•  Bl o o d s peci m e ns : Bl o o d s peci me ns ( 3 x 1 0 ml la ve n der t o p E D T A t u bes) will be 
c ollecte d fr o m eac h p atie nt.  
Eac h p ur ple -t o p ( E D T A) t u be s h o ul d be deli vere d t o t he la b w here it will b e i n verte d 
se veral ti mes, a n d pla ce d o n wet ice u ntil ce ntrif u gati o n. T he t u bes s h o ul d be ce ntrif u ge d 
as s o o n as p ossi ble at a p pr o xi matel y 6 0 0 x g f or 1 0 mi n utes. A p pr o xi matel y 1. 5 m l of 
plas ma s h o ul d be re m o ve d fr o m eac h t u be a n d p o ole d i n a fres h, sterile 1 5 ml c o nical 
t u be. Ce ntrif u ge plas ma a sec o n d ti me at 1 5 0 0 -1 6 0 0 x g f or 5 –  1 0 mi n utes t o pellet a n d 
re mai ni n g cells. After t he sec o n d s pi n, plas ma s h o ul d be re m o ve d a n d pl ace d i n  5 0 0 ul 
ali q u ots i n la bele d cr y ot u bes. Plas ma will be fr oze n a n d st ore d at -7 0 t o -8 0° C.  Plas ma 
sa m ples will be assa ye d b y L u mi ne x t o e val uate s yste mic c yt o ki ne le vels.  
Bl o o d re mai ni n g i n t he ori gi nal E D T A t u bes will be pr ocess e d f or P B M C c ollecti o n.  
Briefl y, bl o o d cells will be res us pe n de d i n r o o m te m perat ur e P B S at a 2: 1 rati o.  T he 
bl o o d will t he n be caref ull y la yere d o ver L y m p h oc yte Se parati o n Me dia ( Fic ol S ol uti o n, 
L S M) a n d ce ntrif u g e d at 4 0 0 x g f or 3 0 mi n utes.  Res ulti n g cells will be was he d t wice i n 
P B S t he n res us pe n de d i n R P MI t o facilitate cell c o u nti n g.  T o retai n via bilit y of cells, 

I L-2 / Pe m br oliz u m a b  
 
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2  
Merc k O T S P # 5 5 5 7 1  
 
Versi o n  0 6 /1 1 /2 0 2 4  
U C D a vis C o m pre he nsi ve C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a ge 8 7  of 9 2  
cells will be fr oze n at a b o ut 1. 0 x 1 0 7 i n a freezi n g me dia c o nsisti n g of 5 0 % R P MI, 4 0 % 
F B S, & 1 0 % D M S O.  Cells will be fr oze n at -1° C/ mi n ute, t he o pti mal rate f or cell 
preser vati o n.  Cr y o preser ve d cells will be st ore d i n a li q ui d nitr o ge n freezer.  
 
 
 

I L-2 / Pe m br oliz u m a b  
 
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2  
Merc k O T S P # 5 5 5 7 1  
 
