UCDCC#271: A Phase I/II Trial of Epacadostat (Indolamine 2,3 Dioxygenase Inhibitor), Intralesional SD101 (Toll-receptor 9 Agonist), and Radiotherapy in Patients With Advanced Solid Tumors and Lymphoma
Phase: PHASE1
Conditions: Advanced Solid Tumors, Lymphoma
Sponsor: University of California, Davis



E p ac a d ost at / S D -1 0 1 / R a di ot her a p y  
 
Cli nic al St u d y Pr ot o c ol U C D C C # 2 7 1  
 
 
Pr ot o c ol v ersi o n: 0 2. 1 9. 2 0  
U C D a vis C o m pre he nsi v e C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a g e 2 of 9 5  
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 1 
Pr ot oc ol Title: A P hase I/ II Trial of E p aca d ostat  (I n d ola mi ne 2, 3 Di o x y ge n ase I n hi bit or), 
I ntr alesi o nal S D- 1 0 1 ( T oll- Rece pt or 9 A g o nist), a n d Ra di ot hera p y i n Patie nts wit h A d va nce d 
S oli d T u m ors a n d L y m p h o ma  
I h a ve r ea 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 d a nce wit h G o o d 
Cli nical Practices, l ocal r e g ulat or y re q uire me nts, a n d t he Declarati o n of H elsi 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 dy. 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 uct 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  
 
 
 
 
 

E p ac a d ost at / S D -1 0 1 / R a di ot her a p y  
 
Cli nic al St u d y Pr ot o c ol U C D C C # 2 7 1  
 
 
Pr ot o c ol v ersi o n: 0 2. 1 9. 2 0  
U C D a vis C o m pre he nsi v e C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a g e 3 of 9 5  
LI S T O F A B B R E VI A TI O N S 
A D M E     
Abs or pti o n, distri b uti o n, meta b olis m, a n d e xcreti o n  
A E   
 
A d verse e ve nt  
A E SI   
 
A d verse e ve nt of s pecial i nterest  
A L 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 R R   
 
A bsc o pal Res p o nse Rate  
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  
B C R P    
Breast Ca ncer Resista nt Pr o tei n 
BI D   
 
T wice a da y  
C N S   
 
Ce ntral ner v o us s yste m  
C R   
  
Co m plete res p o nse  
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 o m p ute d T o m o gra p h y  
C T C A E   
C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts  
C T V   
 
Cli nical tar get v ol u me  
D C R   
 
Disease c o ntr ol rate 
D F S   
 
Disease 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 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 R S   
 
E paca d ostat + ra di ot hera p y + S D -1 0 1  
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 T V   
 
Gr oss t u m or v ol u me  
Hr   
 
H o ur  
H Bs A g    
He patitis B s urface a nti ge n  
H C V   
 
He patitis C vir us  
HI V   
 
H u ma n I m m u n o deficie nc y Vir us 
h P X R     
Hu ma n pre g na ne X rece pt or  
i. v.   
 
I ntra ve n o us(l y) 
I C H   
 
I nter nati o nal C o nfere nce o n Har m o nizati o n 
I D O 1    
In d olea mi ne 2, 3 -di o x y ge nase 1  
I E C   
 
I n de pe n de nt Et hics C o m mittee 
I H C   
 
I m m u n o hist oc he mical 
I D O  
 
I n d ola mi ne 2, 3 Di o x y ge nase  
I M P  
  
In vesti gati o nal me dici nal pr o d uct  

E p ac a d ost at / S D -1 0 1 / R a di ot her a p y  
 
Cli nic al St u d y Pr ot o c ol U C D C C # 2 7 1  
 
 
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C o nfi de nti al  
 
P a g e 4 of 9 5  
I N D  
 
I n vesti gati o nal Ne w Dr u g 
I N R   
  
Inter nati o nal n or malize d rati o  
I R B   
 
I nstit uti o nal Re vie w B oar d 
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  
I T V  
 
I nter nal tar get v ol u me 
I V  
 
i ntra ve n o us 
L V E F    
left ve ntric ular ejecti o n fracti o n  
L F Ts   
 
Li ver f u ncti o n tests   
 
M A OI    
M o n oa mi ne O xi dase I n hi bit or  
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 S C L C     
N o n s mall cell l u n g ca ncer  
O D N   
  
Oli g o de o x y n ucle oti de 
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   
  
Pr 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 
P K   
  
Phar mac o ki netic  
P R   
  
Partial res p o nse  
P T V   
 
Pla n ni n g treat me nt v ol u me   
R E B   
 
Rese arc 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 T   
 
Ra di ot hera p y  
S A E   
 
Seri o us A d verse E ve nt  
S D   
 
Sta ble disease  
S S   
 
Ser ot o ni n s y n dr o me  
S S RI    
Selecti ve ser ot o ni n re u pta ke i n hi bit ors  
S U S A R    
S us pecte d U ne x pecte d Seri o us A d verse Reacti o n 
T D L N    
T u m or drai ni n g l y m p h n o des  
T L R 9    
T oll -li ke rece pt or 9 
T N F   
 
T u m or necr osis fact or  
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 oce d ure  
U C D C C   
U C Da vis C o m pre he nsi ve Ca ncer Ce nter  
U L N   
 
U p per li mit of n or mal  
 
 

E p ac a d ost at / S D -1 0 1 / R a di ot her a p y  
 
Cli nic al St u d y Pr ot o c ol U C D C C # 2 7 1  
 
 
Pr ot o c ol v ersi o n: 0 2. 1 9. 2 0  
U C D a vis C o m pre he nsi v e C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a g e 5 of 9 5  
S C H E M A  
 
Ge ner al E nr oll m e nt Criteri a  
•  
A d va nce d refract or y s oli d t u m ors or l y m p h o ma  
•  
A ge ≥1 8  
•  
1 4 da y treat me nt was h o ut peri o d  
•  
At least o ne ca n di date treat me nt lesi o n (s u bc uta ne o us, n o dal, or visceral)  
o  
Accessi ble f or R T  
o  
Accessi ble  a n d safe f or re peat i ntralesi o nal i njecti o ns  
•  
At  least o ne ca n di date tar get lesi o n, o utsi de of t he R T fiel d e val ua ble f or res p o nse per 
irR E CI S T  
•  
A de q uate he mat ol o gic a n d e n d or ga n f u ncti o n  
•  
N o acti ve a ut oi m m u ne disease  
•  
Patie nts wit h pre vi o us c hec k p oi nt bl oc ka de t hera p y are eli gi ble  
 
C o nc urre nt R T ( D a y s 1 -5)  
•  C o h ort 1 (s oli d t u m ors): ( 8 G y x 3) or ( 4 G y x 5)  
•  C o h ort 2 ( l y m p h o ma): ( 8 G y x 3) or ( 4 G y x 5) or ( 2 G y x 2) 
+ 
I ntr alesi o n al S D-1 0 1 ( D a y 1, 8, 1 5, 2 2, 2 9)  
4 m g i njecti o n i nt o R T treat me nt lesi o n  
+ 
E p ac a d ost at  
5 0 -3 0 0 m g P O bi d  
P h ase II E x p a nsi o n C o h orts  
Si m o n T w o -St a ge Desi g n  
C o h ort 1 : 
S oli d t u m or ( 1 6 -3 0 patie nts)  
P 0 = 0. 0 5, p 1 = 0. 2 0, r 1 = 1, n 1 = 1 6, r T ot = 3, n T ot = 3 0, 
α = 0. 0 5, p o wer = 0. 8  
C o h ort 2 : 
L y m p h o ma ( 7 -1 4  patie nts)  
P 0 = 0. 0 5 , p 1 = 0.3 , r 1 =0 , n 1 =7 , r T ot =2 , n T ot = 14 , 
α = 0. 0 5, p o wer = 0. 8  
P h ase I D ose Fi n di n g  
3 + 3 Desi g n: ( 3 -6 p atie nts per d ose 
le vel, 6-1 8 p atie nts t ot al)  
D ose le vel -3:  
5 0 m g P O bi d  
D ose le vel -2:  
1 0 0 m g P O bi d  
D ose le vel -1:  
2 0 0 m g P O bi d  
D ose le vel 1:  
3 0 0 m g P O bi d  

E p ac a d ost at / S D -1 0 1 / R a di ot her a p y  
 
Cli nic al St u d y Pr ot o c ol U C D C C # 2 7 1  
 
 
Pr ot o c ol v ersi o n: 0 2. 1 9. 2 0  
U C D a vis C o m pre he nsi v e C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a g e 6 of 9 5  
 
T A B L E O F C O N T E N T S   
A P H A S E I/II T RI A L O F E P A C A D O S T A T (I N D O L A MI N E 2, 3  DI O X Y G E N A S E 
I N HI BI T O R), I N T R A L E SI O N A L S D- 1 0 1 ( T O L L- RE C E P T O R 9 A G O NI S T), A N D  
R A DI O T H E R A P Y I N P A TI E N T S WI T H A D V A N C E D S O LI D T U M O R S A N D 
L Y M P H O M A  ......................................................................................................................... 1 
P R O T O C O L SI G N A T U R E P A G E  ................................................................................................. 2 
LI S T O F A B B R E VI A TI O N S .......................................................................................................... 3  
S C H E M A  ......................................................................................................................................... 5 
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  ......................................................................................................................... 9 
1.  
O BJ E C TI V E S  ....................................................................................................................... 1 0 
1. 1  Pri mar y O bjecti ve  ..................................................................................................... 1 0 
1. 2  Sec o n dar y O bj ecti ves ................................................................................................ 1 0 
1. 3  E x pl orat or y O bjecti ves ............................................................................................. 1 0  
2.  
B A C K G R O U N D  .................................................................................................................. 1 1 
2. 1  Ca ncer I m m u n ot hera p y  ............................................................................................. 1 1 
2. 2  Rati o nale: R T + I ntralesi o nal C p G + I D O bl oc k a d e  ................................................ 1 1 
2. 3  Pre -cli nical data  ........................................................................................................ 1 2 
2. 4  E paca d ostat  ............................................................................................................... 1 8 
2. 5  S D - 1 0 1 ...................................................................................................................... 2 6 
2. 6  Safet y C o nsi derati o ns ............................................................................................... 2 8  
2. 7  Bi o mar kers  ................................................................................................................ 3 0 
3.  
S T U D Y D E SI G N .................................................................................................................. 3 1 
4.  
S T U D Y P O P U L A TI O N  ....................................................................................................... 3 3 
4. 1  I n cl usi o n Criteria ...................................................................................................... 3 3 
4. 2  E xcl usi o n Criteria  ..................................................................................................... 3 4 
5.  
T R E A T M E N T P L A N  ........................................................................................................... 3 5 
5. 1  E paca d ostat  ............................................................................................................... 3 6 
5. 2  S D - 1 0 1 ...................................................................................................................... 3 6 
5. 3  Ra di ot hera p y ............................................................................................................. 3 7  
6.  
G E N E R A L P L A N T O M A N A G E S A F E T Y C O N C E R N S  ................................................. 4 3 
6. 1  Eli gi bilit y Criteria  ..................................................................................................... 4 3 
6. 2  M o nit ori n g ................................................................................................................ 4 3  

E p ac a d ost at / S D -1 0 1 / R a di ot her a p y  
 
Cli nic al St u d y Pr ot o c ol U C D C C # 2 7 1  
 
 
Pr ot o c ol v ersi o n: 0 2. 1 9. 2 0  
U C D a vis C o m pre he nsi v e C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a g e 7 of 9 5  
6. 3  Ma na ge me nt of S pecific A d verse E v e nts  ................................................................. 4 3 
6. 4  Ma na ge me nt of A d vers e E ve nts fr o m I m m u n ot hera p y  ............................................ 4 4 
6. 5  Ma na ge me nt of A d vers e E ve nts Ass ociate d fr o m Ra di ot hera p y ............................. 4 9  
6. 6  G ui deli nes f or D osa g e M o dificati o n a n d Treat me nt I nterr u pti o n or 
Disc o nti n uati o n ......................................................................................................... 4 9  
6. 7  Trea t me nt T oler a bilit y .............................................................................................. 5 0 
6. 8  Ma na ge me nt of S u bjects E x hi biti n g Ser ot o ni n S y n dr o me ....................................... 5 0  
7.  
C O N C O MI T A N T A N D E X C L U D E D T H E R A PI E S  .......................................................... 5 1 
7. 1  C o nc o mita nt T hera p y................................................................................................ 5 1  
7. 2  E xcl u de d T her a p y ..................................................................................................... 5 2  
7. 3  Restricte d Me dicati o ns/ Treat me nt  ............................................................................ 5 4 
8.  
T R E A T M E N T D U R A TI O N  ................................................................................................ 5 5 
8. 1  D urati o n of F oll o w U p .............................................................................................. 5 5  
8. 2  Disc o nti n uati o n D ue t o Disease Pr o gressi o n ............................................................ 5 5  
9.  
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  ................................................................ 5 7 
9. 1  St u d y Cale n dar .......................................................................................................... 5 7  
1 0.  A S S E S S M E N T S T Y P E S  ..................................................................................................... 5 9 
1 0. 1  Efficac y  ..................................................................................................................... 5 9 
1 0. 2  Safet y  ........................................................................................................................ 6 4 
1 0. 3  All St u d y V aria bles  ................................................................................................... 6 4 
1 1.  C O R R E L A TI V E S CI E N C E  ................................................................................................. 6 5 
1 1. 1  Rati o nale  ................................................................................................................... 6 5 
1 1. 2  C orrelati ve St u d y Desi g n a n d Met h o d ol o g y............................................................. 6 6  
1 2.  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 7 
1 2. 1  Sa m ple Size  ............................................................................................................... 6 7 
1 2. 2  Statistical A nal ysis Pla n  ............................................................................................ 6 8 
1 2. 3  Safet y  ........................................................................................................................ 6 8 
1 2. 4  Efficac y  ..................................................................................................................... 6 8 
1 2. 5  S u bject C o urse .......................................................................................................... 6 9  
1 2. 6  C orrelati ve La b orat or y Mar kers  ............................................................................... 6 9 
1 3.  S A F E T Y R E P O R TI N G O F A D V E R S E E V E N T S  .............................................................. 6 9 
1 3. 1  Assess me nt of Safet y  ................................................................................................ 6 9 
1 3. 2  Ris ks Ass ociate d Wit h  .............................................................................................. 6 9 
1 3. 3  A d verse E v e nts  ......................................................................................................... 6 9 
1 3. 4  Met h o ds a n d Ti mi n g f or Assessi n g a n d Rec or di n g Safet y Vari a bles ...................... 7 0  
1 3. 5  Pr oce d ures f or S A E Re p orti n g.................................................................................. 7 1  

E p ac a d ost at / S D -1 0 1 / R a di ot her a p y  
 
Cli nic al St u d y Pr ot o c ol U C D C C # 2 7 1  
 
 
Pr ot o c ol v ersi o n: 0 2. 1 9. 2 0  
U C D a vis C o m pre he nsi v e C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a g e 8 of 9 5  
1 3. 6  Re g ulat or y Re p orti n g ................................................................................................ 7 3  
1 3. 7  Pr oce d ure f or Re p orti n g Pre g na nc y  .......................................................................... 7 4 
1 3. 8  A d diti o nal Re p orti n g Re q uire me nts f or I N D H ol d ers .............................................. 7 4  
1 3. 9  St u d y Cl ose- O ut  ........................................................................................................ 7 5 
1 4.  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 6 
1 4. 1  Et hics a n d G o o d Cli nical Practice  ............................................................................ 7 6 
1 4. 2  I nstit uti o nal Re vie w B oar d/I n d e pe n d e nt Et hics C o m mittee..................................... 7 6 
1 4. 3  St u d y D oc u me ntati o n................................................................................................ 7 6  
1 4. 4  I nf or me d C o nse nt...................................................................................................... 7 6 
1 4. 5  Disc o nti n uati o n of St u d y S u p p ort ............................................................................. 7 8  
1 4. 6  A me n d me nts t o t he Pr ot oc ol ..................................................................................... 7 8  
1 4. 7  Patie nt C o nfi de ntialit y  .............................................................................................. 7 8 
1 4. 8  Pr ot oc ol De viati o ns ................................................................................................... 7 8  
1 4. 9  Q ualit y Ass ura nce ..................................................................................................... 7 8  
1 5.  O V E R SI G H T A N D M O NI T O R OI N G  ................................................................................ 7 9 
1 5. 1  Data a n d Saf et y M o nit ori n g ...................................................................................... 7 9  
1 5. 2  I n v esti gat or M o nit ori n g G ui deli nes .......................................................................... 8 0 
1 6.  R E F E R E N C E S  ..................................................................................................................... 8 0 
1 7.  A P P E N DI C E S  ...................................................................................................................... 8 4 
1 7. 1  A p pe n di x 1: Perf or ma n ce Stat us Scale ..................................................................... 8 4  
1 7. 2  A p pe n di x 2: St u d y Re gistrati o n ................................................................................ 8 5  
1 7. 3  A p pe n di x 3: Data S u b missi o n Sc he d ule ................................................................... 8 6  
1 7. 4  A p pe n di x 4: M olec ular C orrelati ve Sa m ple Ha n dli n g ............................................. 8 7  
1 7. 5  A p pe n di x 5: A na p h yla xis Preca uti o ns ...................................................................... 9 2  
1 7. 6  A p pe n di x 6: I m m u ne- Relate d Res p o nse Criteria  ..................................................... 9 3 
1 7. 7  A p pe n di x 7: Pill Diar y f or E paca d ostat .................................................................... 9 5  
 
LI S T O F T A B L E S  
Ta ble 1.  D ose De -Escalati o n R ules ............................................................................................ 3 2 
Ta ble 2.  Treat me nt Pla n  ............................................................................................................. 3 5 
Ta ble 3.    Critical Or g a ns at Ris k D ose - V ol u me Li mits f or 2 4 G y o ver 3 fracti o ns .................... 4 1 
Ta ble 4:  
S pecific Ma na g e me nt of A d verse E v e nts  .................................................................... 4 6 
Ta ble 5:  
D ose M o dificati o ns of E paca d ostat ............................................................................. 4 9  
Ta ble 6:  
Si g n a n d S y m pt o ms of Ser ot o ni n S y n dr o me ............................................................... 5 1  
Ta ble 7:  Warf ari n d ose m o dificati o ns wit h E paca d ostat ........................................................... 5 4  

E p ac a d ost at / S D -1 0 1 / R a di ot her a p y  
 
Cli nic al St u d y Pr ot o c ol U C D C C # 2 7 1  
 
 
Pr ot o c ol v ersi o n: 0 2. 1 9. 2 0  
U C D a vis C o m pre he nsi v e C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a g e 9 of 9 5  
Ta ble 8:  
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 Dis ease  ....... 5 6 
Ta ble 9:  Best O verall Res p o nse E val uati o n  ............................................................................... 6 1 
Ta ble 1 0:  St u d y Varia bles ............................................................................................................ 6 4  
 
LI S T O F FI G U R E S  
Fi g ure 1.  1 M T Li mits Ra diati o n + C p G I n d u ce d I D O U p- R e g ulati o n a n d I m pr o ves 
T hera p e utic Efficac y  .................................................................................................... 1 4 
Fi g ure 2.  Ra diati o n + C p G + 1 M T Re d uces I ntrat u m oral Re g ulat or y C D 4 + T- cells i n Mice 
a n d Ca ni nes. ................................................................................................................. 1 5  
Fi g ure 3.  A nti -t u m or Effects of R a diati o n + C p G + 1 M T are C D 8 + T cell De pe n d e nt ............. 1 6 
Fi g ure 4.  Efficac y of Ra diati o n + C p G + 1 M T i n a Ca ni ne Cli nical Trial  ................................. 1 7 
 
 
 
 

E p ac a d ost at / S D -1 0 1 / R a di ot her a p y  
 
Cli nic al St u d y Pr ot o c ol U C D C C # 2 7 1  
 
 
Pr ot o c ol v ersi o n: 0 2. 1 9. 2 0  
U C D a vis C o m pre he nsi v e C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a g e 1 0  of 9 5  
1.  
O B J E C TI V E S  
1. 1  
Pri m ar y O bjecti ve  
1. 1. 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 e paca d ostat t hat ca n be 
gi ve n wit h ra di ot hera p y a n d i ntralesi o nal S D- 1 0 1 i m m u n ot hera p y ( E R S: E paca d ostat 
+ ra di ot her a p y + i ntral esi o nal S D - 1 0 1). 
1. 1. 2  
P hase 2: T o c har acterize t he safet y pr ofile of t his re gi me n 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 v erse E v e nts versi o n 4. 0 3). 
 
1. 2  
Sec o n d ar y O bjecti ves  
1. 2. 1  
T o pr o vi de efficac y data f or E R S as deter mi ne b y a bsc o pal res p o nse rate ( d efi ne d as   
o bjecti ve res p o nse rate at u nirra diate d sites) usi n g i m m u ne relate d R E CI S T 
(ir R E CI S T) a n d disease c o ntr ol rate ( D C R) defi n e d as c o m plete res p o nse ( C R) + 
partial res p o nse ( P R) + sta ble disease ( S D). 
1. 2. 2  
T o deter mi ne treat me nt t olera bilit y . 
 
1. 3  
E x pl or at or y O bjecti ves  
1. 3. 1  
T o pr o vi de preli mi nar y d ata o n t he o bjecti ve res p o nse rate ( O R R), pr o gressi o n free 
s ur vi val ( P F S), a n d o verall s ur vi val ( O S) f or E R S t hera p y usi n g ir R E CI S T a n d 
R E CI S T 1. 1 criteri a.  
1. 3. 2  
T o a nal yze s erial bl o o d s a m ples f or ser u m c yt o ki ne a n d tr y pt o p ha n / k y n ure ni ne 
levels, a n d t o q ua ntif y t h e n u m ber, f u n cti o n, a n d ge ne e x pressi o n of circ ulati n g 
i m m u ne cell s u bsets. 
1. 3. 3  
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, 
e x pressi o n of i m m u ne re g ulat or y 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. 
1. 3. 4  
T o e val uate pre -tr eat me nt st o ol sa m ples f or micr o bi o me si g nat ures 
1. 3. 5  
T o disc o ver bi o mar k ers of res p o nse fr o m t he data o btai ne d i n 1. 2, 1. 3. 1, 1. 3. 2, 1. 3. 3, 
a n d 1. 3. 4. 
 
 
 
 
 
 

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2.  
B A C K G R O U N D  
2. 1  
C a ncer I m m u n ot her a p y 
T he all ure of ca n cer i m m u n ot hera p y as a ma gic b ullet a gai nst ca ncer has i ntri g ue d researc hers 
f or o ver a ce nt ur y.  T he r ati o nale u n derl yi n g a nti-ca ncer i m m u n ot hera p y st e ms fr o m t he 
c o nce pt of i m m u ne s ur v eilla nce first attri b ute d t o E hrlic h a n d c ollea g ues o ver a ce nt ur y a g o 
[1 ].   It was f o u n de d i n t h e i dea t hat tiss ue rej ecti o n is act uall y a ma nifestati o n of a n i m m u ne 
s ur veilla nce mec ha nis m t hat g uar ds a g ai nst s p o nta ne o us arisi n g t u m ors.  If s uc h a mec h a nis m 
d oes e xist t he n it sta n ds t o reas o n t hat it ca n b e re-i n vi g orate d a n d har nesse d t o battle 
mali g na nc y i n ca n cer p atie nts.  T his i dea, i n its si m plest f or m, is partic ularl y attracti ve gi ve n 
t hat t he i m m u ne s yste m s h o ul d be a ble t o i de ntif y a n d s pecificall y era di cate mali g na nt cells 
base d o n t he e x pressi o n of a b n or mal a nti ge ns n ot e x presse d or pres e nt i n n or mal tiss ues [ 2 ].  
O n a cell ular l e vel a nti ge n prese nti n g cells ( A P Cs), s uc h as de n dritic cells, p ha g oc ytize 
fra g me nts of d yi n g ca ncer cells a n d prese nt t he m o n t heir cell s urface.  C D 8 + T cells ca n 
rec o g nize t hese a b n or mal a nti ge ns a n d bec o m e acti vate d t o kill cells e x pressi n g t hat a nti ge n.  
C D 4 + T cells ca n eit her hel p t his pr ocess b y e x pressi n g li ga n ds a n d c yt o ki nes w hic h hel p 
acti vate a n d s ustai n t he A P Cs or t he y ca n bec o me i m m u n os u p pressi ve re g ulat or y T cells 
( Tre gs) w hic h e x pr ess F O X P 3 (f or k hea d b o x P 3) a n d i n hi bit C D 8 + T cells.  I n realit y t his is a 
gr oss o versi m plificati o n a n d t he tr ue c o m ple xit y of t he i nteracti o ns bet wee n t he h ost i m m u ne 
s yste m a n d ca ncer are n ot f ull y u n derst o o d b ut ma n y cell t y pes a n d fact ors are i n v ol ve d. 
2. 2  
R ati o n ale: R T + I ntr alesi o n al C p G + I D O bl oc k a de 
T here is gr o wi n g i nter est i n u n dersta n di n g mec ha nis ms of resista nce t o i m m u n ot hera p y a n d 
fi n di n g c o m bi nat orial strate gies t o f urt her i ncreas e effi cac y w hile mi ni mizi n g t o xicit y .   
L ocal ra di ot hera p y ( R T) is a n i deal ca n di dat e f or c o m bi ne d m o dalit y  i m m u n ot hera p y 
strate gies. I n a d diti o n t o de b ul ki n g t u m or a n d releasi n g t u m or a nti ge ns, R T has well -
esta blis he d  i m m u n o m o d ulat or y eff ects [3 ].  Precli nical a n d cli nical re p orts c o nfir m t he safet y 
a n d effi cac y of m ulti m o dalit y strate gies e m pl o yi n g R T a n d i m m u n ot hera p y.  O ne partic ularl y 
pr o misi n g strate g y is R T i n c o m bi nati o n wit h t he i m m u ne sti m ulat or y t oll -li ke rece pt or 9 
( T L R 9) a g o nist C p G oli g o de o x y n ucle oti de ( C p G), w hic h has de m o nstrate d si g nifica nt 
s y ner g y i n pre-cli nical m o dels [4 ] a n d t he a bilit y t o i n d uce re gressi o n of s yste mic disease i n 
cli nical trials [5 , 6 ].    S yste mic res p o nse rates were a b o ut 2 0 % wit h diseas e sta bilit y i n 
a n ot her 2 0 % of patie nts wit h refract or y s yste mic [5 ] or c uta n e o us l y m p h o ma [6 ]. H o w e ver, 
patie nts w h ose t u m ors i n d uce d Tr e gs res p o n d e d p o orl y.  T he effects of C p G o n Tre g me diat e d 
i m m u ne s u p pressi o n ca n be para d o xi cal. C p G ca n re d uce Tre gs b y c o n verti n g t he m t o a 
T- hel per p h e n ot y pe via I L- 6 pr o d ucti o n [ 7 ] a n d ca n als o directl y re vers e Tre g f u ncti o n [8 ].  
C o n versel y, C p G ca n dir ectl y i n d uce F o x p 3 e x pressi o n [ 9 ] a n d u p-re g ulate i n d ola mi ne- 2, 3-
di o x y ge nase (I D O) [ 7 ] w hic h is k n o w n t o i n d uce a n d mai ntai n Tre gs.  

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I D O is a n i m m u n os u p pressi ve e nz y me t hat catal yzes t he rate-li miti n g ste p i n t he cata b olis m of 
tr y pt o p ha n t o k y n ure ni ne a n d is e x presse d b y n u m er o us h u ma n mali g na nci es [1 0 , 1 1 ].  I D O 
e x pressi o n ca n i n d uce i m m u ne t olera nce t o mali g na ncies [1 2 ] vi a c o m ple x  mec ha nis ms [1 3 ].  
I n d e n dritic cells I D O ca n acti vate Tr e g s u p pressi ve f u ncti o n i n a C T L A- 4 de pe n de nt ma n n er 
[1 4 ].  It ca n als o pre v e nt de n dritic cell I L- 6 pr o d u cti o n, t here b y pre ve nti n g Tre g c o n v ersi o n 
a n d mai ntai ni n g ele vate d Tre g le vels des pite i nfl a m mat or y si g nals s uc h as C p G [ 1 5 ]. 
F urt her m ore, I D O ca n directl y i n d uce Tre gs fr o m naï ve C D 4 + T cells via 3-
h y dr o x ya nt hra nillic aci d, a d o w nstrea m cata b olite of I D O tr y pt o p ha n m eta b olis m [ 1 6 , 1 7 ].  
I D O ca n, t hr o u g h si milarl y c o m ple x mec ha nis ms, i n hi bit nat ural  killer cells a n d pre ve nt 
effect or T -cell acti vati o n a n d pr olifer ati o n [1 3 , 1 8 ].  I D O e x pressi o n ca n b e para d o xicall y 
u pre g ulate d after i nfla m mat or y si g nals [1 9 , 2 0 ] pres u ma bl y as a mec ha nis m t o li mit  
i nfla m mati o n a n d mai ntai n i m m u ne h o me ostasis.  
I n m uri n e st u dies a n d a ca ni ne cli nical trial w e ha ve de m o nstrate d t hat I D O u pre g ulati o n b y 
R T + C p G li mits t he res p o nse t o t his t hera p y a n d t hat a d diti o n of I D O bl oc ka de i m pr o ves 
t hera pe utic efficac y.  We h y p ot hesize t hat t he a d diti o n of I D O bl oc ka d e will i m pr o ve u p o n t he 
k n o w n hist orical effi cac y of R T + C p G t hera p y, a n d will be hi g hl y effecti v e a n d well t olerate d 
i n t he ma na ge me nt of a d va nce d s oli d t u m ors a n d l y m p h o mas.  
2. 3  
Pre -cli nic al d at a  
Usi n g a n o vel i m m u n ot hera p y strat e g y c o m bi ni n g l ocal R T, i ntrat u m oral C p G, a n d I D O 
bl oc ka de, w e teste d t he h y p ot hesis t hat I D O u pre g ulati o n after R T + C p G mai ntai ns t u m or 
micr oe n vir o n me nt i m m u ne s u p pressi o n a n d li mits treat me nt efficac y. We f o u n d t hat 
i m m u n osti m ulat or y t hera pies, i ncl u di n g C p G a n d R T, ca n para d o xicall y u p-re g ulate I D O 
e x pressi o n ( Fi g ure 1 a- c). T he a d diti o n of I D O bl o c ka de ( usi n g 1- met h yl tr y pt o p ha n) t o R T + 
C p G t hera p y decrease d I D O acti vit y, a n d si g nifica ntl y i m pr o ve d t he a nti- t u m or effects of R T 
+ C p G b ot h i n ter ms of l ocal t u m or gr o wt h a n d s yste mic metastases ( Fi g ure 1 d- l).  
Mec ha nisticall y, t he  tri pl e t hera p y d ecrease d Tre gs ( Fi g ure 2 a-c), ot her i m m u ne s u p pressi ve 
fact ors ( d ata n ot s h o w n), i ncreas e d t u m or-i nfiltrati n g C D 8 + T-cells wit hi n t he t u m or micr o -
e n vir o n me nt a n d t he a nti- t u m or eff ects were C D 8 + T-cell de pe n de nt ( Fi g ure 3).  Alt h o u g h t he 
im m u ne effects wer e pri maril y li mite d t o t he micr oe n vir o n me nt of t he treate d t u m or, r o b ust 
s yste mic a nti-t u m or res p o nses wer e o bser v e d.  We c o nfir me d t h ese res ults i n a veteri nar y 
cli nical trial of c o m pa ni o n ca ni nes si nce ca ni ne ca ncers cl osel y re prese nt h u ma n mali g na nc y 
( Fi g ure 4).  We o bser v e d si g nifica nt res p o nses at t he R T treate d pri mar y t u m or ( Fi g ure 4a- d) 
as well as at u ntreate d sit es of metastatic disease ( Fi g ure 4e - h) i n m ost d o gs wit h a n 8 0 % 
s yste mic disease c o ntr ol rate e v e n t h o u g h t he treat me nt re gi me n o nl y laste d 2 8 da ys.  We als o 
o bser ve d si g nifica nt c ha n ges i n t he i m m u n os u p pressi ve t u m or micr o-e n vir o n me nt i n ca ni nes 
( Fi g ure 2 d- g), c orr o b or ati n g o ur mec ha nistic m o use data.  I n mar ke d c o ntrast t o i m m u ne 
c hec k p oi nt i n hi bit ors, little t o xicit y was o bser ve d i n m o use or ca ni ne st u dies. T hese res ults 
c o nfir m t he p ote nc y of t his c o m bi nat orial i m m u n ot hera p y strate g y a n d s u g gest t hat t he 

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a d diti o n of I D O bl oc ka d e ma y saf el y i m pr o ve t he efficac y of R T + C p G i m m u n ot hera p y.  T he 
safet y a n d efficac y ma k e t his strate g y ver y attracti ve f or cli nical tra nslati o n. 
 
 
 
 
 

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2. 4  
E p ac a d ost at  
E paca d ostat (I N C B 0 2 4 3 6 0) is a n i n hi bit or of t he e nz y me i n d olea mi ne 2, 3- di o x y ge nase 1 
(I D O 1) t h at is pr o p ose d f or de vel o p me nt f or t h e treat me nt of mali g na nt diseases. I D O 1 
me diates t he cat a b olis m of t he esse ntial a mi n o aci d tr y pt o p ha n ( Tr p) t o k y n ure ni ne ( K y n) 
wit hi n i m m u ne cells a n d a s u bset of t u m or cells. T his cata b olis m of Tr p res ults i n t he 
i n hi biti o n of antit u m or cell – me diate d i m m u ne res p o nses. Hist ol o gic e val uati o n of m ost h u ma n 
ca ncers s h o ws e xte nsi v e i nfiltrati o n b y i nfla m mat or y a n d i m m u ne cells, s u g gesti n g t hat t he 
i m m u ne s yste m d oes rec o g nize a n d r es p o n d t o t he prese n ce of t h e mali g na nc y [2 1 ], b ut i n 
m ost cases t he i m m u ne r es p o nse is i neffecti ve i n i n hi biti n g or era dicati n g t u m or gr o wt h. Ma n y 
t u m or cells or t he i nfiltrati n g i m m u ne cells o vere x press I D O 1, a n d t here ha ve bee n m ulti ple 
li nes of e vi de nce t o s u g gest t hat I D O 1 is a ke y re g ulat or i n t he i m m u n os u p pressi ve 
mec ha nis ms res p o nsi ble f or t u m or esca pe fr o m i m m u ne s ur veilla nce [ 2 2 ]. T heref ore, 
i n hi biti o n of t his e nz y me ma y pr o vi de a u ni q ue m et h o d t o treat mali g na nci es, eit her al o n e or 
i n c o m bi nati o n wit h c he m ot hera pe utics or ot her i m m u ne-base d t hera pies.  
2. 4. 1  
P h ar m ac ol o g y S u m m ar y 
E paca d ostat r e pr ese nts a n o vel, p ote nt, a n d selecti ve i n hi bit or of t he e nz y m e I D O 1. Beca use 
I D O 1 cata b olis m of Tr p i n hi bits T-cell– – me diate d i m m u ne res p o nses a n d I D O 1 e x pressi o n 
has bee n s h o w n t o be ele vate d i n ma n y h u ma n ca ncers, I D O 1 i n hi biti o n ma y rest ore a n 
effecti ve a ntit u m or i m m u ne res p o nse a n d ma y pr o vi de a met h o d t o treat mali g na nt diseases 
eit her al o ne or i n c o m bi nati o n wit h c he m ot hera p e utics a n d/ or i m m u n ot hera p y- base d 
strate gies. I n cell- base d assa ys, e paca d ostat p ote ntl y i n hi bits I D O 1 i n b ot h h u ma n t u m or cells 
a n d h u ma n de n dritic cells ( D Cs) res ulti n g i n re d u ce d Tr p t o K y n c o n versi o n (I C 5 0 val ues = 
7. 1- 1 2. 7 n M). E paca d ost at d oes n ot si g nifica ntl y i n hi bit ot her pr otei ns t hat c o ul d i m pact Tr p 
cata b olis m.  
T o assess its selecti vit y pr ofile, e paca d ostat w as e val uate d i n a br o a d pa nel of a p pr o xi matel y 
5 5 differe nt rece pt ors, i o n c ha n nels, tra ns p orters, a n d n o n- ki nase e nz y mes. E paca d os tat 
de m o nstrate d acti vit y at t he h u ma n vas o pressi n 1a rece pt or (I C 5 0  val ue = 0. 6 7 μ M). A n d 
wea k acti vit y at t he h u ma n d o pa mi ne tra ns p ort er ( 2 2 % a n d 7 1 % i n hi biti o n at 1 a n d 1 0 μ M,  
res pecti vel y) a n d h u ma n car b o nic a n h y dras e II e n z y me (I C5 0 = 5. 3 μ M). I n cel l c ult ure, 
e paca d ostat re v erses t he str o n g i n hi bit or y effect o n t he de vel o p me nt of T- cell-me diate d 
res p o nses t hat I D O 1 acti vit y i m parts, res ulti n g i n e n ha nce d T-cell a n d nat ural killer ( N K) cell 
pr oliferati o n, e n h a nce d i nterfer o n g a m ma pr o d u cti o n, re d uce d re g ulat or y T l y m p h oc yte ( T re g) 
differe ntiati o n, r e d uce d D C a p o pt osis, a n d e n ha n ce d e x pressi o n of D C acti vati o n mar kers. 
E paca d ostat r e versal of t he I D O 1 - m e diate d s u p pressi o n of T-cell pr oliferati o n is d ose 
de pe n de nt wit h a p ote n c y c o nsiste nt wit h its i n hi biti o n of Tr p t o K y n c o n versi o n 
( E C5 0 = 1 7. 7 n M). T he i n viv o data d e m o nstrate t hat e paca d ostat ca n i n hi bit I D O 1 

