Conditions: Metastatic Castration-resistant Prostate Cancer
Keywords: Metastatic Castration-resistant Prostate Cancer Immunotherapy Platform study NKTR-214 Nivolumab CDX-301 Poly-ICLC INO-5151
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 43
Healthy volunteers: no

Brief summary:
This study is designed to evaluate multiple clinical hypotheses and mechanistically-defined combinations to evaluate the safety and efficacy of immunotherapy combinations in participants with mCRPC who have received prior secondary androgen receptor signaling inhibitor therapy (eg, abiraterone, enzalutamide, apalutamide).

Detailed description:
This is an open-label, non-randomized, exploratory platform protocol designed to assess the safety and antitumor activity of multiple immunotherapy combinations in participants with mCRPC who have received prior therapy. The platform study will consist of 2 stages: Stage 1, an initial stage to evaluate safety, biomarkers, and clinical activity of a combination and Stage 2, an expanded cohort, when warranted, based on the safety, clinical activity, and/or biomarker results from Stage 1. The Sponsor intends to modify and/or add new combinations to the protocol as data emerge from this and other trials.

Participants must provide consent for archival tissue from a prior biopsy or surgery for prostate cancer and must consent to baseline and on-treatment biopsies, if medically feasible. Participants will be assigned to receive one of the enrolling combination study interventions and will be monitored for safety and response.

Arms:
arm 1: None arm 2: None arm 3: None

Interventions: intervention 1: NKTR-214 (Cohort A) intervention 2: Nivolumab (Cohort A, B and C) intervention 3: Stereotactic body radiation therapy (SBRT) (Cohort B) intervention 4: CDX-301 (Cohort B and C) intervention 5: Poly-ICLC (Cohort B) intervention 6: INO-5151 (Cohort C) intervention 7: Cellectra 2000
Intervention descriptions: intervention 1: NKTR-214 will be administered intravenously every 3 weeks for up to 2 years intervention 2: Nivolumab will be administered intravenously every 3 weeks for up to 2 years to cohort A, every 4 weeks for up to 2 years for cohort B and C. intervention 3: Radiation therapy will be administered at 30 - 50 Gy in 1 - 5 doses, starting on Day 1 or 2 of Cycle 1 intervention 4: CDX-301 will be subcutaneously once a day for 5 days for cohort B. CDX-301 will be subcutaneously once a day for 10 days of immune-priming lead-in for cohort C. intervention 5: Poly-ICLC will be administered intramuscularly twice weekly for 3 weeks starting on Day 1 of Cycle 1 intervention 6: INO-5151 will be administered intramuscularly on Day 8 of the Immune-priming Lead-in, and on day 1 of Cycle 1, 2 and 3, then every 12 weeks thereafter intervention 7: Electroporation device

Protocol document:
SAP_004.pdf: 
 
1 
 
 
 
St atistic al A n al ysis Pl a n f or 
Pr ot oc ol N u m ber:  PI CI 0 0 3 3 
 
Pr ot oc ol Title:  A M ultice nter, O pe n- L a bel, E x pl or at or y Pl atf or m St u d y t o 
E v al u ate Bi o m ar kers a n d I m m u n ot her a p y C o m bi n ati o ns f or t he Tre at me nt 
of P atie nts wit h Met ast atic C astr ati o n-resist a nt Pr o st ate C a ncer 
 
I N D N u m ber:  
1 3 9 2 6 9 
S p o ns or:  
Par ker I nstit ute f or Ca ncer I m m u n ot hera p y 
1 Letter ma n Dri ve 
S uite D 3 5 0 0 
Sa n Fra ncisc o, C A 9 4 1 2 9 
D ate Fi n al:  
2 9 Ja n uar y 2 0 2 1 
 
 
 
 
 
 
 
 
 
 
- C O N FI D E N TI A L- 
T his d oc u me nt a n d its c o nte nts are t he pr o pert y of a n d c o nfi d e ntial t o Par ker I nstit ute f or 
Ca ncer I m m u n ot hera p y.  A n y u na ut h orize d c o p yi n g or use of t his  d oc u me nt is pr o hi bite d. 


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S P O N S O R A P P R O V A L P A G E 
 
 
 
Date:  
 
C hrist o p her Ca ba ns ki, P h D 
Direct or, Bi ostatistics 
 
 
 
 
 
 
 
Date:  
 
J usti n Fairc hil d, M P H  
Vice Presi de nt, Cli nical De vel o p me nt 
 
 
 
 
 
 
1 / 2 9 / 2 0 2 1  |  1 0 : 4 7 : 0 8  A M  P S T
1 / 2 9 / 2 0 2 1  |  1 1 : 0 4 : 3 6  A M  P S T


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1  
T A B L E O F C O N T E N T S 
1  
T A B L E O F C O N T E N T S ................................................................................................ 3  
List of T A B L E S ..................................................................................................... 4  
List of FI G U R E S .................................................................................................... 4  
2  
I N T R O D U C TI O N ........................................................................................................... 5 
3  
S T U D Y D E SI G N ............................................................................................................ 5  
3. 1  
Pr ot oc ol S y n o psis ................................................................................................. 6  
3. 2  
St u d y O bjecti ves a n d E n d p oi nts ........................................................................... 6  
3. 3  
Deter mi nati o n of Sa m ple Size .............................................................................. 8  
3. 4  
A nal ysis Ti mi n g .................................................................................................... 9  
4  
S T U D Y C O N D U C T ...................................................................................................... 1 0  
4. 1  
Ra n d o mizati o n Details ........................................................................................ 1 0  
4. 2  
Bli n di n g .............................................................................................................. 1 0  
4. 3  
Data M o nit ori n g .................................................................................................. 1 0  
5  
S T A TI S TI C A L A N A L Y S E S ........................................................................................ 1 1  
5. 1  
P o p ulati o ns f or A nal ysis ..................................................................................... 1 1  
5. 1. 1  
E val ua ble P o p ulati o n ........................................................................... 1 1  
5. 2  
A nal ysis of St u d y C o n d uct ................................................................................. 1 1  
5. 3  
A nal ysis of Baseli ne C haracteristics ................................................................... 1 1  
5. 4  
Efficac y A nal ysis ................................................................................................ 1 2  
5. 4. 1  
Pri mar y Efficac y E n d p oi nt .................................................................. 1 2  
5. 4. 2  
Sec o n dar y Efficac y E n d p oi nts ............................................................. 1 2  
5. 4. 2. 1  C o m p osite Res p o nse Rate ..................................................... 1 3  
5. 4. 2. 2  Disease C o ntr ol Rate ............................................................. 1 3  
5. 4. 2. 3  Ra di o gra p hic Pr o gressi o n- Free S ur vi val .............................. 1 4  
5. 4. 2. 4  O verall S ur vi val .................................................................... 1 5  
5. 4. 3  
E x pl orat or y Efficac y E n d p oi nts ........................................................... 1 5  
5. 4. 3. 1  Bi o mar ker A nal ysis .............................................................. 1 5  
5. 4. 3. 2  Circ ulati n g T u m or Cell A nal ysis .......................................... 1 5  
5. 4. 3. 3  Pr ostate-s pecific A nti ge n A nal ysis ....................................... 1 5  
5. 4. 3. 4  D urati o n of Res p o nse ............................................................ 1 6  
5. 4. 3. 5  P har mac o ki netic A nal ysis ..................................................... 1 6  
5. 4. 3. 6  A nti- Dr u g A nti b o d y A nal ysis ............................................... 1 7  
5. 5  
Safet y A nal ysis ................................................................................................... 1 7  
5. 5. 1  
E x p os ure t o St u d y Me dicati o n ............................................................. 1 7  


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5. 5. 2  
A d verse E ve nts .................................................................................... 1 7  
5. 5. 3  
La b orat or y Data ................................................................................... 1 8  
5. 5. 4  
Vital Si g ns ............................................................................................ 1 8  
5. 5. 5  
P h ysical E xa mi nati o ns ......................................................................... 1 8  
5. 6  
Missi n g Data ....................................................................................................... 1 8  
5. 6. 1  
Missi n g a n d Partial Missi n g A d verse E ve nt Dates .............................. 1 8  
5. 6. 2  
Missi n g a n d Partial Missi n g Deat h Dates ............................................ 1 8  
5. 7  
I nteri m A nal yses ................................................................................................. 1 9 
5. 7. 1  
C o h ort E x pa nsi o n R ules ...................................................................... 1 9  
6  
DI F F E R E N C E S C O M P A R E D T O P R O T O C O L ......................................................... 2 0  
7  
R E F E R E N C E S .............................................................................................................. 2 2  
8  
A P P E N DI C E S ............................................................................................................... 2 3  
8. 1  
C ore Pr ot oc ol S y n o psis ( Pr ot oc ol A me n d me nt 2; 3 0 A pril 2 0 1 9) ..................... 2 3  
 
LI S T O F T A B L E S 
Ta ble 1:  O bjecti ves a n d C orres p o n di n g E n d p oi nts ................................................................. 6  
Ta ble 2:  C o nfi de nce I nter vals f or t he Tr ue Pr o p orti o n of A d verse E ve nts ............................. 9  
Ta ble 3:  P o p ulati o ns f or Efficac y A nal ysis ........................................................................... 1 2  
 
LI S T O F FI G U R E S 
Fi g ure 1:  St u d y Sc he ma ............................................................................................................ 6  
 


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2  
I N T R O D U C TI O N 
T he p ur p ose of t his d oc u me nt is t o pr o vi de details of t he pla n ne d a nal yses f or PI CI 0 0 3 3. T he 
a nal yses  s pecifie d  i n  t his  d oc u me nt  s u perse de  t he  hi g h-le vel  a nal ysis  pla n  descri be d  i n  t he 
pr ot oc ol  a n d  its  a p pe n dices.  Statistical  a nal yses  will  be  perf or me d  c o nsiste nt  wit h  t he 
pri nci ples of t he I C H/ F D A G ui da nce f or I n d ustr y E 9 Statistic al Pri nci ples f or Cli nical Trials. 
3  
S T U D Y D E SI G N 
PI CI 0 0 3 3 is a n o pe n-la bel, n o n-ra n d o mize d, e x pl orat or y platf or m pr ot oc ol desi g ne d t o assess 
t he safet y a n d a ntit u m or acti vit y of m ulti ple i m m u n ot hera p y c o m bi nati o ns i n partici pa nts wit h 
metastatic castrati o n-resista nt pr ostate ca ncer ( m C R P C) w h o ha ve recei ve d pri or t hera p y. Eac h 
c o h ort of t he platf or m st u d y will c o nsist of u p t o 2 sta ges: Sta ge 1, a n i nitial sta ge t o e val uate 
safet y, bi o mar kers, a n d cli nical acti vit y of a c o m bi nati o n a n d Sta ge 2, a n e x pa n de d c o h ort, 
w he n warra nte d, base d o n t he safet y, cli nical acti vit y, a n d/ or bi o mar ker res ults fr o m Sta ge 1. 
T he S p o ns or i nte n ds t o m o dif y a n d/ or a d d ne w c o m bi nati o ns t o t he pr ot oc ol as data e mer ge 
fr o m t his a n d ot her trials. 
T his is n ot a ra n d o mize d st u d y. Assi g n me nt t o o ne of t he i m m u n ot hera p y c o m bi nati o ns will 
be ma de b y t he I n vesti gat or usi n g his/ her best cli nical discreti o n base d o n t he partici pa nt’s 
me dical hist or y a n d disease stat us a n d k n o wle d ge of t he a vaila ble i m m u n ot hera p y c o m bi nati o n 
c o h orts o pe n f or e nr oll me nt. T he d ose a n d sc he d ule selecte d will be descri be d i n t he pr ot oc ol 
c o h ort a p pe n di x f or eac h res pecti ve c o m bi nati o n (e g, A p pe n di x C o h ort A, A p pe n di x C o h ort 
B, etc.). T he d urati o n of i m m u n ot hera p y c o m bi nati o n st u d y i nter ve nti o n will be de pe n de nt o n 
t he c o m bi nati o n a d mi nistere d. Partici pa nts will be f oll o we d f or u p t o 2. 5 years fr o m t he ti me 
of t he i nitiati o n of st u d y i nter ve nti o n.  
T he st u d y is n ot i nte n de d or p o were d f or h y p ot hesis testi n g or c o m paris o n bet wee n c o h orts. 
T he st u d y is i nte n de d t o pr o vi de preli mi nar y esti mates of a d verse e ve nt ( A E) rates, res p o nse 
rates,  effect  sizes,  a n d  c o nfi de nce  i nter vals  ( CIs)  t o  ai d  t he  desi g n  of  later  st u dies. 
A p pr o xi matel y 1 5 partici pa nts, i ncl u di n g a mi ni m u m of 7 wit h a n o n- b o ne metastatic lesi o n 
t hat ca n be bi o psie d, will be e nr olle d i n eac h i m m u n ot hera p y c o m bi nati o n c o h ort i n Sta ge 1. 
A n  a d diti o nal  a p pr o xi matel y  1 5  partici pa nts,  i ncl u di n g  a  mi ni m u m  of  7  wit h  a  n o n- b o ne 
metastatic lesi o n, will be e nr olle d i n Sta ge 2 if t he c o h ort is e x pa n de d. 
T he ge neral st u d y sc he ma is de picte d i n Fi g ure 1. 


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Fi g ure 1:  
St u d y Sc he m a 
 
3. 1  
Pr ot oc ol S y n o psis 
D ue t o t he platf or m desi g n of t his trial, t here are m ulti ple pr ot oc ol le vels. T he C ore Pr ot oc ol 
c o ntai ns i nf or mati o n o n st u d y c o n d uct t hat is u nif or m acr oss all c o h orts. Eac h c o h ort has a 
u ni q ue pr ot oc ol a p pe n di x t hat descri bes st u d y c o n d uct a n d pr oce d ures t hat are u ni q ue t o t hat 
partic ular  i m m u n ot hera p y  c o m bi nati o n.  T he  C ore  Pr ot oc ol  a n d  c o h ort-s pecific  a p pe n di x 
s h o ul d be use d i n c o nj u ncti o n wit h eac h ot her. 
T he C ore Pr ot oc ol S y n o psis is i ncl u de d i n Secti o n 8. 1.  
3. 2  
St u d y O bjecti ves a n d E n d p oi nts 
T he st u d y o bjecti ves a n d e n d p oi nts f or t he C ore Pr ot oc ol are liste d i n Ta ble 1. A n y c o h ort-
s pecific e n d p oi nts will be ca pt ure d i n a n a p pe n di x t o t his S A P. 
T a ble 1:  
O bjecti ves a n d C orres p o n di n g E n d p oi nts 
O bjecti ves  
E n d p oi nts  
Pri mar y  
 
•  T o deter mi ne t he safet y of eac h i m m u n ot hera p y 
c o m bi nati o n i n partici pa nts wit h m C R P C.  
•  I nci de nce a n d se verit y of A Es . 
Sec o n dar y  
 
•  T o deter mi ne t he C R R of eac h i m m u n ot hera p y 
c o m bi nati o n i n partici pa nts wit h meas ura ble 
m C R P C.  
•  C o m p osite  Res p o nse Rate ( C R R) : A c o m p osite 
e n d p oi nt w here res p o nse is defi ne d as a 
partici pa nt meeti n g at least o ne of t he f oll o wi n g:  


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•  T o deter mi ne  t he D C R of eac h i m m u n ot hera p y 
c o m bi nati o n i n partici pa nts wit h meas ura ble 
m C R P C.  
•  T o e val uate t he r P F S of eac h i m m u n ot hera p y 
c o m bi nati o n i n partici pa nts wit h m C R P C.  
•  T o esti mate t he O S of eac h i m m u n ot hera p y 
c o m bi nati o n i n partici pa nts wit h m C R P C.  
o  C T C res p o nse: C ha n ge fr o m u nfa v ora ble ( ≥ 5 
cells/ 7. 5 m L of bl o o d) t o fa v ora ble ( ≤ 4 
cells/ 7. 5 m L of bl o o d). Partici pa nts wit h a 
base li ne C T C val ue < 5 cells/ 7. 5 m L of bl o o d 
will n ot be e val uate d f or t his criteri o n.  
o  P S A res p o nse: C o nfir me d P S A res p o nse is 
d efi ne d as ≥ 5 0 % re d ucti o n i n P S A fr o m 
baseli ne, wit h a re peat assess me nt c o nfir mi n g 
t he res ult at least 3 wee ks later. Partici pa nts 
wit h o ut a  baseli ne P S A assess me nt  will n ot be 
e val uate d f or t his  criteri o n. 
o  O bjecti ve res p o nse rate ( O R R): C o nfir me d 
res p o nse of C R or P R b y o bjecti ve ra di o gra p hic 
disease assess me nt usi n g P C W G 3 -m o difie d 
R E CI S T versi o n 1. 1 (ie, C R or P R a n d n o 
pr o gressi o n i n b o ne per t he P C W G 3;  Sc her et 
al., 2 0 1 6). Per R E CI S T, t o be assi g ne d a best 
o verall res p o nse of C R or P R, c ha n ges i n t u m or  
meas ure me nts m ust be c o nfir me d b y re peat 
ra di o gra p hic 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 he 
criteria f or res p o nse are first met. Partici pa nts 
wit h meas ura ble disease  at baseli ne w h o 
recei ve d at least 1 d ose of a n y c o m p o ne nt o f 
t he c o m bi nati o n st u d y i nter ve nti o n b ut d o n ot 
ha ve ra di o gra p hic disease assess me nt s f or a n y 
reas o n will be c o u nte d as n ot res p o n di n g. 
Partici pa nts wit h o ut meas ura ble disease at 
baseli ne will n ot be e val uate d f or t his criteri o n.  
•  D C R: Defi ne d as t he pr o p orti o n of partici pa nts 
wit h C R, P R, or S D f or  6 m o nt hs as best res p o nse 
b y P C W G 3 -m o difie d R E CI S T v 1. 1. Partici pa nts 
wit h meas ura ble disease at baseli ne w h o recei ve d 
at least 1 d ose of a n y c o m p o ne nt of t he st u d y 
i nter ve nti o n c o m bi nati o n b ut d o n ot ha ve R E CI S T 
assess me nt f or a n y reas o n will be c o u nte d as n ot 
res p o n di n g. Partici pa nts wit h o ut meas ura ble 
disease at baseli ne will n ot be e val uate d f or t his 
e n d p oi nt.  
•  r P F S: Defi ne d as t he ti me fr o m i nitiati o n of st u d y 
i nter ve nti o n t o t he first o bjecti ve e vi de nce of 
ra di o gra p hic pr o gressi o n per P C W G 3 -m o difie d 
R E CI S T v 1. 1 or deat h d ue t o a n y ca use 
( w hic he ver occ urs first). 
•  O S: Defi ne d as t he ti me fr o m i nitiati o n of st u d y 
i n ve nti o n u ntil deat h d ue t o a n y ca use. 
•  O S rate at 1 2 m o nt hs.  


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E x pl orat or y  
 
•  T o e val uate t u m or a n d i m m u ne bi o mar kers a n d 
t heir ass ociati o n wit h treat me nt o utc o me 
(a ntit u m or acti vit y a n d/ or safet y). 
•  T o esti mate t he ra di o gra p hic D O R of eac h 
i m m u n ot hera p y c o m bi nati o n i n partici pa nts wit h 
m C R P C.  
•  T o e val uate t he P K of t he c o m p o ne nts of t he 
i m m u n ot hera p y c o m binati o n . 
•  T o e val uate t he i m m u n o ge nicit y of t he 
c o m p o ne nts of t he i m m u n ot hera p y c o m bi nati o n. 
•  Ass ociati o n of t u m or a n d i m m u ne bi o mar kers 
fr o m tiss ue, bl o o d, a n d/ or st o ol wit h cli nical 
o utc o mes, i ncl u di n g O R R, D C R, r P F S, a n d 
t olera bilit y. Bi o mar kers t o be st u die d will be 
c h ose n base d o n t he i m m u n ot hera p y c o m bi nati o n.  
•  M olec ular c haracterizati o n of C T C a n d e val uati o n 
of perce nt c ha n ge fr o m baseli ne.  
•  E n u merati o n of C T C  ≥ 1 at baseli ne wit h 
c o n versi o n t o C T C 0 o n treat me nt. 
•  P S A:  
o  Perce nt c ha n ge i n P S A fr o m baseli ne a t 1 2 
wee ks.  
o  Ma xi m u m c ha n ge i n P S A at a n y p oi nt after 
i nitiati o n of st u d y i nter ve nti o n. 
o  Ti me t o P S A pr o gressi o n , defi ne d as t he ti me 
fr o m st u d y treat me nt i nitiati o n t o t he date t hat a 
≥ 2 5 % i ncrease a n d a bs ol ute i ncrease of ≥ 2 
n g/ m L a b o ve t he na dir ( or bas eli ne val ue f or 
partici pa nts w h o di d n ot ha ve a decli ne i n P S A) 
i n P S A. T he i ncrease m ust be c o nfir me d b y a 
seco n d c o nsec uti ve assess me nt c o n d ucte d at 
least 3 wee ks later. 
•  D O R : Defi ne d as ti me fr o m t he first t u m or 
assess me nt t hat d oc u me nts ra di o gra p hic res p o nse 
( C R or P R) t o t he first d oc u me ntati o n of 
ra di o gra p hic pr o gressi o n per P C W G 3-m o difie d 
R E CI S T v 1. 1  or deat h  d ue t o a n y ca use 
(w hic he ver occ urs first ). 
•  S parse P K a nal ysis.  
•  Prese nce of A D A a gai nst bi ol o gic c o m p o ne nts of 
eac h i m m u n ot hera p y c o m bi nati o n.  
A D A = a nti -dr u g a nti b o dies; A E = a d verse e ve nt(s); C R = c o m plete res p o nse; C R R = c o m p osite res p o nse rate; 
C T C = circ ulati n g t u m or cells; C T C 0  = a meas ure of zer o C T C; D C R = disease c o ntr ol rate; D O R = d urati o n of 
res p o nse; m C R P C = metastatic castrati o n -resista nt pr ostate ca ncer; O R R = o bjecti ve res p o nse rate; O S = 
o verall s ur vi val; P C W G 3 = Pr ostate Ca ncer Cli nical Trials W or ki n g Gr o u p 3; P K = p har mac o ki netics; P R = 
partial res p o nse; P S A  = pr ostate -s pecific a nti ge n; R E CI S T = Res p o nse E val uati o n Criteria i n So li d T u m ors; 
r P F S = ra di o gra p hic pr o gressi o n-free s ur vi val; S D = sta ble disease 
 
3. 3  
Deter mi n ati o n of S a m ple Size 
T he st u d y is n ot i nte n de d or p o were d f or h y p ot hesis testi n g or c o m paris o n bet wee n c o h orts. 
T he st u d y is i nte n de d t o pr o vi de preli mi nar y esti mates of A E rates, res p o nse rates, effect sizes 
a n d CIs t o ai d t he desi g n of later st u dies. A sa m ple size of a p pr o xi matel y 1 5 partici pa nts per 
i m m u n ot hera p y  c o m bi nati o n  c o h ort  will  pr o vi de  t hese  preli mi nar y  esti mates  w hile  li miti n g 
e x p os ure. 
 


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Ta ble 2   pr o vi des  9 5 %  e xact  c o nfi de nce  i nter vals  f or  t he  pr o p orti o n  of  partici pa nts 
e x perie nci n g  a  s pecific A E   f or  sa m ple  sizes  of  1 5  a n d  3 0  partici pa nts  per  c o h ort.  T hese 
c o nfi de nce i nter vals, al o n g wit h t he C R R ( descri be d bel o w), pr o vi de i nf or mati o n nee de d t o 
assess t he ris k- be nefit rati o of t he i m m u n ot hera p y c o m bi nati o n f or e x pa n di n g t he c o h ort t o 
Sta ge 2 a n d f or t he desi g n of f urt her st u dies. 
 
T a ble 2:  
C o nfi de nce I nter v als f or t he Tr ue Pr o p orti o n of A d verse E ve nts 
O bser ve d A E r ate  
9 5 % C o nfi de nce I nter v al  
( n = 1 5) 
9 5 % C o nfi de nce I nter v al  
( n = 3 0) 
6. 7 % ( 1/ 1 5 or 2/ 3 0)  
(0. 2 %, 3 1. 9 %)  
( 0. 8 %, 2 2. 1 %) 
1 3. 3 % ( 2/ 1 5 or 4/ 3 0)  
( 1. 7 %, 4 0. 5 %) 
( 3. 8 %, 3 0. 7 %) 
2 0. 0 % ( 3/ 1 5 or 6/ 3 0)  
( 4. 3 %, 4 8. 1 %) 
( 7. 7 %, 3 8. 6 %) 
2 6. 7 % ( 4/ 1 5 or 8/ 3 0)  
( 7. 8 %, 5 5. 1 %)  
( 1 2. 3 %, 4 5. 9 %) 
3 3. 3 % ( 5/ 1 5 or 1 0/ 3 0)  
( 1 1. 8 %, 6 1. 6 %) 
( 1 7. 3 %, 5 2. 8 %) 
4 0. 0 % ( 6/ 1 5 or 1 2/ 3 0)  
( 1 6. 3 %, 6 7. 7 %) 
( 2 2. 7 %, 5 9. 4 %) 
A E = a d verse e ve nt  
 
A Si m o n t w o-sta ge mi ni ma x desi g n ( Si m o n, 1 9 8 9) will be i m ple me nte d f or eac h c o h ort. A 
C R R of at least 2 5 % w o ul d pr o vi de s ufficie nt e vi de nce of cli nical acti vit y t o warra nt f urt her 
i n vesti gati o n, w hile a C R R of 1 0 % w o ul d n ot be of i nterest. I n Sta ge 1, 1 5 partici pa nts will be 
e nr olle d.  If  t he  safet y  pr ofile  is  acce pta ble  a n d  t here  are  2  or  m ore  res p o nses  i n  t hese  1 5 
partici pa nts, 1 5 a d diti o nal partici pa nts ma y  be e nr olle d i n Sta ge 2 f or a t otal of 3 0 partici pa nts 
i n t he c o h ort. If t here are 6 or m ore res p o nses i n t hese 3 0 partici pa nts, t he n t he i m m u n ot hera p y 
c o m bi nati o n  will  be  c o nsi dere d  w ort h y  of  f urt her  i n vesti gati o n. T his  desi g n  yiel ds  a  t y pe  I 
err or rate of 0. 0 7 a n d 7 7 % p o wer w he n t he n ull h y p ot hesis ass u mes t he C R R is 1 0 % a n d t he 
alter nati ve h y p ot hesis ass u mes t he C R R is 2 5 %. U n der t he n ull h y p ot hesis, t he pr o ba bilit y of 
ter mi nati n g a c o h ort after Sta ge 1 is 5 5 %.  
3. 4  
A n al ysis Ti mi n g 
T he pri mar y a nal yses descri be d i n t he mai n b o d y of t his d oc u me nt will be perf or me d f or eac h 
i m m u n ot hera p y c o m bi nati o n c o h ort se paratel y after all partici pa nts f or a s pecific c o h ort ha ve 
at least 6 m o nt hs of f oll o w- u p fr o m t he date of first d ose or ha ve disc o nti n ue d t he st u d y. Eac h 
c o h ort will be assesse d i n de pe n de ntl y of t he ot her c o h orts, a n d t he data fr o m eac h c o h ort will 
be a nal yze d se paratel y. St u d y c o n d uct of o ne or m ore c o h orts ma y be o n g oi n g at t he ti me of 
fi nal a nal ysis f or a gi ve n c o h ort. 
A n y c o h ort-s pecific m o dificati o ns t o t he statistical met h o ds, i ncl u di n g a n y a d diti o nal c o h ort-
s pecific e n d p oi nts, will be ca pt ure d as a n a p pe n di x i n t his S A P.  


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A nal ysis  of  safet y  a n d  efficac y  e n d p oi nts  will  be  perf or me d  pri or  t o  t he  ti me  of  pri mar y 
a nal ysis. T hese a nal yses will hel p i nf or m a da ptati o ns of t he trial, s uc h as e x pa n di n g, m o dif yi n g, 
or ter mi nati n g a c o h ort. M ore i nf or mati o n a b o ut t hese i nteri m a nal yses is prese nte d i n Secti o n 
5. 7. T hese res ults ma y be prese nte d a n d/ or p u blis he d pri or t o t he pri mar y a nal ysis . 
A c o h ort will f or mall y e n d o nce all partici pa nts ha ve bee n f oll o we d f or s ur vi val stat us f or a 
ma xi m u m of 2. 5 years or u ntil deat h, wit h dra wal of c o nse nt, or l oss t o f oll o w- u p. T he S p o ns or 
ma y  c h o ose t o disc o nti n ue s ur vi val f oll o w- u p of a c o h ort at a n y ti me. A s ur vi val a nal ysis of 
l o n g-ter m f oll o w-u p ma y be perf or me d after t he pri mar y a nal ysis has bee n c o m plet e d.   
4  
S T U D Y C O N D U C T  
4. 1  
R a n d o miz ati o n Det ails 
T his is a n o n-ra n d o mize d st u d y. Assi g n me nt t o o ne of t he i m m u n ot hera p y c o m bi nati o ns will 
be ma de b y t he I n vesti gat or usi n g his/ her best cli nical discreti o n base d o n t he partici pa nt’s 
me dical hist or y a n d disease stat us a n d k n o wle d ge of t he a vaila ble i m m u n ot hera p y c o m bi nati o n 
c o h orts o pe n f or e nr oll me nt. 
4. 2  
Bli n di n g 
T his is a n o pe n-la bel st u d y wit h n o bli n di n g. 
4. 3  
D at a M o nit ori n g 
T o e ns ure caref ul re vie w of t he acc u m ulati n g safet y data f or t he PI CI 0 0 3 3 platf or m st u d y, a 
Safet y Assess me nt C o m mittee ( S A C) will be esta blis he d. 
O n g oi n g safet y data re vie w will be c o n d ucte d b y t he S A C f or all c o h orts. T he PI CI 0 0 3 3 S A C 
will  ha ve  a  c ore  me m bers hi p  ma de  u p  of  ge nit o uri nar y  ( G U)  o nc ol o gists  a n d  i m m u n o-
o nc ol o gists  a n d  s u bject  matter  e x pert(s)  as  a p pr o priate  f or  a  s pecific  c o h ort  ( e g,  vacci ne 
e xpertise). Select S p o ns or pers o n nel, i ncl u di n g t he Me dical M o nit or a n d re prese ntati ves fr o m 
ot her  f u ncti o ns  i ncl u di n g,  b ut  n ot  li mite d  t o,  Bi ostatistics,  Cli nical  Scie nce,  a n d 
P har mac o vi gila nce, will be res p o nsi ble f or pr o d uci n g o ut p ut f or re vie w a n d i nf or mi n g t he S A C 
of a n y maj or safet y si g nals i n a ti mel y ma n ner. 
T o  e ns ure  partici pa nts’  safet y  d uri n g  t he  st u d y,  t he  S A C  will  meet  a p pr o xi matel y  e ver y  3 
m o nt hs t o assess t he t otalit y of safet y i nf or mati o n i n t he cli nical st u d y acr oss all c o h orts. I n 
a d diti o n, t he S A C or t he S p o ns or ma y re q uest a d h oc re vie ws at a n y ti me t o a d dress p ote ntial 
safet y c o ncer ns.  
Safet y  m o nit ori n g  b y  t he  S A C  will  i ncl u de  u n bli n de d  e val uati o n  of  all  A Es,  S A Es,  a n d 
la b orat or y  data.  If  t he  S A C  dee ms  a  be nefit-ris k  assess me nt  necessar y,  t he  S A C  ma y  als o 


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re vie w efficac y data. T he S A C ma y rec o m me n d ter mi nati n g a c o h ort or s us pe n di n g e nr oll me nt 
f or safet y reas o ns. R oles a n d res p o nsi bilities of t he S A C are detaile d i n a se parate c harter. 
5  
S T A TI S TI C A L A N A L Y S E S 
T he data fr o m eac h c o h ort will be a nal yze d i n de pe n de ntl y of t he ot her c o h orts. St u d y 
c o n d uct of o ne or m ore c o h orts ma y be o n g oi n g at t he ti me of fi nal a nal ysis f or a gi ve n 
c o h ort. 
S u m mar y statistics will be prese nte d b y c o h ort. Cate g orical varia bles will be s u m marize d 
usi n g fre q ue ncies a n d perce nta ges. C o nti n u o us varia bles will be s u m marize d usi n g mea ns, 
sta n dar d de viati o ns, me dia ns, i nter q uartile ra n ges, mi ni m u ms, a n d ma xi m u ms. 
5. 1  
P o p ul ati o ns f or A n al ysis 
5. 1. 1  E v al u a ble P o p ul ati o n 
T he e val ua ble p o p ulati o n will ser ve as t he pri mar y p o p ulati o n f or t he a nal ysis of safet y a n d 
efficac y data i n t his st u d y. T he e val ua ble p o p ulati o n c o nsists of all partici pa nts i n a c o h ort w h o 
recei ve d at least 1 d ose of a n y c o m p o ne nt of t he c o m bi nati o n st u d y i nter ve nti o n. Partici pa nts 
wil l be gr o u pe d acc or di n g t o t he c o h ort i nt o w hic h t he y were e nr olle d a n d d ose d. 
Efficac y  a nal yses  ma y  be  perf or me d  o n  a  s u bset  of  t he  e val ua ble  p o p ulati o n,  s uc h  as 
partici pa nts wit h meas ura ble disease at baseli ne or partici pa nts wit h a baseli ne C T C val ue ≥ 5  
cells/ 7. 5  m L  of  bl o o d.  T he  s pecific  a nal ysis  p o p ulati o n  use d  f or  eac h  efficac y  a nal ysis is 
f urt her detaile d i n Secti o n 5. 4. 
5. 2  
A n al ysis of St u d y C o n d uct 
T he  n u m ber  of  partici pa nts  w h o  were  e nr olle d  a n d  treate d,  e nr olle d  a n d  n ot  treate d,  a n d 
c o m plete d t he treat me nt peri o d will be prese nte d i n s u m mar y ta bles b y c o h ort. T he reas o n f or 
treat me nt  disc o nti n uati o n  a n d  st u d y  disc o nti n uati o n  will  be  liste d  b y  partici pa nt  a n d 
s u m marize d i n a ta ble.  
5. 3  
A n al ysis of B aseli ne C h ar acteristics 
De m o gra p hic a n d baseli ne c haracteristics of t he st u d y p o p ulati o n will be s u m marize d f or eac h 
c o h ort. Varia bles t o be s u m marize d i ncl u de, b ut are n ot li mite d t o, a ge, se x, race, et h nicit y, 
Easter n  C o o perati ve  O nc ol o g y  Gr o u p  ( E C O G)  perf or ma nce  stat us,  ca ncer  sta ge  at  i nitial 
dia g n osis a n d e nr oll me nt, Gleas o n sc ore, a n d P S A.  
T he baseli ne val ue of a n y varia ble will be defi ne d as t he last a vaila ble val ue rec or de d pri or t o 
t he first a d mi nistrati o n of st u d y i nter ve nti o n.  


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5. 4  
Effic ac y A n al ysis  
T he a nal yses f or cli nical acti vit y will be perf or me d o n t he e val ua ble p o p ulati o n, c o nsisti n g of 
all partici pa nts i n a c o h ort w h o recei ve d at least 1 d ose of a n y c o m p o ne nt of t he c o m bi nati o n 
st u d y  i nter ve nti o n.  S o me  efficac y  e n d p oi nts  ma y  be  a nal yze d  o n  a  s u bset  of  t he  e val ua ble 
p o p ulati o n, as s u m marize d i n Ta ble 3. 
T his st u d y is n ot i nte n de d or p o were d f or h y p ot hesis testi n g or c o m paris o n bet wee n c o h orts. 
D ue t o t he e x pl orat or y nat ure of t his st u d y, n o c o ntr ol of t y pe I err or will be a p plie d f or a n y of 
t he e n d p oi nts. 
 
T a ble 3:  
P o p ul ati o ns f or Effic ac y A n al y sis 
E n d p oi nt  
A n al ysis P o p ul ati o n  
C R R  
E val ua ble p o p ulati o n  
C T C res p o nse (c o m p o ne nt of C R R)  
Partici pa nts wit h a baseli ne C T C val ue ≥ 5 cells/ 7. 5 m L of bl o o d  
P S A res p o nse (c o m p o ne nt of C R R)  
Partici pa nts wit h a P S A val ue at bas eli ne 
O R R (c o m p o ne nt of C R R) 
Partici pa nts wit h meas ura ble disease at baseli ne per P C W G 3 -
m o difie d R E CI S T v 1. 1  
D C R  
E val ua ble p o p ulati o n  
r P F S 
E val ua ble p o p ulati o n  
O S  
E val ua ble p o p ulati o n  
C ha n ge i n C T C fr o m baseli ne  
Partici pa nts wit h a C T C val ue at baseli ne  
C T C 0  
Partici pa nts wit h a baseli ne C T C val ue ≥ 1 cell/ 7. 5 m L of bl o o d  
Perce nt c ha n ge i n P S A fr o m baseli ne  
Partici pa nts wit h a P S A val ue at baseli ne  
Ti me t o P S A pr o gressi o n  
Partici pa nts wit h a P S A val ue at baseli ne  
D O R  
Partici pa nts wit h meas ura ble disease at baseli ne per P C W G 3 -
m o difie d R E CI S T v 1. 1 a n d a best o verall res p o nse of C R or P R  
C R = c o m plete res p o nse; C R R = c o m p osite res p o nse rate; C T C = circ ulati n g t u m or cells;  C T C 0  = a meas ure of 
zer o C T C; D C R = disease c o ntr ol rate; D O R = d urati o n of res p o nse; O R R = o bjecti ve res p o nse rate; O S = o ver all 
s ur vi val; P C W G 3 = Pr ostate Ca ncer Cli nical Trials W or ki n g Gr o u p 3; P R = partial res p o nse; P S A  = pr ostate -
s pecific a nti ge n; R ECI S T = Res p o nse E val uati o n Criteria i n S oli d T u m ors; r P F S = ra di o gra p hic pr o gressi o n -free 
s ur vi val 
 
5. 4. 1  Pri m ar y Effic ac y E n d p oi nt 
T here are n o pri mar y efficac y o bjecti ves or e n d p oi nts f or t his s t u d y. 
5. 4. 2  Sec o n d ar y Effic ac y E n d p oi nts 
Sec o n dar y efficac y e n d p oi nts i ncl u de C R R, O R R, D C R, r P F S, a n d O S. 


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5. 4. 2. 1  C o m p osite Res p o nse Rate 
C R R is a c o m p osite e n d p oi nt w here res p o nse is defi ne d as a partici pa nt meeti n g at least o ne 
of t he f oll o wi n g: 
•  C T C res p o nse: C ha n ge fr o m u nfa v ora ble ( ≥ 5 cells/ 7. 5 m L of bl o o d) t o fa v ora ble ( ≤ 4 
cells/ 7. 5 m L of bl o o d). Partici pa nts wit h a missi n g baseli ne C T C val ue or baseli ne C T C 
val ue < 5 cells/ 7. 5 m L of bl o o d will n ot be e val uate d f or t his criteri o n. T he baseli n e 
C T C val ue is defi ne d as t he last a vaila ble val ue rec or de d pri or t o t he first a d mi nistrati o n 
of st u d y i nter ve nti o n. 
•  P S A res p o nse: C o nfir me d P S A res p o nse is defi ne d as ≥ 5 0 % re d ucti o n i n P S A fr o m 
baseli ne,  wit h  a  re peat  assess me nt  c o nfir mi n g  t he  res ult  at  least  3  wee ks  later. 
Partici pa nts wit h o ut a P S A val ue at baseli ne will n ot be e val ua ble f or t his criteri o n. T he 
baseli ne P S A  val ue is  defi ne d  as  t he  last  a vaila ble  val ue  rec or de d  pri or  t o  t he  first 
a d mi nistrati o n of st u d y i nter ve nti o n. 
•  O bjecti ve  ra di o gra p h ic res p o nse  ( O R R): Best  o verall  res p o nse  of  C R  or  P R  b y 
o bjecti ve  ra di o gra p hic  disease  assess me nt  of  s oft-tiss ue,  n o n- b o ne  lesi o ns, as 
deter mi ne d b y P C W G 3- m o difie d R E CI S T versi o n 1. 1. Per R E CI S T, t o be assi g ne d a 
best o verall res p o nse of C R or P R, c ha n ges i n t u m or meas ure me nts m ust be c o nfir me d 
b y a re peat ra di o gra p hic assess me nt perf or me d n o less t ha n 4 wee ks after t he criteria 
f or i nitial ra di o gra p hic res p o nse we re first met. I n a d diti o n, res p o n ders m ust n ot ha ve 
b o ne lesi o ns t hat ha ve pr o gresse d, as deter mi ne d b y P C W G 3 criteria. Partici pa nts wit h 
mea s ura ble disease at baseli ne w h o recei ve d at least 1 d ose of a n y c o m p o ne nt of t he 
c o m bi nati o n st u d y i nter ve nti o n b ut d o n ot ha ve e val ua ble R E CI S T assess me nts f or a n y 
reas o n will be c o u nte d as n ot res p o n di n g. Pa rtici pa nts wit h o ut meas ura ble, s oft-tiss ue 
disease at baseli ne will n ot be e val ua ble f or t his criteri o n. 
Res p o nse rates will be esti mate d wit hi n eac h c o h ort a n d 9 5 % CIs will be esti mate d usi n g t he 
Cl o p per- Pears o n  met h o d.  Res p o nse  rates  a n d  9 5 %  CIs  will  als o  be  prese nte d  f or  eac h 
i n di vi d ual criteri o n of C R R ( C T C res p o nse, P S A res p o nse, a n d O R R). 
5. 4. 2. 2  Disease C o ntr ol Rate 
D C R is defi ne d as t he pr o p orti o n of partici pa nts wit h a best o verall res p o nse of ( 1) C R, ( 2) P R, 
or ( 3) sta ble disease ( S D ) lasti n g at least 6 m o nt hs. Per R E CI S T, t o be assi g ne d a best o verall 
res p o nse  of  C R  or  P R,  c ha n ges  i n  t u m or  meas ure me nts  m ust  be  c o nfir me d  b y a re peat 
ra di o gra p hic  assess me nt  perf or me d  n o  less  t ha n  4  wee ks  after  t he  criteria  f or  i nitial 
ra di o gra p hic res p o nse we re first met. I n a d diti o n, D C R res p o n ders m ust n ot ha ve b o ne lesi o ns 
t hat ha ve pr o gresse d, as deter mi ne d b y P C W G 3 criteria. T he d urati o n of S D ( or n o n- C R/ n o n-
P D   f or  partici pa nts  wit h o ut  meas ura ble,  s oft-tiss ue  disease)  is  defi ne d  as  t he  ti me  fr o m 


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treat me nt i nitiati o n u ntil t he date of ra di o gra p hic disease pr o gressi o n ( per R E CI S T or P C W G 3). 
If n o ra di o gra p hic pr o gressi o n has occ urre d a n d t he m ost rece nt t u m or assess me nt wit h o verall 
res p o nse of S D occ urre d wit hi n 6 m o nt hs of treat me nt i nitiati o n, t he partici pa nt will n ot ha ve 
met  t he S D d urati o n criteri o n a n d will n ot be c o nsi dere d a D C R resp o n der.  
Res p o nse rates f or D C R will be esti mate d wit hi n eac h c o h ort a n d 9 5 % CIs will be esti mate d 
usi n g t he Cl o p per- Pears o n met h o d. 
5. 4. 2. 3  Ra di o gra p hic Pr o gressi o n- Free S ur vi val 
r P F S is defi ne d as t he ti me fr o m i nitiati o n of st u d y i nter ve nti o n t o t he first o bjecti ve e vi de nce 
of ra di o gra p hic pr o gressi o n or deat h d ue t o a n y ca use ( w hic he ver occ urs first). Ra di o gra p hic 
disease pr o gressi o n is defi ne d as s oft tiss ue ( n o n- b o ne) disease pr o gressi o n per R E CI S T v 1. 1 
or  c o nfir me d  pr o gressi o n  of  b o ne  disease  per  P C W G 3  criteria.  Partici pa nts  w h o  c o nti n ue 
treat me nt be y o n d i nitial disease pr o gressi o n will be c o nsi dere d t o ha ve pr o gressi o n of disease 
(P D ) at t he ti me of t he i nitial pr o gressi o n e ve nt.  
Partici pa nts  w h o  d o  n ot  ha ve  ra di o gra p hic P D   at  t he  ti me  of  a nal ysis  will  be  ce ns ore d as 
f oll o ws: 
•  Partici pa nts  w h o  d o  n ot  ha ve  ra di o gra p hic P D   a n d  are  still  o n  st u d y  at  t he  ti me  of 
a nal ysis will be ce ns ore d at t he date of t he last t u m or assess me nt d oc u me nti n g a bse nce 
of pr o gressi ve disease 
•  Partici pa nts w h o ha ve disc o nti n ue d st u d y treat me nt a n d ha ve starte d s u bse q ue nt a nti-
ca ncer t hera p y or ha d s u bse q ue nt ca ncer s ur ger y or ra diati o n pri or t o d oc u me ntati o n of 
ra di o gra p hic P D will be ce ns ore d at t he date of t he last eval ua ble t u m or assess me nt 
pri or t o t he i nitiati o n of s u bse q ue nt treat me nt. 
•  Partici pa nts w h o disc o nti n ue d t he st u d y pri or t o d oc u me ntati o n of ra di o gra p hic P D will 
be  ce ns ore d  at  t he  date  of  t he  last  t u m or  assess me nt  d oc u me nti n g  a bse nce  of 
pr o gressi ve diseas e. 
•  Partici pa nts w h o d o n ot ha ve ra di o gra p hic P D a n d w h o die m ore t ha n 1 6 wee ks fr o m 
t heir  last  e val ua ble  t u m or  assess me nt  will  be  ce ns ore d  at  t he  date  of  t he  last  t u m or 
assess me nt d oc u me nti n g a bse nce of pr o gressi ve disease. Partici pa nts w h o wit hi n 1 6 
wee ks of t heir last e val ua ble t u m or assess me nt will be c o nsi dere d as ha vi n g a n e ve nt 
at t he date of deat h.   
r P F S will be esti mate d usi n g Ka pla n- Meier tec h ni q ues, a n d t he me dia n s ur vi val ti me a n d 9 5 % 
CIs will be esti mate d wit hi n eac h c o h ort. If me dia n s ur vi val is n ot reac he d, s ur vi val ti mes a n d 
9 5 % CIs will be re p orte d at deciles t hat are esti ma ble gi ve n t he  o bser ve d e ve nts. 


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5. 4. 2. 4  O verall S ur vi val 
O S  is  defi ne d  as  t he  ti me  fr o m  i nitiati o n  of  st u d y  i n ve nti o n  u ntil  deat h  d ue  t o  a n y  ca use. 
Pa rtici pa nts w h o are n ot re p orte d as ha vi n g die d at t he ti me of a nal ysis will be ce ns ore d at t he 
m ost rece nt c o ntact date t he y were k n o w n t o be ali ve. See Secti o n 5. 6. 2 f or ha n dli n g of missi n g 
or partial deat h dates. 
O S will be esti mate d usi n g Ka pla n- Meier tec h ni q ues, a n d t he me dia n s ur vi val ti me a n d 9 5 % 
CIs will be esti mate d wit hi n eac h c o h ort. If me dia n s ur vi val is n ot reac he d, s ur vi val ti mes a n d 
9 5 % CIs will be re p orte d at deciles t hat are esti ma ble gi ve n t he o bser ve d e ve nts. I n a d diti o n, 
t he 1 2- m o nt h O S rate will be esti mate d wit hi n eac h c o h ort a n d 9 5 % CIs will be esti mate d usi n g 
t he Cl o p per- Pears o n met h o d. 
5. 4. 3  E x pl or at or y Effic ac y E n d p oi nts 
T he e x pl orat or y efficac y e n d p oi nts are liste d i n Ta ble 1.  
5. 4. 3. 1  Bi o mar ker A nal ysis 
Descri pti ve statistics will  be  use d  t o  e val uate  t he  e x pl orat or y  bi o mar kers.  Bi o mar ker 
e x pl orat or y a nal yses will be deter mi ne d base d o n st u d y o utc o mes a n d f urt her descri be d i n a 
Tra nslati o nal A nal ysis Pla n. 
5. 4. 3. 2  Circ ulati n g T u m or Cell A nal ysis 
Descri pti ve statistics will be use d t o e val uate C T C c o u nt at eac h ti me p oi nt. C T C c ha n ges fr o m 
baseli ne will be pl otte d a n d s u m marize d at eac h ti me p oi nt. 
T he n u m ber a n d pr o p orti o n of partici pa nts w h o ha ve a baseli ne C T C val ue ≥ 1 cell/ 7. 5 m L a n d 
w h o s u bse q ue ntl y ha ve at least o ne p ost- baseli ne C T C val ue e q ual t o zer o (i.e. C T C 0) will be 
prese nte d  wit hi n  eac h  c o h ort.  9 5 %  CIs  f or  t he  pr o p orti o n  of  C T C 0  partici pa nts  will  be 
esti mate d usi n g t he Cl o p per- Pears o n met h o d. Partici pa nts wit h a missi n g baseli ne C T C val ue 
or baseli ne C T C val ue < 1 cell/ 7. 5 m L will be e xcl u de d fr o m t h e C T C 0 a nal ysis. 
5. 4. 3. 3  Pr ostate-s pecific A nti ge n A nal ysis 
Descri pti ve statistics will be use d t o e val uate P S A at eac h ti me p oi nt. T he perce nt c ha n ge fr o m 
baseli ne  will  be  pl otte d  a n d  s u m marize d  at  eac h  ti me p oi nt.  T he  ma xi m u m  perce nt  c ha n ge 
( decrease)  i n  P S A  at  a n y  p oi nt  after  i nitiati o n  of  st u d y  i n ve nti o n  will  be  s u m marize d  a n d 
dis pla ye d i n a waterfall pl ot. T he a nal ysis of perce nt c ha n ge i n P S A fr o m baseli ne at 1 2 wee k s 
will use t he first P S A val ue t hat is c ollecte d at least 1 2 wee ks ( ±  visit wi n d o ws s pecifie d i n 
t he c o h ort-s pecific pr ot oc ol a p pe n di x) after t he i nitiati o n of st u d y i nter ve nti o n. 
Ti me t o P S A pr o gressi o n is defi ne d as t he ti me fr o m i nitiati o n of st u d y i n ve nti o n t o t he date 
t hat a ≥ 2 5 % i ncrease a n d a bs ol ute i ncrease of ≥ 2 n g/ m L a b o ve t he na dir ( or baseli ne val ue 


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f or partici pa nts w h o di d n ot ha ve a decrease) i n P S A. T he i ncrease m ust be c o nfir me d b y a 
sec o n d c o nsec uti ve P S A assess me nt c o n d ucte d at least 3 wee ks later. If c o nfir me d, t he date 
t hat t he P S A criteria were first met will be c o nsi dere d t he date of P S A pr o gressi o n. Partici pa nts 
w h o  d o  n ot  pr o gress  will  be  ce ns ore d  at  t he  last  a vaila ble  P S A  meas ure me nt  pri or  t o  t he 
i nitiati o n of s u bse q ue nt a nti-ca ncer t hera p y. Ti me t o P S A pr o gressi o n will be esti mate d usi n g 
Ka pla n- Meier  tec h ni q ues,  a n d  t he  me dia n  pr o gressi o n  ti me  a n d  9 5 %  CIs  will  be  esti mate d 
wit hi n eac h c o h ort. If me dia n pr o gressi o n ti me is n ot reac he d, pr o gressi o n ti mes a n d 9 5 % CIs 
will be re p orte d at dec iles t hat are esti ma ble gi ve n t he o bser ve d e ve nts. 
5. 4. 3. 4  D urati o n of Res p o nse 
F or partici pa nts w h o ha ve meas ura ble disease at baseli ne a n d w h o e x perie nce d a n o bjecti ve 
res p o nse (c o nfir me d C R or P R) d uri n g t he st u d y, D O R is defi ne d as t he ti me fr o m t he first 
t u m or assess me nt t hat d oc u me nts res p o nse ( C R or P R, w hic he ver is rec or de d first) t o t he first 
d oc u me ntati o n of ra di o gra p hic P D per P C W G 3- m o difie d R E CI S T v 1. 1 or deat h d ue t o a n y 
ca use ( w hic he ver occ urs first).  
Partici pa nts w h o ha ve n ot pr o gresse d at t he ti me of a nal ysis will be ce ns ore d as f oll o ws: 
•  Partici pa nts  w h o  d o  n ot  ha ve  ra di o gra p hic P D   a n d  are  still  o n  st u d y  at  t he  ti me  of 
a nal ysis will be ce ns ore d at t he date of t he last t u m or assess me nt d oc u me nti n g res p o nse 
•  Partici pa nts w h o ha ve disc o nti n ue d st u d y treat me nt a n d ha ve starte d s u bse q ue nt a nti-
ca ncer t hera p y or ha d s u bse q ue nt ca ncer s ur ger y or ra diati o n pri or t o d oc u me ntati o n of 
ra di o gra p hic P D will be ce ns ore d at t he date of t he last t u m or assess me nt d oc u me nti n g 
res p o nse t hat occ urre d pri or t o t he i nitiati o n of s u bse q ue nt s yste mic treat me nt. 
•  Partici pa nts w h o disc o nti n ue d t he st u d y pri or t o d oc u me ntati o n of ra di o gra p hic P D will 
be ce ns ore d at t he date of t he last t u m or assess me nt d oc u me nti n g res p o nse. 
D O R will be esti mate d usi n g Ka pla n- Me ier tec h ni q ues, a n d t he me dia n D O R a n d 9 5 % CIs 
will be esti mate d wit hi n eac h c o h ort. If me dia n D O R  is n ot reac he d, d urati o n ti mes a n d 9 5 % 
CIs will be re p orte d at d eciles t hat are esti ma ble gi ve n t he o bser ve d e ve nts. 
5. 4. 3. 5  P har mac o ki netic A nal ysis 
S parse  P K  a nal ysis  ma y  be  perf or me d  e val uati n g  tr o u g h  le vels  f or  all  bi ol o gic  st u d y 
i nter ve nti o n a n d ma xi m u m o bser ve d dr u g c o nce ntrati o n ( C ma x) f or e x pl orat or y bi ol o gic st u d y 
i nter ve nti o n ( n o n-P D - 1 a ge nts). T he decisi o n t o perf or m P K a nal ysis will be ma de o n a c o h ort-
b y-c o h ort a n d c o m p o u n d- b y-c o m p o u n d basis.  


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5. 4. 3. 6  A nti- Dr u g A nti b o d y A nal ysis 
T he n u m ber of partici pa nts w h o de vel o p A D A t o bi ol o gic st u d y i nter ve nti o n a n d A D A titer 
ma y be s u m marize d. T he decisi o n t o perf or m A D A  a nal ysis will be ma de o n a c o h ort- b y-
c o h ort a n d c o m p o u n d- b y-c o m p o u n d basis. 
5. 5  
S afet y A n al ysis  
All safet y a nal yses will be perf or me d o n t he e val ua ble p o p ulati o n, c o nsisti n g of all partici pa nts 
w h o recei ve at least 1 d ose of a n y c o m p o ne nt of t he c o m bi nati o n st u d y i nter ve nti o n. Beca use 
t his  is  a  n o n-ra n d o mize d  a n d  o pe n-la bel  st u d y,  it  is  hi g hl y  u nli kel y  t hat  a  partici pa nt  will 
recei ve a n i nc orrect st u d y i nter ve nti o n. T heref ore, partici pa nts will be gr o u pe d acc or di n g t o 
t he  c o h ort  i nt o  w hic h  t he y  were  e nr olle d.  If  a n y  partici pa nts  recei ve  i nc orrect  st u d y 
i nter ve nti on, it will be rec or de d as a pr ot oc ol de viati o n a n d descri be d i n t he Cli nical St u d y 
Re p ort. 
Safet y will be assesse d t hr o u g h s u m maries of A Es, la b orat or y test res ults ( he mat ol o g y, ser u m 
c he mistr y, a n d t h yr oi d f u ncti o n testi n g ), vital si g ns, a n d E C Gs.  
5. 5. 1  E x p o s ure t o St u d y Me dic ati o n 
T he n u m ber of partici pa nts e x p ose d t o eac h st u d y i nter ve nti o n a n d t he e xte nt of e x p os ure (as 
n u m ber of d oses a n d c u m ulati ve d ose recei ve d, as a p plica ble) wi ll be s u m marize d b y c o h ort 
usi n g descri pti ve statistics. 
5. 5. 2  A d verse E ve nts 
All   re p orte d  A Es  will  be  c o de d  usi n g  t he  latest  versi o n  of  t he  Me dical  Dicti o nar y  f or 
Re g ulat or y Acti vities ( Me d D R A) a n d gra de d usi n g t he N CI C o m m o n Ter mi n ol o g y Criteria 
f or A d verse E ve nts ( C T C A E) versi o n 5. 0.  
A t reat me nt-e mer ge nt a d verse e ve nt ( T E A E) is defi ne d as a n y e ve nt t hat eit her occ urs after 
t he i nitiati o n of st u d y i nter ve nti o n, ha vi n g bee n a bse nt at baseli ne, or, if prese nt at baseli ne, 
a p pears  t o  ha ve  w orse ne d  i n  se verit y  or  fre q ue nc y,  w het her  or  n ot  t he  e ve nt  is  c o nsi dere d 
relate d t o st u d y i nter ve nti o n. A Es assesse d b y t he I n vesti gat or t o be “ P ossi bl y”, “ Pr o ba bl y”, 
or “ Defi nitel y” relate d t o a n y st u d y i nter ve nti o n, as well as A Es wit h missi n g relati o ns hi p, will 
be c o nsi dere d treat me nt relate d.  
Ha n dli n g of missi n g a n d partial missi n g A E dates is descri be d i n Secti o n 5. 6. 1. 
T he i nci de nce of T E A Es will be s u m marize d ( o verall, b y s yste m or ga n class a n d preferre d 
ter m a n d b y se verit y) b y c o h ort. I n a d diti o n, se parate s u m maries will be ge nerate d f or S A Es, 
deat hs, treat me nt-relate d A Es, A Es lea di n g t o treat me nt disc o nti n uati o n, a n d A Es lea di n g t o 
te m p orar y i nterr u pti o n a n d/ or d ose re d ucti o n. Partici pa nt deat hs a n d t he pri mar y ca use of deat h 
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5. 5. 3  L a b or at or y D at a 
Cli nical la b orat or y fi n di n gs will be s u m marize d usi n g descri pti ve statistics f or eac h c o h ort. 
C ha n ges fr o m baseli ne t o eac h visit ma y  be prese nte d f or select la b orat or y tests. 
5. 5. 4  Vit al Si g ns 
Vital  si g n  meas ure me nts  will  be  s u m marize d  usi n g  descri pti ve  statistics  f or  eac h  c o h ort. 
C ha n ges fr o m baseli ne t o eac h visit ma y be prese nte d f or eac h c o h ort. 
5. 5. 5  P h ysic al E x a mi n ati o ns 
P h ysical e xa mi nati o n data will n ot be s u m marize d beca use a n y si g nifica nt fi n di n g will be 
ca pt ure d a n d s u m marize d as a n A E.  
5. 6  
Missi n g D at a 
5. 6. 1  Missi n g a n d P arti al Missi n g A d verse E ve nt D ates 
If t he A E start date is n ot a c o m plete date, t he f oll o wi n g r ules will be a p plie d t o deter mi ne 
w het her t he e ve nt is treat me nt e mer ge nt. 
•  If t he start date is c o m pletel y missi n g: The A E will be c o nsi dere d treat me nt e mer ge nt 
u nless t he A E st o p date is earlier t ha n t he date of first d ose of st u d y i nter ve nti o n. 
•  If t he da y of t he A E start date is missi n g:  
o  If t he m o nt h a n d year of t he start date are later t ha n t he m o nt h a n d year of t he 
date of first d ose of st u d y i nter ve nti o n, t he n t he A E will be c o nsi dere d treat me nt 
e mer ge nt.  
o  If t he m o nt h a n d year of t he start date are e q ual t o t he m o nt h a n d year of t he 
date of first d ose of st u d y i nter ve nti o n a n d t he st o p date is u n k n o w n or later 
t ha n t he date of first d ose of st u d y i nter ve nti o n, t he n t he A E will be c o nsi dere d 
treat me nt e mer ge nt.  
•  If t he da y a n d m o nt h of t he start date are missi n g:  
o  If t he year of t he start date is later t ha n t he year of t he date of first d ose of st u d y 
i nter ve nti o n, t he n t he A E will be c o nsi dere d treat me nt e mer ge nt.  
o  If t he year of t he start date is e q ual t o t he year of t he date of first d ose of st u d y 
i nter ve nti o n a n d t he st o p date is u n k n o w n or later t ha n t he date of first d ose of 
st u d y i nter ve nti o n, t he n t he A E will be c o nsi dere d treat me nt e mer ge nt. 
5. 6. 2  Missi n g a n d P arti al Missi n g De at h D ates 
F or deat h dates, t he f o ll o wi n g c o n ve nti o ns will be use d f or i m p uti n g partial dates: 


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•  If  t he  date  of  deat h  is  c o m pletel y  or  partiall y  missi n g,  b ut  t here  is  a n  A E  wit h  t he 
o utc o me as ‘ Fatal ’, t he date of deat h will be re place d b y t he e n d date of t he A E.  
•  If o nl y t he da y of t he m o nt h is missi n g a n d t here is n o A E wit h o utc o me as ‘Fatal ’, t he 
1 st  of  t he  m o nt h  will  be  use d  t o  re place  t he  missi n g  da y.  T he  i m p ute d  date  will  be 
c o m pare d t o t he last k n o w n date ali ve pl us 1 da y, a n d t he ma xi m u m will be c o nsi dere d 
as t he deat h date. 
•  If t he m o nt h or t he year is missi n g, t he deat h date will be i m p ute d as t he last k n o w n 
date ali ve pl us 1 da y. 
•  If t he date is c o m pletel y missi n g b ut t he reas o n f or deat h is prese nt, t he deat h date will 
be i m p ute d as t he last k n o w n date ali ve pl us 1 da y. 
5. 7  
I nteri m A n al yses  
Safet y a n d efficac y will be m o nit ore d o n a re g ular basis b y t he S p o ns or a n d t he S A C. P ossi ble 
a da ptati o ns res ulti n g fr o m t hese data re vie ws i ncl u de: 
•  M o dif yi n g or st o p pi n g a c o h ort earl y base d o n a safet y si g nal 
•  E x pa n di n g a c o h ort t o i ncl u de a n a d diti o nal a p pr o xi matel y 1 5 partici pa nts ( Sta ge 2) 
base d o n acce pta ble safet y data i n a d diti o n t o preli mi nar y si g nals i n cli nical acti vit y 
a n d/ or bi o mar ker res ults 
Ot her  p ossi ble  a da ptati o ns  t o  t he  st u d y  desi g n,  i ncl u di n g  t he  a d diti o n  of  ne w  c o m bi nati o n 
c o h orts,  ma y  be  base d  o n  a  variet y  of  fact ors,  s uc h  as  e mer gi n g  bi ol o gical  k n o wle d ge  of 
m C R P C  bi o mar kers  a n d/ or  i m m u n ot hera p y  mec ha nis ms,  as  well  as  a vaila bilit y  of 
i n vesti gati o nal t hera pies. Fi n di n gs will n ot be use d t o re-esti mate t he sa m ple size. 
D ue t o t he e x pl orat or y nat ure of t his st u d y, effect sizes a n d CIs will n ot be a dj uste d t o acc o u nt 
f or o n g oi n g re vie w of data. 
5. 7. 1  C o h ort E x p a nsi o n R ules 
A Si m o n t w o-sta ge mi ni ma x desi g n ( Si m o n, 1 9 8 9) will be i m ple me nte d f or eac h c o h ort. I n 
Sta ge  1,  1 5  partici pa nts  will  be  e nr olle d.  If  t here  are  2  or  m ore  res p o nses  i n  t hese  1 5 
partici pa nts, 1 5 a d diti o nal partici pa nts ma y  be e nr olle d i n Sta ge 2 f or a t otal of 3 0 partici pa nts 
i n t he c o h ort. F or t he p ur p oses of c o h ort e x pa nsi o n, C R R will be use d t o deter mi ne res p o nse 
(ie, C T C res p o nse, P S A res p o nse, or objecti ve ra di o gra p hic res p o nse). 
I n a d diti o n t o efficac y criteria state d a b o ve, safet y data will als o be assesse d w he n deter mi ni n g 
w het her t o e x pa n d a c o h ort. If t here are ≥ 6 partici pa nts meeti n g c o h ort-s pecific t o xicit y criteria 
re q uiri n g per ma ne nt treat me nt disc o nti n uati o n, a n a d h oc S A C meeti n g will be hel d t o f urt her 
re vie w all safet y data a n d pr o vi de i n p ut o n assessi n g t he be nefit-ris k pr ofile. T he S A C will 


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pr o vi de a rec o m me n dati o n i n re gar d t o e x pa nsi o n t o Sta ge 2, c o nti n uati o n or disc o nti n uati o n 
of  t he  c o h ort.  T his  a d  h oc  re vie w  will  be  i n  a d diti o n  t o  t he  o n g oi n g  safet y  m o nit ori n g 
perf or me d b y t he S A C, w h o ma y rec o m me n d ter mi nati n g a c o m bi nati o n c o h ort at a n y ti me f or 
safet y reas o ns. T he t hres h ol d of 6 partici pa nts was c h ose n beca use t his tra nslates t o a p osteri or 
pr o ba bilit y of 0. 6 9 t hat t he tr ue t o xicit y rate is > 3 0 %, ass u mi n g 1 5 partici pa nts are e nr olle d 
per c o h ort a n d a mi ni mall y i nf or mati ve beta ( 0. 5, 2. 5) pri or. 
If t he c o h ort has a n acce pta ble safet y pr ofile b ut has n ot de m o nstrate d at least 2 res p o nses, n o 
a d diti o nal partici pa nts will be e nr olle d i nt o t he c o h ort. H o we ver, t his decisi o n ma y be re visite d 
if f oll o w- u p tra nslati o nal a nal ysis or e mer gi n g e xter nal data i de ntifies a s u bset of partici pa nts 
m ost li kel y t o deri ve be nefit fr o m t he c o m bi nati o n t hera p y t hat was u n derre prese nte d i n t he 
c o h ort.  U n der  t his  sce nari o,  a n y  m o dificati o ns  t o  t he  st u d y  desi g n  of  t he  c o m bi nati o n, 
i ncl u di n g j ustificati o n f or partici pa nt selecti o n or e nric h me nt, will be detaile d i n a n a me n d me nt 
t o t he a p pr o priate c o h ort a p pe n di x. 
6  
DI F F E R E N C E S C O M P A R E D T O P R O T O C O L 
T he f oll o wi n g list pr o vi des a hi g h-le vel o ver vie w of t he differe nces bet wee n t he S A P a n d t he 
C ore Pr ot oc ol a n d c o h ort-s pecific a p pe n dices. T he C ore Pr ot oc ol will be a me n de d t o a d dre ss 
differe nces relate d t o st u d y e n d p oi nts. 
•  Secti o n 3. 2 ( St u d y O bjecti ves a n d E n d p oi nts):  
o  T he S A P re na mes t he Sec o n dar y c o m p osite e n d p oi nt fr o m O R R t o C o m p osit e 
Res p o nse Rate ( C R R).  
o  T he  S A P  re m o ves  t he  re q uire me nt  t hat  at  least  2  p ost- baseli ne  P S A 
meas ure me nts m ust be a vaila ble f or a partici pa nt t o be e val ua ble f or t he P S A 
res p o nse criteri o n of C R R. 
o  T he  C R R  criteri o n  of  c o nfir me d  res p o nse  of  C R  or  P R  b y  o bjecti ve 
ra di o gra p hic disease assess me nt has bee n na me d O R R ( o bjecti ve res p o nse rate).  
o  T he S A P clarifies t hat partici pa nts wit h o ut meas ura ble disease at baseli ne will 
n ot be e val ua ble f or O R R a nal ysis. 
o  T he S A P m o difies t he mi ni m u m d urati o n of S D re q uire d f or a partici pa nt t o be 
c o nsi dere d a D C R res p o n der fr o m 9 m o nt hs t o 6 m o nt hs. 
o  T he S A P a d ds d urati o n of res p o nse ( D O R) as a n e x pl orat or y e n d p oi nt. 
•  Secti o n  3. 3  ( Deter mi nati o n  of  Sa m ple  Size):  T he  S A P  re na mes  t he  Sec o n dar y 
c o m p osite e n d p oi nt fr o m O R R t o C R R.  
•  Secti o n 5. 1. 1 ( E val ua ble P o p ulati o n): T he S A P clarifies t hat s o me efficac y a nal yses 
ma y be perf or me d o n a s u bset of t he e val ua ble p o p ulati o n, as a p pr o priate a n d detaile d 
i n ot her secti o ns of t he S A P. 