Versi o n  0 6 /1 1 /2 0 2 4  
U C D a vis C o m pre he nsi ve C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a ge 8 8  of 9 2  
A p pe n di x 4 : I m m u ne-Rel ate d Res p o nse Crit eri a (ir R C)  
I n creasi n g cli nical e x p eri e nce i n dicates t hat tra diti o nal res p o nse criteria (e. g., Res p o nse 
E val uati o n Criteria i n S oli d T u m ors, Versi o n 1. 1 [ R E CI S T v 1. 1] a n d W orl d Healt h Or ga nizati o n 
[ W H O]) ma y n ot be s ufficie nt t o c haracteri ze f ull y acti vit y i n t he ne w era of tar get t hera pies 
a n d/ or bi ol o gics.  I n st u di es wit h c yt o ki nes, ca n cer vacci nes, a n d m o n ocl o n al a nti b o dies, 
c o m plete res p o nse, p artial res p o nse, or sta ble dise ase has bee n s h o w n t o occ ur aft er a n i ncrease 
i n t u m or b ur de n as c haracterize d b y pr o gressi ve disease b y tra diti o nal res p o nse criteria.  
T heref ore, c o n ve nti o nal r es p o nse criteria ma y n ot a de q uatel y assess t he acti vit y of 
i m m u n ot hera pe utic a ge nts beca use pr o gressi ve dis ease ( b y i nitial ra di o gra p hic e val uati o n) d oes 
n ot necessaril y reflect t hera pe utic fail ure.  L o n g ter m effect o n t he tar g et disease m ust als o be 
ca pt ure d. T h e i m m u ne relate d res p o nse criteria [ 6 0] (ir R C) are criteri a t hat atte m pt t o d o t hat b y 
e n ha nci n g c h aracteriz ati o n of ne w res p o nse patter ns t hat ha ve bee n o bser ve d wit h 
i m m u n ot hera pe utic a ge nts (i.e., i pili m u ma b). ( N ote: T he ir R C o nl y i n de x a n d meas ura ble ne w 
lesi o ns are ta ke n i nt o acc o u nt.) 
G L O S S A R Y  
Ter m  
Defi niti o n  
S P D  
s u m of t he pr o d ucts of t he t w o lar gest per pe n dic ular dia meters 
T u m or b ur de n  
S P D i n de x lesi o ns +  S P D ne w, meas ura ble lesi o ns  
Na dir  
mi ni mall y rec or de d t u m or b ur de n  
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 S D 
i m m u ne-relate d sta ble disease 
ir B O R 
i m m u ne-relate d best o verall res p o nse 
 
B A S E LI N E A S S E S S M E N T U SI N G ir R C  
Ste p 1. I d e ntif y t he i n de x lesi o ns (fi ve lesi o ns per or ga n, u p t o te n visceral lesi o ns a n d fi ve 
c uta ne o us lesi o ns).   
Ste p 2. Calc ulate t he S P D of all of t hese i n de x l esi o ns:  
S P D = 
( Lar gest dia met er of lesi o n i)  ( Sec o n d lar gest dia meter of lesi o n i). 
 
 

i

I L-2 / Pe m br oliz u m a b  
 
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2  
Merc k O T S P # 5 5 5 7 1  
 
Versi o n  0 6 /1 1 /2 0 2 4  
U C D a vis C o m pre he nsi ve C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a ge 8 9  of 9 2  
P O S T -B A S E LI N E A S S E S S M E N T S U SI N G ir R C  
Ste p 1. Calc ulate t he S P D of t he i n de x lesi o ns.   
Ste p 2. I d e ntif y ne w, meas ura ble lesi o ns ( ≥ 5 × 5 m m; u p t o fi ve ne w lesi o ns per or ga n:  fi v e ne w 
c uta ne o us lesi o ns a n d te n visceral lesi o ns).   
Ste p 3. Calc ulate t he S P D of t he ne w, m eas ura ble lesi o ns.  
Ste p 4. Calc ulate t he t u m or b ur de n:  
T u m or b ur de n  =  S P D i n de x lesi o ns +  S P D ne w, meas ura ble lesi o ns 
Ste p 5. Calc ulate t he c ha n ge i n t u m or b ur de n rel ati ve t o baseli ne a n d t he c h a n ge i n t u m or b ur de n 
relati ve t o na dir. 
Ste p 6. Deri ve t he o verall res p o nse usi n g t he ta ble bel o w.  
O ver all  Res p o nse  
Criteri o n  
ir C R 
C o m plete disa p peara nce of all lesi o ns ( w het her meas ura ble or n ot, a n d n o ne w 
lesi o ns) c o nfir me d b y a re peat, c o nsec uti ve assess me nt  4 wee ks fr o m t he date 
first d oc u me nte d 
ir P R 
Decrease i n t u m or b ur de n  5 0 % relati ve t o baseli ne c o nfir me d b y a c o nsec uti ve 
assess me nt  4 wee ks fr o m t he date first d oc u me nte d  
ir S D 
Criteria f or ir C R, ir P R, a n d ir P D are n ot met; d oes n ot re q uire c o nfir mati o n  
ir P D 
I ncrease i n t u m or b ur de n  2 5 % relati ve t o na dir c o nfir me d b y a c o nsec uti ve 
assess me nt  4 wee ks fr o m t he date first d oc u me nte d  
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 S D  =  i m m u ne-relate d sta ble disease. 
 