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s yste micall y a n d, i m p orta ntl y, i n t u m ors a n d t u m or drai ni n g l y m p h n o des ( T D L N). 
E paca d ostat w as efficaci o us i n m o use m o dels of c ol o n a n d pa ncrea tic ca ncer, a n d its a bilit y t o 
re d uce t u m or gr o wt h was de pe n de nt o n a f u ncti o n al i m m u ne s yste m, c o nsiste nt wit h its 
pr o p ose d mec h a nis m of acti o n. M ore o ver, e paca d ostat e n ha nce d l y m p h oc yte f u ncti o n i n 
t u m ors a n d T D L N. T he c o m bi nati o n of e paca d ost at a n d eit her a n a nti - m o use C T L A 4 or a n 
a nti- m o use P D L 1 a nti b o d y was als o s h o w n t o act s y ner gisticall y i n si g nifica ntl y re d uci n g 
t u m or gr o wt h i n a mela n o ma xe n o graft m o del. Fi nall y, e paca d ostat i m pr o ve d t he t u m or 
gr o wt h c o ntr ol of c yt ot o xic c he m ot hera p y w he n use d i n c o m bi nati o n. T hese data s u p p ort t he 
e val uati o n of e p aca d ost at i n patie nts wit h mali g na nt diseases. E paca d ostat di d n ot pr o d uce a n y 
a d verse eff ects after a si n gle oral d ose t o rats ( 1 0 0 0 m g/ k g) i n ce ntral ner v o us s yste m ( C N S) 
or res pirat or y s afet y p h ar mac ol o g y st u dies, a n d n o a d verse effects were n ot e d i n a 
car di o vas c ular st u d y i n tele meterize d d o gs. T he I C 5 0 f or t he i n hi bit or y effect of e p aca d ost at 
o n h u ma n et her- à- g o- g o-relate d ge n e ( h E R G) p ot assi u m c urre nt w as 2 1 9. 5 μ M. T his val ue is 
a p pr o xi matel y 1 5 0 0- f ol d o ver t he u n b o u n d h u ma n Cma x val ue at a ma xi m u m cli nical d ose of 
6 0 0 m g. 
2. 4. 2  
 N o ncli nic al Dr u g Met a b olis m a n d P h ar m ac o ki netics S u m m ar y  
I n vitr o a n d i n viv o st u dies wer e c o n d uct e d t o c haracterize t he a bs or pti o n, distri b uti o n, 
meta b olis m, a n d e xcr eti o n ( A D M E) pr ofile of e p aca d ostat. I n p har mac o ki n etic ( P K) st u dies 
c o n d ucte d i n mice, r ats, c y n o m ol g us m o n ke ys, a n d bea gle d o gs, e p aca d ost at e x hi bite d oral 
bi oa vaila bilit y val ues ra n gi n g fr o m 1 1 % t o 5 5 %. T he t otal s yste mic cleara nce ( C L) w as 
m o derate i n mice ( 2. 5 L/ h/ k g), rats ( males 1. 1, fe males 1. 9 L/ h/ k g), c y n o m ol g us m o n ke ys 
( 0. 8 1 L/ h/ k g), a n d d o gs ( 0. 4 6 L/ h/ k g) after i ntra v e n o us (I V) a d mi nistrati o n, wit h he patic 
e xtracti o n r ati os of a p pr o xi matel y 2 4 % t o 5 8 %. E paca d ostat e x hi bite d a m o derate v ol u me of 
distri b uti o n ( V dss) a n d t he ter mi nal half-life val u es after I V d oses ra n ge d fr o m 1. 4 t o 3. 3 
h o urs i n t he vari o us s peci es st u die d. Pr otei n bi n di n g of e paca d ostat was hi g h, wit h mea n ex 
viv o fr ee fracti o ns of 2. 5 % i n mice a n d 3. 8 % i n d o gs, w hile t he mea n i n vitr o free fracti o n i n 
h u ma n plas ma was 3. 1 %. 
I n t he 1 3- wee k t o xic o ki n etic st u dies i n mice a n d d o gs, t he Cma x a n d A U C val ues ge nerall y 
i ncreas e d wit h d ose, alt h o u g h n ot al wa ys d ose pr o p orti o nall y. T he A U C val ues o n Da y 9 0 
were si milar t o c orres p o n di n g val ues o n Da y 1, e x ce pt f or t he mi d - a n d hi g h- d ose gr o u ps i n 
mice, w her e e x p os ur es o n Da y 9 0 were l o wer t ha n t hat o n Da y 1. N o ge n d er differe n ces were 
o bser ve d i n d o gs; h o we v er, t he plas ma e x p os ure i n fe male mice was greater t ha n t hat o bser ve d 
i n male mice at c orres p o n di n g d ose le vels.  
Meta b olis m st u dies ha ve s h o w n t hat t he e nz y mes res p o nsi ble f or t he f or mati o n of t he maj or 
meta b olites, M 9 a n d M 1 1, were U G T 1 A 9 a n d g ut fl ora, res p ecti vel y. M 1 2 is a sec o n dar y 
meta b olite of e paca d ostat f or me d via o xi dati o n of M 1 1 b y c yt oc hr o me P 4 5 0 ( C Y P) 3 A 4 a n d t o 
a lesser e xt e nt b y C Y P 2 C 1 9 a n d C Y P 1 A 2. T he maj or plas ma a nal yte prese nt i n mice a n d 

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h u ma n plas ma was M 9, w hile e paca d ostat was t h e maj or plas ma c o m p o n e nt i n d o gs. I n vitr o 
tra ns p orter st u dies s u g geste d t hat e paca d ostat was li kel y a s ubstrate of P -g p a n d Breast Ca ncer 
Resista nt Pr otei n ( B C R P).  
T he meta b olis m of e paca d ostat was e xa mi ne d i n t he plas ma a n d e x creta of mice a n d bile d uct 
ca n n ulate d d o gs gi ve n a si n gle oral or I V d os e of 1 4 C-I N C B 2 4 3 6 0. M 9, a n O- gl uc ur o ni de of 
I N C B 2 4 3 6 0, was t he o nl y maj or meta b olite ( great er t ha n 1 0 % of t otal dr u g-relate d A U C) 
ra di oc he micall y detecte d i n t he plas ma of mice , c o m prisi n g 6 6. 3 % t o 7 4. 1 % of t he t otal A U C. 
Uri nar y M 9 acc o u nte d f or 2 0. 8 % t o 3 0. 8 % of t he a d mi nistere d d ose a n d w as t he o nl y 
meta b olite f o u n d at le vels > 1 0 % of t he a d mi nistere d d ose i n t he feces of mice d ose d orall y 
wit h e pac a d ostat. I n d o g plas ma, e paca d ostat was t he o nl y ra di oc he micall y detecte d 
c o m p o ne nt fr o m t he or al d ose gr o u p. Biliar y M 9 acc o u nte d f or 3 3. 5 % ( P O) t o 4 7. 2 % (I V) of 
a d mi niste d d ose a n d was c o nsi dere d t he o nl y maj or meta b olite f or me d i n d o gs. N o ne of t he 
meta b olites acc o u nte d f or > 5 % of t h e d o g d ose i n uri ne. M 1 1 was t he o nl y meta b olite 
ra di oc he micall y detecte d i n d o g feces as le vels 1. 1 % of d ose i n oral d os e gr o u p.  
Res ults fr o m t he h u ma n pre g na ne X rece pt or ( h P X R) re p orter ge ne assa y s u g gest t hat t he 
p ote ntial f or e paca d ostat t o ca use i n d ucti o n of C Y P 3 A 4 i n h u ma ns at cli nicall y rele va nt 
e x p os ures is l o w. E paca d ostat a n d its maj or meta b olites, M 9, M 1 1, a n d M 1 2, ha ve l o w 
p ote ntial t o ca use dr u g- dr u g i nteracti o ns t hr o u g h C Y P a n d U G T i n hi biti o n base d o n I C 5 0 
val u es. H o we v er, bas e d o n t he i n vitr o I C5 0 f or s orafe ni b i n hi biti o n of U G T 1 A 9 ( 2. 3 μ M), 
t here is a p ote ntial f or dr u g i nteracti o ns if a d mi nistere d c o n c o mita ntl y wit h e paca d ostat, a n d 
f urt her cli nical st u dies ma y be warra nt e d. Si milarl y, t he p ote ntial f or e p aca d ostat t o ca use 
cli nical dr u g - dr u g i nteracti o ns via h u ma n u pta ke tra ns p orters O A T 1, O A T 3, O C T 2, a n d 
O A T P 1 B 1 is l o w. Base d o n i n vitr o data, i n hi biti o n of he patic u pta k e tra ns p orter O A T P 1 B 3 
b y M 9 a n d M 1 1 ca n n ot e ntirel y be e xcl u de d. 
I n mice, e xcreti o n was ra pi d a n d c o m plete aft er a si n gle oral d ose of [1 4C]e paca d ostat. After 
oral a d mi nistrati o n of [ 1 4 C]e paca d ostat at 5 0 0 m g/ k g i n mice, rec o ver y i n feces was greater 
t ha n uri nar y e x creti o n . After or al d ose a d mi nistrati o n, 3 3. 2 % was e x crete d i n t he uri ne a n d 
5 0. 6 % was e x cret e d i n t he feces i n fe mal es. Bl o o d -t o-plas ma ra di o acti vit y c o nce ntrati o n rati os 
were a p pr o xi matel y 0. 6 t o 0. 7 after or al a d mi nistrati o n i n males a n d fe mal es, res pecti vel y. 
T his i n dicates pref ere ntial distri b uti o n of ra di oacti vit y i n t he plas ma p orti o n of bl o o d. A 
c o m paris o n of tiss ue distri b uti o n bet wee n n o n pi g me nte d a n d pi g me nte d m ale mice s h o we d 
si milar patter ns of distri b uti o n a n d tiss ue c o nce ntrati o ns, e xce pt f or hi g h er c o nce ntrati o ns of 
ra di oacti vit y i n t he e ye u vea i n pi g me nte d mice. 
2. 4. 3  
N o ncli nic al T o xic ol o g y S u m m ar y  
T he t o xic ol o gic a n d t o xic o ki netic pr ofiles of e paca d ostat were c haract erize d b y si n gle a n d 
re peat oral d ose st u dies of u p t o 3 m o nt hs i n d urati o n i n mice a n d d o gs. Ass ess me nts of 
p ote ntial ge netic t o xicit y were c o n d ucte d usi n g i n vitr o a n d i n viv o test s yste ms. 

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Oral a d mi nistrati o n st u dies i n mice, rats, a n d d o gs were c o n d ucte d i n or d er t o assess t he 
p ote ntial s yste mic t o xicit y of e paca d ostat. I n si n gl e d ose st u dies, d oses u p t o 4 0 0 0 m g/ k g i n 
mice, u p t o 1 0 0 0 m g/ k g i n rats, a n d u p t o 5 4 0 m g/ k g i n d o gs di d n ot c o m pr o mise t he sal u brit y 
of t he a ni mals. I n r e peat oral d ose st u dies i n mice, n o a d verse e paca d ostat- relate d effects were 
o bser ve d i n a n y p ara met er e val u ate d. T he n o - o bs er ve d-a d vers e-effect-le v el ( N O A E L) f or 
male a n d fe m ale m ice gi ve n e paca d ostat f or 3 m o nt hs was 1 0 0 0 m g/ k g per da y. I n t he 3-
m o nt h re peat or al d ose st u d y i n d o gs, 1 male gi ve n t he hi g h d ose of 1 0 0 0 m g/ k g per da y was 
sacrifice d m ori b u n d o n Da y 2 9 of t he a d mi nistrati o n p hase beca use of p o or c o n diti o n 
ass ociate d wi t h li ver i nfl a m mati o n. Sli g htl y i ncrease d li ver e n z y mes n ote d i n t his a ni mal 
d uri n g t he pre d ose p h ase s u g geste d t hat e paca d ost at ma y ha ve e xacer bat e d a pre- e xisti n g li ver 
c o n diti o n. Cli nical o bser vati o ns ass ociate d wit h e paca d ostat a d mi nistrati o n i n t he 3- m o nt h d o g 
st u d y i ncl u de d t hi n a p peara nce a n d i ncrease d i nci de nce of  e mesis a n d diarr hea ( > 2 5 0 m g/ k g 
per da y) a n d l o wer f o o d c o ns u m pti o n a n d b o d y wei g ht l oss ( 1 0 0 0 m g/ k g per da y). 
Micr osc o pic fi n di n gs i ncl u de d l y m p ha n gectasia i n t he s mall i ntesti ne ( > 2 5 0 m g/ k g per da y), 
he pat ocell ular h y p ertr o p h y, l y m p h oi d de pleti o n of t he t h y m us, a n d c hr o nic i nfla m mati o n wit h 
fi br osis a n d s u bac ute i nfl a m mati o n i n t he lar ge i ntesti ne ( 1 0 0 0 m g/ k g per d a y). Wit h t he 
e xce pti o n of l y m p ha n giectasia i n t he jej u n u m, all e paca d os tat-rel ate d fi n di n gs ha d re verse d 
after t he 4 - wee k rec o ver y peri o d. T he hi g hest n o n –se verel y t o xic d ose ( H N S T D) a n d N O A E L 
were 2 5 0 m g/ k g per da y base d o n t he r e versi bilit y of t he lesi o ns o bser ve d at t his d ose le vel. 
E paca d ostat w as f o u n d t o be de v oi d of clast o g e nic or m uta ge nic p ote ntial i n i n vitr o bacterial 
re vers e m uta ge nicit y a n d c hr o m os o me a berrati o n assa ys as well as i n a n i n viv o b o ne marr o w 
micr o n ucle us test i n rats.  
2. 4. 3. 1  
P ote nti al Ris ks  
I n t he 3- m o nt h d o g st u d y, li ver i nfla m mati o n necessitate d t he e ut hanasia of a si n gle male 
gi ve n t he hi g h d ose of 1 0 0 0 m g/ k g per da y. Ser u m c he mistr y e val uati o ns re veale d el e vate d 
li ver e nz y mes ( as part ate tra nsa mi nase [ A S T], ala ni ne tra nsa mi nase [ A L T], ga m ma-gl uta m yl 
tra nsfer ase [ G G T], a n d al kali ne p h os p hatase [ A L P]) al o n g wit h ele v ate d t otal bilir u bi n. Li ver 
i nfla m mati o n was c o nfir me d hist ol o gicall y. Alt h o u g h t his a ni mal ha d sli g ht li ver e nz y me 
ele vati o ns d uri n g t he prest u d y peri o d, s u g gesti n g a pre-e xisti n g li ver c o n diti o n, a n effect of 
e paca d ostat o n t he li ver ca n n ot be r ule d o ut. A d diti o nal fi n di n gs i n re peat oral d ose d o g 
st u dies i ncl u de d a n i ncrease d i nci de nce of e mesis a n d diarr h ea. H u ma n s u bjects will ha ve li ver 
f u ncti o n tests ( L F Ts) cl osel y m o nit ore d d uri n g partici pati o n i n cli nical st u dies a n d will be 
m o nit ore d f or a n y si g ns of GI distress i ncl u di n g diarr hea, na usea, v o miti n g, a n d/ or a b d o mi nal 
pai n. T hera p y will be wit h dra w n or i nterr u pte d u ntil res ol uti o n if t here are si g ns of si g nifica nt 
gastr oi ntesti nal distress a n d/ or cli nicall y rele va nt ele vati o ns i n L F Ts.  
T he mea n A U C 0- 2 4 ass o ciate d wit h t he N O A E L of 2 5 0 m g/ k g per da y fr o m t he d o g 3- m o nt h 
st u d y is 6 3 9 μ M- h t otal ( 2 4. 3 u M- h u n b o u n d) a b d us a p pr o xi matel y 1 7-f ol d hi g her t ha n t he 

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cli nical A U C 0- 2 4 ass oci ate d wit h t he hi g hest pr o p ose d d ose t o be f urt h er st u die d cli ni call y 
( 6 0 0 m g t wice a da y [ BI D]). 
T he oreticall y, I D O 1 r e pr ese nts a n i m p orta nt i m m u ne c o ntr ol e nz y m e. Cells e x pressi n g I D O 1 
are ca pa ble of s u p pressi n g a m plifie d i m m u ne effect or res p o nses a n d pr o m oti n g i m m u ne 
t olera nce u n d er v ari o us p h ysi ol o gical c o n diti o ns. I n hi biti o n of t he I D O p at h wa y usi n g 1-
met h yl tr y pt o p ha n ( 1- M T) has bee n s h o w n t o i n d uce fet al all o graft rejecti o n i n mice [2 3 ]. 
S y n ge neic pl uri p ote nt b o ne marr o w ste m cells, tra nsferre d t o mice wit h e x p eri me ntal 
a ut oi m m u ne e nce p h al o m yelitis (a m o del of m ulti ple scler osis), e n h a nce d rec o ver y, pre ve nte d 
rela pses, a n d pr o m ote d m yeli n re pair t hr o u g h t heir e x pressi o n of I D O. T his was bl oc ke d b y 
a d mi nistrati o n of 1 -M T [2 4 ], a n d i n hi biti o n of t he I D O pat h w a y b y s yste mic a d mi nistrati o n of 
1- M T at cli nical o nset si g nifica ntl y e xacer bat e d disease sc ores i n t his m o del [2 5 ]. Bl oc ki n g 
I D O wit h 1-M T als o a g gra vate d t he s e verit y of art hritis a n d e n ha nce d t he i m m u ne res p o nses 
i n mice wit h c olla ge n-i n d uce d art hritis [2 6 ]. Rece nt st u dies wit h t he a nti-C T L A - 4 a nti b o d y 
i pili m u ma b ha ve s h o w n d ysre g ulati o n of m uc osal i m m u nit y a n d gastr oi ntesti nal t o xicit y, 
w hic h ma nifests as diarr hea [2 7 ] as well as i ncrease i n li ver  e nz y mes s u c h as A L T a n d A S T. 
F or t hese reas o ns, s u bjects wit h a hist or y of a ut oi m m u ne disease were e x cl u de d fr o m 
partici pati o n i n all c urr e nt st u dies wit h e paca d ostat, a n d st u d y partici pa nts were cl osel y 
m o nit ore d f or si g ns or s y m pt o ms of de vel o pi n g a ut oi m m u ne or i nfla m mat or y disease.  
I n hi biti o n of I D O c o ul d ca use a n i ncreas e i n ser ot o ni n le vels t hat c o ul d ca us e a cl uster of 
a d verse e ve nts ( A Es) ter me d ser ot o ni n s y n dr o me ( S S) w he n a d mi nistere d al o ne or i n 
c o m bi nati o n wit h ot her ser ot o ner gic a ge nts. T his rare s y n dr o me has bee n ass ociate d wit h 
s o me m o n oa mi ne o xi dase ( M A O) i n hi bit ors a n d c o m bi nati o ns of ser ot o ner gic dr u gs [2 8 ]. T h e 
cli nical ma nifestati o ns of S S ra n ge fr o m barel y perce pti ble t o let hal; o nset is ra pi d ( wit hi n 1 2 
h o urs of dr u g a d mi nistrati o n). Base d o n preli mi nar y st u dies i n t he rat, c o nce ntrati o ns of 
e paca d ostat i n t he cer e br os pi nal fl ui d were bel o w t he q ua ntifia ble li mit of detecti o n  ( 2 n M) 
after I V a d mi nistrati o n , a n d t otal brai n h o m o ge nat e c o nce ntrati o ns were a p pr o xi matel y 1 5 % 
of c orr es p o n di n g plas ma c o nce ntr ati o ns. T heref ore, e paca d ostat e x hi bits a p pare nt li mite d 
pe netrati o n acr oss t he bl o o d brai n barri er a n d is li kel y n ot ass ociate d wit h si g nifica nt effects 
o n Tr p meta b olis m i n t he brai n t hat mi g ht i m pact brai n ser ot o ni n le vels. Alt h o u g h t his 
re pres e nts a t he or etical ris k o nl y, use of M A O i n hi bit ors will be pr o hi bite d, a n d all s u bjects 
a n d sites will be i nf or me d of t he p ote ntial ris k. Sites will als o be prese nt e d wit h pr oce d ures f or 
s u bjects e x hi biti n g S S or S S-li ke s y m pt o ms. 
2. 4. 4  
Cli nic al S u m m ar y  
As of 2 9 O C T 2 0 1 6, 1 2 P hase 1 a n d 2 I nc yt e-s p o ns ore d cli nical st u dies ha ve eit her bee n 
c o m plete d or are o n g oi n g. T hree cli nical st u dies ha ve c o m plete d ( St u dies I N C B 2 4 3 6 0- 1 0 1, 
I N C B 2 4 3 6 0- 1 0 2, a n d I N C B 2 4 3 6 0- 2 1 0). Of t he 9 o n g oi n g st u dies 7 (I N C B 2 4 3 6 0- 2 0 1, I N C B 
2 4 3 6 0- 2 0 2, I N C B 2 4 3 6 0- 2 0 3, I N C B 4 3 6 0- 2 0 4, I N C B 2 4 3 6 0- 1 1 0, I N C B 2 4 3 6 0- 3 0 1 a n d 

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I N C B 3 9 1 1 0- 1 0 6) ar e c o m bi nati o n t hera p y st u dies. As of 2 9 O C T 2 0 1 6, 8 9 8 u ni q ue s u bjects 
ha ve bee n e x p ose d t o I N C B 0 2 4 3 6 0 as m o n ot hera p y ( 1 4 9 s u bjects) a n d/ or i n c o m bi nati o n wit h 
c hec k p oi nt i n hi bit ors (a nti - P D - 1 tar gete d t hera p y: 5 4 3 s u bjects; a nti- pr o gra m me d deat h-
li ga n d 1 ( P D- L 1) tar g ete d t hera p y: 1 2 4 s u bjects; a nti-C T L A - 4 tar gete d t h era p y: 5 0 s u bjects; 
a n d a J A K i n hi bit or: 3 2 s u bjects ). 
2. 4. 4. 1  
C o m plete d St u dies  
St u d y I N C B 2 4 3 6 0- 1 0 1 was a c o m plete d P has e 1, m ultice nter, o pe n-la b el, d ose- escalati o n 
st u d y i n s u bjects wit h refract or y s oli d t u m ors t hat use d a 3 + 3 d esi g n t o deter mi ne t he safet y 
a n d t olera bilit y, P K, a n d p har mac o d y n a mics of es calati n g oral d oses of e paca d ostat. S u bjects 
were a d mi nistere d d oses of e paca d ostat ra n gi n g fr o m 5 0 m g o nce dail y ( Q D) t o 7 0 0 m g BI D. 
Of t he 5 2 s u bjects treate d, 8 s u bjects ( 1 5. 4 %) h a d a n A E lea di n g t o deat h. Of t hese 8 s u bjects, 
t he ca use of deat h w as disease pr o gressi o n i n 7 s u bjects a n d h y p o xia i n t he re mai ni n g s u bject. 
D uri n g t he st u d y, 2 5 s u bjects ( 4 8. 1 %) h a d a s eri o us a d verse e ve nt ( S A E). T he m ost fre q ue ntl y 
re p orte d S A Es w ere disease pr o gr essi o n ( 4 s u bjects, 7. 7 %), a b d o mi nal pai n, na usea, a n d 
h y p o xia ( 3 s u bjects eac h, 5. 8 %). Treat me nt- e mer g e nt A Es ( T E A Es) were re p orte d i n all 
s u bjects. 
Fati g ue w as t he m ost fre q ue ntl y re p orte d T E A E ( 3 6 s u bjects, 6 9. 2 %). T w o d ose- li miti n g 
t o xicities ( D L Ts) occ urre d; 1 D L T of ra diatio n p n e u m o nitis at t he 3 0 0 m g BI D d os e le vel a n d 
1 D L T of fati g ue at t he 4 0 0 m g BI D d ose l e vel. A ma xi m u m t olerate d d ose ( M T D) was n ot 
deter mi ne d.  
I n St u d y I N C B 2 4 3 6 0- 1 0 1 after f aste d oral a d mi nistrati o n, e paca d ostat plas ma c o nce ntrati o ns 
attai ne d t he pea k val ues ( C ma x ) t y picall y at 2 h o urs ( me dia n Tma x ) p ost d ose; t he t 1⁄ 2 was 2. 9 
h o urs. A hi g h- fat meal di d n ot ca use a statisticall y si g nifica nt c ha n ge i n e paca d ostat plas ma 
e x p os ures; t her ef or e, e paca d ostat ma y be a d mi nistere d wit h o ut re g ar d t o f o o d. I n hi biti o n of 
I D O 1 was d os e- de p e n de nt, a n d at d oses at or a b o ve 3 0 0 m g BI D, e paca d ostat effecti vel y 
ac hie ve d m a xi mal i n hi biti o n of I D O 1 acti vit y at tr o u g h, as assesse d usi n g c ha n ges i n K y n 
le vels. 
I N C B 2 4 3 6 0- 1 0 2 was a P hase 1, si n gle-ce nter, o pe n -la bel, dr u g- dr u g i nteracti o n st u d y of 
e paca d ostat wit h warf ari n. T his was a 2 - peri o d st u d y c o nsisti n g of 2 treat me nts a d mi nistere d 
i n a fi xe d se q ue n ce. D uri n g Peri o d 1 ( Da ys 1- 7), s u bjects recei ve d a si n gle d ose of warfari n 2 5 
m g orall y ( P O) o n Da y 1. D uri n g Peri o d 2 ( Da ys 8- 2 1), s u bjects recei ve d e p aca d ostat 3 0 0 m g 
BI D P O o n D a ys 8 t o 2 0. O n Da y 1 4 of Peri o d 2, s u bjects als o recei ve d a si n gle d ose of 
warf ari n 2 5 m g. Ei g htee n s u bjects were e nr olle d i n t he st u d y. N o deat hs or S A Es occ urre d. N o 
T E A E was re p orte d i n m ore t ha n 1 s u bject eac h i n a gi ve n peri o d. T E A E occ urre d o nl y o n ce 
i n a gi ve n peri o d, a n d n o T E A E occ urre d i n b ot h p eri o ds f or a gi v e n s u bject. 

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P a g e 2 4  of 9 5  
St u d y I N C B 2 4 3 6 0- 2 1 0 was a r a n d o mize d, o pe n-la bel, P hase 2 st u d y of e p aca d ostat vers us 
ta m o xife n i n w o me n wit h hist ol o gicall y c o nfir me d Fe derati o n of I nter nati o nal G y nec ol o gists 
a n d O bstetricia ns ( FI G O) Sta ge III or I V e pit helial o varia n ca ncer, pri mar y perit o neal ca ncer, 
or fall o pia n t u be carci n o ma w h o ha ve h a d bi oc he mical- rec urre nce, d efi ne d as a n i ncreasi n g 
ca ncer a nti ge n  1 2 5 le v el t hat was greater t ha n t he u p per li mit of n or mal ( U L N) a n d 
s uccessi vel y i ncr easi n g o n 2 c o nsec uti ve meas ure me nts at least 2 wee ks a p art wit h o ut cli nical 
or ra di o gra p hi c e vi de n ce of disease ( at least 2 × U L N o n 2 occasi o ns at least 1 wee k a part 
wi t h o ut e vi de nce of disease is a U K-s pecifi c re q uire me nt). F ort y-t w o s u bjects were e nr olle d 
( 2 2 i n t he e paca d ostat-tr eate d gr o u p a n d 2 0 i n t he t a m o xife n-treate d gr o u p). N o s u bject ha d a n 
A E lea di n g t o deat h. O n e e paca d ostat-treate d s u bj ect ( 4. 5 %) h a d a n S A E of a b d o mi nal pai n, 
a n d 1 ta m o xife n- tr eate d s u bject ( 5 %) h a d a n S A E of ascites. Fati g ue was t h e m ost fre q ue ntl y 
re p orte d T E A E i n t he e p aca d ostat gr o u p ( 8 s u bjects, 3 6. 4 %), f oll o we d b y n a usea ( 6 s u bjects, 
2 7. 3 %), ras h ( 5 s u bjects, 2 2. 7 %) a n d a b d o mi nal diste nti o n, c o nsti pati o n, a n d v o miti n g ( 4 
s u bjects eac h, 1 8. 2 %). T his st u d y was ter mi nate d b y t he s p o ns or; n o ne w s afet y c o n cer ns wit h 
e paca d ostat wer e i de ntifi e d. S u bjects were f oll o w e d acc or di n g t o t he Pr ot oc ol. 
2. 4. 4. 2  
O n g oi n g St u dies  
St u d y I N C B 2 4 3 6 0- 2 0 1 is a n o n g oi n g P hase 1/ P hase 2 st u d y of e paca d ostat a d mi nistere d i n 
c o m bi nati o n wit h i pili m u ma b i n s u bjects wit h u nresecta ble or metastatic m ela n o ma w h o ma y 
ha ve ha d 1 or m ore pri or s yste mic re gi me ns f or a d va nce d mel a n o ma. T he st u d y has 2 p hases. 
T he first p hase is a n  o p e n-la bel, d ose-escal ati o n safet y r u n -i n p h ase. T he s ec o n d p hase is a 
ra n d o mize d, bli n de d, place b o-c o ntr olle d st u d y. C o h orts i n P hase 1 i ncl u de e paca d ostat 3 0 0 
m g BI D, 1 0 0 m g BI D, 2 5 m g BI D, 5 0 m g BI D c o nti n u o us, 5 0 m g BI D i nter mitte nt ( 2 wee ks 
o n, 1 wee k  off), a n d 7 5 m g ( 5 0 m g A M/ 2 5 m g P M) wit h i pili m u ma b 3 m g/ k g e ver y 3 w ee ks. 
St u d y I N C B 2 4 3 6 0- 2 0 2 is a n o n g oi n g P hase 1/ 2 st u d y of e paca d ostat a d mi nistere d i n 
c o m bi nati o n wit h pe m br oliz u ma b, wit h P hase 1 bei n g a d ose- escalati o n p h ase a n d P hase 2 
bei n g a n o p e n-la b el, si n gle ar m, c o h ort e x pa nsi o n p hase. P hase 1 is c o n d u cte d i n s u bjects wit h 
a d va nce d or metastatic s oli d t u m ors i ncl u di n g Sta ge III B, Sta ge I V, or rec urre nt n o n – s mall 
cell l u n g ca ncer ( N S C L C), mela n o ma, tra nsiti o nal cell carci n o ma of t he g e nit o uri n ar y tract, 
re nal cell ca ncer, tri ple n e gati ve breast ca n cer, a d e n ocarci n o ma of t he e n d o metri u m, or 
s q ua m o us cell car ci n o ma of t he hea d a n d nec k ( S C C H N) w h o ha ve diseas e pr o gressi o n o n at 
least 1 li ne of t hera p y f or a d va nce d or metastatic ca ncer (e x ce pt mela n o ma). P hase 2 is 
c o n d ucte d i n s u bjects wit h N S C L C, mela n o ma, tra nsiti o nal cell carci n o ma of t he 
ge nit o uri nar y tract, tri ple ne gati ve breast ca n cer, S C C H N, o varia n ca ncer, diff use lar g e B- cell 
l y m p h o ma ( D L B C L), a n d clear cell re n al cell ca n cer. 
T he p hase 1 h as c o m plet e d e nr oll me nt wit h a t otal of 6 2 s u bjects. S u bjects were treate d wit h 
e paca d ostat 2 5 m g BI D ( n = 4), 5 0 m g BI D ( n = 2 0), 1 0 0 m g BI D ( n = 1 8), a n d 3 0 0 m g BI D ( n = 
2 0) i n c o m bi nati o n wit h pe m br oliz u ma b 2 m g/ k g or 2 0 0 m g I V e ver y 3 wee ks. Tr eat me nt -
relate d A Es w er e re p orte d i n 5 0 s u bjects ( 8 1 %). T he m ost fre q ue ntl y re p ort e d treat me nt-relate d 

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P a g e 2 5  of 9 5  
A Es wer e fati g ue a n d ras h ( 2 9 % eac h). Ras h i ncl u des t he preferre d ter ms ras h, ras h 
er yt he mat o us, ras h g e ner alize d, ras h m ac ul o - pa p ular, ras h pr uritic, a n d ras h f ollic ular. O nl y 1 2 
patie nts ( 1 9 %) e x p erie n ce d ≥ Gra d e 3 treat me nt -relate d A E. T h e m ost fre q ue ntl y re p orte d ≥ 
Gra de 3 tr eat me nt -relate d A E wer e ras h ( 8 %), ele vate d li pase ( 5 %), ele v at e d a m ylase ( 3 %). All 
ot her ≥ Gra d e 3 treat me nt-relate d A E o cc urre d i n o nl y o ne patie nt eac h. Fi ve s u bjects ( 8 %) 
disc o nti n ue d f or a tr eat m e nt- relat e d A E: Gra de 3 art hral gia, Gra de 3 A S T i ncreas e d/ Gra d e 2 
A L T i ncrease d, Gra de 3 li pase i ncrease d, Gra de 3 ase ptic me ni n gitis, a n d Gra de 2 ner v o us 
s yste m dis or der. N o treat me nt-relate d d eat hs occ urre d as of 0 7 J U L 2 0 1 6. 
St u d y I N C B 2 4 3 6 0- 2 0 3 is a n o n g oi n g P hase 1/ 2 o pe n-la bel st u d y of e p aca d ostat a d mi nistere d 
i n c o m bi nati o n wit h M E DI 4 7 3 6 ( d ur v al u ma b) i n s u bjects wit h a d va nce d mela n o ma, N S C L C, 
pa ncreati c ca ncer, or S C C H N. T he d ose-escal ati o n part of t he st u d y ( P hase 1) uses a 3 + 3 
desi g n t o i de ntif y t he M T D or p har mac o d y na micall y acti ve d ose ( P A D) of e paca d ostat i n 
c o m bi nati o n wit h d ur val u ma b. P hase 2 f urt her e x pl ores t he safet y a n d effi cac y of t h e M T D or 
P A D of e paca d ostat i n c o m bi nati o n wit h d ur val u ma b deter mi ne d i n P hase 1 i n o pe n- la bel 
e x pa nsi o n c o h orts i n t he t u m or t y pes descri be d. 
St u d y I N C B 2 4 3 6 0- 2 0 4 is a n o n g oi n g P hase 1/ 2, o pe n-la bel st u d y of e p aca d ostat a d mi nistere d 
i n c o m bi nati o n wit h ni v ol u ma b c o n d ucte d i n 2 parts. T he first part of t he st u d y ( P hase 1) 
c o nsists of a d ose-es calati o n of e paca d ostat wit h a starti n g d ose of 2 5 m g BI D t o assess t he 
safet y a n d t oler a bilit y of e paca d ostat a d mi nistere d wit h ni v ol u ma b 3 m g/ k g e ver y 2 w ee ks i n 
s u bjects wit h select a d va nce d s oli d t u m ors a n d l y m p h o mas. T he f oll o wi n g t u m or t y pes are 
i ncl u de d i n t his part: mela n o ma, N S C L C, c ol orect al ca ncer ( C R C), S C C H N, o varia n ca ncer 
a n d B cell n o n- H o d g ki n l y m p h o ma ( N H L) or H o d g ki n l y m p h o ma ( H L), i ncl u di n g D L B C L. A 
3 + 3 desi g n is utilize d t o i de ntif y t he M T D. T he s ec o n d part ( P hase 2) of t he st u d y i ncl u des 7 
e x pa nsi o n c o h orts i n t u m or t y pes teste d i n P hase 1 (e xce pti o n: D L B C L is t he o nl y l y m p h o ma 
per mitte d) a n d i ncl u des a n a d diti o nal c o h ort f or gli o blast o ma. I n P hase 2, s u bjects are 
a d mi nistere d t he rec o m me n de d P hase 2 d oses of e paca d ostat BI D i n c o m bi nati o n wit h 
ni v ol u ma b 2 4 0 m g flat d ose e ver y 2 wee ks. 
St u d y I N C B 2 4 3 6 0- 1 1 0 is a P hase 1 d ose-escal ati o n st u d y of e paca d ostat a d mi nistere d i n 
c o m bi nati o n wit h M P D L 3 2 8 0 A (atez oliz u m a b) i n s u bjects wit h pre vi o usl y treate d Sta ge III B, 
Sta ge I V, or N S C L C. T his st u d y will utilize a 3 + 3 desi g n t hat will i de ntif y t he M T D or a 
P A D of e paca d ostat i n c o m bi nati o n wit h atez oliz u ma b i n s u bjects w h o ha v e faile d a pl ati n u m-
base d c he m ot hera p y r e gi me n f or Sta ge III B or Sta ge I V N S C L C. A n e x pa nsi o n c o h ort ( u p t o 
a p pr o xi matel y 2 0 s u bjects) will e val uate t he M T D or P A D fr o m t he es calati o n p orti o n of t he 
st u d y t o f urt her deter mi n e t he saf et y, t olera bilit y, efficac y, P K, a n d P D i n t his p o p ulati o n. A 
sec o n d e x pa nsi o n c o h ort (a p pr o xi matel y 6- 1 2 s u bj ects) wit h ma n dat or y pretreat me nt a n d p ost-
treat me nt bi o ps y re q uir e me nts will be e nr olle d t o e val uate t he c ha n ge i n bi o mar ker e x pressi o n 
after i nitial m o n ot hera p y e paca d ostat treat me nt a n d t he n e paca d ostat +  at ez oliz u ma b 
c o m bi nati o n treat me nt.  

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P a g e 2 6  of 9 5  
I N C B 3 9 1 1 0- 1 0 6 is a n o pe n-la bel, P hase 1 b, pl atf or m st u d y i n s u bjects wit h a d va nce d or 
metastatic s oli d t u m ors. T he st u d y is di vi de d i nt o 2 parts ( Part 1a a n d Part 1 b). Part 1a 
e val uates a J A K i n hi bit or wit h J A K 1 select i vit y (I N C B 0 3 9 1 1 0) i n c o m bi nati o n wit h 
e paca d ostat ( Gr o u p A) a n d I N C B 0 3 9 1 1 0 i n c o m bi nati o n wit h a PI 3 K- d elta i n hi bit or 
(I N C B 0 5 0 4 6 5; Gr o u p B) t o deter mi ne t he M T D or P A D a n d t he rec o m me n de d Part 1 b d oses 
f or eac h c o m bi nati o n. O n ce t he r ec o m me n de d d os e is i de ntifie d f or eac h treat me nt gr o u p i n 
Part 1a, s u bjects wit h a d va nce d s oli d t u m ors are e nr olle d i nt o e x pa nsi o n c o h orts base d o n 
treat me nt hist or y wit h a P D- 1 pat h wa y-tar gete d a ge nt ( Part 1 b).. 
2. 5  
S D - 1 0 1   
Bacterial de o x yri b o n ucleic aci d ( D N A) has l o n g b ee n rec o g nize d as ha vi n g p ote nt sti m ulat or y 
effects o n t he i m m u ne s yste m, i ncl u di n g sti m ulati n g rejecti o n of tra ns pla nt a ble t u m ors i n mice 
[2 9 ]. T his acti vit y is me diate d pref ere ntiall y b y s p ecific D N A m otifs e nric h e d wit h c yti di ne-
p h os h o- g ua n osi ne ( C p G) di n ucle oti des a n d ca n b e re plicate d b y s h ort s y nt h etic 
oli g o de o x y n ucle oti des ( O D Ns ) [3 0 , 3 1 ]. C p G-O D Ns sti m ulate s pecific i m m u ne cell t y pes b y 
acti vati o n of t he i n nate r ec o g niti o n rece pt or, T oll- li ke rece pt or- 9 (T L R 9 ) [3 2 ], a n d ha ve n o 
acti vit y i n mice wit h a h o m oz y g o us deleti o n of t he T L R 9  ge ne [3 3 ].  
S D - 1 0 1, a n O D N  e nric he d C p G m otifs .  It is a 3 0- mer p h os p h or ot hi oate ( P S) O D N c o ntai ni n g 
j u xta p ose d C p G m otifs wit h fla n ki n g re gi o ns, i n a self-c o m pli me ntar y pali n dr o mic se q ue nce 
t hat is desi g nate d as a Cl ass C-t y pe se q ue n ce ( C p G-C) . T he C p G-C t y pe s e q ue nces are a n 
a g o nist f or T oll- li ke rece pt or 9 ( T L R 9) a n d p ote nt i n d ucers of i nterfer o n al p ha ( I F N- α) 
pr o d ucti o n fr o m plas mac yt oi d de n dritic cells ( p D Cs ), as well as p D C mat urati o n a n d B cell 
pr oliferati o n . P ote ntial mec ha nis ms b y w hic h T L R 9  sti m ulati o n b y C p G-O D Ns ma y ha v e a 
si g nifica nt a ntit u m or effect i ncl u de e n ha n ce me nt of i n nate a n d T -cell i m m u nit y, sti m ulati o n of 
c yt o ki nes wit h direct or i n direct a ntit u m or acti vities (i ncl u di n g I F N - α), a n d pr o d ucti o n of 
c yt ot o xic a nti b o dies [ 3 4 , 3 5 ]. S D- 1 0 1 Dr u g Pr o d u ct is a clear t o sli g htl y o palesce nt, c ol orless 
t o pale yell o w s ol uti o n free of visi ble particl es f or m ulate d i n p h os p hate b uffere d s ali ne. 
S D - 1 0 1 is a sterile li q ui d d osa ge f or m t hat is a d mi nistere d as a n i ntrat u m oral or s u bc uta ne o us 
i njecti o n. N o  str uct urall y si milar c o m p o u n d (ie, C p G- O D N) has bee n a p pr o ve d as a dr u g 
s ubsta nce f or a n y i n dicati o n. 
Base d o n st u dies wit h c ult ure d h u ma n peri p h eral bl o o d m o n o n uclear cells ( P B M Cs), 
C p G- O D N s ca n sti m ulate i nterfer o n -al p h a (I F N-α)  a n d i nterle u ki n (I L)- 1 2 pr o d ucti o n as well 
as f u ncti o nal mat urati o n i n plas mac yt oi d de n dritic cells  ( p D Cs) [3 6 ] a n d ca n i n d uce 
pr oliferati o n a n d i m m u n o gl o b uli n (I g) pr o d ucti o n i n h u ma n B l y m p h oc ytes ( B cells) [ 3 7 ]. 
Si g nali n g b y C p G- O D N s t hr o u g h T L R 9  re q uires acti ve u pta ke of t he O D N as T L R 9  is prese nt 
o nl y i n s pecific i ntracell ular c o m part me nts [3 8 ]. T he T L R 9 si g nali n g occ urs i n 2 disti nct 
i ntracell ular str uct ures, earl y a n d late e n d os o mes [3 9 , 4 0 ], lea di n g t o differe nt o utco mes . 