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•  Secti o n 5. 4 ( Efficac y A nal ysis): T he S A P clarifies t hat s o me efficac y a nal yses ma y be 
perf or me d o n a s u bset of t he e val ua ble p o p ulati o n, as detaile d i n Ta ble 3. 
•  Se cti o n 5. 4. 2. 1 ( C o m p osite Res p o nse Rate):  
o  T he S A P re na mes t he Sec o n dar y c o m p osite e n d p oi nt fr o m O R R t o C o m p osite 
Res p o nse Rate ( C R R).  
o  T he S A P clarifies t hat partici pa nts wit h a missi n g C T C val ue at baseli ne will 
n ot be e val ua ble f or t he C T C res p o nse criteri o n of C R R. 
o  T he  S A P  re m o ves  t he  re q uire me nt  t hat  at  least  2  p ost- baseli ne  P S A 
meas ure me nts m ust be a vaila ble f or a partici pa nt t o be e val ua ble f or t he P S A 
res p o nse criteri o n of C R R. 
o  T he  C R R  criteri o n  of  c o nfir me d  res p o nse  of  C R  or  P R  b y  o bjecti ve 
ra di o gra p hic disease assess me nt has bee n na me d O R R.  
o  T he S A P clarifies t hat partici pa nts wit h o ut meas ura ble disease at baseli ne will 
n ot be e val ua ble f or O R R a nal ysis. 
o  T he  S A P  clarifies  t hat  O R R  res p o n ders  m ust  n ot  ha ve  b o ne  lesi o ns  t hat 
pr o gresse d, as deter mi ne d b y P C W G 3 criteria. 
o  T he S A P clarifies t hat res p o nse rates a n d 9 5 % CIs will be prese nte d f or eac h 
i n di vi d ual criteri o n of C R R. 
•  Secti o n 5. 4. 2. 2 ( Disease C o ntr ol Rate):  
o  T he S A P m o difies t he mi ni m u m d urati o n of S D re q uire d f or a partici pa nt t o be 
c onsi dere d a D C R res p o n der fr o m 9 m o nt hs t o 6 m o nt hs. 
o  T he  S A P  clarifies  t hat  D C R  res p o n ders  m ust  n ot  ha ve  b o ne  lesi o ns  t hat 
pr o gresse d, as deter mi ne d b y P C W G 3 criteria. 
•  Secti o n 5. 4. 3. 2 ( Circ ulati n g T u m or Cell A nal ysis): T he S A P clarifies t hat partici pa nts 
wit h a missi n g C T C val ue at baseli ne will n ot be e val ua ble  f or t he C T C 0 a nal ysis. 
•  Secti o n 5. 4. 3. 4 ( D urati o n of Res p o nse): T he S A P a d ds D O R as a n e x pl orat or y e n d p oi nt. 
•  Secti o n 5. 7. 1 ( C o h ort E x pa nsi o n R ules): T he S A P re na mes t he Sec o n dar y c o m p osite 
e n d p oi nt use d f or e x pa nsi o n decisi o n ma ki n g fr o m O R R t o C R R. 
 


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7  
R E F E R E N C E S 
1. Eise n ha uer E A, T herasse P, B o gaerts J, Sc h wartz L H, Sar ge nt D , F or d, R, et al. Ne w 
res p o nse e val uati o n criteria i n s oli d t u m o urs: Re vise d R E CI S T g ui deli ne ( versi o n 
1. 1). E ur J Ca ncer 2 0 0 9; 4 5( 2): 2 2 8- 4 7. 
2. I C H / F D A G ui da nce f or I n d ustr y E 9 Statistical Pri nci ples f or Cli nical Trials. U. S. 
De part me nt of Healt h a n d H u ma n Ser vices, F o o d a n d Dr u g A d mi nistrati o n, 
Se pte m ber 1 9 9 8. 
3. Sc her HI, M orris MJ, Sta dler W M, Hi ga n o C, Basc h E, Fizazi K , et al. Trial desi g n a n d 
o bjecti ves f or castrati o n- resista nt pr ostate ca ncer: U p date d rec o m me n dati o ns fr o m t he 
Pr ostate Ca ncer Cli nical Trials W or ki n g Gr o u p 3. J Cli n O nc ol 2 0 1 6; 3 4( 1 2): 1 4 0 2- 1 8. 
4. Si m o n R. O pti mal t w o- sta ge desi g ns f or p hase II cli nical trials. C o ntr ol Cli n Trials 
1 9 8 9; 1 0( 1): 1- 1 0. 
 


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8  
A P P E N DI C E S 
8. 1  
C ore Pr ot oc ol S y n o psis ( Pr ot oc ol A me n d me nt 2; 3 0 A pril 2 0 1 9) 
Pr ot oc ol Title: 
A M ultice nter, O pe n- La bel, E x pl orat or y Platf or m St u d y t o E val uate Bi o mar kers a n d 
I m m u n ot hera p y C o m bi nati o ns f or t he Treat me nt of Patie nts wit h Metastatic Castrati o n-
resista nt Pr ostate Ca ncer 
S h ort Title: 
Platf or m St u d y f or Pr ostate Researc hi n g Tra nslati o nal E n d p oi nts  C orrelate d t o Res p o nse t o 
I nf or m Use of N o vel C o m bi nati o ns ( P O R T E R) 
R ati o n ale:  
T his st u d y is desi g ne d t o test m ulti ple cli nical h y p ot heses a n d mec ha nisticall y- defi ne d 
c o m bi nati o ns t o e val uate t he safet y a n d efficac y of i m m u n ot hera p y c o m bi nati o n i n 
partici pa nts wit h metastatic castrati o n-resista nt pr ostate ca ncer ( m C R P C) w h o ha ve recei ve d 
pri or sec o n dar y a n dr o ge n rece pt or si g nali n g i n hi bit or t hera p y (e g, a birater o ne, e nzal uta mi de, 
a pal uta mi de). 
Ke y O bjecti ves a n d E n d p oi nts:  
O bjecti ves  
E n d p oi nts  
Pri mar y  
 
•  T o deter mi ne t he safet y of eac h i m m u n ot hera p y 
c o m bi nati o n i n partici pa nts wit h m C R P C.  
•  I nci de nce a n d se verit y of A Es. 
Sec o n dar y  
 
•  T o deter mi ne t he O R R of eac h i m m u n ot hera p y 
c o m bi nati o n i n partici pa nts wit h meas ura ble 
m C R P C.  
•  T o deter mi ne t he D C R ≥ 9 m o nt hs of eac h 
i m m u n ot hera p y c o m bi nati o n i n partici pa nts wit h 
meas ura ble m C R P C.  
•  T o e val uate t he r P F S of eac h i m m u n ot hera p y 
c o m bi nati o n i n pa rtici pa nts wit h m C R P C. 
•  T o esti mate t he O S of eac h i m m u n ot hera p y 
c o m bi nati o n i n partici pa nts wit h m C R P C.  
•  O R R: A c o m p osite e n d p oi nt w here res p o nse is 
defi ne d as a  partici pa nt meeti n g at least o ne of t he 
f oll o wi n g: 
o  C T C res p o nse: C ha n ge fr o m u nfa v ora ble ( ≥ 5 
cells/ 7. 5 m L of bl o o d) t o fa v ora ble ( ≤ 4 
cells/ 7. 5 m L of bl o o d). Partici pa nts wit h a 
baseli ne C T C val ue < 5 cells/ 7. 5 m L of bl o o d 
wi ll n ot be e val uate d f or t his criteri o n. 
o  P S A res p o nse: C o nfir me d P S A res p o nse is 
defi ne d as ≥ 5 0 % re d ucti o n i n P S A fr o m 
baseli ne, wit h a re peat assess me nt c o nfir mi n g 
t he res ult at least 3 wee ks later. Partici pa nts 
wit h o ut a baseli ne a n d at least 2 p ost -base li ne 
P S A assess me nts will n ot be e val uate d f or t his 
criteri o n.  
o  C o nfir me d res p o nse of C R or P R b y o bjecti ve 
ra di o gra p hic disease assess me nt usi n g m o difie d 
R E CI S T versi o n 1. 1 (ie, C R or P R a n d n o 
pr o gressi o n i n b o ne per t he P C W G 3; Sc her et 


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al., 2 0 1 6 ). Per R E CI S T, t o be assi g ne d a best 
o verall res p o nse of C R or P R, c ha n ges i n t u m or 
meas ure me nts m u st 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 he criteria f or res p o nse are 
first met. Partici pa nts w h o recei ve d at least 1 
d ose of t he c o m bi nati o n st u d y i nter ve nti o n or 
c o m p o ne nt of t he c o m bi nati o n b ut d o n ot ha ve 
R E CI S T assess me nt f or a n y reas o n will be 
c o u nte d as n ot res p o n di n g.  
•  D C R at 9 m o nt hs: Defi ne d as C R, P R, or S D 
f or 9 m o nt hs as be st res p o nse b y P C W G 3-
m o difie d R E CI S T 1. 1. Partici pa nts w h o recei ve d 
at least 1 d ose of t he st u d y i nter ve nti o n 
c o m bi nati o n or c o m p o ne nt of t he c o m bi nati o n b ut 
d o n ot ha ve R E CI S T assess me nt f or a n y reas o n 
will be c o u nte d as n ot res p o n di n g.  
•  r P F S: Defi ne d as ti me fr o m i nitiati o n of st u d y 
i nter ve nti o n t o t he first o bjecti ve e vi de nce of 
ra di o gra p hic pr o gressi o n, or deat h d ue t o a n y 
cause ( w hic he ver occ urs first).  
•  O S: Defi ne d as t he ti me fr o m i nitiati o n of st u d y 
i n ve nti o n u ntil deat h d ue t o a n y ca use. 
•  O S rate at 1 2 m o nt hs.  
A E(s) = a d verse e ve nt(s); C R = c o m plete res p o nse; C T C = circ ulati n g t u m or cells; D C R = disease c o ntr ol rate; 
E C O G  = Easter n C o o perati ve O nc ol o g y Gr o u p; m C R P C = metastatic castrati o n -resista nt pr ostate ca ncer; 
O R R  = o bjecti ve res p o nse rate; O S = o verall s ur vi val; P C W G 3 = Pr ostate Ca ncer Cli nical Trials W or ki n g 
Gr o u p  3; P R = partial res p o nse; P S A = pr ostate -s pecific a nti ge n; R E CI S T = Res p o nse E val uati o n Criteria i n 
S oli d T u m ors; r P F S = ra di o gra p hic pr o gressi o n -free s ur vi val; S D = sta ble disease 
 
O ver all Desi g n:  
T his is a n o pe n-la bel, n o n- ra n d o mize d, e x pl orat or y platf or m pr ot oc ol desi g ne d t o assess the 
safet y a n d a ntit u m or acti vit y of m ulti ple i m m u n ot hera p y c o m bi nati o ns i n partici pa nts wit h 
m C R P C w h o ha ve recei ve d pri or t hera p y. T he platf or m st u d y will c o nsist of 2 sta ges: Sta ge 
1, a n i nitial sta ge t o e val uate safet y, bi o mar kers, a n d cli nica l acti vit y of a c o m bi nati o n a n d 
Sta ge 2, a n e x pa n de d c o h ort, w he n warra nte d, base d o n t he safet y, cli nical acti vit y, a n d/ or 
bi o mar ker res ults fr o m Sta ge 1. T he S p o ns or i nte n ds t o m o dif y a n d/ or a d d ne w c o m bi nati o ns 
t o t he pr ot oc ol as data e mer ge fr o m t his a n d ot her trials. 
Partici pa nts m ust pr o vi de c o nse nt f or arc hi val tiss ue fr o m a  pri or bi o ps y or s ur ger y f or 
pr ostate ca ncer a n d m ust c o nse nt t o baseli ne a n d o n-treat me nt bi o psies, if me dicall y feasi ble. 
Partici pa nts will be assi g ne d t o recei ve o ne of t he e nr olli n g c o m bi nati o n st u d y i nter ve nti o ns 
a n d will be m o nit ore d f or safet y a n d res p o nse.  
T he d urati o n of i m m u n ot hera p y c o m bi nati o n st u d y i nter ve nti o n wi ll be de pe n de nt o n t he 
co m bi nati o n a d mi nistere d a n d will c o nti n ue f or t he d urati o n desc ri be d i n t he c o h ort a p pe n di x 


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f or eac h res pecti ve c o m bi nati o n, u nless t he partici pa nt: is n o l o n ger cli nicall y be nefiti n g 
( N L C B; as e vi de nce d b y s y m pt o matic or ra di o gra p hic disease pr o gressi o n a n d/ or cli nical 
deteri orati o n); e x perie nces a n y t o xicit y meeti n g s pecifie d disc o nti n uati o n criteria (as 
descri be d i n t he c o h ort a p pe n di x f or eac h res pecti ve c o m bi nati o n) or u nacce pta ble t o xicit y i n 
t he best cli nical discreti o n of t he treati n g p h ysicia n (ie, I n vesti gat or discreti o n); reac hes t he 
ma xi m u m d urati o n of st u d y i nter ve nti o n; or wit h dra ws c o nse nt. P artici pa nts will be f oll o we d 
f or u p t o 2. 5 years fr o m t he ti me of t he i nitiati o n of st u d y inter ve nti o n (see F oll o w- u p). 
De pe n di n g o n t he c o m bi nati o n a d mi n istere d, partici pa nts w h o are cli nicall y be nefiti n g, as 
defi ne d b y t he I n vesti gat or at t he e n d of t he st u d y treat me nt  peri o d, ma y ha ve p ost-st u d y 
access t o t he i m m u n ot hera p y c o m bi nati o n recei ve d d uri n g t he st u d y after writte n a gree me nt 
fr o m t he Me dical M o nit or. 
N u m ber of P artici p a nts: 
T he st u d y is n ot i nte n de d or p o were d f or h y p ot hesis testi n g. T he st u d y is i nte n de d t o pr o vi de 
preli mi nar y esti mates of a d verse e ve nt ( A E) rates, res p o nse rat es, effect sizes, a n d 
c o nfi de nce i nter vals ( CIs) t o ai d t he desi g n of later st u dies. A sa m ple size of a p pr o xi matel y 
1 5 partici pa nts per c o m bi nati o n i nter ve nti o n will pr o vi de t hese  preli mi nar y esti mates w hile 
li miti n g e x p os ure. A n a d diti o nal a p pr o xi matel y 1 5 partici pa nts will be e nr olle d i n Sta ge 2, if 
t he c o h ort is e x pa n de d. 
I nter ve nti o n Gr o u ps a n d D ur ati o n: 
T his is n ot a ra n d o mize d st u d y. Assi g n me nt t o o ne of t he i m m u n ot hera p y c o m bi nati o ns will 
be ma de b y t he I n vesti gat or usi n g his/ her best cli nical discreti o n based o n t he partici pa nt’s 
me dical hist or y a n d disease stat us a n d k n o wle d ge of t he a vaila ble i m m u n ot hera p y 
c o m bi nati o ns o pe n f or e nr oll me nt. 
T he d ose a n d sc he d ule selecte d will be descri be d i n t he c o h ort  a p pe n di x f or eac h res pecti ve 
c o m bi nati o n (e g, A p pe n di x C o h ort A, A p pe n di x C o h ort B, etc.). T he d urati o n of 
i m m u n ot hera p y c o m bi nati o n st u d y i nter ve nti o n will be de pe n de nt o n t he co m bi nati o n 
a d mi nistere d. De pe n di n g o n t he c o m bi nati o n a d mi nistere d, partic i pa nts w h o are cli nicall y 
be nefiti n g as defi ne d b y t he I n vesti gat or at t he e n d of t he st u d y ma y ha ve p ost-st u d y access 
to t he i m m u n ot hera p y c o m bi nati o n after a gree me nt fr o m t he Me dica l M o nit or. 


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F oll o w- u p:  
F or u p t o 2. 5 years fr o m t he i nitiati o n of st u d y i nter ve nti o n, partici pa nts i n t he f oll o w u p 
p hase will be c o ntacte d b y tele p h o ne b y t he site pers o n nel e ve r y 3 m o nt hs t o c ollect alter nate 
a ntica ncer t hera p y i nf or mati o n a n d deter mi ne s ur vi val stat us. 
Partici pa nts will be f oll o we d f or a u p t o 2. 5 years fr o m t he ti me of t he i nitiati o n of st u d y 
i nter ve nti o n u nless t he c o nse nt is wit h dra w n. All partici pa nts will be f oll o we d f or safet y f or 
at least 1 0 0 da ys after disc o nti n uati o n of st u d y i nter ve nti o n. 
De pe n di n g o n t he c o m bi nati o n a d mi nistere d, partici pa nts w h o are  cli nicall y be nefiti n g, as 
defi ne d b y t he I n vesti gat or at t he e n d of t he st u d y treat me nt  peri o d, ma y ha ve p ost-st u d y 
access t o t he i m m u n ot hera p y c o m bi nati o n recei ve d d uri n g t he st u d y after a gree me nt fr o m t he 
Me dical M o nit or. 
A partici pa nt will be c o nsi dere d l ost t o f oll o w- u p if he re peate dl y fails t o ret ur n f or 
sc he d ule d visits a n d is u na ble t o be c o ntacte d b y t he st u d y site. 
D at a M o nit ori n g C o m mittee:   
T his st u d y will use a Safet y Assess me nt C o m mittee ( S A C) of ge ni t o uri nar y ( G U) o nc ol o gists 
a n d i m m u n o- o nc ol o gists, w h o will meet re g ularl y wit h t he S p o ns or t o m o nit or safet y o n a n 
o n g oi n g basis.  
 


C ertifi c at e Of C o m pl eti o n
E n v el o p e I d: 3 6 6 8 B 6 C 0 C 6 3 3 4 1 1 3 A B C 7 E E B 0 6 4 9 2 8 4 5 C
St at u s: C o m pl et e d
S u bj e ct: Pl e a s e D o c u Si g n: PI CI 0 0 3 3 S A P v 1. 0 2 0 2 1- 0 1- 2 9. p df
S o ur c e E n v el o p e: 
D o c u m e nt P a g e s: 2 6
Si g n at ur e s: 2
E n v el o p e Ori gi n at or: 
C ertifi c at e P a g e s: 5
I niti al s: 0
C hri st o p h er C a b a n s ki
A ut o N a v: E n a bl e d
E n v el o p eI d St a m pi n g: Di s a bl e d
Ti m e Z o n e: ( U T C- 0 8: 0 0) P a cifi c Ti m e ( U S & C a n a d a)
1 L ett er m a n Dri v e
S a n Fr a n ci s c o, C A  9 4 1 2 9
c c a b a n s ki @ p ar k eri ci. or g
I P A d dr e s s: 7 3. 1 7 0. 1 4 8. 1 3 6 
R e c or d Tr a c ki n g
St at u s: Ori gi n al
             2 9- J a n- 2 0 2 1 | 1 0: 4 5
H ol d er: C hri st o p h er C a b a n s ki
             c c a b a n s ki @ p ar k eri ci. or g
L o c ati o n: D o c u Si g n
Si g n er E v e nt s
Si g n at ur e
Ti m e st a m p
C hri st o p h er C a b a n s ki
c c a b a n s ki @ p ar k eri ci. or g
Dir e ct or, Bi o st ati sti c s
P ar k er I n stit ut e f or C a n c er I m m u n ot h er a p y
S e c urit y L e v el: E m ail, A c c o u nt A ut h e nti c ati o n 
( R e q uir e d)
Si g n at ur e A d o pti o n: Pr e- s el e ct e d St yl e
Si g n at ur e I D: 
7 3 C C A B A 7- 4 9 D 1- 4 6 3 4- B 5 D 6- 3 1 4 D 8 3 F 0 2 F 8 5
U si n g I P A d dr e s s: 7 3. 1 7 0. 1 4 8. 1 3 6
Wit h Si g ni n g A ut h e nti c ati o n vi a D o c u Si g n p a s s w or d
Wit h Si g ni n g R e a s o n s ( o n e a c h t a b): 
   I a m t h e a ut h or of t hi s d o c u m e nt
S e nt: 2 9- J a n- 2 0 2 1 | 1 0: 4 6
Vi e w e d: 2 9- J a n- 2 0 2 1 | 1 0: 4 6 
Si g n e d: 2 9- J a n- 2 0 2 1 | 1 0: 4 7
El e ctr o ni c R e c or d a n d Si g n at ur e Di s cl o s ur e: 
      N ot Off er e d vi a D o c u Si g n
J u sti n F air c hil d
jf air c hil d @ p ar k eri ci. or g
V P, Cli ni c al D e v el o p m e nt
P ar k er I n stit ut e f or C a n c er I m m u n ot h er a p y
S e c urit y L e v el: E m ail, A c c o u nt A ut h e nti c ati o n 
( R e q uir e d)
Si g n at ur e A d o pti o n: Pr e- s el e ct e d St yl e
Si g n at ur e I D: 
9 4 9 2 7 7 D E- 9 B 0 8- 4 F 2 7- 9 7 3 F- 0 D 2 B B B 8 2 C 4 F 0
U si n g I P A d dr e s s: 7 3. 4. 1 5. 2 0 9
Wit h Si g ni n g A ut h e nti c ati o n vi a D o c u Si g n p a s s w or d
Wit h Si g ni n g R e a s o n s ( o n e a c h t a b): 
   I a p pr o v e t hi s d o c u m e nt
S e nt: 2 9- J a n- 2 0 2 1 | 1 0: 4 6
Vi e w e d: 2 9- J a n- 2 0 2 1 | 1 1: 0 4 
Si g n e d: 2 9- J a n- 2 0 2 1 | 1 1: 0 4
El e ctr o ni c R e c or d a n d Si g n at ur e Di s cl o s ur e: 
      A c c e pt e d: 1 5- M a y- 2 0 1 9 | 0 9: 1 3
      I D: b 1 5 7 3 b 3 d- 0 8 9 b- 4 1 c 9- 8 b 0 3- 7 2 c 1 9 8 e b b 2 5 5
I n P er s o n Si g n er E v e nt s
Si g n at ur e
Ti m e st a m p
E dit or D eli v er y E v e nt s
St at u s
Ti m e st a m p
A g e nt D eli v er y E v e nt s
St at u s
Ti m e st a m p
I nt er m e di ar y D eli v er y E v e nt s
St at u s
Ti m e st a m p
C ertifi e d D eli v er y E v e nt s
St at u s
Ti m e st a m p


C ar b o n C o p y E v e nt s
St at u s
Ti m e st a m p
Wit n e s s E v e nt s
Si g n at ur e
Ti m e st a m p
N ot ar y E v e nt s
Si g n at ur e
Ti m e st a m p
E n v el o p e S u m m ar y E v e nt s
St at u s
Ti m e st a m p s
E n v el o p e S e nt
H a s h e d/ E n cr y pt e d
2 9- J a n- 2 0 2 1 | 1 0: 4 6
C ertifi e d D eli v er e d
S e c urit y C h e c k e d
2 9- J a n- 2 0 2 1 | 1 1: 0 4
Si g ni n g C o m pl et e
S e c urit y C h e c k e d
2 9- J a n- 2 0 2 1 | 1 1: 0 4
C o m pl et e d
S e c urit y C h e c k e d
2 9- J a n- 2 0 2 1 | 1 1: 0 4
P a y m e nt E v e nt s
St at u s
Ti m e st a m p s
El e ctr o ni c R e c or d a n d Si g n at ur e Di s cl o s ur e


E L E C T R O NI C R E C O R D A N D SI G N A T U R E DI S C L O S U R E   
Fr o m ti me t o ti me, Par ker I nstit ute f or Ca ncer I m m u n ot hera p y ( we, us or C o m pa n y) ma y b e 
re q uire d b y la w t o pr o vi de t o y o u certai n writte n n otices or discl os ures. D es cri be d bel o w are t h e 
ter ms a n d c o n diti o ns f or pr o vi di n g t o y o u s uc h n otices a n d discl os ures el ectr o nicall y t hr o u g h t h e 
D oc u Si g n s yste m. Please rea d t he i nf or mati o n bel o w caref ull y a n d t h or o u g hl y, a n d if y o u ca n 
access t his i nf or mati o n electr o nicall y t o y o ur satisfacti o n a n d a gree t o t his Electr o nic Rec or d a n d 
Si g nat ure Discl os ure ( E R S D), please c o nfir m y o ur a gree m e nt b y s electi n g t he c hec k -b o x ne xt t o 
‘I a gree t o use electr o nic rec or ds a n d si g n at ures’ bef ore clic ki n g ‘ C O N TI N U E’ wit hi n t he 
D oc u Si g n s yste m.  
 
Getti n g p a per c o pies   
At a n y ti me, y o u ma y re q uest fr o m us a pa p er c o p y of a n y rec or d pr o vi d e d or ma de a v aila ble 
electr o nicall y t o y o u b y us. Y o u will ha ve t he a bilit y t o d o w nl oa d a n d pri nt d oc u me nts we se n d 
t o y o u t hr o u g h t he D o c u Si g n s yste m d uri n g a n d i m me diatel y after t he si g ni n g sessi o n a n d, if y o u 
elect t o create a D oc u Si g n acc o u nt, y o u ma y  access t he d oc u me nts f or a li mite d peri o d of ti me 
( us uall y 3 0 d a ys) after s u c h d oc u me nts are first se nt t o y o u. After s uc h ti me, if y o u wis h f or us t o 
se n d y o u p a per c o pies of a n y s u c h d oc u me nts fr o m o ur office t o y o u, y o u will be c har ge d a 
$ 0. 0 0  per -pa ge  fee. Y o u ma y re q uest deli ver y of s uc h pa per c o pies fr o m us b y f oll o wi n g t he 
pr oce d ure descri be d bel o w.  
 
Wit h dr a wi n g y o ur c o nse nt   
If y o u deci d e t o recei ve n otices a n d discl os ures fr o m us electr o nicall y, y o u ma y at a n y ti me 
c ha n ge y o ur mi n d a n d t ell us t ha t t hereafter y o u wa nt t o recei v e re q uir e d n otices a n d discl os ures 
o nl y i n pa per f or mat. H o w y o u m ust i nf or m us of y o ur decisi o n t o recei ve f ut ure n otices a n d 
discl os ure i n pa per f or mat a n d wit h dra w y o ur c o ns e nt t o recei v e n otices a n d discl os ures 
electr o nic all y is des cri be d bel o w.  
 
C o nse q ue nces of c h a n gi n g y o ur mi n d   
If y o u ele ct t o recei ve re q uire d n otices a n d discl os ures o nl y i n p a per f or mat, it will sl o w t he 
s pee d at w hic h we ca n c o m plete certai n ste ps i n tr a nsacti o ns wit h y o u a n d deli veri n g s er vices t o 
y o u beca use we will nee d first t o se n d t he re q uir e d n otices or discl os ures t o y o u i n pa per f or mat, 
a n d t he n wait u ntil we recei ve bac k fr o m y o u y o ur ac k n o wle d g m e nt of y o ur recei pt of s uc h 
pa per n otices or discl os ures. F urt her, y o u will n o l o n ger be a bl e t o use t he D oc u Si g n s yste m t o 
recei v e re q uir e d n otices a n d c o nse nts electr o nicall y fr o m us or t o si g n electr o nicall y d o c u me nts 
fr o m us. 
 
All n otices a n d discl os ures will be se nt t o y o u electr o nic all y   
El e ctr o ni c R e c or d a n d Si g n at ur e Di s cl o s ur e cr e at e d o n: 1 6- A pr- 2 0 1 9 | 0 9: 0 6
P arti e s a gr e e d t o: J u sti n F air c hil d


U nless y o u tell us ot her wise i n acc or da nce wit h t he pr oce d ures des cri be d h erei n, we will pr o vi de 
electr o nicall y t o y o u t hr o u g h t he D o c u Si g n s yste m all re q uire d n otices, discl os ures, 
a ut h orizati o ns, ac k n o wle d ge m e nts, a n d ot her d oc u me nts t hat are re q uire d t o be pr o vi de d or ma de 
a vaila ble t o y o u d uri n g t he c o urse of  o ur relati o ns hi p wit h y o u. T o re d u ce t he c ha n ce of y o u 
i na d verte ntl y n ot recei vi n g a n y n otice or discl os ure, we prefer t o pr o vi de all of t he re q uire d 
n otices a n d discl os ures t o y o u b y t he s a me met h o d a n d t o t he sa me a d dress t hat y o u ha v e gi ve n 
us. T h us, y o u ca n recei ve all t he discl os ures a n d n otices electr o nicall y or i n pa per f or mat t hr o u g h 
t he pa per mail deli ver y s yste m. If y o u d o n ot a gree wit h t his pr ocess, pleas e let us k n o w as 
descri be d b el o w. Please als o see t he para gra p h i m me diatel y a b o ve t hat des c ri bes t he 
c o nse q ue nces of y o ur ele cti n g n ot t o recei ve deli ver y of t he n otices a n d dis cl os ures 
electr o nicall y fr o m us.  
 
H o w t o c o nt act P a r ker I nstit ute f or C a ncer I m m u n ot her a p y:   
Y o u ma y c o ntact us t o let us k n o w of y o ur c ha n ges as t o h o w we ma y c o nt act y o u electr o nicall y, 
t o re q uest pa per c o pies of cert ai n i nf or mati o n fr o m us, a n d t o wit h dra w y o ur pri or c o nse nt t o 
recei v e n otices a n d discl os ures electr o nicall y as f oll o ws: 
T o c o ntact us b y e mail se n d messa ges t o: pici -s u p p ort @ par kerici. or g 
 
T o a d vise P ar ke r I nstit ute f or C a ncer I m m u n ot her a p y of y o ur ne w e m ail a d dress   
T o let us k n o w of a c h a n ge i n y o ur e mail a d dress w here we s h o ul d se n d n otices a n d discl os ures 
electr o nicall y t o y o u, y o u m ust se n d a n e mail messa ge t o us at  pici -s u p p ort @ par keri ci. or g a n d i n 
the b o d y of s uc h re q uest y o u m ust state: y o ur pre vi o us e mail a d dress, y o ur ne w e mail 
a d dress.  We d o n ot re q uire a n y ot her i nf or mati o n fr o m y o u t o c ha n ge y o ur e mail a d dress.   
If y o u create d a D oc u Si g n acc o u nt, y o u ma y u p d ate it wit h y o ur ne w e mail a d dress thr o u g h y o ur 
acc o u nt pr efere nces.  
 
T o re q uest p a per c o pies fr o m P ar ker I nstit ute f or C a ncer I m m u n ot her a p y   
T o re q uest deli ver y fr o m us of pa per c o pies of t he n otices a n d discl os ures pre vi o usl y pr o vi de d 
b y us t o y o u ele ctr o nicall y, y o u m ust se n d us a n e mail  t o s b olisett y @ par kerici. or g a n d i n t he 
b o d y of s u c h re q u est y o u m ust state y o ur e m ail a d dress, f ull na me, maili n g a d dress, a n d 
tele p h o ne n u m ber. We will bill y o u f or a n y fees at t hat ti me, if a n y.  
 
T o wit h dr a w y o ur c o nse nt wit h P ar ker I nstit ute f or C a ncer  I m m u n ot h er a p y  
T o i nf or m us t hat y o u n o l o n ger wis h t o recei ve f ut ure n otices a n d discl os ur es i n electr o nic 
f or mat y o u ma y: 


i. decli ne t o si g n a d o c u me nt fr o m wit hi n y o ur si g ni n g sessi o n, a n d o n t he s u bse q ue nt pa ge, 
select t he c h ec k-b o x i n dicati n g y o u wis h t o wit h dra w y o ur c o ns e nt, or y o u ma y;  
ii. se n d us a n e mail t o pici -s u p p ort @ par kerici. or g a n d i n t he b o d y of s uc h re q uest y o u m ust state 
y o ur e mail, f ull na me, m aili n g a d dress, a n d tele p h o ne n u m ber.  We d o n ot nee d a n y ot her 
i nf or mati o n fr o m y o u t o wit h draw c o nse nt..   T h e c o nse q ue nces of y o ur wit h dra wi n g c o nse nt f or 
o nli ne d oc u me nts will be t hat tra nsacti o ns ma y ta ke a l o n ger ti me t o pr o cess..  
 
Re q uire d h ar d w are a n d s oft w are   
T he mi ni m u m s yste m re q uire me nts f or usi n g t he D oc u Si g n s yste m ma y c h a n ge o ver ti me . T h e 
c urre nt s yste m r e q uire me nts are f o u n d h ere: htt ps://s u p p ort. d oc usi g n.c o m/ g ui des/si g ner -g ui de -
si g ni n g-s yste m-re q uire m e nts.  
 
Ac k n o wle d gi n g y o ur ac cess a n d c o nse nt t o recei ve a n d si g n d oc u me nts electr o nic all y   
T o c o nfir m t o us t hat y o u ca n access t his i nf or mati o n electr o nicall y, w hi c h will be si milar t o 
ot her electr o nic n otices a n d discl os ures t hat we will pr o vi de t o y o u, pleas e c o nfir m t hat y o u ha ve  
rea d t his E R S D, a n d (i) t hat y o u are a ble t o pri nt o n pa per or electr o ni call y sa v e t his E R S D f or 
y o ur f ut ure refere n ce a n d access; or (ii) t hat y o u are a ble t o e mail t his E R S D t o a n e mail a d dress 
w here y o u will be a ble t o pri nt o n pa per or s a ve it f or y o u r f ut ur e refere nce a n d access. F urt her, 
if y o u c o nse nt t o recei vi n g n otices a n d discl os ures e x cl usi vel y i n electr o nic f or mat as des cri be d 
herei n, t he n sel ect t he c h ec k -b o x ne xt t o ‘I a gree t o use electr o ni c rec or ds a n d si g nat ur es’ bef ore 
clic ki n g ‘ C O N TI N U E ’ wit hi n t he D oc u Si g n s yst e m. 
B y sele cti n g t he c hec k -b o x ne xt t o ‘I a gree t o use electr o nic rec or ds a n d si g nat ur es’, y o u c o nfir m 
t hat: 
 
Y o u ca n access a n d rea d t his Electr o nic Rec or d a n d Si g nat ure Discl os ure; a n d  
 
Y o u ca n pri nt o n pa per t his Electr o nic Rec or d a n d Si g nat ure Discl os ure, or sa ve or se n d 
t his Electr o nic Rec or d a n d Discl os ure t o a l ocati o n w here y o u ca n pri nt it, f or f ut ure 
refere nce a n d access; a n d 
 
U ntil or u nless y o u n otif y  Par ker I nstit ute f or Ca n cer I m m u n ot hera p y as d escri be d a b o v e, 
y o u c o ns e nt t o recei ve e x cl usi vel y t hr o u g h electr o nic mea ns all n otices, dis cl os ures, 
a ut h orizati o ns, ac k n o wle d ge m e nts, a n d ot her d oc u me nts t hat are re q uire d t o be pr o vi de d 
or ma de a v aila ble t o y o u b y  Par ker I nstit ute f or Ca ncer I m m u n ot hera p y d uri n g t he c o urse 
of y o ur relati o ns hi p wit h Par ker I nstit ute f or Ca n cer I m m u n ot hera p y.  

Prot_003.pdf: 
PORTER – Parker Institute for Cancer Immunotherapy 
Protocol PICI0033 Amendment 2, Version 1.0 
1
 
 
Protocol Title:  A Multicenter, Open-Label, Exploratory Platform Study to Evaluate Biomarkers 
and Immunotherapy Combinations for the Treatment of Patients with Metastatic Castration-
resistant Prostate Cancer 
Protocol Number:  PICI0033 
Amendment Number:  2 
Compound Number:  Not applicable 
Short Title:  Platform Study for Prostate Researching Translational Endpoints Correlated to 
Response to Inform Use of Novel Combinations (PORTER) 
Sponsor Name and Legal Registered Address:   
Parker Institute for Cancer Immunotherapy 
1 Letterman Drive 
Suite D3500 
San Francisco, CA 94129 
Tel: 415-985-7311 
 
Regulatory Agency Identifying Number(s):  
IND NUMBER: 139269 (CDER) and 18853 (CBER) 
EudraCT NUMBER:  Not applicable 
Approval Date:  Final Protocol: 07 December 2018  
 
Amendment 1: 24 January 2019 
 
Amendment 2: 30 April 2019 
 
 
CONFIDENTIAL 
This document and its contents are the property of and confidential to Parker Institute for Cancer 
Immunotherapy. Any unauthorized copying or use of this document is prohibited. 




PORTER – Parker Institute for Cancer Immunotherapy 
Protocol PICI0033 Amendment 2, Version 1.0 
3
INVESTIGATOR PROTOCOL AGREEMENT PAGE 
I agree: 
• 
To assume responsibility for the proper conduct of the study at this site. 
• 
To conduct the study in compliance with this protocol, any future amendments, and with 
any other study conduct procedures provided by Parker Institute for Cancer 
Immunotherapy. 
• 
Not to implement any changes to the protocol without written agreement from Parker 
Institute for Cancer Immunotherapy and prior review and written approval from the 
Institutional Review Board or Independent Ethics Committee except where necessary to 
eliminate an immediate hazard to participants. 
• 
That I am thoroughly familiar with the appropriate use of the study drug(s), as described 
in the protocol cohort appendices and any other information provided by Parker Institute 
for Cancer Immunotherapy including, but not limited to, the current Investigator’s 
Brochure(s). 
• 
That I am aware of, and will comply with, the International Conference on 
Harmonisation for Good Clinical Practice (GCP) and all applicable regulatory 
requirements. 
• 
To ensure that all persons assisting me with the study are adequately informed about the 
study drugs, the Parker Institute for Cancer Immunotherapy study protocol, and of their 
study-related duties and functions as described in the protocol. 
• 
That I agree that persons debarred from conducting or working on clinical studies by any 
court or regulatory agency will not be allowed to conduct or work on studies for the 
Parker Institute for Cancer Immunotherapy or for a partnership in which the Parker 
Institute for Cancer Immunotherapy is involved, and that I will immediately disclose in 
writing to the Parker Institute for Cancer Immunotherapy if any person who is involved 
in the study is debarred, or if any proceeding for debarment is pending. 
 
 
Signature: 
 
 
Date: 
 
 
Name 
(print): 
 
  
 
Site 
Number: 
Principal Investigator 
 
___________ 
  
 
 
  
 


PORTER – Parker Institute for Cancer Immunotherapy 
Protocol PICI0033 Amendment 2, Version 1.0 
4
Amendment(s) to the Protocol 
Text revisions resulting from the amendment(s) are incorporated in the synopsis and body of the 
Protocol Amendment. Major changes to the protocol are summarized below. 
Key Revisions in Amendment 1 (24 January 2019) 
Section # and Name 
Description of Change 
Statistical Considerations 
9.5.2 Cohort Expansion Rules 
Added safety criteria that would inform the decision to proceed to Stage 2 
of each immunotherapy combination. 
Clarification of Document 
General Revisions 
Document updated to address minor typographical errors and editorial 
changes for clarity. 
Appendix B-1 
Reordered the management algorithms to match the order on the 
appendix cover page. 
 
Key Revisions in Amendment 2 (30 April 2019) 
Section # and Name 
Description of Change 
Study Design 
3 Objectives and Endpoints 
Updated primary and secondary endpoints to align with statistical 
analyses for the study cohorts. 
4.1 Overall Design 
Added clarification that all cohorts may be enrolling simultaneously. 
Study Interventions 
6.5.2 Prohibited Therapy 
Provided clarification regarding herbal and natural remedies allowing for 
use of marijuana and derivatives for treatments of cancer or cancer 
treatment-related symptoms. 
Statistical Considerations 
9.2 Sample Size Determination 
Added language and table defining confidence intervals for adverse event 
rates in determining ORR. 
9.3.1.2 Secondary Efficacy 
Endpoints 
Updated language for PSA response endpoint to better define who will 
not be evaluable in the study population. 
9.5.1 Cohort Stopping Criteria 
Added language detailing conditions under which an ad hoc Safety 
Assessment Committee meeting will be held and what stopping criteria 
will be used for cohorts in the event of serious adverse events. 
Clarification of Document 
General Revisions 
Document updated to address minor typographical errors and editorial 
changes for clarity. 
 


PORTER – Parker Institute for Cancer Immunotherapy 
Protocol PICI0033 Amendment 2, Version 1.0 
5
TABLE OF CONTENTS 
 
TABLE OF CONTENTS .................................................................................................................5 
LIST OF TABLES .........................................................................................................................10 
LIST OF APPENDIX TABLES ....................................................................................................10 
LIST OF FIGURES .......................................................................................................................10 
1 
PROTOCOL SUMMARY .................................................................................................11 
1.1 
SYNOPSIS .............................................................................................................11 
1.2 
SCHEMA ...............................................................................................................14 
1.3 
SCHEDULE OF ACTIVITIES..............................................................................14 
2 
INTRODUCTION .............................................................................................................18 
2.1 
STUDY RATIONALE ..........................................................................................18 
2.2 
BACKGROUND ...................................................................................................18 
2.3 
BENEFIT/RISK ASSESSMENT ..........................................................................20 
3 
OBJECTIVES AND ENDPOINTS ...................................................................................20 
4 
STUDY DESIGN...............................................................................................................22 
4.1 
OVERALL DESIGN .............................................................................................22 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN ...........................................23 
4.3 
JUSTIFICATION FOR DOSE ..............................................................................23 
4.4 
TREATMENT BEYOND DISEASE PROGRESSION ........................................23 
4.5 
END OF STUDY DEFINITION ...........................................................................24 
5 
STUDY POPULATION ....................................................................................................24 
5.1 
INCLUSION CRITERIA.......................................................................................24 
5.2 
EXCLUSION CRITERIA .....................................................................................25 
5.3 
LIFESTYLE CONSIDERATIONS .......................................................................25 
5.4 
SCREEN FAILURES ............................................................................................25 
6 
STUDY INTERVENTION ................................................................................................25 
6.1 
STUDY INTERVENTION(S) ADMINISTERED ................................................25 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY ......................25 
6.3 
RANDOMIZATION AND BLINDING................................................................26 
6.3.1 
Intervention Assignment .........................................................................26 
6.3.2 
Blinding ...................................................................................................26 


PORTER – Parker Institute for Cancer Immunotherapy 
Protocol PICI0033 Amendment 2, Version 1.0 
6
6.4 
STUDY INTERVENTION COMPLIANCE .........................................................26 
6.5 
CONCOMITANT THERAPY...............................................................................26 
6.5.1 
Permitted Therapy ...................................................................................27 
6.5.2 
Prohibited Therapy ..................................................................................27 
6.6 
DOSE MODIFICATIONS (ESCALATION/TITRATION/ OTHER) ..................28 
6.7 
INTERVENTION AFTER THE END OF THE STUDY .....................................28 
7 
DISCONTINUATIONS OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL..........................................................................28 
7.1 
DISCONTINUATION OF STUDY INTERVENTION ........................................28 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM STUDY ........29 
7.3 
LOST TO FOLLOW-UP .......................................................................................30 
8 
STUDY ASSESSMENTS AND PROCEDURES .............................................................30 
8.1 
EFFICACY ASSESSMENTS ...............................................................................31 
8.1.1 
Laboratory Assessments of Clinical Activity ..........................................32 
8.2 
SAFETY ASSESSMENTS ....................................................................................32 
8.2.1 
Medical History and Demographic Data .................................................33 
8.2.2 
Physical Examinations .............................................................................33 
8.2.3 
Vital Signs ...............................................................................................33 
8.2.4 
Electrocardiograms ..................................................................................33 
8.2.5 
Clinical Safety Laboratory Assessments .................................................34 
8.2.5.1 
Local Laboratory Assessments ..............................................34 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ..............................35 
8.3.1 
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ......................................................36 
8.3.1.1 
Events Requiring Expedited Reporting to the Sponsor .........36 
8.3.2 
Follow-up Event Reporting .....................................................................37 
8.3.3 
Method of Eliciting Adverse Event Information .....................................37 
8.3.4 
Regulatory Reporting Requirements for SAEs .......................................38 
8.3.5 
Pregnancy ................................................................................................38 
8.3.6 
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs .......................................................................................39 
8.3.7 
Adverse Events of Special Interest ..........................................................39 
8.3.8 
Sponsor Contact Information ..................................................................39 


PORTER – Parker Institute for Cancer Immunotherapy 
Protocol PICI0033 Amendment 2, Version 1.0 
7
8.3.8.1 
Emergency Medical Contacts ................................................39 
8.3.8.2 
Safety Reporting Contacts .....................................................40 
8.4 
TREATMENT OF OVERDOSE ...........................................................................40 
8.5 
PHARMACOKINETICS .......................................................................................40 
8.6 
ANTI-DRUG ANTIBODIES ................................................................................40 
8.7 
BIOMARKERS .....................................................................................................40 
8.7.1 
Genetics ...................................................................................................42 
8.7.2 
Exploratory Biomarkers ..........................................................................42 
8.7.3 
Sample Collection for Long-term Future Biomedical Research .............43 
8.7.3.1 
Overview of Long-term Future Biomedical Research ..........43 
8.7.3.2 
Sample Collection .................................................................43 
8.7.3.3 
Withdrawal from Long-term Sample Storage .......................43 
8.7.3.4 
Protection of Data Privacy and Data Generation ..................44 
8.8 
MEDICAL RESOURCE UTILIZATION AND HEALTH ECONOMICS ..........44 
9 
STATISTICAL CONSIDERATIONS...............................................................................44 
9.1 
STATISTICAL HYPOTHESIS .............................................................................44 
9.2 
SAMPLE SIZE DETERMINATION ....................................................................44 
9.3 
STATISTICAL ANALYSES ................................................................................45 
9.3.1 
Efficacy Analyses ....................................................................................46 
9.3.1.1 
Primary Efficacy Endpoint ....................................................46 
9.3.1.2 
Secondary Efficacy Endpoints ..............................................46 
9.3.1.3 
Exploratory Efficacy Endpoints ............................................47 
9.3.2 
Safety Analyses .......................................................................................48 
9.3.3 
Other Analyses ........................................................................................48 
9.3.3.1 
Pharmacokinetic Analysis .....................................................48 
9.3.3.2 
Biomarker Analysis ...............................................................48 
9.3.3.3 
Anti-Drug Antibody Analysis ...............................................48 
9.4 
POPULATIONS FOR ANALYSIS .......................................................................49 
9.5 
INTERIM ANALYSES .........................................................................................49 
9.5.1 
Interim Safety Monitoring .......................................................................49 
9.5.2 
Cohort Expansion Rules ..........................................................................50 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ....52 


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10.1 
APPENDIX 1: REGULATORY, ETHICAL AND STUDY OVERSIGHT 
CONSIDERATIONS .............................................................................................52 
10.1.1 
Compliance with Laws and Regulations .................................................52 
10.1.2 
Institutional Review Board or Independent Ethics Committee ...............52 
10.1.3 
Financial Disclosure ................................................................................53 
10.1.4 
Informed Consent ....................................................................................53 
10.1.5 
Data Protection ........................................................................................54 
10.1.6 
Dissemination of Clinical Study Data .....................................................54 
10.1.7 
Administrative Structure .........................................................................54 
10.1.8 
Data Quality Assurance ...........................................................................55 
10.1.9 
Source Documentation ............................................................................55 
10.1.10 Study and Site Closure ............................................................................56 
10.1.11 Site Inspections ........................................................................................57 
10.1.12 Retention of Records ...............................................................................57 
10.1.13 Publication Policy and Protection of Trade Secrets ................................57 
10.2 
APPENDIX 2: EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) 
PERFORMANCE STATUS ..................................................................................58 
10.3 
APPENDIX 3: RECIST CRITERIA (VERSION 1.1) WITH MODIFICATIONS 
AS RECOMMENDED BY PCWG3 .....................................................................59 
10.3.1 
Measurability of Tumor at Baseline ........................................................59 
10.3.2 
Tumor Response Evaluation ....................................................................60 
10.3.2.1 
Baseline Documentation of Target and Nontarget Lesions ...60 
10.3.2.2 
Evaluation of Target Lesions .................................................60 
10.3.2.3 
Evaluation of Nontarget Lesions ...........................................61 
10.3.2.4 
New Lesions ..........................................................................61 
10.3.2.5 
Evaluation of Overall Response ............................................61 
10.3.3 
Modifications for mCRPC as Recommended by PCWG3 ......................62 
10.3.3.1 
PCWG3 Recommendations with Regard to Baseline Disease 
Assessments ...........................................................................63 
10.3.3.2 
PCWG3 Recommendations with Regard to Measuring 
Outcomes and Reporting .......................................................64 
10.4 
APPENDIX 4: CLINICAL LABORATORY TESTS ...........................................69 
10.5 
APPENDIX 5: ADVERSE EVENTS: DEFINITIONS AND PROCEDURES 
FOR RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING ........70 


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10.5.1 
Definitions ...............................................................................................70 
10.5.1.1 
Definition of AE ....................................................................70 
10.5.1.2 
Definition of SAE ..................................................................71 
10.5.1.3 
Definition of Unexpected AE ................................................72 
10.5.1.4 
Definition of Treatment-emergent AE ..................................73 
10.5.2 
Additional Events Reported in the Same Manner as an SAE .................73 
10.5.3 
Recording AEs and SAEs ........................................................................74 
10.5.4 
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ....................................................................................................78 
10.5.5 
Additional Reporting Considerations ......................................................79 
10.6 
APPENDIX 6: CONTRACEPTIVE GUIDANCE AND COLLECTION OF 
PREGNANCY INFORMATION ..........................................................................83 
10.6.1 
Definitions ...............................................................................................83 
10.6.1.1 
Woman of Childbearing Potential .........................................83 
10.6.2 
Contraception Guidance ..........................................................................83 
10.6.3 
Collection of Pregnancy Information from Male Participants with 
Partners who Become Pregnant ...............................................................85 
10.7 
APPENDIX 7: GENETICS ...................................................................................86 
10.8 
APPENDIX 8: LISTS OF TERMINOLOGY AND ABBREVIATIONS .............87 
10.8.1 
List of Terminology .................................................................................87 
10.8.2 
List of Abbreviations ...............................................................................87 
10.9 
APPENDIX 9: PROTOCOL AMENDMENT HISTORY ....................................91 
11 
REFERENCES ..................................................................................................................92 
 


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LIST OF TABLES 
Table 1: 
Schedule of Activities ............................................................................................15 
Table 2: 
Objectives and Corresponding Endpoints ..............................................................20 
Table 3: 
Laboratory Tests Sent to the Study Site Local Laboratory for Analysis of Disease-
related Endpoints ...................................................................................................32 
Table 4: 
Laboratory Tests Sent to the Study Site’s Local Laboratory for Analysis of Safety
................................................................................................................................35 
Table 5: 
Confidence Intervals for the True Proportion of Adverse Events .........................45 
Table 6: 
Populations for Analysis ........................................................................................49 
 
 
LIST OF APPENDIX TABLES 
Appendix Table 1: 
Response Based on Evaluation of Target Lesions at Each Assessment ..60 
Appendix Table 2: 
Response Based on Evaluation of Nontarget Lesions at Each Assessment
 
61 
Appendix Table 3: 
Evaluation of Overall Response at Each Assessment .............................61 
Appendix Table 4: 
Criteria for Progression at Trial Entry by Disease Manifestation ...........63 
Appendix Table 5: 
Suggested Outcome Measures for Clinical Trials in Metastatic Prostate 
Cancer: Report by Disease Manifestation..............................................................66 
Appendix Table 6: 
Highly Effective Contraceptive Methods for Partner Use ......................84 
 
 
LIST OF FIGURES 
Figure 1: 
Study Schema.........................................................................................................14 
 
 


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1 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS 
Protocol Title: 
A Multicenter, Open-Label, Exploratory Platform Study to Evaluate Biomarkers and 
Immunotherapy Combinations for the Treatment of Patients with Metastatic Castration-resistant 
Prostate Cancer 
Short Title: 
Platform Study for Prostate Researching Translational Endpoints Correlated to Response to 
Inform Use of Novel Combinations (PORTER) 
Rationale: 
This study is designed to test multiple clinical hypotheses and mechanistically-defined 
combinations to evaluate the safety and efficacy of immunotherapy combination in participants 
with metastatic castration-resistant prostate cancer (mCRPC) who have received prior secondary 
androgen receptor signaling inhibitor therapy (eg, abiraterone, enzalutamide, apalutamide). 
Key Objectives and Endpoints: 
Objectives 
Endpoints 
Primary 
 
• To determine the safety of each immunotherapy 
combination in participants with mCRPC. 
• Incidence and severity of AEs. 
Secondary 
 
• To determine the ORR of each immunotherapy 
combination in participants with measurable 
mCRPC. 
• To determine the DCR ≥ 9 months of each 
immunotherapy combination in participants with 
measurable mCRPC. 
• To evaluate the rPFS of each immunotherapy 
combination in participants with mCRPC. 
• To estimate the OS of each immunotherapy 
combination in participants with mCRPC. 
• ORR: A composite endpoint where response is 
defined as a participant meeting at least one of the 
following: 
o CTC response: Change from unfavorable (≥ 5 
cells/7.5 mL of blood) to favorable (≤ 4 cells/7.5 
mL of blood). Participants with a baseline CTC 
value < 5 cells/7.5 mL of blood will not be 
evaluated for this criterion. 
o PSA response: Confirmed PSA response is 
defined as ≥ 50% reduction in PSA from baseline, 
with a repeat assessment confirming the result at 
least 3 weeks later. Participants without a baseline 
and at least 2 post-baseline PSA assessments will 
not be evaluated for this criterion. 
o Confirmed response of CR or PR by objective 
radiographic disease assessment using modified 
RECIST version 1.1 (ie, CR or PR and no 
progression in bone per the PCWG3; Scher et al., 
2016). Per RECIST, to be assigned a best overall 


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response of CR or PR, changes in tumor 
measurements must be confirmed by repeat 
assessments that should be performed no less than 
4 weeks after the criteria for response are first 
met. Participants who received at least 1 dose of 
the combination study intervention or component 
of the combination but do not have RECIST 
assessment for any reason will be counted as not 
responding. 
• DCR at 9 months: Defined as CR, PR, or SD 
for 9 months as best response by PCWG3-modified 
RECIST 1.1. Participants who received at least 1 
dose of the study intervention combination or 
component of the combination but do not have 
RECIST assessment for any reason will be counted 
as not responding. 
• rPFS: Defined as time from initiation of study 
intervention to the first objective evidence of 
radiographic progression, or death due to any cause 
(whichever occurs first). 
• OS: Defined as the time from initiation of study 
invention until death due to any cause. 
• OS rate at 12 months. 
AE(s) = adverse event(s); CR = complete response; CTC = circulating tumor cells; DCR = disease control rate; 
ECOG = Eastern Cooperative Oncology Group; mCRPC = metastatic castration-resistant prostate cancer; 
ORR = objective response rate; OS = overall survival; PCWG3 = Prostate Cancer Clinical Trials Working Group 3; 
PR = partial response; PSA = prostate-specific antigen; RECIST = Response Evaluation Criteria in Solid Tumors; 
rPFS = radiographic progression-free survival; SD = stable disease 
 
Overall Design: 
This is an open-label, non-randomized, exploratory platform protocol designed to assess the 
safety and antitumor activity of multiple immunotherapy combinations in participants with 
mCRPC who have received prior therapy. The platform study will consist of 2 stages: Stage 1, an 
initial stage to evaluate safety, biomarkers, and clinical activity of a combination and Stage 2, an 
expanded cohort, when warranted, based on the safety, clinical activity, and/or biomarker results 
from Stage 1. The Sponsor intends to modify and/or add new combinations to the protocol as 
data emerge from this and other trials. 
Participants must provide consent for archival tissue from a prior biopsy or surgery for prostate 
cancer and must consent to baseline and on-treatment biopsies, if medically feasible. Participants 
will be assigned to receive one of the enrolling combination study interventions and will be 
monitored for safety and response.  
The duration of immunotherapy combination study intervention will be dependent on the 
combination administered and will continue for the duration described in the cohort appendix for 
each respective combination, unless the participant: is no longer clinically benefiting (NLCB; as 


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evidenced by symptomatic or radiographic disease progression and/or clinical deterioration); 
experiences any toxicity meeting specified discontinuation criteria (as described in the cohort 
appendix for each respective combination) or unacceptable toxicity in the best clinical discretion 
of the treating physician (ie, Investigator discretion); reaches the maximum duration of study 
intervention; or withdraws consent. Participants will be followed for up to 2.5 years from the 
time of the initiation of study intervention (see Follow-up). Depending on the combination 
administered, participants who are clinically benefiting, as defined by the Investigator at the end 
of the study treatment period, may have post-study access to the immunotherapy combination 
received during the study after written agreement from the Medical Monitor. 
Number of Participants: 
The study is not intended or powered for hypothesis testing. The study is intended to provide 
preliminary estimates of adverse event (AE) rates, response rates, effect sizes, and confidence 
intervals (CIs) to aid the design of later studies. A sample size of approximately 15 participants 
per combination intervention will provide these preliminary estimates while limiting exposure. 
An additional approximately 15 participants will be enrolled in Stage 2, if the cohort is 
expanded. 
Intervention Groups and Duration: 
This is not a randomized study. Assignment to one of the immunotherapy combinations will be 
made by the Investigator using his/her best clinical discretion based on the participant’s medical 
history and disease status and knowledge of the available immunotherapy combinations open for 
enrollment. 
The dose and schedule selected will be described in the cohort appendix for each respective 
combination (eg, Appendix Cohort A, Appendix Cohort B, etc.). The duration of immunotherapy 
combination study intervention will be dependent on the combination administered. Depending 
on the combination administered, participants who are clinically benefiting as defined by the 
Investigator at the end of the study may have post-study access to the immunotherapy 
combination after agreement from the Medical Monitor. 
Follow-up: 
For up to 2.5 years from the initiation of study intervention, participants in the follow up phase 
will be contacted by telephone by the site personnel every 3 months to collect alternate 
anticancer therapy information and determine survival status. 
Participants will be followed for a up to 2.5 years from the time of the initiation of study 
intervention unless the consent is withdrawn. All participants will be followed for safety for at 
least 100 days after discontinuation of study intervention. 


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Depending on the combination administered, participants who are clinically benefiting, as 
defined by the Investigator at the end of the study treatment period, may have post-study access 
to the immunotherapy combination received during the study after agreement from the Medical 
Monitor. 
A participant will be considered lost to follow-up if he repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site (see Section 7.3). 
Data Monitoring Committee:  This study will use a Safety Assessment Committee (SAC) of 
genitourinary (GU) oncologists and immuno-oncologists, who will meet regularly with the 
Sponsor to monitor safety on an ongoing basis (see Section 9.5.1). 
1.2 
SCHEMA 
The study schema is depicted in Figure 1. 
Figure 1: 
Study Schema 
 
 
1.3 
SCHEDULE OF ACTIVITIES 
The Schedule of Activities (SOA) shown in Table 1 provides a general overview of the types and 
timing of the tests and procedures that will be performed in this study. The combination-specific 
tests and procedures, as well as the timing, will be described in the cohort appendix for each 
respective combination and will supersede the general overview provided here.   


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Table 1: 
Schedule of Activities 
Tests & Procedures 
Screening/ 
Enrollmenta 
On-Treatment: Immunotherapy Combination Treatment 
End of 
Treatmentb 
Follow up 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Onward 
Day 
 
To be determined based on immunotherapy combination 
Refer to the cohort appendix for each respective combination for 
details on combination-specific timing 
14 - 28 days 
after last 
dose 
110 days 
after last 
dose 
Q3Mc 
Window (days) 
-28 
 
± 3 
± 3 
± 3 
± 3 
± 7 
± 10 
± 14 
Informed consentd 
X 
 
 
 
 
 
 
 
 
Review of I/E criteria 
X 
 
 
 
 
 
 
 
 
Medical and cancer history 
X 
 
 
 
 
 
 
 
 
Physical examination 
X 
X 
X 
X 
X 
X 
X 
 
 
ECOG performance status 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital signs (see Section 
8.2.3) 
X 
X 
X 
X 
X 
X 
X 
 
 
Body weighte 
X 
 
 
X 
 
X (every 
3 cycles) 
X 
 
 
Hematology (see Table 4) 
X 
Xf 
Xf 
Xf 
Xf 
Xf 
X 
X 
 
Clinical chemistry (see 
Table 4) 
X 
Xf 
Xf 
Xf 
Xf 
Xf 
X 
X 
 
Urinalysis 
X 
 
 
 
 
 
X 
 
 
Prostate-specific antigen 
X 
X 
X 
X 
X 
X 
X 
X 
 
Testosterone level 
X 
 
 
 
 
 
 
 
 
12-lead ECGg 
X 
 
X 
 
X 
 
 
 
 
Circulating tumor cellsh 
 
Xf 
Xf 
Xf 
Xf 
Xf 
X 
 
 
cfDNA (blood)i 
X 
 
Xf 
 
Xf 
 
X 
 
 
Circulating soluble 
analytes/PK/ADAj 
X 
Xf 
Xf 
Xf 
Xf, 
 
X 
 
 
Blood immune biomarkersj 
X 
Xf 
Xf 
Xf 
Xf 
 
X 
 
 
Archival tumor tissue 
X 
 
 
 
 
 
 
 
 


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Tests & Procedures 
Screening/ 
Enrollmenta 
On-Treatment: Immunotherapy Combination Treatment 
End of 
Treatmentb 
Follow up 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Onward 
Day 
 
To be determined based on immunotherapy combination 
Refer to the cohort appendix for each respective combination for 
details on combination-specific timing 
14 - 28 days 
after last 
dose 
110 days 
after last 
dose 
Q3Mc 
Window (days) 
-28 
 
± 3 
± 3 
± 3 
± 3 
± 7 
± 10 
± 14 
Tumor biopsyk 
X 
 
X 
 
 
 
X (at PD 
[optional])k 
 
 
Stool collectionl 
X 
 
X 
 
 
 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse events 
All AEs/AESIs/SAEs will be collected for at least 100 days after the last dose of study interventionm 
 
Immunotherapy 
combination administrationn 
 
Refer to the cohort appendix for each respective combination for 
details on study intervention administration 
 
 
 
Radiographic disease 
assessment 
X 
Per PCWG3 guidelines: Every 8 to 9 weeks (± 1 week) for first 24 weeks, and every 12 weeks (± 1 week) 
thereafter until radiographic PD or start of subsequent therapy. 
Refer to the cohort appendix for each respective combination for cohort-specific details 
Review of alternate 
anticancer therapyo 
 
 
 
 
 
 
 
X 
X 
Follow-up for overall 
survival 
 
 
 
 
 
 
 
X 
X 
ADA = anti-drug antibodies; AE(s) = adverse event(s); AESI(s) = adverse event(s) of special interest; cfDNA = cell-free deoxyribonucleic acid; ECG = electrocardiogram; 
ECOG  = Eastern Cooperative Oncology Group; EOT = end of treatment; I/E = inclusion/exclusion; PCWG3 = Prostate Cancer Clinical Trials Working Group 3; PD = progressive 
disease; PD-1 = programmed cell death 1; PK = pharmacokinetics; Q3M = every 3 months; SAE(s) = serious adverse event(s) 
a Tests/procedures performed as standard of care prior to obtaining informed consent and within 28 days prior to the first day of study intervention administration do not have to 
be repeated at screening. 
b The End of Treatment Visit will be completed following the last dose of study intervention, either at completion of the on-treatment phase or at early discontinuation. 
c For up to 2.5 years from the initiation of study intervention, participants in the follow up phase will be contacted by the site to collect alternate anticancer therapy information 
and determine survival status. 
d Informed consent must be obtained prior to any study-specific procedures and may be obtained prior to the 28-day screening window. 
e Body weight may be required more frequently for study interventions using weight-based dosing. Combination-specific frequency will be provided in the cohort appendix for 
each respective combination. 
f Blood samples should be collected prior to administration of any study intervention.  
g 12-Lead ECG will be collected at screening, Cycle 2 and Cycle 4. 


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h Circulating tumor cells will be collected at baseline (ie, Day 1 of Cycle 1 prior to study intervention administration), Day 1 of each cycle (prior to study intervention 
administration), and EOT. 
i cfDNA (blood) will be collected at baseline (ie, screening visit prior to study intervention administration), Day 1 of Cycle 2 and Cycle 4, and EOT. 
j Circulating soluble analytes, PK and ADA blood sample, and/or blood immune biomarkers will be collected at baseline (ie, screening and/or Day 1 of Cycle 1 prior to study 
intervention administration), prior to study intervention administration on Day 1 of Cycles 2-4, and EOT. 
k Participants will undergo 2-3 tumor biopsies: prior to beginning study intervention (ie, baseline biopsy, mandatory for all participants, including those with bone only disease if 
medically feasible), and during treatment (ie, on-treatment biopsy during Cycle 2, if medically feasible). On-treatment biopsy should occur as early as possible after the second 
dose (Day 2 – Day 10 of Cycle 2); however, any on treatment biopsy after Day 1 of Cycle 2 will be accepted. An optional biopsy may be obtained at the time of disease 
progression, including from participants who respond and subsequently progress. Every attempt should be made for the on-treatment biopsies to be taken from the same lesion as 
the pre-treatment biopsy when feasible. 
l Stool will be collected at screening and during Cycle 2, if possible. Otherwise, any on-treatment stool sample will be acceptable. The stool sample may be collected at the clinic 
or at the participant’s home. 
m All SAEs will be collected from the time the participant signs informed consent. Prior to initiation of study intervention, only SAEs that are related to a protocol-mandated 
intervention, including those that occur prior to the assignment of study procedures should be reported. All AEs, including AESIs (as applicable and as defined in the cohort 
appendix for each respective combination), will be collected from the start of study intervention. All AEs/AESIs/SAEs will be collected for at least 100 days after the last dose of 
study intervention. Refer to Section 8.3 for details regarding safety reporting for this study. 
n The duration of the immunotherapy combination will be dependent on the combination administered, and will continue for the duration described in the cohort appendix for each 
respective combination, unless the participant: is no longer clinically benefiting (as evidenced by symptomatic or radiographic disease progression and/or clinical deterioration); 
experiences any toxicity meeting specified discontinuation criteria (as described in the cohort appendix for each respective combination) or unacceptable toxicity in the best 
clinical discretion of the treating physician; reaches the maximum duration of study intervention; or withdraws consent. 
o Collection of information related to any post-study intervention alternate anticancer therapy. 