 
 

I L-2 / Pe m br oliz u m a b  
 
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2  
Merc k O T S P # 5 5 5 7 1  
 
Versi o n  0 6 /1 1 /2 0 2 4  
U C D a vis C o m pre he nsi ve C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a ge 9 0  of 9 2  
D E T E R MI N A TI O N O F ir B O R  
O nce a p atie nt has c o m pl ete d all t u m or assess me nts, his/ her ir B O R ma y be deter mi ne d:  
C o n diti o n  
ir B O R 
At least o ne ir C R  
ir C R 
At least o ne ir P R a n d n o ir C R  
ir P R 
At least o ne ir S D a n d n o ir C R a n d n o ir P R  
ir S D 
At least o ne ir P D a n d n o ir C R, n o ir P R, a n d n o ir S D 
ir P D 
ir B O R =  i m m u ne-relate d best o verall res p o nse; 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 S D =  i m m u ne-relate d sta ble disease. 
 
 
 
 

I L-2 / Pe m br oliz u m a b  
 
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2  
Merc k O T S P # 5 5 5 7 1  
 
Versi o n  0 6 /1 1 /2 0 2 4  
U C D a vis C o m pre he nsi ve C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a ge 9 1  of 9 2  
A p pe n di x 5 : C o m m o n Ter mi n ol o g y Criteri a f or A d verse E ve nts V 4. 0 ( C T C A E)  
T he descri pti o ns a n d gra di n g scales f o u n d i n t he re vise d N CI C o m m o n Ter mi n ol o g y Criteria f or 
A d verse E v e nts ( C T C A E) versi o n 4. 0 will be utilize d f or a d verse e v e nt re p orti n g. 
(htt p://cte p.ca ncer. g o v/re p orti n g/ctc. ht ml ) 
 
 
 

I L-2 / Pe m br oliz u m a b  
 
Cli nic al St u d y Pr ot oc ol U C D C C # 2 7 2  
Merc k O T S P # 5 5 5 7 1  
 
Versi o n  0 6 /1 1 /2 0 2 4  
U C D a vis C o m pre he nsi ve C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a ge 9 2  of 9 2  
A p pe n di x 6 . Ris k Str atific ati o n of Tri als   
Tri al Ris k Le vel  
O versi g ht Le vel  
M o nit ori n g Fre q ue nc y  
A u diti n g 
Fre q ue nc y  
Hi g h Ris k  - T here is a hi g h pr o ba bilit y 
of t he occ urre nce of a seri o us a d verse 
e ve nt a n d/ or st u d y m o nit ori n g a n d 
re p orti n g re q uire me nts of t he trial are 
s uc h t hat e ve nts or e ve nt tre n ds ma y n ot 
be i m me diatel y rec o g nize d.  
•  I n vesti gat or-i nitiate d I N D or I D E 
trials 
•  All P hase I trials  
•  Trials i n ge ne t hera p y or ot her hi g h -
ris k areas as desi g nate d b y t he NI H 
 
Hi g h I nte nsit y O versi g ht  –  T he PI m ust 
pr os pecti vel y re gister partici pa nts a n d s u b mit 
a d verse e ve nt re p orts t o t he D S M C. E ver y t w o 
m o nt hs , t he D S M C re vie ws t hese trial-s pecific 
d oc u me nts i ncl u di n g all a u dits a n d m o nit ori n g 
re p orts, a n d a d verse e ve nts. T he PI is e x pecte d 
t o re vie w a d verse e ve nts wit h t he s u b-
i n vesti gat ors o n t he trial a n d t he st u d y tea m.  
F or p hase I trials, c o nti n u o us m o nit ori n g of 
patie nt safet y a n d d ose li miti n g t o xicities 
occ urs i n wee kl y meeti n g facilitate d b y t he 
P hase I Pr o gra m Direct ors.  C o h ort e x pa nsi o n 
m eeti n gs are le d b y t he PI of t he trial a n d t he 
meeti n g mi n utes are f or war de d t o t he D S M C 
f or re vie w.  F or a n I nstit uti o nal p hase III trial, 
t he S R C, i n c olla b orati o n wit h t he PI, is 
res p o nsi ble f or esta blis hi n g a n i n de pe n de nt 
D S M B.  
•  Wit hi n 2 wee ks of 1st 
patie nt c ycle 1 c o m pleti o n  
•  Wit hi n 2 wee ks of 1st 
res p o nse assess me nt 
c o m pleti o n  
•  1 0 0 % m o nit ori n g q uarterl y 
t hereafter 
E ver y 6 
m o nt hs  
M o der ate Ris k  –  T here is a pr o ba bilit y 
of a m o derate -se verit y e ve nt occ urri n g 
b ut t here is a de q uate safet y m o nit ori n g 
i n t he trial t o i de ntif y e ve nts pr o m ptl y 
a n d t o mi ni mize t heir effects.  
•  All ot her trials i n v ol vi n g t hera pe utic 
i nter ve nti o ns ( P hase II/III trials wit h 
I N D e xe m pti o ns) 
 