E p ac a d ost at / S D -1 0 1 / R a di ot her a p y  
 
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P a g e 2 7  of 9 5  
S D - 1 0 1 bel o n gs t o t he C p G-C class of C p G - O D Ns a n d was selecte d t o sti m ulate ver y hi g h 
le vels o n I F N- α as well as i n d uci n g mat urati o n of p D Cs t o a nti ge n-prese nti n g cells .  
T L R 9  sti m ulati o n b y C p G-O D Ns ma y res ult i n a si g nifica nt a ntit u m or  effect b y e n ha nci n g 
i n nate i m m u nit y, a da pti ve T-cell i m m u nit y a gai nst t u m or -s pecific a nti ge ns, a n d t he 
c yt ot o xicit y of t hera pe uti c a ntit u m or m o n ocl o nal a nti b o dies [4 1- 4 4 ]. A d diti o nall y, 
C p G- O D Ns ha v e si g nifica nt a dj u va nt effects i n i n d uci n g a nti b o d y a n d T-cell res p o nses t o 
i m m u n o ge ns. T L R 9 is hi g hl y c o nser ve d, a n d C p G- O D Ns ca n be st u die d i n a variet y of 
s pecies. N o ncli nical t u m or m o dels ha ve de m o nstrate d de n ov o , e n ha n ce d, or pr ol o n ge d 
a ntit u m or res p o nses w he n usi n g C p G- O D Ns al o n e or i n c o nj u ncti o n wit h ot her acti ve a ge nts. 
T he r o de nt s pecies use d f or m ost a ntit u m or i n vesti gati o ns e x presses T L R 9  o n a wi der 
s pectr u m of cell t y pes, i ncl u di n g m o n oc ytes a n d m yel oi d de n dritic cells ( mD Cs) [4 5 ]. T h us, 
t he differ e nt res ults of T L R 9  sti m ulati o n ma y c o m plicate direct e xt e nsi o n of o bser vati o ns i n 
r o de nts t o h u ma ns. C p G- O D Ns ar e a n i m p orta nt p ote ntial ne w class of a ge nts deser vi n g 
f urt her e x pl orati o n i n t he treat me nt of ca ncers a n d ot her t hera p e utic a p plicati o ns i n h u ma ns 
[3 2 , 4 1 ].  
I n n o n cli nical p har m ac ol o g y st u dies, S D - 1 0 1 is a p ote nt sti m ulator of I F N - α. T o xicit y i n 
pri mates was c h aracterize d b y i nfla m mat or y c h a n ges li kel y res ulti n g fr o m t he 
i m m u n osti m ulat or y effect of S D - 1 0 1 a n d mi ni mal c o m ple me nt acti vati o n w hic h is c o nsiste nt 
wit h a k n o w n class- eff ect of O D Ns . I n n o ncli nical st u dies, t he a bs or pti o n i n plas ma (rats a n d 
m o n ke ys) a n d distri b uti o n i nt o tiss ues (rats) of S D - 1 0 1 f oll o wi n g S C i njecti o n were c o nsiste nt 
wit h t he patter n pre vi o usl y re p orte d f or ma n y ot her str uct urall y si milar O D Ns [ 4 6 ]. W hile t he 
a bs or pti o n, distri b ut i o n, meta b olis m, a n d eli mi nati o n ( A D M E) pr ofile of S D - 1 0 1 has n ot 
f or mall y bee n e xa mi ne d f oll o wi n g i ntrat u m oral i njecti o n (i n n o ncli nical or cli nical st u dies t o 
date), p u blis he d cli nical s t u dies wit h a n ot her i m m u n osti m ulat or y P S  O D N  (s pecificall y C p G 
7 9 0 9) f or t he tr eat me nt of ca ncer a d mi nistere d via S C a n d i ntrat u m oral i njecti o ns 
de m o nstrate d b ot h l ocal a n d s yste mic effects, s u g gesti n g si milar bi oa vaila bilit y b y b ot h r o utes 
[4 7 ]. Gi ve n t he si milar bi oa vaila bilit y, a n d t h e u n dersta n di n g t hat S C a d mi nistrati o n res ults i n 
a p preci a ble de p ositi o n at t he site of i njecti o n [ 4 8 ], it is li kel y t hat i ntrat u m oral i njecti o n uses a 
si milar mec ha nis m f or esta blis hi n g a n A D M E pr ofile per mitti n g b ot h l ocal a n d s yste mic 
effects. S D - 1 0 1 p har m ac o d y na mic  effects o n t he i m m u ne s yste m s h o ul d persist f or se veral 
da ys. 
I n h u ma ns, p h ase 1 trials ha ve bee n c o m plete d wit h S D - 1 0 1 i n: 1) healt h y n or mal v ol u nteers 
(Trial D V 3 -H N V - 0 1), a n d 2) patie nts wit h he patitis C vir us ( H C V ) i nfecti o n (D V 3 -H C V - 0 1). 
P K assess me nts fr o m t he trials i n healt h y n or mal v ol u nteers i n dicate t hat S D - 1 0 1 le vels i n t he 
plas ma pea ke d 2 t o 4 h o urs after s u b c uta ne o us ( S C) dr u g a d mi nistrati o n a n d decli ne d aft er 4 
h o urs. T hese dat a ar e c o nsiste nt wit h t he plas ma dis p ositi o n of P S  O D N s t hat ha ve a s h ort 
plas ma half -life of h o urs after S C a d mi nistrati o n . I n a n ot her cli nical trial  of S D - 1 0 1 i n 2 6 
healt h y male v ol u nteers ( Trial D V 3 -H N V - 0 1), d os e-li miti n g t o xicities of se vere hea dac he, 

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P a g e 2 8  of 9 5  
i njecti o n site i n d urati o n, a n d nec k p ai n were o bser ve d i n 1 s u bject gi ve n 5. 0 m g of S D - 1 0 1, 
res ulti n g i n a halt i n d ose escalati o n a n d accr ual. A d diti o nal a d verse e ve nts ( A Es) i ncl u de d 
i nfl ue nza-li ke s y m pt o ms s uc h as hea d ac h e, c hills, fati g ue, a n d p yre xia, as well as i njecti o n site 
e ve nts s uc h as er yt he ma, i n d urati o n, a n d pai n. Tra nsie nt l y m p h o pe nia was t he m ost c o m m o n 
la b orat or y a b n or malit y o bser ve d. T here w as n o e vi de nce of c o m ple me nt acti vati o n, 
c oa g ulati o n a b n or malities, a ut o-a nti b o d y de vel o p me nt, or ac ute A E s y n dr o me.  I n t h e trial of 
S D - 1 0 1 i n 3 4 patie nts wit h c hr o nic H C V i nfecti o n, u p t o 5. 0 m g of S D - 1 0 1 was a d mi nistere d 
al o ne or i n c o m bi nati o n wit h ri ba viri n ( Trial D V 3 -H C V - 0 1). T h e maj orit y of A Es were 
i njecti o n site reacti o ns (i njecti o n site er yt he ma, i njecti o n site s welli n g, i njecti o n site pai n, a n d 
i njecti o n site pr urit us), i nfl ue nza-li ke s y m pt o ms, p yre xia, a n d m yal gia. M ost A Es were mil d 
or m o derate i n r e p orte d s e verit y. O ne p atie nt  i n t he S D - 1 0 1 0. 1 m g/ri ba viri n gr o u p 
e x perie n ce d a n S A E of h y pert h yr oi dis m t hat was c o nsi dere d pr o ba bl y rel ate d t o S D - 1 0 1 a n d 
u nrelate d t o ri ba viri n. N o deat hs occ urre d d uri n g t he trial. A trial of i ntrat u m oral S D- 1 0 1 i n 
c o m bi nati o n wit h l o w- d ose l ocal ra di ati o n ( X R T) is o n g oi n g i n patie nts (I N D 1 2 2 8 0 9 ) wit h 
u ntreate d l o w- gra de n o n- H o d g ki n’s l y m p h o mas w h o d o n ot re q uire i m me di ate s yste mic 
t hera p y (D V 3 -L Y M - 0 1). I n D V 3 -L Y M - 0 1, 3 pati e nts ha ve recei v e d 5 i ntrat u m oral d oses of 
S D - 1 0 1 1. 0 m g, a n d 3 patie nts ha ve recei ve d 5 i ntrat u m oral d oses of S D- 1 0 1 2. 0 m g. N o D L T 
was o bser v e d a n d t he m ost c o m m o n A Es were tra nsie nt fl u-li ke ill ness i n t he 2. 0 m g  c o h ort. 
D osi n g at 4. 0 m g is pla n ne d b ut has n ot yet be g u n. S D - 1 0 1 has bee n a d mi nistere d t o 5 patie nts 
wit h N H L w h o ha d pr o gr essi ve disease after a n all o ge neic b o ne m arr o w tra ns pla nt i n a n 
o n g oi n g i n vesti gat or s p o ns ore d trial ( Sta nf or d U ni versit y Me dical Ce nter,  I N D 1 1 1 9 8 5). 
T hree p atie nts recei ve d 3 wee kl y i ntrat u m oral d os es of S D- 1 0 1 0. 3 m g a n d 2 patie nts recei ve d 
3 wee kl y i ntrat u m oral d oses of S D- 1 0 1 1. 0 m g. O ne u nrelate d S A E of Kle bsiella bactere mia 
was re p orte d i n a patie nt w h o recei ve d S D - 1 0 1 1. 0 m g. N o ot her A Es ha v e bee n re p orte d 
( D y na va x p ers o nal c o m m u nicati o n wit h i n vesti gat or).  T he rec o m me n d e d d ose of S D- 1 0 1 f or 
c o m bi nati o n trials is 4 m g.  
2. 6  
S afet y C o nsi der ati o ns  
As m o n ot hera p y t he A E of S D- 1 0 1 i ncl u de hea dac he, i njecti o n site reacti o n, tra nsie nt fl u- li ke 
ill ness, m yal gia, a n d p yre xia. As m o n ot hera p y t h e m ost c o m m o n  A E  i n 1 4 9 patie nts treate d 
wit h e paca d ostat w er e ( % ≥ Gra d e 3): diarr h ea  ( 0 %), na usea ( 3. 4 %), v o miti n g ( 2. 7 %), ast he nia 
( 0 %), f ati g ue ( 4 %), ele vate d A S T/ A L T ( 1. 3 %), art hral gia ( 0 %), pr urit us ( 0 %) a n d s ki n ras h 
( 1. 3 %). B ot h a ge nts are well t ole rate d as si n gle a ge nts. T he t o xicit y pr ofile of t hese a ge nts 
de m o nstrates mi ni mal ris k of o verla p pi n g t o xicit y. It is p ossi ble t hat t he s ki n ras h ass ociat e d 
wit h e paca d ostat c o ul d e xacer b ate t he i njecti o n site reacti o n i n d uce d b y S D- 1 0 1 or t hat 
art hral gia ass ociate d wit h e paca d ostat c o ul d e xacer bate t he fl u -li ke s y m pt o ms a n d m yal gia 
i n d uce d b y S D- 1 0 1.  
Gi ve n t he mi ni mal ris k of o verla p pi n g t o xicit y a n d t he t olera bilit y of t he a ge nts as 
m o n ot hera p y, we a ntici pate t hat S D- 1 0 1 will be well t olerate d i n c o m bi nati o n wit h 

E p ac a d ost at / S D -1 0 1 / R a di ot her a p y  
 
Cli nic al St u d y Pr ot o c ol U C D C C # 2 7 1  
 
 
Pr ot o c ol v ersi o n: 0 2. 1 9. 2 0  
U C D a vis C o m pre he nsi v e C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a g e 2 9  of 9 5  
e paca d ostat. F urt h er m ore, t he l ocal i ntralesi o nal a d mi nistrati o n of S D -1 0 1 is li kel y t o li mit t he 
p ote ntial f or s yste mic i nteracti o ns wit h e p aca d ost at.  Li ke wise , b ot h classes of a ge nts are li kel y 
t o be well t olerate d i n c o m bi nati o n wit h ra di ot hera p y gi ve n t he precli nical a n d cli nical data 
o utli ne d i n secti o n 2. 2. T his is c o nfir me d i n o ur pre- cli nical m o use a n d lar g e a ni mal ca ni ne 
st u dies t hat de m o nstrate mi ni mal t o xicit y w he n c o m bi ni n g t hese t hera pies.  A d diti o nall y, 
e paca d ostat has de m o nstr ate d s af et y a n d little e vi de nce of p ot e ntiati n g t o xicit y i n trials wit h 
ot her i m m u n ot hera p y a g e nts w hic h ar e m ore t o xi c t ha n S D- 1 0 1. I n 5 4 3 patie nts treate d wit h 
e paca d ostat a n d a nti -P D - 1 c o m bi nati o n t hera p y t h e m ost c o m m o n A E were ( % ≥ Gra d e 3): 
a dre nal i ns ufficie nc y ( 0. 2 %), h y p ot h yr oi dis m ( 0 %), diarr h ea  ( 1. 5 %), n a usea ( 1. 7 %), v o miti n g 
( 1. 8 %), ast he ni a ( 1. 3 %), fati g ue ( 2 %), ele v ate d A S T/ A L T ( 1. 7 %), art hral gia ( 0. 3 %), 
p ne u m o nitis ( 0. 2 %), pr urit us ( 0. 6 %) a n d s ki n ras h ( 2. 9 %). Si milar res ults are o bser ve d i n 1 2 4 
pa tie nts treate d i n c o m bi nati o n wit h a nti-P D - L 1 t hera p y, a n d 3 2 patie nts treate d wit h a J A K 
i n hi bit or. 
I n t his trial we will i nitiate st u d y wit h t he 3 0 0 m g bi d d osi n g of e paca d ostat. As m o n ot hera p y 
t he M T D of e p aca d ostat was n ot reac he d at 6 0 0 m g bi d. T his 3 0 0 m g bi d d ose is c urre ntl y 
bei n g teste d i n ot her p has e II st u dies of e paca d ostat i n c o m bi nati o n wit h i m m u n ot hera p y. T he 
safet y pr ofile f or t he 3 0 0 m g bi d d ose of e paca d ostat i n c o m bi nati o n wit h pe m br oliz u ma b i n 
t he P hase I/II st u d y (I N C B 2 4 3 6 0- 2 0 2) di d n ot e xcee d t he M T D i n t hat st u d y.  W hile t here w as 
a hi g her i nci de n ce of gra de 3 ras h i n t he 3 0 0 m g bi d c o h ort c o m pare d t o t he 1 0 0 m g bi d c o h ort, 
t hese di d n ot q ualif y as pr ot oc ol-s pecifi e d D L Ts.  T he d ose of 3 0 0 m g e p aca d ostat i n 
c o m bi nati o n wit h pe m br oliz u ma b is c urre ntl y u n der st u d y i n all c urre nt pr ot oc ol. O ne 
e xce pti o n is t he d ose c o m bi nati o n of 1 0 0 m g bi d e paca d ostat pl us pe m br oliz u ma b f or t he 
P hase III mel a n o ma st u d y (I N C B 2 4 3 6 0- 3 0 1) w hi c h  is base d u p o n a b e nefit/ris k assess me nt 
ma de s pecifi call y i n mela n o ma i n  c olla b orati o n wit h Merc k.  I n I N C B 2 4 3 6 0- 2 0 2, t here w as 
e vi de nce of i m pr o ve d efficac y i n mela n o ma s u bjects at all d oses of e p aca d ostat of fr o m 5 0 t o 
3 0 0 m g bi d.  Gi ve n t hat mela n o ma is a n i m m u n ot hera p y res p o nsi ve t u m or, a n d l o wer d oses of 
e paca d ostat a p pear e d t o ha ve si milar acti vit y, t he decisi o n was ma de t o ta k e t he 1 0 0 m g bi d 
d ose c o m bi nati o n f or war d beca use of t he l o wer i nci de nce of d ose i nterr u pti o ns a n d d ose 
re d ucti o ns c o m par e d t o t he 3 0 0 m g bi d d ose. H o w e ver, i n ot her t u m or t y pes, w hic h a p pear t o 
de m o nstrate m ore resista nce t o k n o w n i m m u n ot hera pies, greater t ar get c o v era ge f or i n hi biti o n 
of I D O 1 ma y b e necessar y.  O ur P K/ P D m o delli n g s u g gests t hat d oses of 1 0 0 m g bi d 
e paca d ostat ac hie v e a n a vera ge I C 5 0 at tr o u g h i n m ost patie nts.  At 3 0 0 m g bi d, e paca d osta t 
ac hie ves tar get i n hi biti o n a b o ve t he I C 9 0 at tr o u g h.  T he greater tar get i n hi biti o n necessar y i n 
m ore resista nt t u m ors bal a nces be n efit/ris k i n fa v or of t he hi g her e paca d ost at d ose 
c o m bi nati o n gi ve n t hat t he d ose d oes n ot e x cee d t he M T D.  
T his trial will f oll o w a d ose de-es calati o n desi g n. T his desi g n is c h ose n bas e d o n a ris k/ be nefit 
a nal ysis. T he saf et y of t h e 3 0 0 m g bi d d ose of e paca d ostat i n c o m bi nati o n wit h S D- 1 0 1 is 
u ncertai n. H o we ver, base d o n t he li mite d t o xicit y of t hese a g e nts as m o n ot hera p y; t he n o n-

E p ac a d ost at / S D -1 0 1 / R a di ot her a p y  
 
Cli nic al St u d y Pr ot o c ol U C D C C # 2 7 1  
 
 
Pr ot o c ol v ersi o n: 0 2. 1 9. 2 0  
U C D a vis C o m pre he nsi v e C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a g e 3 0  of 9 5  
o verla p pi n g t o xicit y pr ofile of t hese a g e nts; t he li mite d s yste mic effects of S D- 1 0 1 d ue t o 
l ocal i ntralesi o nal a d mi nistrati o n;  t he t olera bilit y of t his d ose of e paca d ostat i n c o m bi nati o n 
wit h ot her, m ore t o xic, i m m u n o t hera pies; t he lac k of e vi de nce t hat e paca d ostat p ote ntiates t he 
t oxicit y of ot her i m m u n ot hera pies; a n d t he li mite d t o xicit y of t his c o m bi nati o n o bser ve d i n 
precli nical  m o use a n d lar ge a ni mal st u dies; we belie ve t hat t he p ote ntial f or t o xicit y is l o w. 
O ur a nal ysis of t he l o w p ote ntial f or t o xicit y at t he 3 0 0 m g bi d d ose c o u ple d wit h t he p ote ntial 
be nefit of t his d ose i n ter ms of tar get i n hi biti o n s u p p orts t he desi g n of a de-escalati o n st u d y 
i nitiate d at t he 3 0 0 m g bi d d ose of e paca d ostat as t he m ost et hical desi g n b y li miti n g treati n g 
patie nts at a l o wer d os e w hic h ma y be less effecti ve w he n t he d os e wit h s u peri or tar g et 
i n hi biti o n is li kel y t o be t olerate d. 
 
2. 7  
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 orrel ati 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 treat me nt res p o nse or fail ure. 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 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 serial tiss ues sa m ples pre -treat me nt ( d uri n g nee dle place me nt f or t he first S D- 1 0 1 
i njecti o n), d uri n g E R S  t hera p y a n d at pr o gressi o n ( o pti o nal). T he desi g n of t his st u d y all o ws 
us t o c o m pare i m m u ne m ec ha nis ms pre- t o p ost-t hera p y.   
T u m or P D- L 1 e x pr essi o n has bee n li n ke d t o res p o nse rates of P D- 1 c hec k p oi nt bl oc ka de [ 4 9 ].  
Pre -clinical data s u g g ests t hat ra di ot hera p y m a y u pre g ulate i ntrat u m oral P D- L 1 e x pressi o n 
[5 0 ] 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.    D ata pres e nte d at A S C O a n d SI T C i n dicate t hat d ur val u ma b m o n ot hera p y 
res p o nse r ates 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 v e bee 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 1 , 5 2 ].  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 ke 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 3 ] 
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 ne p ote ntial mec ha nis m 
[5 3 ].  R T has bee n de m o nstrate d t o i n d uce TI Ls [5 4 ] a n d ma y p ote ntiall y o verc o me t his 
mec ha nis m of resista n ce t o c hec k p oi nt bl oc ka d e. 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. W het her P D - L 1 e x pressi o n or t he prese n ce of 
TI Ls is i m p orta nt f or res p o nse t o e paca d ostat or S D - 1 0 1 is u n k n o w n. 
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 hec k p oi nt bl oc ka d e i n N S C L C [ 5 5 ].  
W het her m utati o nal l oa d is 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 orrelat es wit h 
res p o nse t o e p aca d ostat or S D- 1 0 1 is u n k n o w n. 

E p ac a d ost at / S D -1 0 1 / R a di ot her a p y  
 
Cli nic al St u d y Pr ot o c ol U C D C C # 2 7 1  
 
 
Pr ot o c ol v ersi o n: 0 2. 1 9. 2 0  
U C D a vis C o m pre he nsi v e C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a g e 3 1  of 9 5  
O ur pre vi o us st u dies de m o nstrate t hat u pre g ulati o n of I D O a n d i ntrat u m oral Tre gs are a 
mec ha nis m of resista n ce t o ra di ot hera p y + C p G i m m u n ot hera p y.  T h us e x a mi ni n g I D O le vels 
a n d t he pres e nce of i ntrat u m oral Tre gs will be critical f or testi n g o ur h y p ot h esis. 
A gr o wi n g b o d y of e vi de nce s u g gests t hat t he g ut micr o bi o me is a n i m p orta nt c o ntri b ut or t o 
t he o verall i m m u ne a n d i nfla m mat or y stat us of a n i n di vi d ual. T he i ntesti nal fl ora ca n pr o d uce 
bi oacti ve m olec ules s uc h as s h ort c hai n fatt y aci ds a n d tr y pt o p ha n meta b o lites w hic h ca n h a ve 
pr of o u n d effects o n i m m u ne res p o nses. T h e micr o bi o me c o ul d i nfl ue nce t h e o utc o me of 
i m m u n ot hera p y a n d pla y a r ole i n re g ul ati n g t he a nti-ca ncer i m m u ne res p o nse.  
 
3.  
S T U D Y D E SI G N  
T his is a p hase I/II st u d y t hat will use a sta n dar d 3 + 3 desi g n f oll o we d b y a S i m o n-t w o sta ge 
patie nt e x pa nsi o n as ill ustrate d i n t he sc he m a. F or t he p hase I p orti o n t he pri mar y e n d p oi nt is 
t o deter mi ne t he ma xi m u m t olerate d d ose ( M T D). F or t he p h ase II p orti o n t he pri mar y 
e n d p oi nt is safet y a n d t o xicit y . Safet y an d t o xicit y will be e val uate d usi n g C T C A E v 4. 0 3. T he 
sec o n dar y e n d p oi nt a n d t he e n d p oi nt use d f or t he Si m o n-t w o sta ge desi g n is t he disease  
c o ntr ol rate (D C R ) defi n e d as c o m plete res p o nse  + partial res p o nse + sta bl e disease 
( C D + P R + S D).  T his e n d p oi nt is bei n g use d beca use se veral st u dies ha ve d e m o nstrate d t hat 
patie nts wit h o ut res p o nse t o i m m u n ot hera p y ca n still ha ve l o n g ter m disease sta bilit y w hic h is 
of cli nical be nefit. Deter mi ni n g treat me nt t olera bilit y (as defi ne d i n secti o n 6. 6)  is als o a 
sec o n dar y e n d p oi nt. E x pl orat or y e n d p oi nts i ncl u de o bjecti ve res p o nse rate ( O R R) , pr o gressi o n 
free s ur vi val ( P F S), o ver all s ur vi val ( O S), a n d c orrelati ve st u dies.    
U p t o f o ur d ose le v els of e paca d ostat will be e val u ate d: 5 0 m g bi d, 1 0 0 m g bi d, 2 0 0 m g bi d 
a n d 3 0 0 m g bi d .  T hese 4 d ose le vels were selecte d base d o n t he cli nical  d ata descri be d a b o ve.  
We ha v e c h ose n 3 0 0 m g bi d as t he starti n g d ose le vel gi ve n t he e xisti n g safet y data f or t his 
d ose a n d t he safe use of t his d ose i n use wit h ot her i m m u n ot hera p y c o m bi nati o ns.  T here is a    
- 1, - 2 a n d - 3 d os e le vel.  If d ose le vel - 3 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 n ci pal i n vesti gat ors a n d st u d y s p o ns ors. E paca d ost at will be 
a d mi nistere d orall y t wice dail y u ntil diseas e pr o gressi o n.  T he e x pa nsi o n p hase will be 
c o n d ucte d usi n g t he M T D defi ne d as t h e hi g hest d ose at w hic h n o m ore t h a n o ne of si x 
patie nt s de vel o ps a D L T or D ose Le v el 1 if t he M T D is n ot reac h e d.  
Ra di ot hera p y will be deli vere d t o t he treat me nt lesi o n d uri n g t he first wee k of E R S t hera p y 
usi n g o ne of t he f oll o wi n g t hree sta n dar d- of-care palliati ve fracti o nati o n re gi me ns: 8 G y x 3 
fracti o ns, 4 G y x 5 fracti o ns, or 2 G y x 2 fracti o ns (c o h ort 2 o nl y).  Fracti o ns ma y be deli vere d 
o n c o nsec 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. T he treat me nt lesi o n 
ma y be i n a pre vi o usl y irra diate d fi el d as l o n g as pre vi o us ra di ot hera p y t o t hat fiel d was 
deli vere d > 6 m o nt hs a g o a n d re- irra diati o n is dee me d safe. 

E p ac a d ost at / S D -1 0 1 / R a di ot her a p y  
 
Cli nic al St u d y Pr ot o c ol U C D C C # 2 7 1  
 
 
Pr ot o c ol v ersi o n: 0 2. 1 9. 2 0  
U C D a vis C o m pre he nsi v e C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a g e 3 2  of 9 5  
F o ur milli gra ms  of S D - 1 0 1 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 
o n da ys 1, 8, 1 5, 2 2, a n d 2 9. O n Da y 1 bi o ps y will prece d e i ntralesi o nal i nj ecti o n, R T, or 
e paca d ostat. I ntralesi o n al i njecti o ns will be perf or me d b y pal pati o n of t he l esi o n or u n der 
ultras o u n d or C T g ui da nce as i n dicat e d. F or patie nts wit h a visceral treat me nt lesi o n Da y 2 2 
a n d 2 9 i njecti o ns are o pti o nal. A visceral lesi o n ca n be use d as t he treat me nt lesi o n o nl y if 
c o nsi dere d safe f or seri al i ntralesi o nal i njecti o ns . Visceral treat me nt lesi o ns m ust be easil y 
i de ntifie d a n d accessi ble f or i ma ge g ui de d n ee dle place me nt, carr y mi ni mal ris k of blee di n g or 
i nfecti o n, a n d mi ni mal ris k of da ma ge t o t he or g a n or s urr o u n di n g tiss ues. F or e x a m ple, li ver 
or a dre n al lesi o ns ma y be s uita ble ca n di date treat me nt lesi o n s w hereas l esi o ns i n t he l u n g, 
b o wel, or heart w o ul d n ot be.  
A D L T is defi ne d as a n y  of t he f oll o wi n g t hat occ ur d uri n g t he 3 0 da y D L T peri o d: gra de > 4 
i njecti o n site reacti o n O R > gra de 3  tr eat me nt-rel ate d n o n- he mat ol o gic t o xicit y  (e xcl udi n g 
i njecti o n site reacti o ns) O R A S T/ A L T > 3 x U L N wit h bilir u bi n > 2 X 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.  All t o xicities at least p ossi bl y relate d t o t he 
i n vesti gati o nal re gi me n will be c o nsi dere d treat m e nt-relat e d. Gra d e 3 ras h will n ot be i ncl u de d 
as a D L T if t here is n o des q ua mati o n, n o m uc osal i n v ol ve me nt, if it res ol ves wit h o ut s yste mic 
c ortic oster oi ds b y t he ne xt sc he d ule d d ose of e paca d ostat or 1 4 da ys, w hic he ver is l o n ger, a n d 
e paca d ostat d ose i nte nsit y is mai ntai ne d at 7 5 % of pla n ne d d ose d uri n g D L T peri o d (i.e < 8 
da ys of d ose i nterr u pti o n). If e p aca d ost at d ose i nte nsit y ca n n ot be mai ntai ne d at 7 5 % of 
pla n ne d d ose d uri n g D L T peri o d as a res ult of t o xicit y of a n y gra d e t his will als o be dee me d a 
d ose li miti n g t o xicit y.  
Ta ble 1 descri bes t he sta n dar d d osi n g r ules t h at will be f oll o we d.    
T a ble 1.  D ose De - Esc al ati o n R ules  
N u m ber of P atie nts wit h D L T   
at a Gi ve n D ose Le vel  
De -Esc al ati o n Decisi o n R ule  
0 or 1 o ut of 3  
E nter 3 a d diti o nal patie nts at t he d ose le vel.  
> 2 o ut of 3  or 6  
De -escalate t he d ose t o t he ne xt l o wer le vel a n d accr ue 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. 
D L T = d ose li miti n g t o xicit y  
 
Patie nts will be m o nit ore d wee kl y d uri n g a 3 0 -da y  D L T peri o d a n d e ver y 3 0 da ys t hereafter or 
m ore fre q u e ntl y if nee d e d.  All patie nts o n acti ve treat me nt will be disc uss e d at wee kl y 
c o nfer e nces of t he trial i n vesti gat ors. Per Ca ncer Ce nter g ui deli nes, a tri al ca n n ot pr ocee d t o 
t he ne xt d ose le vel u ntil a D L T meeti n g is c o n d ucte d t o c o m pre he nsi vel y re vie w all t o xicit y 
data a n d a p pr o ve t he d os e escal ati o n. Preli mi nar y efficac y as d eter mi ne d b y A R R, O R R, 
D C R, O S a n d D F S will be assesse d e ver y 6 0 d a ys . T he patie nt will re mai n o n pr ot oc ol 

E p ac a d ost at / S D -1 0 1 / R a di ot her a p y  
 
Cli nic al St u d y Pr ot o c ol U C D C C # 2 7 1  
 
 
Pr ot o c ol v ersi o n: 0 2. 1 9. 2 0  
U C D a vis C o m pre he nsi v e C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a g e 3 3  of 9 5  
treat ment u ntil pr o gressi o n as deter mi ne d b y ir R E CI S T, treat me nt is n o l o n ger t olerat e d, or t he 
patie nt has c o m plete d 1 2 m o nt hs of treat me nt.  Patie nts o n acti ve treat me nt at 1 2 m o nt hs ma y 
c o nti n ue t o recei ve e p aca d ostat if t he y are t olerati n g t hera p y a n d are free fr o m disease 
pr o gressi o n b y ir R E CI S T criteria. If patie nts ha v e a n o bjecti ve res p o nse a n d st o p treat me nt 
after 1 2 m o nt hs a n d t he n ha ve P D, t he y ca n be c o nsi dere d f or re- treate m e nt at t he discreti o n of 
t he st u d y PI. Aft er st u d y c o m pleti o n P F S, O S a n d l o n g-ter m t o xicit y data will c o nti n ue t o be 
c ollecte d e v er y 3 m o nt hs d uri n g r o uti ne sta n dar d of care visits. 
 
4.  
S T U D Y P O P U L A TI O N  
Patie nts will be recr uite d f r o m t he U C Da vis Ca ncer Ce nter.  All patie nts will be re gistere d at 
t he U C Da vis facilit y after c o ns ultati o n wit h Dr. Dal 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 
Da vis C o m pre he nsi ve Ca ncer Ce nter ( U C D C C) P hase I cli nic.  Bas e d o n t he i ncl usi o n of 
n u mer o us hist ol o gies a n d t he hi g h v ol u me of patie nts wit h a d va n ce d disease treate d at t he 
U C D C C we c o nser v ati vel y pr oject a 3 6 m o nt h accr ual peri o d. 
4. 1  
I ncl usi o n Criteri a 
1.  
A d ults > 1 8 years of a ge wit h hist ol o gicall y pr o ve n s oli d mali g na nc y, hi g h- gra de 
l y m p h o ma or l o w- gra de l y m p h o ma. 
2.  
Patie nts wit h i nc ura ble, a d va nce d or m etastatic dis ease refract or y t o at least o ne pre vi o us 
li ne of t hera p y. 
3.  
E C O G ( Easter n C o o p erati ve O nc ol o g y Gr o u p) p erf or ma nce stat us sc ore of 0 – 2 
( 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, n o dal, or visceral) 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 oc ol. 
5.  
Prese nce of at least o n e tar ge t 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 ir R E CI S T. 
6.  
1 4 da y was h- o ut peri o d fr o m a n y pre vi o us c h e m ot hera p y, tar gete d t hera p y or 
ra di ot hera p y, 2 1 d a y was h o ut peri o d fr o m pre vi o us i m m u n ot hera p y. 
7.  
Life e x pecta nc y ≥ 6 m o nt hs. 
8.  
A de q uate h e mat ol o gic a n d e n d or ga n f u n cti o n, defi ne d b y t he f oll o wi n g la b orat or y 
res ults o btai ne d wit hi n 1 4 da ys of t he first st u d y treat me nt: 
o  A N C > 1 5 0 0 cells/ ul; W B C c o u nt > 2 5 0 0/ u L; Platelet c o u nt > 5 0, 0 0 0/ u L; 
He m o g l o bi n > 9 g/ d L 
9.  
Li ver f u ncti o n tests meeti n g o ne of t he f oll o wi n g criteria: 
a. A S T a n d A L T < 2. 5 x U L N wit h al kali ne p h os p h atase < 2. 5 x U L N  O R 

E p ac a d ost at / S D -1 0 1 / R a di ot her a p y  
 
Cli nic al St u d y Pr ot o c ol U C D C C # 2 7 1  
 
 
Pr ot o c ol v ersi o n: 0 2. 1 9. 2 0  
U C D a vis C o m pre he nsi v e C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a g e 3 4  of 9 5  
b.  A S T a n d A L T < 1. 5 x U L N, wit h al kali ne p h os p h atase > 2. 5 x U L N 
c. Ser u m bilir u bi n < 1. 0 x U L N . Direct bili < 4 0 % if t o tal bili > U L N i n patie nts wit h 
Gil bert’s  s y n dr o me.  
1 0.  
I N R a n d a P T T < 1. 5 x U L N. 
1 1.  
Ser u m Cr < 1. 5 X U L N or Cr Cl > 5 0 ml/ mi n.  
1 2.  
N o acti ve a ut o -i m m u ne disease a n d n ot o n t hera p y f or a ut o-i m m u ne diseas e.  Patie nts 
wit h a hist or y of a ut oi m m u ne-relat e d h y p ot h yr oi dis m o n a sta ble d ose of t h yr oi d 
re place me nt h or m o ne are eli gi ble. Patie nts  w h o ha ve a dre n al i ns ufficie n c y a n d 
h y p o p h ysitis fr o m pri or i m m u n ot hera p y if t he y are o n sta ble me dical re place me nt d oses 
are eli gi ble.   
1 3.  
N o ot her acti ve m ali g na n c y .  
1 4.  
Patie nts wit h c o ntr olle d T y pe 1 dia betes mellit us o n a sta ble i ns uli n re gi me n are eli gi ble.  
1 5.  
F or f e male patie nts of c hil d beari n g p ote ntial a n d male patie nts wit h part ners of 
c hil d beari n g p ote ntial a gree me nt ( b y p atie nt a n d/ or part ner) t o use hi g hl y effecti ve 
f or m(s) of c o ntrace pti o n (i.e., o ne t hat res ults i n a l o w fail ure rate [ < 1 % per year] w he n 
use d c o nsiste ntl y a n d c orrectl y) a n d t o c o nti n ue its use f or 6 m o nt hs after trial 
c o m pleti o n .  
1 6.  
Si g ne d i nf or me d c o nse nt. 
1 7.  
At least 9 m o nt hs fr o m ste m c ell tra ns pla nt wit h n o acti ve graft vers us h ost disease. 
1 8.  
A bilit y t o c o m pl y wit h t he pr ot oc ol. 
 
4. 2  
E xcl usi o n Criteri a  
1.  
U nc o ntr olle d c o nc o mita nt disease t hat i n t he o pi ni o n of t he i n vesti gat or w o ul d i nterfere 
wit h t he patie nt ’s safet y or c o m plia nce o n tri al.  
2.  
Si g nifica nt car di o vasc ul ar disease ( N Y H A Class II or greater); m y ocar dial i nfarcti o n 
wit hi n 3 m o nt h pri or t o ra n d o mizati o n, u nsta ble arr h yt h mias, u nsta ble a n gi na or a patie nt 
wit h a k n o w n L V E F ( Left Ve ntric ular Ejecti o n Fracti o n) < 4 0 % 
3.  
Se vere i nf ecti o n  t hat i n t he o pi ni o n of t he i n vesti gat or w o ul d i nterfere wit h t he patie nts 
safet y or c o m plia n ce o n trial wit hi n 2 wee ks pri or t o e nr oll me nt.  Oral or I V a nti bi otics 
wit hi n 2 wee ks or 5 half- li ves pri or t o e nr oll me nt. 
4.  
Acti ve t u berc ul osis  
5.  
Hist or y of se ver e a ut oi m m u ne disease t hat i n t he o pi ni o n of t he i n vesti gat or w o ul d 
i nterfer e wit h patie nt saf et y or c o m plia nce o n trial. 