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2 
INTRODUCTION 
Immunotherapy is an attractive strategy for patients with advanced prostate cancer because it has 
the potential to lead to durable responses and is generally better tolerated. However, the only 
United States (US) Food and Drug Administration (FDA) approved immunotherapy for prostate 
cancer to date is sipuleucel-T, an autologous cellular vaccine designed to stimulate an immune 
response targeting prostatic acid phosphatase (PAP) (Kantoff et al., 2010). The only phase 3 
randomized controlled trial of immune checkpoint blockade, with ipilimumab in metastatic 
castration-resistant prostate cancer (mCRPC) patients after docetaxel, failed to meet its primary 
endpoint of overall survival (OS; Kwon et al., 2014). Early phase studies of programmed cell 
death 1 (PD-1) blockade in advanced malignancies have not demonstrated clinical activity in 
advanced prostate cancer (Topalian et al., 2012). More recently, anti-PD-1 therapy has been 
shown to have limited activity as a single agent in patients with mCRPC who have programmed 
cell death ligand 1 (PD-L1) expression and tumor-infiltrating leukocytes, including one patient 
with microsatellite instability (MSI) and mismatch repair (MMR) deficiency (Graff et al., 2016). 
Thus, there is a critical need to develop new approaches to make immunotherapy available to 
patients with mCRPC. Using an approach similar to the multi-arm, multi-stage platform trial 
(STAMPEDE), which has provided an innovative trial design for testing new treatment 
approaches against the standard of care for prostate cancer, including mCRPC (Sydes et al, 2018; 
Parmar et al., 2017), a platform study of immunotherapy combinations is proposed. A recently-
opened, ongoing study at the National Cancer Institute is investigating a similar platform design 
for immunotherapy combinations to treat mCRPC (QuEST1; Redman et al., 2018). With the 
development of new immuno-oncology therapies demonstrating enhanced effects within the 
immune system, opportunities for combination clinical trials in the area of antitumor immune 
response in mCRPC have increased. Given the lack of clinical benefit of immunotherapy in 
mCRPC and the multiple hypotheses around the immune evasion and resistance mechanisms, an 
adaptive platform clinical study is well suited to advance the understanding to inform treatment 
of this underserved patient population. 
2.1 
STUDY RATIONALE 
This study is designed to evaluate multiple clinical hypotheses and mechanistically-defined 
combinations to evaluate the safety and efficacy of immunotherapy combinations in participants 
with mCRPC who have received prior secondary androgen receptor signaling inhibitor therapy 
(eg, abiraterone, enzalutamide, apalutamide). 
2.2 
BACKGROUND 
Prostate cancer remains the most commonly diagnosed malignancy, accounting for 19% of 
newly-diagnosed cancer in men in the US. Despite recent decreases, it is estimated that 


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approximately 164,690 new cases will be diagnosed in 2018, and 29,430 men are estimated to 
die of prostate cancer in 2018. Prostate cancer is the second leading cause of cancer death among 
men in the US (Siegel et al., 2018). The 5-year survival for early stage (stage I, II, III) prostate 
cancer is almost 100%, however, almost one-third of the early stage patients will recur with 
metastatic disease (stage IV). For patients with metastatic disease, 5-year survival rates decrease 
to about 30% (Siegel et al., 2018; McNeel et al., 2016). Androgen deprivation therapy (ADT) is 
the mainstay of initial therapy for metastatic disease. Although prostate cancer usually initially 
responds to ADT, resistance frequently develops and progresses to mCRPC. Despite the 
approval of several mCPRC therapies in the past few years, including androgen signaling 
inhibitors, chemotherapy, radiopharmaceutical, and cancer vaccine, currently available 
treatments remain inadequate to manage mCPRC. 
Immunotherapy has changed the landscape of cancer treatments for a number of malignancies, 
resulting in marked clinical benefit in patients with cancers, including metastatic melanoma, non-
small cell lung cancer and renal cell carcinoma. In 2010, the first cancer vaccine, sipuleucel-T 
(Provenge®) was approved for prostate cancer; however, subsequent efforts to demonstrate 
effectiveness of immunotherapies in prostate cancer have been disappointing. While the immune 
responsiveness of prostate tumors has been contested for nearly 30 years, more recent evidence 
suggests prostate cancer is an immunologically recognized disease (Drake, 2010). Intratumoral 
natural killer (NK) cells and macrophages have been observed, and both CD4+ and CD8+ T cells 
that recognize prostate-cancer-specific antigens have been found in tumor sites, as well as in 
peripheral immune cells (Lee and Gujar, 2018). Furthermore, the detection of prostate-specific 
autoantibodies in patients with prostate cancer has strengthened the argument for the 
immunogenicity of prostate cancer (Di Lorenzo et al., 2011). Thus, there is preclinical and 
clinical evidence that prostate could be susceptible to immune-based therapy approaches. 
Notwithstanding, there have been several notable immunotherapy failures in prostate cancer, 
including in clinical trials with novel vaccine-based approaches and immune checkpoint 
inhibitors, including anti-PD-1, anti-PD-L1, and anti- cytotoxic T-lymphocyte-associated 
protein 4 (CTLA-4) (Kwon et al., 2014; Beer et al., 2017; Brahmer et al., 2010; Topalian et al., 
2012). Thus, prostate cancer has been characterized as an immunologically unresponsive, or 
“cold,” tumor with PD-L1 expression in a minority of tumors (Martin et al., 2015). As a “cold” 
tumor, the immunosuppressive microenvironment may contribute to the low responses to 
immunotherapy in prostate cancer (Patel and Fong, 2018), including low mutational burden 
(Alexandrov et al., 2013), low abundance of intratumoral T cells (Flammiger et al. 2012), and 
low cytolytic activity of NK cells (Pasero et al., 2016), as well as a high accumulation of 
regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) in the tumor (Miller et 
al., 2006; Lopez-Bujanda and Drake, 2017). Comprehensive correlative studies of prostate 
cancer in a window of opportunity study also demonstrated that elevated expression of PD-L1 


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and VISTA (V-domain Ig suppressor of T cell activation) on macrophages may contribute to the 
resistance to checkpoint inhibitors (Gao et al., 2017). Therefore, treatment-based approaches that 
address these mechanisms of immune evasion through novel combination therapies using novel 
vaccine strategies, alleviating immunosuppression in the tumor microenvironment and new 
immune agents, or identifying immune-responsive patient subsets may enable effective 
immunotherapy treatment approaches for mCRPC with high unmet medical need. 
2.3 
BENEFIT/RISK ASSESSMENT 
The benefit/risk assessment is dependent on the combination administered and will be described 
in the cohort appendix for each respective combination (eg, Appendix Cohort A, Appendix 
Cohort B, etc.).  
3 
OBJECTIVES AND ENDPOINTS 
The study objectives and endpoints are listed in Table 2. 
Table 2: 
Objectives and Corresponding Endpoints 
Objectives 
Endpoints 
Primary 
 
• To determine the safety of each immunotherapy 
combination in participants with mCRPC. 
• Incidence and severity of AEs. 
Secondary 
 
• To determine the ORR of each immunotherapy 
combination in participants with measurable 
mCRPC. 
• To determine the DCR ≥ 9 months of each 
immunotherapy combination in participants with 
measurable mCRPC. 
• To evaluate the rPFS of each immunotherapy 
combination in participants with mCRPC. 
• To estimate the OS of each immunotherapy 
combination in participants with mCRPC. 
• ORR: A composite endpoint where response is 
defined as a participant meeting at least one of the 
following: 
o CTC response: Change from unfavorable (≥ 5 
cells/7.5 mL of blood) to favorable (≤ 4 cells/7.5 
mL of blood). Participants with a baseline CTC 
value < 5 cells/7.5 mL of blood will not be 
evaluated for this criterion. 
o PSA response: Confirmed PSA response is 
defined as ≥ 50% reduction in PSA from baseline, 
with a repeat assessment confirming the result at 
least 3 weeks later. Participants without a baseline 
and at least 2 post-baseline PSA assessments will 
not be evaluated for this criterion. 
o Confirmed response of CR or PR by objective 
radiographic disease assessment using modified 
RECIST version 1.1 (ie, CR or PR and no 
progression in bone per the PCWG3; Scher et al., 
2016). Per RECIST, to be assigned a best overall 
response of CR or PR, changes in tumor 
measurements must be confirmed by repeat 
assessments that should be performed no less than 
4 weeks after the criteria for response are first 
met. Participants who received at least 1 dose of 
the combination study intervention or component 


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of the combination but do not have RECIST 
assessment for any reason will be counted as not 
responding. 
• DCR at 9 months: Defined as CR, PR, or SD 
for 9 months as best response by PCWG3-modified 
RECIST 1.1. Participants who received at least 1 
dose of the study intervention combination or 
component of the combination but do not have 
RECIST assessment for any reason will be counted 
as not responding. 
• rPFS: Defined as time from initiation of study 
intervention to the first objective evidence of 
radiographic progression, or death due to any cause 
(whichever occurs first). 
• OS: Defined as the time from initiation of study 
invention until death due to any cause. 
• OS rate at 12 months. 
Exploratory 
 
• To evaluate tumor and immune biomarkers and their 
association with treatment outcome (antitumor 
activity and/or safety). 
• To evaluate the PK of the components of the 
immunotherapy combination. 
• To evaluate the immunogenicity (ADA) of the 
components of the immunotherapy combination. 
• Association of tumor and immune biomarkers from 
tissue, blood, and/or stool with clinical outcomes, 
including ORR, DCR, rPFS, and tolerability. 
Biomarkers to be studied will be chosen based on 
the immunotherapy combination. 
• Molecular characterization of CTC and evaluation of 
percent change from baseline. 
• Enumeration of CTC ≥ 1 at baseline with conversion 
to CTC0 on treatment. 
• PSA: 
o Percent change in PSA from baseline at 12 weeks. 
o Maximum change in PSA at any point after 
initiation of study intervention. 
o Time to PSA progression defined as the time 
from study treatment initiation to the date that a 
≥ 25% increase and absolute increase of ≥ 2 
ng/mL above the nadir (or baseline value for 
participants who did not have a decline in PSA) in 
PSA. The increase must be confirmed by a second 
consecutive assessment conducted at least 3 
weeks later. 
• Sparse PK analysis. 
• Presence of ADA against biologic components of 
each immunotherapy combination. 
ADA = anti-drug antibodies; AE(s) = adverse event(s); CR = complete response; CTC = circulating tumor cells; 
CTC0 = a measure of zero CTC; DCR = disease control rate; ECOG = Eastern Cooperative Oncology Group; 
mCRPC = metastatic castration-resistant prostate cancer; ORR = objective response rate; OS = overall survival; 
PCWG3 = Prostate Cancer Clinical Trials Working Group 3; PK = pharmacokinetics; PR = partial response; 
PSA = prostate-specific antigen; RECIST = Response Evaluation Criteria in Solid Tumors; rPFS = radiographic 
progression-free survival; SD = stable disease 


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4 
STUDY DESIGN 
4.1 
OVERALL DESIGN 
This is an open-label, non-randomized, exploratory platform study designed to assess the safety 
and antitumor activity of multiple immunotherapy combinations in participants with mCRPC 
who have received prior therapy. The platform study will consist of 2 stages: Stage 1, an initial 
stage to evaluate safety, biomarkers, and clinical activity of the combination and Stage 2, an 
expanded cohort, when warranted, based on the safety, clinical activity, and/or biomarker results 
from Stage 1. The Sponsor intends to modify and/or add new combinations to the protocol as 
data emerge from this and other trials. 
This study will be conducted in participants with histologically-confirmed mCRPC that is 
measurable or non-measurable by Prostate Cancer Clinical Trials Working Group 3 (PCWG3)-
modified Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Participants with brain 
metastases are excluded unless treated and stable by imaging for at least 4 weeks prior to the first 
dose of study intervention. Participants must have received prior secondary androgen receptor 
signaling inhibitor therapy (eg, abiraterone, enzalutamide, apalutamide) and may have received 
prior chemotherapy for mCRPC. Participants must consent to baseline and on-treatment biopsies, 
if medically feasible. A minimum of 7 participants in each cohort must have a non-bone 
metastatic lesion that can be biopsied. Participants must have adequate organ and hematologic 
function and acceptable performance status. 
After consenting to participate in this clinical trial, participants will be screened for enrollment. 
If they meet all inclusion criteria and do not meet exclusion criteria, they will be referred for a 
pre-treatment biopsy of a metastatic lesion. Participants must also provide consent for archival 
tissue from a prior biopsy or surgery for prostate cancer. Each participant will be assigned per 
the Investigator’s discretion to receive one of the enrolling combination study interventions. 
Participants will be monitored for safety and efficacy. An on-treatment biopsy is required when 
medically feasible, ideally after the second dose of the immunotherapy combination. An optional 
biopsy may be obtained at the time of disease progression, including from participants who 
respond and subsequently progress. The on-treatment biopsies should be taken from the same 
lesion as the pre-treatment biopsy when feasible. 
Approximately 15 participants, including a minimum of 7 with a non-bone metastatic lesion that 
can be biopsied, will be enrolled in each immunotherapy combination cohort in Stage 1. 
Enrollment of participants in each cohort may occur simultaneously. An additional 
approximately 15 participants, including a minimum of 7 with a non-bone metastatic lesion, will 
be enrolled in Stage 2, if the cohort is expanded. 


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The duration of immunotherapy combination study intervention will be dependent on the 
combination administered and will continue for the duration described in the cohort appendix for 
each respective combination, unless the participant is no longer clinically benefiting (as 
evidenced by symptomatic or radiographic disease progression and/or clinical deterioration); 
experiences any toxicity meeting specified discontinuation criteria (as described in the cohort 
appendix for each respective combination) or unacceptable toxicity in the best clinical discretion 
of the treating physician; reaches the maximum duration of study intervention; or withdraws 
consent. Participants will be followed for a up to 2.5 years from the time of the initiation of study 
intervention. Depending on the combination administered, participants who are clinically 
benefiting, as defined by the Investigator at the end of the study treatment period, may have post-
study access to the immunotherapy combination received during the study after agreement from 
the Medical Monitor. 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
The scientific rationale for this study is provided in Section 2. The scientific rationale for the 
individual cohorts will be provided in the cohort appendix for each respective combination. 
4.3 
JUSTIFICATION FOR DOSE 
The dose and schedule selected will be described in the cohort appendix for each respective 
combination (eg, Appendix Cohort A, Appendix Cohort B, etc.). The duration of immunotherapy 
combination study intervention will be dependent on the combination administered. 
4.4 
TREATMENT BEYOND DISEASE PROGRESSION 
Accumulating evidence indicates that a minority of patients treated with immunotherapy may 
derive clinical benefit from continued treatment despite initial evidence of disease progression 
(Wolchok et al., 2009). The PCWG3 introduced the concept of treatment beyond progression 
(where clinical benefit by one or more disease manifestations is being observed) as clinical 
measure for outcome in prostate cancer (Scher et al., 2016). The PCWG3 recommendation 
included a reporting metric of no longer clinically benefiting (NLCB), defined as the date and 
specific reason(s) therapy was ultimately discontinued, to allow individualized provider-patient 
decisions to discontinue or continue treatment. 
Therefore, participants receiving immunotherapy combinations in this study will be permitted to 
continue study intervention beyond initial Investigator-assessed disease progression (according 
to PCWG3-modified RECIST 1.1) provided all of the following criteria are met: 
• Absence of symptoms and signs indicating rapid disease progression, including decline in 
performance status, and confirmation of disease status required 


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• Absence of progressive tumor at critical anatomical sites (eg, cord compression) 
requiring urgent alternative medical intervention 
• Participant is adequately consented regarding the potential risks of continuation of 
ineffective therapy/failure to initiate effective alternative therapy, if any 
• Written agreement from the Medical Monitor. 
 
The assessment of clinical benefit should consider whether the participant is clinically 
deteriorating and unlikely to receive further benefit from continued treatment. 
All decisions to continue treatment beyond initial progression must be discussed with the 
Medical Monitor and written agreement from the Medical Monitor should be documented in the 
study records. 
Participants should discontinue study intervention upon evidence of further progression, defined 
as an additional ≥ 10% increase in tumor burden from the time of initial progression (including 
all target lesions and new measurable lesions, or unequivocal progression of non-target lesions). 
New lesions are considered measurable at the time of initial progression if the diameters are ≥ 10 
mm (except for pathological lymph nodes, which must have a short axis of ≥ 15 mm). Any new 
lesion considered non-measurable at the time of initial progression may become measurable and 
therefore included in the tumor burden measurement if the diameter increases to ≥ 10 mm 
(except for pathological lymph nodes, which must have an increase in short axis to ≥ 15 mm). 
4.5 
END OF STUDY DEFINITION 
The end of this study is defined as the date when the last visit of the last participant occurs or the 
date at which the last data point required for statistical analysis or safety follow-up is received 
from the last participant, whichever occurs later.  
The total length of each study cohort, from screening of the first participant to the end of the 
cohort, will depend on the study intervention administered and will be described in the cohort 
appendix for each respective combination. 
5 
STUDY POPULATION 
This study will enroll participants with mCRPC. Eligibility criteria are provided in the cohort 
appendix for each respective combination (eg, Appendix Cohort A, Appendix Cohort B, etc.). 
5.1 
INCLUSION CRITERIA 
Inclusion criteria are provided in the cohort appendix for each respective combination. 


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5.2 
EXCLUSION CRITERIA 
Exclusion criteria are provided in the cohort appendix for each respective combination. 
5.3 
LIFESTYLE CONSIDERATIONS 
Lifestyle considerations or restrictions, if required, will be provided in the cohort appendix for 
each respective combination (eg, Appendix Cohort A, Appendix Cohort B, etc.). 
5.4 
SCREEN FAILURES 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently enrolled in the study. A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure participants to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility criteria, 
and any serious adverse event (SAE). 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened. 
6 
STUDY INTERVENTION 
Study intervention is defined as any investigational intervention(s), marketed product(s) or 
placebo intended to be administered to a study participant according to the study protocol. 
6.1 
STUDY INTERVENTION(S) ADMINISTERED 
The dose and schedule selected will be described in the cohort appendix for each respective 
combination (eg, Appendix Cohort A, Appendix Cohort B, etc.). The duration of immunotherapy 
combination study intervention will be dependent on the combination administered. 
Administration of study intervention will be performed in a monitored setting in which there is 
immediate access to trained personnel and adequate equipment and medicine to manage 
potentially serious reactions.  
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
The Investigator or designee must confirm that appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are reported 
and resolved before use of the study intervention. 
Only participants enrolled in the study may receive study intervention and only authorized site 
staff may dispense and/or administer study intervention. All study intervention must be stored in 
a secure, environmentally controlled, and monitored (manual or automated) area in accordance 


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with the labeled storage conditions with access limited to the Investigator and authorized site 
staff. 
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records). 
Further guidance and information for the final disposition of unused study interventions are 
provided in the Pharmacy Manuals. 
6.3 
RANDOMIZATION AND BLINDING 
6.3.1 
Intervention Assignment 
This is not a randomized study. Assignment to one of the immunotherapy combinations will be 
made by the Investigator using his/her best clinical discretion based on the participant’s medical 
history and disease status and knowledge of the available immunotherapy combinations open for 
enrollment. 
6.3.2 
Blinding 
This is an open-label trial; therefore, the Sponsor, Investigator, and participant will know the 
study intervention administered. 
6.4 
STUDY INTERVENTION COMPLIANCE 
Study intervention compliance will be described in the cohort appendix for each respective 
combination as compliance measures will be dependent on how the immunotherapy combination 
is administered. 
6.5 
CONCOMITANT THERAPY 
Any medication or vaccine (including over-the-counter [OTC] or prescription medicines, 
vitamins, and/or herbal supplements) that the participant is receiving at the time of enrollment or 
receives during the study must be recorded along with: 
• Reason for use 
• Dates of administration including start and end dates (or indicated as ongoing, as 
applicable) 
• Dosage information including dose, route of administration, and frequency 
 
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 


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6.5.1 
Permitted Therapy 
Concomitant medications or treatments (eg, acetaminophen/paracetamol, diphenhydramine) may 
be prescribed if considered necessary for adequate prophylactic or supportive care except for 
those medications identified as “excluded” in Section 6.5.2 or in the cohort appendix for each 
respective combination (for combination-specific excluded medications). 
All concomitant medication will be recorded on the electronic case report form (eCRF), 
including all prescription, OTC and intravenous (IV) medications and fluids. If changes occur 
during the trial period, documentation of drug dosage, frequency, route, and date should also be 
included on the eCRF. 
All concomitant medications received within 28 days prior to the first dose of study intervention 
and 100 days after the last dose of study intervention should be recorded. Concomitant 
medications administered after 100 days after the last dose of study intervention should be 
recorded for SAEs and adverse events of special interest (AESIs) (as applicable and as defined in 
the cohort appendix for each respective combination). 
6.5.2 
Prohibited Therapy 
The medications listed below are prohibited during the study. The Sponsor must be notified if a 
participant receives any of these during the study. 
• Any concurrent systemic chemotherapy, immunotherapy, biologic, hormonal treatment or 
radiotherapy (except palliative radiotherapy) not specified in this protocol or subsequent 
amendments. Concurrent use of hormones for noncancer-related conditions are permitted. 
o Exception: Androgen deprivation therapy. Participants are required to maintain 
castrate-level testosterone (< 50 ng/dL) with a gonadotropin-releasing hormone 
(GnRH) agonist or antagonist ± antiandrogen. Participants without history of bilateral 
orchiectomy are required to remain on ADT. 
• Any concurrent investigational anticancer therapy not specified in this protocol or 
subsequent amendments. 
• Anti-CTLA-4, anti-PD-L1, or anti-PD-1 agents through 100 days after the last dose of 
study intervention, except for agents that are not part of the immunotherapy 
combinations. 
• Immunosuppressive medications at chronic systemic doses > 10 mg/day prednisone (or 
equivalent) within 28 days before the first dose (note: hormone replacement therapy 
(HRT), such as thyroxine, insulin, or physiologic corticosteroid replacement therapy ≤ 10 
mg of prednisone/day for adrenal or pituitary insufficiency, etc. is not considered a form 
of systemic treatment). A temporary course of steroids (ie, contrast allergy, chronic 


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obstructive pulmonary disease) may be permitted, depending on the duration and dose, 
after discussion and agreement with the Medical Monitor. 
• Live attenuated vaccines within 30 days prior to the first dose of study intervention and 
through 180 days after the last dose of study intervention. Examples of live vaccines 
include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster, 
yellow fever, rabies, bacille Calmette-Guerin (BCG), and typhoid vaccine. 
• Any botanical preparation (eg herbal supplements or traditional Chinese medicines) 
intended to treat the disease under study. Use of marijuana and its derivatives for 
treatment of symptoms related to cancer or to cancer treatment are permitted. 
 
6.6 
DOSE MODIFICATIONS (ESCALATION/TITRATION/ 
OTHER) 
Specific anticipated or potential toxicities associated with the administration of the study 
intervention, as well as the measures taken intended to avoid or minimize such toxicity in this 
trial, are described in the cohort appendix for each respective combination. 
Refer to the Investigator’s Brochure (IB) for the individual components of each combination for 
complete summaries of safety information. 
6.7 
INTERVENTION AFTER THE END OF THE STUDY 
Participants who are clinically benefiting as defined by the Investigator at the end of the study 
may have post-study access to the immunotherapy combination after agreement from the 
Medical Monitor. 
7 
DISCONTINUATIONS OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1 
DISCONTINUATION OF STUDY INTERVENTION 
Participants must discontinue study intervention if they experience any of the following: 
• Intolerable toxicity related to study intervention, including the development of an adverse 
event (AE) determined by the Investigator to be unacceptable even with the participant’s 
potential response to intervention due to the severity of the event 
• Any medical condition that may jeopardize participant safety if he continues to receive 
the study intervention 
• Use of another anticancer therapy (see Section 6.5.2 and as described in the cohort 
appendix for each respective combination, as applicable) 
• Symptomatic deterioration attributed to disease progression 


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• Progression of disease: Either unequivocal symptomatic progression necessitating a 
change in therapy in the opinion of the treating physician or confirmed radiographic 
progression as defined by cross-sectional imaging per PCWG3-modified RECIST 1.1 
(see Appendix 3) in the absence of clinical benefit (refer to Section 4.4). 
 
Participants have the right to voluntarily withdraw from study intervention at any time for any 
reason. In addition, the Investigator has the right to withdraw a participant from study 
intervention at any time. Reasons for withdrawal from the study intervention may include, but 
are not limited to, the following: 
• Investigator or Sponsor determines it is in the best interest of the participant 
• Participant noncompliance 
 
The primary reason for study intervention discontinuation should be documented on the 
appropriate eCRF page. 
The visit at which disease assessment shows progressive disease (PD) may be used as the 
treatment discontinuation visit if it occurs within 28 (± 7) days after the last dose of study 
intervention. Participants who discontinue study intervention for any reason other than PD or 
loss of clinical benefit should have an end of treatment discontinuation assessment as outlined in 
the SOA (see Section 1.3). All participants should continue follow-up as outlined in the SOA. 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM 
STUDY 
The total length of study participation, from participant screening to the end of study, is expected 
to be approximately 31 months.  
When study intervention is discontinued, participants should have an end of treatment 
discontinuation assessment followed up by an assessment 14-28 days after the last dose of study 
intervention as outlined in the SOA (see Section 1.3). Information on survival follow-up and new 
anticancer therapy will be collected every 3 months for up to 2.5 years from the initiation of 
study intervention until any of the following occurs: 
• Death 
• Loss to follow-up 
• Study termination by the Sponsor 
• Participant requests to be withdrawn from follow-up 
 


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A participant may withdraw consent at any time and discontinue study intervention and further 
participation in the study. This request must be documented in the source documents and signed 
by the Investigator. The Sponsor may retain and continue to use any data collected before such 
withdrawal of consent. Participants who withdraw consent will not be followed for any reason 
after consent has been withdrawn. However, the study staff may use a public information source 
(eg, county records) to obtain information about survival status only. 
Other reasons for discontinuation of study intervention and/or participation in a follow-up phase 
of the study may include death, AEs, physician decision, protocol deviation, eligibility not met, 
progressive disease. A participant is considered to have completed all phases of the study as 
defined in the cohort appendix for each respective combination, including the lead-in phase, as 
applicable, the treatment phase, and the safety and survival follow-up after last dose of study 
intervention. 
The primary reason for withdrawal from study should be documented on the appropriate eCRF 
page. 
7.3 
LOST TO FOLLOW-UP 
A participant will be considered lost to follow-up if he repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.  
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study. 
• Before a participant is deemed lost to follow-up, the Investigator or designee will make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record or study file. 
• Should the participant continue to be unreachable, he will be considered to have 
withdrawn from the study. 
 
8 
STUDY ASSESSMENTS AND PROCEDURES 
Please see Section 1.3 for the schedule of activities and procedures to be performed during the 
study. All activities should be performed and documented for each participant in the order of the 
SOA. Participants will be closely monitored for safety and tolerability throughout the study. 


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Participants should be assessed for toxicity prior to each dose; dosing will occur only if the 
clinical assessment and local laboratory test values are acceptable as deemed by the Principal 
Investigator (PI). 
If the timing of a protocol-mandated study visit coincides with a holiday, weekend, or other 
administrative disruption that precludes the visit, the visit should be scheduled on the nearest 
feasible date. The time between doses must not be less than described in the cohort appendix for 
each respective combination.  
Collection of any non-safety-related data or participant samples may be terminated by the 
Sponsor at any time if further collection of such data or samples is also not related to the study’s 
primary or secondary objectives. The decision to discontinue any data collection will be 
communicated to the sites and Institutional Review Board/Independent Ethics Committee 
(IRB/IEC) by means of a memorandum and will not require a protocol amendment. 
8.1 
EFFICACY ASSESSMENTS 
Participants will undergo tumor assessments as designated in the SOA (see Section 1.3) 
regardless of dose delays, until loss of clinical benefit as determined by the Investigator (unless 
the participant withdraws consent, or the Sponsor terminates the study). All participants who 
discontinue study intervention for reasons other than disease progression (eg, AEs) will continue 
tumor assessments for up to 2.5 years from initiation of study intervention or until study 
completion, death, disease progression, loss to follow-up, withdrawal of consent, or study 
termination, whichever occurs first. At the Investigator’s discretion, tumor assessments may be 
repeated at any time if PD is suspected. 
Measurable and evaluable lesions should be assessed and documented at screening. Tumor 
assessments performed as standard of care prior to obtaining informed consent and within 28 
days prior to the first dose of study intervention do not have to be repeated at screening. 
Screening assessments must include computerized tomography (CT) scans (with IV contrast 
unless contraindicated and oral contrast as appropriate per institutional standards) of the chest, 
abdomen, and pelvis. A spiral CT scan of the chest may be obtained but is not a requirement. If a 
CT scan with contrast is contraindicated (ie, in participants with contrast allergy or impaired 
renal clearance), a non-contrast CT scan of the chest maybe performed and magnetic resonance 
imaging (MRI) scans of the abdomen and pelvis should be performed. If the participant has a 
known history of brain metastases or is symptomatic in the opinion of the Investigator, scans of 
the head should be obtained. 
If a CT scan for a tumor assessment is performed in a positron emission tomography (PET)/CT 
scanner, the CT acquisition must be consistent with the standards for a full contrast diagnostic 
CT scan. 


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Bone scans (technetium-99m [TC-99m]) should be performed at screening if clinically indicated. 
If bone metastases are present at screening and cannot be seen on CT or MRI scans, or if 
clinically indicated, TC-99m bone scans should be repeated when complete response (CR) is 
identified in target disease or when progression in bone is suspected. 
CT scans of the neck or extremities should also be performed if clinically indicated and repeated 
throughout the study if there is evidence of disease at screening.  
All measurable and evaluable lesions should be reassessed at each subsequent tumor evaluation. 
The same radiographic procedures used to assess disease sites at screening should be used for 
subsequent tumor assessments (eg, same contrast protocol for CT scans). 
Response will be assessed by the Investigator using PCWG3-modified RECIST 1.1 (see 
Appendix 3). Assessments should be performed by the same evaluator, if possible, to ensure 
internal consistency across visits. Results must be reviewed by the Investigator before dosing at 
the next cycle. 
Radiographic confirmation of disease progression is required by repeat scans 4 – 6 weeks 
following any scan suggesting disease progression. Participants will remain on study and 
continue to receive study intervention during this time. 
8.1.1 
Laboratory Assessments of Clinical Activity 
Samples for the following laboratory assessments of clinical activity and hormone levels will be 
sent to the study site local laboratory for analysis:  
Table 3: 
Laboratory Tests Sent to the Study Site Local Laboratory for Analysis of 
Disease-related Endpoints 
Profile 
Laboratory Test 
Clinical activity 
PSA 
Hormone levels 
testosterone 
PSA = prostate-specific antigen 
 
8.2 
SAFETY ASSESSMENTS 
Safety assessments will consist of monitoring and recording AEs, including SAEs and AESIs, 
performing protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study. Planned timing for all safety assessments is provided in the SOA 
(Section 1.3).  
Certain types of events require immediate reporting to the Sponsor, as described in Section 
8.3.1.1. 


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8.2.1 
Medical History and Demographic Data 
Medical history, including clinically significant diseases, surgeries, cancer history (including 
stage, date of diagnoses, and prior cancer therapies and procedures), reproductive status, 
smoking history, use of alcohol, and drugs of abuse, will be recorded at baseline. In addition, all 
medications (eg, prescription drugs, OTC drugs, vaccines, herbal or homeopathic remedies, 
nutritional supplements) used by the participant within 28 days prior to the first dose of study 
intervention will be recorded. Demographic data may include age, sex, and race/ethnicity. 
8.2.2 
Physical Examinations 
A complete physical examination should be performed at screening and should include an 
evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatological, 
musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurological systems. Any 
abnormality identified at baseline should be recorded on the Medical History eCRF page. 
Eastern Cooperative Oncology Group (ECOG) performance status (see Appendix 2) should be 
assessed per the SOA in Section 1.3. 
At subsequent visits (or as clinically indicated), limited, symptom-directed physical 
examinations should be performed. Changes from baseline abnormalities should be recorded in 
participant notes. New or worsened clinically significant abnormalities should be recorded as 
AEs on the Adverse Event eCRF page. 
8.2.3 
Vital Signs 
Vital signs should include measurements of respiratory rate, pulse rate, systolic and diastolic 
blood pressure, pulse oximetry (required only at screening), and temperature as outlined in the 
SOA (Section 1.3). Vital signs collected at the screening visit should be recorded on the eCRF. 
For each visit thereafter, only vital signs obtained prior to the study intervention administration 
as outlined in the SOA or during an AE (eg, temperature or event of fever) should be recorded on 
the eCRF. All vital signs collected per protocol should be documented in the participant’s 
medical record. 
Vital signs should be measured within 15 minutes prior to and after the administration of study 
intervention. Vital signs may be measured, if medically indicated, at other time points. 
8.2.4 
Electrocardiograms 
A single electrocardiogram (ECG) recording will be obtained at baseline, as outlined in the SOA 
(Section 1.3) and may be obtained at unscheduled time points as indicated.  
All ECG recordings must be performed using an institutionally-approved ECG. Lead placement 
should be as consistent as possible. ECG recordings should be performed after the participant has 
been resting in a supine position for at least 10 minutes. 


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For safety monitoring purposes, the Investigator must review, sign, and date all ECG tracings. 
ECG tracings will be kept as part of the participant's medical record. The Investigator’s 
assessment (ie, normal, abnormal [not clinically significant], or abnormal [clinically significant]) 
should be recorded on the appropriate eCRF page. Any morphologic waveform changes or other 
ECG abnormalities should be documented on the eCRF page. 
8.2.5 
Clinical Safety Laboratory Assessments 
Clinical laboratory tests will be performed at the local institution as described in the SOA 
(Section 1.3). 
The Investigator must review the laboratory report, document this review, and designate results 
as being not clinically significant of clinically significant. Clinically significant abnormal 
findings are those for which an action was taken (ie, providing fluid, transfusion, medication, 
and/or holding, delaying, or discontinuing study intervention) or those that are not associated 
with the underlying disease, unless judged by the Investigator to be more severe than expected 
for the participant's condition. Clinically significant changes occurring during the study should 
be documented on the appropriate eCRF. The laboratory reports much be filed with the source 
documents. 
In the event of a Grade 3 or Grade 4 laboratory toxicity, the test for the abnormal laboratory 
value should be repeated until the event is resolved to ≤ Grade 1 or baseline. 
8.2.5.1 
Local Laboratory Assessments 
Samples for the laboratory tests in Table 4 will be sent to the study site’s local laboratory for 
analysis: 


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Table 4: 
Laboratory Tests Sent to the Study Site’s Local Laboratory for Analysis of 
Safety 
Profile 
Laboratory Test 
Hematology 
RBC count 
hemoglobin 
hematocrit 
WBC count with automated differential (neutrophils, eosinophils, basophils, 
monocytes, lymphocytes, other cells) 
platelet count 
manual differential, if clinically indicated 
Clinical Chemistry 
(Serum or Plasma) 
sodium 
potassium 
chloride 
bicarbonate 
glucose 
BUN or urea 
creatinine 
total protein 
albumin 
calcium 
total bilirubin 
alkaline phosphatase 
ALT 
AST 
LDH 
TSH (T3 and FT4 should be checked if TSH is outside the normal range) 
coagulation assessments (PT, PTT, INR)a 
Urinalysis 
 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; 
INR  = international normalized ratio; LDH = lactate dehydrogenase; PT = prothrombin time; PTT = partial 
thromboplastin time; RBC = red blood cell; TSH = thyroid stimulating hormone; WBC = white blood cell 
a Coagulation assessment not required during treatment phase unless indicated 
 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
The definitions of an AE or SAE can be found in Appendix 5. 
Investigators will seek information on AEs at each participant contact until at least 100 days after 
the last dose of study intervention. AEs reported by the participant (or, when appropriate, by a 
caregiver, surrogate, or the participant's legally authorized representative) or noted by study 
personnel, will be recorded in the participant’s medical record and on the Adverse Event eCRF 
page. If the AE is determined to meet seriousness criteria, the event will be reported as an SAE 
on the study-specific SAE Report Form (SAERF) within 24 hours of awareness. Seriousness 
criteria is defined in Appendix 5. 


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The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE, AESI (as applicable), or SAE and remain 
responsible for following up AEs that are serious, considered related to the study intervention or 
study procedures, or that caused the participant to discontinue the study intervention (see 
Appendix 5). 
8.3.1 
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information 
All SAEs will be collected from the time the participant signs informed consent until at least 
100 days after the last dose of study intervention. Prior to initiation of study intervention, only 
SAEs that are related to a protocol-mandated intervention, including those that occur prior to the 
assignment of study procedures (eg, screening invasive procedures, such as biopsies) should be 
reported. After obtaining informed consent, but prior to initiation of study intervention, other 
medical occurrences will be recorded as medical history. 
All AEs, including AESIs (as applicable), will be collected from the start of study intervention 
until at least 100 days after the last dose of study intervention.  
If the Investigator learns of any SAE, including a death, at any time after the end of the AE 
reporting period, and he/she considers the event to be reasonably related to the study intervention 
or study participation, the Investigator must promptly notify the Sponsor or its designee. The 
Investigator should report these events directly to the Sponsor or its designee, either by faxing or 
emailing the SAERF. 
The method of recording and reporting AEs, AESIs (as applicable), and SAEs are provided in 
Appendix 5. The procedure for submitting SAE reports is provided in Section 8.3.8.2. 
The method of reporting all deaths is provided in Appendix 5. 
8.3.1.1 
Events Requiring Expedited Reporting to the Sponsor 
Certain events require immediate reporting to allow the Sponsor to take appropriate measures to 
address potential new risks in a clinical trial. The Investigator must report such events to the 
Sponsor immediately; under no circumstances should reporting take place more than 24 hours 
after the Investigator becomes aware of the event. The following is a list of events that the 
Investigator must report to the Sponsor within 24 hours of becoming aware of the event, 
regardless of relationship to study intervention: 
• All SAEs (defined in Appendix 5) 
• Protocol-specified AEs, including AESI as applicable, as defined in the cohort appendix 
for each respective combination 


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• Pregnancy (female partners of participants; see Section 8.3.5 for details on reporting 
requirements) 
• Occurrence of overdose (see Section 8.4 for details on reporting requirements) 
 
All reported safety data will be evaluated on a regular basis as described in Section 9.5.1. 
8.3.2 
Follow-up Event Reporting 
The Investigator must report new significant follow-up information for the events requiring 
expedited reported (see Section 8.3.1.1) to the Sponsor immediately (ie, within 24 hours of 
awareness). New significant information includes the following: 
• New signs or symptoms or a change in the diagnosis 
• Significant new diagnostic test results 
• Change in causality based on new information 
• Change in the event’s outcome, including recovery 
• Additional narrative information on the clinical course of the event 
• Hospital notes, diagnostic results, and/or discharge summary 
• Death certificate/Autopsy report 
 
After the initial AE/AESI/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs, SAEs, and AESIs (as applicable and as defined 
in the cohort appendix for each respective combination), will be followed through the follow-up 
phase of the study. Events will be followed until event resolution or death, the participant is lost 
to follow-up (as defined in Section 7.3), or the participant withdraws consent. Further 
information on follow-up procedures is provided in Appendix 5. 
For SAEs, and AESIs, the Sponsor or a designee may follow up by telephone, fax, electronic 
mail, and/or a monitoring visit to obtain additional case details and outcome information (eg, 
from hospital discharge summaries, consultant reports, autopsy reports) in order to perform an 
independent medical assessment of the reported case. If follow up information is obtained during 
a monitoring visit, follow up documentation must be reported to the Parker Institute for Cancer 
Immunotherapy Pharmacovigilance Group. 
8.3.3 
Method of Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted for eliciting AE 
information at all participant evaluation time points. Open-ended and non-leading verbal 
questioning of the participant is the preferred method to inquire about AE occurrences. Examples 


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of non-directive questions include: “How have you felt since your last clinic visit?”, “Have you 
had any new or changed health problems since you were last here?” 
8.3.4 
Regulatory Reporting Requirements for SAEs 
Prompt notification by the Investigator to the Sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a study 
intervention under clinical investigation are met (see Section 8.3.1.1). Investigators must also 
comply with local requirements for reporting SAEs to the IRB/IEC or other local health 
authorities. 
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements relating to safety reporting to 
the regulatory authority, IRB/IEC, and Investigators. The Parker Institute for Cancer 
Immunotherapy Pharmacovigilance Group will report SAEs to regulatory authorities, the overall 
PI, partner companies, and the IRB, as appropriate. The process for such reporting, including 
contact information and specific instructions for reporting to each of these organizations, is 
described in the Safety Monitoring Plan (a separate document). 
Expectedness will be assessed using the IB(s) as reference documents. Reporting requirements 
will also be based on the Investigator's assessment of causality and seriousness, with allowance 
for upgrading by the Sponsor as needed. 
Investigator safety reports must be prepared for suspected unexpected serious adverse reactions 
(SUSAR) according to local regulatory requirements and Sponsor policy and forwarded to 
Investigators as necessary.  
An Investigator who receives specific safety-related information (eg, SUSAR notification; 
summary or listing of SAEs) from the Sponsor will review and then file it along with the IB and 
will notify the IRB/IEC, if appropriate according to local requirements. 
8.3.5 
Pregnancy 
Details of all pregnancies in female partners of participants will be collected after the start of 
study intervention and until at least 7 terminal half-lives after the last dose. Female partners of 
childbearing potential will be instructed to immediately inform the Investigator if they become 
pregnant during the study or within 7-half-lives after the last dose of each component of study 
intervention. If a pregnancy is reported, the Investigator should inform the Sponsor within 24 
hours of becoming aware of the pregnancy and should follow the procedures outlined in 
Appendix 6. Abnormal pregnancy outcomes that meet serious criteria (eg, spontaneous abortion, 
fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are considered SAEs. 


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A clinical trial-specific Pregnancy Reporting Form should be completed and submitted 
immediately to the Parker Institute for Cancer Immunotherapy Pharmacovigilance Group, either 
by faxing or by scanning and emailing the form using the fax number or email address provided 
to Investigators (see Section 8.3.8.2). Pregnancy should not be recorded on the Adverse Event 
eCRF page. The Investigator should counsel the participant’s partner, discussing the risks of the 
pregnancy and the possible effects on the fetus. Monitoring of the participant’s partner should 
continue until conclusion of the pregnancy. Any SAEs associated with the pregnancy (eg, an 
event in the fetus, an event in the mother during or after the pregnancy, or a congenital 
anomaly/birth defect in the child) should be reported on the SAERF. In addition, the Investigator 
will submit a clinical trial-specific Pregnancy Reporting Form when updated information on the 
course and outcome of the pregnancy becomes available. 
8.3.6 
Disease-related Events and/or Disease-related Outcomes Not 
Qualifying as AEs or SAEs 
Progression of the cancer under study, as judged by the Investigator, is not considered a 
reportable event. If, upon further review by the Investigator, the event is determined as not being 
associated with underlying progression of disease, it must be reported as an SAE within 24 hours 
to the Parker Institute for Cancer Immunotherapy Pharmacovigilance Group as described in 
Section 8.3.8.2. 
8.3.7 
Adverse Events of Special Interest 
Selected non-serious and serious AEs known as AESIs are those of scientific and medical 
concern specific to the study intervention or program for which ongoing monitoring and rapid 
communication by the Investigator to the Sponsor is appropriate. These events will be identified 
in the cohort appendix for each respective combination. 
8.3.8 
Sponsor Contact Information 
8.3.8.1 
Emergency Medical Contacts 
Parker Institute for Cancer Immunotherapy Medical Monitor: 
Medical Monitor: 
Joyson Karakunnel, MD, MSc, FACP 
 
Parker Institute for Cancer Immunotherapy  
 
1 Letterman Drive, Ste. D3500 
 
San Francisco, CA 94080 
 
jkarakunnel@parkerici.org 
Telephone No.: 
(415) 539-3165 (Office; United States) 


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8.3.8.2 
Safety Reporting Contacts 
The following contact information should be used when submitting safety-related paper forms 
(SAERF and Pregnancy Report Form) as described in Appendix 5 for SAEs and other reportable 
safety events. These forms should be completed and submitted to the Sponsor immediately (ie, 
no more than 24 hours after becoming aware of the event), by faxing to the Parker Institute for 
Cancer Immunotherapy Pharmacovigilance Group at:  415-610-5471 within 24 hours of event 
awareness. If technical issues arise, please contact Parker Institute for Cancer Immunotherapy 
Pharmacovigilance Group immediately at 415-930-4414, and the form may be scanned and 
emailed to safety@parkerici.org. 
Parker Institute for Cancer Immunotherapy Pharmacovigilance Group: 
• Pharmacovigilance Fax Number:  415-610-5471 
• Pharmacovigilance Email:  safety@parkerici.org 
• Pharmacovigilance Telephone Number:  415-930-4414 
 
8.4 
TREATMENT OF OVERDOSE 
Overdose is defined as any dose higher than the dose specified to be administered in accordance 
with the protocol, whether accidental or intentional. 
The Investigator must immediately notify the Parker Institute for Cancer Immunotherapy 
Pharmacovigilance Group of any occurrence of overdose with study intervention.  
All overdoses should be reported as an SAE with the safety criteria of “other important 
medical event.” Details of signs and symptoms, clinical management, and outcome should be 
reported, if applicable. Overdoses should also be captured as protocol deviations. 
The PI has the obligation to report the deviations to the IRB/IEC. 
8.5 
PHARMACOKINETICS 
Sparse pharmacokinetic (PK) blood sampling may be collected as described in the cohort 
appendix for each respective combination, as applicable. 
8.6 
ANTI-DRUG ANTIBODIES 
Anti-drug antibodies (ADA) to specific biologic components of study intervention may be 
evaluated as described in the cohort appendix for each respective combination, as applicable. 
8.7 
BIOMARKERS 
The exploratory biomarker objective of this study is to assess tumor tissue and circulating 
soluble factors, including, but not limited to, deoxyribonucleic acid (DNA), ribonucleic acid 


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(RNA), enzymes, growth factors, cytokines, antibodies, and immune and tumor cells in tissue 
and blood, and their association with treatment outcome. Additionally, microbiome profiles may 
be evaluated from stool samples.  Evaluation of baseline levels and/or post-treatment changes 
from baseline may be performed to determine association with clinical outcomes, including 
clinical response or lack of response, as well as study intervention tolerability. 
• Collection of samples for biomarker research is part of this study. The following samples 
for biomarker research are required and will be collected from all participants in this 
study as specified in the SOA (Table 1) and process in accordance with the laboratory 
manual: 
o Blood 
o Peripheral blood mononuclear cells (PBMCs) 
o Circulating tumor cells (CTC) 
o DNA 
o RNA 
o Tumor tissue biopsy (archival tumor tissue and fresh biopsies at intervals 
specified in Section 4.1) 
o Stool 
• Samples may be tested for genetic analysis on tumor, stool, and blood samples, including, 
but not limited to, assays on circulating free DNA, DNA from tumor, stool, blood, and/or 
immune cells and T cell receptor sequencing may be performed.  This research may 
evaluate whether genetic variations correspond with outcomes of treatment. If genetic 
variation is found to predict efficacy or AEs, the data might inform optimal use of 
therapies in cancer patients. Circulating soluble analytes may be assessed that may 
include but are not limited to immune cytokines, growth factors, antibodies, and/or 
markers associated with immune characteristics and activation or cancer. Additionally, 
tumor and blood samples will be collected before and on study intervention for immune 
and/or tumor cell profiling that may include immune cell phenotyping, enumerations, 
and/or activation state. Both genome-wide and targeted messenger RNA expression 
profiling and sequencing in tumor, stool, and/or blood may be performed to define gene 
signatures that correlate with treatment outcomes. Epigenetic analyses may also be 
performed as these are important biomarkers for some cancers. Stool samples at baseline 
and on treatment may be evaluated for microbiome profiling to determine if there is any 
association with treatment outcome. 
• Other samples may be used for research, including future research, to develop methods, 
assays, prognostics, and/or companion diagnostics related to immuno-oncology 
treatment, disease process, pathways associated with disease state, and/or mechanisms of 
action of checkpoint inhibitor treatment. 


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8.7.1 
Genetics 
Sample collection, storage, and shipment instructions for planned genetic analysis samples will 
be provided in the Laboratory Manual. Samples should be collected for planned analysis of 
associations between genetic variants in germline/tumor DNA and clinical outcomes to study 
interventions(s). Blood and stool for planned genetic analysis will be collected for DNA as 
described in the SOA (Section 1.3). If a documented law or regulation prohibits (or local 
IRB/IEC does not approve) sample collection for these purposes, then such samples should not 
be collected at the corresponding sites. Additional DNA extracted from planned genetic analysis 
samples will be stored for future biomedical research only if the participant signs the Future 
Biomedical Research consent. 
In the event of DNA extraction failure, a replacement genetic blood sample may be requested 
from the participant. Signed informed consent will be required to obtain a replacement sample 
unless it was included in the original consent. 
See Appendix 7 for Information regarding genetic research. 
8.7.2 
Exploratory Biomarkers 
Archival tumor tissue and a fresh tumor biopsy are required if medically feasible at screening for 
exploratory analysis. Additional on-treatment tumor biopsies are required when medically 
feasible: 1) after 2 treatments with study intervention and 2) an optional biopsy at the time of 
disease progression, including from participants who respond and subsequently progress. Core 
needle or incisional tumor biopsy samples are required. Furthermore, every attempt should be 
made for the on-treatment biopsies to be taken from the same lesion site. Fine needle aspiration 
is not allowed. 
Blood will be collected for exploratory biomarkers. Blood may be used for whole blood, 
PBMCs, CTC, plasma, and/or serum preparation, and nucleic acid extraction. Additionally, 
blood samples may be used for profiling of circulating soluble analytes, PK analysis, and 
assessment of ADA for the biologic study intervention components. These blood samples will be 
collected as described in the SOA in Section 1.3. 
Stool samples will be collected for microbiome analysis, which may include microbiome whole 
metagenomic sequencing and/or metabolites as outlined in the SOA in Section 1.3. 
Tissue, blood, and stool sample collection, storage, and shipment instructions are provided in the 
Laboratory Manual. 


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8.7.3 
Sample Collection for Long-term Future Biomedical Research 
8.7.3.1 
Overview of Long-term Future Biomedical Research  
Participants in this clinical trial will be asked to consent to provide biological samples for long-
term future biomedical research. The objective of collecting/retaining specimens for future 
biomedical research is to explore and identify biomarkers that inform the scientific 
understanding of disease and/or their therapeutic treatments. The overarching goal is to use such 
information to understand disease, safety and potential treatments for future participants. Such 
research is for biomarker testing and hypothesis testing to address emergent questions not 
described elsewhere in the protocol (as part of the main trial). 
This research may include genetic and genomic analyses (DNA), gene expression profiling 
(RNA), proteomics, microbiome, metabolomics (serum, plasma, stool) and/or the measurement 
of other analytes, depending on which specimens are consented for future biomedical research. 
The collection and submission of biological samples to be stored for long-term future biomedical 
research must be detailed in the IRB/IEC-approved informed consent form (ICF). Participants 
who do not wish to participate in the future biomedical research may still participate in the study. 
8.7.3.2 
Sample Collection 
The following samples will be collected and stored in accordance with applicable law for long-
term research purposes, including but not limited to, research on biomarkers related to 
immunotherapies, such as anti-PD-1, and diseases such as cancer or inflammatory disorders: 
• Blood, including but not limited to, PBMCs, CTC, and plasma and/or serum 
• DNA 
• RNA 
• Tumor tissue 
• Stool samples 
 
These samples may be sent to one or more laboratories for analysis and/or storage. 
For sampling procedures, storage conditions, and shipment instructions, see the Laboratory 
Manual. 
8.7.3.3 
Withdrawal from Long-term Sample Storage 
Participants have the right to withdraw their consent for the future biomedical research of his 
specimens at any time for any reason and request that their specimens be destroyed. If the 
participant wishes to withdraw consent for this testing, the Investigator must inform the Sponsor 
in writing. Any analyses in progress at the time of request for withdrawal or already performed 


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prior to the request being received by the Sponsor will continue to be used as part of the overall 
research trial data and results. No new analyses would be generated after the request is received. 
In the event that the medical records for the main trial are no longer available (eg, if the 
Investigator is no longer required by regulatory authorities to retain the main trial records) or the 
specimens have been completely de-identified, there will no longer be a link between the 
participant’s personal information and their specimens. In this situation, the request for specimen 
withdrawal cannot be processed. 
8.7.3.4 
Protection of Data Privacy and Data Generation 
Participant specimens and associated data will be labeled with a unique participant identification 
number. Participant medical information associated with the long-term storage of specimens is 
confidential and may be disclosed to third parties only as permitted by the ICF signed by the 
participant or as permitted or required by law. 
Given the complexity and research nature of the exploratory analyses, data derived from long-
term stored specimens will generally not be provided to study Investigators or participants unless 
required by law. 
Data generated from specimens that are stored long term must be available for inspection upon 
request by representatives of national or local health authorities and Sponsor monitors, 
representatives, and collaborators as appropriate and as described in Section 10.1.11. 
8.8 
MEDICAL RESOURCE UTILIZATION AND HEALTH 
ECONOMICS 
This section is not applicable. 
9 
STATISTICAL CONSIDERATIONS 
9.1 
STATISTICAL HYPOTHESIS 
This exploratory study is designed to evaluate multiple clinical hypotheses and mechanistically-
defined combinations to evaluate the safety and efficacy of immunotherapy combination in 
participants with mCRPC who have received prior secondary androgen receptor signaling 
inhibitor therapy (eg, abiraterone, enzalutamide, apalutamide). 
9.2 
SAMPLE SIZE DETERMINATION 
The study is not intended or powered for hypothesis testing. The study is intended to provide 
preliminary estimates of AE rates, response rates, effect sizes and CIs to aid the design of later 
studies. A sample size of approximately 15 participants per immunotherapy combination cohort 
will provide these preliminary estimates while limiting exposure. 


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Table 5 provides 95% exact confidence intervals for the proportion of participants experiencing a 
specific AE for sample sizes of 15 and 30 participants per immunotherapy combination cohort. 
These confidence intervals, along with the ORR rate (described below), provide information 
needed to assess the risk-benefit ratio of the immunotherapy combination for expanding the cohort 
to Stage 2 and for the design of further studies. 
Table 5: 
Confidence Intervals for the True Proportion of Adverse Events 
Observed AE rate 
95% Confidence Interval  
(n = 15) 
95% Confidence Interval  
(n = 30) 
6.7% (1/15 or 2/30) 
(0.2%, 31.9%) 
(0.8%, 22.1%) 
13.3% (2/15 or 4/30) 
(1.7%, 40.5%) 
(3.8%, 30.7%) 
20.0% (3/15 or 6/30) 
(4.3%, 48.1%) 
(7.7%, 38.6%) 
26.7% (4/15 or 8/30) 
(7.8%, 55.1%) 
(12.3%, 45.9%) 
33.3% (5/15 or 10/30) 
(11.8%, 61.6%) 
(17.3%, 52.8%) 
40.0% (6/15 or 12/30) 
(16.3%, 67.7%) 
(22.7%, 59.4%) 
AE = adverse event 
 
A Simon two-stage minimax design (Simon, 1989) will be implemented for each cohort. An 
ORR of at least 25% would provide sufficient evidence of clinical activity to warrant further 
investigation, while an ORR of 10% would not be of interest. In Stage 1, 15 participants will be 
enrolled. If there are 2 or more responses in these 15 participants, 15 additional participants will 
be enrolled in Stage 2 for a total of 30 participants in the cohort. If there are 6 or more responses 
in these 30 participants, then the immunotherapy combination will be considered worthy of 
further investigation. This design yields a type I error rate of 0.07 and 77% power when the null 
hypothesis assumes the ORR is 10% and the alternative hypothesis assumes the ORR is 25%. 
Under the null hypothesis, the probability of terminating the cohort after Stage 1 is 55%. 
9.3 
STATISTICAL ANALYSES 
Each immunotherapy combination cohort will be assessed independently of the other cohorts, 
and the data from each cohort will be analyzed separately to preserve confidentiality of data 
between companies. 
The statistical analysis plan (SAP) will be developed and finalized before database lock and will 
provide further details regarding the definition of analysis variables, analysis methodology, and 
handling of missing data. Any combination-specific modifications to the statistical methods, 
including any additional combination-specific endpoints, will be captured in the SAP. The SAP 
will serve as a compliment to the protocol and supersedes it in case of differences. 


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9.3.1 
Efficacy Analyses 
The analyses for clinical activity will be performed on the evaluable population, consisting of all 
participants who receive at least 1 dose of the combination study intervention or any component 
of the combination.  
This study is not intended or powered for hypothesis testing. Due to the exploratory nature of 
this study, no control of type I error will be applied for any of the endpoints. 
9.3.1.1 
Primary Efficacy Endpoint 
There are no primary efficacy objectives or endpoints for this study. 
9.3.1.2 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints include: 
• ORR: A composite endpoint where response is defined as a participant meeting at least 
one of the following: 
o CTC response: Change from unfavorable (≥ 5 cells/7.5 mL of blood) to favorable 
(≤ 4 cells/7.5 mL of blood). Participants with a baseline CTC value < 5 cells/7.5 
mL of blood will not be evaluated for this criterion. 
o Prostate-specific antigen (PSA) response: Confirmed PSA response is defined as 
≥ 50% reduction in PSA from baseline, with a repeat assessment confirming the 
result at least 3 weeks later. Participants without a PSA value at baseline and at 
least two post-baseline assessments will not be evaluable for this criterion. 
o Confirmed response of CR or partial response (PR) by objective radiographic 
disease assessment using modified RECIST version 1.1 (ie, CR or PR and no 
progression in bone per the PCWG3; Scher et al., 2016). Per RECIST, to be 
assigned a best overall response of CR or PR, changes in tumor measurements 
must be confirmed by repeat assessments that should be performed no less than 4 
weeks after the criteria for response are first met. Participants who received at 
least 1 dose of the combination study intervention or component of the 
combination but do not have RECIST assessment for any reason will be counted 
as not responding. 
• Disease control rate (DCR) at 9 months: Defined as CR, PR, or stable disease (SD) 
for 9 months as best response by PCWG3-modified RECIST 1.1. Participants who 
received at least 1 dose of the study intervention combination or component of the 
combination but do not have RECIST assessment for any reason will be counted as not 
responding. 


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• Radiographic progression-free survival (rPFS): Defined as time from initiation of study 
intervention to the first objective evidence of radiographic progression, or death due to 
any cause (whichever occurs first). Radiographic disease progression includes soft tissue 
disease progression per PCWG3-modified RECIST 1.1 and confirmed progression of 
bone disease per PCWG3 criteria. Participants who continue treatment beyond initial 
disease progression will be considered to have PD at the time of the initial progression 
event. Participants who do not have radiographic progression will be censored at 
initiation of subsequent anti-cancer therapy. 
• OS: Defined as the time from initiation of study invention until death due to any cause. 
• OS rate at 12 months. 
 
Response rates for ORR, DCR, and OS will be estimated within each immunotherapy 
combination cohort and 95% CIs will be estimated using the Clopper-Pearson method. rPFS and 
OS will be estimated using Kaplan-Meier techniques, and the median survival time and 95% CIs 
will be estimated within each immunotherapy combination cohort. If median survival is not 
reached, survival times and 95% CIs will be reported at deciles that are estimable given the 
observed events. 
9.3.1.3 
Exploratory Efficacy Endpoints 
The exploratory efficacy endpoints include but are not limited to: 
• Association of tumor and immune biomarkers from tissue, blood, and/or stool with 
clinical outcomes, including ORR, DCR, rPFS, and tolerability. Biomarkers to be studied 
will be chosen based on the immunotherapy combination. 
• Molecular characterization of CTC and evaluation of percent change from baseline. 
• Enumeration of CTC ≥ 1 at baseline with conversion to a measure of zero CTC (CTC0) 
on treatment. 
• Percent change in PSA from baseline at 12 weeks. 
• Maximum change in PSA at any point after study treatment initiation. 
• Time to PSA progression defined as the time from study treatment initiation to the date 
that a ≥ 25% increase and absolute increase of ≥ 2 ng/mL above the nadir (or baseline 
value for participants who did not have a decline in PSA) in PSA. The increase must be 
confirmed by a second consecutive assessment conducted at least 3 weeks later. 
• Sparse PK analysis. 


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• Presence of ADA against biologic components of each immunotherapy combination. 
 
9.3.2 
Safety Analyses 
All safety analyses will be performed on the evaluable population, consisting of all participants 
who receive at least 1 dose of the combination study intervention or any component of the 
combination. 
Safety will be assessed through summaries of AEs, laboratory test results (hematology and serum 
chemistry), vital signs, and ECGs. Verbatim descriptions of treatment-emergent AEs (defined in 
Section 10.5.1.4) will be coded, and their incidence will be summarized by immunotherapy 
combination cohort. In addition, separate summaries will be generated for SAEs, deaths, AEs 
leading to study discontinuation, AEs leading to treatment discontinuation, and AEs leading to 
temporary interruption and/or dose reduction. 
9.3.3 
Other Analyses 
The number of participants who were screened, enrolled and treated, enrolled and not treated, 
and completed the study will be presented in summary tables. The reason for discontinuation 
from the study will be listed by participant and summarized in a table. The number of 
participants in each immunotherapy combination cohort and analysis population will be 
summarized. 
Demographic and baseline characteristics of the study population will be summarized overall and 
for each immunotherapy combination cohort. Categorical measures will be summarized using 
frequencies and percentages. Continuous variables will be summarized using means, standard 
deviations, medians, minimums, and maximums. 
9.3.3.1 
Pharmacokinetic Analysis 
Sparse PK analysis may be performed evaluating trough levels for all biologic study intervention 
and maximum observed drug concentration (Cmax) for exploratory biologic study intervention 
(non-PD-1 agents) when possible. 
9.3.3.2 
Biomarker Analysis 
Descriptive statistics will be used to evaluate the exploratory biomarkers. Biomarker exploratory 
analyses will be determined based on study outcomes and further described in a Biomarker 
Analysis Plan.  
9.3.3.3 
Anti-Drug Antibody Analysis 
The number of participants who develop ADA to biologic study intervention and ADA titer may 
be summarized. 


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9.4 
POPULATIONS FOR ANALYSIS 
For purposes of analysis, the following populations are defined as shown in Table 6. 
Table 6: 
Populations for Analysis 
Population 
Description 
Evaluable Population 
All participants who receive at least 1 dose of the combination study 
intervention or any component of the combination  
 
9.5 
INTERIM ANALYSES 
Safety and efficacy will be monitored on a regular basis. Possible adaptations resulting from 
these data reviews include: 
• Modifying or stopping a cohort early based on a safety signal 
• Expanding a cohort to include an additional approximately 15 patients (Stage 2) based on 
acceptable safety data in addition to preliminary signals in clinical activity and/or 
biomarker results 
 
Other possible adaptation to the study design, including the addition of new combination cohorts, 
may be based on a variety of factors, such as emerging biological knowledge of mCRPC 
biomarkers and/or immunotherapy mechanisms, as well as availability of investigational 
therapies. However, it is not anticipated that findings from safety and efficacy monitoring of this 
study will influence these decisions. Findings will not be used to re-estimate the sample size. 
Due to the exploratory nature of this study, effect sizes and CIs will not be adjusted to account 
for ongoing review of data. 
9.5.1 
Interim Safety Monitoring 
To ensure careful review of the accumulating safety data for the PICI0033 platform study, a 
Safety Assessment Committee (SAC) will be established. 
Ongoing safety data review will be conducted by the SAC. The PICI0033 SAC will have a core 
membership made up of genitourinary (GU) oncologists and immuno-oncologists and subject 
matter expert(s) as appropriate for a specific cohort (ie, vaccine expertise). Select Sponsor 
personnel, including the Medical Monitor and representatives from other functions including, but 
not limited to, Biostatistics, Clinical Science, and Drug Safety, will be responsible for producing 
output for review and informing the SAC of any major safety signals in a timely manner. 


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To ensure participants’ safety during the study, the SAC will meet approximately every 3 months 
to assess the totality of safety information in the clinical study. In addition, the SAC or the 
Sponsor may request ad hoc reviews at any time to address potential safety concerns. In the 
event there are a total of 4 or more of the first 15 participants, or 8 or more of 30 participants if a 
cohort is expanded, in a single cohort that meet cohort-specific toxicity criteria, an ad hoc SAC 
meeting will be held. If 1 death in any cohort occurs that is possibly related to the study drugs, 
the specific cohort will be placed in temporary suspension of enrollment until the information 
can be assessed by the Sponsor and in consultation with the SAC. 
Safety monitoring will include unblinded evaluation of all AEs, SAEs, relevant protocol 
deviations, and laboratory data. If the SAC deems a benefit-risk assessment necessary, the SAC 
may also review efficacy data. The SAC may recommend terminating a combination cohort or 
suspending enrollment for safety reasons. 
Roles and responsibilities of the SAC will be detailed in a separate charter. 
9.5.2 
Cohort Expansion Rules 
A Simon two-stage minimax design (Simon, 1989) will be implemented for each cohort. In Stage 
1, 15 participants will be enrolled. If there are 2 or more responses in these 15 participants, 15 
additional participants will be enrolled in Stage 2 for a total of 30 participants in the cohort. For 
the purposes of cohort expansion, ORR will be used to determine response (ie, CTC response, 
PSA response, or confirmed response of CR or PR). 
In addition to efficacy criteria stated above, safety data will also be assessed when determining 
whether to expand a cohort. If there are ≥ 6 participants meeting cohort-specific toxicity criteria 
requiring permanent treatment discontinuation, an ad hoc SAC meeting will be held to further 
review all safety data and provide input on assessing the benefit-risk profile. The SAC will 
provide a recommendation in regard to expansion to Stage 2, continuation or discontinuation of 
the cohort. This ad hoc review will be in addition to the ongoing safety monitoring performed by 
the SAC, who may recommend terminating a combination cohort at any time for safety reasons.  
The threshold of 6 participants was chosen because this translates to a posterior probability of 
0.69 that the true toxicity rate is >30%, assuming 15 participants are enrolled per cohort and a 
minimally informative beta (0.5, 2.5) prior. 
If the cohort has an acceptable safety profile but has not demonstrated at least 2 responses, no 
additional participants will be enrolled into the cohort. However, this decision may be revisited if 
follow-up translational analysis or emerging external data identifies a subset of participants most 
likely to derive benefit from the combination therapy that was underrepresented in the cohort. 
Under this scenario, any modifications to the study design of the combination, including 


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justification for participant selection or enrichment, will be detailed in an amendment to the 
appropriate cohort appendix. 
 


