Clinical trial NCT03322384
Conditions: Advanced Solid Tumors Lymphoma
Sponsor: University of California, Davis
Start date: 2018-01-17; Completion date: 2020-04-08
Enrollment: 20 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Checkpoint blockade immunotherapy has revolutionized the management of a variety of advanced malignancies. Monoclonal antibodies targeting the PD-1 / PD-L1 interaction have received FDA approvals for non-small cell lung cancer, melanoma, Merkel cell carcinoma, renal cell carcinoma, hepatocellular, squamous cell carcinoma of the head and neck, microsatellite instability high colorectal carcinoma, urothelial carcinoma, and classical Hodgkin's lymphoma. Despite the promising evidence for deep and durable responses with these agents, the majority of patients either fail to respond or develop resistance to treatment. Thus, there is interested in developing alternative immunotherapeutic strategies. The investigators hypothesize that a novel immunotherapeutic combination of radiotherapy (RT) with intralesional CpG and indolamine-2,3-dioxygenase blockade may offer significant clinical benefit to patients and proposing a microtrial testing this combination for advanced/refractory solid tumors and lymphoma.

Detailed description:
Checkpoint blockade immunotherapy has revolutionized the management of a variety of advanced malignancies. Monoclonal antibodies targeting the PD-1 / PD-L1 interaction have received FDA approvals for non-small cell lung cancer, melanoma, Merkel cell carcinoma, renal cell carcinoma, hepatocellular, squamous cell carcinoma of the head and neck, microsatellite instability high colorectal carcinoma, urothelial carcinoma, and classical Hodgkin's lymphoma. Despite the promising evidence for deep and durable responses with these agents, the majority of patients either fail to respond or develop resistance to treatment. Thus, there is interested in developing alternative immunotherapeutic strategies. The investigators hypothesize that a novel immunotherapeutic combination of radiotherapy (RT)with intralesional CpG and indolamine-2,3-dioxygenase (IDO) blockade may offer significant clinical benefit to patients and proposing a microtrial testing this combination for advanced/refractory solid tumors and lymphoma.

Unmethylated CpG DNA is a component bacterial genomes and is the agonist of Toll Like Receptor-9, an endosomal pattern recognition receptor of antigen presenting cells. TLR9 activation results in downstream production of IFN-α, interleukin-6 interleukin-12. These cytokines induce naive T cells to differentiate to helper T cells. CpG has demonstrated significant synergy with radiotherapy to induce regression of refractory systemic and cutaneous lymphomas both within radiation treatment field and un-irradiated metastases. SD-101 is a synthetic oligodeoxynucleotide enriched with CpG motifs.

IDO is an enzyme that converts the essential amino acid tryptophan to kynurenine. The availability of tryptophan is essential to sustaining both helper T cell and effector T cell activation. Overexpression of IDO by tumor cells or antigen presenting cells serves to arrest T cell activation thus acting as an immunosuppressive enzyme. Epacadostat (INCB024360) is an inhibitor of the enzyme indoleamine 2,3-dioxygenase 1 (IDO1) that has shown promise in the treatment of solid tumors and lymphomas in ongoing Phase I/II studies.

The investigators have shown in animal studies that IDO upregulation limits tumor response to RT + CpG and that addition of IDO blockade improves therapeutic efficacy. On the basis of these data, the investigators hypothesize that IDO inhibition will improve upon the known historical efficacy of RT + CpG therapy, and will be highly effective and well tolerated in the management of advanced solid tumors and lymphomas.

This is a phase I/II study. For the phase I portion the primary endpoint is to determine the maximum tolerated dose of epacadostat in combination with radiotherapy and SD-101. For the phase II portion the primary endpoint is safety and toxicity per CTCAE v4.03 criteriae. The secondary endpoint is the abscopal response rate defined as the objective response rate at un-irradiated lesions per irRECIST criteria.

Up to three dose levels of epacadostat will be evaluated: 100 mg bid, 200 mg bid and 300 mg bid each day of the study. Radiotherapy will be delivered to the treatment lesion during the first week using standard-of-care palliative fractionation regimens of 8 Gy x 3 fractions, 4 Gy x 5 fractions, or 2 Gy x 2 fractions. Four milligrams of SD-101 will be delivered into the treatment lesion by intralesional injection on days 1, 8, 15, with optional additional injections on days 22, and 29. On Day 1, biopsy will precede intralesional injection, RT, or epacadostat. Intralesional injections will be performed by palpation of the lesion or under ultrasound or CT guidance as indicated. CT response assessments and labs will be performed every 60 days. Patients will continue on epacadostat until progression.

Arms: arm 1: All patients will begin epacadostat on day 1 of radiotherapy, which will consist of three threatments over one week. Epacadostat will continue until disease progression or intolerance occurs. On days 1, 8, 15, 22, 29, intralesional injectinons of SD101 will be given to patients.
Interventions: intervention 1: epacadostat intervention 2: SD-101 intervention 3: Radiotherapy
Intervention descriptions: intervention 1: Epacadostat will be administered orally, in pill form, twice daily until disease progression. intervention 2: Four milligrams of SD-101 will be delivered into the treatment lesion by intralesional injection on days 1, 8, 15, 22, and 29. intervention 3: Radiotherapy will be delivered to the treatment lesion during the first week of ERS therapy.

Protocol documents:
Prot_SAP_000.pdf: 


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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 Si g nat ure  
 
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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  


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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  
 
 


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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  
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1 4 da y treat me nt was h o ut peri o d  
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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  
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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  
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A de q uate he mat ol o gic a n d e n d or ga n f u ncti o n  
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N o acti ve a ut oi m m u ne disease  
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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  


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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  


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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  


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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  


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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 
 
 
 
 


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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 . 


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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, 


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 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  
 
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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 


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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 


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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 


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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 


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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  
 


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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  
 
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 4 3  of 9 5  
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  
 
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 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  
 
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 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  
 
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 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  
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 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  
 
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 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  
 
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 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  
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 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  
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 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 


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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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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  
 
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 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  
 
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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  
 
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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  
 
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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 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  
 
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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  


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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  
 
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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


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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.