E p ac a d ost at / S D -1 0 1 / R a di ot her a p y  
 
Cli nic al St u d y Pr ot o c ol U C D C C # 2 7 1  
 
 
Pr ot o c ol v ersi o n: 0 2. 1 9. 2 0  
U C D a vis C o m pre he nsi v e C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a g e 3 5  of 9 5  
6.  
P ositi ve f or H u ma n I m m u n o deficie nc y Vir us ( HI V), He p atitis B ( He patitis B S urf ace 
A nti ge n [ H Bs A g] r eacti v e), or H e patitis C vir us ( He patitis C Vir us Ri b o n ucleic Aci d 
[ H C V R N A] ( q u alitati ve) is detecte d) 
7.  
Pre vi o us treat me nt wit h e paca d ostat, S D- 1 0 1, or a n y ot her I D O i n hi bit or or C p G 
m olec ule.  
8.  
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 h alf-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 of pre d nis o ne ( or e q ui vale nt) is 
per mitte d.  
9.  
Pre g na nt a n d/ or lactati n g w o me n. 
1 0.  
E vi de nce of acti ve i nterstitial l u n g disease or acti v e n o n -i nfecti o us p ne u m o nitis 
1 1.  
Recei pt o f li ve atte n uat e d vacci ne wit hi n 3 0 da ys bef ore t h e first d ose of st u d y treat me nt. 
1 2.  
Use of a n y U G T 1 A 9 i n hi bit or w hile o n acti ve st u d y treat me nt , i ncl u di n g t he f oll o wi n g:  
dicl ofe nac, i mi pra mi ne, ket oc o naz ol e, mefe n a mic aci d, a n d pr o b e neci d.   
1 3.  
K n o w n aller g y or reacti o n t o a n y c o m p o ne nt of eit her st u d y dr u g f or m ulati o n.  
1 4.  
S u bjects recei vi n g M o n o a mi ne O xi dase I n hi bit ors ( M A OIs ) or dr u g w hic h has si g nifica nt 
M A OI acti vit y ( me peri di ne, li nez oli d, met h yle ne bl ue) fr o m 2 1 da ys pri or t o Da y 1 
t hr o u g h 2 wee ks after t he fi nal d ose of e p aca d ost at has bee n a d mi nistere d .  
1 5.  
A n y hist or y of Ser ot o ni n S y n dr o me ( S S) after recei vi n g ser ot o ner gic dr u gs. 
1 6.  
K n o w n c o ntrai n dicati o ns t o ra di ot hera p y i ncl u di n g b ut n ot li mite d t o ra diati o n se nsiti vit y 
s y n dr o mes s uc h as xer o d er ma pi g me nt os u m a n d ata xia tela n giectasi a m utate d . 
 
5.  
T R E A T M E N T P L A N  
T a ble 2.  Tre at m e nt Pl a n  
A ge nt  
D ose  
R o ute  
Fre q ue nc y  
E paca d ostat  
5 0  - 3 0 0 m g 
BI D  
Oral  
BI D t hr o u g h o ut st u d y peri o d. 
Ra diati o n  
4 - 2 4 G y  
E xter nal bea m  
3 fracti o ns of 8 G y, 5 fracti o ns of 4 G y , or 2 fracti o ns of 2 G y  
(c o h ort 2 o nl y), deli vere d 1 2– 9 6 h o urs a part d uri n g t he first 
wee k of t hera p y.  
S D -1 0 1  
4 m g  
I ntrat u m oral 
5 t otal d oses 1 x wee kl y o n da ys 1, 8, 1 5, 2 2, a n d 2 9 ( Da y 2 2 a n d 
2 9 o pti o nal f or visceral treat me nt lesi o ns). First d ose t o be 
deli vere d pri or t o ra di ot hera p y.  
 

E p ac a d ost at / S D -1 0 1 / R a di ot her a p y  
 
Cli nic al St u d y Pr ot o c ol U C D C C # 2 7 1  
 
 
Pr ot o c ol v ersi o n: 0 2. 1 9. 2 0  
U C D a vis C o m pre he nsi v e C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a g e 3 6  of 9 5  
5. 1  
E p ac a d ost at 
5. 1. 1  
D os a ge a n d A d mi nistr ati o n 
E paca d ostat  will be a d mi nistere d at t he M T D ( 5 0 – 3 0 0 m g) orall y BI D  t hr o u g h o ut t he st u d y 
peri o d. S u bjects will ta ke t heir d ose of e p aca d ost at i n t he m or ni n g a n d e ve ni n g, a p pr o xi matel y 
1 2 h o urs a part wit h o ut re gar d t o f o o d.  If t h e m or ni n g or e ve ni n g d ose is misse d b y m ore t ha n 
4 h o urs, t hat d ose s h o ul d be s ki p pe d a n d t he ne xt s c he d ule d d ose s h o ul d be ta ke n at t he us ual 
ti me. All BI D d oses will be ta ke n i n t he m or ni n g a n d e ve ni n g, a p pr o xi matel y 1 2 h o urs a part. 
5. 1. 2  
F or m ul ati o n, P ac k a gi n g, a n d H a n dli n g 
E paca d ostat is f or m ula t e d as a n i m me diate releas e ta blet i n 2 stre n gt hs ( 2 5 m g a n d 1 0 0 m g) 
ta blets pac ka g e d i n hi g h- de nsit y p ol yet h yle ne b ottles. T he ta blets c o ntai n t he acti ve dr u g 
(e paca d ostat) al o n g wit h c o m m o nl y use d c o m pe n dial e xci pie nts (lact ose m o n o h y drate, 
micr ocr ystall i ne cell ul ose, p o vi d o ne, cr os car mell ose s o di u m, c oll oi dal silic o n di o xi de, 
ma g nesi u m stearate). E p aca d ostat dr u g pr o d uct s h o ul d be st ore d at a m bie nt c o n diti o ns  
( 1 5° C – 3 0° C or 5 9° F – 8 6° F). 
5. 1. 3  
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 or ret ur ne d t o I n c yte wit h t he a p pr o priate 
d oc u me ntati o n. T he site's met h o d of dr u g s u p pl y destr ucti o n m ust be a gree d u p o n b y I n c yte.  
Acc ur ate r ec or ds of all i n vesti g ati o nal pr o d uct recei ve d at, dis pe nse d fr o m, ret 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 d e d o n t he Dr u g L o g. 
5. 2  
S D - 1 0 1 
5. 2. 1  
D os a ge, A d mi nistr ati o n, a n d C o m pli a nce 
S D - 1 0 1 will be a d mi nistere d as a 4 m g d ose 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. Nee dl e place m e nt will be perf or me d b y pal pati o n, 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. 5 i ntralesi o nal i njecti o ns will be a d mi nistere d o ver a 5 
wee k peri o d o n da ys 1, 8, 1 5, 2 2, a n d 2 9.  T he fi n al t w o i njecti o ns are o pti o nal f or patie nts 
wit h visceral treat me nt lesi o ns.    
5. 2. 2  
F or m ul ati o n, P ac k a gi n g , a n d H a n dli n g 
S D - 1 0 1 is s u p plie d i n si n gle use vials. T he sterile, preser v ati ve-free dr u g is s u p plie d at a 
c o nce ntr ati o n of 1 6 m g/ m L . S D - 1 0 1 c o ntai ns n o preser v ati ves a n d m ust be st ore d u n der 
refri gerate d c o n diti o ns ( 2º C t o 8 º C). S D - 1 0 1 is n ot t o be fr oze n. A vaila ble sta bilit y data 
i n dicate t hat S D- 1 0 1 Dr u g Pr o d uct ( 5 m g/ m L) is sta ble f or at least 6 5 m o nt hs w he n st ore d 
refri gerate d at 2°C t o 8 °C, t he rec o m me n de d st ora ge c o n diti o n. S D- 1 0 1 will be br o u g ht t o 
r o o m te m perat ur e a n d a d mi nistere d at a 4 m g d ose acc or di n g t o t he cli nical trial pr ot oc ol.  

E p ac a d ost at / S D -1 0 1 / R a di ot her a p y  
 
Cli nic al St u d y Pr ot o c ol U C D C C # 2 7 1  
 
 
Pr ot o c ol v ersi o n: 0 2. 1 9. 2 0  
U C D a vis C o m pre he nsi v e C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a g e 3 7  of 9 5  
5. 2. 3.  
Pre p ar ati o n of S D- 1 0 1 4 m g/ m L S ol uti o n  
Wit h dra w 1. 5 m L of c o m merciall y s o urce d Na Cl 0. 9 % dil ue nt usi n g a 3 m L s yri n ge a n d 
tra nsfer i nt o an e m pt y sterile 5 m L vial.  Wit h dra w 0. 5 m L of S D- 1 0 1 ( 1 6 m g/ m L) i njecta ble 
s ol uti o n fr o m t he I P vial i n a 1 m L s yri n ge usi n g a 2 5 G, 1 ½” nee dl e. Tra nsfer S D- 1 0 1 t o t he 
sterile vial c o ntai ni n g 1. 5 m L of Na Cl 0. 9 %. T o mi x t he s ol uti o n, ge ntl y i n vert t he vial 1 0 
ti mes. T he sterile vial will c o ntai n a 4 m g/ m L s ol uti o n of S D- 1 0 1. Usi n g a 2 0- 2 5 G nee dl e, 
wit h dra w 1 m L of t he dil ute d S D- 1 0 1 ( 4 m g/ m L) i nt o a 3 m L s yri n ge f or a d mi nistrati o n of a 
4 m g fi xe d d ose of S D- 1 0 1. A 2 5- 3 0 G nee dle m ust be use d t o a d mi nister t he d ose of S D- 1 0 1. 
C o m p o u n de d pre par ati o ns m ust be a d mi nistere d wit hi n 8 h o urs of ma ki n g t he dil uti o n. 
5. 2. 4  
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 or ret ur ne d t o D y na va x wit h t he a p pr o priate 
d oc u me ntati o n. T he site's met h o d of dr u g s u p pl y destr ucti o n m ust be a gree d u p o n b y 
D y na va x.  
Acc ur ate r ec 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, ret 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 d e d o n t he Dr u g L o g. 
5. 3  
R a di ot he r a p y 
5. 3. 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 of 8 G y, 2 0 G y deli vere d o ver 5 
fracti o ns of 4 G y, or 4 G y deli vere d o ver 2 fracti o ns of 2 G y (f or c o h ort 2 o nl y).  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 me nts.  All treat me nts 
m ust c o m me nce o n da y 1 after i ntral esi o nal i njecti o n of S D- 1 0 1 a n d m ust be c o m plete d wit hi n 
st u d y wee k 1.  C ortic oster oi d pre me dicati o n is n ot per mitte d. A nal gesic pre me dicati o n t o 
a v oi d ge neral disc o mf ort d uri n g l o n g treat me nt d urati o ns is rec o m me n de d w he n a p pr o priate.  
T he d ose per fracti o n is t o be prescri be d s uc h t hat t he e ntire pla n ni n g treat me nt v ol u me ( P T V) 
is e nc o m passe d b y 9 5 % of t he prescri pti o n d ose.  
5. 3. 2  
Tec h nic al F act ors  
O nl y p h ot o n ( x-ra y) b ea 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. 3. 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 o es 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 si g nifica nt pr o ba 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 g a v olta ge c o m p ute d 

E p ac a d ost at / S D -1 0 1 / R a di ot her a p y  
 
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t o m o gra p h y) 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. 3. 4  
T ar get V ol u m es   
5. 3. 4. 1  
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.   
5. 3. 4. 2  
T ar get V ol u m e 
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. 
De pe n di n g o n t he sta bilit y a n d re pr o d u ci bilit y of patie nt set u p a n a d diti o nal mar gi n of 0. 5 – 3 
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.   
5. 3. 4. 3  
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 di ati o n T hera p y ( D C A R T), a n d helical 
t o m ot hera p y ar e acce pta ble. Is o d os e li nes c o veri n g t he P T V m ust be > = 9 5 % of t he pres cri be d 
d ose. W he n I V a n d/ or or al c o ntrast ar e 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 be ce ntrall y re vi e we d b y Dr. Dal y  pri or t o d eli ver y of t he first 
fracti o n. 
5. 3. 5  
Or g a ns at Ris k 
 
5. 3. 5. 1  
Defi ni n g Or g a ns at Ris k 
Palliati ve ra di ot hera p y is deli vere d as sta n d ar d of care t o a s u bc uta n e o us, n o dal, or visceral 
treat me nt lesi o n. T he a n at o mic l ocati o n of t he treat me nt lesi o n is u n defi ne d a n d left t o t he 
discreti o n of t he treati n g  p h ysicia n. T heref ore, a d esi g nate d set of or g a ns at ris k t o be i ncl u de d i n 
eac h r a di ot her a p y treat m e nt pla n ca n n ot be d efi ne d.  Or ga ns at ris k will be defi ne d b y t he 
treati n g ra diati o n o nc ol o gist if visi ble wit hi n t he a xial slices c o vere d b y t he P T V. Or ga ns at ris k 
t o be c o nt o ure d i ncl u de b ut are n ot li mite d t o: o ptic ner ves, gl o b es, c oc hlea, brai nste m, s pi nal 
c or d, ca u d a e q ui na, s acr al ple x us, es o p ha g us, brac h ial ple x us, heart, great v essels, trac h ea a n d 
pr o xi mal br o nc hial tree, ri b, s ki n, st o mac h, d u o de n u m, jej u n u m/ile u m, c ol o n, rect u m, bla d der, 
pe nile b ul b, fe m oral h ea ds, re nal hil u m, l u n gs, li ver, a n d ki d ne ys. T hes e c o nt o urs s h o ul d be 

E p ac a d ost at / S D -1 0 1 / R a di ot her a p y  
 
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la bele d acc or di n g Sta n dar d Na mi n g C o n ve nti o ns liste d bel o w i n pare nt hes es as per 
htt ps:// w w w.rt o g. or g/ C ore La b/ Sta n dar dize d Na mi n g C o n ve nti o ns.as p x . Or ga ns at ris k s h o ul d be 
defi ne d  usi n g e xisti n g g ui deli nes a n d atlases a v aila ble at: 
htt ps:// w w w.rt o g. or g/ C ore La b/ C o nt o uri n g Atlases. as p x . If necessar y, t he assista nce of a b o ar d 
certifie d r a di ol o gist s h o ul d be s o u g ht t o ai d i n c o nt o uri n g.   G ui deli nes f or defi ni n g c o m m o nl y 
e nc o u nter e d or ga ns at ris k are des cri be d b el o w . 
- S pi nal c or d ( S pi nalc or d): T he s pi nal c or d will be c o nt o ure d bas e d o n t he b o n y li mits of t he 
s pi nal ca nal. T he s pi nal c or d s h o ul d be c o nt o ure d starti n g at least 1 0 c m a b o ve t he s u peri or 
e xte nt of t he P T V a n d c o nti n ui n g o n e ver y C T slice t o at least 1 0 bel o w t he i nferi or e xte nt of t he 
P T V.  
- Brac hial ple x us ( Br ac hi al Ple x _ L a n d Brac hial Ple x _ R): T he defi ne d i psilat eral brac hial ple x us 
ori gi nates fr o m t he s pi nal ner ves e xiti n g t he ne ur of ora mi na o n t he i n v ol ve d si de fr o m ar o u n d C 5 
t o T 2. H o we ver, f or t he p ur p oses of t his pr ot oc ol, o nl y t he maj or tr u n ks of t he brac hi al ple x us 
will be c o nt o ure d usi n g t he s u bcla via n a n d a xillar y vessels as a s urr o gate f or i de ntif yi n g t he 
l ocati o n of t he brac hial ple x us. T his ne ur o vasc ular c o m ple x will be c o nt o ure d starti n g 
pr o xi mall y at t he bif urcati o n of t he brac hi o ce p hali c tr u n k i nt o t he j u g ular/s u bcla via n vei ns ( or 
car oti d/s u bcla via n arteries) a n d f oll o wi n g al o n g t he r o ute of t he s u b cla via n vei n t o t he a xillar y 
vei n e n di n g after t he ne ur o vasc ular str uct ures cr oss t he sec o n d ri b. 
- Es o p ha g us ( Es o p ha g us): T he es o p ha g us will be c o nt o ure d usi n g me diasti nal wi n d o wi n g o n C T 
t o c orres p o n d t o t he m uc osal, s u b m uc osa, a n d all m usc ular la yers o ut t o t h e fatt y a d ve ntitia. T he 
es o p ha g us s h o ul d be c o nt o ure d starti n g at least 1 0 c m a b o ve t he s u peri or e xte nt of t he P T V a n d 
c o nti n ui n g o n e ver y C T slice t o at least 1 0 bel o w t he i nferi or e xte nt of t he P T V a n d i deall y fr o m 
t he p ost-cric oi d s pace t o t he G E j u ncti o n. 
- Great Vessels ( Great Vessels): T he great vessels (a orta a n d v e na ca va, n ot t he p ul m o nar y art er y 
or vei n) will be c o nt o ur e d  usi n g me diasti nal wi n d o wi n g o n C T t o c orres p o n d t o t he vasc ular 
wall a n d all m usc ular  la yers o ut t o t he fatt y a d v e ntitia. T he great vess el s h o ul d be c o nt o ure d 
starti n g at least 1 0  c m a b o ve t he s u peri or e xte nt of t he P T V a n d c o nti n ui n g o n e ver y C T slice t o 
at least 1 0 c m bel o w t he i nferi or e xt e nt of t he P T V. F or ri g ht si de d t u m ors, t he ve na ca va will be 
c o nt o ure d, a n d f or left si de d t u m ors, t he a orta will be c o nt o ure d. 
- Heart/ pericar di u m ( Heart): T he heart will be c o nt o ure d al o n g wit h t he pericar dial sac. T h e 
s u peri or as pect ( or b ase) f or p ur p oses of c o nt o uri n g will be gi n at t he le vel of t he i nferi or as pect 
of t he a ortic arc h (a ort o p ul m o nar y wi n d o w) a n d e xte n d i nferi orl y t o t he a p e x of t he heart. 
- Trac h ea a n d pr o xi mal br o nc hial tree ( Trac hea, Br o nc hial Tree): T he trac h ea a n d pr o xi mal 
br o nc hial tree i ncl u di n g t he mai nste m a n d l o bar br o nc hi i ncl u di n g trac hea, t he cari n a, t he ri g ht 
a n d left mai nste m br o nc hi, t he ri g ht a n d left u p per l o be br o nc hi, t he i nter me di us br o nc h us, t he 
ri g ht mi d dle l o be br o nc h us, t he li n g ular br o nc h us, a n d t he ri g ht a n d left l o wer l o be br o n c hit o t he 
bif urcati o n of t he first se g me ntal air wa ys will b e c o nt o ure d  usi n g me diasti nal wi n d o ws o n C T t o 

E p ac a d ost at / S D -1 0 1 / R a di ot her a p y  
 
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c orres p o n d t o t he m uc os al, s u b m uc osa a n d cartila ge ri n gs a n d air wa y c h a n nels ass ociate d wit h 
t hese str uct ures.  
- S ki n ( S ki n O A R): T he s ki n will be defi ne d as t he o uter 0. 5 c m of t he b o d y s urface. As s uc h it is 
a ri n d of u nif or m t hic k ness ( 0. 5 c m) w hic h e n v el o pes t he e ntire b o d y i n t he a xial pla nes. T he 
cra nial a n d ca u d al s urface of t he s u peri or a n d i nferi or li mits of t he pla n ni n g C T s h o ul d n ot be 
c o nt o ure d as s ki n u nless s ki n is act uall y prese nt i n t hese l ocati o ns (e. g., t he scal p o n t he t o p of 
t he hea d). 
- St o mac h ( St o mac h): T h e e ntire st o mac h a n d its c o nte nts s h o ul d be c o nt o ure d as a si n gle 
str uct ure as a c o nti n uati o n of t he es o p ha g us a n d e n di n g at t he first part of t he d u o de n u m. 
- D u o de n u m ( D u o d e n u m): T he wa ll a n d c o nte nts of t he 1st, 2 n d, a n d 3r d p arts of t he d u o de n u m 
will be c o nt o ure d as o n e str uct ure be gi n ni n g w here t he st o mac h e n ds a n d fi nis hi n g as t he 
s u peri or mese nteric arter y cr osses o ver t he t hir d p art of t he d u o de n u m 
- Jej u n u m/ilie u m ( S mall b o wel): S m all b o wel fr o m e n d of d u o de n u m t o t he ile ocecal area. 
- Lar ge B o w el ( Lar ge b o wel): Fr o m t he ile o cecal area t o i ncl u d e t he asce n di n g, tra ns verse, 
desce n di n g a n d si g m oi d c ol o n as o ne str uct ure. 
- Re nal hil u m/ vasc ular tr u n k: T he re nal arter y a n d vei n fr o m t he re n al c ort e x t o t he great vessels.  
- Li ver ( Li ver): T he e ntir e li ve mi n us t he G T V  
- Ki d ne ys ( Ki d ne y _ L a n d Ki d ne y _ R): B ot h t he ri g ht a n d left ki d ne y, e xcl u di n g re nal 
pel vis/c ollecti n g s yste m, s h o ul d be c o nt o ure d i n t h eir e ntiret y (t he re nal c ort e x) 
- L u n g ( L u n gs):  B ot h t he ri g ht a n d left l u n gs s h o ul d be c o nt o ure d as o n e str uct ure. C o nt o uri n g 
s h o ul d be carri e d o ut usi n g p ul m o nar y wi n d o ws. All i nflate d a n d c olla pse d l u n g s h o ul d be 
c o nt o ure d; h o we v er, gr oss t u m or ( G T V) a n d trac h ea/i psilateral br o n c h us as defi n e d a b o v e 
s h o ul d n ot be i ncl u de d i n t his str uct ure. 
- Rect u m : T he m usc ular wall of t he rect u m s h o ul d be c o nt o ure d, e xte n di n g fr o m t he a n us t o 
t he rect osi g m oi d j u ncti o n 
 
- Fe m or al Hea ds : T he ri g ht a n d left fe m oral hea ds e xte n di n g t o t he lesser tr oc ha nter s h o ul d be 
c o nt o ure d se p aratel y  
 
- Bla d der :  O uter m usc ul ar wall s h o ul d be c o nt o ure d 

E p ac a d ost at / S D -1 0 1 / R a di ot her a p y  
 
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5. 3. 5. 2  
Or g a ns at Ris k D ose C o nstr ai nts 
Liste d bel o w are t h e  ma xi m u m d ose li mits t o a p oi nt or  critical v ol u me wit hi n or ga ns at ris k. 
Ma xi m u m p oi nt d ose will be defi ne d as t h e ma xi m u m d ose t o a 0. 0 3 5 cc v ol u me. T hese are 
a bs ol ute li mits, a n d treat me nt deli ver y t hat e xcee ds t hese li mits will c o nstit ute a maj or 
pr ot oc ol vi olati o n. As o utli ne d a b o ve ot her or g a ns at ris k ma y be defi n e d b y t he treati n g 
p h ysicia n base d o n t he l o cati o n of t he treat me nt lesi o n a n d t hese or ga ns s h o ul d be c o nstrai ne d 
usi n g sta n dar d acce pte d d ose c o nstrai nts. Ra di ot hera p y will be deli vere d as 2 4 G y o ver 3 
fracti o ns of 8 G y, 2 0 G y deli vere d o ver 5 fracti o ns of 4 G y,  or 4 G y deli vere d o ver 2 fracti o ns 
of 2 G y a n d t he c o nstrai nts will var y base d o n t he prescri be d d os e. I n all cases t he ma xi m u m 
h ots p ot f or a gi ve n pla n s h o ul d n ot e xcee d 1 2 0 % of t he prescri be d d ose. F or 4 G y deli vere d 
o ver 2 fr acti o ns of 2 G y t here are n o d ose c o nstrai nts f or or ga ns at ris k. 
F or 2 0 G y d eli vere d o v er 5 fracti o ns of 4 G y  d os e c o nstrai nt f or t he o ptic n er ves, gl o bes, 
c oc hlea, brai nste m, a n d s pi nal c or d is a ma x p oi nt d ose of 2 2 G y ( 4. 4 G y / f x). F or t he l u n g 
(ri g ht a n d left) 1 5 0 0 cc s h o ul d recei ve l ess t ha n 1 2. 5 G y. F or t he li ver 7 0 0cc s h o ul d recei ve 
less t ha n 1 5 G y. F or t h e ki d ne ys (ri g ht a n d left) 2 0 0c s h o ul d recei ve less t ha n 1 5 G y. All ot her 
or ga ns at ris k s h o ul d be c o nstrai ne d t o bel o w 1 2 0 % of t he pres cri be d d os e. 
F or 2 4 G y d eli vere d o v er 3 fracti o ns of 8 G y t h e d ose c o nstrai nts f or or ga ns at ris k are liste d i n 
t he Ta ble 3. Rece nt st u dies ha ve s h o w n t hat t he ri b a n d c hest w all i n pr o xi mit y t o t he treate d 
lesi o n ma y re pres e nt a n or ga n at ris k f or c o m plicati o n s uc h as c hest w all pai n a n d ri b fract ure. 
W hile tar get c o v era g e s h o ul d n ot be c o m pr o mise d t o li mit d ose t o t he ri b/c hest wall  a n d 
f or mal c o nstrai nt is n ot pr o vi de d, e ver y eff ort s h o ul d be ma de t o mi ni mize d ose a n d h ost p ots 
t o t his or ga n at ris k. 
Ta ble 3.    Critical Or g a ns at Ris k D ose -V ol u me Li mits f or 2 4 G y o ver 3 fracti o ns  
Str uct ure  
V ol u m e ( m L)  
V ol u m e M a x 
( G y)  
M a x P oi nt D ose 
( G y) 
V ol u m etric 
C o nstr ai nt  
O ptic ner ves  
 
 
1 5  
 
Gl o bes  
 
 
1 5  
 
C oc hlea  
 
 
1 8  
 
Brai nste m  
 
 
1 8  
 
S pi nal c or d  
< 0. 2 5  
1 7  
1 8  
 
Sacral Ple x us  
< 5  
2 1. 9  
2 4  
 
Brac hial ple x us  
< 3  
2 0 .4  
2 4  
 

E p ac a d ost at / S D -1 0 1 / R a di ot her a p y  
 
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Ca u da e q ui na  
< 5  
2 1. 9  
2 4  
 
Es o p ha g us  
< 5  
2 1  
2 7  
 
Great Vessels  
- 
- 
2 5. 2 ( 1 0 5 % of 
R x d ose)  
 
Heart/ pericar di u
m 
< 1 5  
2 4  
2 5. 2 ( 1 0 5 % of 
R x d ose)  
 
Trac hea a n d 
i psilateral 
br o nc h us  
< 4  
1 5  
2 5. 2 ( 1 0 5 % of 
R x d ose)  
 
S ki n  
 
 
2 8. 8  
 
St o mac h  
< 1 0  
2 1  
2 4  
 
D u o de n u m  
< 5  
1 5  
2 2. 2  
 
Jej u n u m/ilie u m 
< 5  
1 6. 2  
2 5. 2 ( 1 0 5 % of 
R x d ose)  
 
C ol o n/ Rect u m  
< 2 0  
2 4  
2 8 . 2 ( 1 0 5 % of 
R x d ose)  
 
Bla d der  
< 1 5  
1 6. 8  
2 8. 2  
 
Re nal Hil u m  
< 1 5  
1 9. 5  
- 
 
Fe m oral Hea ds  
< 1 0  
2 1. 9  
 
 
Li ver  
7 0 0 m L s pare d 
fr o m v ol u me 
ma x   
1 5  
 
 
Ki d ne ys  
2 0 0 m L s pare d 
fr o m v ol u me 
ma x  
1 4. 4  
 
 
L u n g (left a n d 
ri g ht) 
1 5 0 0 m L s pare d 
fr o m v ol u me 
ma x  
1 0. 5  
 
V 2 0 < 1 0 %  
 

E p ac a d ost at / S D -1 0 1 / R a di ot her a p y  
 
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6.  
G E N E R A L P L A N T O M A N A G E S A F E T Y C O N C E R N S  
Meas ures will be ta k e n t o e ns ure t he s afet y of p atie nts partici pati n g i n t his trial, i ncl u di n g t he 
use of stri n ge nt i ncl usi o n a n d e xcl usi o n criteria (s ee Secti o ns 4. 1 a n d 4. 2) a n d cl ose 
m o nit ori n g (as i n dicate d bel o w a n d i n t he st u d y cale n dar). 
6. 1  
Eli gi bilit y Criteri a  
Eli gi bilit y crit eria were s electe d t o g uar d t he safet y of patie nts i n t his trial.  Res ults fr o m t he 
n o ncli nical t o xic ol o g y st u dies as well as t he n o ncli nical/cli nical data fr o m ot her st u dies wer e 
ta ke n i nt o acc o u nt. 
6. 2  
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 d e 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 s afet 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 or u ntil recei pt of a n ot her 
a ntica ncer t her a p y, w hic he ver c o m es first. Ge n eral safet y ass ess me nts will i ncl u de serial 
i nter val hist ories, p h ysical e xa mi nati o ns, a n d s pecific la b orat or y st u dies, i ncl u di n g ser u m 
c he mistries a n d bl o o d c o u nts (see St u d y Cale n dar f or t he list a n d ti mi n g of st u d y assess me nts).  
All  seri o us a d verse e ve nts ( S A Es) will be re p orte d i n a n e x pe dite d f as hi o n. I n a d diti o n, t he 
i n vesti gat ors will re vie w a n d e val uat e o bser v e d A Es o n a re g ular basis. 
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 n cer 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 nse 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.  
6. 3  
M a n a ge m e nt of S pecific A d verse E ve nts  
T o xicities ass ociate d or p ossi bl y ass o ciate d wit h pr ot oc ol treat me nt s h o ul d be ma na ge d 
acc or di n g t o sta n d ar d me dical practice.  A d diti o nal tests, s uc h as a ut oi m m u ne ser ol o g y or 
bi o psies, ma y be use d t o deter mi ne a p ossi ble i m m u n o ge nic eti ol o g y. 
Alt h o u g h m ost i m m u ne- relate d a d v erse e ve nts o bs erve d wit h i m m u n o m o d ulat or y a ge nts ha v e 
bee n mil d a n d self-li miti n g, s uc h e ve nts s h o ul d b e rec o g ni ze d earl y a n d treate d pr o m ptl y t o 
a v oi d p ote ntial maj or c o m p licati o ns.  Disc o nti n uati o n of pr ot oc ol t hera p y ma y n ot ha ve a n 
i m me diate t hera pe utic effect a n d i n se v ere cas es, i m m u ne-relate d t o xicities ma y re q uire ac ute 
ma na ge me nt wit h t o pical c ortic oster oi ds, s yste mic c ortic oster oi ds, m yc o p h e n olate, or T N F- α 
i n hi bit ors. 

E p ac a d ost at / S D -1 0 1 / R a di ot her a p y  
 
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C o nfi de nti al  
 
P a g e 4 4  of 9 5  
6. 4  
M a n a ge m e nt of A d vers e E ve nts fr o m I m m u n ot her a p y  
T he pri mar y a p pr oac h t o Gra de 1- 2 i m m u ne- rel ated a d verse e ve nts is s u p p orti ve a n d 
s y m pt o matic care wit h c o nti n ue d pr ot oc ol t hera p y; f or hi g her gra de i m m u ne-rel ate d a d v erse 
e ve nts, t hera p y s h o ul d be hel d a n d oral/ pare ntal st er oi ds a d mi nistere d.  Rec urre nt Gra de 2 
i m m u ne-relate d a d vers e e ve nts ma y als o ma n dat e h ol di n g t hera p y or t he use of ster oi ds.  I n 
t he case of all t o xicities co nsi derati o n f or be n efit/ris k bala nce s h o ul d be ma de b y t he 
i n vesti gat or, wit h c o nsi derati o n of t he t otalit y of i nf or mati o n as it pertai ns t o t he nat ure of t he 
t o xicit y a n d t he de gree of cli nical be nefit a gi v e n p atie nt ma y be e x p erie nci n g pri or t o f urt her 
a d mi nistrati o n of  E R S t hera p y . E R S t hera p y  s h o ul d be per ma n e ntl y disc o nti n ue d i n patie nts 
wit h life -t hreate ni n g i m m u ne relate d A Es (ir A E). Ma na ge me nt of A E b y gra de ( T a ble 3) a n d 
s y m pt o matic ma na ge me nt of s pecific A Es ( Ta ble 4) are o utli ne d b el o w. 
 
 

E p ac a d ost at / S D -1 0 1 / R a di ot her a p y  
 
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C o nfi de nti al  
 
P a g e 4 5  of 9 5  
T a ble 4.  Ge ner al M a n a ge m e nt of  A E b y Gr a de (refer t o T a ble 4 f or s pecific A Es)  
irA E  
T o xicit y 
Gr a de  
Wit h h ol d/  
Disc o nti n ue  
Acti o n T a k e n Wit h Res pect t o 
E p ac a d ost at  
S u p p orti ve C are   
(see als o T a ble 4) 
Gra de 1  
N o acti o n.  
N ot a p plica ble.  
Pr o vi de s y m pt o matic treat me nt.  
Gra de 2  
Ma y wit h h ol d 
st u d y treat me nt 
per 
i n vesti gat or's 
discreti o n.  
If A E res ol ves wit hi n 3 0 da ys , 
s u bject ma y restart at t he sa me 
d ose a n d sc he d ule f or e paca d ostat.  
F or a n A E t hat d oes n ot res ol ve 
wit hi n 3 0 da ys , c o nsi der re d uci n g 
e paca d ostat  1 d ose le vel.   
C o nsi der s yste mic c ortic oster oi ds i n 
a d diti o n t o a p pr o priate s y m pt o matic 
treat me nt. 
Gra de 3  
Wit h h ol d st u d y 
treat me nt u ntil 
A E res ol ves t o 
≤ Gra de 2. 
Disc o nti n ue  if 
st u d y treat me nt 
ca n n ot be 
res u me d wit hi n 
3 0 da ys.   
Restart e paca d ostat  at re d uce d 
d ose le vel  e xce pt i n t he case of 
Gra de 3 ras h t hat res ol ves wit h o ut 
oral ster oi ds . If A E d oes n ot 
res ol ve t o < Gra de 2 wit hi n 3 0 
da ys after re -i nitiati n g st u d y 
treat me nt or pr o gresses a gai n t o 
gra de 3 after i nitiati n g st u d y 
treat me nt re d uce e paca d ostat 1 
d ose le vel.  Disc o nti n ue t hera p y f or 
gra de 3 p n ue m o nitis.  
S yste mic c ortic oster oi ds are i n dicate d i n 
a d diti o n t o a p pr o priate s y m pt o matic 
treat me nt.  Ma y use 1- 2 m g/ k g pre d nis o ne 
or e q ui vale nt per da y.  
Ster oi d ta per s h o ul d be c o nsi dere d o n ce 
s y m pt o ms i m pr o ve t o ≤ Gra de 2 a n d 
ta pere d o ver at least 4 wee ks i n m ost 
cases.  
Gra de 4  
Wit h h ol d st u d y 
treat me nt u ntil 
A E res ol ves t o 
≤ Gra de 2. 
Disc o nti n ue if 
st u d y treat me nt 
ca n n ot be 
res u me d wit hi n 
3 0 da ys.  
Restart e paca d ostat at re d uce d 
d ose le vel  if t he A E res ol ves t o ≤ 
Gra de 2 or baseli ne . If t here is 
rec urre nce of a Gra de 3/ 4 A E wit h 
re d uce d d ose of e paca d ostat, t he n 
disc o nti n ue partici pati o n i n t he 
st u d y. 
 
S yste mic c ortic oster oi ds are i n dicate d i n 
a d diti o n t o a p pr o priate s y m pt o matic 
treat me nt.  Ma y use 1- 2 m g/ k g pre d nis o ne 
or e q ui vale nt per da y.  
 
Ster oi d ta per s h o ul d be c o nsi dere d o nce  
s y m pt o ms i m pr o ve t o ≤ Gra de 2 a n d 
ta pere d o ver at least 4 wee ks i n m ost 
cases.  
 
 
 

E p ac a d ost at / S D -1 0 1 / R a di ot her a p y  
 
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Pr ot o c ol v ersi o n: 0 2. 1 9. 2 0  
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C o nfi de nti al  
 
P a g e 4 6  of 9 5  
T a ble 4: 
S pecific M a n a ge m e nt of A d verse E ve nt s 
A d verse E ve nt  
C T C A E 
v 4. 0 3 
Gr a de  
Rec o m m e n de d S y m pt o m S pecific M a n a ge m e nt  
(t o be use d at discreti o n of tre ati n g p h ysici a n) 
I njecti o n site 
reacti o n 
1- 3 
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 ote: Ma xi m u m 
c u m ulati ve dail y d ose of aceta mi n o p he n is 4 gra ms dail y d ue t o ris k of se vere li ver 
t o xicit y. 
I njecti o n site 
reacti o n 
4 
H ol d st u d y treat me nt u ntil i njecti o n site reacti o n res ol ves  
Ras h  
1- 2 
S u p p orti ve care i ncl u di n g t o pical e m ollie nts, s u n pr otec ti o n, c o nsi der t o pical 
ster oi ds 
Ras h  
3 
I nterr u pt e paca d ostat, use t o pical c ortic oster oi ds, c o nsi der oral c ortic oster oi ds.  
W he n ras h ≤ gra de 1, ta per ster oi ds if use d, t he n restart at re d uce d d ose.  If o nl y 
t o pical ster oi ds use d, ca n restart at sa me or re d uce d d ose w he n ≤ gra de 1.. 
Ras h  
4 
I nterr u pt e paca d ostat a n d start oral ster oi ds.  C o nti n ue u ntil ≤ gra de 1 a n d ta per 
ster oi ds.  O nce ster oi ds < 1 0 m g/ da y, restart at re d uce d d ose  
Fl u -li ke 
s y m pt o ms 
1- 3 
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 ote: Ma xi m u m 
c u m ulati ve dail y d ose of aceta mi n o p he n is 4 gra ms dail y d ue t o ris k of se vere li ver 
t o xicit y. 
Hea dac he  
1- 3 
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 ote: Ma xi m u m 
c u m ulati ve dail y d ose of aceta mi n o p he n is 4 gra ms dail y d ue t o ris k of se vere li ver 
t o xicit y. 
Na usea/ v o miti n g  
1 or 2  
Prescri be a ntie metics per treati n g p h ysicia n’s rec o m me n dati o n  
Na usea/ v o miti n g  
3 or 4  
I nterr u pt st u d y treat me nt.  Prescri be a ntie metics per treati n g p h ysicia n’s 
rec o m me n dati o n. Fl ui d a n d electr ol ytes s h o ul d be s u bstit ute d via I V i nf usi o n if 
i n dicate d.  W he n na usea/ v o mitti n g res ol ves t o  ≤ Gra de 2  restart e paca d ostat at a 
re d uce d d ose le vel.   
Diarr hea/c olitis  
1 
S u bjects s h o ul d be caref ull y m o nit ore d f or si g ns a n d s y m pt o ms of e nter oc olitis 
(s uc h as diarr hea, a b d o mi nal pai n, bl o o d, or m uc us i n st o ol, wit h or wit h o ut fe ver) 
a n d of b o wel perf orati o n (s uc h as perit o neal si g ns a n d ile us).  
C o nti n ue treat me nt wit h e paca d ostat, a n d i nitiate s u p p orti ve care meas ures, w hic h 
i ncl u de dri n ki n g li beral q ua ntities of clear fl ui ds.  If s ufficie nt oral fl ui d i nta ke is 
n ot feasi ble, fl ui d a n d electr ol ytes s h o ul d be s u bstit ute d via I V i nf usi o n.  A n 
a nti diarr heal ca n be starte d.  
2 
I nterr u pt st u d y treat me nt if i n dicate d, a n d i nitiate s u p p orti ve care meas ures, w hic h 
i ncl u de dri n ki n g li beral q ua ntities of clear fl ui ds.  If s ufficie nt oral fl ui d i nta ke is 
n ot feasi ble, fl ui d a n d electr ol ytes s h o ul d be s u bstit ute d via I V i nf usi o n.  A n 
a nti diarr heal s h o ul d be starte d.  
W he n diarr hea res ol ves t o baseli ne, restart e paca d ostat at t he sa me d ose.  