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10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1 
APPENDIX 1: REGULATORY, ETHICAL AND STUDY 
OVERSIGHT CONSIDERATIONS 
10.1.1 
Compliance with Laws and Regulations 
This study will be conducted in accordance with the protocol and with the following: 
• Applicable International Council for Harmonisation (ICH) guidelines, including E6(R2) 
for Good Clinical Practice (GCP) and E2A for Clinical Safety Data Management: 
Definitions and Standards for Expedited Reporting 
• Consensus ethical principles derived from international guidelines, including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines 
• Applicable laws and regulations. 
 
Studies conducted in the US or under a US Investigational New Drug (IND) application will 
comply with US FDA regulations and applicable local, state, and federal laws.  
10.1.2 
Institutional Review Board or Independent Ethics Committee 
The protocol, protocol amendments, ICF(s), IB, any information to be given to the participant, 
and relevant supporting information must be submitted to the IRB/IEC and reviewed and 
approved by the IRB/IEC before the study is initiated. In addition, any participant recruitment 
materials (eg, advertisements) must be approved by the IRB/IEC. 
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants or changes that involve logistical or administrative aspects only (eg, 
change in Medical Monitor or contact information).  
The Investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC 
• Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
• Promptly documenting and reporting any deviations that might have an impact on 
participant safety and data integrity to the Sponsor and to the IRB/IEC in accordance with 
established requirements, policies and procedures 


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• Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical 
studies (if applicable), and all other applicable local regulations. 
 
10.1.3 
Financial Disclosure 
Investigators and Sub-investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate health authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study (see definition of end of study in Section 4.5). 
10.1.4 
Informed Consent 
The Investigator or his/her representative will explain the nature of the study to the participant or 
his legally authorized representative and answer all questions regarding the study. 
Participants must be informed that their participation is voluntary. Participants or their legally 
authorized representative will be required to sign a statement of informed consent that meets the 
requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC or study center. 
The medical record must include a statement that written informed consent was obtained before 
the participant was enrolled in the study and the date the written consent was obtained. The 
authorized person obtaining the informed consent must also sign the ICF. 
If applicable, the ICF will contain separate sections for any optional procedures. The Investigator 
or authorized designee will explain to each participant the objectives, methods, and potential 
risks associated with each optional procedure. Participants will be told that they are free to refuse 
to participate and may withdraw their consent at any time for any reason. A separate, specific 
signature will be required to document a participant’s agreement to participate in optional 
procedures. Participants who decline to participate will not provide a separate signature. 
Participants must be re-consented to the most current version of the ICF(s) (or to a significant 
new information/findings addendum in accordance with applicable laws and IRB/IEC policy) 
during their participation in the study. The medical record should document the re-consent 
process and that written informed consent was obtained using the updated/revised ICF for 
continued participation in the study. 
A copy of the signed and dated ICF(s) must be provided to the participant or to the participant’s 
legally authorized representative. All signed and dated ICFs must remain in the participant’s 


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study file or in the site study file and must be available for verification by study monitors at any 
time. 
The final revised IRB/IEC-approved ICFs must be provided to the Sponsor for the purpose of 
health authority submission. 
A participant who is rescreened is not required to sign another ICF if the rescreening occurs 
within 30 days from the previous ICF signature date and provided the ICF has not been updated 
during that time. 
The ICF will contain a separate section that addresses the use of remaining mandatory samples 
for optional exploratory research. The Investigator or authorized designee will explain to each 
participant the objectives of the exploratory research. Participants will be told that they are free 
to refuse to participate and may withdraw their consent at any time and for any reason during the 
storage period. A separate signature will be required to document a participant's agreement to 
allow any remaining specimens to be used for exploratory research. Participants who decline to 
participate in this optional research will not provide this separate signature. 
10.1.5 
Data Protection 
The Sponsor maintains confidentiality standards by assigning a unique participant identification 
number to each participant enrolled in the study. This means that participant names are not 
included in data sets that are transmitted to any Sponsor location. 
Participant medical information obtained by this study is confidential and may be disclosed to 
third parties only as permitted by the ICF (or separate authorization for use and disclosure of 
personal health information) signed by the participant or as permitted or required by law. 
Medical information may be given to a participant’s personal physician or other appropriate 
medical personnel responsible for the participant’s welfare, for treatment purposes. 
Data generated by this study must be available for inspection upon request by representatives of 
national and local health authorities, Sponsor monitors, representatives and collaborators, and the 
IRB/IEC for each study site, as appropriate. 
10.1.6 
Dissemination of Clinical Study Data 
The results of this study may be reported to the public, in the form of a publication or 
presentation at scientific congresses, before completion of the study. 
10.1.7 
Administrative Structure 
This trial will be sponsored and managed by the Parker Institute for Cancer Immunotherapy. The 
Sponsor will provide clinical operations management, data management, medical monitoring, 
and safety oversight. 


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Central facilities will be used for certain study assessments throughout the study (eg, specified 
laboratory tests, PK analyses, biomarker analyses), as specified in Section 8.2.5, Section 8.5, and 
Section 8.7, respectively. Accredited local laboratories will be used for routine monitoring; local 
laboratory ranges will be collected. 
10.1.8 
Data Quality Assurance 
All participant data relating to the study will be collected via the electronic data collection (EDC) 
on an eCRF unless transmitted to the Sponsor or designee electronically (eg, central laboratory 
data, biomarker and other biological sample data). Sites will be responsible for data entry into 
the EDC system and will receive training for appropriate eCRF completion. The Investigator is 
responsible for verifying that data entries are accurate and correct by electronically signing and 
dating the eCRF. 
The Investigator must maintain accurate documentation (source data, see Section 10.1.9) that 
supports the information entered on the eCRF. The Investigator must permit study-related 
monitoring, audits, IRB/IEC review, and regulatory agency inspections and provide direct access 
to source data documents. 
The Sponsor is responsible for the data management of this study, including quality checking of 
the data. Study monitors will perform ongoing source data verification to confirm that data 
entered on the eCRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements. 
At the end of the study, the Investigator will receive participant data for his/her site in a readable 
format on a compact disc (or other readable digital format) that must be kept with the study 
records. Acknowledgement of receipt of the compact disc is required. 
10.1.9 
Source Documentation 
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site. Data entered 
on the eCRF that are transcribed from source documents must be consistent with the source 
documents or the discrepancies must be explained. The Investigator may need to request 
previous medical records or transfer records, depending on the study. Also, current medical 
records must be available. 
Source documents (paper or electronic) are those in which participant data are recorded and 
documented for the first time. They include, but are not limited to, hospital records, clinical and 
office charts, laboratory notes, memoranda, clinical outcomes assessment (COA)/patient-
reported outcomes (PRO), evaluation checklists, pharmacy dispensing records, recorded data 


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from automated instruments, copies of transcriptions that are certified after verification as being 
accurate and complete, microfiche, photographic negatives, microfilm or magnetic media, 
X-rays, participant files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial. 
When clinical observations are entered directly into a study site’s computerized medical record 
system (ie, in lieu of original hardcopy records), the electronic record can serve as the source 
document if the system has been validated in accordance with health authority requirements 
pertaining to computerized systems used in clinical research. An acceptable computerized data 
collection system allows preservation of the original entry of data. If original data are modified, 
the system should maintain a viewable audit trail that shows the original data as well as the 
reason for the change, name of the person making the change, and date of the change. 
Source documents that are required to verify the validity and completeness of data entered on the 
eCRFs must not be obliterated or destroyed and must be retained as described in Section 10.1.12. 
10.1.10 
Study and Site Closure 
The Sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. Reasons for terminating the study may 
include, but are not limited to, the following: 
• Discontinuation of further study intervention development 
• The incidence or severity of AEs in this or other studies indicate the potential hazard to 
participants 
• Participant enrollment is unsatisfactory 
 
The Sponsor will notify the Investigator if the Sponsor decides to discontinue the study. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include, but are 
not limited to, the following: 
• Poor protocol adherence 
• Inaccurate or incomplete data recording 
• Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the Sponsor's procedures, or GCP guidelines 
• No study activity (ie, all participants have completed the study and all obligations have 
been fulfilled) 
 


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10.1.11 
Site Inspections 
Site visits will be conducted by the Sponsor or an authorized representative for inspection of 
study data, participants’ medical records, and eCRFs. The Investigator will permit national and 
local health authorities; Sponsor monitors, representatives and collaborators; and the IRBs/IECs 
to inspect facilities and records relevant to this study. 
10.1.12 
Retention of Records 
Records and documents pertaining to the conduct of this study and distribution of the 
investigational medicinal product, including signed eCRFs, electronic or paper COA/PRO data 
(if applicable), signed ICFs, laboratory test results, and medication inventory records, must be 
retained by the Investigator for the maximum period required by applicable regulations of 
relevant national or local health authorities. No records may be disposed of without the written 
approval of the Sponsor. The Sponsor will notify the Investigator when the records are no longer 
needed. Following notification from the Sponsor, the documents may be destroyed, subject to 
local regulations.  
Written notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location. 
10.1.13 
Publication Policy and Protection of Trade Secrets 
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing information on 
the trial to healthcare professionals and to the public, both at scientific congresses and in peer-
reviewed journals. The Sponsor will comply with all requirements for publication of study 
results. 
The Investigator must agree to submit all manuscripts or abstracts to the Sponsor prior to 
submission for publication or presentation. This allows the Sponsor to protect proprietary 
information and to provide comments based on information from other studies that may not yet 
be available to the Investigator. 
The Sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter trials only in their entirety and not as individual center data. In this case, a 
Coordinating Investigator will be designated in accordance with the Parker Institute for Cancer 
Immunotherapy publication policy. Authorship will be based on overall scientific contribution 
and participant enrollment. 


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10.2 
APPENDIX 2: EASTERN COOPERATIVE ONCOLOGY 
GROUP (ECOG) PERFORMANCE STATUS 
Grade 
ECOG Performance Status 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, eg, light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities; up and about more than 50% of waking hours 
3 
Capable of only limited self-care; confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled; cannot carry on any self-care; totally confined to bed or 
chair 
5 
Dead 
Source: Oken et al., 1982 
 


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10.3 
APPENDIX 3: RECIST CRITERIA (VERSION 1.1) WITH 
MODIFICATIONS AS RECOMMENDED BY PCWG3 
Tumor response will be assessed according to RECIST v1.1 (Eisenhauer et al., 2009; 
Section 10.3.1 and Section 10.3.2), with modifications as recommended by PCWG3 (Scher et al., 
2016; Section 10.3.3), as described below. 
10.3.1 
Measurability of Tumor at Baseline 
At baseline, tumor lesions/lymph nodes will be categorized as measurable or nonmeasurable as 
follows: 
• Measurable 
Tumor lesions: Must be accurately measured in ≥ 1 dimension (longest diameter in the 
plane of measurement to be recorded) with a minimum size of: 
o 10 mm by CT scan (CT scan slice thickness no greater than 5 mm) 
o 10 mm caliper measurement by clinical examination (lesions that cannot be 
accurately measured with calipers should be recorded as nonmeasurable) 
o 20 mm by chest X-ray 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a 
lymph node must be ≥ 15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm). 
• Nonmeasurable 
o All other lesions (or disease sites), including small lesions (longest diameter < 10 mm 
or pathological lymph nodes with ≥ 10 to < 15 mm short axis) 
o Lesions considered truly nonmeasurable include the following: leptomeningeal 
disease, ascites, pleural/pericardial effusion, inflammatory breast disease, 
lymphangitic involvement of skin or lung, and abdominal masses/abdominal 
organomegaly identified by physical examination that is not measurable by 
reproducible imaging techniques 
 


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10.3.2 
Tumor Response Evaluation 
10.3.2.1 
Baseline Documentation of Target and Nontarget Lesions 
• Target lesions 
o When > 1 measurable lesion is present at baseline, all lesions up to a maximum of 5 
lesions total (and a maximum of 2 lesions per organ) representative of all involved 
organs should be identified as target lesions 
o It may be the case that, on occasion, the largest lesion that can be measured 
reproducibly should be selected 
• Nontarget lesions 
o All other lesions (or disease sites), including pathological lymph nodes, should be 
identified as nontarget lesions 
o It is possible to record multiple nontarget lesions involving the same organ as a single 
item (eg, ‘multiple enlarged pelvic lymph nodes’ or ‘multiple liver metastases’) 
10.3.2.2 
Evaluation of Target Lesions 
Target lesions will be evaluated and response recorded as defined in Appendix Table 1. 
Appendix Table 1: 
Response Based on Evaluation of Target Lesions at Each Assessment 
Complete response 
Disappearance of all target lesions; if a pathologic lymph node, 
reduction in the shortest axis to < 10 mma 
Partial responseb 
≥ 30% decrease in the sum of the diameters of target lesions relative 
to the baseline sum diametersc 
Stable diseaseb,d 
Neither a sufficient reduction to qualify as a partial response nor a 
sufficient increase to qualify as progressionc 
Progressive diseaseb 
≥ 20% increase in the sum diameters relative to the smallest sum 
diameters recorded (including the baseline sum diameters) in 
conjunction with an increase of at least 5 mm in that smallest sum 
diameters, or the appearance of 1 or more new lesionsc,e 
a For each pathologic lymph node considered a target lesion, the node must have a short axis measuring < 10 mm to 
be considered as a complete response. In such cases, the sum diameters may not be zero (as a normal lymph node 
can have a short axis of < 10 mm). 
b For each pathologic lymph node considered a target lesion, the measurement of the short axis of the node is to be 
included in the sum diameters when determining partial response, stable disease, and progression. 
c In this study, the “baseline sum diameters” is calculated based on the lesion measurements obtained at screening. 
d Duration of stable disease is measured from the date of the first dose of Study treatment until criteria for 
progressive disease are met based on the smallest sum diameters recorded (including the baseline sum diameters). 
e The finding of a new lesion should be unequivocal and not possibly attributable to a difference in imaging 
modality or scanning technique. Post-baseline, fluorodeoxyglucose positron emission tomography (FDG-PET) 
may be useful in assessing new lesions apparent on CT scan. 


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10.3.2.3 
Evaluation of Nontarget Lesions 
Nontarget lesions will be evaluated and response recorded as defined in Appendix Table 2. 
Appendix Table 2: 
Response Based on Evaluation of Nontarget Lesions at Each 
Assessment 
Complete response 
Disappearance of all non-target lesions; all lymph nodes must be 
nonpathologic in size (ie, < 10 mm on the short axis) 
Not complete response nor 
progressive disease 
Persistence of 1 or more non-target lesions 
Progressive disease 
Unequivocal progressiona of any existing non-target lesion or the 
appearance of 1 or more new lesionsb 
a The participant should stop study intervention, even in the presence of a partial response or stable disease, based 
on assessment of target lesions. 
b The finding of a new lesion should be unequivocal and not possibly attributable to a difference in imaging 
modality or scanning technique. Post-baseline, fluorodeoxyglucose positron emission tomography (FDG-PET) 
may be useful in assessing new lesions apparent on CT scan. 
 
10.3.2.4 
New Lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important. There are no specific criteria for the 
identification of new radiographic lesions; however, the finding of a new lesion should be 
unequivocal, ie, not attributable to differences in scanning technique, change in imaging 
modality or findings thought to represent something other than tumor (eg, some ‘new’ bone 
lesions may be simply healing or flare of pre-existing lesions). This is particularly important 
when the participant’s baseline lesions show PR or CR. For example, necrosis of a liver lesion 
may be reported on a CT scan as report as a ‘new’ cystic lesion, which it is not. 
10.3.2.5 
Evaluation of Overall Response 
Overall response based on the evaluation of target and nontarget lesions will be determined as 
shown in Appendix Table 3. 
Appendix Table 3: 
Evaluation of Overall Response at Each Assessment 
Target Lesions 
Nontarget Lesions 
New Lesions 
Overall Response 
Complete response 
Complete response 
No 
Complete response 
No target lesiona 
Complete response 
No 
Complete response 
Complete response 
Not evaluableb 
No 
Partial response 
Complete response 
Not complete response/ 
non-progressive disease 
No 
Partial response 


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Target Lesions 
Nontarget Lesions 
New Lesions 
Overall Response 
Partial response 
Non-progressive disease and 
not evaluableb 
No 
Partial response 
Stable disease 
Non-progressive disease and 
not evaluableb 
No 
Stable diseasec 
Not all evaluated 
Non-progressive disease 
No 
Not evaluable 
No target lesiona 
Not all evaluated 
No 
Not evaluable 
No target lesiona 
Non-complete response/ 
non-progressive disease 
No 
Non-complete response/ 
non-progressive disease 
Progressive disease 
Any 
Yes or no 
Progressive disease 
Any 
Progressive disease 
Yes or no 
Progressive disease 
Any 
Any 
Yes 
Progressive disease 
No target lesiona 
Unequivocal progressive disease 
Yes or No 
Progressive disease 
No target lesiona 
Any 
Yes 
Progressive disease 
a Defined as no target lesions at baseline. 
b Not evaluable is defined as either when no or only a subset of lesion measurements are made at an assessment. 
c The minimum duration on-study required for an overall assessment of stable disease is 49 days. 
 
10.3.3 
Modifications for mCRPC as Recommended by PCWG3 
In 2016, the PCWG3 (Scher et al., 2016) updated the recommendations of the Prostate Cancer 
Working Group 2 (PCWG2; Scher et al., 2008). The key new recommendations related to 
disease assessment, including the following, which are described in more detail in Section 
10.3.3.1 and Section 10.3.3.2: 
• emphasizing the importance of serial biologic profiling of the disease using minimally 
invasive blood-based assays of tumor material, imaging, or biopsy of a metastatic tumor 
site to identify and target mechanisms of primary or adaptive resistance and to better 
enable treatment selection to be based on disease biology; 
• including clinically relevant time-to-event end points, such as symptomatic skeletal 
events (SSEs); 
• with increased recognition of disease heterogeneity and emerging resistance, focusing 
more on determining when a treatment should be discontinued when the patient is NLCB 
rather than strictly at the first evidence of progression. 
 


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10.3.3.1 
PCWG3 Recommendations with Regard to Baseline Disease 
Assessments 
A summary of major changes in PCWG3 recommendations compared with PCWG2 with regard 
to baseline disease assessments follows: 
• Expands baseline assessments to include tumor histology; the timing, duration, and 
response (if available) for all prior systemic treatments; a standardized assessment of 
blood-based, PRO-based, and imaging-based biomarkers; and the molecular 
characterization of the tumor (detailed in Appendix Table 4). 
• Emphasizes molecular/biologic subtypes of castration-resistant prostate cancer in 
addition to the 5 clinical subtypes (defined by extent and location of metastases) 
• Defines the type of progression at trial entry as PSA-only progression, radiographic 
progression by site of disease spread, or both; for radiographic progression, records 
whether progression was caused by growth of existing lesions, appearance of new 
lesions, or both 
 
Appendix Table 4: 
Criteria for Progression at Trial Entry by Disease Manifestation 
Variable 
PCWG3 Recommendation 
Blood-based 
PSA 
Obtain sequence of rising values at a minimum of 1-week intervals 
1.0 ng/mL minimal starting value 
(1.0 ng/mL is the minimal starting value if confirmed rise is only indication of 
progression unless pure small-cell carcinoma) 
Estimate pretherapy PSA doubling time if at least 3 values available ≥ 4 weeks apart 
Imaging 
Nodes 
Nodal progression sufficient for trial entry independent of PSA 
Measurable lesions not required for entry 
Modified RECIST 1.1 criteria, separate pelvic and disease, up to five nodal lesions total 
recorded 
Previously normal (< 1.0-cm) lymph nodes must have grown by ≥ 5 mm in the short 
axis from baseline or nadir and be ≥ 1.0 cm in the short axis to be considered to have 
progressed 
If the node progresses to ≥ 1.5 cm in the short axis, it is measurable; nodes that have 
progressed to 1.0 to less than 1.5 cm are pathologic, subject to clinical discretion, and 
nonmeasurable 
For existing pathologic adenopathy, progression is defined per RECIST 1.1 
Record presence of nodal and/or visceral disease separately 
Nodal sites: 
Locoregional: pelvic only 
Extrapelvic: retroperitoneal, mediastinal, thoracic, or other 


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Variable 
PCWG3 Recommendation 
Viscera 
Visceral progression sufficient for trial entry independent of PSA; recorded separately 
by site of spread (lung, liver, adrenal, CNS); up to 5 lesions per site of spread 
recorded 
Measurable lesions not required for entry 
Use RECIST to record visceral lesions as target or nontarget 
Visceral sites: lung, liver, adrenal, CNS 
Prostate/prostate bed 
(primary site) 
Record prior treatment of primary tumor 
Perform directed pelvic imaging (CT, MRI, PET/CT, endorectal MRI, transrectal 
ultrasound) to document presence or absence of disease 
Bone 
Two new lesions 
Confirm ambiguous results by other imaging modalities (eg, CT or MRI); only 
positivity on the bone scan defines metastatic disease to bone 
Other sites of disease 
Patients with treated epidural lesions and no other epidural progression are eligible 
Type of progression at trial entry 
 
Report separately: 
PSA only 
Bone only ± nodal disease 
Nodal disease only (no bone disease present) 
Visceral (lung, liver, adrenal, CNS) disease (± other sites) 
Record new lesions and site of new lesions vs growth of pre-existing lesions, or both 
Other markers 
Patient-reported 
outcomes 
For pain palliation analyses, presence of clinically meaningful pain at baseline (eg, ≥ 4 
on a 10-point pain intensity scale) is a prerequisite; for pain progression analyses, 
patients may have any level of pain at baseline, including no pain 
Source: Scher et al., 2016  
CNS = central nervous system; CT = computed tomography; MRI = magnetic resonance imaging; 
PCWG3 = Prostate Cancer Clinical Trials Working Group 3; PET = positron emission tomography; PSA = prostate-
specific antigen; RECIST = Response Evaluation Criteria in Solid Tumors; vs = versus 
 
10.3.3.2 
PCWG3 Recommendations with Regard to Measuring Outcomes 
and Reporting 
PCWG3 reaffirmed the PCWG2 recommendation for the use of the following endpoints to assess 
antitumor effects, and suggested the outcome measures described in Appendix Table 5 are 
differentiated according to these endpoints, where applicable: 
• Control/relieve/eliminate endpoints for therapies that are anticipated to kill tumor cells, 
particularly in early clinical development 
• Delay/prevent endpoints for therapies not expected to kill tumor cells 
 
A summary of major changes in PCWG3 recommendations compared with PCWG2 with regard 
to measuring outcomes and reporting follows: 


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Blood-based and Molecular Measures 
• When there are progressing lesions, recommends rebiopsy of the progressing metastatic 
site for histology and biomarker assessment 
• Suggests that PSA outcomes should be interpreted within the context of a drug’s 
mechanism of action, and the anticipated timing of a potential favorable/unfavorable 
effect on PSA should be considered 
• Includes suggestions on how to define and report outcomes related to CTC enumeration 
(using CellSearch platform) 
 
Patient-reported Outcomes 
• Recognizes the importance of the patient perspective in prostate cancer clinical trials and 
the need to further optimize the assessment, collection, analysis, and presentation of PRO 
data 
• Recommends measuring disease-related symptoms including pain intensity and 
interference, and physical functioning, using validated instruments 
• Recommends collecting patient-reported AEs using the National Cancer Institute’s 
(NCI’s) PRO- Common Terminology Criteria for Adverse Events (CTCAE) 
 
Imaging and Clinical Measures 
• Reconsiders the mixed response designation, which may be a manifestation of disease 
heterogeneity 
• Advises recording whether disease progression represents growth of pre-existing lesions, 
development of new lesions, or both, and separately recording whether progression is 
occurring in a single organ or disease site versus (vs) multiple sites 
• Suggests that the first post-treatment bone scan be used as the baseline scan with which 
all future bone scans are compared; also emphasizes the notion of response in bone, 
caused by the advent of novel bone-targeting agents 
• Advises recording the location of nodal disease (pelvic vs extrapelvic) and visceral 
disease (lung/liver/adrenal/central nervous system [CNS]) separately, because these sites 
have separate prognostic implications 
• Also advises monitoring up to 5 individual lesions per site of spread (eg, nodes, lung, 
liver as separate sites) to address disease heterogeneity 


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• Proposes new criteria to define the first occurrence of metastatic disease in men with 
nonmetastatic CRPC (nmCRPC) at enrollment 
• Highlights and defines the bone-related outcomes, skeletal-related events (SREs) and 
SSEs, but suggests focusing on SSEs, which represent a more direct clinical benefit to 
patients 
• Introduces the concept of treatment beyond progression where clinical benefit by one or 
more disease manifestations is being observed, thus defining an objective of NLCB 
 
Appendix Table 5: 
Suggested Outcome Measures for Clinical Trials in Metastatic 
Prostate Cancer: Report by Disease Manifestation 
Variable 
PCWG3 Recommendation 
Histology 
 
Encourage rebiopsy of metastatic sites or local recurrence at progression to evaluate for 
histologic (ie, neuroendocrine/ small cell) transformation; in the context of clinical 
trials, encourage rebiopsy for biomarker assessment 
Blood-based markers 
PSA 
Recognize that a favorable effect on PSA may be delayed for ≥ 2 weeks, even for a 
cytotoxic drug 
Monitor PSA by cycle but plan to continue through early rises for a minimum of 8-9 or 
12 weeks (depending on trial design) unless other evidence of progression 
Ignore early rises (before 12 weeks) in determining PSA response 
For control/relieve/eliminate end points: 
Record the percent change from baseline (rise or fall) at 12 weeks, and separately, the 
maximal change (rise or fall) at any time using a waterfall plot 
Separately report the proportion of patients who have undergone radical 
prostatectomy and achieved a nadir less than 0.2 ng/mL v primary radiation 
therapy–treated patients who achieved a nadir less than 0.5 ng/mL 
Describe absolute changes in PSA over time from baseline to best response 
For delay/prevent end points (progression): 
After decline from baseline: record time from start of therapy to first PSA increase 
that is ≥ 25% and ≥ 2 ng/mL above the nadir, and which is confirmed by a second 
value ≥ 3 weeks later (ie, a confirmed rising trend); the requirement for an increase 
of 5 ng/mL was decreased to 2 ng/mL, and the requirement for a 50% increase was 
reduced to 25% 
Recording the duration of PSA decline of little value 
No decline from baseline: PSA progression ≥ 25% increase and ≥ 2 ng/mL increase 
from baseline beyond 12 weeks; relate to mechanism of drug and anticipated timing 
of potential favorable/unfavorable effects on PSA, if present 
CTC 
Enumerate at the start of treatment: Record as favorable (≤ 4 cells/7.5 mL of blood) or 
unfavorable (≥ 5 cells/7.5 mL) 
If unfavorable, monitor for changes after treatment 
For control/relieve/eliminate end points: 
Report as change from unfavorable (≥ 5 cells/7.5 mL of blood) to favorable (≤ 4 
cells/7.5 mL) and separately, the percent change from baseline using a waterfall plot 


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Variable 
PCWG3 Recommendation 
For delay/prevent end points: no validated definition exists (however, rising CTC 
counts are associated with a poor prognosis) 
LDH, total alkaline 
phosphatase, bone-
specific alkaline 
phosphatase, urine 
N-telopeptide, 
hemoglobin, NLR 
Descriptively report changes over time, may include the proportion showing 
normalization of a given biomarker and/or waterfall plots of percent change from 
baseline in a given biomarker 
Report institutional normal ranges to determine normalization of a given biomarker 
Imaging biomarkers: nodal and visceral 
For control/relieve/eliminate endpoints 
General 
Record up to 5 lesions per site of disease 
Use RECIST 1.1 with caveats: 
Record changes in size using waterfall plot 
Confirm favorable change with second scan 
Record complete elimination of disease at any site separately 
Nodes 
Only report changes in lymph nodes that were ≥ 1.5 cm in the short axis 
Record changes in pelvic (regional) nodes vs extrapelvic (distant/metastatic) nodes 
separately 
Visceral 
Use RECIST 1.1 with caveats: 
Record changes in liver, lung, adrenal, and CNS separately 
Only report changes in lesions ≥ 1.0 cm in the longest dimension 
For delay/prevent endpoints 
Nodal and visceral 
Record changes in nodal and visceral (lung, liver, adrenal, and CNS) disease separately 
Use RECIST 1.1 but clearly record type of progression (growth of existing lesions vs 
development of new lesions) separately by site 
The recommendations apply to both nmCRPC and mCRPC 
Record up to 5 lesions per site of spread 
Report the proportion who have not progressed at fixed time points (6 or 12 months) 
Note that for some treatments, a lesion may increase in size before it decreases 
Nodal 
Previously normal (< 1.0-cm) lymph nodes must have grown by ≥ 5 mm in the short 
axis from baseline or nadir and be ≥ 1.0 cm in the short axis to be considered to have 
progressed 
Nodes that have progressed to 1.0 to less than 1.5 cm are pathologic, subject to clinical 
discretion, and nonmeasurable 
For existing pathologic adenopathy (≥ 1.5 cm), progression is defined per RECIST 1.1 
Imaging biomarkers: bone 
Metastatic 
For control/relieve/eliminate endpoints: 
Record changes as resolved, improved, or stable (no new lesions) or worse (new 
lesions) 
Changes in intensity of uptake alone do not constitute progression or regression 
No new lesions: continue therapy in absence of other signs of progression 
New lesions (See Progression below) 
For delay/prevent endpoints (progression): 
Progression: 
Exclude pseudoprogression in the absence of symptoms or other signs of 
progression 
At least 2 new lesions on first post-treatment scan, with at least 2 additional lesions 
on the next scan (2+2 rule) 


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Variable 
PCWG3 Recommendation 
If at least 2 additional new lesions are seen on the next (confirmatory) scan, the date 
of progression is the date of the first post-treatment scan, when the first 2 new 
lesions were documented 
For scans after the first post-treatment scan, at least 2 new lesions relative to the first 
post-treatment scan confirmed on a subsequent scan 
Date of progression is the date of the scan that first documents the second lesion 
Changes in intensity of uptake alone do not constitute either progression or 
regression 
Report the proportion of patients who have not progressed at fixed time intervals 
(6 and 12 months) 
nmCRPC 
Nonmetastatic to metastatic progression: 
Any new unequivocal bone lesion, except if that lesion appears in the first post-
treatment scan; in that case, document the event, continue treatment until 2 additional 
new lesions appear, and record both events 
Patient-reported outcomes 
 
Pain palliation assessment requires a patient population with clinically meaningful pain 
at baseline (eg, ≥ 4 on a 10-point pain intensity scale) and response defined as a 
clinically meaningful score improvement at a subsequent time point (eg, a 30% 
relative or 2-point absolute improvement from baseline at 12 weeks, confirmed at 
least 2 weeks later, without an overall increase in opiate use) 
For control/relieve/eliminate endpoints: 
Document pain and analgesia at entry with a lead-in period and measure repeatedly at 
3- to 4-week intervals; serial (eg, daily x 7 days) assessments at each time point can 
improve the stability of values 
Perform serial assessments of global changes in HRQoL, urinary or bowel 
compromise, pain management, additional anticancer therapy; principles may be 
extended for any PRO for which a clinically meaningful baseline PRO score has 
been determined together with a responder definition that is based on a sustained 
clinically meaningful score improvement 
Ignore early changes (≤ 12 weeks) in pain or HRQoL in absence of compelling 
evidence of disease progression 
For delay/prevent endpoints: 
Confirm response or progression of pain or HRQoL end points ≥ 3 weeks later; 
patients with any level of baseline pain, including no pain, are eligible to be 
evaluated for prevent/delay end points; those without pain are followed for 
development of pain, whereas those with baseline pain are followed for progression 
(eg, a 2-point increase without an overall decrease in opiate use) 
Pain assessment should be administered at treatment discontinuation and once again if 
feasible (eg, 2 to 4 weeks later) 
Time to deterioration of physical function and/or HRQoL scores should also be 
included, with a priori thresholds defining clinically meaningful deterioration 
score changes that are based on prior published data for the selected questionnaire 
Source: Scher et al., 2016  
CNS = central nervous system; CTC = circulating tumor cell; HRQoL = health-related quality of life; LDH = lactate 
dehydrogenase; mCRPC = metastatic castration-resistant prostate cancer; NLR = neutrophil/lymphocyte ratio; 
nmCRPC = nonmetastatic castration-resistant prostate cancer; PCWG3 = Prostate Cancer Clinical Trials Working 
Group 3; PSA = prostate-specific antigen; RECIST = Response Evaluation Criteria in Solid Tumors; vs = versus 
 


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10.4 
APPENDIX 4: CLINICAL LABORATORY TESTS 
• Protocol-specific requirements for inclusion or exclusion of participants are detailed in the 
cohort appendix for each respective combination. 
• Additional tests may be performed at any time during the study as determined necessary by 
the Investigator or required by local regulations. 
• Investigators must document their review of each laboratory safety report. 


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10.5 
APPENDIX 5: ADVERSE EVENTS: DEFINITIONS AND 
PROCEDURES FOR RECORDING, EVALUATING, 
FOLLOW-UP, AND REPORTING 
10.5.1 
Definitions 
10.5.1.1 
Definition of AE 
AE Definition 
• An AE is any untoward medical occurrence in a participant, temporally associated with the 
use of study intervention, whether or not considered related to the study intervention. 
• NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention. 
 
Events Meeting the AE Definition  
• Any abnormality or deterioration in a laboratory test results (hematology, clinical 
chemistry, or urinalysis) or other safety assessments (eg, ECG, radiological scans, vital 
signs measurements), including those that worsen from baseline, or are considered 
clinically significant in the medical and scientific judgment of the Investigator. 
• Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• A new condition detected or diagnosed after study intervention administration even though 
it may have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.  
• Serious events that are related to a protocol-mandated intervention, including those that 
occur prior to assignment of study procedures (eg, screening invasive procedures, such as 
biopsies, discontinuation of non-study medications that may be required by protocol such 
as a prohibited medication). 
• Any new cancer (that is not a condition of the study).  
• Note: Progression of the cancer under study is not a reportable event. Refer to Section 
8.3.6 for additional details. 
 


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Events NOT Meeting the AE Definition  
• Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE. 
• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
• Surgery planned prior to informed consent to treat a pre-existing condition that has not 
worsened. 
 
10.5.1.2 
Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met. 
A SAE is defined as any AE that suggests a significant hazard, contraindication, side 
effect, or untoward medical occurrence that, at any dose: 
a. 
Results in death 
b. 
Is life-threatening 
The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe. 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been detained at the hospital or 
emergency ward for observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Hospitalization is defined as an inpatient admission, 
regardless of length of stay, even if the hospitalization is a precautionary measure for 
continued observation. 
Note: Hospitalizations for the following reasons are not considered SAEs in this study: 
• a visit to the emergency room or other hospital department for < 24 hours, that does not 
result in admission (unless considered an important medical or life-threatening event) 
• elective surgery planned prior to signing consent 
• admissions as per protocol for a planned medical/surgical procedure 
• routine health assessment requiring admission for baseline/trending of health status 
(eg, routine colonoscopy) 


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• medical/surgical admission other than to remedy ill health and planned prior to entry 
into the study. Appropriate documentation is required in these cases 
• admission encountered for another life circumstance that carries no bearing on health 
status and requires no medical/surgical intervention (eg, lack of housing, economic 
inadequacy, caregiver respite, family circumstances, administrative reason). 
d. 
Results in persistent or significant disability/incapacity 
• The term disability means a substantial disruption of a person’s ability to conduct normal 
life functions. 
• This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and 
accidental trauma (eg, sprained ankle) which may interfere with or prevent everyday life 
functions but do not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect 
In offspring of a participant exposed to the study intervention for timing as determined for 
study intervention based on product half-life. Any spontaneous abortion should be reported in 
the same fashion (as the Sponsor considers spontaneous abortions to be medically significant). 
f. 
Other important medical events: 
• Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
participant or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These events should usually be considered serious. 
Examples of such events include invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions 
that do not result in hospitalization, or development of drug dependency or drug abuse. 
 
10.5.1.3 
Definition of Unexpected AE 
Unexpected AE Definition 
• Any AE, the specificity or severity of which is not consistent with the current IB. Expected 
means that the event has previously been observed with the study intervention and is 
identified and/or described in the current IB. It does not mean that the event is expected 
with the underlying disease(s), co-morbidities or concomitant medications. 
 


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10.5.1.4 
Definition of Treatment-emergent AE 
Treatment-emergent AE Definition 
• Any unfavorable and unintended diagnosis, symptom, sign (including an abnormal 
laboratory finding that is considered to be clinically significant), syndrome or disease that 
either occurs during the study, having been absent at baseline, or, if present at baseline, 
appears to have worsened in severity or frequency, whether or not the event is considered 
related to the study intervention. 
 
10.5.2 
Additional Events Reported in the Same Manner as an SAE 
Additional Events Reported in the Same Manner as a SAE 
• In addition to the SAE criteria in Section 10.5.1.2, AEs meeting any of the below criteria, 
although not serious per ICH definition, are reportable to the Sponsor in the same 
timeframe as SAEs to meet certain local requirements. Therefore, these events are 
considered serious by the Sponsor for collection purposes. 
o A new cancer (not the indicated condition of the study) 
o An overdose or is an associated event that meets safety criterion with an 
overdose (as specified in Section 8.4) 
o Protocol-specified AEs, including AESIs (as applicable and as defined in the 
cohort appendix for each respective combination) 
o Pregnancy (as specified in Section 8.3.5) 
 


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10.5.3 
Recording AEs and SAEs 
AE and SAE Recording 
• When an AE/AESI/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event. Only a single AE term should be recorded for the event. 
• The Investigator will record all relevant AE/AESI/SAE information on the eCRF. 
• It is not acceptable for the Investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the Adverse Event eCRF/Serious Adverse 
Event Report Form (SAERF). 
• There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be redacted on the copies of the medical records before submission to the 
Sponsor. 
• The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.  
 
Assessment of Severity 
• The terms ‘severe’ and ‘serious’ are not synonymous. An event is defined as ‘serious’ 
when it meets at least 1 of the predefined outcomes as described in the definition of an 
SAE, NOT when it is rated as severe. Severity (intensity) and seriousness need to be 
independently assessed for each AE recorded on the eCRF. 
• The Investigator will assess the intensity for each AE, including AESI, and SAE (and other 
reportable safety events) according to the NCI Common Terminology for Adverse Events 
(CTCAE), version 5.0, which can be found at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
The following grading will be used for assessing intensity for AEs not specifically listed in 
the NCI CTCAE: 
o Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
o Grade 2: Moderate; minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental activities of daily living. 
o Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care activities of daily living. 
o Grade 4: Life threatening consequences; urgent intervention indicated. 


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o Grade 5: Death related to AE. 
• Any AE that changes CTCAE grade over the course of a given episode (ie, persistent AE) 
will have each change of grade recorded on the Adverse Event eCRF. 
 
Assessment of Causality 
• The Investigator is obligated to assess the relationship between study intervention and each 
occurrence of each AE/AESI/SAE. 
• A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
• The Investigator will use their clinical judgment, knowledge of the participant, the 
circumstances surrounding the event, and an evaluation of any potential alternative causes 
to determine the relationship. 
• The following guidance will be considered and investigated: 
o Temporal relationship of the event onset to study intervention administration 
o Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study intervention, or reintroduction of study intervention (as 
applicable) 
o Known association of the event with the study intervention or with similar 
treatments 
o Known association of the event with the disease under study 
o Presence of risk factors in the participant or use of concomitant medications 
known to increase the occurrence of the event 
o Presence of non-treatment-related factors that are known to be associated with 
the occurrence of the event 
• The Investigator will also consult the IB and/or Product Information, for marketed 
products, in his/her assessment. 
• For each AE/AESI/SAE, the Investigator must document in the medical notes that he/she 
has reviewed the AE/AESI/SAE and has provided an assessment of causality. 
• There may be situations in which an SAE has occurred and the Investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the Investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor. 
• The Investigator may change his/her opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment. 
• The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 


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• For studies in which multiple agents are administered as part of a combination regimen, 
the Investigator may attribute each AE causality to the combination regimen or to a single 
agent of the combination.  In general, causality attribution should be assigned to the 
combination regimen (ie, to all agents in the regimen). However, causality attribution may 
be assigned to a single agent if in the Investigator’s opinion, there are sufficient data to 
support full attribution of the AE to the single agent. 
Causality for this protocol should be assessed as follows: 
• Unrelated: This category applies to those AEs that are clearly and incontrovertibly due to 
extraneous causes (disease, environment, etc.). 
Note: If an AE is assessed as unrelated to the study intervention(s), there must be an 
alternative etiology in the Investigator’s assessment for that event documented in the 
participant’s medical records. 
• Unlikely Related: This category applies to those AEs that are judged to be unrelated to the 
study intervention(s), but for which no extraneous cause may be found. An AE may be 
considered unlikely to be related to study intervention(s) if or when it meets 2 of the 
following criteria: 
o it does not follow a reasonable temporal sequence from administration of the 
study intervention(s); 
o it could readily have been produced by the participant’s clinical state, 
environmental or toxic factors, or other modes of therapy administered to the 
participant; 
o it does not follow a known pattern of response to the study intervention(s); or 
o it does not reappear or worsen when the study intervention(s) is 
re-administered. 
• Possibly Related: This category applies to those AEs for which a connection with the 
study intervention administration appears unlikely but cannot be ruled out with certainty. 
An AE may be considered possibly related if or when it meets 2 of the following criteria: 
o it follows a reasonable temporal sequence from administration of the study 
intervention(s); 
o it could not readily have been produced by the participant’s clinical state, 
environmental or toxic factors, or other modes of therapy administered to the 
participant; or 
o it follows a known pattern of response to the study intervention(s). 
• Probably Related: This category applies to those AEs that the Investigator feels with a 
high degree of certainty are related to the study intervention(s). An AE may be considered 
probably related if or when it meets 3 of the following criteria: 
o it follows a reasonable temporal sequence from administration of the study 
intervention(s); 


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o it could not be reasonably explained by the known characteristics of the 
participant’s clinical state, environmental or toxic factors, or other modes of 
therapy administered to the participant; 
o it disappears or decreases on cessation or reduction in dose (note that there are 
exceptions when an AE does not disappear upon discontinuation of the study 
intervention, yet study intervention relatedness clearly exists; for example, as in 
bone marrow depression, fixed study intervention eruptions, or tardive 
dyskinesia); or 
o it follows a known pattern of response to the study intervention(s). 
• Definitely Related: This category applies to those AEs that the Investigator believes are 
incontrovertibly related to study intervention(s). An AE may be assigned an attribution of 
definitely related if or when it meets all of the following criteria: 
o it follows a reasonable temporal sequence from administration of the study 
intervention(s); 
o it could not be reasonably explained by the known characteristics of the 
participant’s clinical state, environmental or toxic factors, or other modes of 
therapy administered to the participant; 
o it disappears or decreases on cessation or reduction in dose and recurs with 
re-exposure to study intervention(s) (if rechallenge occurs); and 
o it follows a known pattern of response to the study intervention(s). 
 
Follow-up of AEs and SAEs 
• The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals. 
• New or updated information will be recorded on the eCRF. 
• The Investigator will submit any updated data related to SAEs or AESIs to the Sponsor 
within 24 hours of receipt of the information. 
 


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10.5.4 
Reporting of AEs, SAEs, and Other Reportable Safety Events to 
the Sponsor 
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor via an 
Electronic Data Collection Tool  
• The primary mechanism for reporting AEs to the Sponsor will be via the electronic data 
collection (EDC) tool. 
• Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent). 
• If the electronic system is unavailable for more than 24 hours, then the site will use the 
paper AE reporting tool (see next section). 
• Reference Section 8.3.1 – Time Period and Frequency for Collecting AE, AESI, SAE, and 
Other Reportable Safety Event Information for reporting time requirements  
• After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data. 
• The site will report all AESIs, as applicable, on the study-specific SAERF to the Parker 
Institute for Cancer Immunotherapy Pharmacovigilance Group within 24 hours of site 
awareness. The AESI should also be reported on the Adverse Event eCRF. 
• The site will report all SAE data on the study-specific SAERF to the Parker Institute for 
Cancer Immunotherapy Pharmacovigilance Group within 24 hours of site awareness. 
• Contacts for reporting SAEs, AESIs, and other reportable safety events can be found in 
Section 8.3.8.2. 
 
SAE and Other Reportable Safety Event Reporting to the Sponsor 
• In the instance where an SAE or AESI occurs, a facsimile transmission of the SAERF 
and/or Pregnancy Report Form is the preferred method to transmit this information to the 
Parker Institute for Cancer Immunotherapy Pharmacovigilance Group. 
• In rare circumstances and in the absence of facsimile equipment, notification by telephone 
is acceptable with a copy of the SAERF sent via email. 
• Initial notification via telephone does not replace the need for the Investigator to complete 
and sign the SAERF within the designated reporting time frames. 
• Contacts for SAE, AESI, and other reportable safety event reporting can be found in 
Section 8.3.8.2. 
 


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10.5.5 
Additional Reporting Considerations 
AE and SAE Recording for Special Circumstances 
Diagnosis versus Signs and Symptoms 
• A diagnosis (if known) or cause of death should be recorded on the Adverse Event eCRF 
page rather than individual signs and symptoms (eg, record only liver failure or hepatitis 
rather than jaundice, asterixis, and elevated transaminases). 
• If a constellation of signs and/or symptoms cannot be medically characterized as a single 
diagnosis or syndrome at the time of reporting, each individual event should be recorded 
separately on the Adverse Event eCRF page. 
• If a diagnosis is subsequently established, all previously reported AEs based on signs and 
symptoms should be nullified and replaced by one AE report based on the single diagnosis, 
with a starting date that corresponds to the starting date of the first symptom of the 
eventual diagnosis. 
Adverse Events That Are Secondary to Other Events 
• In general, AEs that are secondary to other events (eg, cascade events or clinical sequelae) 
should be identified by their primary cause, with the exception of severe or serious 
secondary events. A medically significant secondary AE that is separated in time from the 
initiating event should be recorded as an independent event on the Adverse Event eCRF 
page. For example: 
o If vomiting results in mild dehydration with no additional treatment in a healthy 
adult, only vomiting should be reported on the eCRF. 
o If vomiting results in severe dehydration, both events should be reported 
separately on the eCRF. 
o If a severe gastrointestinal hemorrhage leads to renal failure, both events should 
be reported separately on the eCRF. 
o If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF. 
o If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF. 
• All AEs should be recorded separately on the Adverse Event eCRF page if it is unclear 
as to whether the events are associated. 


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Persistent or Recurrent Adverse Events 
• A persistent AE is one that extends continuously, without resolution, between participant 
evaluation time points. Such events should only be recorded once on the Adverse Event 
eCRF page. The initial severity (intensity or grade) of the event will be recorded at the 
time the event is first reported. 
• If a persistent AE becomes more severe, the most extreme severity should also be recorded 
on the Adverse Event eCRF page, and details regarding any increases or decreases in 
severity will be captured on the Adverse Event eCRF. 
• If the event becomes serious, it should be reported to the Sponsor as a SAE, and the 
Adverse Event eCRF page should be updated by changing the event from “non-serious” to 
“serious,” providing the date that the event became serious, and completing all data fields 
related to SAEs. 
• A recurrent AE is one that resolves between participant evaluation time points and 
subsequently recurs. Each recurrence of an AE should be recorded as a separate event on 
the Adverse Event eCRF page. 
Abnormal Laboratory Values 
• A clinical laboratory test value must be reported as an AE if it meets any of the following 
criteria: 
o is accompanied by clinical symptoms 
o results in a change in study intervention (eg, dose modification, treatment 
interruption, or treatment discontinuation) 
o results in a medical intervention or change in concomitant medication 
o is clinically significant in the Investigator’s judgment 
Abnormal Vital Sign Values 
• Medical and scientific judgment should be exercised in deciding whether an isolated vital 
sign abnormality should be classified as an AE. 
• If a clinically significant vital sign abnormality is a sign of a disease or syndrome (eg, high 
blood pressure), only the diagnosis (ie, hypertension) should be recorded on the Adverse 
Event eCRF page. 
• Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF page (see above for details on 
recording persistent AE). 


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Abnormal Liver Function Tests 
• The finding of an elevated alanine aminotransferase (ALT) or aspartate aminotransferase 
(AST) (> 3 x baseline value) in combination with either an elevated total bilirubin 
(> 2 x upper limit of normal [ULN]) or clinical jaundice in the absence of cholestasis or 
other causes of hyperbilirubinemia is considered to be an indicator of severe liver injury 
(as defined by Hy’s Law). Therefore, Investigators must report as an AE the occurrence of 
either of the following: 
o Treatment-emergent ALT or AST > 3 x baseline value in combination with 
total bilirubin > 2 x ULN (of which ≥ 35% is direct bilirubin) 
o Treatment-emergent ALT or AST > 3 x baseline value in combination with 
clinical jaundice 
• The most appropriate diagnosis or if a diagnosis cannot be established, the abnormal 
laboratory values should be recorded on the Adverse Event eCRF page and reported to the 
Sponsor immediately, either as an SAE or an AESI (as applicable and as defined in the 
cohort appendix for each respective combination). 
Lack of Efficacy or Worsening of Underlying Disease 
• Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as AEs. These data will be captured as efficacy 
assessment data only. In most cases, the expected pattern of progression will be based on 
the PCWG3-modified RECIST 1.1 used in this study. In rare cases, the determination of 
clinical progression will be based on symptomatic deterioration. However, every effort 
should be made to document progression through use of objective criteria. If there is any 
uncertainty as to whether an event is due to disease progression, it should be reported as an 
AE. 
Deaths 
• All deaths that occur during the protocol-specified AE reporting period, regardless of 
relationship to study intervention, must be recorded on the Death eCRF page and 
immediately reported to the Sponsor (see Section 8.3.1), unless the death is attributed to 
progression of disease. 
• Death should be considered an outcome and not a distinct event. The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF page. Generally, only one such event should be 
reported. 
• If the cause of death is unknown and cannot be ascertained at the time of reporting, 
“unexplained death” should be recorded on the Adverse Event eCRF page. 
• If the cause of death later becomes available (eg, after autopsy), “unexplained death” 
should be replaced by the established cause of death. 
• The term “sudden death” should not be used unless combined with the presumed cause of 
death (eg, “sudden cardiac death”). 


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• If the death is attributed to progression of underlying disease, “underlying disease” should 
be recorded on the appropriate eCRF page; no SAERF is necessary. 
• Deaths that occur after the AE reporting period should be reported as described in 
Section 8.3.2. 
Pre-existing Medical Conditions 
• A pre-existing medical condition is one that is present at the baseline visit for this study. 
Such conditions should be recorded on the Medical History eCRF page. 
• A pre-existing medical condition should be recorded as an AE only if the frequency, 
severity, or character of the condition worsens during the study. When recording such 
events on the Adverse Event eCRF page, it is important to convey the concept that the pre-
existing condition has changed by including applicable descriptors (eg, “more frequent 
headaches”). 
Adverse Events Associated with Overdose or Error in Drug Administration 
• Overdose should be reported as specified in Section 8.4. 
• All AEs associated with an overdose or incorrect administration of study intervention 
should be recorded on the Adverse Event eCRF page. 
• If the associated AE fulfills seriousness criteria, the event should be reported to the 
Sponsor as a separate SAE. 
 


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10.6 
APPENDIX 6: CONTRACEPTIVE GUIDANCE AND 
COLLECTION OF PREGNANCY INFORMATION 
It is acknowledged that only men will be enrolled in this study. Although women will not be 
enrolled, participants in this study may have female partners of childbearing potential. Therefore, 
sections have been included in this appendix to provide information relevant to women of 
childbearing potential (WOCBP) who may be partners of study participants. 
10.6.1 
Definitions 
10.6.1.1 
Woman of Childbearing Potential 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below). 
Women in the following categories are not considered WOCBP 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
o Documented hysterectomy 
o Documented bilateral salpingectomy 
o Documented bilateral oophorectomy 
Note:  Documentation can come from the site personnel’s: review of the participant’s 
medical records, medical examination, or medical history interview. 
3. Postmenopausal female 
o A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. A high follicle stimulating hormone (FSH) level in the 
postmenopausal range may be used to confirm a postmenopausal state in women 
not using hormonal contraception or hormonal replacement therapy (HRT). 
However, in the absence of 12 months of amenorrhea, a single FSH measurement 
is insufficient.  
o Females on HRT and whose menopausal status is in doubt will be required to use 
one of the non-estrogen hormonal highly effective contraception methods if they 
wish to continue their HRT while their partner participates in the study. 
 
10.6.2 
Contraception Guidance 
Male participants with female partners of childbearing potential are eligible to participate if they 
agree to ONE of the following (during the protocol-defined time frame in the cohort appendix 
for each respective combination):  


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• Are abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent 
• Agree to use a male condom plus partner use of a contraceptive method with a failure rate 
of <1% per year as described in Appendix Table 6 when having penile-vaginal 
intercourse with a WOCBP who is not currently pregnant. In addition, male participants 
must refrain from donating sperm for the duration of the study and for 5 half-lives after 
the last dose of study intervention. 
 
Male participants with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile vaginal intercourse or use a male condom during each episode of penile penetration during 
the protocol-defined time frame and for 5 half-lives after the last dose of study intervention. 
Appendix Table 6: 
Highly Effective Contraceptive Methods for Partner Use 
Highly Effective Contraceptive Methods That Are User Dependenta 
Failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulationb  
• Oral  
• Intravaginal  
• Transdermal 
Progestogen only hormonal contraception associated with inhibition of ovulation 
• Oral  
• Injectable 
Highly Effective Methods That Are User Independenta 
Implantable progestogen only hormonal contraception associated with inhibition of ovulationb 
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS) 
• Bilateral tubal occlusion 
Vasectomized partner  
A vasectomized partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used. 


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Sexual abstinence  
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study intervention. 
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the 
study and the preferred and usual lifestyle of the participant. 
NOTES:  
a) Typical use failure rates may differ from those when used consistently and correctly. Use 
should be consistent with local regulations regarding the use of contraceptive methods for 
participants participating in clinical studies.  
b) Hormonal contraception may be susceptible to interaction with the study intervention, 
which may reduce the efficacy of the contraceptive method. In this case, two highly 
effective methods of contraception should be utilized during the treatment period and for at 
least 5 half-lives after the participant’s last dose of study intervention 
 
10.6.3 
Collection of Pregnancy Information from Male Participants with 
Partners who Become Pregnant 
• The Investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study. This 
applies only to male participants who receive study intervention. 
• After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the Investigator will record pregnancy information on the appropriate form and 
submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy. The 
female partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to the Sponsor. 
Generally, the follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of fetal status 
(presence or absence of anomalies) or indication for the procedure. 


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10.7 
APPENDIX 7: GENETICS 
Use/Analysis of DNA 
• Genetic variation may impact a participant’s response to study intervention, susceptibility 
to, and severity and progression of disease. Variable response to study intervention may 
be due to genetic determinants that impact immune response, drug absorption, 
distribution, metabolism, and excretion; mechanism of action of the drug; disease 
etiology; and/or molecular subtype of the disease being treated. Therefore, where local 
regulations and IRB/IEC allow, a blood and tumor sample will be collected for DNA 
analysis from consenting participants. 
• DNA samples will be used for research related to study intervention and/or mCRPC and 
related diseases or evaluation of new assay technologies. They may also be used to 
develop tests/assays including diagnostic tests related to study intervention and/or 
therapies of this drug class and/or immuno-oncology therapies and mCRPC. Genetic 
research may consist of the analysis of one or more candidate genes or the analysis of 
genetic markers throughout the genome or analysis of the entire genome (as appropriate). 
• Stool samples will be collected, and microbiome nucleic acid extracted and analyzed to 
evaluate a participant's response to study intervention, susceptibility to, and severity and 
progression of disease. Variable response to study intervention may be due to bacterial 
genetic determinants that impact immune response, drug absorption, distribution, 
metabolism, and excretion; or by the mechanism of action of the drug. 
• DNA samples may be analyzed for whole genome sequencing and bacterial DNA may be 
analyzed by 16s and/or whole metagenomic sequencing and relationship to clinical 
outcomes in response to study intervention. Additional analyses may be conducted if it is 
hypothesized that this may help further understand the clinical data and/or treatment of 
mCRPC. 
• The samples may be analyzed as part of a multi-study assessment of genetic factors 
involved in the response to study intervention or study interventions of this class to 
understand study disease or related conditions. 
• The results of genetic analyses may be reported in the clinical study report (CSR) or in a 
separate study summary. 
• The Sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 
• The samples will be retained while research on study intervention or study interventions 
of this class or indication (eg, immunotherapy) continues in accordance with applicable 
law. 


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10.8 
APPENDIX 8: LISTS OF TERMINOLOGY AND 
ABBREVIATIONS 
10.8.1 
List of Terminology 
Terminology 
Description 
Cohort 
A group of participants receiving the same immunotherapy 
combination. 
Cohort appendix 
A document that guides the treatment of participants in a given 
cohort. The cohort appendices are identified using a letter 
designation (eg, Appendix Cohort A, Appendix Cohort B, 
etc.).  
Core protocol 
The master document that provides the elements common 
across the study and among all cohorts, unless otherwise 
specified. 
Immunotherapy combination 
Two or more study interventions administered to a cohort of 
participants. 
 
10.8.2 
List of Abbreviations 
Abbreviation 
Definition 
ADA 
anti-drug antibody(ies) 
ADT 
androgen deprivation therapy 
AE(s) 
adverse event(s) 
AESI(s) 
AE(s) of special interest 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BCG 
bacille Calmette-Guerin 
BUN 
blood urea nitrogen 
C 
cycle 
Cmax 
maximum observed drug concentration 
cfDNA 
cell-free deoxyribonucleic acid 
CI(s) 
confidence interval(s) 
CIOMS 
Council for International Organizations of Medical Sciences 
CNS 
central nervous system 
COA 
clinical outcomes assessment 
CONSORT 
Consolidated Standards of Reporting Trials 
CR 
complete response 
CSR 
clinical study report 
CT 
computerized tomography 
CTC 
circulating tumor cells 


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Abbreviation 
Definition 
CTC0 
a measure of zero CTC 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA-4 
cytotoxic T-lymphocyte-associated protein 4 
DCR 
disease control rate 
DNA 
deoxyribonucleic acid 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data collection 
EOT 
end of treatment 
FDA 
Food and Drug Administration 
FDG-PET 
fluorodeoxyglucose positron emission tomography 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
GnRH 
gonadotropin-releasing hormone 
GU 
genitourinary 
HIPAA 
Health Insurance Portability and Accountability Act 
HRQoL 
health-related quality of life 
HRT 
hormone (hormonal) replacement therapy 
I/E 
inclusion/exclusion 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IND 
Investigational New Drug 
INR 
international normalized ratio 
IRB/IEC 
Institutional Review Board/Independent Ethics Committee 
IUD 
intrauterine device 
IUS 
intrauterine hormone-releasing system 
IV 
intravenous(ly) 
LDH 
lactate dehydrogenase 
mCRPC 
metastatic castration-resistant prostate cancer 
MDSC(s) 
myeloid-derived suppressor cell(s) 
MMR 
mismatch repair 
MRI 
magnetic resonance imaging 
MSI 
microsatellite instability 
NCI 
National Cancer Institute 
NK 
natural killer 
NLCB 
no longer clinically benefiting 


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Abbreviation 
Definition 
NLR 
neutrophil/lymphocyte ratio 
nmCRPC 
nonmetastatic castration-resistant prostate cancer 
ORR 
objective response rate 
OS 
overall survival 
OTC 
over-the-counter 
PAP 
prostatic acid phosphatase 
PBMC(s) 
peripheral blood mononuclear cell(s) 
PCWG2 
Prostate Cancer Clinical Trials Working Group 2 
PCWG3 
Prostate Cancer Clinical Trials Working Group 3 
PD 
progressive disease 
PD-1 
programmed cell death 1 
PD-L1 
programed cell death ligand 1 
PET 
positron emission tomography 
PI 
Principal Investigator 
PK 
pharmacokinetic 
PORTER 
Prostate Researching Translational Endpoints Correlated to Response 
PR 
partial response 
PRO 
patient-reported outcome 
PSA 
prostate-specific antigen 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
Q3M 
every 3 months 
RBC 
red blood cell 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
ribonucleic acid 
rPFS 
radiographic progression-free survival 
SAC 
Safety Assessment Committee 
SAE(s) 
serious adverse event(s) 
SAERF 
Serious Adverse Event Report Form 
SAP 
statistical analysis plan 
SD 
stable disease 
SOA 
Schedule of Activities 
SRE(s) 
skeletal-related event(s) 
SSE(s) 
symptomatic skeletal event(s) 
SUSAR 
suspected unexpected serious adverse reactions 
TC-99m 
technetium-99m 
Treg(s) 
regulatory T cell(s) 
TSH 
thyroid stimulating hormone 


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Abbreviation 
Definition 
ULN 
upper limit of normal 
US 
United States 
VISTA 
V-domain Ig suppressor of T cell activation 
vs 
versus 
WBC 
white blood cell 
WOCBP 
woman of childbearing potential 
 


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10.9 
APPENDIX 9: PROTOCOL AMENDMENT HISTORY 
 
DOCUMENT HISTORY 
Documents 
Date of Issue 
Amendment 2 
30 April 2019 
Amendment 1 
24 Jan 2019 
Original Protocol 
07 Dec 2018 
 
 


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11 
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Prot_002.pdf: 
PORTER Appendix Cohort C - Parker Institute for Cancer Immunotherapy 
Protocol PICI0033, Amendment 1, Version 1.0 
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Protocol Title:  A Multicenter, Open-Label, Exploratory Platform Study to Evaluate Biomarkers 
and Immunotherapy Combinations for the Treatment of Patients with Metastatic Castration-
resistant Prostate Cancer 
Appendix Cohort C 
Protocol Number:  PICI0033 
Amendment Number:  1 
Compound Number:  CDX-301, INO-5151, Nivolumab 
Short Title:  Platform Study for Prostate Researching Translational Endpoints Correlated to 
Response to Inform Use of Novel Combinations (PORTER) 
Sponsor Name and Legal Registered Address:   
Parker Institute for Cancer Immunotherapy 
1 Letterman Drive 
Suite D3500 
San Francisco, CA 94129 
Tel: 415-985-7311 
 
Regulatory Agency Identifying Number(s):  
IND NUMBER: 18853 
EudraCT NUMBER:  Not applicable 
Approval Date:  Final Protocol: 26 February 2019 
 
Amendment 1: 30 April 2019 
 
CONFIDENTIAL 
This document and its contents are the property of and confidential to Parker Institute for Cancer 
Immunotherapy. Any unauthorized copying or use of this document is prohibited. 
 
 




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INVESTIGATOR PROTOCOL AGREEMENT PAGE 
I agree: 
• 
To assume responsibility for the proper conduct of the study at this site. 
• 
To conduct the study in compliance with this protocol, any future amendments, and with 
any other study conduct procedures provided by Parker Institute for Cancer 
Immunotherapy. 
• 
Not to implement any changes to the protocol without written agreement from Parker 
Institute for Cancer Immunotherapy and prior review and written approval from the 
Institutional Review Board or Independent Ethics Committee except where necessary to 
eliminate an immediate hazard to participants. 
• 
That I am thoroughly familiar with the appropriate use of the study drug(s), as described 
in this cohort appendix and any other information provided by Parker Institute for Cancer 
Immunotherapy including, but not limited to, the current Investigator’s Brochure(s). 
• 
That I am aware of, and will comply with, the International Conference on 
Harmonisation for Good Clinical Practices (GCP) and all applicable regulatory 
requirements. 
• 
To ensure that all persons assisting me with the study are adequately informed about the 
study drugs, the Parker Institute for Cancer Immunotherapy study protocol, and of their 
study-related duties and functions as described in the protocol. 
• 
That I agree that persons debarred from conducting or working on clinical studies by any 
court or regulatory agency will not be allowed to conduct or work on studies for the 
Parker Institute for Cancer Immunotherapy or for a partnership in which the Parker 
Institute for Cancer Immunotherapy is involved, and that I will immediately disclose in 
writing to the Parker Institute for Cancer Immunotherapy if any person who is involved 
in the study is debarred, or if any proceeding for debarment is pending. 
 
 
Signature: 
 
 
Date: 
 
 
Name 
(print): 
 
  
 
Site 
Number: 
Principal Investigator 
 
___________ 
  
 
 
  
 


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4
Amendment(s) to Appendix Cohort C 
Text revisions resulting from the amendment(s) are incorporated in the synopsis and body of the 
Appendix Cohort Amendment. Major changes to the appendix cohort are summarized below. 
Key Revisions in Amendment 1 (30 April 2019) 
Section # and Name 
Description of Change 
Study Design 
1.2 Schema, Figure 1 
Modified to improve identification of key research procedure time points. 
1.3 Schedule of Activities 
Updated collection schedule for circulating tumor cells and cfDNA to 
remove complexity in collection timing and amount of material collected 
from participants. 
Study Intervention 
6.6.1 Dose Modifications for 
CDX-301, INO-5151, and 
Nivolumab 
Added text stating enrollment for the initial 6 participants will be split 
into 2 groups (of 3 participants each) separated by an 8 week enrollment 
hold to allow for safety monitoring with this first-in-human combination. 
Additionally, a second 8 week enrollment hold will follow the second 
group enrolled to continue monitoring for safety risks before the 
remaining participants are enrolled. 
Clarification of Document 
General Revisions 
Document updated to address minor typographical errors and editorial 
changes for clarity. 
 