 
M o der ate I nte nsit y O versi g ht  –  T he PI m ust 
pr os pecti vel y re gister partici pa nts a n d s u b mit 
a d verse e ve nt re p orts t o t he D S M C. Q u arterl y , 
t he D S M C re vie ws t hese trial-s pecific 
d oc u me nts i ncl u di n g all a u dits a n d m o nit ori n g 
re p orts, a n d a d verse e ve nts. T he PI is e x pecte d 
t o re vie w all a d verse e ve nts wit h t he s u b-
i n vesti gat ors a n d t he st u d y tea m. 
 
•  Wit hi n 2 wee ks of 1st 
patie nt c ycle 1 c o m pleti o n  
•  Wit hi n 2 wee ks of 1st 
res p o nse assess me nt 
c o m pleti o n  
•  1 0 0 % m o nit ori n g 
eli gi bilit y/c o nse nt q uarterl y 
t hereafter 
•  1 0 % c o m plete m o nit ori n g 
re vie w q uarterl y t hereafter 
E ver y 
year  
 
Mi ni m al Ris k  –  T he pr o ba bilit y a n d 
ma g nit u de of har m or disc o mf ort 
a ntici pate d i n t he researc h are n ot 
greater t ha n t h ose or di naril y 
e nc o u ntere d i n dail y life or d uri n g t he 
perf or ma nce of r o uti ne p h ysical a n d 
ps yc h ol o gical e xa mi nati o ns or tests a n d 
w here c o nfi de ntiali t y is a de q uatel y 
pr otecte d.  
•  Trials i n v ol vi n g n o n -t hera pe utic 
i nter ve nti o ns ( Ca ncer Pre ve nti o n & 
C o ntr ol, Dia g n ostic, C orrelati ve, 
Be ha vi oral, or S u p p orti ve Care) t hat 
are n o greater t ha n mi ni mal ris k  
--------------O R ------------- 
N o n -i nter ve nti o nal trials 
 
Mi ni m al I nte nsit y O versi g ht  –  T his le vel 
a p plies t o t h ose st u dies t hat i ncl u de a p h ysical 
i nter ve nti o n wit h a partici pa nt. A n e xa m ple of 
t his t y pe of trial is a dietar y i nter ve nti o n or 
e xercise st u d y ai me d at s y m pt o m ma na ge me nt.  
E ver y si x m o nt hs , t he D S M C re vie ws t hese 
trial-s pecific d oc u me nts i ncl u di n g all a u dits 
re p orts a n d a d verse e ve nts. 
 
 
 
 
 
---------------------------------------- 
L o w I nte nsit y O versi g ht  –  T his le vel a p plies 
t o t h ose st u dies t hat d o n ot i ncl u de a p h ysical 
i nter ve nti o n wit h a partici pa nt. E xa m ples of 
t his t y pe of trial is a c o m p uter or i nter net-base d 
strate g y ai me d at i ncreasi n g a ware ness of 
ca ncer iss ues, o bser vati o nal trials, or 
e pi de mi ol o gical st u dies. O versi g ht b y t he 
D S M C is n ot re q uire d f or t hese trials.  
N o m o nit ori n g re q uire me nt  
 
 
 
 
 
 
 
 
 
 
 
N o m o nit ori n g re q uire me nt  
 
E ver y 
year  
 
 
 
 
 
 
 
 
 
 
 
N o 
a u diti n g 
re q uire
me nt  
S o urce: U C Da vis C o m pre he nsi ve Ca ncer Ce nter Data a n d Safet y M o nit ori n g Pla n, Re vise d: J ul y 2 0 2 0, Ta ble  3.