E p ac a d ost at / S D -1 0 1 / R a di ot her a p y  
 
Cli nic al St u d y Pr ot o c ol U C D C C # 2 7 1  
 
 
Pr ot o c ol v ersi o n: 0 2. 1 9. 2 0  
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C o nfi de nti al  
 
P a g e 4 7  of 9 5  
A d verse E ve nt  
C T C A E 
v 4. 0 3 
Gr a de  
Rec o m m e n de d S y m pt o m S pecific M a n a ge m e nt  
(t o be use d at discreti o n of tre ati n g p h ysici a n) 
3 or 4  
I nterr u pt st u d y treat me nt.  W he n diarr hea res ol ves t o baseli ne, restart e paca d ostat 
at a re d uce d d ose.   
M o nit or s u bjects f or si g ns a n d s y m pt o ms of e nter oc olitis (s uc h as diarr hea, 
a b d o mi nal pai n, m uc us or bl o o d i n st o ol, wit h or wit h o ut fe ver) a n d of  b o wel 
perf orati o n (s uc h as perit o neal si g ns a n d ile us).  I n s y m pt o matic s u bjects, r ule o ut 
i nfecti o us eti ol o gies a n d c o nsi der e n d osc o pic e val uati o n f or persiste nt or se vere 
s y m pt o ms.  
F or rec urre nt or persiste nt Gra de  3 or 4 diarr hea, c o nsi der f urt her d ose re d ucti o n of 
e paca d ostat, or st u d y treat me nt disc o nti n uati o n.  
P ne u m o nitis  
2  
I nterr u pt st u d y dr u g a n d i nitiate s yste mic c ortic oster oi ds.  Ta per as necessar y.  
Ma y ret ur n t o st u d y treat me nt if c o n diti o n i m pr o ves t o ≤ Gra de 1.  Per ma ne ntl y 
disc o nti n ue if t o xicit y d oes n ot res ol ve wit hi n 1 2 wee ks of last d ose or if s u bject 
s h o ws i na bilit y t o re d uce c ortic oster oi d t o ≤ 1 0 m g pre d nis o ne or e q ui vale nt per 
da y wit hi n 1 2  wee ks.  
3 or 4  
Per ma ne ntl y disc o nti n ue st u d y dr u g.  I m me diatel y treat wit h i ntra ve n o us 
c ortic oster oi ds.  A d mi nister a d diti o nal a nti -i nfla m mat or y meas ures, as nee de d. 
A d d pr o p h ylactic a nti bi otics f or o p p ort u nistic i nfecti o ns i n t he case of pr ol o n ge d 
ster oi d a d mi nistrati o n. 
T y pe I dia betes 
mellit us ( TI D M; 
if ne w o nset, 
i ncl u di n g dia betic 
ket oaci d osis 
[ D K A]) or 
≥ Gra de  3 
h y per gl yce mia, if 
ass ociate d wit h 
ket osis 
( ket o n uria) or 
meta b olic aci d osis 
( D K A) 
3 or 4  
I ns uli n re place me nt t hera p y is rec o m me n de d f or T y pe I dia betes mellit us a n d f or 
Gra de 3 -4 h y per gl yce mia ass ociate d wit h meta b olic aci d osis or ket o n uria.  
E val uate s u bjects wit h ser u m gl uc ose a n d a meta b olic pa nel, uri ne ket o nes, 
gl yc os ylate d he m o gl o bi n, a n d C -pe pti de.  
H y p o p h ysitis  
2 or 3  
Treat wit h oral c ortic oster oi ds.  W he n s y m pt o ms i m pr o ve t o ≤ Gra de 1, ster oi d 
ta per s h o ul d be starte d a n d c o nti n ue d o ver n o less t ha n 4 wee ks.  Re place me nt of 
a p pr o priate h or m o nes ma y be re q uire d as t he ster oi d d ose is ta pere d.  
4 
Disc o nti n ue st u d y dr u g.  Treat wit h a n i nitial d ose of I V c ortic oster oi ds f oll o we d 
wit h oral c ortic oster oi ds.  W he n s y m pt o ms i m pr o ve t o ≤ Gra de 1, ster oi d ta per 
s h o ul d be starte d a n d c o nti n ue d o ver n o less t ha n 4 wee ks.  Re place me nt of 
a p pr o priate h or m o nes ma y be re q uire d as t he ster oi d d ose is ta pere d.  
H y pert h yr oi dis m 
or 
h y p ot h yr oi dis m  
2 
T h yr oi d dis or ders ca n occ ur at a n y ti me d uri n g treat me nt.  M o nit or s u bjects f or 
c ha n ges i n t h yr oi d f u ncti o n (at t he start of treat me nt, peri o dicall y d uri n g treat me nt, 
a n d as i n dicate d base d o n cli nical e val uati o n) a n d f or cli nical si g ns a n d s y m pt o ms 
of t h yr oi d dis or ders.  
I n h y pert h yr oi dis m, n o nselecti ve beta-bl oc kers (e g, pr o pra n ol ol) are s u g geste d as 
i nitial t hera p y. 
I n h y p ot h yr oi dis m, t h yr oi d h or m o ne re place me nt t hera p y, wit h le v ot h yr o xi ne or 
li ot h yr o ni ne, is i n dicate d per sta n dar d of care. 

E p ac a d ost at / S D -1 0 1 / R a di ot her a p y  
 
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Pr ot o c ol v ersi o n: 0 2. 1 9. 2 0  
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C o nfi de nti al  
 
P a g e 4 8  of 9 5  
A d verse E ve nt  
C T C A E 
v 4. 0 3 
Gr a de  
Rec o m m e n de d S y m pt o m S pecific M a n a ge m e nt  
(t o be use d at discreti o n of tre ati n g p h ysici a n) 
3 or 4  
I n h y p ot h yr oi dis m, t h yr oi d h or m o ne re place me nt t hera p y, wit h le v ot h yr o xi ne or 
li ot h yr o ni ne, is i n dicate d per sta n dar d of care. 
I n h y pert h yr oi dis m, treat wit h a n i nitial d ose of I V c ortic oster oi d f oll o we d b y oral 
c ortic oster oi ds.  W he n s y m pt o ms i m pr o ve t o ≤ Gra de 1, ster oi d ta per s h o ul d be 
starte d a n d c o nti n ue d o ver n o less t ha n 4 wee ks.  Re place me nt of a p pr o priate 
h or m o nes ma y be re q uire d as t he ster oi d d ose is ta pere d.  
He patic  
2 
M o nit or li ver f u ncti o n tests m ore fre q ue ntl y u ntil ret ur ne d t o baseli ne val ues 
(c o nsi der wee kl y or t wice wee kl y if ster oi ds are n ot i nitiate d).  Treat wit h I V or 
oral c ortic oster oi ds.  
3 or 4  
Treat wit h i ntra ve n o us c ortic oster oi ds.  W he n li ver c he mistr y tests i m pr o ve t o ≤ 
Gra de 1, a ster oi d ta per s h o ul d be starte d a n d c o nti n ue d o ver n o less t ha n 4 wee ks. 
F or rec urre nt or persiste nt Gra de  3 li ver c he mistr y tests, c o nsi der f urt her d ose 
re d ucti o n of e paca d ostat (see Ta ble 5 f or e paca d ostat d ose m o dificati o ns), or st u d y 
treat me nt disc o nti n uati o n. 
F or p ersiste nt Gra de 4 li ver c he mistr y tests, disc o nti n ue st u d y treat me nt.  
H y's la w case a 
4 
Per ma ne ntl y disc o nti n ue st u d y t hera p y at t he first occ urre nce of li ver e nz y me 
ele vati o ns meeti n g t he criteria f or H y's la w. 
Re nal fail ure or 
ne p hritis  
2  
Treat wit h oral c ortic oster oi ds.  
3 or 4  
Treat wit h s yste mic c ortic oster oi ds.  W he n se verit y of t he e ve nt i m pr o ves t o ≤ 
Gra de 1, ster oi d ta per s h o ul d be starte d a n d c o nti n ue d o ver n o less t ha n 4 wee ks.  
F or rec urre nt or persiste nt Gra de  3 re nal fail ures or ne p hritis, c o nsi der f urt her d ose 
re d ucti o n of e paca d ostat (see Ta ble 5 f or e paca d ostat d ose m o dificati o ns), or st u d y 
treat me nt disc o nti n uati o n. 
F or persiste nt Gra de 4 re nal fail ure or ne p hritis, disc o nt i n ue st u d y treat me nt. 
a 
H y's la w is defi ne d as f oll o ws:  1 . A mi n otra nsferase ele vati o n ( A L T or A S T) > 3 × U L N; 2. T otal bilir u bi n 
> 2 × U L N, wit h o ut i nitial fi n di n gs of c h olestasis (ele vate d ser u m A L P); 3. N o ot her i m me diatel y a p pare nt 
p ossi ble ca use of a mi n otra nsferase ele vati o n a n d h y per bilir u bi ne mia, i ncl u di n g, b ut n ot li mite d t o, viral 
he patitis, li ver metastases, pre -e xisti n g c hr o nic or ac ute li ver disease, or t he a d mi nistrati o n of ot her dr u g(s)  
k n o w n t o be he pat ot o xic.  Per ma ne ntl y disc o nti n ue st u d y t hera p y at t he first occ urre nce of li ver e nz y me 
ele vati o ns meeti n g t he criteria f or H y's la w.  
 
 
 

E p ac a d ost at / S D -1 0 1 / R a di ot her a p y  
 
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Pr ot o c ol v ersi o n: 0 2. 1 9. 2 0  
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C o nfi de nti al  
 
P a g e 4 9  of 9 5  
6. 5  
M a n a ge m e nt of A d vers e E ve nts Ass oci ate d fr o m R a di ot her a p y  
Ra di ot hera p y is deli ver e 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 ma l a d verse effects f or t h e treat me nt of der mal, 
s u bc uta ne o us, n o dal, or visceral lesi o ns.  
6. 6  
G ui deli nes f or D os a ge M o dific ati o n a n d Tre at me nt I nterr u pti o n or Disc o nti n u ati o n  
D osi n g i nterr u pti o ns ma y be per mitte d i n t he cas e of me dical/s ur gical e ve nts or l o gistical 
reas o ns n ot rel ate d t o st u d y t hera p y ( e. g., electi ve s ur ger y, u nrelate d me dical e ve nts, s u bject 
vacati o n, a n d/ or h oli da ys).  S u bjects will  be place d bac k o n st u d y t hera p y wit hi n 4 wee ks of 
t he sc he d ule d i nterr u pti o n.  T he reas o n f or i nterr u pti o n s h o ul d be d oc u me nte d i n t he s u bject's 
st u d y rec or d. 
Criteria f or d ose m o dificati o n, treat me nt i nterr u pti o n or disc o nti n uati o n are o utli ne d i n Ta ble 3 
a n d Ta ble 4. 
A d ose of e p aca d ost at  ma y be hel d u p t o 3 0 da ys. Patie nts u na ble t o res u me e paca d ostat afte r 
3 0 d a ys d ue t o t o xicit y will disc o nti n ue E R S  t hera p y d ue t o treat me nt i nt olera bilit y. 
E paca d ostat ma y b e d ose re d uce d f or a gi v e n patie nt after t he D L T wi n d o w of p hase 1 or at 
a n y ti me i n p hase 2. Criteria f or d os e re d u cti o n of e paca d ostat are o utli ne d i n Ta ble 3 a n d 
T a ble 4. D ose le v els of e paca d ostat  f or d ose re d ucti o ns are o utli ne d i n Ta ble 5. T he d ose of 
e paca d ostat ma y n ot be r e d uce d b el o w 5 0 m g BI D  e ve n if t he M T D is deter mi ne d t o be 
1 0 0 m g BI D . Patie nts re q uiri n g d ose re d ucti o ns bel o w 5 0 m g bi d will disc o nti n ue E R S 
t hera p y d ue t o tr eat me nt i nt olera bilit y.   
T a ble 5: 
D ose M o dific ati o ns of E p ac a d ost at 
D ose le vel 1  
D ose Le vel - 1 
D ose Le vel - 2 
D ose Le vel - 3 
3 0 0 m g BI D  
2 0 0 m g BI D  
1 0 0  m g BI D  
5 0 m g BI D  
 
If necessar y, d os es of S D- 1 0 1 ca n be d ela ye d u p t o 5 da ys, b ut m ust be gi ve n wit hi n t he 
i nte n de d treat me nt w ee k.  If this is n ot p ossi ble, t he d ose will be s ki p pe d c o m pletel y. E ver y 
atte m pt s h o ul d be ma de t o deli ver at least 3 d oses d uri n g t he treat me nt peri o d. If a d o se is 
dela ye d , t he f oll o wi n g d ose s h o ul d be deli vere d d uri n g t he ne xt treat me nt w ee k, a mi ni m u m of 
5 da ys after t h e pre vi o usl y gi ve n d ose. S u bse q ue nt d oses i n s u bse q ue nt wee ks s h o ul d als o be 
a d mi nistere d a mi ni m u m of 5 da ys after t he pre vi o us d ose. T he d ose ma y n ot be m o difie d. If 
m ore t ha n t w o c o nsec uti ves d oses ar e misse d d ue t o t o xicit y, t he patie nt ma y c o nti n ue E R S 
t hera p y, b ut will be la bel e d as ha vi n g treat me nt i nt olera bilit y.  

E p ac a d ost at / S D -1 0 1 / R a di ot her a p y  
 
Cli nic al St u d y Pr ot o c ol U C D C C # 2 7 1  
 
 
Pr ot o c ol v ersi o n: 0 2. 1 9. 2 0  
U C D a vis C o m pre he nsi v e C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a g e 5 0  of 9 5  
T he prescri be d d ose of ra di ot hera p y ca n b e re d uce d t o n o l o wer t ha n 6 0 % of t he d ose as 
s pecifie d per fr acti o n i n r es p o nse t o 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 m al tiss ue t olera nces as dee m e d necess ar y b y the treati n g 
ra diati 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 a d mi nistere d later wit hi n t he 
first wee k of t h era p y.  A n y ra di ot hera p y fracti o ns n ot deli vere d d uri n g t he first wee k of 
t hera p y ca n n ot be ma de u p a n d t h ose d oses will be s ki p pe d. Patie nts u na ble t o recei ve at least 
6 0 % of t he pr escri be d ra di ot hera p y d ose d ue t o treat me nt t o xicit y ma y c o nti n ue E R S t hera p y 
b ut will be la bele d as ha vi n g treat me nt i nt olera bilit y.  
6. 7  
Tre at m e nt T oler a bilit y  
D L Ts a n d a n y ot her treat me nt relate d a d v erse e v e nt re q uiri n g disc o nti n uati o n of E R S t hera p y 
will be dee me d treat me nt i nt olera bilit y. Patie nts u na b le t o res u me e paca d ostat afte r 3 0 da ys 
d ue t o t o xicit y will disc o nti n ue E R S  t hera p y a n d will be la belle d as ha vi n g treat me nt 
i nt olerab ilit y.  If m or e t ha n t wo c o nsec uti ves d oses of S D- 1 0 1 are misse d d ue t o t o xicit y t he 
patie nt ma y c o nti n ue E R S t hera p y b ut will be la bele d as ha vi n g treat me nt i nt olera bilit y. 
Patie nts u na ble t o recei ve at least 6 0 % of t h e pres cri be d ra di ot hera p y d os e d ue t o treat me nt 
t o xicit y ma y c o nti n ue E R S t hera p y b ut will be la bele d as ha vi n g treat me nt i nt olera bilit y. 
E paca d ostat d ose re d u cti o ns will n ot be la belle d as treat me nt i nt olera bilit y b ut will be re p orte d 
se parat el y. 
6. 8  
M a n a ge m e nt of S u bjects E x hi biti n g Ser ot o ni n S y n dr o me  
T here is a t he oretical c ha nce t hat e p aca d ostat c o ul d ca use a n i n crease i n ser ot o ni n le vels i n t he 
brai n t hat mi g ht tri g ger S S ( htt p:// w w w. nej m. or g/ d oi/f ull/ 1 0. 1 0 5 6/ N EJ Mra 0 4 1 8 6 7) w he n 
a d mi nistere d i n c o m bi nati o n wit h ot her ser ot o ner gic a ge nts.  T his s y n dr o me has bee n m ost 
cl osel y ass ociate d wit h use of M A OIs, D e mer ol ® , li nez oli d, or met h yle ne bl ue; all of t hese 
a ge nts ar e pr o hi bite d d uri n g t he st u d y.  Selecti ve ser ot o ni n re u pta k e i n hi bit ors ( S S RIs) a n d 
ser ot o ni n/ n ore pi ne p hri ne re u pta ke i n hi bit ors ( S N RIs) are p er mitte d i n t he st u d y.  T he 
f oll o wi n g pr oce d ur es will be i m ple me nte d if s u bjects e x hi bit t he si g ns/s y m pt o ms of S S 
descri be d i n Ta bl e 6 , i ncl u di n g tre m or; h y perrefle xia; a n d s p o nta ne o us, oc ular, or i n d uci ble 
cl o n us, t o get her wit h a git ati o n, fe ver, di a p h oresis, or m uscle ri gi dit y: 
•  I m me diat el y i nterr u pt e p aca d ostat a d mi nistrati o n.  A d mi nistrati o n of ot her st u d y dr u gs 
ma y c o nti n ue. 
•  I m me diat el y i nterr u pt a n y S S RI or S N RI a d mi nistrati o n. 
•  Pr o vi de a p pr o priate m e dical ma na g e me nt of t he s u bject u ntil all si g ns/s y m pt o ms are 
res ol ve d (e g, I V fl ui ds a n d/ or s y m pat h o mi metic a mi nes f or h y p ote nsi o n, be nz o diaze pi nes 
f or a gitati o n, a d mi nistrati o n of 5- h y dr o x ytr y pta mi ne a nta g o nists, s uc h as 
c y pr o he pta di ne). 

E p ac a d ost at / S D -1 0 1 / R a di ot her a p y  
 
Cli nic al St u d y Pr ot o c ol U C D C C # 2 7 1  
 
 
Pr ot o c ol v ersi o n: 0 2. 1 9. 2 0  
U C D a vis C o m pre he nsi v e C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a g e 5 1  of 9 5  
•  If s u bject c h o os es t o re m ai n i n t he st u d y, restart treat me nt wit h e paca d ostat after t he 
S S RI or S N RI h as bee n disc o nti n ue d, n o s o o ner t ha n 5 half- li ves ha v e ela ps e d f or t he 
s pecific S S RI or S N RI i n q uesti o n a n d after res ol uti o n of si g ns/s y m pt o ms of S S.  T he 
S S RI or S N RI tr eat me nt M A Y N O T be restart e d.  
•  If s u bject c h o os es t o wit h dra w fr o m the st u d y or m ust restart treat me nt wit h S S RI or 
S N RI, t he s u bject s h o ul d be sc he d ule d f or a f oll o w- u p visit.  Treat me nt wit h S S RI or 
S N RI ma y be i nitiate d 2 wee ks after res ol uti o n of si g ns a n d s y m pt o ms of S S. 
 
T a ble 6: 
Si g n a n d S y m pt o ms of Ser ot o ni n S y n dr o me  
Tre m or a n d h y perrefle xia  
S p o nta ne o us cl o n us  
M uscle ri gi dit y, te m perat ure > 3 8 °C  ( 1 0 0. 4° F), a n d eit her oc ular cl o n us or i n d uci ble cl o n us 
Oc ular cl o n us a n d eit her a gitati o n or dia p h oresis  
I n d uci ble cl o n us a n d eit her a gitati o n or dia p h oresis  
 
 
7.  
C O N C O MI T A N T A N D E X C L U D E D T H E R A PI E S  
7. 1  
C o nc o mit a nt T her a p y 
T he patie nt m ust be t ol d t o n otif y t he i n vesti gati o nal site a b o ut a n y ne w m e dicati o ns he/s he 
ta kes after t he start of t h e st u d y dr u g. All me dicati o ns ( ot her t ha n st u d y dr u g) a n d si g nifica nt 
n o n- dr u g t her a pies (i ncl u di n g bl o o d tra nsf usi o ns) a d mi nistere d d uri n g t he st u d y s h o ul d be 
rec or d e d.  
C o nc o mita nt t hera p y i ncl u des a n y pres cri pti o n me dicati o ns or o ver- t h e-c o u nter pre p arati o ns 
use d b y a patie nt bet w ee n t he 7 da ys prece di n g t h e scree ni n g e val u ati o n a n d t he treat me nt 
disc o nti n uati o n visit.  
Patie nts w h o e x perie n ce i nf usi o n- ass ociate d s y m pt o ms ma y be treate d s y m pt o maticall y wit h 
a nti p yretics (i b u pr of e n pr eferre d), di p h e n h y dra mi n e, a n d/ or ci meti di ne or a n ot her H 2 rece pt or 
a nta g o nist, as per sta n d ar d practice. Seri o us i nf usi o n-ass ociate d e ve nts ma nifeste d b y d ys p nea, 
h y p ote nsi o n, w heezi n g, br o nc h os pas m, tac h y car di a, re d uce d o x y ge n s at urati o n, or res pirat or y 
distress s h o ul d be ma na g e d wit h s u p p orti ve t hera pies as cli nicall y i n d icate d (e. g. s u p ple me ntal 
o x y ge n a n d β 2-a dre n er gi c a g o nists).  
S yste mic c ortic oster oi ds a n d T N F α  i n hi bit ors ma y atte n uate p ote ntial be n eficial i m m u n ol o gic 
effects of treat me nt  b ut ma y be a d mi nistere d at t he discreti o n of t he treati n g p h ysicia n.  If 
feasi ble, alter nati ves t o c ortic oster oi ds s h o ul d be c o nsi dere d.  Pre me dicati o n ma y be 
a d mi nistere d f or C ycles ≥ 2 at t he discreti o n of t h e treati n g p h ysicia n.  T h e use of i n hale d 

E p ac a d ost at / S D -1 0 1 / R a di ot her a p y  
 
Cli nic al St u d y Pr ot o c ol U C D C C # 2 7 1  
 
 
Pr ot o c ol v ersi o n: 0 2. 1 9. 2 0  
U C D a vis C o m pre he nsi v e C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a g e 5 2  of 9 5  
c ortic oster oi ds a n d mi ner al oc ortic oi ds (e. g., fl u dr o c ortis o ne) f or patie nts wit h ort h ostatic 
h y p ote nsi o n or a dre n o c ortical i ns ufficie nc y is all o we d.  Me gastr ol a d mi nistere d as a p petite 
sti m ula nt is acce pta ble w hile t he patie nt is e nr olle d i n t he st u d y.  
Patie nts w h o use oral c o ntrace pti ves, h or m o n e- re place me nt t hera p y, pr o p h ylactic or 
t hera pe utic a ntic oa g ulati o n t hera p y (s u c h as l o w-m olec ular -w ei g ht he pari n or warfari n at a 
sta ble d ose le vel), or ot her all o we d mai nte n a nce t hera p y s h o ul d c o nti n ue t heir use.  Males a n d 
fe males of re pr o d u cti ve p ote ntial s h o ul d use hi g hl y effecti ve mea ns of c o ntrace pti o n. 
7. 2  
E xcl u de d T her a p y  
A n y c o nc o mita nt t hera p y i nte n de d f or t he treat me nt of ca ncer, w h et her healt h 
a ut h orit y-a p pr o ve d or e x peri me ntal, is pr o hi bite d.  T his i ncl u des b ut is n ot li mite d t o t he 
f oll o wi n g: 
•  C he m ot hera p y, h or m o nal t hera p y, i m m u n ot hera p y, ra di ot hera p y, i n v esti gati o nal a ge nts, 
or her bal t hera p y  
o  After da y 2 9, cert ai n f or ms of ra di ot hera p y m a y be c o nsi dere d f or p alliati o n if 
patie nts are d eri vi n g be n efit (e. g., treat me nt of k n o w n b o n y metastases); E R S  
a d mi nistrati o n s h o ul d be c o nti n ue d d uri n g s uc h palliati ve ra di ot hera p y. 
It is str o n gl y rec o m me n d e d t hat:  
•  Tra diti o nal her bal me di ci nes n ot be a d mi nistere d b eca use t h e i n gre die nts of ma n y her bal 
me dici nes ar e n ot f ull y st u die d a n d t heir use ma y res ult i n u na ntici pate d dr u g- dr u g 
i nteracti o ns t hat ma y ca use, or c o nf o u n d assess me nt of, t o xicit y 
Patie nts are n ot all o we d t o recei v e i m m u n osti m ulat or y a ge nts, i ncl u di n g b ut n ot li mite d t o 
I F N-α , I F N-γ, or I L- 2, d uri n g t he e ntire st u d y.  T hese a ge nts, i n c o m bi nati o n wit h st u d y 
treat me nt, c o ul d p ote ntiall y i ncrease t he ris k f or a ut oi m m u ne c o n diti o ns. 
Patie nts s h o ul d als o n ot be recei vi n g i m m u n os u p pressi ve me dicati o ns, i ncl u di n g b ut n ot 
li mite d t o c ycl o p h os p ha mi de, azat hi o pri ne, met h otre xate, a n d t h ali d o mi de.  T hese a g e nts 
c o ul d p ote ntiall y alter t he acti vit y a n d t he safet y of E R S t hera p y .  S yste mic c ortic oster oi ds a n d 
a nti-T N F α  a ge nts ma y atte n uate p ote ntial be nefici al i m m u n ol o gic effects of t he E R S t hera p y 
b ut ma y be a d mi nistere d at t he discreti o n of t he treati n g p h ysicia n a n d if n ee de d t o ma n a ge 
treat me nt t o xicit y per g ui deli nes o utli ne d i n t his pr ot oc ol.  If feasi ble, alter n ati ves t o t hese 
a ge nts s h o ul d be c o nsi dere d. 
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 ot hera p y a g e nts f or at least 1 4 d a ys after disc o nti n ui n g st u d y t hera 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 starti n g fr o m st u d y treat me nt 
i nitiati o n t hr o u g h e n d of treat me nt p hase of t his st u d y u nless ot her wise n ot e d bel o w: 

E p ac a d ost at / S D -1 0 1 / R a di ot her a p y  
 
Cli nic al St u d y Pr ot o c ol U C D C C # 2 7 1  
 
 
Pr ot o c ol v ersi o n: 0 2. 1 9. 2 0  
U C D a vis C o m pre he nsi v e C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a g e 5 3  of 9 5  
•  A n y  i n vesti gati o nal me dicati o n ot her t ha n t he st u d y dr u gs.  
•  A n y c hr o nic i m m u n ol o gical-s u p pressi v e treat me nt f or a n y reas o n.  ( N ote:   I n hale d or 
t o pical ster oi ds are all o w e d, a n d s yste mic ster oi ds at d oses ≤1 0 m g/ da y pre d nis o ne or 
e q ui vale nts ar e all o we d a n d i m m u ne s u p pressa nts are all o w e d f or s h ort- ter m treat me nt 
f or i m m u ne t o xicities or as pr o p h yla xis f or c o ntrast aller g y f or i ma gi n g pr o ce d ures.) 
•  A d mi nistrati o n of a li ve atte n uate d vacci ne wit hi n 3 0 da ys bef ore t he first d ose of st u d y 
treat me nt a n d w hile p artici pati n g i n t he st u d y.  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, c hic ke n p o x, y ell o w fe ver, ra bies, 
B C G, a n d t y p h oi d vacci n e.  Seas o nal i nfl ue n za vacci nes f or i njecti o n are g e nerall y kille d 
vir us vacci nes a n d ar e all o we d; h o we ver, i ntra nas al i nfl ue nza v acci n es (e g, Fl u Mist ®) 
are li ve atte n u ate d vacci n es a n d are n ot all o we d.  
•  Use of a n y M A OI or dr u g ass ociate d wit h si g nifica nt M A OI acti vit y a ge nts is pr o hi bite d 
fr o m 2 1 da ys pri or t o D a y 1 t hr o u g h 2 wee ks after t he fi nal d ose of e p aca d ostat has bee n 
a d mi nistere d  
•  Use of a n y i m m u n ol o gical- base d treat me nt f or a n y reas o n fr o m st u d y treat me nt i nitiati o n 
t hr o u g h f oll o w- u p visit is pr o hi bite d. 
•  N ote:  C o m plete d a dj u va nt t hera p y (e g, v acci nes) wit h me dical m o nit or a p pr o val, i n hale d 
or t o pical ster oi ds, a n d s yste mic ster oi ds at d oses ≤ 1 0 m g/ da y pre d nis o ne e q ui vale nts are 
all o we d, as des cri be d i n Restricte d Me dicati o ns . 
•  A n y U G T 1 A 9 i n hi bit or, i ncl u di n g acitreti n, a mitri pt yli ne, a n dr oster o ne, c y cl os p ori ne, 
dasati n i b, dicl ofe nac, difl u nisal, efa vire n z, erl oti ni b, estra di ol ( 1 7-bet a), fl uta mi de, 
gefiti ni b, ge mfi br ozil, gl yc yrr heti nic aci d gl yc yrr hizi n, i mati ni b, i mi pra mi ne, 
ket oc o naz ol e, li n oleic aci d s u p ple me nts, mefe na mic aci d, m yc o p he n olic aci d, nifl u mic 
aci d, nil oti ni b, p he n o bar bital, p he n yl b utaz o ne, p h e n yt oi n, pr o be neci d, * pr o p of ol, 
q ui ni di ne, rit o na vir, s oraf e ni b, s ulfi n p yraz o ne, v al pr oic aci d, a n d v era pa mil. 
•  * N ote – Pr o p of ol, w he n use d f or s h ort-ter m se d ati o n d uri n g s ur gic al/ bi o psy pr oce d ures, 
is all o we d.  T he e p ac a d ost at d ose m ay be t ake n o n t he m or ni n g of t he pr oce d ure, a n d t he 
eve ni n g d ose h el d f oll o wi n g t he pr oce d ure.  E p a c a d ost at m ay be res u me d t h e next d ay  
 
S u bjects ma y recei ve ot h er me dicati o ns t hat t he i n vesti gat or dee ms t o be m e dicall y necessar y.  
T he e x cl usi o n criteria descri be ot her me di cati o ns t hat are pr o hi bite d d uri n g t his st u d y.  T here 
are n o pr o hi bite d t hera pi es d uri n g t he p ost- treat m e nt f oll o w- u p p hase. 
 
 

E p ac a d ost at / S D -1 0 1 / R a di ot her a p y  
 
Cli nic al St u d y Pr ot o c ol U C D C C # 2 7 1  
 
 
Pr ot o c ol v ersi o n: 0 2. 1 9. 2 0  
U C D a vis C o m pre he nsi v e C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a g e 5 4  of 9 5  
7. 3  
Restricte d Me dic ati o ns/ Tre at me nt  
•  S yste mic ster oi ds ma y be use d at d oses ≤ 1 0 m g/ da y pre d nis o ne or e q ui val e nts. 
•  Use of c o u mari n- bas e d a ntic oa g ula nts (e g, C o u ma di n) is disc o ura ge d.  L o w - d ose 
C o u ma di n ®  ( 1 m g) is acce pta ble; h o we v er, d oses t hat i ncreas e t he I N R are disc o ura ge d 
a n d will re q uire d ose m o dificati o n.  If a n alter nati ve t o c o u mari n-b ase d a ntic oa g ula nts 
ca n n ot be use d, d os e m o dificati o ns of t he C o u ma di n ® ma y be nee d e d.  Base d o n t he 
o bser ve d ma g nit u de of e paca d ostat/ warfari n P K i nteracti o n a n d P K/ P D m o deli n g res ults, 
f or a n e p aca d ostat d ose of 3 0 0 m g BI D, t h e d ose of warfari n s h o ul d be re d u ce d b y 
a p pr o xi matel y o ne- t hir d after i nitiati o n of e paca d ostat a d mi nistrati o n base d o n 
a p pr o xi matel y 3 0 % t o 4 0 % re d ucti o n i n S- a n d R- warfari n oral cleara nce v al ues.   Cl ose 
I N R m o nit ori n g is rec o m men de d f or s u bjects o n a sta ble d ose of w arfari n w h o are 
starti n g treat me nt wit h e paca d ostat.  Base d o n P K/ P D m o deli n g, rec o m me n dati o ns f or 
warf ari n d ose m o dificati o ns f or s u bjects recei vi n g ot her e paca d ostat d oses, are 
s u m marize d i n Ta ble 7 b ase d o n t he I N R pri or t o starti n g e paca d ostat. 
 
T a ble 7 :   W arf ari n d ose m o dific ati o ns wit h E p ac a d ost at 
St a ble B aseli ne I N R  
E p ac a d ost at   D ose  
≤ 5 0 -1 0 0 m g BI D  
2 0 0 m g BI D  
3 0 0 m g BI D  
I N R  ≤ 2. 5  
Cl ose I N R 
m o nit ori n g  
Cl ose I N R m o nit ori n g  
Re d uce warfari n b y ~ 3 3 % 
a n d m o nit or I N R 
I N R  > 2. 5  
Cl ose I N R 
m o nit ori n g  
Re d uce warfari n b y 
2 0 %- 2 5 % a n d m o nit or 
I N R 
Re d uce warfari n b y ~ 3 3 % 
a n d m o nit or I N R 
•  Use of t he a ntic o n v ulsa nt car ba m aze pi n e (a U G T 1 A 9 i n d ucer) is disc o ura g e d .  Beca us e 
t here is a p ote ntial i nter act i o n t hat c o ul d res ult i n l o wer e paca d ostat e x p os ures, a n 
alter nati ve t o car ba maze pi ne s h o ul d be use d, if p ossi ble. 
 
 
 

E p ac a d ost at / S D -1 0 1 / R a di ot her a p y  
 
Cli nic al St u d y Pr ot o c ol U C D C C # 2 7 1  
 
 
Pr ot o c ol v ersi o n: 0 2. 1 9. 2 0  
U C D a vis C o m pre he nsi v e C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a g e 5 5  of 9 5  
8.  
T R E A T M E N T D U R A TI O N  
Patie nts will c o m plete t hera p y u nless o n e of t he f oll o wi n g criteria a p plies:  
•  C o nfir me d Disease pr o gr essi o n per ir R E CI S T  
•  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  or D L T  
•  Patie nt wit h dra wal fr o m st u d y ( patie nt c h oice)  
•  Pre g na nc y  
•  Dela y i n  e paca d ostat  tr eat me nt > 3 0 da ys d ue t o t o xicit y 
•  Fai l ure of patie nt t o a d here t o st u d y re q uire m e nts 
•  P h ysicia n Discreti o n  
8. 1  
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 treat me nt wit h t he a ge nt u n der 
t his I N D or u ntil all treat me nt relate d cli nical si g nifica nt t o xicities res ol ve t o baseli ne or 
gra de ≤ 1. A d v erse e ve nts wit h attri b uti o n of p ossi ble, pr o ba ble or d efi 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 re p orti n g a n d all S A Es will be re p orte d f or 3 0 da ys 
after t he l ast d ose.   Patie nts will be f oll o w e d e ver y 3 m o nt hs per sta n dar d of care f or P F S a n d 
O S.  
8. 2  
Disc o nti n u ati o n D ue t o  Dise ase Pr o g ressi o n   
I m m u n ot her a pe utic a ge nts s uc h as e paca d ostat a n d S D- 1 0 1 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 o ac 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 n e 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 8. S u bjects w h o are dee me d cli nicall y u nsta ble or 
w h o ha ve bi o ps y pr o ve n ne w metastatic lesi o ns are n ot re q uire d t o h a 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 
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 criteri a f or c o nti n ue d treat me nt o n st u d y after 
disease pr o gr essi o n is i de ntifie d at a t u m or assess me nt: 

E p ac a d ost at / S D -1 0 1 / R a di ot her a p y  
 
Cli nic al St u d y Pr ot o c ol U C D C C # 2 7 1  
 
 
Pr ot o c ol v ersi o n: 0 2. 1 9. 2 0  
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C o nfi de nti al  
 
P a g e 5 6  of 9 5  
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 
i n vesti gat or's discreti o n base d o n t he cli nical stat us of t he s ubject . 
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 n e d b y t he f oll o wi n g criteri a:  
•  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 o f disease. 
•  A bse nce of pr o gr essi ve t u m or at critical a n at 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 alter nati ve me dical i nter v e nti o n. 
 
T a ble 8:  I m a gi n g a n d Tre at m e nt after Fi rst R a di ol o gic E vi de nce of Pr o gressi ve Dise 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 nce of P D  
Re peat 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 peat 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 peat sca n 
s h o ws S D, P R, or 
C R a 
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  fr o m Wee k 
1 2 t o Wee k 4 8 t he n 
e ver 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 gin g 
assess me nts e ver y 
6 wee ks  fr o m 
Wee k  1 2 t o Wee k 
4 8 t he n 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  
a 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.  
 