 


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TABLE OF CONTENTS 
 
TABLE OF CONTENTS .................................................................................................................4 
LIST OF TABLES ...........................................................................................................................8 
LIST OF FIGURES .........................................................................................................................8 
1 
PROTOCOL SUMMARY ...................................................................................................9 
1.1 
SYNOPSIS ...............................................................................................................9 
1.2 
SCHEMA ...............................................................................................................10 
1.3 
SCHEDULE OF ACTIVITIES..............................................................................12 
2 
INTRODUCTION .............................................................................................................17 
2.1 
STUDY RATIONALE ..........................................................................................17 
2.2 
BACKGROUND ...................................................................................................17 
2.2.1 
Background on INO-5151 (PSA, PSMA, Interleukin-12) DNA Delivered 
via Intramuscular Electroporation (Inovio Pharmaceuticals) ..................18 
2.2.1.1 
PSA and PSMA Immunotherapy ...........................................18 
2.2.1.2 
Interleukin-12 Plasmid with DNA Vaccines .........................20 
2.2.1.3 
Rationale for Use of Electroporation .....................................21 
2.2.2 
Background on rhuFLT3L/CDX-301 (Celldex Therapeutics, Inc.) ........22 
2.2.3 
Background on Nivolumab (Bristol-Myers Squibb Company) ...............24 
2.2.4 
Rationale for CDX-301 + INO-5151 + Nivolumab Immunotherapy 
Combination ............................................................................................24 
2.3 
BENEFIT/RISK ASSESSMENT ..........................................................................28 
3 
OBJECTIVES AND ENDPOINTS ...................................................................................30 
4 
STUDY DESIGN...............................................................................................................31 
4.1 
OVERALL DESIGN .............................................................................................31 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN ...........................................31 
4.3 
JUSTIFICATION FOR DOSE ..............................................................................31 
4.3.1 
Rationale for Nivolumab Dose and Schedule .........................................32 
4.3.2 
Rationale for INO-5151 Dose and Schedule ...........................................33 
4.3.3 
Rationale for CDX-301 Dose and Schedule ............................................33 
4.4 
TREATMENT BEYOND DISEASE PROGRESSION ........................................34 
4.5 
END OF STUDY DEFINITION ...........................................................................34 
5 
STUDY POPULATION ....................................................................................................35 


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5.1 
INCLUSION CRITERIA.......................................................................................35 
5.1.1 
Common Inclusion Criteria .....................................................................35 
5.1.2 
Combination-specific Inclusion Criteria .................................................37 
5.2 
EXCLUSION CRITERIA .....................................................................................37 
5.2.1 
Common Exclusion Criteria ....................................................................37 
5.2.2 
Combination-specific Exclusion Criteria ................................................39 
5.3 
LIFESTYLE CONSIDERATIONS .......................................................................39 
5.4 
SCREEN FAILURES ............................................................................................39 
6 
STUDY INTERVENTION ................................................................................................39 
6.1 
STUDY INTERVENTION(S) ADMINISTERED ................................................39 
6.1.1 
Investigational Device .............................................................................41 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY ......................41 
6.3 
RANDOMIZATION AND BLINDING................................................................41 
6.4 
STUDY INTERVENTION COMPLIANCE .........................................................41 
6.5 
CONCOMITANT THERAPY...............................................................................42 
6.5.1 
Permitted Therapy ...................................................................................42 
6.5.2 
Prohibited Therapy ..................................................................................42 
6.6 
DOSE MODIFICATIONS ....................................................................................42 
6.6.1 
Dose Modifications for CDX-301, INO-5151, and Nivolumab ..............42 
6.6.1.1 
Potential for Overlapping Toxicities with CDX-301, INO-
5151, and Nivolumab ............................................................44 
6.6.1.2 
Dose Modifications and Toxicity Management for Adverse 
Events Associated with CDX-301, INO-5151, and Nivolumab
 ...............................................................................................45 
6.6.1.3 
Dose Modifications and Toxicity Management for 
Infusion/Injection-related Reactions Associated with the 
Administration of CDX-301, INO-5151, and/or Nivolumab 46 
6.6.1.4 
Dose Delays and Interruptions of CDX-301, INO-5151, and 
Nivolumab .............................................................................48 
6.6.2 
Dose Modifications for Nivolumab .........................................................48 
6.6.3 
Dose Modifications for INO-5151 ..........................................................50 
6.6.4 
Dose Modifications for CDX-301 ...........................................................50 
7 
DISCONTINUATIONS OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL..........................................................................51 
7.1 
DISCONTINUATION OF STUDY INTERVENTION ........................................51 


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7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM STUDY ........51 
7.3 
LOST TO FOLLOW-UP .......................................................................................52 
8 
STUDY ASSESSMENTS AND PROCEDURES .............................................................52 
8.1 
EFFICACY ASSESSMENTS ...............................................................................52 
8.1.1 
Laboratory Assessments of Clinical Activity ..........................................52 
8.2 
SAFETY ASSESSMENTS ....................................................................................52 
8.2.1 
Clinical Safety Laboratory Assessments .................................................52 
8.2.1.1 
Local Laboratory Assessments ..............................................52 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ..............................53 
8.3.4 
Regulatory Reporting Requirements for SAEs .......................................53 
8.3.7 
Adverse Events of Special Interest ..........................................................54 
8.4 
TREATMENT OF OVERDOSE ...........................................................................54 
8.5 
PHARMACOKINETICS .......................................................................................54 
8.6 
IMMUNOGENICITY AND ANTI-DRUG ANTIBODIES ..................................54 
8.7 
BIOMARKERS .....................................................................................................54 
8.8 
MEDICAL RESOURCE UTILIZATION AND HEALTH ECONOMICS ..........54 
9 
STATISTICAL CONSIDERATIONS...............................................................................54 
9.5.1 
Interim Safety Monitoring .......................................................................55 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ....56 
10.1 
APPENDIX C-1: MANAGEMENT ALGORITHMS ..........................................57 
10.2 
APPENDIX C-2: LISTS OF TERMINOLOGY AND ABBREVIATIONS .........65 
10.2.1 
List of Terminology .................................................................................65 
10.2.2 
List of Abbreviations ...............................................................................65 
10.3 
APPENDIX C-3: APPENDIX COHORT C AMENDMENT HISTORY ............69 
11 
REFERENCES ..................................................................................................................70 
 


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LIST OF TABLES 
Table 1: 
Schedule of Activities ............................................................................................13 
Table 2 
Adverse Events Reported in Studies of Inovio DNA Delivered IM with 
Electroporation Occurring in at Least 5% of Subjects ...........................................22 
Table 3: 
Clinical Studies Supporting the Co-administration of Components of this Study 
Intervention ............................................................................................................27 
Table 4: 
Cohort-Specific Objectives and Corresponding Endpoints ...................................30 
Table 5: 
Study Intervention ..................................................................................................39 
Table 6: 
Toxicity Criteria Requiring Permanent Treatment Discontinuation ......................44 
Table 7:  
Dose Modification and Toxicity Management Guidelines for Infusion/Injection-
related Reactions Associated with the Administration of CDX-301, INO-5151, 
and/or Nivolumab ..................................................................................................47 
Table 8: 
Dose Modification and Toxicity Management Guidelines for Adverse Events 
Associated with Nivolumab ...................................................................................49 
Table 9: 
Dose Modification and Toxicity Management Guidelines for Adverse Events 
Associated with CDX-301 .....................................................................................51 
Table 10: 
Laboratory Tests Sent to the Study Site’s Local Laboratory for Analysis of 
Disease-related Endpoints ......................................................................................52 
Table 11: 
Laboratory Tests Sent to the Study Site’s Local Laboratory for Analysis of Safety
................................................................................................................................53 
Table 12: 
Probability of Proceeding to Full Enrollment ........................................................55 
Table 13: 
Incidence with 95% Confidence Intervals of Possible Observed Adverse Events 
Described in Table 6 ..............................................................................................55 
 
 
LIST OF FIGURES 
Figure 1: 
Study Schema.........................................................................................................11 
 


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1 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS 
Protocol Title: 
A Multicenter, Open-Label, Exploratory Platform Study to Evaluate Biomarkers and 
Immunotherapy Combinations for the Treatment of Patients with Metastatic Castration-resistant 
Prostate Cancer 
Appendix Cohort C 
Short Title: 
Platform Study for Prostate Researching Translational Endpoints Correlated to Response to 
Inform Use of Novel Combinations (PORTER) 
Note to Investigators:  This cohort appendix is intended to supplement the core protocol, and as 
such, will focus on combination-specific (CDX-301, INO-5151, and nivolumab) information that 
is not already available in the core protocol. 
Rationale: 
This study cohort is designed to explore a multi-pronged approach to stimulate antitumor 
immunity by enhancement of a deoxyribonucleic acid (DNA) vaccination targeting prostate 
cancer tumor antigens through electroporation (EP), cytokine adjuvants, mobilization and 
activation of dendritic cells (DCs), and relieving immune suppression of cytotoxic T cells by 
administration of an anti-programmed cell death 1 (PD-1) monoclonal antibody (mAb) in 
metastatic castration-resistant prostate cancer (mCRPC): 
• Flt-3 ligand (CDX-301) to induce mobilization, activation and/or expansion of DCs 
• DNA vaccine INO-5151 encoding human prostate-specific membrane antigen (PSMA), 
human prostate-specific antigen (PSA), and human interleukin-12 (IL-12) to stimulate 
antitumor-directed CD8 T-cell responses to castration-resistant prostate cancer (CRPC)-
specific tumor antigens 
• Anti-PD-1 mAb (nivolumab) to overcome immune suppression of tumoral T cells 
 
Objectives and Endpoints: 
Refer to the core protocol. 
Combination-specific exploratory objectives include: 


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Combination-specific Exploratory Objectives 
Endpoints 
• To evaluate the PK of CDX-301 and/or nivolumab. 
• To evaluate the immunogenicity of INO-5151, 
CDX-301, and/or nivolumab. 
• Sparse PK analysis. 
• Presence of immune response against PSA and/or 
PSMA 
• ADA against CDX-301 and/or nivolumab. 
ADA = anti-drug antibodies; IL-12 = interleukin-12; PK = pharmacokinetics; PSA = prostate-specific antigen; 
PSMA = prostate-specific membrane antigen 
 
Overall Design, Number of Participants, Follow-up, and Data Monitoring Committee: 
Refer to the core protocol. 
Intervention Groups and Duration: 
Participants will be assigned to receive one of the enrolling immunotherapy combination study 
interventions. In this cohort, participants will receive CDX-301, INO-5151, and nivolumab as 
follows: 
Intervention 
Dose 
Frequency 
Route 
Schedule 
CDX-301 
75 µg/kg 
QD x 5 days x 2 
(ie, twice) 
SC 
Immune-priming Lead-in 
Days 1-5 and 22-26 
INO-5151 
3 mg 
Immune-priming 
dose, followed by 
 
Q4W x 3 doses,  
then Q12W 
IM followed by EP 
Day 8 of 
Immune-priming Lead-in 
 
Starting Day 1 of Cycle 1a 
Nivolumab 
480 mg 
Q4W 
IV over 30 minutes 
Starting Day 1 of Cycle 1 
IV = intravenous(ly); IM = intramuscular(ly); EP = electroporation; QD = daily; Q4W = every 4 weeks; 
Q12W = every 12 weeks; SC = subcutaneous(ly) 
a Day 1 of Cycle 1 follows 1 week after Day 22 of the Immune-priming Lead-in 
 
CDX-301 will be administered during the Immune-priming Lead-in only. INO-5151 and 
nivolumab will be administered for up to 2 years, unless the participant: is no longer clinically 
benefiting (as evidenced by symptomatic or radiographic disease progression and/or clinical 
deterioration); experiences any toxicity meeting specified discontinuation criteria (see Section 
6.6) or unacceptable toxicity in the best clinical discretion of the treating physician (ie, 
Investigator discretion); reaches the maximum duration of study intervention; or withdraws 
consent. In this cohort, a cycle is defined as 4 calendar weeks. 
1.2 
SCHEMA 
The study schema is depicted in Figure 1. 


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Figure 1: 
Study Schema 
 
EP = electroporation; IM = intramuscularly; IV = intravenously; mCRPC = metastatic castration-resistant prostate cancer; Q4W = every 4 weeks; 
Q12W = every 12 weeks; SC = subcutaneously 
Note: The horizontal axis is not linearly scaled, so the interval for Immune-priming Lead-in appears to be much longer than for the subsequent cycles. 
a INO-5151 will be administered IM followed by EP. 
b Day 1 of Cycle 1 follows 1 week after Day 22 of the Immune-priming Lead-in. 
CDX-301 will be administered during the Immune-priming Lead-in only. INO-5151 and nivolumab will be administered for up to 2 years, unless the 
participant: is no longer clinically benefiting (as evidenced by symptomatic or radiographic disease progression and/or clinical deterioration); experiences any 
toxicity meeting specified discontinuation criteria (see Section 6.6) or unacceptable toxicity in the best clinical discretion of the treating physician; reaches the 
maximum duration of study intervention; or withdraws consent. A cycle is defined as 4 calendar weeks. Participants will be followed for up to 2.5 years from 
the time of the initiation of study intervention. 
This study design is applicable to Stage 1, as well as Stage 2 if the cohort is expanded. 


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1.3 
SCHEDULE OF ACTIVITIES 
The Schedule of Activities (SOA) shown in Table 1 is specific for this combination and 
supersedes the SOA provided in the core protocol. 


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Table 1: 
Schedule of Activities 
Tests & Procedures 
Screening/ 
Enrollmenta 
On-Treatment: CDX-301 + INO-5151 + Nivolumab 
End of 
Treatment 
Visitc 
Follow up 
Immune-priming Lead-in 
Cycle 1b (Q4W) 
Cycles 
2,3, and 4 
Cycle 5 
Onward 
Day 
Day -28 to 
Day -1 
Days 
1 - 5  
Day 
8 
Day 
15 
Days 
22 - 26 
Day 1 
Day 8 
Day 1 
Day 1 
14 - 28 
days after 
last dose 
110 days 
after last 
dose 
Q3Md 
Window (days) 
-28 
 
 
± 1 
± 1 
± 1 
± 1 
± 3 
± 3 
± 7 
± 10 
± 14 
Informed consente 
X 
 
 
 
 
 
 
 
 
 
 
 
Review of I/E criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical/cancer history 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
X 
 
 
 
X 
 
X 
X 
X 
 
 
ECOG performance 
status 
X 
X 
 
 
 
X 
 
X 
X 
X 
X 
 
Vital signs (see Core 
Protocol Section 8.2.3) 
X 
X 
 
 
 
X 
 
X 
X 
X 
 
 
Body weight 
X 
X 
X 
X 
X 
X 
 
X 
X 
(Cycles 5, 
8, 11, 14, 
17, 20, 23, 
and 26) 
X 
 
 
Hematology (see Table 
11) 
X 
Xf 
(Day 1) 
Xf 
X 
Xf 
(Day 22) 
Xf 
X 
Xf 
Xf 
X 
X 
 
Clinical chemistry (see 
Table 11) 
X 
Xf 
(Day 1) 
Xf 
X 
Xf 
(Day 22) 
Xf 
X 
Xf 
Xf 
X 
X 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
X 
 
 
Prostate-specific 
antigen 
X 
X 
(Day 1) 
 
 
X 
(Day 22) 
X 
 
X 
X 
X 
X 
 
Testosterone level 
X 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECG 
X 
 
 
 
 
 
 
X 
(Cycles 2 
and 4) 
 
 
 
 


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Tests & Procedures 
Screening/ 
Enrollmenta 
On-Treatment: CDX-301 + INO-5151 + Nivolumab 
End of 
Treatment 
Visitc 
Follow up 
Immune-priming Lead-in 
Cycle 1b (Q4W) 
Cycles 
2,3, and 4 
Cycle 5 
Onward 
Day 
Day -28 to 
Day -1 
Days 
1 - 5  
Day 
8 
Day 
15 
Days 
22 - 26 
Day 1 
Day 8 
Day 1 
Day 1 
14 - 28 
days after 
last dose 
110 days 
after last 
dose 
Q3Md 
Window (days) 
-28 
 
 
± 1 
± 1 
± 1 
± 1 
± 3 
± 3 
± 7 
± 10 
± 14 
Circulating tumor cellsg 
 
Xf 
(Day 1) 
 
 
 
Xf 
 
Xf 
Xf 
X 
 
 
cfDNA (blood)h 
 
 
 
 
 
Xf 
 
Xf (Cycles 
2, 3, and 4) 
 
X 
 
 
Circulating soluble 
analytes/PK/ADAi 
X 
Xf 
(Day 1, 
Day 5) 
Xf 
Xf 
Xf 
(Day 26) 
Xf 
Xf 
Xf (Cycles 
2, 3, and 4) 
 
X 
X 
 
Blood immune 
biomarkersi 
X 
Xf 
(Day 1, 
Day 5) 
Xf 
Xf 
Xf 
(Day 26) 
Xf 
Xf 
Xf (Cycles 
2, 3, and 4) 
 
X 
 
 
Archival tumor tissue 
X 
 
 
 
 
 
 
 
 
 
 
 
Tumor biopsyj 
X 
 
 
 
 
 
 
X 
(Cycle 2) 
 
X (at PD 
[optional])j 
 
 
Stool collectionk 
X 
 
 
 
 
 
 
X 
(Cycle 2)k 
 
 
 
 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse events 
All AEs and SAEs will be collected for at least 100 days after the last dose of study interventionl 
 
CDX-301 
administrationm 
 
X 
 
 
X 
 
 
 
 
 
 
 
INO-5151 
administrationn 
 
 
X 
 
 
X 
 
X 
(Cycles 
2 and 3) 
X 
(Cycles 6, 
9, 12, 15, 
18, 21, 
and 24) 
 
 
 


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Tests & Procedures 
Screening/ 
Enrollmenta 
On-Treatment: CDX-301 + INO-5151 + Nivolumab 
End of 
Treatment 
Visitc 
Follow up 
Immune-priming Lead-in 
Cycle 1b (Q4W) 
Cycles 
2,3, and 4 
Cycle 5 
Onward 
Day 
Day -28 to 
Day -1 
Days 
1 - 5  
Day 
8 
Day 
15 
Days 
22 - 26 
Day 1 
Day 8 
Day 1 
Day 1 
14 - 28 
days after 
last dose 
110 days 
after last 
dose 
Q3Md 
Window (days) 
-28 
 
 
± 1 
± 1 
± 1 
± 1 
± 3 
± 3 
± 7 
± 10 
± 14 
Nivolumab 
administrationo 
 
 
 
 
 
X 
 
X 
X 
 
 
 
Radiographic disease 
assessment 
X 
 
 
 
 
 
 
X (prior 
to 
Cycle 3) 
At Week 8 (± 1 week), repeat every 8 weeks (± 1 
week) for the first 24 weeks, and every 12 weeks 
(± 1 week) thereafter until radiographic PD or 
start of subsequent therapy 
Review of alternate 
anticancer therapyp 
 
 
 
 
 
 
 
 
 
 
X 
X 
Follow up for overall 
survival 
 
 
 
 
 
 
 
 
 
 
X 
X 
ADA = anti-drug antibodies; AE(s) = adverse event(s); cfDNA = cell-free deoxyribonucleic acid; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; 
EOT = end of treatment; EP = electroporation; I/E = inclusion/exclusion; IV = intravenously; PD = progressive disease; PK = pharmacokinetics; Q3M = every 3 months; 
Q4W = every 4 weeks; QD = daily; SAE(s) = serious adverse event(s); SC = subcutaneously 
a Tests/procedures performed as standard of care prior to obtaining informed consent and within 28 days prior to the first dose of study intervention do not have to be repeated at 
screening. 
b Day 1 of Cycle 1 follows 1 week after Day 22 of the Immune-priming Lead-in. 
c The End of Treatment Visit will be completed following the last dose of study intervention, either at the completion of the on-treatment phase or at early discontinuation. 
d For up to 2.5 years from the initiation of study intervention, participants in the follow up phase will be contacted by the site to collect alternate anticancer therapy information 
and determine survival status. 
e Informed consent must be obtained prior to any study-specific procedures and may be obtained prior to the 28-day screening window. 
f Blood samples should be collected prior to administration of any study intervention. 
g Circulating tumor cells will be collected at baseline (ie, Day 1 of the Immune-priming Lead-in prior to study intervention administration), Day 1 of each cycle (prior to study 
intervention administration), and EOT. 
h cfDNA (blood) will be collected Day 1 of Cycle 1-Cycle 4, and EOT. 
i Circulating soluble analytes, PK and ADA blood sample, and/or blood immune biomarkers will be collected at baseline (ie, screening and/or Day 1 of Cycle 1 prior to study 
intervention administration), prior to study intervention administration on Days 1. 5, 8, 15, and 26 of the Immune-priming Lead-in, Days 1 and 8 of Cycle 1, Day 1 of Cycles 2-4, 
at EOT, and the first follow up visit. 
j Participants will undergo 2-3 tumor biopsies: prior to beginning protocol therapy (ie, baseline biopsy, mandatory for all participants, including those with bone only disease if 
medically feasible), and during treatment (ie, on-treatment biopsy during Cycle 2, if medically feasible). On- treatment biopsy should occur as early as possible after the second 


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dose (Day 2 – Day 10 of Cycle 2); however, any on treatment biopsy after Day 1 of Cycle 2 will be accepted. An optional biopsy may be obtained at the time of disease 
progression, including from participants who respond and subsequently progress. Every attempt should be made for the on-treatment biopsies to be taken from the same lesion as 
the pre-treatment biopsy when feasible. 
k Stool will be collected at screening and during Cycle 2, if possible. Otherwise, any on-treatment stool sample will be acceptable. The stool sample may be collected at the clinic 
or at the participant’s home. 
l All SAEs will be collected from the time the participant signs informed consent. Prior to initiation of study intervention, only SAEs that are related to a protocol-mandated 
intervention, including those that occur prior to the assignment of study procedures should be reported. All AEs will be collected from the start of study intervention. All AEs 
and SAEs will be collected for at least 100 days after the last dose of study intervention. Refer to Section 8.3 of the core protocol for details regarding safety reporting for this 
study. 
m CDX-301 will be administered at a dose of 75 µg/kg subcutaneously (SC) QD x 5 days [ie, Monday – Friday] twice during the Immune-priming Lead-in (Days 1 – 5 and 
Days 22 – 26). 
n INO-5151 will be administered at a dose of 3 mg intramuscularly (IM) followed by EP on Day 8 of the Immune-priming Lead-in, Starting with Cycle 1, INO-5151 will be given 
on the same day as nivolumab on Day 1 of Cycle 1, Cycle 2, and Cycle 3, and every 12 weeks (ie, every 3 cycles) thereafter. A cycle is defined as 4 calendar weeks. 
o Nivolumab will be administered at a dose of 480 mg IV over 30 minutes Q4W starting on Day 1 of Cycle 1 and will continue for up to 2 years unless the participant: is no 
longer clinically benefiting (as evidenced by symptomatic or radiographic disease progression and/or clinical deterioration); experiences any toxicity meeting specified 
discontinuation criteria (see Section 6.6) or unacceptable toxicity in the best clinical discretion of the treating physician; reaches the maximum duration of study intervention; or 
withdraws consent. A cycle is defined as 4 calendar weeks. The time between nivolumab doses must not be less than 24 days. 
p Collection of information related to any post-study intervention alternate anticancer therapy. 
 


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2 
INTRODUCTION 
Refer to the core protocol. 
2.1 
STUDY RATIONALE 
Refer to the core protocol. 
2.2 
BACKGROUND 
Immune checkpoint blockade, particularly with programmed cell death 1 (PD-1) or programmed 
cell death ligand 1 (PD-L1) antibodies, has changed the landscape for the treatment of a variety 
of advanced solid tumors. Though the majority of patients with a specific tumor type don’t 
respond to treatment, a notable subset of patients across tumor types achieve durable responses 
in the context of relatively well tolerated therapy leading to the substantial enthusiasm for this 
therapeutic class. However, not only is there intra-tumor-type variability in the likelihood of 
response to PD-1/PD-L1 blockade but there is also substantial inter-tumor type heterogeneity 
(Yarchoan et al., 2017). Prostate cancer has been among the tumor types for which single-agent 
PD-1/PD-L1 blockade has been associated with relatively rare responses, and the responses that 
do occur are typically in the context of a genomically-defined subset of cancers (ie, mismatch 
repair deficient tumors) (Graff et al; 2016). Therefore, there is a critical need to develop rational 
combination strategies to extend the benefits of PD-1/PD-L1 blockade to patients with metastatic 
castration-resistant prostate cancer (mCRPC). Strategies that mobilize immune cells to the tumor 
microenvironment, stimulate cytotoxic CD8 T cells to recognize tumor specific antigens, and 
induce tumor cell killing offer a potential way to extend those benefits. 
Deoxyribonucleic acid (DNA) immunization has been recognized as a promising vaccine 
platform for almost 20 years for a number of reasons (Hokey and Weiner, 2006). Both DNA 
vaccines and various viral vector vaccines have been explored for diseases where a potent T-cell 
response may be required to achieve clinical improvement. Prophylactic and therapeutic DNA 
vaccines have generated immunogenicity that is similar to what has been achieved with viral 
vectors (Morrow and Weiner, 2010). Potent T-cell immune responses can be generated to 
virtually any antigenic sequence after antigen processing and presentation. Although traditional 
live attenuated and viral vector vaccines may also elicit potent T-cell responses, these viral 
approaches bear safety concerns associated with their vector backbone, which DNA vaccines 
should and do circumvent. In addition, as opposed to viral-based vaccines which carry a risk of 
mutation back to a virulent state or spread to unintended individuals, DNA vaccines are not 
based on an intact natural pathogen and therefore cannot revert to a virulent form. Finally, 
repeated dosing of viral-based vaccines may be hindered by neutralization of targeted viral 
vector sequences. The plasmid backbones of DNA vaccines are associated with virtually no 
immune response, thus allowing repeated dosing to increase or maintain the immune responses 


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against the DNA encoded antigen over long periods. Additionally, toxicology studies have found 
no evidence of genome integration as measured by polymerase chain reaction (PCR) in two 
previous studies of several DNA vaccine products (Sheets et al., 2006a; Sheets et al., 2006b) 
expressing a variety of inserts, such as human immunodeficiency virus (HIV), Ebola, severe 
acute respiratory syndrome (SARS), West Nile Virus and malaria antigens (INO-5151/INO-5150 
and INO-9012 Investigator’s Brochure, 2019). In contrast, pre-existing anti-vector immunity can 
reduce the immunogenicity and ability to utilize the viral vector for future immunizations. 
Finally, DNA vaccines are simple and relatively inexpensive to construct, are readily produced 
in large quantities, and are generally stable for long periods of time. These advantages make 
DNA-based immunization a desirable immune-based modality for the prevention or treatment of 
disease. 
2.2.1 
Background on INO-5151 (PSA, PSMA, Interleukin-12) DNA 
Delivered via Intramuscular Electroporation (Inovio 
Pharmaceuticals) 
2.2.1.1 
PSA and PSMA Immunotherapy 
Prostate-specific antigen (PSA) is a protein member of the kallikrein-related peptidase family 
and is secreted by the epithelial cells of the prostate gland. PSA is present in small quantities in 
the serum of normal men with healthy prostates, but is often elevated in the presence of prostate 
cancer or other prostate disorder (Williams et al., 2007). Serum PSA has been utilized as one 
prostate cancer biomarker in conjunction with other techniques for diagnosis, prognosis, prostate 
cancer disease recurrence and progression. Previous studies also indicate a role of PSA in the 
initiation and progression of prostate cancer, making it a potential functional target (Williams et 
al., 2007). 
Prostate specific membrane antigen (PSMA) is a multi-domain protein expressed in either an 
integral membrane or cytoplasmic form in a variety of cell types, including the neovasculature of 
several types of solid tumors. Further, PSMA expression is increased in prostate cancer cells as 
the disease progresses making it a highly relevant target for tumors that are diagnosed later in 
disease progression rather than earlier (Schmittgen et al, 2003). In a study examining 
intratumoral PSMA expression in 902 subjects at prostatectomy, Kasperzyk et al. found a 
positive association between PSMA levels and risk of lethal prostate cancer, which was not 
independent of the clinical parameters examined, and therefore, did not support the clinical 
utility of PSMA expression as a biomarker for lethal prostate cancer (Kasperzyk et al., 2013). 
Much like PSA, previous studies have indicated that PSMA is preferentially expressed in the 
prostate compared to normal tissues (Cunha et al., 2006). PSMA-specific T cell mediated 
responses can confer antitumor effects and an increase in the percentage of PSMA-specific T 


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cells producing interferon gamma (IFN-γ) correlates with clinical improvement in prostate 
cancer patients (Tjoa et al., 1999; Mincheff et al., 2001). 
In contrast to PSA, PSMA expression is more prevalent in extraprostatic tissues (Cunha et al., 
2006). PSMA messenger ribonucleic acid (mRNA) and protein expression have been found in 
both normal tissue and prostate cancer tissue by quantitative PCR and immunohistochemistry, 
respectively, although the actual levels and location of PSMA expression in normal tissue remain 
unclear (Cunha et al., 2006; Silver et al., 1997). Despite its reported limited extraprostatic 
expression, PSMA has also been reported in the brain, duodenum, colon, liver, proximal kidney 
tubules, and salivary gland (Horoszewicz et al., 1987; Israeli et al., 1994; Lopes et al., 1990; 
Luthi-Carter et al., 1998; Sácha et al., 2007). Cunha et al. found PSMA mRNA expression in the 
brain, liver and kidney, although the levels in these organs were approximately 12-18-fold less 
than the mRNA expression level in the prostate (Cunha et al., 2006). Silver et al. also reported 
PSMA immunoreactive tissue in prostate epithelium, kidney (luminal site of the proximal renal 
tubules), duodenum and colon (Silver et al., 1997). This study did not show any PSMA 
immunoreactivity in the brain as was shown by other groups, and the differentiated prostate 
tissue expression and over expression of PSMA in metastatic tissues support the study of this 
unique prostate tumor-associated biomarker for developing new strategies for immune therapy of 
prostate cancer. Because of its relevance in metastatic prostate cancer, this antigen has been 
targeted in a variety of both diagnostic evaluations (eg, PSMA positron emission tomography 
[PET]), as well as therapeutic targets such as antibody drug conjugates (ADC), vaccine therapies, 
and nanoparticles. 
Immunotherapy is a promising approach to develop tumor antigen-specific therapies for prostate 
cancer (Gulley and Drake, 2011; Troyer et al., 1995; Rice et al., 2008). In antigen-specific 
approaches, a tumor-associated antigen is directly targeted, either by loading that antigen onto 
antigen-presenting cells (APC) ex vivo or by incorporating the antigen into a vaccine cellular 
delivery system at a protein or DNA level. In the absence of immunotherapy, however, T-cell 
response to tumor antigens such as PSA are difficult to detect in patients, which indicates that 
some level of pre-existing tolerance may exist (Drake, 2010). 
Approximately 1,400 human subjects have been treated or are being enrolled in clinical trials to 
evaluate immunotherapy based on DNA or viral vectors that encode various prostate-specific 
antigens (INO-5151/INO-5150 and INO-9012 Investigator’s Brochure, 2019). While 
measurable, anti-prostate tumor-specific immunoglobulin has been difficult to detect, the T-cell 
antigen-specific activity has been measured somewhat consistently. Measurable tumor responses 
(National Prostate Cancer Project [NPCP] criteria) to these immunotherapies have also been 
reported. In general, safety and tolerability has been shown to be acceptable (Drake, 2010; Felici 


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et al., 2012). Local injection site reactions were the most common safety event observed. 
Additionally, cellular based vaccines were associated with acceptable systemic safety profile. 
In a recently-reported phase 1 study of 62 biochemically recurrent prostate cancer patients, 
INO-5150 (PSA and PSMA), with and without INO-9012 (interleukin-12 [IL-12] plasmid), was 
demonstrated to be safe and immunogenic, with observed humoral and cellular responses, 
including generation of functional antigen-specific CD8 T cells (Shore et al., 2018b). In addition, 
clinical activity was observed in the form of significantly increased PSA doubling times and 
reduced percent rise in PSA, which was significantly different in the patients with demonstrated 
immunogenicity to INO-5150 (Shore et al., 2018a; Shore et al., 2018b).The INO-5151 to be used 
in this clinical trial is a single-vial combination of INO-5150 and INO-9012, which will facilitate 
administration. 
Refer to the Investigator’s Brochure (IB; INO-5151/INO-5150 and INO-9012 Investigator’s 
Brochure, 2019) for additional background information. 
2.2.1.2 
Interleukin-12 Plasmid with DNA Vaccines 
IL-12 is an immune cytokine that is produced by dendritic cells (DCs), macrophage, neutrophils, 
and B cells in response to antigen stimulation. IL-12 plays an important role in the eliciting 
effective immune responses through activation of antigen-presenting activity of DCs and 
promoting the cytotoxic activity of CD8 T cells and natural killer (NK) cells. Thus, IL-12 is an 
important cytokine in promoting an antitumor immune response. Given its immunomodulatory 
and additionally anti-angiogenic function, recombinant IL-12 has been evaluated in clinical 
studies as an anti-cancer agent. A review of clinical applications of recombinant IL-12 lists 17 
separate clinical studies conducted in more than 500 patients with advanced solid tumors and 
various hematologic malignancies (Del Vecchio et al., 2007). Recombinant human IL-12 
(rhIL-12) has been evaluated both as monotherapy and in combination with vaccines, other 
cytokines, or antitumor monoclonal antibodies in these clinical studies. Systemic delivery of 
rhIL-12 protein can cause significant toxicity (Gollob et al., 2000). In contrast, IL-12 DNA 
therapy has minimal toxic effects in non-human primates and human subjects (Shore et al., 
2018a; Shore et al., 2018b; Schadeck et al., 2006; Boyer et al., 2005; Chong et al., 2007; Kalams 
et al., 2012; Kalams et al., 2013; Daud et al., 2008). In a recent human trial, the combination of 
INO-5150 ± INO-9012 was shown to be safe, well tolerated and immunogenic (Shore et al., 
2018a; Shore et al., 2018b). 
In preclinical studies, use of IL-12 plasmid with DNA vaccines has been shown to substantially 
increase the immunogenicity of DNA vaccines (Hanlon et al., 2001; Kim et al., 1998a; Kutzler et 
al., 2005; Operschall et al., 1999; Chattergoon et al., 2004; Egan et al., 2006; Kim et al., 1998b; 
Calarota and Weiner, 2004; Umemura et al., 2001). Co-administration of cytokine plasmids with 
DNA vaccines has been studied in rodents (Kim et al., 1997) and have demonstrated a dramatic 


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increase in specific cytotoxic T-lymphocyte (CTL) activity and provides the basis for evaluation 
of INO-5151 in the proposed clinical trial. These preclinical studies demonstrated a dramatic 
increase in specific CTL activity when plasmid DNA was co-administered with an IL-12 
plasmid, as compared with results in animals receiving plasmid alone (Chattergoon et al., 2004; 
Egan et al., 2006; Kim et al., 1998b; Calarota and Weiner, 2004). In summary, DNA vaccine 
administration in combination with IL-12 DNA has been shown to be generally safe and well 
tolerated, and possibly more immunogenic, although further studies need to be done (Kalams et 
al., 2013). 
2.2.1.3 
Rationale for Use of Electroporation 
Several groups are developing methods to improve the immune responses of DNA vaccines 
using genetic optimization (including use of highly concentrated DNA formulations, multiple 
ribonucleic acid (RNA) optimizations and addition of improved leader sequences), cytokine 
adjuvants, and alternative cellular delivery (ie, electroporation [EP]) (Kutzler and Weiner, 2008). 
The approach being studied in this trial employs all these methods with delivery of IL-12 as an 
immune cytokine and an emphasis on improving the transfection of DNA using EP. EP is the 
application of a localized electrical field at the site of injection to facilitate cell uptake of DNA 
by permeabilizing cell membranes and may also induce local inflammation (Kutzler and Weiner, 
2008; Sardesai and Weiner, 2011). This physical process exposes the target tissue to a brief 
electric field pulse that induces temporary and reversible pores in the cell membrane to enhance 
the cellular uptake of large molecules such as DNA. By temporarily increasing the permeability 
of cell membranes, EP has been shown to be an efficient way to introduce DNA into cells 
(Aihara and Miyazaki, 1998; Gehl and Mir, 1999) and to increase the expression level of 
antigens encoded by DNA (Hirao et al., 2008). The EP technology has been used for more than 
three decades by molecular biologists for in vitro cell transfection. Clinical applications of EP 
have been used in human studies of gene therapy and more recently in cancer (Sardesai and 
Weiner, 2011). 
The hypothesis is that EP will increase the uptake and expression of plasmid DNA (pDNA), 
generating significantly increased immunogenicity. Electroporation enhances both cellular and 
humoral immune responses, using less DNA than intramuscular immunizations alone (Schoenly 
and Weiner, 2008). Studies have demonstrated the ability of EP to augment specific cellular 
immune responses in mice (Liu et al., 2008) and in macaques (Luckay et al., 2007). Luckay et al. 
found that delivering simian immunodeficiency virus (SIV) DNA vaccines intramuscularly (IM) 
followed by EP increased the potency of these vaccines 50-200 fold (Luckay et al., 2007). There 
are various means of delivering EP (ie, constant current vs. constant voltage) and testing these 
strategies in mice and pigs has shown a constant current device may be the most effective at 
generating immune responses (Draghia-Akli et al., 2008). Studies in macaques found that EP of 


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SIV DNA + IL-12 plasmids yielded 10-fold higher responses than DNA injections without EP 
(Hirao et al., 2008), and that this immune response was boosted with additional doses. The 
magnitude of achievable responses is similar to that seen with natural SIV infection, in the order 
of 10,000 spot forming units (SFU)/million peripheral blood mononuclear cells (PBMC) in an 
enzyme-linked immunospot (ELISpot) assay. These responses are also polyfunctional, as defined 
by the ability of immune cells from treated animals to generate IFN-γ, tumor necrosis factor 
alpha (TNF-α) and interleukin-2. Furthermore, the functional consequence of EP delivery of 
DNA encoding an antigen in combination with IL-12 includes an improved ability of specific 
CD8+ T-cells to proliferate in cell culture in response to antigenic stimulation compared to 
delivery without EP (Hirao et al., 2008). 
As of 30-Jun-2018, 3,319 doses had been administered to 1,096 subjects via the CELLECTRA® 
2000 by either IM or intradermal administration. Among subjects who received PSA, PSMA, 
and plasmids with a DNA backbone identical to that of INO-5150 and delivered IM followed by 
EP alone or in combination with IL-12 plasmid DNA (eg, INO-9012), the most commonly 
reported adverse event reported was injection site pain (Table 2). 
Table 2 
Adverse Events Reported in Studies of Inovio DNA Delivered IM with 
Electroporation Occurring in at Least 5% of Subjects 
Adverse Event Preferred Term 
Number of Subjects (%) 
(N = 1022) 
Injection site pain 
570 (55.8) 
Fatigue 
228 (22.3) 
Injection site erythema 
190 (18.6) 
Headache 
187 (18.3) 
Myalgia 
148 (14.5) 
Upper respiratory tract infection 
130 (12.7) 
Injection site swelling 
128 (12.5) 
Injection site pruritus 
110 (10.8) 
Nausea 
110 (10.8) 
Arthralgia 
  89 (  8.7) 
Injection site bruising 
  81 (  7.9) 
Malaise 
  76 (  7.4) 
Source: INO-5151/INO-5150 and INO-9012 Investigator’s Brochure, 2019 
 
2.2.2 
Background on rhuFLT3L/CDX-301 (Celldex Therapeutics, Inc.) 
rhuFLT3L/CDX-301 is the soluble recombinant human (rhu) protein form of the FMS-related 
tyrosine kinase 3 ligand (Flt3L), a hematopoietic cytokine. CDX-301 represents the 153 


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N-terminal amino acids of the human Flt3L extracellular domain after the cleavage of the 
N-terminal signal peptide. 
Flt3L is a hematopoietic growth factor that plays an important role in the mobilization and 
expansion of stem cells and progenitors (Lyman and Jacobsen, 1998). In particular, it has been 
shown to facilitate the differentiation of both DCs and natural killer cells from hematopoietic 
stem cell precursors (Blom et al., 2000; Chen et al., 2005; Gilliet et al., 2002; Miller et al., 1999). 
Specifically, Flt3L directly induces the differentiation of a proportion of CD34+ CD45RA- early 
progenitor cells into pre-DCs, and results in increased numbers of activated DCs (Blom et al., 
2000; Breton et al., 2016). In healthy human volunteers it has been demonstrated that Flt3L 
administration increases the number of DCs, as well as CD14+ monocytes (Chen et al., 2005; 
Anandasabapathy et al., 2015; Maraskovsky et al., 1996; Pulendran et al., 1997). 
Numerous preclinical models have shown the ability of Flt3L administration to mobilize a range 
of immune cell subsets, DCs predominant among these (Brasel et al., 1996; Fernandez et al., 
1998; Kutzler and Weiner, 2004; Miller et al., 2003). Flt3L administration has demonstrated 
antitumor activity in a variety of tumor models including melanoma, lymphoma, leukemia, 
breast, colon, prostate, lung and hepatocellular carcinoma (Averbook et al., 2002; Ciavarra et al., 
2000; Drexler et al., 1999; Esche et al., 1998; Hou et al., 2007; Wang et al., 2000; Chakravarty et 
al., 1999). Preclinical models have also shown that Flt3L administration can enhance the 
antitumor immunity of checkpoint inhibitors such as PD-1 and cytotoxic T-lymphocyte-
associated protein 4 (CTLA-4) antibodies to promote tumor regression of non-immunogenic 
tumors (Lynch et al., 1997).  
Flt3L has been used in many early phase human clinical trials of different immunotherapeutic 
approaches—as an adjuvant or in order to mobilize DCs for collection to produce a cellular 
vaccine—in patients with colorectal cancer, non-small cell lung cancer, mesothelioma, and 
prostate cancer among others and demonstrated safety with minimal toxicity from Flt3L 
administration through multiple routes of administration (Fong et al., 2001; Freedman et al., 
2003; Higano et al., 2004; Morse et al., 2000).  
A study in 31 patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) 
evaluated the impact of Flt3L administration on peripheral blood DCs and post-treatment 
changes in PSA (Higano et al., 2004). DCs increased markedly from baseline to Day 15, and the 
increase was consistently observed after administration of Flt3L in each cycle. Mean percentages 
of DCs in peripheral blood ranged from 1.4% to 1.9% pre-cycle and from 10.1% to 13.9% on 
Day 15, and after the first cycle, absolute counts on Day 15 were approximately 29-fold higher 
than pre-cycle levels. NK cell counts (CD56+) were found to be elevated after cycle 1 (154% 
increase versus 2.8% decrease in placebo group at Day 22). The most frequently experienced 
toxicity was injection site reaction, followed by asthenia, rash, and diarrhea. Although median 


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PSA levels did not vary during any cycle, a significant slowing in velocity of PSA was observed 
while patients were on-study (relative velocity = 0.002) compared with prestudy PSA velocity 
(relative velocity = 0.007). Given that Flt3L consistently produced an increase in DC numbers 
and the slowing of PSA velocity after administration, the authors concluded that Flt3L warrants 
further study for the immunotherapy of prostate cancer. Furthermore, mobilization of DCs by 
administration of Flt3L followed by exposure to IL-12, PSA, and PSMA may lead to improved 
activation of DCs and antigen presentation for eliciting a robust antitumor immune response to 
vaccination with tumor antigens. 
Refer to the IB (CDX-301/Recombinant Human Flt3 Ligand [rhuFlt3L] Investigator’s Brochure, 
2018) for detailed background information on rhuFLT3L/CDX-301. 
2.2.3 
Background on Nivolumab (Bristol-Myers Squibb Company) 
Nivolumab is a human immunoglobulin G4 (IgG4) monoclonal antibody that binds to the PD-1 
receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated 
inhibition of the immune response, including the antitumor immune response. Opdivo® 
(nivolumab) is approved in the United States (US) for the treatment of several cancer types, 
including unresectable or metastatic melanoma (as monotherapy or in combination with 
ipilimumab) and as monotherapy in previously-treated metastatic non-small cell lung cancer 
(NSCLC), advanced renal cell carcinoma (RCC), relapsed or refractory classical Hodgkin 
lymphoma (cHL), locally advanced or metastatic urothelial carcinoma (UC), recurrent or 
metastatic squamous cell carcinoma of the head and neck (SCCHN), microsatellite instability-
high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC), and 
hepatocellular carcinoma (HCC). In phase 1 investigation, nivolumab did not demonstrate 
clinical activity in 17 participants with advanced mCRPC. This is consistent with mCRPC 
having a low level of immune cell infiltrate and tumor mutational burden (TMB). Treatment 
strategies to increase antigen presentation and immune infiltration and activation may improve 
the immune responsiveness of mCRPC to nivolumab. 
Refer to the IB (Nivolumab Investigator’s Brochure, 2018) and approved US prescribing 
information (Opdivo [nivolumb] US Prescribing Information [USPI], 2018) for detailed 
background information on nivolumab. 
2.2.4 
Rationale for CDX-301 + INO-5151 + Nivolumab Immunotherapy 
Combination 
This study cohort is designed to explore a multi-pronged approach to stimulate antitumor 
immunity by enhancement of a DNA vaccination targeting prostate cancer tumor antigens 
through EP, cytokine adjuvants, mobilization and activation of DCs, and relieving immune 


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suppression of cytotoxic T cells by administration of an anti-PD-1 monoclonal antibody (mAb) 
in mCRPC: 
• Flt3L (CDX-301) to induce mobilization, activation, and/or expansion of DCs 
• DNA vaccine INO-5151 for expression of human PSMA, PSA, and IL-12 to stimulate 
antitumor directed CD8 T-cell responses to CRPC-specific tumor antigens 
• Anti-PD-1 mAb (nivolumab) to overcome immune suppression of tumoral T cells 
 
Flt3L binds CD135 (Flt3 receptor) and induces proliferation, differentiation, and mobilization of 
hematopoietic stem cells, early progenitor cells, and DCs. Flt3L is a key regulator of DCs, 
inducing marked increases and activation of both myeloid and plasmacytoid DCs. Immunologic 
analyses have shown 10 to 100+ fold increase in DCs (including CD141+ DCs), as well as 
augmentation of humoral and cellular responses to the NY-ESO-1 vaccine; however, no clear 
activity as monotherapy was noted in patients with advanced cancer (Ohri et al., 2018), 
suggesting CDX-301 promotes antitumor immunity but not sufficiently to result in clinical 
benefit. These observations suggest that combination of CDX-301 with immunotherapies 
generating effective CD8 T cell responses, such as INO-5151, may lead to an effective antitumor 
response, specifically in the presence of a checkpoint inhibitor. The combination of CDX-301, 
which increases innate immune cells, with a DNA-encoding vaccine and immune-stimulatory 
cytokine IL-12 is hypothesized to induce potent antitumor immunity (Shore et al., 2018a; 
Schadeck et al., 2006; Boyer et al., 2005; Chong et al., 2007; Kalams et al., 2012; Kalams et al., 
2013; Daud et al., 2008; Gollob et al., 2000; Bhardwaj et al., 2016, Gao et al., 2018). A 29-fold 
increase in DCs was seen at Day 15 in a trial of CDX-301 in nmCRPC, which support the 
rationale for this agent in the immune-priming period prior to vaccination. INO-5151 is a DNA 
based vaccine encoding PSA and PSMA, 2 antigens that are widely expressed in advanced 
prostate cancer and also encodes IL-12, an adjuvant cytokine with preclinical and clinical data 
supporting that it increases CD8 T cell responses (Shore et al., 2018a; Shore et al., 2018b). These 
plasmids will be administered IM followed by EP to enhance cellular uptake of DNA and 
increase potency. In a recently reported phase 1 study in patients with non-metastatic 
biochemically recurrent prostate cancer, INO-5150, with and without INO-9012, was safe and 
immunogenic with demonstrated clinical activity (Shore et al., 2018a; Shore et al., 2018b). The 
majority of patients experienced a slowing of pre-treatment PSA doubling times (a reflection of 
disease activity). Patients who experienced disease stabilization by Week 27 continued to Week 
72, and importantly, this trend was seen in those with a pre-study PSA doubling time (DT) of 
< 6 months. PSA DT of < 6 months in a biochemically recurrent population are associated with a 
worse prognosis and greater likelihood of developing overt metastatic disease. The final 
component of this regimen, nivolumab, an anti-PD-1 agent, will be given as systemic therapy to 


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target adaptive resistance pathways and provide ongoing immune stimulation throughout the 
vaccine regimen cycle. 
Further, ongoing clinical studies support this combination approach. The combination of 
vaccines and anti-PD-(L)1 therapy is being assessed in ongoing studies in several tumor types, 
including SCCHN, glioblastoma, UC, and human papillomavirus cancers (Table 3). CDX-301, in 
combination with a vaccine (CDX-1401) and polyinosinic-polycytidylic acid stabilized with 
polylysine and carboxymethylcellulose (poly-ICLC), has been studied in patients with melanoma 
(Table 3). Results of the study demonstrated that subjects receiving CDX-301 pretreatment 
showed substantial increases in DC, monocytes, and NK cells. Further, subjects receiving 
CDX-301 developed higher anti-vaccine antibody titers than those who did not receive 
CDX-301. The authors concluded that DC mobilization with Flt3L is safe and may enhance 
responses to DC-targeted vaccines (Bhardwaj et al., 2016). 
While each component is unlikely to yield clinical benefit on its own in mCRPC, these 
individual components (CDX-301, INO-5151, and nivolumab) provide different mechanisms to 
target and enhance immunogenicity by activating innate and adaptive immune mechanisms in 
order to elicit an antitumor immune response. 


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Table 3: 
Clinical Studies Supporting the Co-administration of Components of this Study Intervention 
Study 
Disease Site 
N 
Combination 
Findings  
Vaccine + Anti-PD-(L)1 Combinations 
NCT03162224 
SCCHN 
(HPV associated) 
50 
MEDI0457 (INO-3112) 
vaccine + durvalumab 
Single arm, open-label study ongoing to assess safety and tolerability, antitumor 
activity (ORR, PFS, DCR, OS), and immunogenicity. 
NCT03439085 
HPV cancers 
77 
MEDI0457 (INO-3112) 
vaccine + durvalumab 
Non-randomized, parallel assignment, open-label study to assess efficacy (ORR, 
PFS, DCR, OS) and safety. 
NCT03491683 
Glioblastoma 
52 
INO-5401 + INO-9012 
vaccine + cemiplimab + 
XRT + temozolomide (if 
clinically indicated) 
Non-randomized, parallel assignment, open-label study ongoing to assess safety, 
immunogenicity, and preliminary efficacy (OS). 
NCT03502785 
UC 
85 
INO-5401 + INO-2012 
vaccine + atezolizumab 
Non-randomized, parallel assignment, open-label study ongoing to assess safety, 
immunogenicity, and preliminary efficacy (ORR, DoR, PFS, OS). 
Vaccine + CDX-301 Combinations 
NCT02129075 
Melanoma 
60 
CDX-1401 vaccine + 
Poly-ICLC ± CDX-301 
Randomized study (CDX-301 + CDX-1401+ poly-ICLC vs CDX-1401+ poly-
ICLC) demonstrated DC mobilization with Flt3L is safe and may enhance 
responses to DC-targeted vaccines. Preliminary analyses showed substantial 
(between ~15- to ~200-fold) increases of PBMC innate immune cells (DC, 
monocytes and NK cells) in subjects with CDX-301 pretreatment vs subjects 
without CDX-301. Further, there was development of higher anti-NY-ESO-1 
antibody titers in subjects with CDX-301 pretreatment vs subjects without 
CDX-301. (Bhardwaj et al., 2016) 
CDX-1401 = DEC-201/NY-ESO-1 fusion protein vaccine; DC = dendritic cell; DCR = disease control rate; DoR = duration of response; Flt3L = FMS-related 
tyrosine kinase 3 ligand; HPV = human papillomavirus; NK = natural killer; ORR = objective response rate; OS = overall survival; PBMC = peripheral blood 
mononuclear cell; PD-(L)1 = programmed cell death 1 or anti-programmed cell death ligand 1; PFS = progression-free survival; poly-ICLC = polyinosinic-
polycytidylic acid stabilized with polylysine and carboxymethylcellulose; SCCHN = squamous cell carcinoma of the head and neck; UC = urothelial carcinoma; 
XRT = radiation therapy 
 
 


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2.3 
BENEFIT/RISK ASSESSMENT 
There are data supporting the use of the individual components of the study intervention in this 
cohort (ie, CDX-301, INO-5151, and nivolumab); however, the combination has not been 
previously studied in animal models or in human studies. Each component has been studied 
specifically in prostate cancer and was well tolerated (Higano et al., 2004; Brahmer et al., 2010; 
Topalian et al., 2012; Shore et al., 2018a; Shore et al., 2018b). Toxicity profiles are non-
overlapping. 
Nivolumab 
Nivolumab has demonstrated durable responses exceeding 6 months as monotherapy in several 
tumor types, including NSCLC, melanoma, RCC, and SCCHN. In confirmatory trials, 
nivolumab demonstrated a statistically significant improvement in OS as compared with the 
current standard of care in subjects with advanced or metastatic NSCLC, unresectable or 
metastatic melanoma, advanced RCC, or SCCHN. 
The monotherapy safety profile is similar across tumor types. Most adverse events (AEs) were 
low-grade (Grade 1 to 2) with relatively few related high-grade (Grade 3 to 4) AEs. There is no 
pattern in the incidence, severity, or causality of AEs to nivolumab dose level. Clinically relevant 
AEs typical of stimulation of the immune system were infrequent and manageable by delaying or 
stopping nivolumab treatment and timely immunosuppressive therapy or other supportive care 
(Nivolumab Investigator’s Brochure, 2018).  
In several ongoing clinical trials, the safety of nivolumab in combination with other therapeutics 
such as ipilimumab, cytotoxic chemotherapy, anti-angiogenics, and targeted therapies is being 
explored. Most studies are ongoing and, as such, the safety profile of nivolumab combinations 
continues to evolve. 
Overall, these findings support a favorable benefit-risk profile for nivolumab across various 
tumor types. More detailed information about the known and expected benefits and risks and 
reasonably expected AEs of nivolumab may be found in the prescribing information (Opdivo 
USPI, 2018). 
INO-5151 
DNA vaccines are simple and relatively inexpensive to construct, are readily produced in large 
quantities, and are generally stable for long periods of time, making them a desirable immune-
based modality for the prevention or treatment of disease. Additionally, nonclinical studies have 
demonstrated no evidence of genome integration as measured by PCR in 2 previous studies of 
several DNA vaccine products expressing a variety of inserts (INO-5151/INO-5150 and INO-
9012 Investigator’s Brochure, 2019). In contrast, pre-existing anti-vector immunity can reduce 
immunogenicity and ability to utilize the viral vector for future immunizations. 


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The plasmid backbones of DNA vaccines are associated with limited, if any, immune response, 
allowing repeated dosing to increase or maintain immune responses over long periods. Repeated 
dosing of viral-based vaccines may be hindered by neutralization of targeted viral vector 
sequences. As opposed to viral-based vaccines, which carry a risk of mutation back to a virulent 
state or spread to unintended individuals, DNA vaccines are not based on an intact natural 
pathogen, and therefore, cannot revert to a virulent form. 
The combined safety data from completed and ongoing trials with IL-12 plasmid DNA have 
demonstrated that there have been no significant safety concerns identified in the studies in 
which IL-12 (eg, INO-9012) is used as an adjuvant in combination with other plasmids. In 
addition, up to 5.8 mg of IL-12 DNA has been administered intratumorally followed by EP, and 
no safety signals were observed. 
In contrast to high-dose intravenous (IV) recombinant human IL-12 protein, IL-12 plasmid DNA 
has showed an acceptable safety profile in clinical studies when delivered intramuscularly either 
alone or when followed by EP. The use of IL-12 DNA has also been associated with expansion 
of antigen-specific IFN-γ positive effector cells, as well as granzyme B production. The induced 
immunity included both a CD8+ as well a CD4+ component. 
The most frequently reported AEs across studies in which PSA, PSMA and plasmids with a 
DNA backbone identical to that of INO-5150 and delivered via IM+EP alone or in combination 
with IL-12 plasmid DNA (eg, INO-9012) are provided in Table 2. Injection site pain was the 
most frequently reported treatment-related AE across all studies. There were few treatment-
related Grade 3 or Grade 4 AEs or serious adverse events (SAEs).  
These data indicate that synthetic consensus antigenic sequences inserted into the plasmid 
backbone generate significant cellular and humoral immune responses, without compromising 
the acceptable safety profile of naked DNA delivery (Doukas et al., 2011; Ledwith et al., 2000). 
The generally acceptable benefit/risk profile of DNA vaccines delivered using EP supports 
further study in selected diseases, such as prostate cancer. 
CDX-301 
Conclusions regarding the benefit/risk of CDX-301 should be considered in the context of a drug 
in the early stages of development, and therefore by definition, is uncertain and evolving. 
CDX-301 has been well-tolerated and demonstrates the potential for utility in a number of life-
threatening disease states by mobilizing and increasing the number of hematopoietic stem cells 
and DCs in healthy volunteers and cancer patients. CDX-301 administered in combination with 
vaccines was well tolerated, without SAEs, and promoted integrated immunity (Bhardwaj et al., 
2016). Data collected to date indicate that CDX-301 has an acceptable toxicity profile, and the 


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overall benefit/risk remains in favor of continued clinical evaluation (CDX-301/Recombinant 
Human Flt3 Ligand [rhuFlt3L] Investigator’s Brochure, 2018). 
CDX-301, INO-5151, and Nivolumab 
Data from studies of the individual components of the study intervention in this cohort, as well 
as clinical studies of the co-administration of the components of the combination, provide 
support for the study of this immunotherapy combination. Nonclinical data and clinical 
experience indicate the potential for improvement of response compared with nivolumab 
monotherapy. Thus, the potential benefit of this immunotherapy combination appears to 
outweigh the known risks of these agents and warrants clinical investigation. 
3 
OBJECTIVES AND ENDPOINTS 
The cohort-specific objectives and endpoints are listed in Table 4. 
Table 4: 
Cohort-Specific Objectives and Corresponding Endpoints 
Objectives 
Endpoints 
Primary 
 
• To determine the safety of CDX-301 + INO-5151 
followed by INO-5151 + nivolumab in participants 
with mCRPC. 
Refer to the core protocol. 
Secondary 
 
• To determine the ORR of CDX-301 + INO-5151 + 
nivolumab in participants with measurable mCRPC. 
• To determine the DCR ≥ 9 months of CDX-301 + 
INO-5151 + nivolumab in participants with 
measurable mCRPC. 
• To evaluate the rPFS of CDX-301 + INO-5151 + 
nivolumab in participants with mCRPC. 
• To estimate the OS of CDX-301 + INO-5151 + 
nivolumab in participants with mCRPC. 
Refer to the core protocol. 
Exploratory 
 
• To evaluate the PK of CDX-301 and/or nivolumab. 
• To evaluate the immunogenicity of INO-5151, 
CDX-301, and/or nivolumab. 
 
Refer to the core protocol for overall exploratory 
objective(s). 
• Sparse PK analysis. 
• Presence of immune response against PSA and/or 
PSMA 
• ADA against CDX-301 and/or nivolumab. 
 
Refer to the core protocol for overall exploratory 
endpoint(s). Note that biomarker evaluation for this 
cohort will include immune profiles, including 
dendritic cells. 
ADA = anti-drug antibodies; DCR = disease control rate; IL-12 = interleukin-12; mCRPC = metastatic castration-
resistant prostate cancer; ORR = objective response rate; OS = overall survival; PK = pharmacokinetics; 


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PSA = prostate-specific antigen; PSMA = prostate-specific membrane antigen; rPFS = radiographic progression-free 
survival 
 
4 
STUDY DESIGN 
4.1 
OVERALL DESIGN 
In this study intervention cohort, INO-5151 and CDX-301 will be administered during the 
Immune-priming Lead-in. CDX-301 will be administered on Days 1-5 and Days 22-26 and INO-
5151 will be administered on Day 8 of the Immune-priming Lead-in. Thereafter, INO-5151 will 
be administered in Cycle 1, Cycle 2, and Cycle 3 and every 12 weeks (Q12W; ie, every 3 cycles) 
thereafter for up to 2 years, concurrent with nivolumab. Nivolumab will be administered every 4 
weeks (Q4W) starting in Cycle 1 for up to 2 years (Figure 1), unless the participant: is no longer 
clinically benefiting (as evidenced by symptomatic or radiographic disease progression and/or 
clinical deterioration); experiences any toxicity meeting specified discontinuation criteria (see 
Section 6.6) or unacceptable toxicity in the best clinical discretion of the treating physician; 
reaches the maximum duration of study intervention; or withdraws consent. The preferred 
sequence when INO-5151 and nivolumab are administered on the same day is:  INO-5151 via EP 
followed by nivolumab infusion. 
Participants will be monitored for safety and response and will be followed on-study for up to 
2.5 years from the time of the initiation of study intervention. All participants will be followed 
for safety for at least 100 days after discontinuation of study intervention. Approximately 15 
participants, including a minimum of 7 with a non-bone metastatic lesion that can be biopsied, 
will be enrolled in Stage 1. An additional approximately 15 participants, including a minimum of 
7 with a non-bone metastatic lesion, will be enrolled in Stage 2, if the cohort is expanded. 
A pre-treatment biopsy of a metastatic lesion is required for all participants, including those with 
bone only disease, if medically feasible. Participants must also provide consent for archival 
tissue from a prior biopsy or surgery for prostate cancer. An on-treatment biopsy is required, 
when medically feasible, usually after the second dose of nivolumab (ie, Cycle 2). An optional 
biopsy may be obtained at the time of disease progression, including from participants who 
respond and subsequently progress following a response to treatment. The on-treatment biopsies 
should be taken from the same lesion as the pre-treatment biopsy when feasible. 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
The scientific rationale for this combination is provided in Section 2.2.4. 
4.3 
JUSTIFICATION FOR DOSE 
The doses of INO-5151 and CDX-301 proposed for this study have established as being safe in 
previous and ongoing clinical trials (Section 4.3.2 and Section 4.3.3, respectively). Nivolumab 


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will be administered as a fixed dose of 480 mg intravenously Q4W, an established dosing 
regimen and US Food and Drug Administration (FDA)-approved for a majority of approved 
nivolumab indications (Section 4.3.1).  
All agents are being administered at the recommended dose determined in prior studies in cancer 
patients and based on the safety profiles of the individual components, there does not appear to 
be overlapping toxicities. Therefore, the combination of CDX-301, INO-5151, and nivolumab at 
the doses proposed is considered warranted for the evaluation of safety and clinical activity in 
this population. 
4.3.1 
Rationale for Nivolumab Dose and Schedule 
In the US, single-agent nivolumab was approved in 2014 at a dose of 3 mg/kg every 2 weeks 
(Q2W). Subsequently, population pharmacokinetics (PPK) and exposure response analyses were 
performed to support use of flat dosing regimens (ie, nivolumab 240 mg Q2W, 360 mg every 
3 weeks [Q3W], and 480 mg Q4W) in participants with cancer. A flat dose of nivolumab 240 mg 
Q2W was selected since it is identical to a dose of 3 mg/kg for participants weighing 80 kg, the 
observed median body weight in nivolumab-treated cancer patients, while the nivolumab 360 mg 
Q3W and 480 mg Q4W regimens allow flexibility of dosing with less frequent visits and in 
combination with other agents using alternative dosing schedules to Q2W, such as ipilimumab. 
Using a PPK model, the overall distributions of nivolumab exposures (average steady-state 
concentration [Cavgss], minimum steady-state plasma concentration [Cminss], maximum steady-
state plasma concentration [Cmaxss], and trough concentration after the first dose [Cmin1]) are 
comparable after treatment with either nivolumab 3 mg/kg or 240 mg Q2W (Nivolumab 
Investigator’s Brochure, 2018). 
Following nivolumab 480 mg Q4W, Cavgss are expected to be similar to those following 
nivolumab 3 mg/kg or 240 mg Q2W, while Cminss are predicted to be ~16% lower and are not 
considered to be clinically relevant. Cmaxss are predicted to be approximately ~43% greater 
relative to that following nivolumab 3 mg/kg Q2W dosing. However, the range of nivolumab 
exposures (median and 90% prediction intervals) following administration of 240 mg flat Q2W, 
360 mg Q3W, and 480 mg Q4W regimens across the 35 to 160 kg weight range are predicted to 
be maintained well below the corresponding exposures observed with the well tolerated 10 
mg/kg nivolumab Q2W dosing regimen (Nivolumab Investigator’s Brochure, 2018) 
The 240 mg Q2W dose was approved in the USPI in September 2016 for use in metastatic 
melanoma, NSCLC, and RCC indications. In March 2018, the 480 mg Q4W dose was approved 
in the USPI for use in metastatic melanoma, NSCLC, RCC, cHL, SCCHN, UC, and HCC 
indications (Opdivo USPI, 2018). 


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4.3.2 
Rationale for INO-5151 Dose and Schedule 
INO-5151 will be administered at a dose of 3 mg followed by EP in Immune-priming Lead-in, 
followed by 3 doses administered Q4W starting at Cycle 1, and then Q12W thereafter. 
Administration of INO-5151 will commence on Day 8 of the Immune-priming Lead-in, based on 
doses studied in the phase 1 clinical study (PCa-001) and a schedule that has been modified to 
Q4W by the inclusion of a dose at Cycle 2. The PCa-001 study which assessed the safety, 
tolerability, and antigen-specific immune responses of INO-5150 with or without INO-9012 
delivered via IM EP at 2 doses of INO-5150 (high-dose: 8.5 mg or low-dose: 2 mg) alone or in 
combination with INO-9012 1 mg in patients with prostate cancer (INO-5151/INO-5150 and 
INO-9012 Investigator’s Brochure, 2019). The doses selected for Study PCa-001 were based on 
previous human experience with other DNA vaccines and preclinical data with INO-5150 and 
INO-9012. A total dose of 8.5 mg INO-5150 DNA was selected for Study PCa-001 based on the 
safety and immunogenicity data generated in Studies HPV-001 and FLU-001, where 6 mg of 
DNA were delivered via IM+EP, which showed trends toward higher response rates and 
magnitudes of IFN-γ ELISpot responses in the high dose cohort compared to the low (0.6 mg) 
and mid-dose (2 mg) cohorts without significant safety issues (INO-5151/INO-5150 and INO-
9012 Investigator’s Brochure, 2019). In combination with INO-9012 1 mg (ie, the same dose 
equivalent of INO-9012 proposed for this study), the mid-dose of 2 mg proved effective at 
generating an immune response (Shore et al., 2017). 
Grade 1 – 3 AEs were reported in 82% of the 62 patients enrolled in study PCa-001, including 
75% treated with low-dose INO-5150 and 87% treated with low-dose INO-5150 in combination 
with INO-9012. Common AEs included injection site pain, swelling, and erythema, all of which 
were Grade 1 – 2. Grade 3 SAEs of presyncope, cardiac disorder, fall, neoplasm, and alanine 
aminotransferase (ALT) and aspartate aminotransferase (AST) elevation occurred in 5 patients, 
and none were considered treatment-related; there were no Grade 4 or 5 SAEs (Shore et al., 
2017). 
Among the 61 evaluable patients across the 4 cohorts in study PCa-001, 77% demonstrated T 
cell immunogenicity, 60% had IFN-γ reactivity by ELISpot, 10% and 8% had antibody titers 
against PSA and PSMA, respectively, and 38% exhibited CD38, perforin + CD8 T cell 
responses. A clinical effect was demonstrated by evidence of dampening of the percent rise in 
PSA and increased PSA doubling times in the majority of patients (Shore et al., 2018a; Shore et 
al., 2018b). 
4.3.3 
Rationale for CDX-301 Dose and Schedule 
CDX-301 will be administered as a subcutaneous (SC) injection at a dose of 75 μg/kg daily (QD) 
for 5 days, the highest dose studied using the 5-day schedule in the phase 1 clinical study in 
healthy volunteers (CDX301-02), which assessed the safety, tolerability, pharmacokinetic and 


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pharmacodynamic profile of daily SC injections of CDX-301 at multiple dose levels 
(1 μg/kg/day to 75 μg/kg/day) and durations (5 to 10 days; CDX-301/Recombinant Human Flt3 
Ligand [rhuFlt3L] Investigator’s Brochure, 2018). 
Results of CDX301-02 showed that CDX-301 exhibited a typical absorption profile for SC 
administration with mean times to maximum serum concentration (Tmax) of 19.8 hours at 
75 μg/kg/day for 5 days. Mean maximum serum concentrations (Cmax) increased linearly with 
dose across the dose range when administered over 5 days and was 667.4 ng/mL following 
75 μg/kg/day for 5 days. Similarly, area under the curve (AUC) values increased across the entire 
range in a dose-independent manner. The half-life was 28 hours at 75 μg/kg/day for 5 days. 
Treatment-related toxicity was infrequent and reported only at the 25 and 75 μg/kg/day dose 
levels (number of subjects at these dose levels was 9 and 15, respectively). One Grade 3 event, 
community acquired pneumonia, was considered treatment-related. However, no additional 
infections, dose-limiting toxicities, SAEs, or Grade 3 toxicities were reported. All other 
treatment-related AEs were Grade 1; these included lymphadenopathy in 6 subjects and single 
cases of diarrhea, injection site erythema, folliculitis and dry mouth. There were no reported 
clinically significant laboratory toxicities attributed to CDX-301. 
As of October 2018, of 89 subjects (cancer patients, healthy volunteers, and stem cell donors) 
tested from 5 studies (Celldex-sponsored and investigator-initiated), 1 patient (receiving 
CDX-301 25 μg/kg/day for 10 days) has tested positive for the presence of specific 
anti-CDX-301 antibodies. Subsequent characterization of this patient’s serum has shown the 
response to be non-neutralizing. 
Dosing with 75 μg/kg daily for 5 days was sufficient to increase CD34+ stem cells and DCs by at 
least 10-fold over baseline values. 
Refer to the IB (CDX-301/Recombinant Human Flt3 Ligand [rhuFlt3L] Investigator’s Brochure, 
2018) for an additional description of overall safety, immunogenicity, and efficacy in humans. 
4.4 
TREATMENT BEYOND DISEASE PROGRESSION 
Refer to the core protocol. 
4.5 
END OF STUDY DEFINITION 
Refer to the core protocol for the end of study definition. 
The total length of this study cohort, from screening of the first participant to the end of the 
cohort, is expected to be approximately 3 years, 9 months. 


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5 
STUDY POPULATION 
Prospective requests for approval of protocol deviations to recruitment and enrollment criteria, 
also known as waivers or exemptions, is not allowed. 
5.1 
INCLUSION CRITERIA 
Participants are eligible to be included in the study only if all the following criteria apply: 
5.1.1 
Common Inclusion Criteria 
1. Participant must be ≥ 18 years of age at the time the informed consent is signed. 
2. Participants must agree to use an adequate method of contraception as outlined in 
Appendix 6 of the core protocol starting with the first dose of study intervention and for 
at least 7 months after the last dose of study intervention and refrain from donating sperm 
during this period. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for 
the participant. 
3. Participants must be able and willing to comply with the study visit schedule and study 
procedures. 
4. Histologically documented adenocarcinoma of the prostate. 
5. Metastatic castration resistant prostate cancer with castrate-level testosterone 
(< 50 ng/dL) at screening. 
6. Have received and progressed on prior secondary androgen receptor signaling inhibitor 
therapy (eg, abiraterone, enzalutamide, apalutamide). Progression is defined by one or 
more of the following 3 criteria: 
a. Prostate-specific antigen (PSA) ≥ 1.0 ng/mL and rising PSA by at least 2 
consecutive measurements a minimum of 1-week apart. 
b. Soft tissue progression as defined by Response Evaluation Criteria in Solid 
Tumors (RECIST) version 1.1 (Eisenhauer et al., 2009). 
c. Bone disease progression as defined by 2 new bone lesions (as per Prostate 
Cancer Clinical Trials Working Group 3 [PCWG3; Scher et al., 2016]).  
7. Have measurable disease or non-measurable disease based on PCWG3-modified 
RECIST 1.1. 
8. Provide fresh pre-treatment core needle or incisional biopsy of a metastatic tumor lesion 
not previously irradiated. Fine needle aspiration is not acceptable. 
a. Additionally, if a pre-treatment biopsy is not medically feasible for participants 
with bone only disease, formalin-fixed paraffin-embedded (FFPE) tumor 
specimen in a paraffin block (preferred) or at least 10 slides containing unstained, 
freshly cut, serial sections must be provided. 
b. For all participants, in addition to fresh pre-treatment biopsy, consent for archival 
tissue is required. 


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9. Must be willing to undergo tumor biopsy(ies) on treatment, if medically feasible. 
10. Participants must discontinue antiandrogen therapy (ie, bicalutamide, flutamide, 
nilutamide) at least 4-6 weeks prior to registration with no evidence of PSA decline after 
washout. 
a. Bicalutamide: Washout period at least 6 weeks 
b. Flutamide and nilutamide: Washout period at least 4 weeks 
11. Participants must discontinue therapies for mCRPC for 5 half-lives or 28 days, whichever 
is shorter. 
a. Participants will remain on gonadotropin-releasing hormone (GnRH) agents 
throughout this study. 
b. Prior chemotherapy is allowed if no progression of disease on chemotherapy as 
defined by PCWG3-modified RECIST 1.1.  
c. Prior treatment with sipuleucel-T, radium-223, or poly adenosine diphosphate 
(ADP)-ribose polymerase (PARP) inhibitor (eg, olaparib) is allowed. 
d. Tissue biopsy may be performed during washout period. 
12. Participants with prior or concurrent malignancies are permitted if any one of the 
following applies: 
a. Previously treated malignancy for which all treatment of that malignancy was 
completed at least 2 years before enrollment and no evidence of disease exists, or 
b. With agreement from the Medical Monitor and Principal Investigator (PI), 
participants who have a concurrent malignancy that is clinically stable and does 
not require tumor-directed treatment are eligible to participate if the risk of the 
prior malignancy interfering with either safety or efficacy endpoints is very low, 
or 
c. With agreement from the Medical Monitor and PI, other malignancies may be 
permitted if the risk of the prior malignancy interfering with either safety or 
efficacy end points is very low. 
13. Have a performance status of 0 or 1 according to the Eastern Cooperative Oncology 
Group (ECOG) scale. 
14. Demonstrate adequate organ function on screening laboratory tests performed within 
14 days of treatment initiation and as evidenced by: 
a. Hemoglobin ≥ 9.0 g/dL or ≥ 5.6 mmol/L without transfusion or erythropoietin 
(EPO) dependency (within ≤ 7 days of assessment) 
b. Absolute neutrophil count ≥ 1,500/mm3 without growth factor support (within 
< 28 days of assessment) 
c. Platelet count ≥ 100,000/mm3 
d. Estimated glomerular filtration rate (GFR) ≥ 45 mL/min using the Cockcroft-
Gault formula 


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e. Serum total bilirubin < 1.5 x upper limit of normal (ULN) or ≤ 2.0 x ULN for 
participants with liver metastases 
i. Participants with Gilbert's syndrome must have ≤ 3 x ULN and no liver 
lesions 
f. Aspartate aminotransferase (AST) (SGOT) and alanine aminotransferase (ALT) 
(SGPT) ≤ 3.0 x ULN or ≤ 5.0 x ULN for participants with liver metastases. 
g. Albumin ≥ 2.5 mg/dL. 
h. International normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 x ULN 
unless participant is receiving anticoagulant therapy, as long as PT is within 
therapeutic range of intended use of anticoagulants. 
i. Activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN unless participant is 
receiving anticoagulant therapy, as long as PTT is within therapeutic range of 
intended use of anticoagulants. 
15. Willing and capable of giving signed informed consent as described in Appendix 1 of the 
core protocol, which includes compliance with the requirements and restrictions listed in 
the informed consent form (ICF) and in this protocol. 
 
5.1.2 
Combination-specific Inclusion Criteria 
1. No known histologic evidence of neuroendocrine differentiation or small cell histology. 
 
5.2 
EXCLUSION CRITERIA 
Participants are excluded from the study if any of the following criteria apply: 
5.2.1 
Common Exclusion Criteria 
1. Is currently participating and receiving study therapy or has participated in a study of an 
investigational agent and received study therapy or used an investigational device within 
4 weeks of the first dose of treatment. 
a. Recent or concurrent non-therapeutic investigational agents that are not 
anticipated to interfere with study intervention, such as certain investigational 
imaging tracers, may be permitted with written agreement from the Medical 
Monitor. 
2. Has a diagnosis of immunodeficiency or conditions that need systemic corticosteroid 
replacement therapy > 10 mg/day prednisone (or equivalent) or other immunosuppressive 
medications within 28 days prior to the first dose of study intervention. Inhaled steroids 
are permitted if necessary. 
3. Has any active known or suspected autoimmune disease. Participants with vitiligo, type I 
diabetes mellitus, controlled autoimmune hypothyroidism, psoriasis not requiring 
systemic treatment, or other conditions under control are permitted to enroll. 
Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement 


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therapy ≤ 10 mg of prednisone/day for adrenal or pituitary insufficiency, etc.) is not 
considered a form of systemic treatment.  
4. Has a known history of active TB (Bacillus Tuberculosis). 
5. Has known history of, or any evidence of active, non-infectious pneumonitis. 
6. Has an active infection requiring systemic therapy. 
7. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the participant’s participation 
for the full duration of the trial, or is not in the best interest of the participant to 
participate, in the opinion of the treating Investigator. 
8. Has known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the trial. 
9. Is expecting to father children within the projected duration of the trial, starting with the 
pre-screening or screening visit through 7 months after the last dose of study intervention. 
10. Known history of testing positive for human immunodeficiency virus (HIV), known 
acquired immunodeficiency syndrome (AIDS), or any positive test for hepatitis B or 
hepatitis C virus representing acute or chronic disease. 
11. Has received a live vaccine within 30 days of planned start of study intervention. 
Note:  Seasonal influenza vaccines for injection are generally inactivated flu vaccines and 
are allowed; however intranasal influenza vaccines (eg, Flu-Mist®) are live attenuated 
vaccines, and are not allowed. 
12. Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis. Participants with previously treated brain metastases may participate provided 
they are stable (without evidence of progression by imaging for at least 4 weeks prior to 
the first dose of study intervention and any neurologic symptoms have returned to 
baseline), have no evidence of new or enlarging brain metastases, and are not using 
steroids for at least 7 days prior to study intervention.  This exception does not include 
carcinomatous meningitis which is excluded regardless of clinical stability.   
13. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study 
Day 1 or who has not recovered (ie, ≤ Grade 1 or at baseline) from AEs due to agents 
administered more than 4 weeks earlier. 
a. Participants with controlled autoimmune disease as described in exclusion 
criterion #3 are permitted to enroll. 
14. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 
2 weeks prior to study Day 1 or who has not recovered (ie, ≤ Grade 1 or at baseline) from 
AEs due to a previously administered agent. 
a. Note:  Participants with ≤ Grade 2 neuropathy and/or hearing loss are an 
exception to this criterion and may qualify for the study. 
b. Note:  If a participant received major surgery, he must have recovered adequately 
from the toxicity and/or complications from the intervention prior to starting 
therapy.   


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15. History of allergy to any of the study intervention components. 
 
5.2.2 
Combination-specific Exclusion Criteria 
1. Has had prior therapy with any anti-PD-1 or anti-PD-L1 antibody (prior therapy with an 
anti-CTLA-4 antibody is permitted). 
2. Has had prior cancer vaccine therapy. 
3. Has a history of acute myeloid leukemia (AML). 
4. History of unstable or deteriorating cardiac disease within the previous 6 months prior to 
screening including but not limited to the following: 
a. Unstable angina or myocardial infarction 
b. Congestive heart failure (New York Heart Association [NYHA] Class III or IV) 
c. Uncontrolled clinically significant arrhythmias 
5. Any pre-excitation syndromes (eg, Wolff-Parkinson-White syndrome). 
 
5.3 
LIFESTYLE CONSIDERATIONS 
No lifestyle considerations/restrictions are required for this cohort. 
5.4 
SCREEN FAILURES 
Refer to the core protocol. 
6 
STUDY INTERVENTION 
Study intervention is defined as any investigational intervention(s), marketed product(s) or 
placebo intended to be administered to a study participant according to the study protocol. 
6.1 
STUDY INTERVENTION(S) ADMINISTERED 
The study interventions to be administered in this study are summarized in Table 5. 
Table 5: 
Study Intervention 
Study 
Intervention 
Name 
Dosage Formulation 
Unit Dose 
Strength(s) 
Dosage 
Level(s) 
Route of 
Administration 
Sourcing 
CDX-301 
Sterile solution for single 
use. Single-use vial 
containing CDX-301 in 
buffered solution 
composed of sodium 
phosphate and sodium 
chloride, with a pH of 7.0 
2.5 mg/mL 
75 µg/kg 
SC 
Celldex 
Therapeutics 


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Study 
Intervention 
Name 
Dosage Formulation 
Unit Dose 
Strength(s) 
Dosage 
Level(s) 
Route of 
Administration 
Sourcing 
INO-5151 
Single-use vial containing 
pGX1101 (plasmid 
encoding PSA; INO-5101), 
pGX1108 (plasmid 
encoding PSMA; INO-
5108), and pGX6001 
(plasmid encoding IL-12) 
(1:1:1 ratio w/w) in 1x 
SSC, pH 7 for injection 
3 mg/mL 
3 mg 
IM followed 
by EP 
Inovio 
Pharmaceuticals 
Nivolumab 
Aqueous solution 
10 mg/mL 
480 mg 
IV infusion 
Bristol-Myers 
Squibb 
EP = electroporation; IL-12 = interleukin-12; IM = intramuscular(ly); IV = intravenous(ly); PSA = prostate-specific 
antigen; PSMA = prostate-specific membrane antigen; SC = subcutaneous(ly); SSC = Saline Sodium Citrate 
formulation 
 
The preferred sequence when INO-5151 and nivolumab are administered on the same day (eg, 
Day 1 of Cycle 1) is:  INO-5151 via electroporation (EP) followed by infusion of nivolumab. 
Study intervention will be administered as follows: 
• CDX-301 will be administered only during the Immune-priming Lead-in at a dose of 
75 µg/kg SC QD x 5 days (Immune-priming Lead-in Days 1 – 5 and Days 22 – 26 [ie, 
Monday – Friday on the weeks administered]). 
• INO-5151 will be administered intramuscularly (IM) at a dose of 3 mg followed by EP 
(Section 6.1.1) on Day 8 of the Immune-priming Lead-in, Day 1 of Cycles 1, 2, and 3, 
and every 12 weeks thereafter (ie, Cycles 6, 9, 12, etc. for up to 2 years) on the same day 
as nivolumab. 
• Nivolumab will be administered at a dose of 480 mg IV over approximately 30 minutes 
Q4W, starting on Day 1 of Cycle 1, for up to 2 years, unless the participant: is no longer 
clinically benefiting (as evidenced by symptomatic or radiographic disease progression 
and/or clinical deterioration); experiences any toxicity meeting specified discontinuation 
criteria (see Section 6.6) or unacceptable toxicity in the best clinical discretion of the 
treating physician; reaches the maximum duration of study intervention; or withdraws 
consent. 
Note: Day 1 of Cycle 1 follows 1 week after Day 22 of the Immune-priming Lead-in. A 
cycle is defined as 4 calendar weeks. 
 


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Administration of study intervention will be performed in a monitored setting in which there is 
immediate access to trained personnel and adequate equipment and medicine to manage 
potentially serious reactions. 
6.1.1 
Investigational Device 
The CELLECTRA® 2000 device is intended for the enhanced uptake and expression of plasmid 
DNA-based biologics in order to enhance vaccine efficacy (ie, via EP). The system is battery 
powered and includes a pulse generator, applicator, and disposable sterile needle array. The 
plasmid is delivered manually by IM injection. All device components are designed to fulfill 
international standards, where applicable, and manufactured in accordance to Inovio design and 
quality specifications. 
CELLECTRA® 2000 generates minimally-controlled, pulsed electrical currents that temporarily 
and reversibly increase cellular membrane permeability without damaging the tissue. An injected 
plasmid DNA formulation can be introduced into the cells with enhanced uptake during the 
period of increased permeability. 
Refer to the IB (INO-5151/INO-5150 and INO-9012 Investigator’s Brochure, 2019) and the 
CELLECTRA® 2000 User’s Manual for complete information and instructions on the use of this 
device. 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
Refer to the core protocol for general guidance on handling, storage, and accountability. 
INO-5151 should be stored in a secure, locked area at 2-8°C. 
CDX-301 should be stored in a secure, locked area at 2-8°C and protected from light. CDX-301 
should not be frozen, and CDX-301 vials should not be shaken. CDX-301 liquid should be 
withdrawn from vial gently, avoiding foaming and excess shearing. 
Nivolumab must be stored at 2°-8°C and protected from light and freezing.  
The instructions for reconstitution and administration of the study intervention are described in 
the Pharmacy Manual(s). 
6.3 
RANDOMIZATION AND BLINDING 
This is not a randomized study, and study intervention will be administered in an open-label 
fashion. 
6.4 
STUDY INTERVENTION COMPLIANCE 
Study intervention will be administered by authorized site personnel and tracked using drug 
accountability records. No additional measures of compliance will be instituted. 


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6.5 
CONCOMITANT THERAPY 
Refer to the core protocol. 
6.5.1 
Permitted Therapy 
Refer to the core protocol. 
6.5.2 
Prohibited Therapy 
Refer to the core protocol. 
6.6 
DOSE MODIFICATIONS 
6.6.1 
Dose Modifications for CDX-301, INO-5151, and Nivolumab 
There will be no dose escalation or dose reduction in this study. 
An 8-week enrollment hold will be implemented following treatment of the first 3 participants in 
order to monitor for acute and sub-acute adverse events and ensure that no unanticipated safety 
risks are identified. If no unanticipated safety risks are identified, 3 additional participants may 
be enrolled and initiated on study intervention. After treatment of the 6th participant, another 8-
week enrollment hold will be implemented. During this enrollment hold, new participants may 
be consented and screened, but not initiated on study intervention. 
The initial 6 participants treated in this cohort will be observed for the occurrence of any of the 
AEs described in Table 6 that are observed from the beginning of treatment through completion 
of the first cycle of nivolumab (ie, 8 weeks) and that are considered by the Investigator to be 
possibly, probably, or definitely related to CDX-301, INO-5151, nivolumab, or the 
immunotherapy combination, unless there is a clear alternative explanation. If 1 or no AEs 
described in Table 6 are observed in the first 6 participants, enrollment will continue as planned 
until a total of approximately 15 participants are enrolled. If AEs described in Table 6 are 
observed in 2 or more of the first 6 participants, enrollment into the cohort will be suspended, 
and the Safety Assessment Committee (refer to Section 9.5.1 of the core protocol) will be 
convened to review the available data and provide a recommendation, which may include, but is 
not limited to, modification or discontinuation of the cohort. 
Participants who experience any AE described in Table 6 will be discontinued from all study 
intervention and should continue follow-up assessments as outlined in the SOA (Section 1.3). 
Grade 3 and 4 toxicities are observed in all trials of nivolumab in multiple tumor types. As such 
toxicities are anticipated; however, given the unique nature of this protocol, monitoring for AEs 
described in Table 6 will continue throughout the study. 
The Investigator may attribute each AE to the combination or any individual component of the 
study intervention. Study participants may not have any dose escalations or reductions of 


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CDX-301, INO-5151, or nivolumab in this study. If an Investigator believes a toxicity is 
uniquely related to one agent drug, then appropriate documentation is required regarding the 
drug to which the Investigator is attributing the AE. The following retreatment requirements will 
apply: 
• During the Immune-priming Lead-in if, in the opinion of the Investigator, the toxicity is 
related to CDX-301, then CDX-301 should be withheld (eg, skipped) according to 
recommended dose modifications. 
o If CDX-301-related toxicities prevent the administration of CDX-301 on Days 
22 – 26, administration may be held for up to 1 week to allow for recovery.  
• Cycle 1 may commence following the completion of the Immune-priming Lead-in 
provided the participant meets the retreatment criteria for INO-5151. 
o Starting with Cycle 1 if, in the opinion of the Investigator, the toxicity is related to 
INO-5151 and/or nivolumab then both drugs should be held according to 
recommended dose modifications. If toxicity does not resolve or the criteria for 
resuming study intervention are not met within 8 weeks after the last dose, the 
participant must be discontinued from the combination therapy, unless written 
approval to restart therapy is provided by the Medical Monitor. 
 
The anticipated important safety risks associated with the administration of CDX-301, 
INO-5151, and/or nivolumab, as well as the measures to be taken, are outlined in the following 
sections. Refer to the Investigator’s Brochures for CDX-301, INO-5151, and nivolumab for 
complete summaries of safety information. 


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Table 6: 
Toxicity Criteria Requiring Permanent Treatment Discontinuation 
Participants should be monitored for the occurrence of any of the following AEs that are considered by the 
Investigator to be possibly, probably, or definitely related to CDX-301, INO-5151, nivolumab, or the 
immunotherapy combination. Treatment with all study intervention should be permanently discontinued for the 
following: 
• 
Grade 4 non-hematological toxicity (not laboratory) 
• 
Grade 4 hematologic toxicity lasting ≥ 7 days 
• 
Grade 3 thrombocytopenia in the presence of clinically significant active bleeding (eg, requiring 
transfusion or hospitalization) 
• 
Any non-hematologic toxicity ≥ Grade 3 in severity, with the following exceptions: 
o 
Grade 3 fatigue lasting ≤ 3 days 
o 
Grade 3 nausea, vomiting, or diarrhea lasting ≤ 3 days 
o 
Grade 3 rash without use of corticosteroids or anti-inflammatory agents per standard of care 
o 
Grade 4 fever 
o 
Grade 4 flu-like symptoms lasting ≤ 48 hours 
• 
Any new Grade 3 or Grade 4 non-hematologic laboratory abnormality, if 
o 
the abnormality leads to hospitalization, or 
o 
the abnormality persists for > 1 week and is believed to be clinically significant. For example, 
exceptions would include asymptomatic pancreatitis. 
• 
Febrile neutropenia Grade 3 or Grade 4 
• 
Any elevated AST or ALT laboratory value that is ≥ 3 × ULN and an elevated total bilirubin lab value that 
is ≥ 2 × ULN and an alkaline phosphatase lab value that is < 2 × ULN, in which no alternative reasons can 
be found to explain the combination of increased AST/ALT and total bilirubin, such as viral hepatitis A, B 
or C, preexisting or acute liver diseases, pre-existing known liver metastases, or another drug capable of 
causing the observed injury 
• 
Grade 5 toxicity 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; ULN = upper limit of normal 
 
6.6.1.1 
Potential for Overlapping Toxicities with CDX-301, INO-5151, 
and Nivolumab 
In general, the toxicities associated with the monotherapy administration of CDX-301, 
INO-5151, and nivolumab are not expected to be overlapping when administered in combination. 
The safety data for nivolumab are described in the USPI (Opdivo USPI, 2018). Nivolumab 
therapy is associated with immune-mediated adverse reactions, which can be severe and fatal in 
some cases. With appropriate medical therapy, immune-related adverse reactions resolved in 
most cases. Immune-mediated adverse reactions may involve any organ system; however, the 
most common severe immune-mediated adverse reactions are enterocolitis, endocrinopathies, 
hepatitis, dermatitis (including toxic epidermal necrolysis [TEN] and Stevens-Johnson syndrome 
[SJS]), and neuropathy. The safety profile of nivolumab combination therapy varies with the 
agent combined with nivolumab but is generally consistent with the safety profiles observed with 
either agent alone and, in some cases, both frequency and severity of AEs were greater than that 
observed with either agent alone. 


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The most common toxicity reported with the administration of INO-5151 has been mild to 
moderate administration site pain, which often resolves spontaneously within 5 to 10 minutes 
and may be accompanied by swelling and erythema. Evaluation of creatine phosphokinase for 
risk of muscle damage and electrocardiogram for risk of cardiac conduction abnormalities has 
been clinically unremarkable, and no EP-related safety issues have been identified other than 
transient injection site pain as mentioned above. 
In human studies to date, rhuFlt3L has been well tolerated, with many AEs attributable to 
patients’ underlying malignancy or other compounds/therapies being administered 
concomitantly, and no dose reductions of Flt3L for toxicity were reported in any of these trials. 
Erythematous nodules of up to 1 to 2 cm at the skin injection sites lasting several days were the 
only manifestation of toxicity in most patients. One patient who injected doses into the same area 
daily for 3 consecutive days developed diffuse erythema of the upper arm and adenopathy in the 
axilla that resolved spontaneously. Arthralgias, myalgias, and fever were not reported, nor were 
liver function test abnormalities. With CDX-301 administration, specifically, leukocytosis, 
especially monocytosis, is expected during administration. Injection site reactions have been 
reported and are generally mild to moderate, but occasionally severe. Lymphadenopathy 
occurred in < 20% of study participants, was not associated with AEs, and resolved after 
discontinuation of treatment. When administered in combination with CDX-1401, a DEC-
201/NY-ESO-1 fusion protein, treatment was well tolerated, with the most commonly reported 
AEs being Grade 1-2 chills, injection site erythema and pain, fever, and myalgias. 
6.6.1.2 
Dose Modifications and Toxicity Management for Adverse Events 
Associated with CDX-301, INO-5151, and Nivolumab 
Immuno-oncology agents are associated with AEs that can differ in severity and duration from 
AEs caused by other therapeutic classes. Early recognition and management of AEs associated 
with immuno-oncology agents may mitigate severe toxicity. Management algorithms (Appendix 
C-1) have been developed to assist Investigators in assessing and managing the following groups 
of drug-related AEs: 
• Immune-mediated colitis 
• Immune-mediated nephritis and renal dysfunction 
• Immune-mediated pneumonitis 
• Immune-mediated hepatitis 
• Immune-mediated endocrinopathies (hypophysitis, adrenal insufficiency, hypothyroidism 
and hyperthyroidism, Type 1 diabetes mellitus) 
• Immune-mediated skin adverse reactions 


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• Immune-mediated encephalitis 
 
6.6.1.3 
Dose Modifications and Toxicity Management for 
Infusion/Injection-related Reactions Associated with the 
Administration of CDX-301, INO-5151, and/or Nivolumab 
Interrupt or slow the rate of infusion in participants with mild or moderate infusion reactions. 
Discontinue the immunotherapy combination in participants with severe or life-threatening 
infusion reactions. 
All Grade 3 or 4 infusion reactions must be reported within 24 hours to the study Medical 
Monitor and reported as an SAE if it meets the criteria. Infusion reactions should be graded as 
described in Section 10.5.3 of the core protocol. 
Dose modification and toxicity management guidelines for infusion/injection-related reactions 
are provided in Table 7.  


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Table 7:  
Dose Modification and Toxicity Management Guidelines for Infusion/Injection-related Reactions Associated 
with the Administration of CDX-301, INO-5151, and/or Nivolumab 
Grade 
(NCI CTCAE v 5.0) 
 
Treatment 
Premedication at 
Subsequent Dosing 
Grade 1 
Mild reaction; infusion interruption not indicated; 
intervention not indicated 
Increase monitoring of vital signs as medically indicated until the participant is 
deemed medically stable in the opinion of the Investigator 
None 
Grade 2 
Requires therapy or infusion interruption but responds 
promptly to symptomatic treatment (eg, antihistamines, 
NSAIDs, narcotics, IV fluids); prophylactic medications 
indicated for ≤ 24 hours 
Stop Infusion 
Additional appropriate medical therapy may include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDs 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically indicated until the participant is 
deemed medically stable in the opinion of the Investigator 
If symptoms resolve within 1 hour of stopping drug infusion, the infusion may 
be restarted at 50% of the original infusion rate (eg, from 100 mL/h to 50 mL/h). 
Otherwise dosing will be held until symptoms resolve and the participant should 
be premedicated for the next scheduled dose 
Participants who develop Grade 2 toxicity related to the study intervention, 
and not related to electroporation, despite adequate premedication should 
be permanently discontinued from further study intervention 
Participant may be premedicated 
according to local treatment 
guidelines 
Grades 3 or 4 
Grade 3: 
Prolonged (ie, not rapidly responsive to symptomatic 
medication and/or brief interruption of infusion); 
recurrence of symptoms following initial improvement; 
hospitalization indicated for other clinical sequelae (eg, 
renal impairment, pulmonary infiltrates) 
Grade 4: 
Life-threatening; pressor or ventilatory support indicated 
Stop Infusion 
Administer urgent medical therapy as appropriate/clinically indicated 
Increase monitoring of vital signs as medically indicated until the participant is 
deemed medically stable in the opinion of the Investigator 
Hospitalization may be indicated 
**In cases of anaphylaxis, epinephrine should be used immediately 
Participant is permanently discontinued from further study intervention 
No subsequent dosing 
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of drug administration. 
For further information, please refer to the Common Terminology Criteria for Adverse Events v5.0 (CTCAE) at http://ctep.cancer.gov 
CTCAE = Common Terminology Criteria for Adverse Events; NCI = National Cancer Institute; NSAIDs = nonsteroidal anti-inflammatory drugs; IV = intravenous 
 


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6.6.1.4 
Dose Delays and Interruptions of CDX-301, INO-5151, and 
Nivolumab 
Dose delays and interruptions are permitted for toxicity reasons (see Section 6.6.2, Section 6.6.3, 
and Section 6.6.4). 
The Investigator may attribute each AE to the combination or to either individual intervention. 
• If, in the opinion of the Investigator, the toxicity is related to the combination of the 
agents, then all drugs should be held according to recommended dose modifications. 
• If the toxicity is considered clearly related to 1 agent, but not the others, 
o then the other agents can continue unless toxicity related to that study intervention 
would warrant a dose delay.  
 
Appropriate documentation is required regarding the drug to which the Investigator is attributing 
the AE. If toxicity does not resolve or the criteria for resuming study intervention are not met 
within 8 weeks after the last dose, the participant must be discontinued from the combination 
therapy. 
Dose delays and interruptions for reasons other than toxicity, such as surgical procedures, may 
be allowed with Medical Monitor approval. The acceptable length of interruption will depend on 
agreement between Investigator and Medical Monitor. 
6.6.2 
Dose Modifications for Nivolumab 
This study will include set dosing for nivolumab (480 mg Q4W). Dose escalation or reduction of 
nivolumab will not be allowed. If toxicity does not resolve or the criteria for resuming study 
intervention are not met within 8 weeks after the last dose, the participant must discontinue study 
intervention, unless written approval to restart therapy is provided by the Medical Monitor. 
Specific anticipated or potential toxicities associated with the administration of nivolumab, as 
well as the measures to be taken to avoid or minimize such toxicity in this trial, are described in 
Table 8. 
AEs associated with nivolumab exposure may represent an immunologic etiology. These 
immune-related adverse events (irAEs) may occur shortly after the first dose or several months 
after the last dose of treatment and may affect more than one body system simultaneously. 
Therefore, early recognition and initiation of treatment is critical to reduce complications. Based 
on existing clinical study data, drug-related AEs have included pulmonary toxicity, renal toxicity 
(including acute renal failure), endocrine abnormalities, gastrointestinal toxicity, dermatologic 
toxicity (including rash), and hepatotoxicity. For nivolumab monotherapy, as well as when 
administered in combination, the majority of these AEs have been managed successfully with 


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supportive care and, in more severe cases, a combination of dose delay, permanent 
discontinuation, and/or use of corticosteroids or hormone replacement therapy 
(endocrinopathies). For suspected irAEs, ensure adequate evaluation to confirm etiology or 
exclude other causes. Additional procedures or tests such as bronchoscopy, endoscopy, and skin 
biopsy may be included as part of the evaluation. 
Dose modification and toxicity management guidelines for irAEs associated with nivolumab are 
provided in Table 8. 
Table 8: 
Dose Modification and Toxicity Management Guidelines for Adverse Events 
Associated with Nivolumab 
Adverse Reaction 
Severitya 
Dose Modifications 
Colitis 
Grade 2 diarrhea or colitis 
Withhold doseb 
Grade 3 diarrhea or colitis 
Withhold doseb 
Grade 4 diarrhea or colitis 
Permanently discontinue 
Pneumonitis 
Grade 2 pneumonitis 
Withhold doseb 
Grade 3 or 4 pneumonitis 
Permanently discontinue 
Hepatitis/non-HCC 
Aspartate aminotransferase (AST) or alanine 
aminotransferase (ALT) more than 3 and up 
to 5 times the upper limit of normal (ULN) 
or total bilirubin more than 1.5 and up to 3 
times the ULN 
Withhold doseb 
AST or ALT more than 5 times the ULN or 
total bilirubin more than 3 times the ULN 
Permanently discontinue 
Hepatitis/HCC 
• If AST/ALT is within normal limits at 
baseline and increases to more than 3 and 
up to 5 times the ULN 
• If AST/ALT is more than 1 and up to 3 
times ULN at baseline and increases to 
more than 5 and up to 10 times the ULN 
• If AST/ALT is more than 3 and up to 5 
times ULN at baseline and increases to 
more than 8 and up to 10 times the ULN 
Withhold dosec 
If AST or ALT increases to more than 10 
times the ULN or total bilirubin increases to 
more than 3 times the ULN 
Permanently discontinue 
Hypophysitis 
Grade 2 or 3 hypophysitis 
Withhold doseb 
Grade 4 hypophysitis 
Permanently discontinue 
Adrenal insufficiency 
Grade 2 adrenal insufficiency 
Withhold doseb 
Grade 3 or 4 adrenal insufficiency 
Permanently discontinue 
Type 1 diabetes mellitus 
Grade 3 hyperglycemia 
Withhold doseb 
Grade 4 hyperglycemia 
Permanently discontinue 
Nephritis and renal 
dysfunction 
Serum creatinine more than 1.5 and up to 6 
times the ULN 
Withhold doseb 


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Adverse Reaction 
Severitya 
Dose Modifications 
Serum creatinine more than 6 times the 
ULN 
Permanently discontinue 
Skin 
Grade 3 rash or suspected Stevens-Johnson 
syndrome (SJS) or toxic epidermal 
necrolysis (TEN) 
Withhold doseb 
Grade 4 rash or confirmed SJS or TEN 
Permanently discontinue 
Encephalitis 
New onset moderate or severe neurologic 
signs or symptoms 
Withhold doseb 
Immune-mediated encephalitis 
Permanently discontinue 
Other 
Other Grade 3 adverse reaction 
• First occurrence 
• Recurrence of the same Grade 3 adverse 
reaction 
 
Withhold doseb 
Permanently discontinue 
Life-threatening or Grade 4 adverse reaction 
Permanently discontinue 
Grade 3 myocarditis 
Permanently discontinue 
Requirement for 10 mg per day or greater 
prednisone or equivalent for more than 12 
weeks 
Permanently discontinue 
Persistent Grade 2 or 3 adverse reactions 
lasting 12 weeks or longer 
Permanently discontinue 
Source: Opdivo USPI, 2018  
ALT = alanine aminotransferase; AST = aspartate aminotransferase; HCC = hepatocellular carcinoma; 
SJS = Stevens-Johnson syndrome; TEN = toxic epidermal necrolysis; ULN = upper limit of normal 
a Guidelines based on toxicity graded per National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI CTCAE), where applicable. 
b Resume treatment when adverse reaction improves to Grade 0 or 1. 
c Resume treatment when AST/ALT return(s) to baseline. 
 
6.6.3 
Dose Modifications for INO-5151 
Dose modifications of INO-5151 will not be allowed in this study. If toxicity does not resolve or 
the criteria for resuming study intervention are not met within 8 weeks after the last dose, the 
participant must discontinue the combination therapy, unless written approval to restart therapy 
is provided by the Medical Monitor. 
6.6.4 
Dose Modifications for CDX-301 
Dose escalation or reduction of CDX-301 will not be allowed in this study. Doses of CDX-301 
that are withheld (eg, skipped) for toxicity attributed to CDX-301 (Table 9), and doses that are 
skipped should not be made up. If CDX-301-related toxicities prevent the administration of 
CDX-301 on Days 22 – 26 of the Immune-priming Lead-in, administration may be held for up to 
1 week to allow for recovery. 


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Leukocytosis, especially monocytosis, is expected during administration of CDX-301 and may 
be particularly pronounced when combined with other hematopoietic growth factors. 
Hematological parameters, including white blood cell (WBC) and differential, should be 
monitored in participants receiving CDX-301. 
Specific anticipated or potential toxicities associated with the administration of CDX-301, as 
well as the measures to be taken to avoid or minimize such toxicity in this trial, are described in 
Table 9. 
Table 9: 
Dose Modification and Toxicity Management Guidelines for Adverse Events 
Associated with CDX-301 
Adverse Reaction 
Severity 
Dose Modifications 
Leukocytosis 
WBC count > 50,000 cells/mm3 
Withhold (skip) dosea 
Injection site reaction 
Grade 1 or 2 
No action required regarding CDX-301 
dose. 
Pre-medication with diphenhydramine 
may be considered for participants who 
experience local reactions after treatment 
with CDX-301  
Grade 3 
Permanently discontinue 
Grade 4 
Permanently discontinue 
Other ≥ Grade 2 adverse 
reaction 
• First occurrence 
Withhold (skip) dosea 
• Recurrence of the same 
≥ Grade 2 adverse reaction 
Permanently discontinue 
WBC = white blood cell 
a Resume treatment at the same CDX-301 dose level when adverse reaction returns to baseline, except for instances 
where the potential recurrence of the event poses an undue risk for the participant. Doses that are withheld (eg, 
skipped) should not be made up. 
 
7 
DISCONTINUATIONS OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1 
DISCONTINUATION OF STUDY INTERVENTION 
Refer to the core protocol. 
In addition to the discontinuation criteria described in the core protocol, refer to Table 6, 
Section 6.6.2, Section 6.6.3, and Section 6.6.4 for toxicities requiring permanent discontinuation 
of nivolumab, INO-5151, and/or CDX-301. 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM 
STUDY 
Refer to the core protocol. 


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7.3 
LOST TO FOLLOW-UP 
Refer to the core protocol. 
8 
STUDY ASSESSMENTS AND PROCEDURES 
Refer to the core protocol. Any combination-specific supplementary information or 
modifications from the core protocol are described in the following sections. 
In this study cohort, the time between nivolumab doses must not be less than 24 days. 
8.1 
EFFICACY ASSESSMENTS 
Refer to the core protocol. 
8.1.1 
Laboratory Assessments of Clinical Activity 
Samples for the laboratory assessments of clinical activity and hormone levels in Table 10 will 
be sent to the study site’s local laboratory for analysis: 
Table 10: 
Laboratory Tests Sent to the Study Site’s Local Laboratory for Analysis of 
Disease-related Endpoints 
Profile 
Laboratory Test 
Clinical activity 
PSA 
Hormone levels 
testosterone 
PSA = prostate-specific antigen 
 
 
8.2 
SAFETY ASSESSMENTS 
Refer to the core protocol. 
8.2.1 
Clinical Safety Laboratory Assessments 
8.2.1.1 
Local Laboratory Assessments 
Samples for the laboratory tests in Table 11 will be sent to the study site’s local laboratory for 
analysis: 


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Table 11: 
Laboratory Tests Sent to the Study Site’s Local Laboratory for Analysis of 
Safety 
Profile 
Laboratory Test 
Hematology 
RBC count 
hemoglobin 
hematocrit 
WBC count with automated differential (neutrophils, eosinophils, basophils, 
monocytes, lymphocytes, other cells) 
platelet count 
manual differential, if clinically indicated 
Clinical Chemistry 
(Serum or Plasma) 
sodium 
potassium 
chloride 
bicarbonate 
glucose 
BUN or urea 
creatinine 
total protein 
albumin 
calcium 
total bilirubin 
alkaline phosphatase 
ALT 
AST 
LDH 
TSH (T3 and FT4 should be checked if TSH is outside the normal range) 
coagulation assessments (PT, PTT, INR)a 
Urinalysis 
 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; 
INR = international normalized ratio; LDH = lactate dehydrogenase; PT = prothrombin time; PTT = partial 
thromboplastin time; RBC = red blood cell; TSH = thyroid stimulating hormone; WBC = white blood cell 
a Coagulation assessment not required during treatment phase unless indicated 
 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
Refer to the core protocol for the SAE and AE collection periods and for details regarding safety 
reporting. 
8.3.4 
Regulatory Reporting Requirements for SAEs 
Refer to the core protocol for the regulatory reporting requirements for SAEs. 
For this cohort, the Parker Institute for Cancer Immunotherapy Pharmacovigilance Group will 
report SAEs to regulatory authorities, the overall PI, Bristol-Myers Squibb, Inovio 
Pharmaceuticals, Celldex Therapeutics, and the Institutional Review Board/Independent Ethics 
Committee (IRB/IEC), as appropriate. The process for such reporting, including contact 


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information and specific instructions for reporting to each of these organizations, is described in 
the Safety Monitoring Plan. 
8.3.7 
Adverse Events of Special Interest 
There are no identified adverse events of special interest for this immunotherapy combination. 
8.4 
TREATMENT OF OVERDOSE 
Refer to the core protocol. 
8.5 
PHARMACOKINETICS 
Sparse pharmacokinetics (PK) blood sampling will be collected according to the SOA to assess 
the PK of CDX-301 and/or nivolumab. 
PK profiles for CDX-301 and/or nivolumab will be performed using a validated assay method 
under the supervision of the Sponsor’s designee. 
8.6 
IMMUNOGENICITY AND ANTI-DRUG ANTIBODIES 
Immunogenicity samples will be collected according to the SOA to enable evaluation of immune 
response against PSMA and/or PSA and anti-drug antibodies (ADA) to CDX-301 and/or 
nivolumab. Additionally, blood samples should also be collected at the final visit from 
participants who discontinued study intervention or were withdrawn from the study. These 
samples may be tested by the Sponsor's designee. 
The detection and characterization of antibodies to CDX-301 and/or nivolumab may be 
performed using a validated assay method under the supervision of the Sponsor’s designee.  
The detection and characterization of immune response against PSA and/or PSMA may be 
performed using enzyme-linked immunospot (ELISpot) assays or other assays. 
8.7 
BIOMARKERS 
Refer to the core protocol. 
Immune profiling may be performed, including evaluation of dendritic cell numbers and 
activation using flow cytometry or other assays. Additionally, immune response against PSMA 
and PSA maybe be evaluated by ELISpot. 
8.8 
MEDICAL RESOURCE UTILIZATION AND HEALTH 
ECONOMICS 
Refer to the core protocol. 
9 
STATISTICAL CONSIDERATIONS 
Refer to the core protocol. 


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9.5.1 
Interim Safety Monitoring 
Refer to the core protocol for details related to the Safety Assessment Committee (SAC), the 
committee charged with safety review for this study. 
With the inclusion of a safety period for the first 6 participant for this study cohort (see 
Section 6.6.1), the likelihood of proceeding to full enrollment decreases as the risk of toxicity 
from an AEs described in Table 6, as demonstrated in Table 12. 
Table 12: 
Probability of Proceeding to Full Enrollment 
True Risk of Toxicity 
0.10 
0.20 
0.30 
0.40 
0.50 
0.60 
Probability of Full Enrollment 
0.89 
0.66 
0.42 
0.23 
0.11 
0.04 
Assumes P(X≤1) where X is a binomial random variable with sample size n = 6 and p = true risk of toxicity. 
 
Table 13 shows the width of 95% confidence intervals calculated for possible observed rates of 
AEs described in Table 6 within the study. 
Table 13: 
Incidence with 95% Confidence Intervals of Possible Observed Adverse 
Events Described in Table 6 
Number of Participants with Adverse 
Eventsa/Number of Participants 
Incidence of Adverse Eventsa 
95% Confidence Intervalb 
0/6 
0 
[0, 0.39] 
1/6 
0.17 
[0.03, 0.56] 
2/6 
0.33 
[0.10, 0.70] 
3/6 
0.50 
[0.19, 0.81] 
a Adverse events described in Table 6  
b Wilson method for computing confidence interval 
 
 


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10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
Refer to the core protocol for the following appendices: 
Appendix 1: Regulatory, Ethical and Study Oversight Considerations 
Appendix 2: Eastern Cooperative Oncology Group (ECOG) Performance Status 
Appendix 3: RECIST Criteria (Version 1.1) with Modifications as Recommended by 
PCWG3 
Appendix 4: Clinical Laboratory Tests 
Appendix 5: Adverse Events: Definitions and Procedures for Recording, Evaluating, Follow-
up, and Reporting 
Appendix 6: Contraceptive Guidance and Collection of Pregnancy Information 
Appendix 7: Genetics 


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10.1 
APPENDIX C-1: MANAGEMENT ALGORITHMS 
Management algorithms have been developed to provide guidance for Investigators in assessing 
and managing immune-mediated events in participants receiving nivolumab. Section 6.6.2 
describes the criteria for dose delay and discontinuation to be followed for nivolumab in this 
cohort. These algorithms are intended to provide clinical recommendations. In cases in which the 
modification criteria in Section 6.6.2 and the algorithms differ, the criteria in Section 6.6.2 
should take precedence.  
The management algorithms are provided for the following groups of drug-related AEs: 
• Immune-mediated gastrointestinal adverse events (diarrhea, colitis) 
• Immune-mediated renal adverse events (nephritis and renal dysfunction) 
• Immune-mediated pulmonary adverse events (pneumonitis) 
• Immune-mediated hepatic adverse events (hepatitis) 
• Immune-mediated endocrinopathy adverse events (hypophysitis, adrenal insufficiency, 
hypothyroidism and hyperthyroidism, Type 1 diabetes mellitus) 
• Immune-mediated skin adverse events 
• Immune-mediated neurologic adverse events (encephalitis) 
 
 


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10.2 
APPENDIX C-2: LISTS OF TERMINOLOGY AND 
ABBREVIATIONS 
10.2.1 
List of Terminology 
Terminology 
Description 
Cohort 
A group of participants receiving the same immunotherapy 
combination. 
Cohort appendix 
A document that guides the treatment of participants in a given 
cohort. The cohort appendices are identified using a letter 
designation (eg, Appendix Cohort C).  
Core protocol 
The master document that provides the elements common 
across the study and among all cohorts, unless otherwise 
specified. 
Immunotherapy combination 
Two or more study interventions administered to a cohort of 
participants. 
 
10.2.2 
List of Abbreviations 
Abbreviation 
Definition 
ADA 
anti-drug antibody(ies) 
ADC 
antibody drug conjugates 
ADP 
adenosine diphosphate 
AE(s) 
adverse event(s) 
AIDS 
acquired immunodeficiency syndrome 
ALT 
alanine aminotransferase 
AML 
acute myeloid leukemia 
APC 
antigen-presenting cells 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
BUN 
blood urea nitrogen 
C 
cycle 
Cavgss 
average steady-state concentration 
CDX-1401 
DEC-201/NY-ESO-1 fusion protein vaccine 
cfDNA 
cell-free deoxyribonucleic acid 
cHL 
classical Hodgkin lymphoma 
Cmax 
maximum observed drug concentration 
Cmaxss 
maximum steady-state plasma concentration 
Cminss 
minimum steady-state plasma concentration 
Cmin1 
trough concentration after the first dose 


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Abbreviation 
Definition 
CNS 
central nervous system 
CRC 
colorectal cancer 
CRPC 
castration-resistant prostate cancer 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTL 
cytotoxic T-lymphocyte 
CTLA-4 
cytotoxic T-lymphocyte-associated protein 4 
D 
day 
DC(s) 
dendritic cell(s) 
DCR 
disease control rate 
dMMR 
mismatch repair deficient 
DNA 
deoxyribonucleic acid 
DoR 
duration of response 
DT 
doubling time 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
ELISpot 
enzyme-linked immunospot 
EOT 
end of treatment 
EP 
electroporation 
EPO 
erythropoietin 
FDA 
Food and Drug Administration 
FFPE 
formalin-fixed paraffin-embedded 
Flt3L 
FMS-related tyrosine kinase 3 ligand 
GCP 
Good Clinical Practice 
GFR 
glomerular filtration rate 
HCC 
hepatocellular carcinoma 
HIV 
human immunodeficiency virus 
HPV 
human papillomavirus 
I/E 
inclusion/exclusion 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
IFN-γ 
interferon gamma 
IgG4 
immunoglobulin G4 
IM 
intramuscular(ly) 
IL-12 
interleukin-12 
INR 
international normalized ratio 
irAE(s) 
immune-related AE(s) 
IRB/IEC 
Institutional Review Board/Independent Ethics Committee 
IV 
intravenous(ly) 


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Abbreviation 
Definition 
LDH 
lactate dehydrogenase 
mAb 
monoclonal antibody 
mCRPC 
metastatic castration-resistant prostate cancer 
mRNA 
messenger ribonucleic acid 
MSI-H 
microsatellite instability-high 
NCI 
National Cancer Institute 
NK 
natural killer 
nmCRPC 
nonmetastatic castration-resistant prostate cancer 
NPCP 
National Prostate Cancer Project 
NSAIDs 
nonsteroidal anti-inflammatory drugs 
NSCLC 
non-small cell lung cancer 
NYHA 
New York Heart Association 
ORR 
objective response rate 
OS 
overall survival 
PARP 
poly ADP ribose polymerase 
PBMC 
peripheral blood mononuclear cell 
PCR 
polymerase chain reaction 
PCWG3 
Prostate Cancer Clinical Trials Working Group 3 
PD 
progressive disease 
PD-1 
programmed cell death 1 
PD-L1 
programed cell death ligand 1 
pDNA 
plasmid DNA 
PET 
positron emission tomography 
PFS 
progression-free survival 
PI 
Principal Investigator 
PK 
pharmacokinetics 
poly-ICLC 
polyinosinic-polycytidylic acid stabilized with polylysine and 
carboxymethylcellulose 
PORTER 
Prostate Researching Translational Endpoints Correlated to Response 
PPK 
population pharmacokinetics 
PSA 
prostate-specific antigen 
PSMA 
prostate-specific membrane antigen 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
Q2W 
every 2 weeks 
Q3M 
every 3 months 
Q3W 
every 3 weeks 
Q4W 
every 4 weeks 


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Abbreviation 
Definition 
Q12W 
every 12 weeks 
QD 
daily 
RBC 
red blood cell 
RCC 
renal cell carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
rhIL-12 
recombinant human IL-12 
rhu 
recombinant human 
rhuFlt3L 
recombinant human Flt3 ligand 
RNA 
ribonucleic acid 
rPFS 
radiographic progression-free survival 
S 
screening 
SAC 
Safety Assessment Committee 
SAE(s) 
serious adverse event(s) 
SARS 
severe acute respiratory syndrome 
SC 
subcutaneous(ly) 
SCCHN 
squamous cell carcinoma of the head and neck 
SFU 
spot forming units 
SGOT 
serum glutamic-oxaloacetic transaminase 
SGPT 
serum glutamic-pyruvic transaminase 
SIV 
simian immunodeficiency virus 
SJS 
Stevens-Johnson syndrome 
SOA 
Schedule of Activities 
TB 
tuberculosis 
TEN 
toxic epidermal necrolysis 
Tmax 
mean time to maximum serum concentration 
TMB 
tumor mutational burden 
TNF-α 
tumor necrosis factor alpha 
TSH 
thyroid stimulating hormone 
UC 
urothelial carcinoma 
ULN 
upper limit of normal 
US 
United States 
USPI 
US Prescribing Information 
WBC 
white blood cell 
XRT 
radiation therapy 
 


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10.3 
APPENDIX C-3: APPENDIX COHORT C AMENDMENT 
HISTORY 
 
DOCUMENT HISTORY 
Documents 
Date of Issue 
Amendment 1 
30 Apr 2019 
Original Appendix Cohort C 
26 Feb 2019 
 
 
 


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glutamate carboxypeptidase II in human brain. Neuroscience 2007;144(4):1361–72.  
Sardesai NY, Weiner DB. Electroporation delivery of DNA vaccines: Prospects for success. 
Current Opinion in Immunology. 2011;23(3):421-29. 
Schadeck EB, Sidhu M, Egan MA, Chong S-Y, Piacente P, Masood A, et al. A dose sparing 
effect by plasmid encoded IL-12 adjuvant on a SIVgag-plasmid DNA vaccine in rhesus 
macaques. Vaccine 2006;24(21):4677–87. 
Scher HI, Morris MJ, Stadler WM, Higano C, Basch E, Fizazi K, et al. Trial design and 
objectives for castration-resistant prostate cancer: Updated recommendations from the Prostate 
Cancer Clinical Trials Working Group 3. J Clin Oncol 2016;34(12):1402–18. 
Schmittgen TD, Teske S, Vessella RL, True LD, Zakrajsek BA. Expression of prostate specific 
membrane antigen and three alternatively spliced variants of PSMA in prostate cancer patients. 
Int J Cancer 2003;107(2):323–9.  
Schoenly KA, Weiner DB. Human immunodeficiency virus type 1 vaccine development: recent 
advances in the cytotoxic T-lymphocyte platform “spotty business.” J Virol 2008;82(7):3166–80.  
Sheets RL, Stein J, Manetz TS, Duffy C, Nason M, Andrews C, et al. Biodistribution of DNA 
plasmid vaccines against HIV-1, Ebola, Severe Acute Respiratory Syndrome, or West Nile virus 
is similar, without integration, despite differing plasmid backbones or gene inserts. Toxicol Sci 
2006a;91(2):610–9.  
Sheets RL, Stein J, Manetz TS, Andrews C, Bailer R, Rathmann J, et al. Toxicological safety 
evaluation of DNA plasmid vaccines against HIV-1, Ebola, Severe Acute Respiratory Syndrome, 
or West Nile virus is similar despite differing plasmid backbones or gene-inserts. Toxicol Sci 
2006b;91(2):620–30.  
Shore ND, Heath EI, Nordquist LT, Cheng HH, Bhatt K, McMullan T, et al. A clinical trial for 
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Annual Meeting; June 2-6, 2017; Chicago, IL. J Clin Oncol 2017;35(15_suppl; abstract e14634). 
Available at: https://meetinglibrary.asco.org/record/145240/abstract. Accessed on 18-Oct-2018. 


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76
Shore ND, Heath EI, Nordquist LT, Cheng HH, Bhatt K, Morrow M, et al. Evaluation of an 
immunotherapeutic DNA-vaccine in biochemically relapsed prostate cancer. Presented at: 
American Society of Clinical Oncology; June 1-5, 2018; Chicago, IL. J Clin Oncol 
2018a;36(15_suppl; abstract 5078). Available at: 
https://meetinglibrary.asco.org/record/162763/abstract. Accessed on 18-Oct-2018. 
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Immunotherapy in Biochemically Relapsed Prostate Cancer. Presented at: European Society for 
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antigen expression in normal and malignant human tissues. Clin Cancer Res 1997;3(1):81–5.  
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activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 
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augmentation of NK and T cytotoxic 1 responses. J Immunol 2001;167(2):946–56. 
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Williams SA, Singh P, Isaacs JT, Denmeade SR. Does PSA play a role as a promoting agent 
during the initiation and/or progression of prostate cancer? Prostate 2007;67(3):312–29. 
Yarchoan M, Hopkins A, Jaffee EM. Tumor mutational burden and response rate to PD-1 
inhibition. N Engl J Med 2017;377(25):2500–1. 

Prot_001.pdf: 
PORTER Appendix Cohort B - Parker Institute for Cancer Immunotherapy 
Protocol PICI0033 Appendix Amendment 1, Version 2.0 
1
 
 
Protocol Title:  A Multicenter, Open-Label, Exploratory Platform Study to Evaluate Biomarkers 
and Immunotherapy Combinations for the Treatment of Patients with Metastatic Castration-
resistant Prostate Cancer 
Appendix Cohort B 
Protocol Number:  PICI0033 
Amendment Number: Not applicable 
Compound Number:  CDX-301, Poly-ICLC, Nivolumab 
Short Title:  Platform Study for Prostate Researching Translational Endpoints Correlated to 
Response to Inform Use of Novel Combinations (PORTER) 
Sponsor Name and Legal Registered Address:   
Parker Institute for Cancer Immunotherapy 
1 Letterman Drive 
Suite D3500 
San Francisco, CA 94129 
Tel: 415-985-7311 
Fax: 415-872-5305 
Regulatory Agency Identifying Number(s):  
IND NUMBER: 139269 
EudraCT NUMBER:  Not applicable 
Approval Date:  Final Protocol: 11 December 2018  
 
Amendment 1: 24 January 2019 
 
CONFIDENTIAL 
This document and its contents are the property of and confidential to Parker Institute for Cancer 
Immunotherapy. Any unauthorized copying or use of this document is prohibited. 
 
 




PORTER Appendix Cohort B - Parker Institute for Cancer Immunotherapy 
Protocol PICI0033 Appendix Amendment 1, Version 2.0 
3
INVESTIGATOR PROTOCOL AGREEMENT PAGE 
I agree: 
• 
To assume responsibility for the proper conduct of the study at this site. 
• 
To conduct the study in compliance with this protocol, any future amendments, and with 
any other study conduct procedures provided by Parker Institute for Cancer 
Immunotherapy. 
• 
Not to implement any changes to the protocol without written agreement from Parker 
Institute for Cancer Immunotherapy and prior review and written approval from the 
Institutional Review Board or Independent Ethics Committee except where necessary to 
eliminate an immediate hazard to participants. 
• 
That I am thoroughly familiar with the appropriate use of the study drug(s), as described 
in this cohort appendix and any other information provided by Parker Institute for Cancer 
Immunotherapy including, but not limited to, the current Investigator’s Brochure(s). 
• 
That I am aware of, and will comply with, the International Conference on 
Harmonisation for Good Clinical Practice (GCP) and all applicable regulatory 
requirements. 
• 
To ensure that all persons assisting me with the study are adequately informed about the 
study drugs, the Parker Institute for Cancer Immunotherapy study protocol, and of their 
study-related duties and functions as described in the protocol. 
• 
That I agree that persons debarred from conducting or working on clinical studies by any 
court or regulatory agency will not be allowed to conduct or work on studies for the 
Parker Institute for Cancer Immunotherapy or for a partnership in which the Parker 
Institute for Cancer Immunotherapy is involved, and that I will immediately disclose in 
writing to the Parker Institute for Cancer Immunotherapy if any person who is involved 
in the study is debarred, or if any proceeding for debarment is pending. 
 
 
Signature: 
 
 
Date: 
 
 
Name 
(print): 
 
  
 
Site 
Number: 
Principal Investigator 
 
___________ 
  
 
 
  
 


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Protocol PICI0033 Appendix Amendment 1, Version 2.0 
4
Amendment(s) to Appendix Cohort B 
Text revisions resulting from the amendment(s) are incorporated in the synopsis and body of the 
Appendix Cohort Amendment. Major changes to the appendix cohort are summarized below. 
Key Revisions in Amendment 1 (24 January 2019) 
Section # and Name 
Description of Change 
Study Design 
1.3 Schema, Figure 2 
Modified to improve identification of key research procedure time points. 
Study Intervention 
6.6.4 Dose Modifications for 
CDX-301 
Added text to reinforce that doses of CDX-301 should be withheld (eg, 
skipped) for toxicity attributed to CDX-301. 
Add text to clarify that toxicities attributed to CDX-301 that require dose 
delays greater than 6 weeks will require Medical Monitor approval for 
the participant to restart treatment. 
6.6.5 Dose Modifications for Poly-
ICLC 
Add text to clarify that toxicities attributed to poly-ICLC that require 
dose delays greater than 6 weeks will require Medical Monitor approval 
for the participant to restart treatment. 
Clarification of Document 
General Revisions 
Document updated to address minor typographical errors and editorial 
changes for clarity. 
Appendix B-1 
Reordered the management algorithms to match the order on the 
appendix cover page. 
 
 


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Protocol PICI0033 Appendix Amendment 1, Version 2.0 
5
TABLE OF CONTENTS 
 
TABLE OF CONTENTS .................................................................................................................5 
LIST OF TABLES ...........................................................................................................................8 
LIST OF FIGURES .........................................................................................................................8 
1 
PROTOCOL SUMMARY ...................................................................................................9 
1.1 
SYNOPSIS ...............................................................................................................9 
1.2 
SCHEMA ...............................................................................................................11 
1.3 
SCHEDULE OF ACTIVITIES..............................................................................13 
2 
INTRODUCTION .............................................................................................................17 
2.1 
STUDY RATIONALE ..........................................................................................17 
2.2 
BACKGROUND ...................................................................................................17 
2.2.1 
Background on Radiation Therapy ..........................................................19 
2.2.2 
Background on rhuFLT3L/CDX-301 (Celldex Therapeutics, Inc.) ........20 
2.2.3 
Background on Poly-ICLC (Oncovir, Inc.) .............................................22 
2.2.4 
Background on Nivolumab (Bristol-Myers Squibb Company) ...............23 
2.2.5 
Rationale for SBRT + CDX-301+ Poly-ICLC+ Nivolumab 
Immunotherapy Combination ..................................................................24 
2.3 
BENEFIT/RISK ASSESSMENT ..........................................................................27 
3 
OBJECTIVES AND ENDPOINTS ...................................................................................28 
4 
STUDY DESIGN...............................................................................................................29 
4.1 
OVERALL DESIGN .............................................................................................29 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN ...........................................30 
4.3 
JUSTIFICATION FOR DOSE ..............................................................................30 
4.3.1 
Rationale for Nivolumab Dose and Schedule .........................................30 
4.3.2 
Rationale for CDX-301 Dose and Schedule ............................................31 
4.3.3 
Rationale for Poly-ICLC Dose and Schedule ..........................................32 
4.3.4 
Rationale for Stereotactic Body Radiation Therapy Dose and Schedule 33 
4.4 
TREATMENT BEYOND DISEASE PROGRESSION ........................................33 
4.5 
END OF STUDY DEFINITION ...........................................................................34 
5 
STUDY POPULATION ....................................................................................................34 
5.1 
INCLUSION CRITERIA.......................................................................................34 


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6
5.1.1 
Common Inclusion Criteria .....................................................................34 
5.1.2 
Combination-specific Inclusion Criteria .................................................36 
5.2 
EXCLUSION CRITERIA .....................................................................................36 
5.2.1 
Common Exclusion Criteria ....................................................................36 
5.2.2 
Combination-specific Exclusion Criteria ................................................38 
5.3 
LIFESTYLE CONSIDERATIONS .......................................................................38 
5.4 
SCREEN FAILURES ............................................................................................38 
6 
STUDY INTERVENTION ................................................................................................38 
6.1 
STUDY INTERVENTION(S) ADMINISTERED ................................................38 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY ......................39 
6.3 
RANDOMIZATION AND BLINDING................................................................40 
6.4 
STUDY INTERVENTION COMPLIANCE .........................................................40 
6.5 
CONCOMITANT THERAPY...............................................................................40 
6.5.1 
Permitted Therapy ...................................................................................40 
6.5.2 
Prohibited Therapy ..................................................................................40 
6.6 
DOSE MODIFICATIONS ....................................................................................40 
6.6.1 
Dose Modifications for the Combination of Nivolumab, CDX-301, and 
Poly-ICLC ...............................................................................................40 
6.6.1.1 
Potential for Overlapping Toxicities with the Combination of 
SBRT, Nivolumab, CDX-301, and Poly-ICLC .....................42 
6.6.1.2 
Dose Modifications and Toxicity Management for Adverse 
Events Associated with the Combination of Nivolumab, 
CDX-301, and Poly-ICLC .....................................................43 
6.6.1.3 
Dose Modifications and Toxicity Management for 
Infusion/Injection-related Reactions Associated with the 
Administration of CDX-301, Poly-ICLC, and/or Nivolumab
 ...............................................................................................44 
6.6.1.4 
Dose Delays and Interruptions of Nivolumab, CDX-301, and 
Poly-ICLC .............................................................................46 
6.6.2 
Dose Modification for SBRT ..................................................................46 
6.6.3 
Dose Modifications for Nivolumab .........................................................46 
6.6.4 
Dose Modifications for CDX-301 ...........................................................48 
6.6.5 
Dose Modifications for Poly-ICLC .........................................................49 
7 
DISCONTINUATIONS OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL..........................................................................49 


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Protocol PICI0033 Appendix Amendment 1, Version 2.0 
7
7.1 
DISCONTINUATION OF STUDY INTERVENTION ........................................49 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM STUDY ........50 
7.3 
LOST TO FOLLOW-UP .......................................................................................50 
8 
STUDY ASSESSMENTS AND PROCEDURES .............................................................50 
8.1 
EFFICACY ASSESSMENTS ...............................................................................50 
8.1.1 
Laboratory Assessments of Clinical Activity ..........................................50 
8.2 
SAFETY ASSESSMENTS ....................................................................................50 
8.2.1 
Clinical Safety Laboratory Assessments .................................................50 
8.2.1.1 
Local Laboratory Assessments ..............................................50 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ..............................51 
8.3.4 
Regulatory Reporting Requirements for SAEs .......................................51 
8.3.7 
Adverse Events of Special Interest ..........................................................52 
8.4 
TREATMENT OF OVERDOSE ...........................................................................52 
8.5 
PHARMACOKINETICS .......................................................................................52 
8.6 
ANTI-DRUG ANTIBODIES ................................................................................52 
8.7 
BIOMARKERS .....................................................................................................52 
8.8 
MEDICAL RESOURCE UTILIZATION AND HEALTH ECONOMICS ..........52 
9 
STATISTICAL CONSIDERATIONS...............................................................................52 
9.5.1 
Interim Safety Monitoring .......................................................................52 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ....54 
10.1 
APPENDIX B-1: MANAGEMENT ALGORITHMS ..........................................55 
10.2 
APPENDIX B-2: LISTS OF TERMINOLOGY AND ABBREVIATIONS .........63 
10.2.1 
List of Terminology .................................................................................63 
10.2.2 
List of Abbreviations ...............................................................................63 
10.3 
APPENDIX B-3: APPENDIX COHORT B AMENDMENT HISTORY ............67 
11 
REFERENCES ..................................................................................................................68 
 


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Protocol PICI0033 Appendix Amendment 1, Version 2.0 
8
LIST OF TABLES 
Table 1: 
Schedule of Activities ............................................................................................14 
Table 2: 
Clinical Studies Supporting the Co-administration of Components of this Study 
Intervention ............................................................................................................25 
Table 3: 
Cohort-Specific Objectives and Corresponding Endpoints ...................................28 
Table 4: 
Study Intervention ..................................................................................................38 
Table 5: 
Toxicity Criteria Requiring Permanent Treatment Discontinuation ......................42 
Table 6:  
Dose Modification and Toxicity Management Guidelines for Infusion/Injection-
related Reactions Associated with the Administration of CDX-301, Poly-ICLC, 
and/or Nivolumab ..................................................................................................45 
Table 7: 
Dose Modification and Toxicity Management Guidelines for Adverse Events 
Associated with Nivolumab ...................................................................................47 
Table 8: 
Dose Modification and Toxicity Management Guidelines for Adverse Events 
Associated with CDX-301 .....................................................................................49 
Table 9: 
Laboratory Tests Sent to the Study Site’s Local Laboratory for Analysis of 
Disease-related Endpoints ......................................................................................50 
Table 10: 
Laboratory Tests Sent to the Study Site’s Local Laboratory for Analysis of Safety
................................................................................................................................51 
Table 11: 
Probability of Proceeding to Full Enrollment ........................................................53 
Table 12: 
Incidence with 95% Confidence Intervals of Possible Observed Adverse Events 
Described in Table 5 ..............................................................................................53 
 
 
LIST OF FIGURES 
Figure 1: 
Mechanism of Action for SBRT + CDX-301 + Poly-ICLC + Nivolumab ............10 
Figure 2: 
Study Schema.........................................................................................................12 
Figure 3: 
Correlation Between Tumor Mutational Burden and Objective Response Rate 
with Anti-PD-1 or Anti-PD-L1 Therapy in 27 Tumor Types ................................17 
Figure 4: 
Spectrum of Inflamed Tumor Microenviroment Phenotype and Tumor Mutational 
Burden Across Human Cancer Types ....................................................................18 
 


PORTER Appendix Cohort B - Parker Institute for Cancer Immunotherapy 
Protocol PICI0033 Appendix Amendment 1, Version 2.0 
9
1 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS 
Protocol Title: 
A Multicenter, Open-Label, Exploratory Platform Study to Evaluate Biomarkers and 
Immunotherapy Combinations for the Treatment of Patients with Metastatic Castration-resistant 
Prostate Cancer 
Appendix Cohort B 
Short Title: 
Platform Study for Prostate Researching Translational Endpoints Correlated to Response to 
Inform Use of Novel Combinations (PORTER) 
Note to Investigators:  This cohort appendix is intended to supplement the core protocol, and as 
such, will focus on combination-specific (stereotactic body radiation therapy [SBRT], CDX-301, 
poly-ICLC [polyinosinic-polycytidylic acid stabilized with polylysine and 
carboxymethylcellulose], and nivolumab) information that is not already available in the core 
protocol. 
Rationale: 
This study cohort is designed to explore a multi-pronged approach to induce immunogenic cell 
death, mobilizing and activating dendritic cells (DCs), and overcoming adaptive immune 
resistance (T cells) in metastatic castration-resistant prostate cancer (mCRPC) (Figure 1). 
Immunogenic cell death induces the release of tumor antigens. Maturation and activation of DCs, 
an antigen presenting cell, mediates antigen presentation to CD8 T cells to stimulate antitumor 
immunity. Programmed cell death 1 (PD-1) blocking antibodies allow for the activation of 
tumoral CD8 T cells and the promotion of antitumor immunity. Specifically: 
• Radiation therapy to induce immunogenic cell death of the tumor 
• Flt3 ligand (CDX-301) to induce mobilization and activation of DCs 
• Poly-ICLC and radiation therapy to induce maturation/activation of DCs 
• Anti-PD-1 monoclonal antibody (nivolumab) to overcome immune suppression of 
tumoral T cells 
 


PORTER Appendix Cohort B - Parker Institute for Cancer Immunotherapy 
Protocol PICI0033 Appendix Amendment 1, Version 2.0 
10
Figure 1: 
Mechanism of Action for SBRT + CDX-301 + Poly-ICLC + Nivolumab 
 
 
Objectives and Endpoints: 
Refer to the core protocol. 
Combination-specific exploratory objectives include: 
Combination-specific Exploratory Objectives 
Endpoints 
• To evaluate the PK of CDX-301 and/or nivolumab. 
• To evaluate the immunogenicity (ADA) of 
CDX-301 and/or nivolumab. 
• Sparse PK analysis. 
• Presence of ADA against CDX-301 and/or 
nivolumab. 
ADA = anti-drug antibodies; PK = pharmacokinetics 
 
Overall Design, Number of Participants, Follow-up, and Data Monitoring Committee: 
Refer to the core protocol. 
Intervention Groups and Duration: 
Participants will be assigned to receive one of the enrolling immunotherapy combination study 
interventions. In this cohort, participants will receive SBRT, CDX-301, poly-ICLC, and 
nivolumab as follows: 


PORTER Appendix Cohort B - Parker Institute for Cancer Immunotherapy 
Protocol PICI0033 Appendix Amendment 1, Version 2.0 
11
Intervention 
Dose 
Frequency 
Route 
Schedule 
CDX-301 
75 µg/kg 
QD 
SC 
Days 1 -5 
SBRT 
30-50 Gy in 1-5 doses. Radiation will start on Day 1 or 2 
Poly-ICLC 
1 mg 
Twice weekly x 3 weeks 
IM 
Starting on Day 1 
Nivolumab 
480 mg 
Q4W 
IV over 30 minutes 
Starting Day 1 
Gy = gray; IM = intramuscular(ly); IV = intravenous(ly); QD = daily; Q4W = every 4 weeks; SBRT = stereotactic 
body radiation therapy; SC = subcutaneous(ly) 
 
SBRT and CDX-301/poly-ICLC will be administered during the first cycle only. Nivolumab will 
be administered for up to 2 years, unless the participant: is no longer clinically benefiting (as 
evidenced by symptomatic or radiographic disease progression and/or clinical deterioration); 
experiences any toxicity meeting specified discontinuation criteria (see Section 6.6) or 
unacceptable toxicity in the best clinical discretion of the treating physician (ie, Investigator 
discretion); reaches the maximum duration of study intervention; or withdraws consent. In this 
cohort, a cycle is defined as 4 calendar weeks. 
1.2 
SCHEMA 
The study schema is depicted in Figure 2. 