 

E p ac a d ost at / S D -1 0 1 / R a di ot her a p y  
 
Cli nic al St u d y Pr ot o c ol U C D C C # 2 7 1  
 
 
Pr ot o c ol v ersi o n: 0 2. 1 9. 2 0  
U C D a vis C o m pre he nsi v e C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a g e 5 8  of 9 5  
a 
Patie nts will b e m o nit ore d o n ce d uri n g t h e first wee k of ra di ot h era p y, a n d wit h  eac h i ntralesi o n al S D -1 0 1 i njecti o n.  Patie nts 
will be m o nit ore d e v er y 3 0 d a ys ( +/ - 7 d a ys) t h ereafter f or safet y.  
b 
He mat ol o g y  a n d ser u m c h e mistr y  assess m e nts s h o ul d b e o btai n e d wit hi n 1 4 d a ys of t h e first st u d y treat me nt  a n d d o n’t nee d 
t o be re peate d o n d a y 1. A c o m plete bl o o d c o u nt  wit h differe ntial  a n d a c o m p re h e nsi v e meta b olic pr ofile  s h o ul d b e o btai ne d 
f or t hese st u dies. D uri n g f oll o w -u p t h ese tests will b e d o n e e v er y t hirt y d a ys.  
c 
Refer t o Secti o n 1 3. 5 f or pr o ce d ures f or re p orti n g S A Es.  
d 
O R R, D C R, a n d P F S will b e assesse d e v er y 6 0 d a ys usi n g R E CI S T 1. 1 a n d ir R E CI S T.  
e 
E paca d ostat : 5 0 -3 0 0 m g P O BI D t hr o u g h o ut t h e st u d y p eri o d u ntil pr o gressi o n. 
f 
I ntralesi o n al S D-1 0 1 : 4 m g i njecti o n i nt o R T treat me nt lesi o n. 5 i ntralesi o n al i njecti o ns will b e a d mi nistere d o v er a 5 wee k 
peri o d o n d a ys 1, 8, 1 5, 2 2, a n d 2 9.  T h e fi n al t w o i njecti o ns ( o n d a y 2 2 a n d 2 9) are o pti o n al f or p atie nts wit h visceral 
treat me nt lesi o ns. 
g 
Ra diati o n t h era p y: C o h ort 1 (s oli d t u m ors): 8 G y × 3) or 4 G y × 5); C o h ort 2 (l y m p h o ma):  8 G y × 3, 4 G y × 5 , or 2 G y × 2.  
All treat me nts m ust c o m me n ce o n d a y 1 after i ntralesi o n al i njecti o n of S D -1 0 1. Fracti o ns ma y b e d eli v ere d o n c o nsec uti ve 
or e ver y ot h er d a y (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 b et wee n treat me nts), b ut m ust b e  c o m plete d d uri n g 
wee k 1.  
h 
C T or M RI  at pre-treat me nt a n d e v er y 6 0 d a ys  t hr o u g h o ut t h e st u d y p eri o d.  
i 
C orrelati ves: Bl o o d sa m ples f or i m m u n e assa ys will b e c ollecte d o n Da y 1 a n d Da y 1 5  a n d at 6 0 d a y cli nical visits . See t he 
c orrelati ve st u dies secti o n f or d etaile d i nf or mati o n ( Secti o n 1 1. 0). 
j 
Bi o ps y: O n Da y 1  a n d Da y 1 5  t u m or bi o ps y will prece d e i ntralesi o n al i njecti o n, R T, a n d  e p aca d ostat . See t h e c orrelati ve 
st u dies secti o n f or d etaile d i nf or mati o n ( Secti o n 1 1. 0). N O T E:  T he Da y 1 bi o ps y a n d la bs m ust b e c o m plete d b ef ore starti n g 
pr ot oc ol treat me nt.  
k 
q 6 0 Da y Visits: Patie nts will b e f oll o we d wit h a i ma gi n g, la bs, a n d cli nic visit e v er y 6 0 d a ys d uri n g t h e first y ear of st u d y.  
Brief visits f or safet y m o nit ori n g will o cc ur e v er y 3 0 d a ys ( +/ - 7 d a ys).  
l 
F oll o w -u p:  All p atie nts will b e f oll o we d f or 3 0 d a ys after t h e last d ose of treat me nt wit h t h e a g e nt u n d er t his I N D or u ntil all 
cli nical si g nifica nt t o xicities res ol v e t o  b aseli ne or gra d e ≤ 1.  A d diti o n al f oll o w -u p d ata will b e g at h ere d e v er y 3 m o nt hs 
fr o m sta n d ar d of care f oll o w u p visits a n d assess me nts after trial disc o nti n u ati o n. 
m  
S t o ol sa m ple will b e c ollecte d fr o m p atie nts bef ore i nitiati o n of treat me nt. 
 
 
 
 
 
 
 
 

E p ac a d ost at / S D -1 0 1 / R a di ot her a p y  
 
Cli nic al St u d y Pr ot o c ol U C D C C # 2 7 1  
 
 
Pr ot o c ol v ersi o n: 0 2. 1 9. 2 0  
U C D a vis C o m pre he nsi v e C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a g e 5 9  of 9 5  
1 0.  
A S S E S S M E N T S T Y P E S  
1 0. 1  
Effic ac y  
Res p o nse a n d pr o gr essi o n will be e val uate 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 r e vise d Res p o nse E val uati o n Criteria i n S oli d T u m ors ( R E CI S T) g ui deli ne 
( versi o n 1. 1) [5 6 ] as w ell as ir R E CI S T criteria. A d diti o nall y, i ma gi n g will be re vie w e 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-ra di ot her a p y s carri n g. C ha n g es i n t he lar gest 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 d ia meter i n t he cas e of mali g na nt l y m p h 
n o des a re us e d i n t he R E CI S T criteria. 
Disease Par a meters  
Me as ur a ble D ise ase 
T he  prese n ce  of  at least o ne meas ur a ble  lesi o n. If t he meas ura ble  diseas e  is restricte d t o a 
s olitar y lesi o n, its ne o plastic  nat ure  s h o ul d be  c o nfir me d  b y  c yt ol o g y/ hist ol o g y.   
 
Me as ur a ble Lesi o ns 
Lesi o ns t hat ca n be acc ur atel y  meas ur e d  i n at least o ne di me nsi o n wit h l o n gest dia meter  
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.  
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 ni tis, 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 uati 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, prefer a bl y wit hi n t w o wee ks of treat me nt i nitiati o n, a n d ne ver  m ore  t ha n 4  wee ks  
bef ore  t h e be gi n ni n g  of  t he treat me nt.  
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 der e 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 h e cas e  of  s ki n lesi o ns, d oc u me ntati o n  b y  c ol or 
p h ot o gra p h y,  i ncl u di n g a  r uler t o esti mate t he size of  t he lesi o n, is rec o m m e n de d.  
 
 

E p ac a d ost at / S D -1 0 1 / R a di ot her a p y  
 
Cli nic al St u d y Pr ot o c ol U C D C C # 2 7 1  
 
 
Pr ot o c ol v ersi o n: 0 2. 1 9. 2 0  
U C D a vis C o m pre he nsi v e C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a g e 6 0  of 9 5  
Met h o ds of Meas ur e me nts  
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 nse assessme nt. C o n ve nti o nal C T a n d M RI s h o ul d be 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 perf or me d usi n g a 5 
m m c o nti g u o us rec o nstr u cti 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- r a 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 ver, 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 ul es. 
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 os c 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 he ir 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 pecialize d ce nters. H o w e 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  r es p o nse w he n  bi o psies  are  o btai ne 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 tr eat me nt t o differe ntiate  bet wee n  resi d ual b e 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 Criteria  
E val uati o n of T ar g et 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  R es p o nse ( P R):  At least a 3 0 % decrease i n t he s u m of t he L D of t ar get lesi o ns, 
ta ki n g as ref ere 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 n e or m ore ne w l esi o ns  
•  S t 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 
started 
 

E p ac a d ost at / S D -1 0 1 / R a di ot her a p y  
 
Cli nic al St u d y Pr ot o c ol U C D C C # 2 7 1  
 
 
Pr ot o c ol v ersi o n: 0 2. 1 9. 2 0  
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C o nfi de nti al  
 
P a g e 6 1  of 9 5  
E v al u ati o n of B est Over all  Res p o nse   
T he best o ver all 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 gr essi 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 d e d si nce t he treat m e nt starte d). I n g e 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 9 :   Best O ver all Res p o nse E v al u ati o n 
Best O ver all Res p o nse E v al u ati o n  
T ar get 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  disease  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 after 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 vesti gate d  (fi ne nee 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.  
 
I m m u ne Rel ate d Res p o nse Criteri a 
A gr o wi n g b o d y of literat ure i n dicates t hat ra di o gra p hic res p o ns es t o i m m u n ot hera p y ma y 
ha ve diff ere nt patter ns a n d ki netics t ha n w hat w o ul d be e x pect e 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 diff ere n ces w e will als o c haracterize ra di o gra p hic o utc o mes 
usi n g t he i m m u ne relate d res p o nse criteria o utli ne d b y W olc h o k a n d c ollea g ues [5 7 ]. See 
A p pe n di x 6. T his criteria will be use d t o meas ure t he a bsc o pal res p o nse rate a n d D C R 
( C R + P R + S D) a n d deter mi ne w het her t he st u d y s h o ul d pr ocee d t o sta g e 2 a n d is w ort h y of 
f urt her st u d y d uri n g t he Si m o n t w o-sta ge st u d y.  

E p ac a d ost at / S D -1 0 1 / R a di ot her a p y  
 
Cli nic al St u d y Pr ot o c ol U C D C C # 2 7 1  
 
 
Pr ot o c ol v ersi o n: 0 2. 1 9. 2 0  
U C D a vis C o m pre he nsi v e C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a g e 6 2  of 9 5  
C o nfir m ati o n  
T he  mai n  g oal  of  c o nfir mati o n  of  o bjecti ve  res p o nse is t o a v oi d o veresti mati n g  t he res p o nse 
rate o bser v e d . F or r e p orti n g t he st u d y  o utc o me s t he res p o nse rate a n d c o nfir me d res p o nse rate 
will be ma de clear . F or i nter val e val u ati o n of res p o nse rates d uri n g t he Si m o n-t w o sta ge st u d y 
res p o nses d o n ot nee d t o be c o nfir me d f or t he st u d y t o pr o gress. T o  be  assi g ne d t he stat us of 
c o nfir me d  r es p o nses m ust  be  c o nfir me d  b y  re peat assess me nts  t hat s h o ul d be  perf or me d  n o  
less t ha n 4  wee ks  after t h e criteri a f or res p o nse are  first met.  L o n ger  i nter v als as deter mi ne d  b y  
t he st u d y pr ot oc ol  ma y  als o be  a p pr o pri ate.  I n t he case of  S D,  f oll o w-u p  meas ure m e nts  m ust  
ha ve  met  t he S D  criteria at least o nce  after st u d y e ntr y at a mi ni m u m  i nter val (i n ge neral,  n ot  
less t ha n 6 -8  wee ks)  t hat is defi ne d  i n t he st u d y pr ot oc ol. F or P D all res ults s h o ul d be 
c o nfir me d  as d escri be d i n secti o n 8. 2.  
D ur ati o n of O ver all Res p o nse  
T he  d urati o n  of  o verall  r es 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 stat 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 ref ere n ce f or P D  t he s mallest meas ure m e nts  rec or d e 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 ref ere n ce t he s mallest meas ure m e nts  rec or d e d si nce 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, b ut i n 
ge neral, if t w o c o nsec uti ve C T/ M RI sca ns s h o w sta ble disease, or t h e patie nt e x perie nces f o ur 
m o nt hs of sta ble disease, t he n we will c o nsi der t his t o be sta ble disease 
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 uire d b et wee n  t w o m eas ure me 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 p ecte d  cli nical be nefit  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.  
Tre at m e nt T oler a bilit y  
Treat me nt t oler a bilit y will be meas ure d as t he perce nta ge of patie nts w h o re mai n free of 
treat me nt i nt olera bilit y as defi ne d i n secti o n 6. 6. 
A bsc o p al Res p o nse R ate ( A R R)  
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 d iate d lesi o ns as d e fi ne d b y ir R E CI S T criteria  

E p ac a d ost at / S D -1 0 1 / R a di ot her a p y  
 
Cli nic al St u d y Pr ot o c ol U C D C C # 2 7 1  
 
 
Pr ot o c ol v ersi o n: 0 2. 1 9. 2 0  
U C D a vis C o m pre he nsi v e C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a g e 6 3  of 9 5  
 
O bjecti ve R es p o nse R at e  
O R R is defi ne d as t he perce nta g e of patie nts t hat ac hie v e P R or C R.  
Dise ase C o ntr ol R at e ( 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 h a ve 
sta ble disease t o t her a p y as best res p o nse a n d is defi ne d as c o m plete res p o nse  ( C R) + partial 
res p o nse ( P R) + sta bl e disease ( S D).  T his e n d p oi nt has bee n s h o w n t o be m ore mea ni n gf ul, 
a n d tra nslati n g t o s ur vi val a d va nta ge, i n a n u m b er of t u m or i m m u n ot hera p y st u dies.  
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 ur ati 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 o cc urs first.  
O ver all S ur vi v al ( O S)  
O S is defi ne d as t he d ur ati o n of ti me fr o m t he start of tre at me nt t o deat h fr o m a n y ca use.  
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 ories:  1)  c o m plete res p o nse, 2)  partial  res p o ns e, 3)  st a ble disease,  4)  
pr o gressi ve  disease,  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 her  ca us e, or  8)  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 r ate. Patie nts  i n res p o nse cat e g ories  4 -8  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 ( dis ease pr o gressi o n).  T h us,  a n i nc orrect treat me nt sc he d ule or  dr u g  
a d mi nistrati o n , or fail ure t o c o m plete all prescri be d st u d y t hera p y, d oes  n ot  res ult i n e xcl usi o n 
fr o m t he a nal ysis  of  t he r es p o nse rate. S u b- a nal ys es  ma y  t he n be  perf or m e d  o n  t he basis  of  a 
s u bset of  patie 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 v e  bee n  i de ntifie d 
(e. g., earl y deat h  d u e  t o ot her  reas o ns, earl y disc o nti n uati o n  of  treat me nt, maj or  pr ot oc ol  
vi olati o ns,  etc.). T he  r eas o ns f or e xcl 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 h ere  will be a pla n ne d a nal ysis of patie nts w h o are e v al ua ble f or res p o nse (s ee 
secti o n 1 2. 4) w hic h will be use d f or t h e Si m o n t w o-sta ge desi g n. 
T he  9 5 %  c o nfi d e nce i nter vals s h o ul d be  pr o vi de d. 

E p ac a d ost at / S D -1 0 1 / R a di ot her a p y  
 
Cli nic al St u d y Pr ot o c ol U C D C C # 2 7 1  
 
 
Pr ot o c ol v ersi o n: 0 2. 1 9. 2 0  
U C D a vis C o m pre he nsi v e C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a g e 6 4  of 9 5  
1 0. 2  
S afet y  
Safet y assess me nts will c o nsist of m o nit ori n g a n d rec or di n g all a d vers e e ve nts, i ncl u di n g 
seri o us a d vers e e v e nts, t he m o nit ori n g of he mat ol o g y, bl o o d c he mistr y, c oa g ulati o n 
para meters, uri nal ysis a n d t he re g ular m o nit ori n g of vital si g ns, a n d p h ysical c o n diti o n a s 
s h o w n i n c orres p o n di n g t a bles. F or d etails o n A E c ollecti o n a n d re p orti n g, refer t o t he Safet y 
secti o n i n t he pr ot oc ol. 
1 0. 3  
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 Ta ble  1 0. 
T a ble 1 0 :  St u d y V ari a bles  
E n d p oi nt  
V a ri a ble  
Me as ure m e nt  
C o m m e nt  
Pri mar y - P hase 1  
M T D  
C T C A E V 4. 0 3  
O utli n e d i n secti o n 3. T h e ma xi m u m d ose at 
w hic h < 2 of 6 p atie nts e x p erie n ce d a D L T  
Pri mar 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 3. A D L T is defi n e d as 
> gra d e 4 i njecti o n site react o n O R > gra de  3  
treat me nt-relate d n o n-h e mat ol o gic t o xicit y  
(e x cl udi n g i njecti o n site reacti o ns) O R 
O R A S T/ A L T > 3 x U L N wit h bilir u bi n > 2 X 
U L N, O R  p n e u m o nitis t h at re q uires h ol di n g 
treat me nt > 1 4 d a ys.  Gra d e 3 ras h will n ot be 
i n cl u d e d as a D L T if t h ere is n o 
d es q u a mati o n, n o m u c osal i n v ol ve me nt, if it 
res ol v es wit h o ut s yste mic c ortic oster oi ds b y 
t h e n e xt sc h e d ule d d ose of e p aca d ostat or 1 4 
d a ys, w hic h e v er is l o n g er, a n d e paca d ostat  
d ose i nte nsit y is mai ntai n e d at 7 5 % of 
pla n n e d d ose d uri n g D L T p eri o d (i.e < 8 da ys 
of d ose i nterr u pti o n). If e p aca d ostat d ose 
i nte nsit y ca n n ot b e mai ntai n e d at 7 5 % of 
pla n n e d d ose d uri n g D L T p eri o d as a res ult of 
t o xicit y of a n y gra d e t his will als o b e dee me d 
a d ose li miti n g t o xicit y. 
Pri mar y - P hase 2  
Safet y  
C T C A E V 4. 0 3  
 
Pri mar y -P hase 2  
D C R  ( C R + P R + S D) 
ir R E CI S T 
D C R is  t h e e n d p oi nt f or t h e Si m o n t w o-sta ge 
p h ase 2 st u d y  
Sec o n dar y - P h ase 2  
A R R  
ir R E CI S T 
O bjecti v e 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  
Sec o n dar y - P h ase 2  
Treat me nt t olera bilit y  
C T C A E V 4. 0 3  
O utli n e d i n secti o n 6. 6. D L Ts a n d a n y ot her 
treat me nt relate d a d v erse e v e nt re q uiri n g 
disc o nti n u ati o n of E R S t h era p y will be 
d ee me d treat me nt i nt olera bilit y. Patie nts 
u n a ble t o res u me e p aca d ostat after 3 0 da ys 
d u e t o t o xicit y will b e la b elle d as h a vi n g 
treat me nt i nt olera bilit y.  If m ore t h a n t w o 
c o nsec uti v es d oses of S D -1 0 1 are misse d d ue 
t o t o xicit y t h e p atie nt will b e la b ele d as 
h a vi n g treat me nt i nt olera bilit y. Patie nt s 
u n a ble t o recei v e at least 5 0 % of t h e 
prescri b e d ra di ot h era p y d ose d u e t o treat me nt 

E p ac a d ost at / S D -1 0 1 / R a di ot her a p y  
 
Cli nic al St u d y Pr ot o c ol U C D C C # 2 7 1  
 
 
Pr ot o c ol v ersi o n: 0 2. 1 9. 2 0  
U C D a vis C o m pre he nsi v e C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a g e 6 5  of 9 5  
t o xicit y will b e la b ele d as ha vi n g treat me nt 
i nt olera bilit y. 
C orrelati ve 
O R R  
R E CI S T a n d ir R E CI S T  
 
C orrelati ve 
P F S  
R E CI S T a n d ir R E CI S T  
 
C orrelati ve 
O S  
R E CI S T a n d ir R E CI S T  
 
C orrelati ve 
P B M C I m m u n o p h e n ot y p e  F A C S  
Bl o o d  
C orrelati ve 
P B M C g e n e e x pressi o n  
q P C R / Na n ostri n g 
Bl o o d  
C orrelati ve 
S yste mic C yt o ki n e 
Si g n at ure  
L u mi n e x  
Ser u m  
C orrelati ve 
Tr y/ K y n rati o  
Mass s p ectr o metr y  
Ser u m  
C orrelati ve 
Tiss u e I m m u n e Mar k ers 
I H C / I F 
Tiss u e  
C orrelati ve 
T u m or g e n e e x pressi o n  
q P C R / Na n ostri n g 
Tiss u e  
C orrelati ve 
M utati o n al l o a d  
W h ole e x o me se q u e n ci n g / 
R N A se q u e n ci n g  
Bl o o d a n d Tiss u e  
C orrelati ve 
T cell rece pt or di v ersit y  
T C R d ee p se q u e n ci n g  
Bl o o d a n d Tiss u e  
C orrelati ve 
St o ol Micr o bi o me  
1 6s r R N A  
St o ol  
1 1.  
C O R R E L A TI V E S CI E N C E  
1 1. 1  
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 orrel ati ve st u dies t o hel p i de ntif y t he mec ha nis m of acti o n of t hese t h era pi es, 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 o ac h es.  T o 
a d dress t his we pla n t o p erf 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.  Pre- a n d p ost-tr eat me nt bl o o d a n d t u m or bi o psies ( w he n a v aila ble) will be o btai ne d 
as o utli ne d i n t he st u d y cale n dar. Briefl y, bl o o d a n d t u m or s a m ples will be c ollecte d pre -
treat me nt o n Da y 1 a n d a gai n at Da y 1 5. Bl o o d sa m ples will als o be c ollecte d at 6 0 da y c h ec k-
u p visits. O pti o nal bl o o d a n d t u m or bi o psies ca n b e o btai ne d at pr o gressi o n. Partici pati o n i n 
t he c orr elati ve st u dies is ma n dat or y u nless wai ve d b y t he st u d y pri nci pal i n vesti gat or d ue t o 
safet y c o n cer ns or ot her r eas o ns. Ar c hi val t u m or bl oc ks will als o be c ollect e d w he n a v aila ble. 
We will e val uate 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 a n d t u m or 
micr oe n vir o n me nt wit hi n patie n t’s pre t o p ost t hera p y a n d acr oss t he c o h ort of patie nts t o 
i de ntif y pre dicti ve bi o mar kers a n d el uci date t he m ec ha nistic i m m u n ol o gic effects of t hera p y.  
F or f urt her det ails, refer t o A p pe n di x 4 a n d Ta ble  1 0 i n Secti o n 1 0. 3. C orrelati ve st u dies will 
i ncl ude (i n or der of pri orit y):  
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  

E p ac a d ost at / S D -1 0 1 / R a di ot her a p y  
 
Cli nic al St u d y Pr ot o c ol U C D C C # 2 7 1  
 
 
Pr ot o c ol v ersi o n: 0 2. 1 9. 2 0  
U C D a vis C o m pre he nsi v e C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a g e 6 6  of 9 5  
•  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), macr o p h a ge p olarizati o n, etc.  
•  Na n ostri n g ge ne p a nel  
•  W h ole e x o me se q u e nci n g  
•  E val uati o n of s yste mic plas ma  tr y pt o p ha n t o k y n ure ni ne rati os 
•  L u mi ne x e val uati o n of pl as 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  
•  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 
Ti ss ue   
•  I H C t o deter mi ne e x pressi o n of mar kers i ncl u di n g P D - 1, P D- L 1, C D 8, C D 4, I D O a n d 
F O X P 3  
•  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 na se, 
C T L A 4, P D - 1/ P D-L 1),  macr o p ha g e p olarizati o n, etc.  
•  Na n ostri n g ge ne p a nel o n F F P E tiss ues  or s na p fr oze n tiss ues 
•  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 o ol 
•  St o ol micr o bi o me a nal ysis  
 
A c o m pre he nsi v e a nal ysis of t u m or, bl o o d, a n d st o ol sa m ples will pr o vi de val ua ble i nsi g ht 
i nt o p ote ntial bi o mar kers a n d i nt o t he mec ha nis m of acti o n of o ur c o m bi ne d t hera p y.  
1 1. 2  
C orrel ati v e St u d y Desi g n a n d Met h o d ol o g y 
We ha v e e xte nsi ve e x pertise i n all of t he t ec h ni q ues descri be d at t he U C D a vis La b orat or y of 
T u m or I m m u n ol o g y.  Bl o o d sa m ples will be se parate 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 h e 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 s uc h as C D 4 5, C D 3, C D 4, C D 8, F O X P 3, Gra nz y me B, I nterfer o n 
ga m ma, t u m or necr osis f act or ( T N F) al p ha, P D- 1, etc.  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.  A n ali q u ot of P B M Cs will als o be 
set asi de f or R NA is olati o n a n d batc he d a nal ysis of ge ne e x pressi o n. m R N A ( messe n ger 
ri b o n ucleic aci d) will be e xtracte d usi n g R Neas y kits ( Qia ge n) a n d re verse tra nscri be d t o 
c D N A.  Cell ular R N A will be a nal yze d b y q R T- P C R (real -ti me re v erse tra nscri pti o n-
p ol y merase c h ai n  reacti o n) usi n g verifie d pri mers t o i n vesti gate t he e x pressi o n of ge nes 

E p ac a d ost at / S D -1 0 1 / R a di ot her a p y  
 
Cli nic al St u d y Pr ot o c ol U C D C C # 2 7 1  
 
 
Pr ot o c ol v ersi o n: 0 2. 1 9. 2 0  
U C D a vis C o m pre he nsi v e C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a g e 6 7  of 9 5  
i ncl u di n g I D O, ar gi nas e, 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. R N A will als o be a nal yze d usi n g a Na n ostri n g ge ne pa nel. T o d eter mi ne if certai n 
cl o nes of T cells are pref ere ntiall y e x pa n di n g after t hera p y, a n ali q u ot of P B M Cs will als o be 
use d f or T C R dee p s e q ue nci n g. Plas ma will be e val uate d f or s yste mic c yt o ki ne a n d c he m o ki ne 
si g nat ures usi n g L u mi ne x tec h n ol o g y.  Mar kers will i ncl u de  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- macr 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 press e d a n d secret e d), MI P 1 ( Macr o p ha g e I nfla m mat or y Pr otei n) al p ha, MI P 1 beta, 
T G F - b eta a n d ot hers. Tiss ue bi o psies will be f or mali n fi xe d a n d paraffi n e m be d de d usi n g 
sta n dar d pr ot oc ols.  Tiss ue will be a nal yze d b y I H C stai ni n g f or P D - 1, P D- L 1, F O X P 3, C D 8, 
a n d C D 4 mar kers.  If s ufficie nt bi o ps y material is a vaila ble t he n a tiss ue s a m ple will be st ore d 
i n R N A later f or b atc he d a nal ysis b y q P C R / Na n ostri n g as descri be d a b o ve. W h ole e x o me 
se q ue nci n g will als o be p erf or me d o n t u m or tiss ue a n d c o m pare d t o t he peri p heral bl o o d as a 
n or mal tiss ue c o ntr ol t o deter mi ne t he m ut ati o nal l oa d of t he t u m or. Pre- treat me nt st o ol 
sa m ples will be c ollecte d t o a nal yze t he g ut micr o bi o me. 
 
1 2.  
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  
1 2. 1  
S a m ple Size  
F or t he d ose escalati o n p hase a tr a diti o nal 3 + 3 d esi g n will be use d wit h t he g oal of 
deter mi ni n g t he M T D t hr o u g h D L T assess me nt.  Per desi g n eac h c o h ort will c o nsist of 3- 6 
patie nts.  T he n u m ber of patie nts will de pe n d o n t he occ urre n ce of D L T ( T a ble 1 ).  We 
esti mate a mi ni m u m of 6 patie nts a n d a ma xi m u m of 1 8 patie nts ( 6 patie nts/c o h ort) w o ul d be 
e nr olle d.  O nce t he M T D is deter mi ne d patie nts will be e nr olle d i nt o eit her a l y m p h o ma or a 
s oli d t u m or p hase 2 c o h ort w hic h will ge nerate preli mi nar y efficacy d ata t o deter mi ne if t he 
treat me nt re gi me n s h o ul d be c o nsi der e d f or a ra n d o mize d st u d y. Patie nts treate d at t he M T D 
d uri n g t he p hase I will als o be use d as part of t he p hase II c o h orts t o mi ni mize patie nt 
n u m bers.  F or t h e s oli d t u m or c o h ort (c o h ort 1) w e ha ve set a t hres h ol d D C R  res p o nse rate of 
2 0 % b y ir R E CI S T as w ort h y of f urt her st u d y a n d t his c o h ort will e nr oll 1 6- 3 0 e val ua ble 
patie nts.  I n t h e first sta g e 1 6 patie nts ( n 1) will be e nr olle d a n d greater t ha n 1 res p o nse (r 1) is 
re q uire d f or t he trial t o pr ocee d. I n t h e sec o n d sta g e a n a d diti o nal 1 4 patie nts will be e nr olle d 
f or a t otal of 3 0 patie nts ( n T ot) a n d greater t ha n 3 res p o nses (r T ot) are re q uire d f or t he t hera p y 
t o be dee me d w ort h y of f urt her st u d y i n a ra n d o mi ze d trial.  F or t he l y m p h o ma c o h ort (c o h ort 
2) we ha v e set a t hr es h ol d D C R res p o nse rate of 3 0 % b y ir R E CI S T as w ort h y of f urt her st u d y 
a n d t his c o h ort will e nr oll 7- 1 4 e val ua ble p atie nts.  I n t he first sta ge 7 patie nts ( n 1) will be 
e nr olle d a n d gr eater t ha n 0 res p o nses (r 1) are re q uire d f or t he trial t o pr ocee d. I n t he s ec o n d 
sta ge a n a d diti o nal 7 pati e nts will be e nr olle d f or a t otal of 1 4 patie nts ( n T ot) a n d greater t ha n 
2 res p o nses (r T ot) ar e re q uire d f or t he t hera p y t o be dee me d w ort h y of f urt her st u d y i n a 
ra n d o mize d trial.  Patie nts w h o are n o t e v al ua ble f or treat me nt efficac y (see secti o n 1 2. 4)  will 

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n ot be i ncl u de d i n t he si m o n t w o-sta ge a nal ysis a n d will be re place d b y a d diti o nal patie nt 
e nr oll me nt t o e ns ure a f ull c o h ort of e val ua bl e patie nts.  
T he pri mar y e n d p oi nt of t his st u d y is t o deter mi ne t he M T D of e p aca d ostat w he n c o m bi ne d 
wit h S D - 1 0 1 a n d ra di ot h era p y. I n t h e t w o p hase II e x pa nsi o n c o h orts w e will f urt her assess 
safet y a n d efficac y of t his re gi me n at t he pr o p os e d M T D. T he e x p a nsi o n will e m pl o y a Si m o n 
t w o-sta ge desi g n t o determi ne if t he treat me nt effi cac y w arra nts f urt her i n vesti gati o n i n a 
ra n d o mize d st u d y. The s a m ple size  was d eter mi n e d b y t he  d ose-escalati o n desi g n c o m bi ne d 
wit h a Si m o n t w o-sta ge desi g n f or o ur re q uire d efficac y e n d p oi nts. W h e n t he tr ue res p o nse 
rates ar e at t heir res pecti ve t hres h ol ds b ot h t w o-sta ge desi g ns ha v e 8 0 % t o reject at t he 0. 0 5 
le vel ( 1-si de d) t h e n ull h y p ot hesis t hat t he D C R  res p o nse rate is a n u nacce pta bl y l o w 5 %. 
Si nce patie nts treate d at t he M T D will be i ncl u de d i n t he p hase II e x pa nsi o n a nal y sis a 
ma xi m u m of 5 6 e val ua bl e patie nts will be e nr olle d. 
1 2. 2  
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. A pla n ne d s u bset a nal ysis o n patie nts w h o ha ve or ha v e n ot 
recei v e d pre vi o us i m m u n ot hera p y will be perf or m e d. A pla n ne d s u bset a nal ysis base d o n 
hist ol o gic t u m or t y pe will be perf or m e d. 
1 2. 3  
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 xact 9 5 % c o nfi de n ce i nt er val f or pr o p orti o n, cat e g orize d b y t y pe ( or ga n affecte d or 
la b orat or y det er 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 nset (i.e. c o urse n u m ber), d urati o n, a n d re v ersi bilit y or 
o utc o me.  Ta bl es will be creat e d t o s u m marize t hese t o xicities b y d ose a n d c o urse.   
1 2. 4  
Effic ac y  
As a sec o n d ar y e n d p oi nt, all res p o nses will be re p orte d usi n g ir R E CI S T a n d R E CI S T 1. 1 
defi niti o ns [ 5 6 ].  Beca us e of t he p ote ntial heter o g e neit y of t he patie nts, all res ults will be 
c o nsi dere d pr eli 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 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 val 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.  
If a patie nt is e nr olle d o n t he st u d y a n d is s u bse q ue ntl y re m o ve d fr o m treat me nt f or a n y reas o n 
pri or t o t he first C T/ M RI sca n  t he y are n ot e v al ua ble f or treat me nt effi cac y, t hat patie nt will 
n ot be i ncl u de d i n a nal ysis of treat me nt efficac y s pecific t o res p o nse criteri a, b ut will still be 
i ncl u de d i n t he ge ner al safet y a nal ysis wit h all ot her patie nts.  Patie nts w h o are n ot e v al ua ble 
f or treat me nt efficac y will be re place d b y a d diti o n al patie nt e nr oll me nt t o e ns ure a f ull c o h ort 
of e val ua ble p atie nts.  

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1 2. 5  
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 ur e disc o nti n uati o n a n d maj or pr ot oc ol vi olati o n will be ta b ulate d a n d 
s u m marize d. 
1 2. 6  
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 haracteri ze differe n ces wit hi n a gi ve n patie nt pre-treat me nt t o 
p ost-treat me nt a n d acr oss t he c o h orts of patie nts. C ha n ges i n t he c orrelati v e e n d p oi nts will be 
e val uate 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 vari 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 nal ysis wit h or di nal cate g or y f or res p o ns e ( ge n eralize d li near m o dels) or 
ti me t o e ve nt ( pr o p orti o n al hazar ds re gressi o n) as t he o utc o me. 
 
1 3.  
S A F E T Y R E P O R TI N G O F A D V E R S E E V E N T S  
1 3. 1  
Assess m e nt of S af et y  
Safet y assess me nts will c o nsist of m o nit ori n g a n d re p orti n g a d verse e v e nts ( A Es) a n d s eri o us 
a d verse e ve nts ( S A Es) t h at are c o nsi dere d relate d t o T H E R A P Y , all e ve nts of deat h, a n d a n y 
st u d y s pecific iss ue of c o ncer n. 
1 3. 2  
Ris ks Ass oci ate d Wit h  
Alt h o u g h m ost i m m u ne-relate d A Es o bser ve d wit h i m m u n o m o d ulat or y a ge nts ha ve bee n mil d 
a n d self-li miti n g, s uc h e v e nts s h o ul d be rec o g nize d earl y a n d treate d pr o m ptl y t o a v oi d 
p ote ntial maj or c o m plicati o ns.  
1 3. 3  
A d verse E ve nts  
A n A E is a n y u nfa v ora bl e a n d u ni nte n de d si g n, s y m pt o m, or disease te m p orall y ass ociate d 
wit h t he use of a n i n vesti gati o nal me dici nal pr o d u ct (I M P) or ot her pr ot oc ol-i m p ose d 
i nter ve nti o n, re gar dless of attri b uti o n. 
T his i ncl u des t he f oll o wi n g: 
•  A Es n ot pre vi o usl y o bser ve d i n t he s u bject t hat e mer ge d uri n g t he pr ot o c ol- s pecifie d A E 
re p orti n g peri o d, i ncl u di n g si g ns or s ym pt o ms ass ociate d wit h disease  t h at were n ot 
prese nt pri or t o t he A E re p orti n g peri o d. 
•  C o m plicati o ns t hat occ ur as a res ult of pr ot oc ol- m a n date d i nter v e nti o ns (e. g., i n vasi ve 
pr oce d ur es s uc h as car di ac cat heterizati o ns).  

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•  If a p plica bl e, A Es t hat occ ur pri or t o assi g n me nt of st u d y treat me nt ass ociat e d wit h 
me dicati o n was h o ut, n o treat me nt r u n-i n, or ot her pr ot oc ol- ma n date d i nter v e nti o n. 
•  Pree xisti n g me dical c o n diti o ns ( ot her t ha n t he c o n diti o n bei n g st u die d) j u d ge d b y t he 
i n vesti gat or t o ha ve w ors e ne d i n se verit y or fre q u e nc y or c ha n g e d i n c haracter d uri n g t he 
pr ot oc ol-s pecifi e d A E r e p orti n g peri o d. 
 
1 3. 3. 1  
Seri o us A d verse E ve nts  
A n A E s h o ul d be classifi e d as a n S A E if t he f oll o wi n g criteria are met:  
•  It r es ults i n deat h (i.e., t h e A E act u all y ca uses or lea ds t o deat h). 
•  It is life t hr eate ni n g (i.e., t he A E, i n t he vie w of t h e i n vesti gat or, places t he s u bject at 
i m me diate ris k of deat h. It d oes n ot i ncl u d e a n A E t hat, ha d it occ urre d i n a m ore se vere 
f or m, mi g ht ha ve ca us e d deat h.). 
•  It r e q uires or pr ol o n gs i n patie nt h os pitalizati o n. 
•  It r es ults i n persiste nt or si g nifica nt disa bilit y/i nca pacit y (i.e., t he A E res ults i n 
s u bsta ntial disr u pti o n of t he s u bject’s a bilit y t o c o n d uct n or mal life f u ncti o ns). 
•  It r es ults i n a c o n ge nital a n o mal y/ birt h defect i n a ne o nate/i nfa nt b or n t o a m ot her 
e x p ose d t o t he I M P. 
•  It is c o nsi dere d a si g nifica nt me dical e ve nt b y t he i n vesti gat or base d o n me dical 
j u d g me nt (e. g., ma y je o p ar dize t he s u bj ect or ma y re q uire me di cal/s ur gical i nter ve nti o n 
t o pre ve nt o ne of t h e o utc o mes liste d a b o ve). 
 
1 3. 4  
Met h o ds a n d Ti mi n g f or Assessi n g a n d Rec or di n g S afet y V ari a bles  
T he i n vesti gat or is res p o nsi ble f or e ns uri n g t hat all A Es a n d S A Es t hat are o bser ve d or 
re p orte d d uri n g t he st u d y are c ollecte d a n d re p ort e d t o t he F D A, ap pr o priat e I R B(s), I nc yt e, 
I n c. a n d, D y n a va x, I n c. i n acc or d a nce wit h C F R 3 1 2. 3 2 (I N D Safet y Re p orts).  
1 3. 4. 1  
A d verse E ve nt R e p orti n g Peri o d  
T he st u d y peri o d d uri n g w hic h all A Es a n d S A Es m ust be re p orte d be gi ns at i nitiati o n of st u d y 
treat me nt a n d e n ds 3 0 d a ys f oll o wi n g t he last a d mi nistrati o n of st u d y treat me nt or st u d y 
disc o nti n uati o n/ter mi nati o n, w hic he ver is earlier. After t his peri o d, i n vesti gat ors s h o ul d o nl y 
re p ort S A Es t hat ar e attrib ute d t o pri or st u d y treat me nt. 
1 3. 4. 2  
Asse ss m e nt of A d verse E ve nts 
All A Es a n d S A Es w het h er v ol u nteer e d b y t he s u bject, disc o vere d b y st u d y pers o n nel d uri n g 
q uesti o ni n g, or detecte d t hr o u g h p h ysical e xa mi nati o n, la b orat or y test, or ot her mea ns will be 
re p orte d a p pr o priat el y. Eac h re p orte d A E or S A E will be descri be d b y its d urati o n (i.e., start 

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P a g e 7 1  of 9 5  
a n d e n d dates), re g ulat or y seri o us ness criteria if a p plica ble, s us pecte d relati o ns hi p t o t he 
t hera p y a n d ra di ot her a p y (see f oll o wi n g g ui da nce), a n d acti o ns ta ke n. 
T o e ns ure c o nsiste n c y of A E a n d S A E ca us alit y assess me nts, i n vesti gat ors s h o ul d a p pl y t he 
f oll o wi n g ge neral g ui deli ne: 
Yes ( P ossi bl y, Pr o ba bl y, or Defi nitel y)  
T here is a pla usi ble t e m p oral relati o ns hi p bet wee n t he o nset of t he A E a n d a d mi nistrati o n of 
t he t hera p y, a n d t h e A E ca n n ot be rea dil y e x plai ne d b y t he s u bject’s cli nical state, i nterc urre nt 
ill ness, or c o nc o mita nt t hera pies; a n d/ or t h e A E f oll o ws a k n o w n patter n of res p o nse t o t he 
t hera p y; a n d/ or t he A E a bates or res ol v es u p o n disc o nti n uati o n of t he t hera p y or d ose 
re d ucti o n a n d, if a p plica ble, rea p p ears u p o n re-c halle n ge. 
N o ( U nli kel y, U nrel ate d) 
E vi de nce e xists t hat t he A E has a n eti ol o g y ot her t ha n t he t hera p y (e. g., pree xisti n g me dical 
c o n diti o n, u n derl yi n g disease, i nter c urre nt ill ness, or c o nc o mita nt me dicati o n); a n d/ or t he A E 
has n o pla usi ble te m p oral relati o ns hi p t o t hera p y a d mi nistrati o n (e. g., ca ncer dia g n ose d 2 da ys 
after first d ose of st u d y dr u g). 
E x pecte d a d v erse e ve nts are t h ose a d vers e e ve nts t hat are liste d or c haracterize d i n t he 
Pac ka ge I ns ert or c urr e nt I n v esti gat or Br oc h ure.  
U ne x pect e d a d verse e v e nts are t h ose n ot liste d i n t he Pac ka g e I nsert ( P.I.) or c urre nt 
I n v esti gat or Br oc h ur e (I. B.) or n ot i de ntifie d. T his i ncl u des a d vers e e ve nts f or w hic h t he 
s pecificit y or se v erit y is n ot c o nsiste nt wit h t he descri pti o n i n t he P.I. or I. B. F or e x a m ple, 
u n der t his defi niti o n, he patic necr osis w o ul d be u n e x pecte d if t h e P.I. or I. B. o nl y referre d t o 
ele vate d h e patic e n z y mes or he patitis.  
1 3. 5  
Pr oce d ures f or S A E Re p orti n g  
1 3. 5. 1  
I niti al Re p orts 
1.  
T he I n vesti gat or r e p orts t o I n c yte e v er y S A E, re gar dless of s us pecte d ca us alit y, w hic h 
occ urs after t he s u bject h as si g ne d i nf or me d c o ns e nt a n d u p t o t he ti me t hat s u bject has 
c o m plete d t he trial,  i ncl u di n g a n y p ost-treat me nt f oll o w- u p re q uire d b y t he pr ot oc ol.  
S uc h cases are r e gar d e d as ori gi nati n g i n t he I S T f or t he p ur p ose of n otificati o n t o I nc yt e. 
2.  
T he i n vesti gati o nal site n otifies I n c yte of a n S A E wit hi n 2 4 h o urs  of t he I n vesti gat or 
bec o mi n g a ware of t h e S A E, re gar dless of ca usalit y t o t he i n vesti gati o nal pr o d uct.   
 