PORTER Appendix Cohort B - Parker Institute for Cancer Immunotherapy 
Protocol PICI0033 Appendix Amendment 1, Version 2.0 
12
Figure 2: 
Study Schema 
 
IM = intramuscularly; IV = intravenously; mCRPC = metastatic castration-resistant prostate cancer; Q4W = every 4 weeks; SBRT = stereotactic body radiation 
therapy; SC = subcutaneously 
Note: The horizontal axis is not linearly scaled, so the interval for Cycle 1 appears to be much longer than for the subsequent cycles. 
SBRT, CDX-301, and poly-ICLC will be administered during the first cycle only. Nivolumab will be administered for up to 2 years, unless the participant: is no 
longer clinically benefiting (as evidenced by symptomatic or radiographic disease progression and/or clinical deterioration); experiences any toxicity meeting 
specified discontinuation criteria (see Section 6.6) or unacceptable toxicity in the best clinical discretion of the treating physician; reaches the maximum 
duration of study intervention; or withdraws consent. A cycle is defined as 4 calendar weeks. Participants will be followed for up to 2.5 years from the time of 
the initiation of study intervention. 
This study design is applicable to Stage 1, as well as Stage 2 if the cohort is expanded. 


PORTER Appendix Cohort B - Parker Institute for Cancer Immunotherapy 
Protocol PICI0033 Appendix Amendment 1, Version 2.0 
13
 
1.3 
SCHEDULE OF ACTIVITIES 
The Schedule of Activities (SOA) shown in Table 1 is specific for this combination and 
supersedes the SOA provided in the core protocol. 


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Protocol PICI0033 Appendix Amendment 1, Version 2.0 
14
Table 1: 
Schedule of Activities 
Tests & Procedures 
Screening/ 
Enrollmenta 
On-Treatment: SBRT + CDX-301 + poly-ICLC + Nivolumab 
End of 
Treatmentb 
Follow up 
Cycle 1 (Q4W) 
Cycles 
2,3, and 4 
Cycle 5 
Onward 
Day 
Day -28 to 
Day -1 
Day 1 
Day 2 - 5 
Day 8 
Day 15 
Day 1 
Day 1 
14 - 28 days 
after last 
dose 
110 days 
after last 
dose 
Q3Mc 
Window (days) 
-28 
 
 
± 1 
± 1 
± 3 
± 3 
± 7 
± 10 
± 14 
Informed consentd 
X 
 
 
 
 
 
 
 
 
 
Review of I/E criteria 
X 
 
 
 
 
 
 
 
 
 
Medical/cancer history 
X 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
X 
 
 
 
X 
X 
X 
 
 
ECOG performance status 
X 
X 
 
 
 
X 
X 
X 
X 
 
Vital signs (See Core 
Protocol Section 8.2.3) 
X 
X 
 
 
 
X 
X 
X 
 
 
Body weight 
X 
X 
 
X 
X 
X 
X 
(Cycles 5, 
8, 11, 14, 
17, 20, 23, 
and 26) 
X 
 
 
Hematology (see Table 10) 
X 
Xe 
 
Xe 
Xe 
Xe 
Xe 
X 
X 
 
Clinical chemistry (see 
Table 10) 
X 
Xe 
 
Xe 
Xe 
Xe 
Xe 
X 
X 
 
Urinalysis 
X 
 
 
 
 
 
 
X 
 
 
Prostate-specific antigen 
X 
X 
 
 
 
X 
X 
X 
X 
 
Testosterone level 
X 
 
 
 
 
 
 
 
 
 
12-lead ECG 
X 
 
 
 
 
X (Cycles 
2 and 4) 
 
 
 
 
Circulating tumor cellsf 
 
Xe 
 
 
 
Xe 
Xe 
X 
 
 
cfDNA (blood)g 
X 
 
 
 
 
Xe (Cycles 
2 and 4) 
 
X 
 
 


PORTER Appendix Cohort B - Parker Institute for Cancer Immunotherapy 
Protocol PICI0033 Appendix Amendment 1, Version 2.0 
15
Tests & Procedures 
Screening/ 
Enrollmenta 
On-Treatment: SBRT + CDX-301 + poly-ICLC + Nivolumab 
End of 
Treatmentb 
Follow up 
Cycle 1 (Q4W) 
Cycles 
2,3, and 4 
Cycle 5 
Onward 
Day 
Day -28 to 
Day -1 
Day 1 
Day 2 - 5 
Day 8 
Day 15 
Day 1 
Day 1 
14 - 28 days 
after last 
dose 
110 days 
after last 
dose 
Q3Mc 
Window (days) 
-28 
 
 
± 1 
± 1 
± 3 
± 3 
± 7 
± 10 
± 14 
Circulating soluble 
analytes/PK/ADAh 
X 
Xe 
Xe  
(Day 5) 
Xe 
Xe 
Xe (Cycles 
2, 3, and 4) 
 
X 
X 
 
Blood immune 
biomarkersh 
X 
Xe 
Xe 
(Day 5) 
X 
X 
Xe (Cycles 
2, 3, and 4) 
 
X 
 
 
Archival tumor tissue 
X 
 
 
 
 
 
 
 
 
 
Tumor biopsyi 
X 
 
 
 
 
X (Cycle 2) 
 
X (at PD 
[optional])i 
 
 
Stool collectionj 
X 
 
 
 
 
X (Cycle 2)j 
 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse events 
All AEs and SAEs will be collected for at least 100 days after the last dose of study interventionk 
 
Radiation therapyl 
 
X 
X 
 
 
 
 
 
 
 
CDX-301 administrationm 
 
X 
X 
 
 
 
 
 
 
 
Poly-ICLC administrationn 
 
X 
X (twice 
weeklyn)  
X (twice 
weeklyn) 
X (twice 
weeklyn) 
 
 
 
 
 
Nivolumab administrationo 
 
X 
 
 
 
X 
X 
 
 
 
Radiographic disease 
assessment 
X 
At Week 8 (± 1 week), repeat every 8 weeks (± 1 week) for the first 24 weeks, and every 12 weeks (± 1 week) 
thereafter until radiographic PD or start of subsequent therapy 
Review of alternate 
anticancer therapyp 
 
 
 
 
 
 
 
 
X 
X 
Follow up for overall 
survival 
 
 
 
 
 
 
 
 
X 
X 
ADA = anti-drug antibodies; AE(s) = adverse event(s); cfDNA = cell-free deoxyribonucleic acid; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; 
EOT = end of treatment; Gy = grays; I/E = inclusion/exclusion; IM = intramuscularly; IV = intravenously; PD = progressive disease; PK = pharmacokinetics; Q3M = every 3 
months; Q4W = every 4 weeks; QD = every day; SAE(s) = serious adverse event(s); SC = subcutaneously 


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a Tests/procedures performed as standard of care prior to obtaining informed consent and within 28 days prior to the first dose of study intervention do not have to be repeated at 
screening. 
b The End of Treatment Visit will be completed following the last dose of study intervention, either at the completion of the on-treatment phase or at early discontinuation. 
c For up to 2.5 years from the initiation of study intervention, participants in the follow up phase will be contacted by the site to collect alternate anticancer therapy information 
and determine survival status. 
d Informed consent must be obtained prior to any study-specific procedures and may be obtained prior to the 28-day screening window. 
e Blood samples should be collected prior to administration of any study intervention. 
f Circulating tumor cells will be collected at baseline (ie, Day 1 of Cycle 1 prior to study intervention administration), Day 1 of each cycle (prior to study intervention 
administration), and EOT. 
g cfDNA (blood) will be collected at baseline (ie, screening visit prior to study intervention administration), Day 1 of Cycle 2 and Cycle 4, and EOT. 
h Circulating soluble analytes, PK and ADA blood sample, and/or blood immune biomarkers may be assessed at baseline (ie, screening and/or Day 1 of Cycle 1 prior to study 
intervention administration), prior to study intervention administration on Days 1, 5, 8, and 15 of Cycle 1 and Day 1 of Cycles 2-4, and at EOT and the first follow up visit. 
i Participants will undergo 2-3 tumor biopsies: prior to beginning protocol therapy (ie, baseline biopsy, mandatory for all participants, including those with bone only disease if 
medically feasible), and during treatment (ie, on-treatment biopsy during Cycle 2, if medically feasible). On- treatment biopsy should occur as early as possible after the second 
dose (Day 2 – Day 10 of Cycle 2); however, any on treatment biopsy after Day 1 of Cycle 2 will be accepted. An optional biopsy may be obtained at the time of disease 
progression, including from participants who respond and subsequently progress. Every attempt should be made for the on-treatment biopsies to be taken from the same lesion as 
the pre-treatment biopsy when feasible. 
j Stool will be collected at screening and during Cycle 2, if possible. Otherwise, any on-treatment stool sample will be acceptable. The stool sample may be collected at the clinic 
or at the participant’s home. 
k All SAEs will be collected from the time the participant signs informed consent. Prior to initiation of study intervention, only SAEs that are related to a protocol-mandated 
intervention, including those that occur prior to the assignment of study procedures should be reported. All AEs will be collected from the start of study intervention. All AEs 
and SAEs will be collected for at least 100 days after the last dose of study intervention. Refer to Section 8.3 of the core protocol for details regarding safety reporting for this 
study. 
l Radiation therapy will be administered at 30 – 50 Gy in 1 – 5 doses, starting on Day 1 or 2.  
m CDX-301 will be administered at a dose of 75 µg/kg SC QD x 5 days (Days 1 – 5 [ie, Monday – Friday]), concurrent with SBRT. 
n Poly-ICLC will be administered at a dose of 1 mg IM twice weekly, at least 2 days apart, for 3 weeks starting on Day 1. The dose may be administered at any time of the day but 
should occur at approximately the same time on poly-ICLC administration days. 
o Nivolumab will be administered at a dose of 480 mg IV over 30 minutes Q4W starting on Day 1 of Cycle 1 and will continue for up to 2 years, unless the participant: is no 
longer clinically benefiting (as evidenced by symptomatic or radiographic disease progression and/or clinical deterioration); experiences any toxicity meeting specified 
discontinuation criteria (see Section 6.6) or unacceptable toxicity in the best clinical discretion of the treating physician; reaches the maximum duration of study intervention; or 
withdraws consent. A cycle is defined as 4 calendar weeks. The time between nivolumab doses must not be less than 24 days. 
p Collection of information related to any post-study intervention alternate anticancer therapy. 
 


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2 
INTRODUCTION 
Refer to the core protocol. 
2.1 
STUDY RATIONALE 
Refer to the core protocol. 
2.2 
BACKGROUND 
Immune checkpoint blockade, particularly with programmed cell death 1 (PD-1) or programmed 
cell death ligand 1 (PD-L1) antibodies, has changed the landscape for the treatment of a variety 
of advanced solid tumors. Though the majority of patients with a specific tumor type don’t 
respond to treatment, a notable subset of patients across tumor types achieve durable responses 
in the context of relatively well tolerated therapy leading to the substantial enthusiasm for this 
therapeutic class (Figure 3). However, not only is there intra-tumor-type variability in the 
likelihood of response to PD-1/PD-L1 blockade but there is also substantial inter-tumor type 
heterogeneity (Yarchoan et al., 2017). Prostate cancer has been among the tumor types for which 
single-agent PD-1/PD-L1 blockade has been associated with relatively rare responses, and the 
responses that do occur are typically in the context of a genomically-defined subset of cancers 
(ie, mismatch repair deficient tumors) (Graff et al; 2016). Therefore, there is a critical need to 
develop rational combination strategies to extend the benefits of PD-1/PD-L1 blockade to 
patients with metastatic castration-resistant prostate cancer (mCRPC). 
Figure 3: 
Correlation Between Tumor Mutational Burden and Objective Response 
Rate with Anti-PD-1 or Anti-PD-L1 Therapy in 27 Tumor Types 
 
Source: Adapted from Yarchoan et al., 2017 


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Clues as to why prostate cancers may be less responsive to single-agent PD-1/PD-L1 blockade 
may be derived from studies exploring biomarkers predictive of response and resistance to 
treatment in tumor types associated with a higher likelihood of response. Indeed, multiple studies 
have demonstrated that patients with tumors harboring a higher tumor mutational burden (TMB) 
and/or with a pre-existing infiltration of T cells (or other measures of “hot” tumors) are more 
likely to respond to PD-1/PD-L1 blockade (Yarchoan et al., 2017; Tumeh et al., 2014). 
Interestingly, these two general categories of biomarkers have been shown to confer independent 
predictive/prognostic information in prior analyses such that patients with low TMB but high T 
cell infiltration have a similar likelihood of response compared with patients with high TMB but 
low T cell infiltration (Galsky et al., 2017). These observations may be extended to the 
heterogeneity in responses to PD-1/PD-L1 blockade across different tumor types; for example, 
renal cancer, despite generally harboring a relatively low TMB is frequently associated with high 
T cell infiltration and is felt to be a PD-1/PD-L1 treatment responsive tumor type. Prostate 
cancer, on the other hand, is generally associated with both a low TMB and low T cell 
infiltration (Figure 4). 
Figure 4: 
Spectrum of Inflamed Tumor Microenviroment Phenotype and Tumor 
Mutational Burden Across Human Cancer Types 
 
(A) the “inflamed” tumor microenvironment phenotype and (B) tumor mutational burden across human cancer types 
(Source: Spranger et al., 2016). 
 


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Consistent with observations from other groups, Spranger et al. reported a lack of correlation 
between measures of T cell infiltration and TMB across various tumor types (Figure 4; Spranger 
et al., 2016). This critical observation indicates that the lack of spontaneous immune infiltration 
in solid tumors is unlikely to be due simply to a lack of immunogenic tumor antigens. Rather, 
Spranger et al. demonstrated that tumors lacking T cell infiltration were also lacking in 
transcriptional profiles indicating the presence of dendritic cells (DCs). Together, these findings 
suggest that (a) strategies to restore T-cell entry into non-inflamed tumors should be developed 
to further improve outcomes with PD-1/PD-L1 blockade and (b) recruitment of DCs, key to the 
development of an adaptive immune response, may be a rate limiting step in the development of 
an inflamed tumor regardless of TMB, and furthermore, an immune response may be activated if 
this is combined with agents that induce immunogenic cell death.  
2.2.1 
Background on Radiation Therapy 
External beam radiotherapy induces immunogenic cell death (Obeid et al., 2007) and production 
of maturation signals for DCs leading to improved cross presentation (Rovere et al., 1998; 
Golden et al., 2014) which are likely mechanisms for recurrently observed ‘abscopal effects,’ in 
which local radiotherapy causes regression of metastatic cancer at a distant site by itself or in 
combination with immune checkpoint blockade (Postow et al., 2012; Golden et al., 2013). The 
rationale behind combining with immunotherapy is to co-localize the immunogenic cell death 
and antigen release induced by radiation with effective antigen presenting cell (APC) processing 
and cross-presentation to cytotoxic T-cells (Gulley et al., 2005). 
Given the potentially complimentary mechanisms of action of radiation therapy and immune 
checkpoint blockade, and the potential for therapeutic synergy, several studies have explored 
combination regimens. Indeed, in the randomized trial of ipilimumab versus placebo in patients 
with mCRPC progressing despite docetaxel, patients received one fraction of bone-directed 
radiotherapy (8 grays [Gy]) prior to ipilimumab versus placebo (Kwon et al., 2014). 
Unfortunately, this study failed to demonstrate a survival benefit with ipilimumab though this 
outcome may have been attributed to a variety of factors including the patient population, use of 
cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) blockade, and/or dose of radiation 
therapy.   
Luke et al. recently reported the results of a large phase 1 study for patients with metastatic solid 
tumors progressing despite standard treatment (Luke et al., 2018). The primary aim was to 
evaluate the safety of pembrolizumab given in combination with multi-organ site ablative 
stereotactic body radiation therapy (SBRT). Two to four metastases were chosen for each patient 
and not all sites of disease were targeted with SBRT. Metastases > 65 cubic centimeters were 
partially irradiated. Pembrolizumab was initiated within 7 days after the final SBRT treatment. 
Among 73 patients included and treated with SBRT and at least 1 cycle of pembrolizumab, the 


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vast majority (94.5%) had two lesions treated with SBRT. Response Evaluation Criteria in Solid 
Tumors (RECIST) overall objective response rate was 13.5% in the 68 patients with imaging 
follow-up. Superior control of irradiated lesions was observed compared to non-irradiated target 
lesions for the 52 patients with paired data (p = 0.0005) with a mean percent tumor burden 
change -21.7% (standard deviation [SD] 24.3%) for irradiated lesions vs. 1.7% (SD 46.3%) for 
non-irradiated lesions (p = 0.0008). While abscopal response defined by 30% reduction in any 
single non-irradiated measurable lesion was present in 26.9% of patients, abscopal response was 
13.2% when defined by 30% reduction in aggregate diameter of non-irradiated measurable 
lesions. Treatment was generally well tolerated with acceptable toxicity. Expression of interferon 
(IFN)-γ–associated genes from post–SBRT tumor biopsy specimens significantly correlated with 
nonirradiated tumor response. These findings provide rationale for further studies of combination 
SBRT plus PD-1 blockade.  
The safety of SBRT has been demonstrated in the treatment of adrenal metastases, in which 
SBRT was associated with excellent local control and very low toxicity rates, providing an 
alternative to image-guided ablative procedures (Toesca et al., 2018). Furthermore, the analysis 
suggested that adrenal SBRT has minimal, if any, significant impact on renal function. Further 
studies with a larger patient population are needed to confirm these findings. 
The acute toxicities associated with the use of SBRT in patients with localized prostate cancer 
have been primarily genitourinary (GU) and gastrointestinal (GI) in nature (Syed et al., 2017; 
Haque et al., 2017; King et al., 2013). In most studies, acute toxicities were limited to Grade 1 
or 2; the incidence of ≥ Grade 3 toxicities was typically < 5%. While most late toxicities were 
Grade 1 or 2, the majority of studies have reported at least 1 ≥ Grade 3 late urinary toxicity (Syed 
et al., 2017). 
2.2.2 
Background on rhuFLT3L/CDX-301 (Celldex Therapeutics, Inc.) 
rhuFLT3L/CDX-301 is the soluble recombinant human (rhu) protein form of the FMS-related 
tyrosine kinase 3 ligand (Flt3L), a hematopoietic cytokine. CDX-301 represents the 153 N-
terminal amino acids of the human Flt3L extracellular domain after the cleavage of the N-
terminal signal peptide. 
Flt3L is a hematopoietic growth factor that plays an important role in the mobilization and 
expansion of stem cells and progenitors (Lyman and Jacobsen, 1998). In particular, it has been 
shown to facilitate the differentiation of both DCs and natural killer cells from hematopoietic 
stem cell precursors (Blom et al., 2000; Chen et al., 2005; Gilliet et al., 2002; Miller et al., 1999). 
Specifically, Flt3L directly induces the differentiation of a proportion of CD34+ CD45RA- early 
progenitor cells into pre-DCs, and results in increased numbers of activated DCs (Blom et al., 
2000; Breton et al., 2016). In healthy human volunteers it has been demonstrated that Flt3L 


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administration increases the number of DCs, as well as CD14+ monocytes (Chen et al., 2005; 
Anandasabapathy et al., 2015; Maraskovsky et al., 1996; Pulendran et al., 1997). 
Numerous pre-clinical models have shown the ability of Flt3L administration to mobilize a range 
of immune cell subsets, DCs predominant among these (Brasel et al., 1996; Fernandez et al., 
1998; Kutzler and Weiner, 2004; Miller et al., 2003). Flt3L administration has demonstrated 
antitumor activity in a variety of tumor models including melanoma, lymphoma, leukemia, 
breast, colon, prostate, lung and hepatocellular carcinoma (Averbook et al., 2002; Ciavarra et al., 
2000; Drexler et al., 1999; Esche et al., 1998; Hou et al., 2007; Wang et al., 2000; Chakravarty et 
al., 1999). Several preclinical studies have suggested combining Flt3L with radiation, checkpoint 
inhibitors, and/or poly-ICLC (polyinosinic-polycytidylic acid stabilized with polylysine and 
carboxymethylcellulose) results in significant antitumor activity and the ability to elicit an 
antitumor immune response in cold or resistant tumors. Preclinical studies have demonstrated 
improved antitumor effects and tumor-specific immunity when Flt3L is combined with 
radiotherapy. In a breast adenocarcinoma model, radiotherapy alone led to growth delay only in 
the irradiated tumors, whereas growth of distant (non-irradiated) tumors was also impaired by the 
combination of radiotherapy and Flt3L. Importantly, in this breast cancer adenocarcinoma 
model, Flt3L alone had no effect without radiotherapy and systemic tumor-specific immunity, 
known as the abscopal effect, was elicited by the combined therapy and shown to be T-cell 
mediated (Demaria et al., 2004). Additionally, radiotherapy plus Flt3L administration (500 
μg/kg/day) over 10 days reduced pulmonary metastases in a murine model of Lewis lung 
carcinoma, retarded the growth of established tumors, induced tumor-specific T- cell immunity 
and significantly improved survival in C57BI/6 mice with established footpad tumors 
(Chakravarty et al., 1999). Preclinical models have also shown that Flt3L administration can 
enhance the antitumor immunity of checkpoint inhibitors such as PD-1 and CTLA-4 antibodies 
to promote tumor regression of non-immunogenic tumors (Lynch et al., 1997). When Flt3L is 
administered with poly-ICLC, a TLR3 agonist, it results in a marked increase in activated 
intratumoral DCs and renders resistant tumors susceptible to PD-1 blockage in mouse tumor 
models (Salmon et al., 2016). 
Flt3L has been used in many early phase human clinical trials of different immunotherapeutic 
approaches—as an adjuvant or in order to mobilize DCs for collection to produce a cellular 
vaccine—in patients with colorectal cancer, non-small cell lung cancer, mesothelioma, and 
prostate cancer, among others, and demonstrated safety with minimal toxicity from Flt3L 
administration through multiple routes of administration (Fong et al., 2001; Freedman et al., 
2003; Higano et al., 2004; Morse et al., 2000).  
A study in 31 patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) 
evaluated the impact of Flt3L administration on peripheral blood DCs and post-treatment 


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changes in prostate-specific antigen (PSA; Higano et al., 2004). DCs increased markedly from 
baseline to Day 15, and the increase was consistently observed after administration of Flt3L in 
each cycle. Mean percentages of DCs in peripheral blood ranged from 1.4% to 1.9% pre-cycle 
and from 10.1% to 13.9% on Day 15, and after the first cycle, absolute counts on Day 15 were 
approximately 29-fold higher than pre-cycle levels. Natural killer (NK) cell counts (CD56+) 
were found to be elevated after cycle 1 (154% increase versus 2.8% decrease in placebo group at 
Day 22). The most frequently experienced toxicity was injection site reaction, followed by 
asthenia, rash, and diarrhea. Although median PSA levels did not vary during any cycle, a 
significant slowing in velocity of PSA was observed while patients were on-study (relative 
velocity = 0.002) compared with prestudy PSA velocity (relative velocity = 0.007). Given that 
Flt3L consistently produced an increase in DC numbers and the slowing of PSA velocity after 
administration, the authors concluded that Flt3L warrants further study for the immunotherapy of 
prostate cancer. 
Preliminary results of a single-arm study exploring CDX-301 plus SBRT for non-small cell lung 
cancer (NSCLC) were reported at the American Association for Cancer Research 2018 Annual 
Meeting (Ohri et al., 2018). In this study, SBRT was administered to a single lung lesion in 1-5 
fractions concurrently with CDX-301 (75 μg/kg subcutaneously [SC] daily x 5). Among 9 
patients enrolled at the time of the presentation, 7 had previously been treated with PD-1/PD-L1 
blockade. Intriguingly, partial responses (excluding the irradiated lesion) were seen in 3/9 
patients. Further, the regimen was demonstrated to be safe with no unexpected toxicities. 
Refer to the Investigator’s Brochure (IB; CDX-301/Recombinant Human Flt3 Ligand [rhuFlt3L] 
Investigator’s Brochure, 2018) for detailed background information on rhuFLT3L/CDX-301. 
2.2.3 
Background on Poly-ICLC (Oncovir, Inc.) 
Poly-ICLC (also known as Hiltonol®), is a stabilized double-stranded ribonucleic acid (dsRNA) 
‘host-targeted’ therapeutic viral-mimic that exhibits broad innate and adaptive immune 
enhancing effects. It was used as an interferon inducer at high doses (up to 300 μg/kg 
intravenously [IV]) in cancer trials; at lower doses (10 to 50 μg/kg) it achieves a broader host 
defense stimulation, a potent adjuvant effect, anti-proliferative and antiviral effects (Maluish et 
al., 1985). 
The possible antitumor and antiviral activity of poly-ICLC is thought to be dependent on its 
stimulation of at least 4 interrelated systems that may work independently or in concert with one 
another. These include the induction of IFN, the modulation of gene expression, a direct 
antiviral/antineoplastic effect, and a broad immune-enhancing effect. 
While initially developed as an IFN inducer, poly-ICLC also has much broader biological effects 
in humans, including specific antiviral and antitumor actions. It is, more accurately, a synthetic, 


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stabilized dsRNA therapeutic viral mimic or pathogen associated molecular pattern ‘danger 
signal’ that activates multiple elements of innate and adaptive immunity, including induction of 
interferons, cytokines, and chemokines, NK cells, T-cells, myeloid DCs via the TLR3 and 
MDA5, RIG-I, 2'5'oligoadenylate synthetase (OAS), the P68 protein kinase (PKR), and other 
dsRNA-dependent host defense systems. In the current study, we seek to specifically exploit the 
ability of poly-ICLC to induce maturation of DCs (Longhi et al., 2009) for tumor antigen 
presentation. However, it is possible that the other immunomodulatory effects of poly-ICLC will 
also result in enhanced antitumor effects with the other components of the treatment protocol.  
Poly-ICLC has a well-established history of use in the setting of clinical trials evaluating both its 
safety and efficacy in various malignancies. To date, over 85 clinical trials utilizing poly-ICLC 
have been registered at the clinicaltrials.gov website, dating back to a 1996 phase 1/2 trial of 
poly-ICLC for use in malignant gliomas.  
Refer to the IB (Poly-ICLC Investigator’s Brochure, 2018) for detailed background information 
on poly-ICLC. 
2.2.4 
Background on Nivolumab (Bristol-Myers Squibb Company) 
Nivolumab is a human immunoglobulin G4 (IgG4) monoclonal antibody that binds to the PD-1 
receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated 
inhibition of the immune response, including the antitumor immune response. Opdivo® 
(nivolumab) is approved in the United States (US) for the treatment of several cancer types, 
including unresectable or metastatic melanoma (as monotherapy or in combination with 
ipilimumab) and as monotherapy in previously-treated metastatic NSCLC, advanced renal cell 
carcinoma (RCC), relapsed or refractory classical Hodgkin lymphoma (cHL), locally advanced 
or metastatic urothelial carcinoma (UC), recurrent or metastatic squamous cell carcinoma of the 
head and neck (SCCHN), microsatellite instability-high (MSI-H) or mismatch repair deficient 
(dMMR) metastatic colorectal cancer (CRC), and hepatocellular carcinoma (HCC). In phase 1 
investigation, nivolumab did not demonstrate clinical activity in 17 participants with mCRPC. 
This is consistent with mCRPC having a low level of immune cell infiltrate and TMB. Treatment 
strategies to increase antigen presentation and immune infiltration and activation may improve 
the immune responsiveness of mCRPC to nivolumab. 
Refer to the IB (Nivolumab Investigator’s Brochure, 2018) and approved US prescribing 
information (Opdivo [nivolumab] US Prescribing Information [USPI], 2018) for detailed 
background information on nivolumab. 


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2.2.5 
Rationale for SBRT + CDX-301+ Poly-ICLC+ Nivolumab 
Immunotherapy Combination 
This study cohort is designed to explore a multi-pronged approach to overcome the low T cell 
infiltrate and TMB by promoting antitumor immunity in mCRPC by inducing immunogenic cell 
death, mobilizing and activating DCs to increase tumor antigen presentation and overcoming 
adaptive immune resistance in mCRPC (Figure 1). Specifically: 
• Radiation therapy to induce immunogenic cell death of the tumor 
• Flt3 ligand (CDX-301) to induce mobilization and activation of DCs 
• Poly-ICLC and radiation therapy to induce maturation/activation of DCs, antigen 
presenting cells that mediate tumor antigen presentation to the CD8 T cells to stimulate 
antitumor immunity 
• Anti-PD-1 monoclonal antibody (nivolumab) to overcome immune suppression of 
tumoral T cells 
 
Data derived from preclinical studies support this combination approach. Salmon and colleagues, 
in mouse melanoma models, demonstrated that a specific subset of DCs, CD103+ DCs, were the 
only APCs transporting intact antigens to lymph nodes and priming tumor-specific CD8+ T cells 
(Salmon et al., 2016). CD103+ DCs were required to promote antitumoral effects upon blockade 
of the checkpoint ligand PD-L1; however, PD-L1 inhibition only led to partial responses. 
Systemic administration of the growth factor Flt3L plus poly I:C expanded and activated 
CD103+ DC progenitors in the tumor, enhancing responses to PD-L1 blockade and protecting 
mice from tumor rechallenge. Thus, similar to the in silico work described from Spranger and 
colleagues (Spranger et al., 2016), the paucity of activated CD103+ DCs in tumors was shown in 
this model by Salmon et al. to limit immune checkpoint blockade efficacy and combined Flt3L 
and poly I:C therapy was shown to enhance tumor responses to immune checkpoint blockade. 
Further, data from clinical studies support this combination approach. The combinations of 
SBRT and anti-PD-1 therapy and SBRT and CDX-301 have been studied and/or are being 
assessed in ongoing studies in a number of tumor types, including NSCLC (Table 2). Results 
demonstrate that both combinations are well tolerated, with evidence of abscopal responses. 
Similarly, CDX-301 and poly-ICLC, in combination with CDX-1401 vaccine, have been studied 
in patients with melanoma (Table 2). Results of the study demonstrated that subjects receiving 
CDX-301 pretreatment showed substantial increases in DC, monocytes, and NK cells. Further, 
subjects receiving CDX-301 developed higher anti-vaccine antibody titers than those who did 
not receive CDX-301. The authors concluded that DC mobilization with Flt3L is safe and may 
enhance responses to DC-targeted vaccines (Bhardwaj et al., 2016). A study of nivolumab and 
poly-ICLC, in combination with CDX-1401 vaccine and decitabine, is ongoing. 


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Table 2: 
Clinical Studies Supporting the Co-administration of Components of this Study Intervention 
Study 
Disease Site 
N 
Combination 
Findings  
SBRT + Anti-PD-1 Combinations 
NCT02608385 
Advanced Cancer 
79 
SBRT + anti-PD-1 
Single arm study demonstrated treatment was well tolerated, with no radiation 
dose reductions. The overall ORR was 13.2% in the 68 patients with imaging 
follow-up. When defined as a 30.0% reduction in any single nonirradiated 
measurable lesion, the abscopal response was present in 26.9% of patients. Six 
dose-limiting toxicities defined as ≥ Grade 3, related to treatment. (Luke et al., 
2018) 
NCT02492568 
NSCLC 
64 
SBRT + anti-PD-1 
Randomized study (SBRT + anti-PD-1 vs anti-PD-1 therapy alone) demonstrated 
combination was well-tolerated and a promising strategy to augment the 
antitumor immune response with checkpoint blockade. ORR at 12 weeks was 
41% vs 19%, respectively. Toxicity ≥ Grade 3 was experienced in 17% vs 22%, 
respectively. (Theelen et al., 2018) 
NCT02684253 
SCCHN 
53 
SBRT + anti-PD-1 
Randomized study (SBRT + anti-PD-1 vs anti-PD-1 therapy alone) demonstrated 
combination was safe, but addition of SBRT to anti-PD-1 therapy failed to 
improve ORR (22.2% vs. 26.9%, respectively) or 1-year OS (53% vs 64%, 
respectively) in subjects with SCCHN. Treatment-related ≥ Grade 3 toxicities 
occurred in 11% vs. 15% of patients, respectively. (McBride et al., 2018) 
NCT02826564 
Urothelial Cancer 
23 
SBRT + anti-PD-1 
Study ongoing to assess 2 groups of 10 patients each in phase 1, with an 
additional expansion of 13 patients in phase 2, to assess the safety and response 
rate of 2 different sequences of SBRT and anti-PD-1 therapy (SBRT prior to C1 
vs prior to C3 of anti-PD-1 therapy). (Sundahl et al., 2017) 
NCT02648282 
Pancreatic Cancer 
54 
SBRT + anti-PD-1 + 
GVAX 
Single arm, open-label study ongoing to assess distant metastasis free survival, 
OS, surgical resectability, pathologic response, QoL, and toxicity. (Lee et al., 
2017) 
SBRT + CDX-301 Combinations 
NCT02839265 
NSCLC 
9 
SBRT + CDX-301 
Single arm study yielded promising early results, with frequent abscopal effects 
and a high 4-month PFS (PFS4) rate. PR of lesions not targeted with SBRT 
(“abscopal effect”) was observed in 5/9 subjects. PFS4 was achieved in 5/9 
subjects overall. PR and PFS4 were achieved in 5/7 subjects who were previously 
treated with immunotherapy and in 0/2 subjects who were not previously treated 
with immunotherapy. No dose-limiting toxicities were observed. (Ohri et al., 
2018) 


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CDX-301 + Poly-ICLC Combinations 
NCT01976585 
Non-Hodgkin 
Lymphoma 
30 
CDX-301 + Poly-ICLC + 
low dose XRT 
Study ongoing to assess 2 cohorts of 15 patients each with either previously 
untreated or relapsed/refractory iNHL to test the hypothesis that in situ 
vaccination will induce clinical remissions at distant (untreated) tumor sites. Data 
from this trial suggest that non‐responders have larger populations of exhausted T 
cells. The addition of PD‐1 reverses this exhaustion in mice, and results in 
significantly improved tumor regression. (Marron et al., 2015; Marron et al., 
2017) 
NCT02129075 
Melanoma 
60 
CDX-1401 vaccine + 
Poly-ICLC ± CDX-301 
Randomized study (CDX-301 + CDX-1401+ poly-ICLC vs CDX-1401+ poly-
ICLC) demonstrated DC mobilization with Flt3L is safe and may enhance 
responses to DC-targeted vaccines. Preliminary analyses showed substantial 
(between ~15- to ~200-fold) increases of PBMC innate immune cells (DC, 
monocytes and NK cells) in subjects with CDX-301 pretreatment vs subjects 
without CDX-301. Further, there was development of higher anti-NY-ESO-1 
antibody titers in subjects with CDX-301 pretreatment vs subjects without 
CDX-301. (Bhardwaj et al., 2016) 
Anti-PD-1 + Poly-ICLC Combinations 
NCT03358719 
Myelodysplastic 
Syndrome or AML 
18 
CDX-1401 vaccine + 
Poly-ICLC + Decitabine + 
Anti-PD-1 
Single arm, open-label study ongoing to assess safety, immune and epigenetic 
responses, response rate, OS, PFS, and time to AML transformation. 
anti-PD-1 = anti-programmed cell death 1; AML = acute myeloid leukemia; C = cycle; CDX-1401 = DEC-201/NY-ESO-1 fusion protein vaccine; 
DC  = dendritic cell; Flt3L = FMS-related tyrosine kinase 3 ligand; GVAX = GM-CSF secreting allogenic pancreatic cancer vaccine; iNHL = indolent non-
Hodgkin lymphoma; NK = natural killer; NSCLC = non-small cell lung cancer; ORR = objective response rate; OS = overall survival; PBMC = peripheral blood 
mononuclear cell; PFS = progression-free survival; PR = partial response; QoL = quality of life; SBRT  = stereotactic body radiation therapy; 
SCCHN = squamous cell carcinoma of the head and neck; XRT = radiation therapy 
 
 


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2.3 
BENEFIT/RISK ASSESSMENT 
There are data supporting the use of the individual components of the study intervention in this 
cohort (ie, SBRT, CDX-301, poly-ICLC, and nivolumab), as well as clinical studies supporting 
the co-administration of the components as previously described (Table 2); however, the 
combination has not been previously studied in animal models or in human studies. Additionally, 
each component has been studied specifically in prostate cancer and was well tolerated (Higano 
et al., 2004; Brahmer et al., 2010; Patel et al., 2011; Topalian et al., 2012; Kwon et al., 2014). 
Toxicity profiles are non-overlapping. 
Nivolumab 
Nivolumab has demonstrated durable responses exceeding 6 months as monotherapy in several 
tumor types, including NSCLC, melanoma, RCC, and SCCHN. In confirmatory trials, 
nivolumab demonstrated a statistically significant improvement in overall survival (OS) as 
compared with the current standard of care in subjects with advanced or metastatic NSCLC, 
unresectable or metastatic melanoma, advanced RCC, or SCCHN. 
For monotherapy, the safety profile is similar across tumor types. Most adverse events (AEs) 
were low-grade (Grade 1 to 2) with relatively few related high-grade (Grade 3 to 4) AEs. There 
is no pattern in the incidence, severity, or causality AEs to nivolumab dose level. Clinically 
relevant AEs typical of stimulation of the immune system were infrequent and manageable by 
delaying or stopping nivolumab treatment and timely immunosuppressive therapy or other 
supportive care (Nivolumab Investigator’s Brochure, 2018).  
In several ongoing clinical trials, the safety of nivolumab in combination with other therapeutics 
such as ipilimumab, cytotoxic chemotherapy, anti-angiogenics, and targeted therapies is being 
explored. Most studies are ongoing and, as such, the safety profile of nivolumab combinations 
continues to evolve. 
Overall, these findings support a favorable benefit-risk profile for nivolumab across various 
tumor types. More detailed information about the known and expected benefits and risks and 
reasonably expected AEs of nivolumab may be found in the prescribing information (Opdivo 
USPI, 2018). 
CDX-301 
Conclusions regarding the benefit/risk of CDX-301 should be considered in the context of a drug 
in the early stages of development, and therefore by definition, is uncertain and evolving. 
CDX-301 has been well-tolerated and demonstrates the potential for utility in a number of life-
threatening disease states by mobilizing and increasing the number of hematopoietic stem cells 
and DCs in healthy volunteers and cancer patients. Data collected to date indicate that CDX-301 
has an acceptable toxicity profile, and the overall benefit/risk remains in favor of continued 


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clinical evaluation (CDX-301/Recombinant Human Flt3 Ligand [rhuFlt3L] Investigator’s 
Brochure, 2018). 
SBRT, CDX-301, Poly-ICLC, and Nivolumab 
The safety profile of nivolumab is well characterized and manageable when administered alone 
or in combination, including regimens where it is administered in combination with additional 
immuno-oncology products. Data from studies of the individual components of the study 
intervention in this cohort, as well as clinical studies of the co-administration of the components 
of the combination, provide support for the study of this immunotherapy combination. 
Nonclinical data and clinical experience indicate the potential for improvement of response 
compared with nivolumab monotherapy. Thus, the potential benefit of this immunotherapy 
combination appears to outweigh the known risks of these agents and warrants clinical 
investigation. 
3 
OBJECTIVES AND ENDPOINTS 
The cohort-specific objectives and endpoints are listed in Table 3. 
Table 3: 
Cohort-Specific Objectives and Corresponding Endpoints 
Objectives 
Endpoints 
Primary 
 
• To determine the safety of SBRT + CDX-301 + 
poly-ICLC + nivolumab in participants with 
mCRPC. 
Refer to the core protocol. 
Secondary 
 
• To determine the ORR of SBRT + CDX-301 + 
poly-ICLC + nivolumab in participants with 
measurable mCRPC. 
• To determine the DCR ≥ 9 months of SBRT + 
CDX-301 + poly-ICLC + nivolumab in participants 
with measurable mCRPC. 
• To evaluate the rPFS of SBRT + CDX-301 + 
poly-ICLC + nivolumab in participants with 
mCRPC. 
• To estimate the OS of SBRT + CDX-301 + poly-
ICLC + nivolumab in participants with mCRPC. 
Refer to the core protocol 


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Exploratory 
 
• To evaluate the PK of CDX-301 and/or nivolumab. 
• To evaluate the immunogenicity (ADA) of 
CDX-301 and/or nivolumab. 
 
Refer to the core protocol for overall exploratory 
objective(s). 
• Sparse PK analysis. 
• Presence of ADA against CDX-301 and/or 
nivolumab. 
 
Refer to the core protocol for overall exploratory 
endpoint(s). Note that biomarker evaluation for this 
cohort will include DC mobilization and activation. 
ADA = anti-drug antibodies; DCR = disease control rate; mCRPC = metastatic castration-resistant prostate cancer; 
ORR = objective response rate; OS = overall survival; PK = pharmacokinetics; rPFS = radiographic progression-free 
survival 
 
4 
STUDY DESIGN 
4.1 
OVERALL DESIGN 
In this study intervention cohort, SBRT, CDX-301, and poly-ICLC will be administered during 
the first cycle only. Nivolumab will be administered every 4 weeks (Q4W) for up to 2 years 
(Figure 2), unless the participant: is no longer clinically benefiting (as evidenced by symptomatic 
or radiographic disease progression and/or clinical deterioration); experiences any toxicity 
meeting specified discontinuation criteria (see Section 6.6) or unacceptable toxicity in the best 
clinical discretion of the treating physician; reaches the maximum duration of study intervention; 
or withdraws consent. The preferred sequence when study intervention is administered on the 
same day (eg, Day 1) is:  SBRT followed by CDX-301; followed by poly-ICLC; followed by 
nivolumab. 
Participants will be monitored for safety and response and will be followed on-study for up to 
2.5 years from the time of the initiation of study intervention. All participants will be followed 
for safety for at least 100 days after discontinuation of study intervention. Approximately 15 
participants, including a minimum of 7 with a non-bone metastatic lesion that can be biopsied, 
will be enrolled in Stage 1. An additional approximately 15 participants, including a minimum of 
7 with a non-bone metastatic lesion, will be enrolled in Stage 2, if the cohort is expanded. 
A pre-treatment biopsy of a metastatic lesion is required for all participants, including those with 
bone only disease, if medically feasible. Participants must also provide consent for archival 
tissue from a prior biopsy or surgery for prostate cancer. An on-treatment biopsy is required, 
when medically feasible, usually after the second dose of study intervention. An optional biopsy 
may be obtained at the time of disease progression, including from participants who respond and 
subsequently progress following a response to treatment. The on-treatment biopsies should be 
taken from the same lesion as the pre-treatment biopsy when feasible. 


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4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
The scientific rationale for this combination is provided in Section 2.2.5. 
4.3 
JUSTIFICATION FOR DOSE 
The doses of CDX-301 and poly-ICLC proposed for this study have been established as being 
safe in previous and ongoing clinical trials (Section 4.3.2 and Section 4.3.3, respectively). 
Nivolumab will be administered as a fixed dose of 480 mg intravenously Q4W, an established 
dosing regimen and US Food and Drug Administration (FDA)-approved for a majority of 
approved nivolumab indications (Section 4.3.1). 
SBRT has been administered in combination with CDX-301 (Ohri et al., 2018) or anti-PD-1 
therapy (Luke et al, 2018; McBride et al., 2018; Theelen et al., 2018) and has been well tolerated 
to date without a significant safety signal. All agents are being administered at the recommended 
dose determined in prior studies in cancer patients and based on the safety profiles of the 
individual components, as well as the combinations of components that have been co-
administered (Table 2), toxicities are not expected to be overlapping when administered in 
combination Therefore, the combination of SBRT, CDX-301, poly-ICLC, and nivolumab at the 
doses proposed is warranted for the evaluation of safety and efficacy in this population. 
4.3.1 
Rationale for Nivolumab Dose and Schedule 
In the US, single-agent nivolumab was approved in 2014 at a dose of 3 mg/kg every 2 weeks 
(Q2W). Subsequently, population pharmacokinetics (PPK) and exposure response analyses were 
performed to support use of flat dosing regimens (ie, nivolumab 240 mg Q2W, 360 mg every 
3 weeks [Q3W], and 480 mg Q4W) in participants with cancer. A flat dose of nivolumab 240 mg 
Q2W was selected since it is identical to a dose of 3 mg/kg for participants weighing 80 kg, the 
observed median body weight in nivolumab-treated cancer patients, while the nivolumab 360 mg 
Q3W and 480 mg Q4W regimens allow flexibility of dosing with less frequent visits and in 
combination with other agents using alternative dosing schedules to Q2W, such as ipilimumab. 
Using a PPK model, the overall distributions of nivolumab exposures (average steady-state 
concentration [Cavgss], minimum steady-state plasma concentration [Cminss], maximum steady-
state plasma concentration [Cmaxss], and trough concentration after the first dose [Cmin1]) are 
comparable after treatment with either nivolumab 3 mg/kg or 240 mg Q2W (Nivolumab 
Investigator’s Brochure, 2018).  
Following nivolumab 480 mg Q4W, Cavgss are expected to be similar to those following 
nivolumab 3 mg/kg or 240 mg Q2W, while Cminss are predicted to be ~16% lower and are not 
considered to be clinically relevant. Cmaxss are predicted to be approximately ~43% greater 
relative to that following nivolumab 3 mg/kg Q2W dosing. However, the range of nivolumab 
exposures (median and 90% prediction intervals) following administration of 240 mg flat Q2W, 


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360 mg Q3W, and 480 mg Q4W regimens across the 35 to 160 kg weight range are predicted to 
be maintained well below the corresponding exposures observed with the well tolerated 10 
mg/kg nivolumab Q2W dosing regimen (Nivolumab Investigator’s Brochure, 2018).  
The 240 mg Q2W dose was approved in the USPI in September 2016 for use in metastatic 
melanoma, NSCLC, and RCC indications. In March 2018, the 480 mg Q4W dose was approved 
in the USPI for use in metastatic melanoma, NSCLC, RCC, cHL, SCCHN, UC, and HCC 
indications (Opdivo USPI, 2018).  
4.3.2 
Rationale for CDX-301 Dose and Schedule 
CDX-301 will be administered as a subcutaneous (SC) injection at a dose of 75 μg/kg daily (QD) 
for 5 days, the highest dose studied using the 5-day schedule in the phase 1 clinical study in 
healthy volunteers (CDX301-02), which assessed the safety, tolerability, pharmacokinetic and 
pharmacodynamic profile of daily SC injections of CDX-301 at multiple dose levels 
(1 μg/kg/day to 75 μg/kg/day) and durations (5 to 10 days; CDX-301/Recombinant Human Flt3 
Ligand [rhuFlt3L] Investigator’s Brochure, 2018). Notably, this is also the same dose and 
schedule utilized in combination with SBRT reported by Ohri et al. (Ohri et al., 2018). 
Results of CDX301-02 showed that CDX-301 exhibited a typical absorption profile for SC 
administration with mean times to maximum serum concentration (Tmax) of 19.8 hours at 
75 μg/kg/day for 5 days. Mean maximum serum concentrations (Cmax) increased linearly with 
dose across the dose range when administered over 5 days and was 667.4 ng/mL following 
75 μg/kg/day for 5 days. Similarly, area under the curve (AUC) values increased across the entire 
range in a dose-independent manner. The half-life was 28 hours at 75 μg/kg/day for 5 days. 
Treatment-related toxicity was infrequent and reported only at the 25 and 75 μg/kg/day dose 
levels (number of subjects at these dose levels was 9 and 15, respectively). One Grade 3 event, 
community acquired pneumonia, was considered treatment-related. However, no additional 
infections, dose-limiting toxicities, serious AEs (SAEs), or Grade 3 toxicities were reported. All 
other treatment-related AEs were Grade 1; these included lymphadenopathy in 6 subjects and 
single cases of diarrhea, injection site erythema, folliculitis and dry mouth. There were no 
reported clinically significant laboratory toxicities attributed to CDX-301. 
As of October 2018, of 89 subjects (cancer patients, healthy volunteers, and stem cell donors) 
tested from 5 studies (Celldex-sponsored and investigator-initiated), 1 patient (receiving 
CDX-301 25 μg/kg/day for 10 days) has tested positive for the presence of specific 
anti-CDX-301 antibodies. Subsequent characterization of this patient’s serum has shown the 
response to be non-neutralizing. 
Dosing with 75 μg/kg daily for 5 days was sufficient to increase CD34+ stem cells and DCs by at 
least 10-fold over baseline values. 


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Refer to the IB (CDX-301/Recombinant Human Flt3 Ligand [rhuFlt3L] Investigator’s Brochure, 
2018) for an additional description of overall safety, immunogenicity, and efficacy in humans. 
4.3.3 
Rationale for Poly-ICLC Dose and Schedule 
Poly-ICLC will be administered at a dose of 1 mg intramuscularly (IM) twice weekly for 
3 weeks. 
Poly-ICLC has a well-established history of use in the setting of clinical trials evaluating both its 
safety and efficacy in various malignancies. To date, over 85 clinical trials utilizing poly-ICLC 
have been registered at clinicaltrials.gov dating back to a 1996 phase 1/2 trial of poly-ICLC for 
use in malignant gliomas.  
In its earliest use in human trials, poly-ICLC was originally employed as an inducer of IFN. 
Several studies were conducted, and although interest in the efficacy of poly-ICLC mediated 
through the mechanism of IFN-induction would subsequently diminish, it was these studies 
which provided the foundation for safety profiling and dosage which would be employed in later 
trials evaluating the efficacy of poly-ICLC via different mechanisms. 
Early phase 1 trials were conducted to determine the maximum tolerated dose (MTD) under the 
assumption that this was also the most effective dose. It was found that the MTD was 12 mg/m2 
in cancer patients who were not terminally ill (Levine et al., 1979). Phase 1 and 2 clinical trials 
were subsequently conducted in patients with many types of cancers including leukemia, 
lymphoma, brain tumors, myeloma, juvenile laryngeal papillomatosis, renal cell carcinoma, 
breast cancer, ovarian cancer, and melanoma (Droller, 1987; Hawkins et al., 1985; Krown et al., 
1985; Stevenson et al., 1985; Butowski et al., 2009; Salazar et al., 1996). In most of these early 
trials, about 6 mg/m2 poly-ICLC was generally used intravenously. Fever, often with 
temperatures greater than 40°C, was a universal AE in the trials and was the primary dose-
limiting factor. Other common AEs reported in these trials included nausea, vomiting, 
hypotension, thrombocytopenia, leukopenia, arthralgia, myalgia, and fatigue. 
For patients receiving intramuscular or other non-intravenous routes of administration common 
side effects include discomfort at injection site, with transient discomfort and occasionally 
transient mild to moderate grade 1 or 2 erythematous skin reaction (Caskey et al., 2011). 
Alongside transient fever, patients occasionally experienced other flu-like symptoms 
approximately 8 to 12 hours after doses of 10 to 50 μg/kg IM, which may last for another 12 
hours, but responds readily to acetaminophen or aspirin. These symptoms include mild myalgias, 
arthralgias, sometimes nausea, and malaise can be present during this period of time. This flu-
like syndrome typically diminishes markedly after the first 2-3 poly-ICLC treatments.  
Most recent and ongoing trials are using set dosing of 1-2 mg through IM, intratumoral or 
subcutaneous administration, well below the MTD of 12 mg/m2 when given IV. More extensive 


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information regarding poly-ICLC—including pre-clinical pharmacology, toxicology and 
pharmacokinetics (PK), as well as multiple clinical studies—may be found in the poly-ICLC IB 
(Poly-ICLC Investigator’s Brochure, 2018). 
4.3.4 
Rationale for Stereotactic Body Radiation Therapy Dose and 
Schedule 
The optimal dose of radiation to administered in combination with immune checkpoint blockade 
has not been defined. As noted in the Background section, safety and intriguing activity have 
been demonstrated with SBRT in standard treatment doses in combination with PD-1 blockade. 
Therefore, this cohort will use a similar approach to that previously described (Luke et al., 2018) 
and employ standard treatment doses of SBRT. SBRT offers ablative dose-escalation to tumor 
targets with simultaneous dose-restraint to normal tissues, which is not possible using 
conventional radiotherapy. SBRT utilizes high-precision radiotherapy delivery machines, 
integrated image guidance systems, advanced planning software, and a high level of professional 
and technical expertise. Unlike conventional radiation therapy, which is delivered in multiple 
fractions of 1.8-2 Gy, SBRT is delivered in 1 to 5 fractions of typically 8 Gy or greater. 
Participants will undergo SBRT to up to 4 sites of metastases, as long as at least 1 metastasis 
remains outside the irradiated target. SBRT will be delivered in 3 to 5 fractions. SBRT 5 fraction 
regimens should deliver a total dose of 30 to 50 Gy. SBRT 3 fraction regimens should deliver a 
total dose of 24-45 Gy. Dose selection will depend on adequate sparing of normal tissue with 
maximization of dose delivered to metastatic sites. A biologically equivalent dose (BED) to 
tumor of > 100 Gy (for an alpha–beta ratio of 3) is a goal but is not required. Dose constraints 
per NRG (RTOG) B001 are recommended. Suggested regimens based on site of metastasis are 
defined as follows: 
• 45 Gy in 3 fractions for peripheral lung, liver, and abdominal/pelvic; 
• 50 Gy in 5 fractions for central lung and mediastinal/cervical; 
• 30 Gy in 3 fractions for osseous and spinal/paraspinal 
 
The optimal sequence of radiation and immune checkpoint blockade has not been established. 
Modeling studies suggest that immune checkpoint (Kosinsky et al., 2018) blockade prior to, or 
concurrent with, radiation maximizes the potential synergistic effects of these modalities. Given 
these considerations, as well as emerging data in model systems and patients also supporting a 
concurrent rather than sequential approach (Azad et al., 2017; Aliru et al., 2018; Pinnamanerni et 
al., 2017), this cohort will employ concurrent treatment. 
4.4 
TREATMENT BEYOND DISEASE PROGRESSION 
Refer to the core protocol. 


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4.5 
END OF STUDY DEFINITION 
Refer to the core protocol for the end of study definition. 
The total length of this study cohort, from screening of the first participant to the end of the 
cohort, is expected to be approximately 3 years, 9 months. 
5 
STUDY POPULATION 
Prospective requests for approval of protocol deviations to recruitment and enrollment criteria, 
also known as waivers or exemptions, is not allowed. 
5.1 
INCLUSION CRITERIA 
Participants are eligible to be included in the study only if all the following criteria apply: 
5.1.1 
Common Inclusion Criteria 
1. Participant must be ≥ 18 years of age at the time the informed consent is signed. 
2. Participants must agree to use an adequate method of contraception as outlined in 
Appendix 6 of the core protocol starting with the first dose of study intervention and for 
at least 7 months after the last dose of study intervention and refrain from donating sperm 
during this period. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for 
the participant. 
3. Participants must be able and willing to comply with the study visit schedule and study 
procedures. 
4. Histologically documented adenocarcinoma of the prostate. 
5. Metastatic castration resistant prostate cancer with castrate-level testosterone 
(< 50 ng/dL) at screening. 
6. Have received and progressed on prior secondary androgen receptor signaling inhibitor 
therapy (eg, abiraterone, enzalutamide, apalutamide). Progression is defined by one or 
more of the following 3 criteria: 
a. Prostate-specific antigen (PSA) ≥ 1.0 ng/mL and rising PSA by at least 2 
consecutive measurements a minimum of 1-week apart. 
b. Soft tissue progression as defined by Response Evaluation Criteria in Solid 
Tumors (RECIST) version 1.1 (Eisenhauer et al., 2009). 
c. Bone disease progression as defined by 2 new bone lesions (as per Prostate 
Cancer Clinical Trials Working Group 3 [PCWG3; Scher et al., 2016]).  
7. Have measurable disease or non-measurable disease based on PCWG3-modified 
RECIST 1.1. 
8. Provide fresh pre-treatment core needle or incisional biopsy of a metastatic tumor lesion 
not previously irradiated. Fine needle aspiration is not acceptable. 


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a. Additionally, if a pre-treatment biopsy is not medically feasible for participants 
with bone only disease, formalin-fixed paraffin-embedded (FFPE) tumor 
specimen in a paraffin block (preferred) or at least 10 slides containing unstained, 
freshly cut, serial sections must be provided. 
b. For all participants, in addition to fresh pre-treatment biopsy, consent for archival 
tissue is required. 
9. Must be willing to undergo tumor biopsy(ies) on treatment, if medically feasible. 
10. Participants must discontinue antiandrogen therapy (ie, bicalutamide, flutamide, 
nilutamide) at least 4-6 weeks prior to registration with no evidence of PSA decline after 
washout. 
a. Bicalutamide: Washout period at least 6 weeks 
b. Flutamide and nilutamide: Washout period at least 4 weeks 
11. Participants must discontinue therapies for mCRPC for 5 half-lives or 28 days, whichever 
is shorter. 
a. Participants will remain on gonadotropin-releasing hormone (GnRH) agents 
throughout this study. 
b. Prior chemotherapy is allowed if no progression of disease on chemotherapy as 
defined by PCWG3-modified RECIST 1.1.  
c. Prior treatment with sipuleucel-T, radium-223, or poly adenosine diphosphate 
(ADP)-ribose polymerase (PARP) inhibitor (eg, olaparib) is allowed. 
d. Tissue biopsy may be performed during washout period. 
12. Participants with prior or concurrent malignancies are permitted if any one of the 
following applies: 
a. Previously treated malignancy for which all treatment of that malignancy was 
completed at least 2 years before enrollment and no evidence of disease exists, or 
b. With agreement from the Medical Monitor and Principal Investigator (PI), 
participants who have a concurrent malignancy that is clinically stable and does 
not require tumor-directed treatment are eligible to participate if the risk of the 
prior malignancy interfering with either safety or efficacy endpoints is very low, 
or 
c. With agreement from the Medical Monitor and PI, other malignancies may be 
permitted if the risk of the prior malignancy interfering with either safety or 
efficacy end points is very low. 
13. Have a performance status of 0 or 1 according to the Eastern Cooperative Oncology 
Group (ECOG) scale. 
14. Demonstrate adequate organ function on screening laboratory tests performed within 
14 days of treatment initiation and as evidenced by: 
a. Hemoglobin ≥ 9.0 g/dL or ≥ 5.6 mmol/L without transfusion or erythropoietin 
(EPO) dependency (within ≤ 7 days of assessment) 


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b. Absolute neutrophil count ≥ 1,500/mm3 without growth factor support (within 
< 28 days of assessment) 
c. Platelet count ≥ 100,000/mm3 
d. Estimated glomerular filtration rate (GFR) ≥ 45 mL/min using the Cockcroft-
Gault formula 
e. Serum total bilirubin < 1.5 x upper limit of normal (ULN) or ≤ 2.0 x ULN for 
participants with liver metastases 
i. Participants with Gilbert's syndrome must have ≤ 3 x ULN and no liver 
lesions 
f. Aspartate aminotransferase (AST) (SGOT) and alanine aminotransferase (ALT) 
(SGPT) ≤ 3.0 x ULN or ≤ 5.0 x ULN for participants with liver metastases. 
g. Albumin ≥ 2.5 mg/dL. 
h. International normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 x ULN 
unless participant is receiving anticoagulant therapy, as long as PT is within 
therapeutic range of intended use of anticoagulants. 
i. Activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN unless participant is 
receiving anticoagulant therapy, as long as PTT is within therapeutic range of 
intended use of anticoagulants. 
15. Willing and capable of giving signed informed consent as described in Appendix 1 of the 
core protocol, which includes compliance with the requirements and restrictions listed in 
the informed consent form (ICF) and in this protocol. 
 
5.1.2 
Combination-specific Inclusion Criteria 
1. Participants must have at least one lesion amenable to SBRT as determined by the 
treating radiation oncologist. Participants must have lesions in organs/locations that can 
be treated with at least 30 Gy. 
 
5.2 
EXCLUSION CRITERIA 
Participants are excluded from the study if any of the following criteria apply: 
5.2.1 
Common Exclusion Criteria 
1. Is currently participating and receiving study therapy or has participated in a study of an 
investigational agent and received study therapy or used an investigational device within 
4 weeks of the first dose of treatment. 
a. Recent or concurrent non-therapeutic investigational agents that are not 
anticipated to interfere with study intervention, such as certain investigational 
imaging tracers, may be permitted with written agreement from the Medical 
Monitor. 


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2. Has a diagnosis of immunodeficiency or conditions that need systemic corticosteroid 
replacement therapy > 10 mg/day prednisone (or equivalent) or other immunosuppressive 
medications within 28 days prior to the first dose of study intervention. Inhaled steroids 
are permitted if necessary. 
3. Has any active known or suspected autoimmune disease. Participants with vitiligo, type I 
diabetes mellitus, controlled autoimmune hypothyroidism, psoriasis not requiring 
systemic treatment, or other conditions under control are permitted to enroll. 
Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement 
therapy ≤ 10 mg of prednisone/day for adrenal or pituitary insufficiency, etc.) is not 
considered a form of systemic treatment.  
4. Has a known history of active TB (Bacillus Tuberculosis). 
5. Has known history of, or any evidence of active, non-infectious pneumonitis. 
6. Has an active infection requiring systemic therapy. 
7. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the participant’s participation 
for the full duration of the trial, or is not in the best interest of the participant to 
participate, in the opinion of the treating Investigator. 
8. Has known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the trial. 
9. Is expecting to father children within the projected duration of the trial, starting with the 
pre-screening or screening visit through 7 months after the last dose of study intervention. 
10. Known history of testing positive for human immunodeficiency virus (HIV), known 
acquired immunodeficiency syndrome (AIDS), or any positive test for hepatitis B or 
hepatitis C virus representing acute or chronic disease. 
11. Has received a live vaccine within 30 days of planned start of study intervention. 
Note:  Seasonal influenza vaccines for injection are generally inactivated flu vaccines and 
are allowed; however intranasal influenza vaccines (eg, Flu-Mist®) are live attenuated 
vaccines, and are not allowed. 
12. Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis. Participants with previously treated brain metastases may participate provided 
they are stable (without evidence of progression by imaging for at least 4 weeks prior to 
the first dose of study intervention and any neurologic symptoms have returned to 
baseline), have no evidence of new or enlarging brain metastases, and are not using 
steroids for at least 7 days prior to study intervention. This exception does not include 
carcinomatous meningitis which is excluded regardless of clinical stability. 
13. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study 
Day 1 or who has not recovered (ie, ≤ Grade 1 or at baseline) from AEs due to agents 
administered more than 4 weeks earlier. 
a. Participants with controlled autoimmune disease as described in exclusion 
criterion #3 are permitted to enroll. 