T he i n vesti gati o nal site rec or ds all S A E details o n t he Seri o us A d verse E ve nt Re p ort 
F or m, or o n t he S A E f or m bei n g use d b y t he I n vesti gat or c o n d ucti n g t he trial, a n d e-
mails t he re p ort t o I nc yte via t he a d dress : I n c yte P h V O psI S T @i nc yte.c o m.   

E p ac a d ost at / S D -1 0 1 / R a di ot her a p y  
 
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P a g e 7 2  of 9 5  
 
T he i n vesti gati o nal site d oes n ot  pr o vi de me dical rec or ds (e. g., disc har ge s u m mar y, 
rele va nt test r es ults) u nless re q ueste d b y I n c yte.  I nstea d, t he i n vesti gati o nal site 
rec or ds t he i nf or mati o n r ele va nt t o t he S A E o n t he S A E f or m a n d pr o vi d es t he f or m t o 
I n c yte. 
 
If a n o n-s eri o us A E bec o mes seri o us, t he i n vesti gati o nal site f oll o ws t he pr ocess f or 
S A E re p orti n g.   
T he I nc yte P h V re pr ese ntati ve, i n c o nj u ncti o n wit h t he I n c yte P h V Ser vice Pr o vi der, 
re vie ws t he i nitial S A E i nf or mati o n a n d deter mi nes w het her t h e criteria f or a vali d cas e 
( patie nt I D, e nr ol me nt n u m ber, ra n d o mizati o n n u m ber, a ge, s e x, e ve nt, re p orter na me, 
site n u m ber, a n d s us pect dr u g) are pres e nt, a n d ass esses t he re p ort f or c o m plete ness.   
 
If necessar y, t he Inc yte P h V re prese ntati ve or d esi g nee q ueri es t he i n vesti gati o nal site 
( wit hi n 4 8 h o urs of recei pt) f or a d diti o nal i nf or mati o n t o e ns ure a vali d case pri or t o 
distri b uti n g t he re p ort f or i nter nal I nc yte re vie w.   
 
T he i nter nal I n c yte re vi e w occ urs as s pe cifi e d i n t he i nter nal I n c yte S A E distri b uti o n 
list f or I S T pr ot oc ols.   
 
T he re p ort s h o ul d n ot be dela ye d pe n di n g a n I n vesti gat or ca usalit y assess m e nt.   
3.  
T he I nc yte P h V re pr ese ntati ve, i n c o nj u ncti o n wit h t he I n c yte re vie w tea m, e ns ures t hat 
all i nf or mati o n a vaila ble at t he ti me, w hic h is rele va nt t o t he me dical/safet y e val uati o n of 
t he re p ort, is c ollect e d a n d i ncl u de d wit h o ut c o m pr o misi n g t he ti mefra mes f or re g ulat or y 
re p orti n g.   
 
If o nl y partial i nf or mati o n is a vaila ble, t he re p ort will n ot be dela ye d a n d m ust be 
re p orte d t o satisf y t he re p orti n g ti mefra me.  A n y a d diti o nal i nf or mati o n s h o ul d be 
c ollecte d f or a f oll o w - u p re p ort t o Healt h Aut h orities  ( H As). 
 
1 3. 5. 2  
F oll o w- u p Re p orts  
1.  
W he n ne w i nf or mati o n r e gar di n g t he S A E, or o ut c o me of pre g na nc y, b ec o mes a vaila ble, 
t he i n vesti gati o nal site pers o n nel u p date all rele va nt data o n t he a p pr o priate S A E Re p ort 
F or m, or e q ui v ale nt, wit h a n y ne w or c ha n g e d i nf or mati o n a n d se n d t he f oll o w- u p S A E 
re p ort t o I nc yte wit hi n 2 4 h o urs  of bec o mi n g a ware of t h e ne w i nf or mati o n, via e- mail t o 
I n c yte P h V O psI S T @i nc yte.c o m. 
 
T his i ncl u des a n y S A E t hat is u p gra de d t o fat al or life -t hreat e ni n g. 

E p ac a d ost at / S D -1 0 1 / R a di ot her a p y  
 
Cli nic al St u d y Pr ot o c ol U C D C C # 2 7 1  
 
 
Pr ot o c ol v ersi o n: 0 2. 1 9. 2 0  
U C D a vis C o m pre he nsi v e C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a g e 7 3  of 9 5  
2.  
I n c yte’s P h V Ser vice Pr o vi der trac ks a n y critical o utsta n di n g f oll o w- u p i nf or mati o n a n d 
q uesti o ns, a n d c o ntacts t he i n vesti gati o nal site via a fa xe d Data Clarificati o n F or m ( D C F) 
t o re q uest t he i nf or mati o n u ntil all o utsta n di n g q ueries are res ol ve d.   
T his ma y i ncl u de re q uests f or h os pital disc har ge s u m maries, a ut o ps y re p orts, deat h 
certificates (if a p plica ble), a n d/ or res ults of rele va nt la b orat or y a n d dia g n ostic tests.   
 
After t hree atte m pts t o res ol ve q ueries, w hic h are se nt at t w o - wee k i nter vals, t he P h V 
Ser vice Pr o vi der  n otifies t he I n c yte P h V re pres e nt ati ve of a n y o utsta n di n g q ueries.  
T he I nc yte P h V re pr ese nt ati ve n otifies t he I nc yte  I S T P M of t he o utsta n di n g q ueries 
t hat re q uire f oll o w- u p.   
 
In c yte  P h V will disc uss wit h t he In c yte  I S T P M acti o n pla ns f or n o n-res p o nsi ve sites 
(e. g., certifie d letter, site visit), as nee de d.  
3.  
T he i n vesti gati o nal site fa xes t he D C F res p o nse t o t he P h V Ser vice Pr o vi der, usi n g t he 
fa x n u m ber pr o vi de d o n t he Fa x tra ns missi o n s heet fr o m t he P h V Ser vice Pr o vi der.   
4.  
T he P h V Ser vice Pr o vi der a p pe n ds t o t he case , i n t he safet y d ata base , all a d diti o nal 
d oc u me ntati o n s u b mitte d b y t he site a n d ge nerate d d uri n g f oll o w- u p S A E c ollecti o n, 
i ncl u di n g t he I n c yte i nter nal S A E q uesti o ns a n d/ or c o pies of t he a m e n de d S A E re p orts. 
 
1 3. 6  
Re g ul at or y Re p orti n g 
If a n e v e nt is seri o us, u ne x pecte d, a n d s us p ecte d t o be relate d t o t he i n v esti gati o nal pr o d uct, 
t he e ve nt is c o nsi der e d t o be re p ort a ble t o Healt h A ut h orities ( H As) as a S us pecte d 
U ne x pect e d Seri o us A d v erse Reacti o n ( S U S A R).   
A n e ve nt is deter mi ne d t o be u ne x pecte d if it is n ot liste d i n t he c urre nt Refere n ce Safet y 
I nf or mati o n (e. g., I n vesti gat or’s Br oc h ure (I B)) or w he n t he s pecificit y or s e verit y of t he e ve nt 
is n ot c o nsiste nt wit h t he c urre nt Refere nce Safet y I nf or mati o n.   
Fatal or lif e -t hreate ni n g S U S A Rs m ust be re p orte d t o t he re q uire d H A(s) wit hi n 7 cale n dar 
da ys after t h e S p o ns or’s i nitial recei pt of i nf or mati o n.   
All ot her S U S A Rs m ust be re p ort e d t o t he re q uire d H A(s) wit hi n 1 5 cal e n d ar da ys after 
S p o ns or’s i nitial recei pt of i nf or mati o n. 
T he S p o ns or-I n vesti gat or re p orts all S U S A Rs t o t he F D A u n d er t he I n vesti g at or’s I N D.  
I n c yte is res p o nsi ble f or t he f oll o wi n g: 
•  Meeti n g e x pe dite d r e p orti n g re q uire me nts t o H As i n t heir res pecti ve t errit ories 

E p ac a d ost at / S D -1 0 1 / R a di ot her a p y  
 
Cli nic al St u d y Pr ot o c ol U C D C C # 2 7 1  
 
 
Pr ot o c ol v ersi o n: 0 2. 1 9. 2 0  
U C D a vis C o m pre he nsi v e C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a g e 7 4  of 9 5  
•  Cr oss -re p orti n g a n y S U S A R ori gi nati n g fr o m t he I S T t o t he a p plica ble I n c yte I N D(s) 
•  Distri b uti n g I n vesti gat or N otificati o ns t o I n v esti gat ors partici pati n g i n t he a p plica ble 
I n c yte I N D(s) 
 
1 3. 7  
Pr oce d ure f or R e p orti n g Pre g n a nc y  
Data o n fet al o utc o me ar e c ollecte d f or re g ulat or y re p orti n g a n d dr u g s afet y e val uati o n.  
F oll o w- u p s h o ul d be c o n d ucte d f or eac h pre g na n c y t o deter mi ne o utc o me, i ncl u di n g 
s p o nta ne o us or v ol u ntar y ter mi nati o n, details of t he birt h, a n d t he prese nce or a bse nce of a n y 
birt h defects, c o n g e nital a b n or malities, or mater n al a n d/ or ne w b or n c o m plicati o ns. 
Wit hi n 7 2 h o urs of lear ni n g of t he pre g n a nc y, t he i n vesti gati o nal site c o m pletes t he Cli nical 
Trial Pre g na nc y F or m (s ecti o ns I, II, a n d q uesti o n 1 8 i n secti o n III) or e q ui vale nt, a n d e- m ails 
t he re p ort t o I nc yt e at I n c yte P h V O psI S T @i nc yt e.c o m.  
Wit hi n 7 2 h o urs of lear ni n g of t he a b n or mal o utc o me of t he pre g n a nc y (f or e xa m ple, deli ver y, 
ter mi nati o n, or miscarria ge, a b n or mal ne w b or n), t he i n vesti gati o nal site c o m pletes t he Cli nical 
Trial Pre g na nc y F or m (s ecti o ns II, III, I V, a n d V) or e q ui vale nt, a n d e- mails t he re p o rt t o 
I n c yte at I n c yte P h V O psI S T @i nc yte.c o m. Deli ver y of n or mal ne w b or n will be re p orte d t o 
I n c yte i n 7 da ys of lear ni n g. 
N O T E :  If a w o m a n has a p ositi ve pre g na n c y test at Baseli ne, t he i n vesti gati o nal site c o m pletes 
Cli nical Trial Pre g na nc y F or m (secti o ns I, II, a n d III ( q u esti o n 1 8)) or e q ui vale nt a n d e- m ails t he 
re p ort t o I nc yte at I nc yt e P h V O psI S T @i nc yte. c o m, as per esta blis he d ti meli nes.  
A n y S A E occ urri n g d uri n g pre g na nc y m ust be re p orte d t o I nc yte as a n S A E, i n acc or d a nce 
wit h Secti o n 3 of t his Pla n. 
1 3. 8  
A d diti o n al Re p orti n g Re q uire me nts f or I N D H ol ders  
F or I n v esti gat or - S p o ns or e d I N D St u dies, s o me a d diti o nal re p orti n g re q uire me nts f or t he F D A 
a p pl y i n acc or d a nce wit h t he g ui da nce set f ort h i n 2 1 C F R § 3 1 2. 3 2. E ve nts meeti n g t he 
f oll o wi n g criteria nee d t o be s u b mitte d t o t he F o o d a n d Dr u g A d mi nistrati o n ( F D A) as 
e x pe dite d I N D Safe t y Re p orts acc or di n g t o t he f oll o wi n g g ui da nce a n d ti m eli nes: 
7 C ale n d ar D a y Tele p h o ne or F a x Re p ort : 
T he I n vesti gat or is r e q uir e d t o n otif y t he F D A of a n y fatal or life- t hreat e ni n g a d verse e ve nt 
t hat is u ne x pecte d a n d assesse d b y t he i n vesti gat or t o be p ossi bl y relate d t o t he use of t hera p y. 
A n u ne x pect e d a d verse e ve nt is o ne t hat is n ot alrea d y descri be d i n t he t hera p y I n vesti gat or 
Br oc h ure. S uc h r e p orts are t o be tele p h o n e d or fa xe d t o t he F D A a n d I n c yte wit hi n 7 cale n dar 
da ys of first lear ni n g of t he e v e nt.  

E p ac a d ost at / S D -1 0 1 / R a di ot her a p y  
 
Cli nic al St u d y Pr ot o c ol U C D C C # 2 7 1  
 
 
Pr ot o c ol v ersi o n: 0 2. 1 9. 2 0  
U C D a vis C o m pre he nsi v e C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a g e 7 5  of 9 5  
1 5 C ale n d ar D a y Writt e n Re p ort 
T he I n vesti gat or is als o r e q uire d t o n otif y t he F D A a n d all partici pati n g i n vesti gat ors, i n a 
writte n I N D Saf et y Re p ort, of a n y seri o us, u n e x pecte d A E t hat is c o nsi dere d reas o na bl y or 
p ossi bl y relate d t o t he use of T H E R A P Y . A n u ne x pecte d a d v erse e ve nt is o ne t hat is n ot 
alrea d y d escri be d i n t he T H E R A P Y  i n vesti gat or br oc h ure. 
Writte n I N D Safet y re p orts s h o ul d i ncl u de a n A nal ysis of Si milar E ve nts i n acc or d a nce wit h 
re g ulati o n 2 1 C F R § 3 1 2. 3 2. All safet y re p orts pre vi o usl y file d b y t he i n vesti gat or wit h t he 
I N D c o n cer ni n g si milar e ve nts s h o ul d be a nal yze d a n d t he si g nifica nce of t he ne w re p ort i n 
li g ht of t he pre vi o us, si milar re p orts c o m me nt e d o n. 
Writte n I N D s afet y r e p orts wit h A nal ysis of Si milar E ve nts are t o be s u b mitte d t o t he F D A, 
I n c yte, a n d all partici pati n g i n vesti gat ors wit hi n 1 5 cale n dar da ys of first lear ni n g of t he e v e nt. 
T he F D A prefers t hes e re p orts o n a Me d Watc h 3 5 0 0 f or m, b ut alter nati ve f or mats are 
acc e pta ble ( e. g., s u m mar y letter). 
U n der r e q uire me nts of 2 1 C F R 3 1 2. 2 3, t he c o m plete d Me d Watc h f or m a n d F D A F or m 1 5 7 1 
m ust be se nt t o t he F D A..   
F D A f a x  n u m ber f or I N D Safet y Re p orts:   
1 ( 8 0 0) F D A 0 1 7 8 
All writte n I N D Saf et y Re p orts s u b mitte d t o t he F D A b y t he I n vesti ga t or m ust als o be fa xe d t o 
U C Da vis I R B per i nstit uti o nal p olicies:  
I R B A d mi nistrati o n 
2 9 2 1 St oc kt o n Bl v d 
S uite 1 4 0 0, R o o m 1 4 2 9 
Sacra me nt o, C A 9 5 8 1 7 
P h o ne: ( 9 1 6) 7 0 3- 9 1 5 1 
Fa x: ( 9 1 6) 7 0 3- 9 1 6 0 
 
1 3. 9  
St u d y Cl ose -O ut  
A n y st u d y re p ort s u b mitte d t o t he F D A b y t h e S p o ns or-I n vesti gat or s h o ul d be c o pie d t o 
I n c yte. T his i ncl u des all I N D a n n ual r e p orts a n d t h e Cli nical St u d y Re p ort (fi nal st u d y re p ort). 
A d diti o nall y, a n y literat ure articl es t hat are a res ult of t he st u d y s h o ul d be se nt t o I n c yte.  
 

E p ac a d ost at / S D -1 0 1 / R a di ot her a p y  
 
Cli nic al St u d y Pr ot o c ol U C D C C # 2 7 1  
 
 
Pr ot o c ol v ersi o n: 0 2. 1 9. 2 0  
U C D a vis C o m pre he nsi v e C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a g e 7 6  of 9 5  
1 4.  
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  
1 4. 1  
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.  
I C H H ar 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.  
Declar ati 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, V e 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 gr ees, 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 ur es descri be d i n it a n d t here b y t o a d h ere 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. 
1 4. 2  
I nstit uti o n al Re vie w B o ar d/I n de pe n de nt Et hics C o m mittee 
Bef ore i m ple me nti n g t his st u d y, t he pr ot oc ol, t he pr o p ose d i nf or me d c o nse nt f or m a n d ot her 
i nf or mati o n t o s u bjects, m ust be re vie we d b y a pr o perl y c o nstit ute d I nstit uti o nal Re vie w 
B oar d/I n de pe n d e nt Et hics C o m mittee (I R B/I E C/ R E B). A si g ne d a n d date d state me nt t hat t he 
pr ot oc ol a n d i nf or me d c o nse nt ha ve bee n a p pr o v e d b y t he I R B/I E C/ R E B m ust be gi ve n t o 
I n c yte bef ore st u d y i nitiati o n. T he na me a n d occ u pati o n of t he c hair m a n a n d t he me m bers of 
t he I R B/I E C/ R E B m ust be s u p plie d t o I n c yte. A n y a me n d me nts t o t he pr ot o c ol, ot her t ha n 
a d mi nistrati ve o nes, m ust be a p pr o ve d b y t his c o m mittee. 
1 4. 3  
St u d y D oc u m e nt ati o n  
T he re q uir e d d oc u me nts i ncl u de, b ut are n ot li mite d t o t he f oll o wi n g: I R B a p pr o vals (i.e., 
pr ot oc ol, c o nse nt f or m, a me n d me nts, patie nt br oc h ures a n d recr uit me nt material, etc.), I R B 
me m bers hi p r osters, s u m mar y of u na ntici pat e d pr o ble ms or pr ot oc ol de viati o ns, a n d 
d oc u me ntati o n of e x pertise of t he i n vesti gat ors.  
1 4. 4  
I nf or m e 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 pect e d d urati o n, t h e 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 bject 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 

E p ac a d ost at / S D -1 0 1 / R a di ot her a p y  
 
Cli nic al St u d y Pr ot o c ol U C D C C # 2 7 1  
 
 
Pr ot o c ol v ersi o n: 0 2. 1 9. 2 0  
U C D a vis C o m pre he nsi v e C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a g e 7 7  of 9 5  
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 u a ge. 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 n e d d oc u me 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 pr ese ntati o n ma y be ma de or si g nat ure gi ve n b y t he s u bject’s le gall y 
a p p oi nte d re pr ese ntati ve, if wit nesse d b y a pers o n n ot i n v ol ve 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 bef ore his/ her 
i nf or me d c o nse nt has b ee n o btai ne d. 
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/I E C/ RE B a p pr o val.  
Fertile me n a n d w o me n of c hil d beari n g p ote ntial 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 if pre g na nc y were t o occ ur d uri n g t he 
st u d y a n d a gree t hat i n or der t o partici pate i n t he st u d y t he y m ust a d here t o t he c o ntrace pti o n 
re q uire me nt f or t he d ur ati o n of t he st u d y. 
Acce pt a ble met h o ds of birt h c o ntr ol f or me n a n d w o me n are t h e f oll o wi n g: 
Hi g hl y effecti ve met h o ds 
•  Male sterilizati o n ( vas ect o m y). F or fe male patie nts, t he vasect o mize d m ale part ner 
s h o ul d be t he o nl y part ner 
•  Tr ue a bsti ne nce, if t his is y o ur pref erre d a n d us ual lifest yle  
•  H or m o nal birt h c o nt r ol f or male patie nt’s part ner  
Effecti ve m et h o ds  
•  Place me nt of i ntr a uteri ne de vice or i ntra uteri ne s yste m 
•  C o n d o m wit h s per mici dal f oa m/ gel/fil m/cre a m/s u p p osit or y 
•  Occl usi ve ca p ( dia p hr a g m or cer vical/ va ul t ca ps) wit h s per mici dal 
f oa m/ gel/fil m/crea m/s u p p osit or y 
U nacce pta ble met h o ds  
•  A bsti ne nce at certai n ti mes of t he c y cle o nl y, s uc h  as d uri n g t he da ys of o v ulati o n, after 
o v ulati o n ( base d o n s y m pt o ms or te m perat ure) 
•  Pre -ejac ulat or y wit h dra w al 
If t here is a n y q uesti o n t hat t he patie nt will n ot relia bl y c o m pl y, t he y s h o ul d n ot be e ntere d i n 
t he st u d y. 

E p ac a d ost at / S D -1 0 1 / R a di ot her a p y  
 
Cli nic al St u d y Pr ot o c ol U C D C C # 2 7 1  
 
 
Pr ot o c ol v ersi o n: 0 2. 1 9. 2 0  
U C D a vis C o m pre he nsi v e C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a g e 7 8  of 9 5  
I n acc or da n ce wit h U C D O C R  p olic y a n ori gi nal si g ne d a n d date d p artici pa nt I nf or me d 
C o nse nt d oc u me nt will resi de i n a sec ure d l ocati o n at partici pati n g i nstit uti o ns. C o pies of t he 
si g ne d a n d date d I nf or me d C o nse nt d oc u me nt will be pr o vi de d t o t he st u d y partici pa nt a n d a 
c o p y will be st ore d i n t he patie nt’s electr o ni c me di cal rec or d at t he p artici pati n g i nstit uti o n.  
1 4. 5  
Disc o nti n u ati o n of St u d y S u p p ort  
I n c yte r eser v es t he ri g ht t o disc o nti n ue s u p p ort f or a n y st u d y u n der t he c o n diti o ns s pecifie d i n 
t he cli nical trial a gr ee me nt. 
1 4. 6  
A m e n d m e nts  t o t he Pr ot oc ol 
A n y c ha n ge or a d diti o n t o t his pr ot oc ol re q uires a writte n pr ot oc ol a me n d m e nt t hat m ust be 
a p pr o ve d b y I n c yte a n d t he i n vesti gat or bef ore i m ple me ntati o n. A n y pr ot oc ol a me n d me nt 
re q uires a p pr o val b y t he I R B/I E C/ R E B. A c o p y of t he writte n a p pr o v al of t he I R B/I E C/ R E B, 
m ust be se nt t o I nc yt e. 
1 4. 7  
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.  Data ca pt ure rec or ds a n d dr u g 
acc ou nta bilit y rec or ds will be st ore d i n sec ure ca bi nets i n t he de part me nt of ra diati o n 
o nc ol o g y, U C Da vis or at t he partici pati n g i nstit uti o ns.  Me dical rec or ds of patie 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 i n vesti g at or will gra nt 
m o nit or(s) a n d a u dit or(s) fr o m I nc yte or its desi g nees a n d re g ulat or y a ut h orit y(ies) access t o 
t he patie nt’s ori gi nal me dical rec or ds f or v erificati o n of data gat here d o n t he data ca pt ure 
rec or ds a n d t o a u dit t he d ata c ollecti o n pr o cess.  The patie nt’s c o nfi d e ntialit y will be 
mai ntai ne d a n d will n ot be ma de p u blicl y a v aila ble t o t he e xte nt per mitte d b y t he a p plica ble 
la ws a n d re g ul ati o ns. 
1 4. 8  
Pr ot oc ol D e vi ati o ns 
All pr ot oc ol de viati o ns will be re p orte d i n acc or d a nce wit h U C D I R B A d mi nistrati o n a n d 
U C D Ca ncer Ce nt er O C R  p olicies . 
1 4. 9  
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 mittee s at partici pati n g i nstit uti o ns or U C Da vis 
Ca ncer Ce nter as o utli ne d i n t he U C Da vis Ca ncer Ce nter Dat a a n d Safet y M o nit ori n g pla n. 
 

E p ac a d ost at / S D -1 0 1 / R a di ot her a p y  
 
Cli nic al St u d y Pr ot o c ol U C D C C # 2 7 1  
 
 
Pr ot o c ol v ersi o n: 0 2. 1 9. 2 0  
U C D a vis C o m pre he nsi v e C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a g e 7 9  of 9 5  
1 5.  
O V E R SI G H T A N D M O NI T O R OI N G  
1 5. 1  
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 re p orti n g as o utli ne d i n Secti o n 7. 0, t his 
pr ot oc ol is als o s u bject t o t he U C Da vis Ca n cer Ce nter’s ( U C D C C) Dat a a n d Safet y 
M o nit ori n g Pla n. T he U C D 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 h as 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 uct of cli nical researc h st u dies. T h e U C D 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 s afet 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 he Scie ntific Re vie w C o m mittee ( S R C) ass u mes 
o verall o versi g ht of ca ncer st u dies, wit h assista nce a n d i n p ut fr o m t w o i n d e pe n de nt, b ut 
i nteracti n g, c o m mittees: t he Q ualit y Ass ura n ce C o m mittee a n d t he Data a n d Safet y 
M o nit ori n g C o m mittee. A m ulti -le vel re vie w s yst e m stre n gt he ns t he a bilit y of t he U C D C C t o 
f ulfill its missi o n i n c o n d ucti n g hi g h q ualit y cli nical ca ncer researc h. 
T he  pri nci pal i n vesti gat or ( PI) a n d cli nical res earc h c o or di nat or will  meet at least m o nt hl y f or 
o n g oi n g st u d y i nf or mati o n, t o disc uss patie nt data a n d a d vers e e v e nts a n d t o deter mi ne if d ose 
escalati o n i s warra nte d, w he n a p plica bl e.   
Acc or di n g t o t he U C D C C Data a n d Safet y M o nit ori n g Pla n, a n y ne w seri o us a d verse e ve nts 
relate d t o t he dr u gs b ei n g use d o n t his trial are re vie we d m o nt hl y b y t he U C D C C Data a n d 
Safet y M o nit ori n g C o m mittee a n d a n y a p plica bl e c ha n g es t o t he st u d y are rec o m me n d e d t o 
t he PI, if n ecess ar y. 
T he U C D C C S R C deter mi nes if a U C D C C Data a n d Safet y M o nit ori n g B oar d ( D S M B) is 
re q uire d.  If re q uire d, t he Data a n d Safet y M o nit ori n g C o m mittee will a p p oi nt a D S M B. T he 
D S M B is res p o nsi ble f or re vie wi n g st u d y accr ual l o gs, a d verse e ve nt i nf or mati o n a n d d ose 
escalati o n meeti n g mi n utes ( w here a p plica ble) t o e ns ure s u bject s afet y a n d c o m plia nce wit h 
pr ot oc ol defi ne d g ui deli n es. 
T he Researc h M o nit or is res p o nsi ble t o o versee t he safet y of t h e res earc h a n d re p ort 
o bser vati o ns/fi n di n gs t o t he I R B or a desi g nate d i nstit uti o nal official. T he Researc h M o nit or 
will re vie w all u na ntici pate d pr o ble ms i n v ol vi n g ris ks t o s u bjects or ot hers ass ociate d wit h t he 
pr ot oc ol a n d pr o vi de a n i n de pe n de nt r e p ort of t he e ve nt t o t he I R B. T he Researc h M o nit or 
ma y disc uss t he researc h pr ot oc ol wit h t he i n vesti gat ors; s hall ha ve a ut h orit y t o st o p a researc h 
pr ot oc ol i n pr o gress, r e m o ve i n di vi d ual h u ma n s u bjects fr o m a researc h pr ot oc ol, a n d ta ke 
w hate ver st e ps ar e necessar y t o pr otect t he s afet y a n d well - bei n g of h u m a n s u bjects u ntil t he 
I R B ca n assess t he m o nit or’s re p ort; a n d s hall ha v e t he res p o nsi bilit y t o pr o m ptl y re p ort t heir 
o bser vati o ns a n d fi n di n gs t o t he I R B or ot her d esi g nate d offici al a n d t he H R P O. 

E p ac a d ost at / S D -1 0 1 / R a di ot her a p y  
 
Cli nic al St u d y Pr ot o c ol U C D C C # 2 7 1  
 
 
Pr ot o c ol v ersi o n: 0 2. 1 9. 2 0  
U C D a vis C o m pre he nsi v e C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a g e 8 0  of 9 5  
1 5. 2  
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. As me nti o ne d i n secti o n 3. 0, 
patie nts will be m o nit ore d wee kl y d uri n g t he 3 0 d a y D L T peri o d a n d e ver y 3 0 da ys f or t he 
re mai ni n g of t he st u d y.  All patie nts o n acti ve treat me nt will be disc ussed at wee kl y 
c o nfer e nces t hat ar e hel d at t he U ni versit y of Calif or nia Da vis . Per Ca n cer Ce nter g ui deli nes, a 
trial ca n n ot pr ocee d t o t h e ne xt d ose le vel u ntil a D L T meeti n g is c o n d ucte d t o 
c o m pre he nsi vel y r e vie w all t o xicit y data a n d a p pr o ve t he d ose de- escalati o n. T he disc ussi o n 
will i ncl u de f or eac h d os e le vel: t he n u m ber of patie nts, si g nifica nt t o xicities as descri be d i n 
t he pr ot oc ol, d oses a dj ust me nts, a n d res p o nses o bs er ve d. 
All patie nts will be m o nit ore d f or a mi n i m u m of 1 2 m o nt hs t o e val uate f or l o n g-ter m ra diati o n 
effects.  Preli mi nar y efficac y as det er mi ne d b y A R R, O R R, D C R  a n d D F S will be assesse d 
e ver y 6 0 da ys d uri n g t he st u d y peri o d. 
 
1 6.  
R E F E R E N C E S  
1.  
Erlic h, P., Ue ber de n jetzi ge n st a n d der k arzi n o mf orsc h u n g.  Ne d Tij dsc hr Ge nees k d 1 9 0 9. 5 : 
p. 2 7 3- 9 0. 
2.  
Ol d, L.J. a n d E. A. B o yse, I m m u n ol o gy of ex peri me nt al t u m ors. A n n u Re v Me d 1 9 6 4. 1 5 : p. 
1 6 7- 8 6. 
3.  
F or me nti, S. C. a n d S. De maria, Syste mic effects of l oc al r a di ot her a py.  La ncet O nc ol, 2 0 0 9. 
1 0 ( 7): p. 7 1 8- 2 6. 
4. 
Milas, L., et al., C p G oli g o de oxy n ucle oti de e n h a nces t u m or res p o nse t o r a di ati o n.  Ca ncer Res, 
2 0 0 4. 6 4 ( 1 5): p. 5 0 7 4- 7. 
5. 
Br o d y, J. D., et al., I n sit u v acci n ati o n wit h a T L R 9 a g o nist i n d uces syste mic ly m p h o m a 
re gressi o n: a p h ase I/II st u dy. J Cli n O nc ol, 2 0 1 0. 2 8 ( 2 8): p. 4 3 2 4- 3 2. 
6.  
Ki m, Y. H., et al., I n sit u v acci n ati o n a g ai nst myc osis f u n g oi des by i ntr at u m or al i njecti o n of a 
T L R 9 a g o nist c o m bi ne d wit h r a di ati o n: a p h ase 1/ 2 st u dy.  Bl o o d, 2 0 1 2. 1 1 9 ( 2): p. 3 5 5- 6 3. 
7.  
Ba ba n, B., et al., I D O activ ates re g ul at ory T cells a n d bl ocks t heir c o nversi o n i nt o T h 1 7-like T 
cells. J I m m u n ol, 2 0 0 9. 1 8 3 ( 4): p. 2 4 7 5- 8 3. 
8.  
Pe n g, G., et al., T oll -like rece pt or 8- me di ate d revers al of C D 4 + re g ul at ory T cell f u ncti o n. 
Scie nce, 2 0 0 5. 3 0 9 ( 5 7 3 9): p. 1 3 8 0- 4. 
9.  
Wa n g, Z., et al., D N A met hyl ati o n i m p air s T L R 9 i n d uce d F ox p 3 ex pressi o n by atte n u ati n g 
I R F- 7 bi n di n g activity i n f ul mi n a nt ty pe 1 di a betes. J A ut oi m m u n, 2 0 1 3. 4 1 : p. 5 0- 9. 
1 0.  
Mits u ka, K., et al., Ex pressi o n of i n d ole a mi ne 2, 3- di oxy ge n ase a n d c orrel ati o n wit h 
p at h ol o gic al m ali g n a ncy i n gli o m as.  Ne ur os ur ger y, 2 0 1 3. 7 2 ( 6): p. 1 0 3 1- 8; disc ussi o n 1 0 3 8- 9. 
1 1.  
Ye, J., et al., T u m or al i n d ole a mi ne 2, 3 -di oxy ge n ase ex pressi o n pre dicts p o or o utc o me i n 
l ary n ge al s q u a m o us cell c arci n o m a. Virc h o ws Arc h, 2 0 1 3. 4 6 2 ( 1): p. 7 3- 8 1. 
1 2.  
U ytte n h o ve, C., et al., Evi de nce f or a t u m or al i m m u ne resist a nce mec h a nis m b ase d o n 
try pt o p h a n de gr a d ati o n by i n d ole a mi ne 2, 3-di oxy ge n ase.  Nat Me d, 2 0 0 3. 9 ( 1 0): p. 1 2 6 9- 7 4. 
1 3.  
M u n n, D. H. a n d A. L. Mell or, I n d ole a mi ne 2, 3-di oxy ge n ase a n d t u m or -i n d uce d t oler a nce. J 
Cli n I n vest, 2 0 0 7. 1 1 7 ( 5): p. 1 1 4 7- 5 4. 

E p ac a d ost at / S D -1 0 1 / R a di ot her a p y  
 
Cli nic al St u d y Pr ot o c ol U C D C C # 2 7 1  
 
 
Pr ot o c ol v ersi o n: 0 2. 1 9. 2 0  
U C D a vis C o m pre he nsi v e C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a g e 8 1  of 9 5  
1 4.  
S har ma, M. D., et al., Pl as m acyt oi d de n dritic cells fr o m m o use t u m or - dr ai ni n g ly m p h n o des 
directly activ ate m at ure Tre gs vi a i n d ole a mi ne 2, 3 -di oxy ge n ase.  J Cli n I n vest, 2 0 0 7. 1 1 7 ( 9): p. 
2 5 7 0- 8 2. 
1 5. 
S har ma, M. D. , et al., I n d ole a mi ne 2, 3-di oxy ge n ase c o ntr ols c o nversi o n of F ox p 3 + Tre gs t o 
T H 1 7 -like cells i n t u m or- dr ai ni n g ly m p h n o des. Bl o o d, 2 0 0 9. 1 1 3 ( 2 4): p. 6 1 0 2- 1 1. 
1 6. 
C he n, W., et al., T he i n d ole a mi ne 2, 3- di oxy ge n ase p at h w ay is esse nti al f or h u m a n 
pl as m acyt oi d de n dritic cell -i n d uce d a d a ptive T re g ul at ory cell ge ner ati o n. J I m m u n ol, 2 0 0 8. 
1 8 1 ( 8): p. 5 3 9 6- 4 0 4. 
1 7.  
Ya n, Y., et al., I D O u pre g ul ates re g ul at ory T cells vi a try pt o p h a n c at a b olite a n d s u p presses 
e nce p h alit o ge nic T cell res p o nses i n ex peri me nt al a ut oi m m u n e e nce p h al o myelitis.  J I m m u n ol, 
2 0 1 0. 1 8 5 ( 1 0): p. 5 9 5 3- 6 1. 
1 8.  
Mell or, A. L. a n d D. H. M u n n, I D O ex pressi o n by de n dritic cells: t oler a nce a n d try pt o p h a n 
c at a b olis m. Nat Re v I m m u n ol, 2 0 0 4. 4 ( 1 0): p. 7 6 2- 7 4. 
1 9.  
Mell or, A. L., et al., C utti n g e d ge: C p G oli g o n ucle oti des i n d uce s ple nic C D 1 9 + de n dritic cells 
t o ac q uire p ote nt i n d ole a mi ne 2, 3- di oxy ge n ase- de pe n de nt T cell re g ul at ory f u ncti o ns vi a I F N 
Ty pe 1 si g n ali n g.  J I m m u n ol, 2 0 0 5. 1 7 5 ( 9): p. 5 6 0 1- 5. 
2 0.  
V o n B u b n off, D., et al., I de ntific ati o n of I D O-p ositive a n d I D O- ne g ative h u m a n de n dritic cells 
after activ ati o n by v ari o us pr oi nfl a m m at ory sti m uli.  J I m m u n ol, 2 0 1 1. 1 8 6 ( 1 2): p. 6 7 0 1- 9. 
2 1.  
Gal o n, J., et al., Ty pe, de nsity, a n d l oc ati o n of i m m u ne cells wit hi n h u m a n c ol orect al t u m ors 
pre dict cli nic al o utc o me.  Scie nce , 2 0 0 6. 3 1 3 ( 5 7 9 5): p. 1 9 6 0- 4. 
2 2.  
Li u, X., et al., I n d ole a mi ne 2, 3- di oxy ge n ase, a n e mer gi n g t ar get f or a nti-c a ncer t her a py.  C urr 
Ca ncer Dr u g Tar gets, 2 0 0 9. 9 ( 8): p. 9 3 8- 5 2. 
2 3.  
M u n n, D. H., et al., Preve nti o n of all o ge neic fet al rejecti o n by try pt o p h a n c at a b olis m.  Scie nce, 
1 9 9 8. 2 8 1 ( 5 3 8 0): p. 1 1 9 1-3.  
2 4.  
Mat ysia k, M., et al., Ste m cells a meli or ate E A E vi a a n i n d ole a mi ne 2, 3- di oxy ge n ase (I D O) 
mec h a nis m.  J Ne ur oi m m u n ol, 2 0 0 8. 1 9 3 ( 1- 2): p. 1 2-2 3.  
2 5.  
Sa k urai, K., et al., Effect of i n d ole a mi ne 2, 3- di oxy ge n ase o n i n d ucti o n of ex peri me nt al 
a ut oi m m u ne e nce p h al o myelitis.  J Ne ur oi m m u n ol, 2 0 0 2. 1 2 9 ( 1-2): p. 1 8 6 - 9 6. 
2 6.  
Sza nt o, S., et al., I n hi biti o n of i n d ole a mi ne 2, 3- di oxy ge n ase-me di ate d try pt o p h a n c at a b olis m 
acceler ates c oll a ge n -i n d uce d art hritis i n mice.  Art hritis Res T her, 2 0 0 7. 9 ( 3): p. R 5 0. 
2 7.  
Ber ma n, D., S. M. Par ker, a n d S. D. C hasal o w, P ote nti al i m m u ne bi o m arkers of g astr oi ntesti n al 
t oxicities a n d effic acy i n p atie nts wit h a dv a nce d mel a n o m a tre ate d wit h i pili m u m a b wit h or 
wit h o ut pr o p hyl actic b u des o ni de.  J Cli n O nc ol, 2 0 0 8. 2 6 : p. 3 0 2 2. 
2 8.  
B o yer, E. W. a n d M. S ha n n o n, T he ser ot o ni n sy n dr o me.  N E n gl J Me d, 2 0 0 5. 3 5 2 ( 1 1): p. 1 1 1 2-
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2 9.  
Ya ma m ot o, S., et al., I n vitr o a u g me nt ati o n of n at ur al killer cell activity a n d pr o d ucti o n of 
i nterfer o n-al p h a/ bet a a n d - g a m m a wit h de oxyri b o n ucleic aci d fr acti o n fr o m Myc o b acteri u m 
b ovis B C G.  J p n J Ca ncer Res, 1 9 8 8. 7 9 ( 7): p. 8 6 6- 7 3. 
3 0.  
K ura m ot o, E., et al., Oli g o n ucle oti de se q ue nces re q uire d f or n at ur al killer cell activ ati o n.  J p n 
J Ca ncer Res, 1 9 9 2. 8 3 ( 1 1): p. 1 1 2 8- 3 1. 
3 1.  
R o ma n, M., et al., I m m u n osti m ul at ory D N A se q ue nces f u ncti o n as T hel per- 1- pr o m oti n g 
a dj uv a nts.  Nat Me d, 1 9 9 7. 3 ( 8): p. 8 4 9- 5 4. 
3 2.  
Krie g, A. M., T her a pe utic p ote nti al of T oll -like rece pt or 9 activ ati o n. Nat Re v Dr u g Disc o v, 
2 0 0 6. 5 ( 6): p. 4 7 1- 8 4. 

E p ac a d ost at / S D -1 0 1 / R a di ot her a p y  
 
Cli nic al St u d y Pr ot o c ol U C D C C # 2 7 1  
 
 
Pr ot o c ol v ersi o n: 0 2. 1 9. 2 0  
U C D a vis C o m pre he nsi v e C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a g e 8 2  of 9 5  
3 3.  
Ca m p bell, J. D., et al., C p G -c o nt ai ni n g i m m u n osti m ul at ory D N A se q ue nces elicit T N F- al p h a-
de pe n de nt t oxicity i n r o de nts b ut n ot i n h u m a ns.  J Cli n I n vest, 2 0 0 9. 1 1 9 ( 9): p. 2 5 6 4- 7 6. 
3 4.  
Mars hall, J. D., et al., S u peri or activity of t he ty pe C cl ass of I S S i n vitr o a n d i n viv o acr oss 
m ulti ple s pecies.  D N A Cell Bi ol, 2 0 0 5. 2 4 ( 2): p. 6 3-7 2.  
3 5.  
Mars hall, J. D., et al., N ovel c hi meric i m m u n o m o d ul at ory c o m p o u n ds c o nt ai ni n g s h ort C p G 
oli g o de oxyri b o n ucle oti des h ave differe nti al activities i n h u m a n cells.  N ucleic Aci ds Res, 2 0 0 3. 
3 1 ( 1 7): p. 5 1 2 2- 3 3. 
3 6.  
D ura ma d, O., et al., I n hi bit ors of T L R- 9 act o n m ulti ple cell s u bsets i n m o use a n d m a n i n vitr o 
a n d preve nt de at h i n viv o fr o m syste mic i nfl a m m ati o n.  J I m m u n ol, 2 0 0 5. 1 7 4 ( 9): p. 5 1 9 3- 2 0 0. 
3 7.  
Krie g, A. M., et al., C p G m otifs i n b acteri al D N A tri g ger direct B -cell activ ati o n. Nat ure, 1 9 9 5. 
3 7 4 ( 6 5 2 2): p. 5 4 6- 9. 
3 8.  
Krie g, A. M., C p G m otifs i n b acteri al D N A a n d t heir i m m u ne effects.  A n n u Re v I m m u n ol, 
2 0 0 2. 2 0 : p. 7 0 9- 6 0. 
3 9.  
H o n da, K., et al., S p ati ote m p or al re g ul ati o n of My D 8 8 -I R F- 7 si g n alli n g f or r o b ust ty pe-I 
i nterfer o n i n d ucti o n. Nat ure, 2 0 0 5. 4 3 4 ( 7 0 3 6): p. 1 0 3 5- 4 0. 
4 0.  
G ui d ucci, C., et al., Pr o perties re g ul ati n g t he n at ure of t he pl as m acyt oi d de n dritic cell 
res p o nse t o T oll-like rece pt or 9 activati o n.  J E x p Me d, 2 0 0 6. 2 0 3 ( 8): p. 1 9 9 9- 2 0 0 8. 
4 1.  
Krie g, A. M., Devel o p me nt of T L R 9 a g o nists f or c a ncer t her a py.  J Cli n I n vest, 2 0 0 7. 1 1 7 ( 5): p. 
1 1 8 4- 9 4. 
4 2.  
Ballas, Z. K., W. L. Ras m usse n, a n d A. M. Krie g, I n d ucti o n of N K activity i n m uri ne a n d h u m a n 
cells by C p G m otifs i n oli g o de oxy n ucle oti des a n d b acteri al D N A. J I m m u n ol, 1 9 9 6. 1 5 7 ( 5): p. 
1 8 4 0- 5. 
4 3.  
Ka wara da, Y., et al., N K - a n d C D 8( +) T cell-me di ate d er a dic ati o n of est a blis he d t u m ors by 
perit u m or al i njecti o n of C p G -c o nt ai ni n g oli g o de oxy n ucle oti des. J I m m u nol, 2 0 0 1. 1 6 7 ( 9): p. 
5 2 4 7- 5 3. 
4 4.  
Hec kels miller, K., et al., Perit u m or al C p G D N A elicits a c o or di n ate d res p o nse of C D 8 T cells 
a n d i n n ate effect ors t o c ure est a blis he d t u m ors i n a m uri ne c ol o n c arci n o m a m o del.  J 
I m m u n ol, 2 0 0 2. 1 6 9 ( 7): p. 3 8 9 2- 9. 
4 5.  
Li u, Y.J., I P C: pr ofessi o n al ty pe 1 i nterfer o n- pr o d uci n g cells a n d pl as m acyt oi d de n dritic cell 
prec urs ors.  A n n u Re v I m m u n ol, 2 0 0 5. 2 3 : p. 2 7 5- 3 0 6. 
4 6. 
Gear y, R. S., et al., P h ar m ac oki netic/ P h ar m ac o dy n a mic Pr o perties of P h os p h or ot hi o ate 2'- O-
( Met h oxyet hyl)-M o difie d A ntise nse Oli g o n ucle oti des i n A ni m als a n d M a n , i n A ntise nse Dr u g 
Tec h n ol o gy:  Pri nci ples, Str ate gies, a n d A p plic ati o ns , S. T. Cr o o ke, E dit or. 2 0 0 8, C R C Press: 
B oca Rat o n, F L. p. 3 0 5- 3 2 6. 
4 7.  
E n gel, A. L., G. E. H olt, a n d H. L u, T he p h ar m ac oki netics of T oll- like rece pt or a g o nists a n d t he 
i m p act o n t he i m m u ne syste m. E x pert Re v Cli n P har mac ol, 2 0 1 1. 4 ( 2): p. 2 7 5- 8 9. 
4 8.  
Gear y, R. S., A ntise nse oli g o n ucle oti de p h ar m ac oki netics a n d met a b olis m.  E x pert O pi n Dr u g 
Meta b T o xic ol, 2 0 0 9. 5 ( 4): p. 3 8 1- 9 1. 
4 9.  
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. 
5 0.  
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 ock a de.  Ca ncer R esearc h, 2 0 1 4. 7 4 ( 1 9): p. 5 4 5 8- 6 8. 
5 1.  
Gaje ws ki, T. F., J. L o ua he d, a n d V. G. Bric har 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.  Ca ncer J, 2 0 1 0. 1 6 ( 4): p. 
3 9 9- 4 0 3. 

E p ac a d ost at / S D -1 0 1 / R a di ot her a p y  
 
Cli nic al St u d y Pr ot o c ol U C D C C # 2 7 1  
 
 
Pr ot o c ol v ersi o n: 0 2. 1 9. 2 0  
U C D a vis C o m pre he nsi v e C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a g e 8 3  of 9 5  
5 2.  
Harli n, H., et al., C he m oki ne ex pressi 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 3.  
S pra n ger, S., R. Ba o, a n d T. F. Gaje 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 4.  
Kl u g, F., et al., L o w -D ose 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 5.  
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 de 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 6.  
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 7.  
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 Res, 2 0 0 9. 1 5 ( 2 3): p. 7 4 1 2- 2 0. 
 
 
 

E p ac a d ost at / S D -1 0 1 / R a di ot her a p y  
 
Cli nic al St u d y Pr ot o c ol U C D C C # 2 7 1  
 
 
Pr ot o c ol v ersi o n: 0 2. 1 9. 2 0  
U C D a vis C o m pre he nsi v e C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a g e 8 4  of 9 5  
1 7.  
A P P E N DI C E S  
1 7. 1  
A p pe n di x 1: 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 he 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.  
 
 
 

E p ac a d ost at / S D -1 0 1 / R a di ot her a p y  
 
Cli nic al St u d y Pr ot o c ol U C D C C # 2 7 1  
 
 
Pr ot o c ol v ersi o n: 0 2. 1 9. 2 0  
U C D a vis C o m pre he nsi v e C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a g e 8 5  of 9 5  
1 7. 2  
A p pe n di x 2: St u d y Re gistr ati o n 
 
A.   
Re gistrati o ns f or t his pr ot oc ol m ust be ma de t hr o u g h t he de part me nt of ra di ati o n 
o nc ol o g y, U ni versit y of Calif or nia, Da vis Ca ncer Ce nter bet wee n n or mal b usi ness h o urs 
( Pacific Ti me), M o n d a y t hr o u g h Fri da y (e x ce pt h oli da ys).  D oc u me ntati o n of c urre nt 
I R B a p pr o v al of t his pr ot oc ol b y n o n-U C D i nstit uti o n s m ust be o n file pri or t o 
re gistrati o n of patie nts at t hese i nstit uti o ns. 
B.  
Pre -st u d y la b orat or y tests, sca ns, a n d x-ra ys, m ust be c o m plete d pri or t o re gistrati o n, 
wit hi n t he ti me fra me s pecifie d i n t he pr ot oc ol.  T h e eli gi bilit y c hec klist m ust be 
c o m plete d.  Patie nts m ust si g n a n i nf or me d c o nse nt pri or t o re gistrati o n. 
C.  
If t he patie nt is t o be r e gistere d t he sa me d a y as t h e pr o p ose d treat me nt start date, t he U C 
Da vis St u d y C o or di nat or m ust be n otifie d b y fa x (
) a n d/ or e mail 2 4 hrs 
pri or t o pr o p ose d treat me nt start date t hat t he site has a patie nt t o re gister.   
D.   
Patie nts ma y be re gister e d u p t o 7 2 hrs pri or t o treat me nt i nitiati o n. T he si g ne d c o nse nt, 
c o m plete d c hec klist a n d re p orts fr o m all pre-st u d y la b orat or y tests, sca ns a n d x- ra ys 
m ust be fa xe d/e mail t o t he U ni versit y of Calif or ni a, Da vis C o m pre he nsi ve Ca ncer 
Ce nter Offi ce of Cli nical Researc h  i n or der t o re gister t he patie nt. T he U C Da vis St u d y 
C o or di nat or will re vie w t hese d oc u me nts a n d fa x a re gistrati o n c o nfir mati o n wit hi n 2 4 
h o urs. N O T E: A d mi nistr ati o n of st u d y me dic ati o n m a y n ot be i niti ate d u ntil t he 
re gistr ati o n c o nfir m ati o n h as bee n recei ve d.  
E.   
A patie nt faili n g t o meet all pr ot oc ol re q uire m e nts ma y n ot be re gistere d.  If y o u ha ve 
a n y q uesti o ns re gar di n g eli gi bilit y, please c o ntact t he PI or St u d y C o or di n at or  
 
 
 

E p ac a d ost at / S D -1 0 1 / R a di ot her a p y  
 
Cli nic al St u d y Pr ot o c ol U C D C C # 2 7 1  
 
 
Pr ot o c ol v ersi o n: 0 2. 1 9. 2 0  
U C D a vis C o m pre he nsi v e C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a g e 8 6  of 9 5  
1 7. 3  
A p pe n di x 3: D at a S u b missi o n Sc he d ule  
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 h o ul d be mai ntai ne d.  
 
 S U B MI T WI T HI N 2 4 H O U R S O F R E GI S T R A TI O N:  
Patie nt Re gistrati o n F or m  
 S U B MI T WI T HI N 1 4 D A Y S O F R E GI S T R A TI O N:  
I n‐H o use Pre ‐St u d y E val uati o n F or m (I H ‐1 0 2)  
 S U B MI T WI T HI N 7 D A Y S O F S C R E E NI N G F AI L U R E:  
Patie nt Scree n Fail ure F or m  
 S U B MI T WI T H 1 4 D A Y S O F C Y C L E C O M P L E TI O N:  
A d verse E v e nt/ Dr u g Rel ati o ns hi p F or m  
 S U B MI T WI T HI N 1 4 D A Y S O F E N D O F E A C H T R E A T M E N T C Y C L E:  
I n‐H o use T r eat me nt C ycl e F or m – I nf usi o n  
 S U B MI T WI T HI N 1 4 D A Y S O F E A C H R E S P O N S E A S S E S S M E N T:  
T u m or Meas ur e me nt L o g  
 S U B MI T WI T HI N 1 4 D A Y S O F O F F T R E A T M E N T:  
Off Tr eat me nt/I n F oll o w - u p/ Off St u d y/ E x pirati o n F or m (I H‐3 0 1)  
 S U B MI T WI T HI N 1 4 D A Y S O F K N O W L E D G E O F D E A T H I F P A TI E N T I S S TI L L 
O N S T U D Y O R 3 0 – D A Y S I F O F F S T U D Y:  
Off Tr eat me nt/I n F oll o w - u p/ Off St u d y/ E x pirati o n F or m (I H‐3 0 1)  
 S U B MI T WI T HI N 2 D A Y S O F K N O W L E D G E O F P R O T O C O L D E VI A TI O N:  
Cli nical Trials S u p p ort U nit : N otice of Pr ot oc ol De viati o n  
 S U B MI T WI T HI N 1 4 D A Y S O F E A C H R E Q UI R E D F O L L O W ‐U P E N C O U N T E R:  
F oll o w ‐U p F or m (I H ‐3 0 2)  
 A L L S E RI O U S A D V E R S E E V E N T S M U S T B E R E P O R T E D A S O U T LI N E D I N 
T H E P R O T O C O L.  
 
 
 
 

E p ac a d ost at / S D -1 0 1 / R a di ot her a p y  
 
Cli nic al St u d y Pr ot o c ol U C D C C # 2 7 1  
 
 
Pr ot o c ol v ersi o n: 0 2. 1 9. 2 0  
U C D a vis C o m pre he nsi v e C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a g e 8 7  of 9 5  
1 7. 4  
A p pe n di x 4: 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 :  
P artici pati o n i n t hese m olec ular c orrel ati ve st u dies  is ma n dat or y. 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 n e w patie nt I D n u m ber t o pr otect patie nt’s i de ntit y. 
A s peci me n s u b missi o n f or m s h o ul d be fille d o ut f or eac h s p eci me n o btai n e d. All s peci me ns 
m ust be la bele d wit h pr ot oc ol n u m ber, site i de ntificati o n, patie nt re gistrati o n n u m ber, date of 
s peci me n c ollecti o n, a n d n u m ber of cells (f or P B M Cs) or wei g ht of tiss ue (f or tiss ue bi o psies). 
C orrelati ve st u dies will be perf or me d at U C D a vis or sa m ples will be s hi p pe d i n a de -
i de ntifie d ma n ner t o ot her i nstit uti o ns / c o m pa nies f or a nal ysis. 
F or c orrelati ve st u dies t h e f oll o wi n g sa m ples s h o ul d be c ollecte d: 
1)  Peri p heral bl o o d sa m ples o btai ne d pre-treat me nt o n da y 1, t he n a gai n at da y 1 6 a n d at  
t he q 6 0 da y f oll o w- u p visits. 
2)  Fres h t u m or bi o ps y pr e-treat me nt o n da y 1 a n d at da y 1 5. O pti o nal bi o ps y at pr o gressi o n.  
3)  St o ol sa m ple c ollecte d pr e -treat me nt. 
C orrelati ve st u dies will i ncl u de (i n or der of pri orit y):  
 
Bl o o d  
 
1)  Fl o w C yt o metr y q ua ntificati o n, i m m u n o p he n ot y pi n g, a n d acti vati o n / f u ncti o nal 
assess me nt of t u m or i nfiltrati n g i m m u ne cells i ncl u di n g m yel oi d - deri ve d s u p press or cells 
( M D S C), re g ulat or y T ( Tre g) cells, T/ B/ N K cell i m m u n o p he n ot y pi n g a n d acti vate d T 
cells  
2)  R N A e xtracti o n f or q P C R a n d Na n ostri n g a nal ysis 
3)  W h ole e x o me se q u e nci n g ( W E S) as a n or mal tiss ue c o ntr ol t o i de ntif y p utati ve ne o-
a nti ge ns 
4)  E val uati o n of s yste mic plas ma tr y pt o p ha n t o k y n ure ni ne rati os 
5)  Peri p heral bl o o d c yt o ki n e / c he m o ki ne pr ofili n g b y L u mi ne x 
6)  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  
7)  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  
1)  I H C t o assess t u m or i nfiltrati n g i m m u ne cells ( C D 8, C D 4, F o x P 3) a n d e x pressi o n of 
ot her mar kers wit h p ote ntial pr o g n ostic a n d/ or pre dicti ve val ue o n effica c y o utc o mes 
i ncl u di n g I D O, P D- 1 a n d P D - L 1 as well as ne w bi o mar kers.  
2)  R N A e xtracti o n f or q P C R a n d Na n ostri n g a nal ysis 

E p ac a d ost at / S D -1 0 1 / R a di ot her a p y  
 
Cli nic al St u d y Pr ot o c ol U C D C C # 2 7 1  
 
 
Pr ot o c ol v ersi o n: 0 2. 1 9. 2 0  
U C D a vis C o m pre he nsi v e C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a g e 8 8  of 9 5  
3)  I d entificati o n of t u m or n e o -a nti ge ns b y R N A d ee p se q ue nci n g i n c o nj u ncti o n wit h 
peri p her al bl o o d W E S data. 
4)  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 o ol 
1) St o ol micr o bi o mes a nal ysis b y 1 6s R N A se q ue nci n g 
 
 
1 . 0 Peri p her al Bl o o d 
1. 1 Bl o o d C ollecti o n 
Bl o o d s peci me ns ( 4 x 5 ml la ve n der t o p E D T A t u b es ) will be c ollect e d fr o m eac h p atie nt pri or 
t o i nitiati n g treat me nt at da y 1 t he n a gai n at Da y 1 5 a n d at q 6 0 da y f oll o w u p visits as 
i n dicate d i n t he st u d y cal e n dar. It is i m p orta nt t hat eac h t u be b e fille d t o 5 ml t o e ns ure 
s ufficie nt s peci me ns f or t he pla n ne d a n al yses. If p ossi ble, a bl o o d s peci me n s h o ul d be 
o btai ne d at t he ti me t he p atie nt is re m o ve d fr o m pr ot oc ol treat me nt or if t he patie nt's disease 
pr o gresses. 
2. 2 Bl o o d S peci me n Pr ocessi n g a n d ha n dli n g – la v e n der t o p E D T A t u bes 
F o ur 5 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 patie nt at eac h ti me p oi nt. 
Eac h p ur ple-t o p ( E D T A) t u be s h o ul d be i n verte d se veral ti mes, place d o n wet ice, a n d 
deli vere d t o t he la b i m me diatel y. E ver y eff ort s h o ul d be ma de t o pr ocess bl o o d sa m ples wit hi n 
1 h o ur of c ollecti o n. Sa m ples s h o ul d be pr ocess e d i n sterile fas hi o n. 
T he t u be 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 1, 0 0 0- 1, 5 0 0 r p m ( 4 0 0 x 
g) f or 1 0 mi n utes. T he Plas ma la yer s h o ul d be re m o ve d a n d ke pt o n ice (see 1. 2. 1).  P B M Cs 
s h o ul d be se par ate d usi n g sterile a n d e n d ot o xi n free Fi c oll de nsit y gra die nt s ol uti o n.  T he 
peri p her al bl o o d m o n o n uclear cells ( P B M Cs) s h o ul d be re m o ve d a n d p o ol e d. T he P B M C 
la yer s h o ul d be r es us pe n de d i n t hree ti mes t he v ol u me of c ol d sterile P B S. Cells s h o ul d be 
c o u nte d usi n g a he m oc yt o meter a n d t he t otal cell n u m ber s h o ul d be n ote d. T he e x pecte d yiel d 
is 1- 2 milli o n cells per ml of bl o o d.   
T he P B M Cs c ollecte d f r o m 4 l a ve n der t o p t u bes w ill be di vi de d i nt o t hree ali q u ots. 
R o u g hl y half of t he cells s h o ul d be cr y o preser v e d f or f ut ure a nal ysis. T he s ec o n d ali q u ot 
c o nsisti n g of r o u g hl y 2 5 % of t he cells will be place d i n R N Alater a n d 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 R N A e xtracti o n. T h e t hir d ali q u ot c o nsisti n g of 
t he last 2 5 % of cells will be s na p fr o ze n i n 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 xtr acti o n. If t here are m or e t ha n 2 0 x 1 0 6 via ble cells t he R N A a n d D N A e xtracti o n 
ali q u ots s h o ul d be li mite d t o a t otal of 5 x 1 0 6 cells eac h a n d t h e a d diti o nal cells s h o ul d be 
cr y o pres er ve d t h us d e viati n g fr o m t he 2: 1: 1 ali q u oti n g. 

E p ac a d ost at / S D -1 0 1 / R a di ot her a p y  
 
Cli nic al St u d y Pr ot o c ol U C D C C # 2 7 1  
 
 
Pr ot o c ol v ersi o n: 0 2. 1 9. 2 0  
U C D a vis C o m pre he nsi v e C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a g e 8 9  of 9 5  
1. 2. 1 Bl o o d pl as m a 
T he re m o ve d pl as ma la y ers s h o ul d be p o ole d a n d ce ntrif u ge d at 1 0 0 0 x g f or 1 0 mi n utes t o 
clarif y t he plas ma. T he plas ma s h o ul d t he n be place d i n u p t o ei g ht 0. 5 ml ali q u ots i n la bele d 
cr y ot u bes. A n y a d diti o nal plas ma ca n be discar de d. T he plas ma will be fr o ze n (s na p fr oze n 
wit h li q ui d nitr o ge n if p ossi ble) a n d st ore d at - 7 0 t o - 8 0° C. Sa m ples s h o ul d b e batc he d a n d 
s hi p pe d o ver ni g ht o n dr y ice t o U C Da vis at t he a d dress i n dicate d. O n e t o t w o t u bes of plas ma 
per patie nt will be s hi p pe d t o Tra ns ge ne i n a b atc h e d ma n ner fr o m U C Da vis.  
1. 2. 2 Cry o preserv ati o n 
After c o u nti n g, P B S was he d P B M Cs s h o ul d be di vi de d i nt o ali q u ots of 5 milli o n cells a n d 
s p u n d o w n at a p pr o xi mat el y 1, 0 0 0- 1, 5 0 0 r p m ( 4 0 0 x g) f or 1 0 mi n utes. Eac h ali q u ot s h o ul d be 
res us pe n de d i n 1 ml of c ol d sterile Cr y o St or C S 1 0 freeze me di a (catal o g n u m ber 0 7 9 3 0, 
S T E M C E L L tec h n ol o gies) w hic h c o ntai ns 1 0 % D M S O. Eac h 1 ml ali q u ot s h o ul d be place d i n 
a cr y o pr eser v ati o n t u be a n d t he li d s h o ul d be ti g htl y sec ure d. T u b es s h o ul d be place d i nt o a 
“ Mr. Fr ost y” or ot her sl o w freeze c o ntai ner a n d pl ace d i nt o a - 7 0 t o - 8 0° C freezer f or 1 2 - 2 4 
h o urs. T u bes s h o ul d t he n be tra nsferre d t o a n d st ore d i n va p or p h ase li q ui d nitr o ge n (- 1 3 5° C). 
I n a batc h e d ma n ner t u bes s h o ul d be s hi p pe d o ver ni g ht i n li q ui d nitr o ge n t o U C Da vis at t he 
i n dicate d a d dr ess.  
1. 2. 3 R N A l ater 
After c o u nti n g, P B S was he d P B M Cs s h o ul d be s p u n d o w n at a p pr o xi matel y 1, 0 0 0- 1, 5 0 0 r p m 
( 4 0 0 x g) f or 1 0 mi n utes. T he cell pellet s h o ul d be re-s us pe n d e d i n 1 ml of R N Alater s ol uti o n 
s na p fr oze n i n li q ui d nitr o ge n a n d st ore d at  - 7 0 t o - 8 0° C. I n a batc h e d ma n ner t u bes s h o ul d be 
s hi p pe d o ver ni g ht o n dr y ice t o U C Da vis at t he i n dicate d a d dress. Please n ote t hat P A X ge ne 
t u bes will n ot be use d f or c ollecti o n of P B M Cs f or R N A a nal ysis. 
1. 2. 4 S n a p fr oze n f or D N A extr acti o n 
T his s peci me n will be c ollecte d fr o m t he pr e-treat me nt bl o o d dra w o nl y. After c o u nti n g, P B S 
was he d P B M Cs s h o ul d be s p u n d o w n at a p pr o xi m atel y 1, 0 0 0- 1, 5 0 0 r p m ( 4 0 0 x g) f or 1 0 
mi n utes. T he cell pellet s h o ul d be s na p fr o ze n i n li q ui d nitr o ge n a n d st ore d at  - 7 0 t o - 8 0° C. I n 
a batc he d m a n ner t u bes s h o ul d be s hi p pe d o ver ni g ht o n dr y ice t o U C Da vis at t he i n dicate d 
a d dress.  
1. 3 Peri p heral Bl o o d A nal ysis 
1. 3. 1 Pl as m a  

E p ac a d ost at / S D -1 0 1 / R a di ot her a p y  
 
Cli nic al St u d y Pr ot o c ol U C D C C # 2 7 1  
 
 
Pr ot o c ol v ersi o n: 0 2. 1 9. 2 0  
U C D a vis C o m pre he nsi v e C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a g e 9 0  of 9 5  
Plas ma sa m ples will be st ore d at U C Da vis f or bat c he d a n al ysis. Plas ma will be i nterr o gate d 
f or c he m o ki ne a n d c yt o ki ne le vels usi n g t he l umi ne x platf or m. A d diti o nall y , plas ma sa m ples 
will be e val uate d f or tr y pt o p ha n t o k y n ure ni ne rati os. 
1. 3. 2 Cry o preserve d s a m ples  
Cr y o preser v e d sa m ples will be st ore d at U C Da vis f or batc he d a nal ysis. Sa m ples will be 
t ha we d a n d stai ne d wit h fl u or o p h ore- c o nj u gate d a nti b o dies a gai nst C D 4, C D 8, C D 2 5, C D 6 2 L, 
C D 4 5 R A, C D 1 2 7, I C O S, P D- 1, P D- L 1, F o x P 3, C D 3, C D 5 6, C D 1 6, C D 8 3, TI M- 3, Ki- 6 7, 
C D 1 9, C D 2 0, C D 3 3, C D 1 5, C D 1 1 b, H L A- D R  a n d ot hers. Stai ne d cells will be i nterr o gate d b y 
fl o w c yt o metr y a n d r es ults a nal yze d usi n g Fl o wJ o s oft ware.  
1. 3. 3 R N Al ater s a m ples 
Cells i n R N A later will be st ore d at U C D a vis f or batc he d a n al ysis. Sa m ples will be t ha we d 
a n d R N A will be e xtracte d. T he tra nscri pt o me will be a nal yze d usi n g a na n ostri n g 7 7 0 ge ne 
pa nel. Tar g ete d R T -P C R will be use d t o vali date g e nes of i nterest .  
1. 3. 4 S n a p fr oze n s a m ples 
S na p fr oze n cell pellets will be st ore d at U C Da vis f or batc he d a nal ysis. Sa m ples will be 
t ha we d a n d g e n o mic D N A will be e xtract e d. W h ole e x o me se q ue n ci n g will be perf or me d 
usi n g t he Ill u mi na Hi Se q platf or m.  
2. 0 Fres h t u m or bi o ps y  
2. 1 T u m or bi o ps y c ollecti o n 
Fres h t u m or bi o ps y is c ollecte d pre-treat me nt a n d at da y 1 5. O pti o nal bi o ps y ca n be o btai n e d 
at pr o gressi o n.  T u m or bi o psies s h o ul d be c ollecte d b y c ore nee dle bi o ps y usi n g t he lar gest 
b ore nee dl e a n d n u m ber of passes dee me d safe. T he sa me lesi o ns s h o ul d be tar gete d f or all 
fres h tiss ue bi o psies. C o nfir mati o n t hat t he c ore bi o psies c o ntai n t u m or s h o ul d be perf or m e d at 
t he ti me of bi o ps y usi n g t o uc h pre p. 
2. 2 T u m or bi o ps y pr ocessi n g a n d ha n dli n g 
O n site at t he ti me of t he bi o ps y t u m or tiss ues s h o ul d be ali q u ote d i nt o t w o p orti o ns. T he t o p 
pri orit y assa y is I H C/I F a n d bi o ps y sa m ples s h o ul d be place d i n f or mali n fi xati ve a n d later 
e m be d de d i nt o F F P E bl oc ks. I n ge neral sa m ples s h o ul d be place d i n fi xati v e at a 1 0: 1 rati o 
a n d fi xe d f or at least 4 8 h o urs b ut t hic ker tiss ue sa m ples ma y re q uire l o n ger fi xati o n.  
 If s ufficie nt tiss ue is a v aila ble ( w hic h t here ge n erall y s h o ul d be if m ore t ha n o ne bi o ps y pass 
has bee n u n derta ke n) t he n n o less t ha n 1 0 m g a n d b ut prefera bl y 2 0 - 5 0 m g of t u m or tiss ue 
s h o ul d be place d i n 1 ml of R N Alater s na p fr oze n i n li q ui d nitr o ge n a n d st ore d at - 7 0 t o - 8 0° C.  

E p ac a d ost at / S D -1 0 1 / R a di ot her a p y  
 
Cli nic al St u d y Pr ot o c ol U C D C C # 2 7 1  
 
 
Pr ot o c ol v ersi o n: 0 2. 1 9. 2 0  
U C D a vis C o m pre he nsi v e C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a g e 9 1  of 9 5  
2. 3 T u m or bi o ps y a nal ysis 
F F P E tiss ue bi o ps y bl oc ks will be c ollecte d a n d st ore d at U C Da vis. Tiss ues will be secti o ne d, 
pre par e d, a n d m o u nte d f or I H C/I F usi n g sta n dar d pr oce d ures. W he n p ossi ble, I H C/I F s h o ul d 
be perf or me d wit hi n t w o wee ks of sli de secti o ni n g. Bi o ps y sa m ples will be stai ne d b y m ulti-
ple x I H C/I F at U C Da vis or c olla b orati n g la b orat ories t o i m m u n ol o g icall y pr ofile t he t u m or 
micr oe n vir o n me nt. Mar k ers e xa mi ne d will i ncl u de C D 3, C D 8, C D 4, F o x P 3, Ki- 6 7, P D- 1 a n d 
P D - L 1.  
Tiss ue i n R N A later will be st ore d at U C D a vis f or batc he d a nal ysis. Sa m ples will be t ha we d 
a n d R N A will be e xtracte d. T he tra nscri pt o me will be a nal yze d usi n g a na n ostri n g 7 7 0 ge ne 
pa nel. Tar g ete d R T -P C R will be use d t o vali date g e nes of i nterest. R N Ase q data will als o be 
use d i n c o nj u ncti o n wit h P B M C W E S t o i de ntif y m utati o nal l oa d a n d p utati ve ne oa nti ge ns. 
3. 0 St o ol S a m ple C ollecti o n 
3. 1 St o ol sa m ple  c ollecti o n 
St o ol sa m ples will be c ollecte d b y t he patie nt pre -treat me nt usi n g t he pr o vi de d st o ol c ollecti o n 
kit. St o ol sa m ples will be st ore d o n ice i n t he kit pr o vi de d a n d ret ur ne d t o U C Da vis prefera bl y 
wit hi n 1 2 h o urs (a n n o l o n ger t ha n 2 4 h o urs) of c ollecti o n. 
3. 2 St o ol sa m ple  pr ocessi n g a n d ha n dli n g 
St o ol sa m ples will be  s na p fr oze n i n li q ui d nitr o ge n a n d st ore d at - 7 0 t o - 8 0° C f or b atc he d 
a nal ysis. 
3. 3 T u m or bi o ps y a nal ysis 
1 6s R N A will be e xtracte d a n d se q ue nce d fr o m st o ol sa m ples t o de ter mi ne t he micr o bi o me 
pr ofile.   
 
 
 

E p ac a d ost at / S D -1 0 1 / R a di ot her a p y  
 
Cli nic al St u d y Pr ot o c ol U C D C C # 2 7 1  
 
 
Pr ot o c ol v ersi o n: 0 2. 1 9. 2 0  
U C D a vis C o m pre he nsi v e C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a g e 9 2  of 9 5  
1 7. 5  
A p pe n di x 5: A n a p h yl a xis Prec a uti o ns  
 
E Q UI P M E N T N E E D E D  
•  
T o ur ni q uet 
•  
O x y ge n 
•  
E pi ne p hri ne f or s u bc uta ne o us, i ntra ve n o us, a n d/ or e n d otrac heal use i n acc or da nce 
•  
wit h sta n dar d practice 
•  
A nti hista mi nes  
•  
C ortic oster oi ds 
•  
I ntra ve n o us i nf usi o n s ol uti o ns, t u bi n g, cat heters, a n d ta pe 
 
P R O C E D U R E S  
1.  I n t he e ve nt of a s us pecte d a na p h ylactic reacti o n d uri n g dr u g a d mi nistrati o n, t he f oll o wi n g 
pr oce d ures s h o ul d be perf or me d: 
2.  St o p t he st u d y dr u g a d mi nistrati o n. 
3.  A p pl y a t o ur ni q uet pr o xi mal t o t he i njecti o n site t o sl o w s yste mic a bs or pti o n of dr u g. D o n ot 
o bstr uct arterial fl o w i n t he li m b.  
4.  Mai ntai n a n a de q uate air wa y.  
5.  A d mi nister a nti hista mi nes, e pi ne p hri ne, or ot her me dicati o ns as re q uire d b y patie nt stat us a n d 
directe d b y t he p h ysicia n i n c har ge.  
6.  C o nti n ue t o o bser ve t he patie nt a n d d oc u me nt o bser vati o ns. 
 
 
 
 

E p ac a d ost at / S D -1 0 1 / R a di ot her a p y  
 
Cli nic al St u d y Pr ot o c ol U C D C C # 2 7 1  
 
 
Pr ot o c ol v ersi o n: 0 2. 1 9. 2 0  
U C D a vis C o m pre he nsi v e C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a g e 9 3  of 9 5  
1 7. 6  
A p pe n di x 6: I m m u ne -Rel ate d Res p o nse Criteri a  
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]) m a y n ot be s ufficie nt t o c h aract erize f ull y acti vit y i n t he ne w era  of 
tar get t her a pies a n d/ or bi ol o gics.  I n st u dies wit h c yt o ki nes, ca ncer vacci nes, a n d m o n ocl o nal 
a nti b o dies, c o m plete res p o nse, partial res p o ns e, or sta ble disease has b ee n s h o w n t o occ ur 
after a n i ncrease i n t u m or b ur de n as c h aracteri ze d b y pr o gressi ve disease b y tra diti o nal 
res p o nse criteria.  T h eref ore, c o n ve nti o nal res p o nse criteria m a y n ot a de q u atel 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 diseas e ( b y i nitial ra di o gra p hi c 
e val uati o n) d oes n ot necessaril y reflect t hera p e utic fail ure.  L o n g- t er m effect o n t he tar get 
disease m ust als o be ca pt ure d.  T he i m m u ne-relate d res p o nse criteria (ir R C) are criteria t hat 
atte m pt t o d o t hat b y e n ha nci n g c haract erizati 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) [5 7 ].  ( N ote:  T he ir R C o nl y i n de x 
a n d meas ur a ble ne w l esi o ns are ta k e 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 ul ar 
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 p artial 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 b est 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 l esi o ns).   
Ste p 2 .  
Calc ulate t he S P D of all of t hese i n de x lesi 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

E p ac a d ost at / S D -1 0 1 / R a di ot her a p y  
 
Cli nic al St u d y Pr ot o c ol U C D C C # 2 7 1  
 
 
Pr ot o c ol v ersi o n: 0 2. 1 9. 2 0  
U C D a vis C o m pre he nsi v e C a ncer Ce nter  
 
 
C o nfi de nti al  
 
P a g e 9 4  of 9 5  
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 bl e lesi o ns (≥ 5 ×  5 m m; u p t o fi ve ne w lesi o ns per or ga n:  
fi ve ne w c ut a 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, meas ura ble lesi o ns.  
Ste p 4 . Calc ulate t he t u m or b ur d e 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 
St e p 5. Calc ulate t he c h a n ge i n t u m or b ur de n relati ve t o baseli ne a n d t he c ha n ge i n t u m or 
b ur de n rel ati ve t o na dir. 
Ste p 6 . Deri ve t he o v erall r es 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 v e 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 fi rst 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 n e-relate d pr o gressi v e disease; ir P R =  i m m u n e-relate d p artial res p o nse; 
ir S D =  i m m u ne-relate d sta ble disease. 
 
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 n e-relate d b est o v erall res p o nse; ir C R =  i m m u n e-relate d c o m plete res p o nse; ir P D =  i m m u n e-relate d pr o gressi ve 
disease; ir P R  =  i m m u n e-relate d partial res p o nse; ir S D =  i m m u n e-relate d sta ble disease.