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14. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 
2 weeks prior to study Day 1 or who has not recovered (ie, ≤ Grade 1 or at baseline) from 
AEs due to a previously administered agent. 
a. Note:  Participants with ≤ Grade 2 neuropathy and/or hearing loss are an 
exception to this criterion and may qualify for the study. 
b. Note:  If a participant received major surgery, he must have recovered adequately 
from the toxicity and/or complications from the intervention prior to starting 
therapy.   
15. History of allergy to any of the study intervention components. 
 
5.2.2 
Combination-specific Exclusion Criteria 
1. Has had prior therapy with any anti-PD-1 or anti-PD-L1 antibody (prior therapy with an 
anti-CTLA-4 antibody is permitted). 
2. Has a history of acute myeloid leukemia (AML). 
 
5.3 
LIFESTYLE CONSIDERATIONS 
No restrictions are required. 
5.4 
SCREEN FAILURES 
Refer to the core protocol. 
6 
STUDY INTERVENTION 
Study intervention is defined as any investigational intervention(s), marketed product(s) or 
placebo intended to be administered to a study participant according to the study protocol. 
6.1 
STUDY INTERVENTION(S) ADMINISTERED 
The study interventions to be administered in this study are summarized in Table 4. 
Table 4: 
Study Intervention 
Study 
Intervention 
Name 
Dosage Formulation 
Unit Dose 
Strength(s) 
Dosage 
Level(s) 
Route of 
Administration 
Sourcing 
SBRT 
30-50 Gy in 1-5 doses. Radiation will start on Day 1 or 2 
CDX-301 
Sterile solution for single 
use. Single-use vial 
containing CDX-301 in 
buffered solution 
composed of sodium 
phosphate and sodium 
chloride, with a pH of 7.0 
2.5 mg/mL 
75 µg/kg 
SC 
Celldex 
Therapeutics 


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Study 
Intervention 
Name 
Dosage Formulation 
Unit Dose 
Strength(s) 
Dosage 
Level(s) 
Route of 
Administration 
Sourcing 
Poly-ICLC 
Single-dose vial containing 
opalescent white 
suspension poly-IC, poly-
L-lysine, and sodium 
carboyxmethylcelluose in 
0.9% sodium chloride, 
adjusted to a pH of 6 – 8 
with sodium hydroxide 
2 mg/mL 
1 mg 
IM 
Oncovir, Inc. 
Nivolumab 
Aqueous solution 
10 mg/mL 
480 mg 
IV infusion 
Bristol-Myers 
Squibb 
Gy = gray; IV = intravenous(ly); IM = intramuscular(ly); SBRT = stereotactic body radiation therapy; 
SC = subcutaneous(ly) 
 
SBRT, CDX-301, and poly-ICLC will be administered during the first cycle only. The preferred 
sequence when study intervention is administered on the same day (eg, Day 1) is:  SBRT 
followed by CDX-301; followed by poly-ICLC; followed by nivolumab: 
• Radiation therapy will be administered at 30 – 50 Gy in 1 – 5 doses, starting on Day 1 
or 2 of Cycle 1.   
• CDX-301 will be administered at a dose of 75 µg/kg SC QD x 5 days (Days 1 – 5 [ie, 
Monday – Friday] of Cycle 1). 
• Poly-ICLC will be administered at a dose of 1 mg intramuscularly (IM) twice weekly for 
3 weeks (ie, Days 1, 5, 8, 12, 15, and 19) starting on Day 1 of Cycle 1. 
• Nivolumab will be administered at a dose of 480 mg IV over approximately 30 minutes 
Q4W, starting on Day 1 of Cycle 1, for up to 2 years, unless the participant: is no longer 
clinically benefiting (as evidenced by symptomatic or radiographic disease progression 
and/or clinical deterioration); experiences any toxicity meeting specified discontinuation 
criteria (see Section 6.6) or unacceptable toxicity in the best clinical discretion of the 
treating physician; reaches the maximum duration of study intervention; or withdraws 
consent. A cycle is defined as 4 calendar weeks. 
 
Administration of study intervention will be performed in a monitored setting in which there is 
immediate access to trained personnel and adequate equipment and medicine to manage 
potentially serious reactions. 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
Refer to the core protocol for general guidance on handling, storage, and accountability. 


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CDX-301 should be stored in a secure, locked area at 2-8°C and protected from light. CDX-301 
should not be frozen, and CDX-301 vials should not be shaken. CDX-301 liquid should be 
withdrawn from vial gently, avoiding foaming and excess shearing. 
Poly-ICLC should be stored refrigerated at 2-8°C but should not be frozen. 
Nivolumab must be stored at 2°-8°C and protected from light and freezing.  
The instructions for reconstitution and administration of the study intervention are described in 
the Pharmacy Manual(s). 
6.3 
RANDOMIZATION AND BLINDING 
This is not a randomized study, and study intervention will be administered in an open-label 
fashion. 
6.4 
STUDY INTERVENTION COMPLIANCE 
Study intervention will be administered by authorized site personnel and tracked using drug 
accountability records. No additional measures of compliance will be instituted. 
6.5 
CONCOMITANT THERAPY 
Refer to the core protocol. 
6.5.1 
Permitted Therapy 
Refer to the core protocol. 
6.5.2 
Prohibited Therapy 
Refer to the core protocol. 
6.6 
DOSE MODIFICATIONS 
6.6.1 
Dose Modifications for the Combination of Nivolumab, CDX-301, 
and Poly-ICLC 
There will be no dose escalation or dose reductions in this study. 
The initial 6 participants enrolled in this cohort will be observed for the occurrence of any of the 
AEs described in Table 5 that are observed from the beginning of treatment through completion 
of the first cycle of nivolumab (ie, 4 weeks) and that are considered by the Investigator to be 
possibly, probably, or definitely related to nivolumab, CDX-301, poly-ICLC, or the 
immunotherapy combination, unless there is a clear alternative explanation.  
After enrollment of the initial 6 participants, enrollment will pause until all 6 participants have 
completed Cycle 1 (ie, 4 weeks). During the pause, new participants may be consented and 
screened, but not initiated on study intervention. If 1 or no AEs described in Table 5 are 
observed in the first 6 participants, enrollment will continue as planned until a total of 


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approximately 15 participants are enrolled. If AEs described in Table 5 are observed in 2 or more 
of the first 6 participants, enrollment into the cohort will be suspended, and the Safety 
Assessment Committee (refer to Section 9.5.1 of the core protocol) will be convened to review 
the available data and provide a recommendation, which may include, but is not limited to, 
modification or discontinuation of the cohort. 
Participants who experience any AE described in Table 5 will be discontinued from all study 
intervention and should continue follow-up assessments as outlined in the SOA (Section 1.3). 
Grade 3 and 4 toxicities are observed in all trials of nivolumab in multiple tumor types. As such 
toxicities are anticipated; however, given the unique nature of this protocol, monitoring for AEs 
described in Table 5 will continue throughout the study. 
The Investigator may attribute each AE to the combination or any individual component of the 
study intervention. Study participants may not have any dose escalations or reductions of 
nivolumab, CDX-301, or poly-ICLC in this study. If an Investigator believes a toxicity is 
uniquely related to one agent, then appropriate documentation is required regarding the drug to 
which the Investigator is attributing the AE. The following retreatment requirements will apply: 
• During Cycle 1 if, in the opinion of the Investigator, the toxicity is related to CDX-301 
and/or poly-ICLC, then CDX-301 and/or poly-ICLC drugs should be withheld (eg, 
skipped) according to recommended dose modifications.  
• Cycle 2, in which only nivolumab is administered, may commence as scheduled provided 
the participant meets the retreatment criteria for nivolumab. 
o Starting with Cycle 2 if toxicity does not resolve or the criteria for resuming study 
intervention are not met within 8 weeks after the last dose of nivolumab, the 
participant must be discontinued from nivolumab therapy, unless written approval 
to restart therapy is provided by the Medical Monitor. 
 
The anticipated important safety risks associated with the administration of SBRT, nivolumab, 
CDX-301, and/or poly-ICLC, as well as the measures to be taken, are outlined in the following 
sections. Guidance with respect to the individual agents is provided in Section 6.6.3, 
Section  6.6.4, and Section 6.6.5, respectively. Refer to the USPI for nivolumab (Opdivo USPI, 
2018)  to the Investigator’s Brochures for nivolumab, CDX-301, and poly-ICLC for complete 
summaries of safety information. 


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Table 5: 
Toxicity Criteria Requiring Permanent Treatment Discontinuation 
Participants should be monitored for the occurrence of any of the following AEs that are considered by the 
Investigator to be possibly, probably, or definitely related to nivolumab, CDX-301, poly-ICLC, or the 
immunotherapy combination. Treatment with all study intervention should be permanently discontinued for the 
following: 
• 
Grade 4 non-hematological toxicity (not laboratory) 
• 
Grade 4 hematologic toxicity lasting ≥ 7 days 
• 
Grade 3 thrombocytopenia in the presence of clinically significant active bleeding (eg, requiring 
transfusion or hospitalization) 
• 
Any non-hematologic toxicity ≥ Grade 3 in severity, with the following exceptions: 
o 
Grade 3 fatigue lasting ≤ 3 days 
o 
Grade 3 nausea, vomiting, or diarrhea lasting ≤ 3 days 
o 
Grade 3 rash without use of corticosteroids or anti-inflammatory agents per standard of care 
o 
Grade 4 fever 
o 
Grade 4 flu-like symptoms lasting ≥ 48 hours 
• 
Any new Grade 3 or Grade 4 non-hematologic laboratory abnormality, if 
o 
the abnormality leads to hospitalization, or 
o 
the abnormality persists for > 1 week and is believed to be clinically significant. For example, 
exceptions would include asymptomatic pancreatitis. 
• 
Febrile neutropenia Grade 3 or Grade 4 
• 
Any elevated AST or ALT laboratory value that is ≥ 3 × ULN and an elevated total bilirubin lab value that 
is ≥ 2 × ULN and an alkaline phosphatase lab value that is < 2 × ULN, in which no alternative reasons can 
be found to explain the combination of increased AST/ALT and total bilirubin, such as viral hepatitis A, B 
or C, preexisting or acute liver diseases, pre-existing known liver metastases, or another drug capable of 
causing the observed injury 
• 
Grade 5 toxicity 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; ULN = upper limit of normal 
 
6.6.1.1 
Potential for Overlapping Toxicities with the Combination of 
SBRT, Nivolumab, CDX-301, and Poly-ICLC 
In general, the toxicities associated with the monotherapy administration of nivolumab, 
CDX-301, and poly-ICLC are not expected to be overlapping when administered in combination. 
The safety data for nivolumab are described in the USPI (Opdivo USPI, 2018). Nivolumab 
therapy is associated with immune-mediated adverse reactions, which can be severe and fatal in 
some cases. With appropriate medical therapy, immune-related adverse reactions resolved in 
most cases. Immune-mediated adverse reactions may involve any organ system; however, the 
most common severe immune-mediated adverse reactions are enterocolitis, endocrinopathies, 
hepatitis, dermatitis (including toxic epidermal necrolysis [TEN] and Stevens-Johnson syndrome 
[SJS]), and neuropathy. The safety profile of nivolumab combination therapy varies with the 
agent combined with nivolumab but is generally consistent with the safety profiles observed with 
either agent alone and, in some cases, both frequency and severity of AEs were greater than that 
observed with either agent alone. 


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In human studies to date, Flt3L has been well tolerated, with many AEs attributable to patients’ 
underlying malignancy or other compounds/therapies being administered concomitantly, and no 
dose reductions of Flt3L for toxicity were reported in any of these trials. Erythematous nodules 
of up to 1 to 2 cm at the skin injection sites lasting several days were the only manifestation of 
toxicity in most patients. One patient who injected doses into the same area daily for 3 
consecutive days developed diffuse erythema of the upper arm and adenopathy in the axilla that 
resolved spontaneously. Arthralgias, myalgias, and fever were not reported, nor were liver 
function test abnormalities. With CDX-301 administration, specifically, leukocytosis, especially 
monocytosis, is expected during administration. Injection site reactions have been reported and 
are generally mild to moderate, but occasionally severe. Lymphadenopathy occurred in < 20% of 
study participants, was not associated with AEs, and resolved after discontinuation of treatment 
(CDX-301/Recombinant Human Flt3 Ligand [rhuFlt3L] Investigator’s Brochure, 2018). 
In most of the early trials of poly-ICLC, about 6 mg/m2 poly-ICLC was generally administered 
IV. Fever, often with temperatures greater than 40°C, was a universal AE in these trials and was 
the primary dose-limiting factor. Other common AEs reported in these trials included nausea, 
vomiting, hypotension, thrombocytopenia, leukopenia, arthralgia, myalgia, and fatigue (Poly-
ICLC Investigator’s Brochure, 2018). 
SBRT has been associated with mild to moderate GU and GI acute and late toxicities in patients 
with localized prostate cancer (Syed et al., 2017; Haque et al., 2017; King et al., 2013). The 
incidence of ≥ Grade 3 acute toxicities was typically < 5%, while at least 1 late urinary ≥ Grade 3 
late toxicity has been reported in the majority of studies (Syed et al., 2017). 
6.6.1.2 
Dose Modifications and Toxicity Management for Adverse Events 
Associated with the Combination of Nivolumab, CDX-301, and 
Poly-ICLC 
Immuno-oncology agents are associated with AEs that can differ in severity and duration from 
AEs caused by other therapeutic classes. Early recognition and management of AEs associated 
with immuno-oncology agents may mitigate severe toxicity. Management algorithms (Appendix 
B-1) have been developed to assist Investigators in assessing and managing the following groups 
of drug-related AEs: 
• Immune-mediated colitis 
• Immune-mediated nephritis and renal dysfunction 
• Immune-mediated pneumonitis 
• Immune-mediated hepatitis 


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• Immune-mediated endocrinopathies (hypophysitis, adrenal insufficiency, hypothyroidism 
and hyperthyroidism, Type 1 diabetes mellitus) 
• Immune-mediated skin adverse reactions 
• Immune-mediated encephalitis 
 
6.6.1.3 
Dose Modifications and Toxicity Management for 
Infusion/Injection-related Reactions Associated with the 
Administration of CDX-301, Poly-ICLC, and/or Nivolumab 
Interrupt or slow the rate of infusion in participants with mild or moderate infusion reactions. 
Discontinue the immunotherapy combination in participants with severe or life-threatening 
infusion reactions. 
All Grade 3 or 4 infusion reactions must be reported within 24 hours to the study Medical 
Monitor and reported as an SAE if it meets the criteria. Infusion reactions should be graded as 
described in Section 10.5.3 of the core protocol. 
Dose modification and toxicity management guidelines for infusion/injection-related reactions 
are provided in Table 6.  
 


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Table 6:  
Dose Modification and Toxicity Management Guidelines for Infusion/Injection-related Reactions Associated 
with the Administration of CDX-301, Poly-ICLC, and/or Nivolumab 
Grade 
(NCI CTCAE v 5.0) 
 
Treatment 
Premedication at 
Subsequent Dosing 
Grade 1 
Mild reaction; infusion interruption not indicated; 
intervention not indicated 
Increase monitoring of vital signs as medically indicated until the participant is 
deemed medically stable in the opinion of the Investigator 
None 
Grade 2 
Requires therapy or infusion interruption but responds 
promptly to symptomatic treatment (eg, antihistamines, 
NSAIDs, narcotics, IV fluids); prophylactic medications 
indicated for ≤ 24 hours 
Stop Infusion 
Additional appropriate medical therapy may include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDs 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically indicated until the participant is 
deemed medically stable in the opinion of the Investigator 
If symptoms resolve within 1 hour of stopping drug infusion, the infusion may 
be restarted at 50% of the original infusion rate (eg, from 100 mL/h to 50 mL/h). 
Otherwise dosing will be held until symptoms resolve and the participant should 
be premedicated for the next scheduled dose 
Participants who develop Grade 2 toxicity despite adequate premedication 
should be permanently discontinued from further study intervention 
Participant may be premedicated 
according to local treatment 
guidelines 
Grades 3 or 4 
Grade 3: 
Prolonged (ie, not rapidly responsive to symptomatic 
medication and/or brief interruption of infusion); 
recurrence of symptoms following initial improvement; 
hospitalization indicated for other clinical sequelae (eg, 
renal impairment, pulmonary infiltrates) 
Grade 4: 
Life-threatening; pressor or ventilatory support indicated 
Stop Infusion 
Administer urgent medical therapy as appropriate/clinically indicated 
Increase monitoring of vital signs as medically indicated until the participant is 
deemed medically stable in the opinion of the Investigator 
Hospitalization may be indicated 
**In cases of anaphylaxis, epinephrine should be used immediately 
Participant is permanently discontinued from further study intervention 
No subsequent dosing 
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of drug administration. 
For further information, please refer to the Common Terminology Criteria for Adverse Events v5.0 (CTCAE) at http://ctep.cancer.gov 
CTCAE = Common Terminology Criteria for Adverse Events; NCI = National Cancer Institute; NSAIDs = nonsteroidal anti-inflammatory drugs; IV = intravenous 


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6.6.1.4 
Dose Delays and Interruptions of Nivolumab, CDX-301, and Poly-
ICLC 
Dose delays and interruptions are permitted for toxicity reasons (see Section 6.6.3 and 
Section 6.6.4). 
The Investigator may attribute each AE to the combination or to either individual intervention. 
• If, in the opinion of the Investigator, the toxicity is related to the combination of the 
agents, then all drugs should be held according to recommended dose modifications. 
• If the toxicity is considered clearly related to 1 agent, but not the others, then the other 
agents can continue unless toxicity related to that study intervention would warrant a 
dose delay. 
 
6.6.2 
Dose Modification for SBRT 
The short duration time of this treatment may not require adjustments and may limit the need for 
dose modification, but due to organ sites involved with the treatment, it may be necessary to 
modify the dosage to address acute AEs related to SBRT. Dose modification of SBRT will be 
managed according to institutional guidelines. 
Appropriate documentation is required regarding the component of treatment to which the 
Investigator is attributing the AE. If toxicity does not resolve or the criteria for resuming study 
intervention are not met within 8 weeks after the last dose, the participant must be discontinued 
from the combination therapy. 
Dose delays and interruptions for reasons other than toxicity, such as surgical procedures, may 
be allowed with Medical Monitor approval. The acceptable length of interruption will depend on 
agreement between Investigator and Medical Monitor. 
6.6.3 
Dose Modifications for Nivolumab 
This study will include set dosing for nivolumab (480 mg Q4W). Dose escalation or reduction of 
nivolumab will not be allowed. If toxicity does not resolve or the criteria for resuming study 
intervention are not met within 8 weeks from the last dose, the participant must discontinue 
nivolumab therapy, unless written approval to restart therapy is provided by the Medical 
Monitor. 
Specific anticipated or potential toxicities associated with the administration of nivolumab, as 
well as the measures to be taken to avoid or minimize such toxicity in this trial, are described in 
Table 7. 
AEs associated with nivolumab exposure may represent an immunologic etiology. These 
immune-related adverse events (irAEs) may occur shortly after the first dose or several months 


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after the last dose of treatment and may affect more than one body system simultaneously. 
Therefore, early recognition and initiation of treatment is critical to reduce complications. Based 
on existing clinical study data, drug-related AEs have included pulmonary toxicity, renal toxicity 
(including acute renal failure), endocrine abnormalities, gastrointestinal toxicity, dermatologic 
toxicity (including rash), and hepatotoxicity. For nivolumab monotherapy, as well as when 
administered in combination, the majority of these AEs have been managed successfully with 
supportive care and, in more severe cases, a combination of dose delay, permanent 
discontinuation, and/or use of corticosteroids or hormone replacement therapy 
(endocrinopathies). For suspected irAEs, ensure adequate evaluation to confirm etiology or 
exclude other causes. Additional procedures or tests such as bronchoscopy, endoscopy, and skin 
biopsy may be included as part of the evaluation. 
Dose modification and toxicity management guidelines for irAEs associated with nivolumab are 
provided in Table 7. 
Table 7: 
Dose Modification and Toxicity Management Guidelines for Adverse Events 
Associated with Nivolumab 
Adverse Reaction 
Severitya 
Dose Modifications 
Colitis 
Grade 2 diarrhea or colitis 
Withhold doseb 
Grade 3 diarrhea or colitis 
Withhold doseb 
Grade 4 diarrhea or colitis 
Permanently discontinue 
Pneumonitis 
Grade 2 pneumonitis 
Withhold doseb 
Grade 3 or 4 pneumonitis 
Permanently discontinue 
Hepatitis/non-HCC 
Aspartate aminotransferase (AST) or alanine 
aminotransferase (ALT) more than 3 and up 
to 5 times the upper limit of normal (ULN) 
or total bilirubin more than 1.5 and up to 3 
times the ULN 
Withhold doseb 
AST or ALT more than 5 times the ULN or 
total bilirubin more than 3 times the ULN 
Permanently discontinue 
Hepatitis/HCC 
• If AST/ALT is within normal limits at 
baseline and increases to more than 3 and 
up to 5 times the ULN 
• If AST/ALT is more than 1 and up to 3 
times ULN at baseline and increases to 
more than 5 and up to 10 times the ULN 
• If AST/ALT is more than 3 and up to 5 
times ULN at baseline and increases to 
more than 8 and up to 10 times the ULN 
Withhold dosec 
If AST or ALT increases to more than 10 
times the ULN or total bilirubin increases to 
more than 3 times the ULN 
Permanently discontinue 
Hypophysitis 
Grade 2 or 3 hypophysitis 
Withhold doseb 
Grade 4 hypophysitis 
Permanently discontinue 


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Adverse Reaction 
Severitya 
Dose Modifications 
Adrenal insufficiency 
Grade 2 adrenal insufficiency 
Withhold doseb 
Grade 3 or 4 adrenal insufficiency 
Permanently discontinue 
Type 1 diabetes mellitus 
Grade 3 hyperglycemia 
Withhold doseb 
Grade 4 hyperglycemia 
Permanently discontinue 
Nephritis and renal 
dysfunction 
Serum creatinine more than 1.5 and up to 6 
times the ULN 
Withhold doseb 
Serum creatinine more than 6 times the 
ULN 
Permanently discontinue 
Skin 
Grade 3 rash or suspected Stevens-Johnson 
syndrome (SJS) or toxic epidermal 
necrolysis (TEN) 
Withhold doseb 
Grade 4 rash or confirmed SJS or TEN 
Permanently discontinue 
Encephalitis 
New onset moderate or severe neurologic 
signs or symptoms 
Withhold doseb 
Immune-mediated encephalitis 
Permanently discontinue 
Other 
Other Grade 3 adverse reaction 
 
• First occurrence 
Withhold doseb 
• Recurrence of the same Grade 3 adverse 
reaction 
Permanently discontinue 
Life-threatening or Grade 4 adverse reaction 
Permanently discontinue 
Grade 3 myocarditis 
Permanently discontinue 
Requirement for 10 mg per day or greater 
prednisone or equivalent for more than 12 
weeks 
Permanently discontinue 
Persistent Grade 2 or 3 adverse reactions 
lasting 12 weeks or longer 
Permanently discontinue 
Source: Opdivo USPI, 2018  
ALT = alanine aminotransferase; AST = aspartate aminotransferase; HCC = hepatocellular carcinoma; 
SJS = Stevens-Johnson syndrome; TEN = toxic epidermal necrolysis; ULN = upper limit of normal 
a Guidelines based on toxicity graded per National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI CTCAE), where applicable. 
b Resume treatment when adverse reaction improves to Grade 0 or 1. 
c Resume treatment when AST/ALT return(s) to baseline. 
 
6.6.4 
Dose Modifications for CDX-301 
Dose escalation or reduction of CDX-301 will not be allowed in this study. Doses of CDX-301 
should be withheld (eg, skipped) for toxicity attributed to CDX-301 (Table 8), and doses that are 
skipped should not be made up. Toxicities attributed to CDX-301 that require dose delays greater 
than 6 weeks will require Medical Monitor approval for the participant to restart treatment. 
Leukocytosis, especially monocytosis, is expected during administration of CDX-301 and may 
be particularly pronounced when combined with other hematopoietic growth factors. 


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Hematological parameters, including white blood cell (WBC) and differential, should be 
monitored in participants receiving CDX-301. 
Specific anticipated or potential toxicities associated with the administration of CDX-301, as 
well as the measures to be taken to avoid or minimize such toxicity in this trial, are described in 
Table 8. 
Table 8: 
Dose Modification and Toxicity Management Guidelines for Adverse Events 
Associated with CDX-301 
Adverse Reaction 
Severity 
Dose Modifications 
Leukocytosis 
WBC count > 50,000 cells/mm3 
Withhold (skip) dosea 
Injection site reaction 
Grade 1 or 2 
No action required regarding CDX-301 
dose. 
Pre-medication with diphenhydramine 
may be considered for participants who 
experience local reactions after treatment 
with CDX-301  
Grade 3 
Permanently discontinue 
Grade 4 
Permanently discontinue 
Other ≥ Grade 2 adverse 
reaction 
• First occurrence 
Withhold (skip) dosea 
• Recurrence of the same 
≥ Grade 2 adverse reaction 
Permanently discontinue 
WBC = white blood cell 
a Resume treatment at the same CDX-301 dose level when adverse reaction returns to baseline, except for instances 
where the potential recurrence of the event poses an undue risk for the participant. Doses that are withheld (eg, 
skipped) should not be made up. 
 
6.6.5 
Dose Modifications for Poly-ICLC 
Dose escalation or reduction of poly-ICLC will not be allowed in this study. Poly-ICLC may be 
withheld (eg, skipped) if the participant experiences ≥ Grade 2 AEs considered at least possibly 
related to poly-ICLC. Doses of poly-ICLC that are skipped should not be made up. Toxicities 
attributed to poly-ICLC that require dose delays greater than 6 weeks will require Medical 
Monitor approval for the participant to restart treatment. 
7 
DISCONTINUATIONS OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1 
DISCONTINUATION OF STUDY INTERVENTION 
Refer to the core protocol. 
In addition to the discontinuation criteria described in the core protocol, refer to Table 5, 
Section 6.6.3, Section 6.6.4, and Section 6.6.5 for management of toxicities requiring permanent 
discontinuation of nivolumab, CDX-301, and/or poly-ICLC. 


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7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM 
STUDY 
Refer to the core protocol. 
7.3 
LOST TO FOLLOW-UP 
Refer to the core protocol. 
8 
STUDY ASSESSMENTS AND PROCEDURES 
Refer to the core protocol. Any combination-specific supplementary information or 
modifications from the core protocol are described in the following sections. 
In this study cohort, the time between nivolumab doses must not be less than 24 days. 
8.1 
EFFICACY ASSESSMENTS 
Refer to the core protocol. 
8.1.1 
Laboratory Assessments of Clinical Activity 
Samples for the laboratory assessments of clinical activity and hormone levels in Table 9 will be 
sent to the study site’s local laboratory for analysis: 
Table 9: 
Laboratory Tests Sent to the Study Site’s Local Laboratory for Analysis of 
Disease-related Endpoints 
Profile 
Laboratory Test 
Clinical activity 
PSA 
Hormone levels 
testosterone 
PSA = prostate-specific antigen 
 
 
8.2 
SAFETY ASSESSMENTS 
Refer to the core protocol. 
8.2.1 
Clinical Safety Laboratory Assessments 
8.2.1.1 
Local Laboratory Assessments 
Samples for the laboratory tests in Table 10 will be sent to the study site’s local laboratory for 
analysis: 


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Table 10: 
Laboratory Tests Sent to the Study Site’s Local Laboratory for Analysis of 
Safety 
Profile 
Laboratory Test 
Hematology 
RBC count 
hemoglobin 
hematocrit 
WBC count with automated differential (neutrophils, eosinophils, basophils, 
monocytes, lymphocytes, other cells) 
platelet count 
manual differential, if clinically indicated 
Clinical Chemistry 
(Serum or Plasma) 
sodium 
potassium 
chloride 
bicarbonate 
glucose 
BUN or urea 
creatinine 
total protein 
albumin 
calcium 
total bilirubin 
alkaline phosphatase 
ALT 
AST 
LDH 
TSH (T3 and FT4 should be checked if TSH is outside the normal range) 
coagulation assessments (PT, PTT, INR)a 
Urinalysis 
 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; 
INR = international normalized ratio; LDH = lactate dehydrogenase; PT = prothrombin time; PTT = partial 
thromboplastin time; RBC = red blood cell; TSH = thyroid stimulating hormone; WBC = white blood cell 
a Coagulation assessment not required during treatment phase unless indicated 
 
 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
Refer to the core protocol for the SAE and AE collection periods and for details regarding safety 
reporting. 
8.3.4 
Regulatory Reporting Requirements for SAEs 
Refer to the core protocol for the regulatory reporting requirements for SAEs. 
For this cohort, the Parker Institute for Cancer Immunotherapy Pharmacovigilance Group will 
report SAEs to regulatory authorities, the overall PI, Bristol-Myers Squibb, Celldex 
Therapeutics, Oncovir, Inc., and the Institutional Review Board/Independent Ethics Committee 
(IRB/IEC), as appropriate. The process for such reporting, including contact information and 


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specific instructions for reporting to each of these organizations, is described in the Safety 
Monitoring Plan. 
8.3.7 
Adverse Events of Special Interest 
There are no identified adverse events of special interest for this immunotherapy combination. 
8.4 
TREATMENT OF OVERDOSE 
Refer to the core protocol. 
8.5 
PHARMACOKINETICS 
Sparse PK blood sampling will be collected according to the SOA to assess the PK of CDX-301 
and/or nivolumab. 
PK profiles for CDX-301 and/or nivolumab may be performed using a validated assay method 
under the supervision of the Sponsor’s designee. 
8.6 
ANTI-DRUG ANTIBODIES 
Immunogenicity samples will be collected according to the SOA to enable evaluation of anti-
drug antibodies (ADA) to either CDX-301 and/or nivolumab. Additionally, blood samples 
should also be collected at the final visit from participants who discontinued study intervention 
or were withdrawn from the study. These samples may be tested by the Sponsor's designee. 
The detection and characterization of antibodies to CDX-301 and/or nivolumab may be 
performed using a validated assay method under the supervision of the Sponsor’s designee. 
8.7 
BIOMARKERS 
Refer to the core protocol. 
Immune profiling may be performed, including evaluation of dendritic cell numbers and 
activation using flow cytometry or other assays. 
8.8 
MEDICAL RESOURCE UTILIZATION AND HEALTH 
ECONOMICS 
Refer to the core protocol. 
9 
STATISTICAL CONSIDERATIONS 
Refer to the core protocol. 
9.5.1 
Interim Safety Monitoring 
Refer to the core protocol for details related to the Safety Assessment Committee (SAC), the 
committee charged with safety review for this study. 


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With the inclusion of a safety period for the first 6 participant for this study cohort (see 
Section 6.6.1), the likelihood of proceeding to full enrollment decreases as the risk of toxicity 
from an AE described in Table 5 increases, as demonstrated in Table 11. 
Table 11: 
Probability of Proceeding to Full Enrollment 
True Risk of Toxicity 
0.10 
0.20 
0.30 
0.40 
0.50 
0.60 
Probability of Full Enrollment 
0.89 
0.66 
0.42 
0.23 
0.11 
0.04 
Assumes P(X≤1) where X is a binomial random variable with sample size n = 6 and p = true risk of toxicity. 
 
Table 12 shows the width of 95% confidence intervals calculated for possible observed rates of 
AEs described in Table 5 within the study. 
Table 12: 
Incidence with 95% Confidence Intervals of Possible Observed Adverse 
Events Described in Table 5 
Number of Participants with Adverse 
Eventsa/Number of Participants 
Incidence of  
Adverse Eventsa 
95% Confidence Intervalb 
0/6 
0 
[0, 0.39] 
1/6 
0.17 
[0.03, 0.56] 
2/6 
0.33 
[0.10, 0.70] 
3/6 
0.50 
[0.19, 0.81] 
a Adverse events described in Table 5  
b Wilson method for computing confidence interval 
 
 


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10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
Refer to the core protocol for the following appendices: 
Appendix 1: Regulatory, Ethical and Study Oversight Considerations 
Appendix 2: Eastern Cooperative Oncology Group (ECOG) Performance Status 
Appendix 3: RECIST Criteria (Version 1.1) with Modifications as Recommended by 
PCWG3 
Appendix 4: Clinical Laboratory Tests 
Appendix 5: Adverse Events: Definitions and Procedures for Recording, Evaluating, Follow-
up, and Reporting 
Appendix 6: Contraceptive Guidance and Collection of Pregnancy Information 
Appendix 7: Genetics 


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10.1 
APPENDIX B-1: MANAGEMENT ALGORITHMS 
Management algorithms have been developed to provide guidance for Investigators in assessing 
and managing immune-mediated events in participants receiving nivolumab. Section 6.6.3 
describes the criteria for dose delay and discontinuation to be followed for nivolumab in this 
cohort. These algorithms are intended to provide clinical recommendations. In cases in which the 
modification criteria in Section 6.6.3 and the algorithms differ, the criteria in Section 6.6.3 
should take precedence.  
The management algorithms are provided for the following groups of drug-related AEs: 
• Immune-mediated gastrointestinal adverse events (diarrhea, colitis) 
• Immune-mediated renal adverse events (nephritis and renal dysfunction) 
• Immune-mediated pulmonary adverse events (pneumonitis) 
• Immune-mediated hepatic adverse events (hepatitis) 
• Immune-mediated endocrinopathy adverse events (hypophysitis, adrenal insufficiency, 
hypothyroidism and hyperthyroidism, Type 1 diabetes mellitus) 
• Immune-mediated skin adverse events 
• Immune-mediated neurologic adverse events (encephalitis) 
 
 


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10.2 
APPENDIX B-2: LISTS OF TERMINOLOGY AND 
ABBREVIATIONS 
10.2.1 
List of Terminology 
Terminology 
Description 
Cohort 
A group of participants receiving the same immunotherapy 
combination. 
Cohort appendix 
A document that guides the treatment of participants in a given 
cohort. The cohort appendices are identified using a letter 
designation (eg, Appendix Cohort B).  
Core protocol 
The master document that provides the elements common 
across the study and among all cohorts, unless otherwise 
specified. 
Immunotherapy combination 
Two or more study interventions administered to a cohort of 
participants. 
 
10.2.2 
List of Abbreviations 
Abbreviation 
Definition 
ADA 
anti-drug antibody(ies) 
ADP 
adenosine diphosphate 
AE(s) 
adverse event(s) 
AIDS 
acquired immunodeficiency syndrome 
ALT 
alanine aminotransferase 
AML 
acute myeloid leukemia 
APC(s) 
antigen-presenting cell(s) 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
BED 
biologically equivalent dose 
BUN 
blood urea nitrogen 
C 
cycle 
Cavgss 
average steady-state concentration 
CDX-1401 
DEC-201/NY-ESO-1 fusion protein vaccine 
cfDNA 
cell-free deoxyribonucleic acid 
cHL 
classical Hodgkin lymphoma 
Cmax 
maximum observed drug concentration 
Cmaxss 
maximum steady-state plasma concentration 
Cminss 
minimum steady-state plasma concentration 
Cmin1 
trough concentration after the first dose 


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Abbreviation 
Definition 
CNS 
central nervous system 
CRC 
colorectal cancer 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA-4 
cytotoxic T-lymphocyte-associated protein 4 
DC(s) 
dendritic cell(s) 
DCR 
disease control rate 
dMMR 
mismatch repair deficient 
dsRNA 
double-stranded ribonucleic acid 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EOT 
end of treatment 
EPO 
erythropoietin 
FDA 
Food and Drug Administration 
FFPE 
formalin-fixed paraffin-embedded 
Flt3L 
FMS-related tyrosine kinase 3 ligand 
GCP 
Good Clinical Practice 
GFR 
glomerular filtration rate 
GI 
gastrointestinal 
GnRH 
gonadotropin-releasing hormone 
GU 
genitourinary 
GVAX 
GM-CSF secreting allogenic pancreatic cancer vaccine 
Gy 
gray 
HCC 
hepatocellular carcinoma 
HIV 
human immunodeficiency virus 
I/E 
inclusion/exclusion 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
IFN 
interferon 
IgG4 
immunoglobulin G4 
IM 
intramuscular(ly) 
iNHL 
indolent non-Hodgkin lymphoma 
INR 
international normalized ratio 
irAE(s) 
immune-related AE(s) 
IRB/IEC 
Institutional Review Board/Independent Ethics Committee 
IV 
intravenous(ly) 
LDH 
lactate dehydrogenase 
mAb 
monoclonal antibody 
mCRPC 
metastatic castration-resistant prostate cancer 


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Abbreviation 
Definition 
MSI-H 
microsatellite instability-high 
MTD 
maximum tolerated dose 
NCI 
National Cancer Institute 
NK 
natural killer 
nmCRPC 
nonmetastatic castration-resistant prostate cancer 
NSAIDs 
nonsteroidal anti-inflammatory drugs 
NSCLC 
non–small-cell lung cancer 
OAS 
2'5'oligoadenylate synthetase 
ORR 
objective response rate 
OS 
overall survival 
PARP 
poly ADP ribose polymerase 
PBMC(s) 
peripheral blood mononuclear cell(s) 
PCWG3 
Prostate Cancer Clinical Trials Working Group 3 
PD 
progressive disease 
PD-1 
programmed cell death 1 
PD-L1 
programed cell death ligand 1 
PFS 
progression-free survival 
PI 
Principal Investigator 
PK 
pharmacokinetics 
PKR 
P68 protein kinase 
poly-ICLC 
polyinosinic-polycytidylic acid stabilized with polylysine and 
carboxymethylcellulose 
PORTER 
Prostate Researching Translational Endpoints Correlated to Response 
PPK 
population pharmacokinetics 
PR 
partial response 
PSA 
prostate-specific antigen 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
Q2W 
every 2 weeks 
Q3M 
every 3 months 
Q3W 
every 3 weeks 
Q4W 
every 4 weeks 
QD 
daily 
QoL 
quality of life 
RBC 
red blood cell 
RCC 
renal cell carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
rhu 
recombinant human 


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Abbreviation 
Definition 
rhuFlt3L 
recombinant human Flt3 ligand 
rPFS 
radiographic progression-free survival 
S 
screening 
SAC 
Safety Assessment Committee 
SAE(s) 
serious adverse event(s) 
SBRT 
stereotactic body radiation therapy 
SC 
subcutaneous(ly) 
SCCHN 
squamous cell carcinoma of the head and neck 
SD 
standard deviation 
SGOT 
serum glutamic-oxaloacetic transaminase 
SGPT 
serum glutamic-pyruvic transaminase 
SJS 
Stevens-Johnson syndrome 
SOA 
Schedule of Activities 
TB 
tuberculosis 
TEN 
toxic epidermal necrolysis 
Tmax 
mean time to maximum serum concentration 
TMB 
tumor mutational burden 
TSH 
thyroid stimulating hormone 
UC 
urothelial carcinoma 
ULN 
upper limit of normal 
US 
United States 
USPI 
US prescribing information 
WBC 
white blood cell 
XRT 
radiation therapy 
 


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10.3 
APPENDIX B-3: APPENDIX COHORT B AMENDMENT 
HISTORY 
 
DOCUMENT HISTORY 
Documents 
Date of Issue 
Amendment 1 
24 Jan 2019 
Original Appendix Cohort B 
11 Dec 2018 
 
 
 


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11 
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Salmon H, Idoyaga J, Rahman A, Leboeuf M, Remark R, Jordan S, et al. Expansion and 
activation of CD103(+) dendritic cell progenitors at the tumor site enhances tumor responses to 
therapeutic PD-L1 and BRAF inhibition. Immunity 2016;44(4):924–38.  
Scher HI, Morris MJ, Stadler WM, Higano C, Basch E, Fizazi K, et al. Trial design and 
objectives for castration-resistant prostate cancer: Updated recommendations from the Prostate 
Cancer Clinical Trials Working Group 3. J Clin Oncol 2016;34(12):1402–18. 
Spranger S, Luke JJ, Bao R, Zha Y, Hernandez KM, Li Y, et al. Density of immunogenic 
antigens does not explain the presence or absence of the T-cell-inflamed tumor 
microenvironment in melanoma. Proc Natl Acad Sci USA 2016;113(48):E7759–68.  
Stevenson HC, Abrams PG, Schoenberger CS, Smalley RB, Herberman RB, Foon KA. A phase I 
evaluation of poly(I,C)-LC in cancer patients. J Biol Response Mod 1985;4(6):650–5. 
Sundahl N, De Wolf K, Rottey S, Decaestecker K, De Maeseneer D, Meireson A, et al. A phase 
I/II trial of fixed-dose stereotactic body radiotherapy with sequential or concurrent 
pembrolizumab in metastatic urothelial carcinoma: Evaluation of safety and clinical and 
immunologic response. J Transl Med 2017;15(1):150. 
Syed YA, Patel-Yadav AK, Rivers C, Singh AK. Stereotactic radiotherapy for prostate cancer: A 
review and future directions. World J Clin Oncol 2017;8(5):389–97. 
Theelen W, Lalezari F, de Vries J, De Langen J, Aerts J, Monkhorst K, et al. Randomized phase 
II study of pembrolizumab after stereotactic body radiotherapy (SBRT) versus pembrolizumab 
alone in patients with advanced non-small cell lung cancer: The PEMBRO-RT study. Presented 
at: American Society of Clinical Oncology; June 1-5, 2018; Chicago, IL. Available at: 
https://meetinglibrary.asco.org/record/160784/abstract. Accessed on 18-Oct-2018. 
Toesca DAS, Koong AJ, van Eyben R, Koong AC, Chang E. Stereotactic body radiation therapy 
for adrenal gland metastases: Outcomes and toxicity. Adv Radiat Oncol [Internet] [cited 2018 
Oct 9];Available from: https://www.advancesradonc.org/article/S2452-1094(18)30084-8/pdf. 
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2012;366(26):2443–54. 
Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJM, Robert L, et al. PD-1 blockade 
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Prot_000.pdf: 
PORTER Appendix Cohort A - Parker Institute for Cancer Immunotherapy 
Protocol PICI0033 Appendix Amendment 1, Version 2.0 
1
 
 
Protocol Title:  A Multicenter, Open-Label, Exploratory Platform Study to Evaluate Biomarkers 
and Immunotherapy Combinations for the Treatment of Patients with Metastatic Castration-
resistant Prostate Cancer 
Appendix Cohort A 
Protocol Number:  PICI0033 
Amendment Number:  Not applicable 
Compound Number:  NKTR-214, Nivolumab 
Short Title:  Platform Study for Prostate Researching Translational Endpoints Correlated to 
Response to Inform Use of Novel Combinations (PORTER) 
Sponsor Name and Legal Registered Address:   
Parker Institute for Cancer Immunotherapy 
1 Letterman Drive 
Suite D3500 
San Francisco, CA 94129 
Tel: 415-985-7311 
Fax: 415-872-5305 
Regulatory Agency Identifying Number(s):  
IND NUMBER: 139269 
EudraCT NUMBER:  Not applicable 
Approval Date:  Final Protocol: 07 December 2018 
 
Amendment 1: 24 January 2019 
 
CONFIDENTIAL 
This document and its contents are the property of and confidential to Parker Institute for Cancer 
Immunotherapy. Any unauthorized copying or use of this document is prohibited. 
 
 




PORTER Appendix Cohort A - Parker Institute for Cancer Immunotherapy 
Protocol PICI0033 Appendix Amendment 1, Version 2.0 
3
INVESTIGATOR PROTOCOL AGREEMENT PAGE 
I agree: 
• 
To assume responsibility for the proper conduct of the study at this site. 
• 
To conduct the study in compliance with this protocol, any future amendments, and with 
any other study conduct procedures provided by Parker Institute for Cancer 
Immunotherapy. 
• 
Not to implement any changes to the protocol without written agreement from Parker 
Institute for Cancer Immunotherapy and prior review and written approval from the 
Institutional Review Board or Independent Ethics Committee except where necessary to 
eliminate an immediate hazard to participants. 
• 
That I am thoroughly familiar with the appropriate use of the study drug(s), as described 
in this cohort appendix and any other information provided by Parker Institute for Cancer 
Immunotherapy including, but not limited to, the current Investigator’s Brochure(s). 
• 
That I am aware of, and will comply with, the International Conference on 
Harmonisation for Good Clinical Practice (GCP) and all applicable regulatory 
requirements. 
• 
To ensure that all persons assisting me with the study are adequately informed about the 
study drugs, the Parker Institute for Cancer Immunotherapy study protocol, and of their 
study-related duties and functions as described in the protocol. 
• 
That I agree that persons debarred from conducting or working on clinical studies by any 
court or regulatory agency will not be allowed to conduct or work on studies for the 
Parker Institute for Cancer Immunotherapy or for a partnership in which the Parker 
Institute for Cancer Immunotherapy is involved, and that I will immediately disclose in 
writing to the Parker Institute for Cancer Immunotherapy if any person who is involved 
in the study is debarred, or if any proceeding for debarment is pending. 
 
 
Signature: 
 
 
Date: 
 
 
Name 
(print): 
 
  
 
Site 
Number: 
Principal Investigator 
 
___________ 
  
 
 
  
 


PORTER Appendix Cohort A - Parker Institute for Cancer Immunotherapy 
Protocol PICI0033 Appendix Amendment 1, Version 2.0 
4
Amendment(s) to Appendix Cohort A 
Text revisions resulting from the amendment(s) are incorporated in the synopsis and body of the 
Appendix Cohort Amendment. Major changes to the appendix cohort are summarized below. 
Key Revisions in Amendment 1 (24 January 2019) 
Section # and Name 
Description of Change 
Eligibility Criteria 
5.1 Inclusion Criteria 
Combined previous inclusion criteria #6 and #10 into a single inclusion 
criterion #6. 
Study Design 
1.3 Schema, Figure 1 
Modified to improve identification of key research procedure time points. 
Study Intervention 
6.6.1 Dose Modifications for the 
Combination of Nivolumab and 
NKTR-214 
Added text related to written approval from the Medical Monitor to 
clarify that participants with toxicity that does not resolve or met 
retreatment criteria within 6 weeks of the last dose, must be discontinued 
from the combination therapy, unless written approval to restart therapy 
is provided by the Medical Monitor. 
6.6.2 Dose Modifications Nivolumab 
Added text related to written approval from the Medical Monitor to 
clarify that participants with toxicity that does not resolve or met 
retreatment criteria within 6 weeks of the last dose, must discontinue 
study intervention, unless written approval to restart therapy is provided 
by the Medical Monitor. 
Clarification of Document 
General Revisions 
Document updated to address minor typographical errors and editorial 
changes for clarity. 


PORTER Appendix Cohort A - Parker Institute for Cancer Immunotherapy 
Protocol PICI0033 Appendix Amendment 1, Version 2.0 
5
TABLE OF CONTENTS 
 
TABLE OF CONTENTS .................................................................................................................5 
LIST OF TABLES ...........................................................................................................................8 
LIST OF FIGURES .........................................................................................................................8 
1 
PROTOCOL SUMMARY ...................................................................................................9 
1.1 
SYNOPSIS ...............................................................................................................9 
1.2 
SCHEMA ...............................................................................................................10 
1.3 
SCHEDULE OF ACTIVITIES..............................................................................12 
2 
INTRODUCTION .............................................................................................................17 
2.1 
STUDY RATIONALE ..........................................................................................17 
2.2 
BACKGROUND ...................................................................................................17 
2.2.1 
Background on Nivolumab (Bristol-Myers Squibb Company) ...............18 
2.2.2 
Background on NKTR-214 (Nektar Therapeutics) .................................18 
2.2.3 
Rationale for NKRT-214 + Nivolumab Immunotherapy Combination ..20 
2.3 
BENEFIT/RISK ASSESSMENT ..........................................................................24 
3 
OBJECTIVES AND ENDPOINTS ...................................................................................25 
4 
STUDY DESIGN...............................................................................................................26 
4.1 
OVERALL DESIGN .............................................................................................26 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN ...........................................27 
4.3 
JUSTIFICATION FOR DOSE ..............................................................................27 
4.3.1 
Rationale for Nivolumab Dose and Schedule .........................................27 
4.3.1.1 
Nivolumab 360 mg Q3W Dosing Regimen ..........................28 
4.3.2 
Rationale for NKTR-214 Dose and Schedule .........................................28 
4.4 
TREATMENT BEYOND DISEASE PROGRESSION ........................................29 
4.5 
END OF STUDY DEFINITION ...........................................................................29 
5 
STUDY POPULATION ....................................................................................................29 
5.1 
INCLUSION CRITERIA.......................................................................................29 
5.1.1 
Common Inclusion Criteria .....................................................................29 
5.1.2 
Combination-specific Inclusion Criteria .................................................32 
5.2 
EXCLUSION CRITERIA .....................................................................................32 
5.2.1 
Common Exclusion Criteria ....................................................................32 


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Protocol PICI0033 Appendix Amendment 1, Version 2.0 
6
5.2.2 
Combination-specific Exclusion Criteria ................................................33 
5.3 
LIFESTYLE CONSIDERATIONS .......................................................................34 
5.3.1 
Meals and Dietary Restrictions ...............................................................34 
5.3.2 
Activity ....................................................................................................34 
5.4 
SCREEN FAILURES ............................................................................................34 
6 
STUDY INTERVENTION ................................................................................................34 
6.1 
STUDY INTERVENTION(S) ADMINISTERED ................................................34 
6.1.1 
Hydration Guidelines for NKTR-214 ......................................................35 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY ......................36 
6.3 
RANDOMIZATION AND BLINDING................................................................36 
6.4 
STUDY INTERVENTION COMPLIANCE .........................................................36 
6.5 
CONCOMITANT THERAPY...............................................................................36 
6.5.1 
Permitted Therapy ...................................................................................36 
6.5.2 
Prohibited Therapy ..................................................................................36 
6.6 
DOSE MODIFICATIONs .....................................................................................36 
6.6.1 
Dose Modifications for the Combination of Nivolumab and NKTR-214
 .................................................................................................................36 
6.6.1.1 
Potential for Overlapping Toxicities with Nivolumab and 
NKTR-214 .............................................................................38 
6.6.1.2 
Dose Modifications and Toxicity Management for Adverse 
Events Associated with Nivolumab and NKTR-214 .............39 
6.6.1.3 
Dose Modifications and Toxicity Management for Infusion-
related Reactions Associated with the Administration of 
NKTR-214 and/or Nivolumab ...............................................40 
6.6.1.4 
Dose Delays and Interruptions of NKTR-214 + Nivolumab 
Combination Immunotherapy ................................................42 
6.6.2 
Dose Modifications for Nivolumab .........................................................42 
6.6.3 
Dose Modifications for NKTR-214 .........................................................44 
6.6.3.1 
Permanent Treatment Discontinuation Criteria .....................46 
7 
DISCONTINUATIONS OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL..........................................................................48 
7.1 
DISCONTINUATION OF STUDY INTERVENTION ........................................48 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM STUDY ........48 
7.3 
LOST TO FOLLOW-UP .......................................................................................48 
8 
STUDY ASSESSMENTS AND PROCEDURES .............................................................48 


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Protocol PICI0033 Appendix Amendment 1, Version 2.0 
7
8.1 
EFFICACY ASSESSMENTS ...............................................................................48 
8.1.1 
Laboratory Assessments of Clinical Activity ..........................................48 
8.2 
SAFETY ASSESSMENTS ....................................................................................49 
8.2.1 
Increased Monitoring and Vital Sign Guidelines for Infusion-related 
Reaction or Hypotension .........................................................................49 
8.2.2 
Echocardiograms .....................................................................................49 
8.2.3 
Clinical Safety Laboratory Assessments .................................................49 
8.2.3.1 
Local Laboratory Assessments ..............................................49 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ..............................50 
8.3.4 
Regulatory Reporting Requirements for SAEs .......................................50 
8.3.7 
Adverse Events of Special Interest ..........................................................51 
8.4 
TREATMENT OF OVERDOSE ...........................................................................51 
8.5 
PHARMACOKINETICS .......................................................................................51 
8.6 
ANTI-DRUG ANTIBODIES ................................................................................51 
8.7 
BIOMARKERS .....................................................................................................51 
8.8 
MEDICAL RESOURCE UTILIZATION AND HEALTH ECONOMICS ..........51 
9 
STATISTICAL CONSIDERATIONS...............................................................................51 
9.5.1 
Interim Safety Monitoring .......................................................................51 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ....52 
10.1 
APPENDIX A-1: MANAGEMENT ALGORITHMS ..........................................53 
10.2 
APPENDIX A-2: LISTS OF TERMINOLOGY AND ABBREVIATIONS ........61 
10.2.1 
List of Terminology .................................................................................61 
10.2.2 
List of Abbreviations ...............................................................................61 
10.3 
APPENDIX A-3: APPENDIX COHORT A AMENDMENT HISTORY ............65 
11 
REFERENCES ..................................................................................................................66 
 


PORTER Appendix Cohort A - Parker Institute for Cancer Immunotherapy 
Protocol PICI0033 Appendix Amendment 1, Version 2.0 
8
LIST OF TABLES 
Table 1: 
Schedule of Activities ............................................................................................13 
Table 2: 
Overall Tumor Response by Cancer Type: PIVOT-02 Dose-escalation Phase .....21 
Table 3: 
Overall Tumor Response by Cancer Type: PIVOT-02 Expansion at 
Recommended Phase 2 Dose .................................................................................22 
Table 4: 
Safety: PIVOT-02 Expansion at Recommended Phase 2 Dose .............................23 
Table 5: 
Cohort-Specific Objectives and Corresponding Endpoints ...................................26 
Table 6: 
Study Intervention ..................................................................................................34 
Table 7: 
Toxicity Criteria Requiring Permanent Treatment Discontinuation ......................38 
Table 8:  
Dose Modification and Toxicity Management Guidelines for Infusion-related 
Reactions Associated with the administration of NKTR-214 and/or Nivolumab .41 
Table 9: 
Dose Modification and Toxicity Management Guidelines for Adverse Events 
Associated with Nivolumab ...................................................................................43 
Table 10: 
Laboratory Tests Sent to the Study Site’s Local Laboratory for Analysis of 
Disease-related Endpoints ......................................................................................49 
Table 11: 
Laboratory Tests Sent to the Study Site’s Local Laboratory for Analysis of Safety
................................................................................................................................50 
 
 
LIST OF FIGURES 
Figure 1: 
Study Schema.........................................................................................................11 
 
 


PORTER Appendix Cohort A - Parker Institute for Cancer Immunotherapy 
Protocol PICI0033 Appendix Amendment 1, Version 2.0 
9
1 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS 
Protocol Title: 
A Multicenter, Open-Label, Exploratory Platform Study to Evaluate Biomarkers and 
Immunotherapy Combinations for the Treatment of Patients with Metastatic Castration-resistant 
Prostate Cancer 
Appendix Cohort A 
Short Title: 
Platform Study for Prostate Researching Translational Endpoints Correlated to Response to 
Inform Use of Novel Combinations (PORTER) 
Note to Investigators:  This cohort appendix is intended to supplement the core protocol, and as 
such, will focus on combination-specific (ie, NKTR-214 and nivolumab) information that is not 
already available in the core protocol. 
Rationale: 
This study cohort is designed to explore the immune activation properties of NKTR-214 by 
induction of tumor infiltrating T and natural killer (NK) lymphocytes when used in combination 
with anti-programmed cell death 1 (PD-1) therapy in metastatic castration-resistant prostate 
cancer (mCRPC). 
Objectives and Endpoints: 
Refer to the core protocol. 
Combination-specific exploratory objectives include: 
Combination-specific Exploratory Objectives 
Endpoints 
• To evaluate the PK of NKTR-214 and/or nivolumab. 
• To evaluate the immunogenicity (ADA) of 
NKTR-214 and/or nivolumab. 
• Sparse PK analysis 
• Presence of ADA against NKTR-214 and/or 
nivolumab. 
ADA = anti-drug antibodies; PK = pharmacokinetics 
 
Overall Design, Number of Participants, Follow-up, and Data Monitoring Committee: 
Refer to the core protocol. 


PORTER Appendix Cohort A - Parker Institute for Cancer Immunotherapy 
Protocol PICI0033 Appendix Amendment 1, Version 2.0 
10
Intervention Groups and Duration: 
Participants will be assigned to receive one of the enrolling immunotherapy combination study 
interventions. In this cohort, participants will receive NKTR-214 and nivolumab as follows: 
Intervention 
Dose 
Frequency 
Route 
Schedule 
NKTR-214 
0.006 mg/kg 
Q3W 
IV over 30 (± 5) minutes 
Starting Day 1 
Nivolumab 
360 mg 
Q3W 
IV over 30 minutes 
Starting Day 1 
IV = intravenous(ly); Q3W = every 3 weeks 
 
Participants will be administered intravenous (IV) fluid and provided guidelines for self-
administered oral hydration following administration of NKTR-214. 
NKTR-214 and nivolumab will be administered for up to 2 years, unless the participant: is no 
longer clinically benefiting (as evidenced by symptomatic or radiographic disease progression 
and/or clinical deterioration); experiences any toxicity meeting specified discontinuation criteria 
(see Section 6.6) or unacceptable toxicity in the best clinical discretion of the treating physician 
(ie, Investigator discretion); reaches the maximum duration of study intervention; or withdraws 
consent. In this cohort, a cycle is defined as 3 calendar weeks. 
1.2 
SCHEMA 
The study schema is depicted in Figure 1. 


PORTER Appendix Cohort A - Parker Institute for Cancer Immunotherapy 
Protocol PICI0033 Appendix Amendment 1, Version 2.0 
11
Figure 1: 
Study Schema 
 
IV = intravenously; mCRPC = metastatic castration-resistant prostate cancer; Q3W = every 3 weeks; S = screening 
NKTR-214 and nivolumab will be administered for up to 2 years, unless the participant: is no longer clinically benefiting (as evidenced by symptomatic or 
radiographic disease progression and/or clinical deterioration); experiences any toxicity meeting specified discontinuation criteria (see Section 6.6) or 
unacceptable toxicity in the best clinical discretion of the treating physician; reaches the maximum duration of study intervention; or withdraws consent. A cycle 
is defined as 3 calendar weeks. Participants will be followed for up to 2.5 years from the time of the initiation of study intervention. 
This study design is applicable to Stage 1, as well as Stage 2 if the cohort is expanded. 


PORTER Appendix Cohort A - Parker Institute for Cancer Immunotherapy 
Protocol PICI0033 Appendix Amendment 1, Version 2.0 
12
 
1.3 
SCHEDULE OF ACTIVITIES 
The Schedule of Activities (SOA) shown in Table 1 is specific for this combination and 
supersedes the SOA provided in the core protocol. 


PORTER Appendix Cohort A - Parker Institute for Cancer Immunotherapy 
Protocol PICI0033 Appendix Amendment 1, Version 2.0 
13
Table 1: 
Schedule of Activities 
Tests & Procedures 
Screening/ 
Enrollmenta 
On-Treatment: NKTR-214 + Nivolumab 
End of 
Treatmentb 
Follow-up 
Cycle 1 (Q3W) 
Cycles 2, 3, and 4 
Cycle 5 Onward 
Day 
Day -28 to 
Day -1 
Day 1 
Day 2 
Day 3 
Day 8 
Day 1 
Day 8 
Day 1 
Day 
8 
14 – 28 
days after 
last dose 
110 days 
after last 
dose 
Q3Mc 
Window (days) 
-28 
 
± 1 
± 1 
± 1 
± 3 
± 1 
± 3 
± 3 
± 7 
± 10 
± 14 
Informed consentd 
X 
 
 
 
 
 
 
 
 
 
 
 
Review of I/E criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical/cancer history 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
X 
 
 
 
X 
 
X 
 
X 
 
 
ECOG performance 
status 
X 
X 
 
 
 
X 
 
X 
 
X 
X 
 
Vital signs (see Core 
Protocol Section 8.2.3) 
X 
X 
 
 
 
X 
 
X 
 
X 
 
 
Body weight 
X 
X 
 
 
 
X 
 
X 
 
X 
 
 
Hematology (see Table 
11) 
X 
Xe 
X 
X 
X 
Xe 
X 
Xe 
X 
X 
X 
 
Clinical chemistry (see 
Table 11) 
X 
Xe 
 
 
X 
Xe 
X 
Xe 
X 
X 
X 
 
Urinalysis 
X 
X 
 
 
 
X 
 
X 
 
X 
 
 
Prostate-specific antigen 
X 
X 
 
 
 
X 
 
X 
 
X 
X 
 
Testosterone level 
X 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECG 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
 
ECHO/MUGA 
X 
 
 
 
 
 
 
 
 
X 
X 
 
Circulating tumor cellsf 
 
Xe 
 
 
 
Xe 
 
Xe 
 
X 
 
 
cfDNA (blood)g 
X 
 
 
 
 
Xe (Cycles 
2 and 4) 
 
 
 
X 
 
 
Circulating soluble 
analytes/PK/ADAh 
X 
Xe 
X 
 
X 
Xe (Cycles 
2, 3, and 4) 
 
 
 
X 
 
 


PORTER Appendix Cohort A - Parker Institute for Cancer Immunotherapy 
Protocol PICI0033 Appendix Amendment 1, Version 2.0 
14
Tests & Procedures 
Screening/ 
Enrollmenta 
On-Treatment: NKTR-214 + Nivolumab 
End of 
Treatmentb 
Follow-up 
Cycle 1 (Q3W) 
Cycles 2, 3, and 4 
Cycle 5 Onward 
Day 
Day -28 to 
Day -1 
Day 1 
Day 2 
Day 3 
Day 8 
Day 1 
Day 8 
Day 1 
Day 
8 
14 – 28 
days after 
last dose 
110 days 
after last 
dose 
Q3Mc 
Window (days) 
-28 
 
± 1 
± 1 
± 1 
± 3 
± 1 
± 3 
± 3 
± 7 
± 10 
± 14 
NKTR-214 PKi 
X 
Xe 
X 
 
X 
Xe (Cycles 
2, 3, and 4) 
 
 
 
X 
 
 
Blood immune 
biomarkersh 
X 
Xe 
 
 
X 
Xe 
(Cycles 2, 
3, and 4) 
 
 
 
X 
 
 
Archival tumor tissue 
X 
 
 
 
 
 
 
 
 
 
 
 
Tumor biopsyj 
X 
 
 
 
 
X 
(Cycle 2) 
 
 
 
X (at PD 
[optional])j 
 
 
Stool collectionk 
X 
 
 
 
 
X 
(Cycle 2)k 
 
 
 
 
 
 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse events 
All AEs and SAEs will be collected for at least 100 days after the last dose of study intervention.l 
 
NKTR-214 
administrationm 
 
X 
 
 
 
X 
 
X 
 
 
 
 
Administer IV fluidsn 
 
X 
 
 
 
X 
 
X 
 
 
 
 
Nivolumab 
administrationo 
 
X 
 
 
 
X 
 
X 
 
 
 
 
Radiographic disease 
assessment 
X 
At Week 9 (± 1 week), repeat every 9 weeks (± 1 week) for the first 27 weeks, and every 12 weeks (± 1 week) 
thereafter until radiographic PD or start of subsequent therapy 
Review of alternate 
anticancer therapyp 
 
 
 
 
 
 
 
 
 
 
X 
X 
Follow up for overall 
survival 
 
 
 
 
 
 
 
 
 
 
X 
X 
ADA = anti-drug antibodies; AE(s) = adverse event(s); cfDNA = cell-free deoxyribonucleic acid; ECG = electrocardiogram; ECHO = echocardiogram; ECOG = Eastern 
Cooperative Oncology Group; EOT = end of treatment; I/E =  inclusion/exclusion; IV = intravenously; MUGA = multigated acquisition; PD = progressive disease; 
PK = pharmacokinetics; Q3M = every 3 months; Q3W = every 3 weeks; SAE(s) = serious adverse event(s) 


PORTER Appendix Cohort A - Parker Institute for Cancer Immunotherapy 
Protocol PICI0033 Appendix Amendment 1, Version 2.0 
15
a Tests/procedures performed as standard of care prior to obtaining informed consent and within 28 days prior to the first dose of study intervention do not have to be repeated at 
screening. 
b The End of Treatment Visit will be completed following the last dose of study intervention, either at the completion of the on-treatment phase or at early discontinuation. 
c For up to 2.5 years from the initiation of study intervention, participants in the follow up phase will be contacted by the site to collect alternate anticancer therapy information 
and determine survival status. 
d Informed consent must be obtained prior to any study-specific procedures and may be obtained prior to the 28-day screening window. 
e Blood samples should be collected prior to administration of any study intervention. 
f Circulating tumor cells will be collected at baseline (ie, Day 1 of Cycle 1 prior to study intervention administration), Day 1 of each cycle (prior to study intervention 
administration), and EOT. 
g cfDNA (blood) will be collected at baseline (ie, screening visit prior to study intervention administration), Day 1 of Cycle 2 and Cycle 4, and EOT. 
h Circulating soluble analytes, PK (nivolumab) and ADA blood sample, and/or blood immune biomarkers will be collected at baseline (ie, screening and/or Day 1 of Cycle 1 prior 
to study intervention administration), Day 2 of Cycle 1 (circulating soluble analytes), Day 8 of Cycle 1 (circulating soluble analytes, and blood immune biomarkers), prior to 
study intervention administration on Day 1 of Cycles 2-4, and at EOT. 
i Pre-infusion blood samples will be collected to allow for PK evaluation of NKTR-214. PK blood samples will also be collected immediately post-infusion of NKTR-214 (prior 
to nivolumab administration) on Day 1 of Cycles 1-4. Additionally, PK blood samples will be collected on Day 2 and Day 8 of Cycle 1. 
j Participants will undergo 2-3 tumor biopsies: prior to beginning study intervention (ie, baseline biopsy, mandatory for all participants, including those with bone only disease if 
medically feasible), and during treatment (ie, on-treatment biopsy during Cycle 2, if medically feasible). On- treatment biopsy should occur as early as possible after the second 
dose (Day 2 – Day 10 of Cycle 2); however, any on treatment biopsy after Day 1 of Cycle 2 will be accepted. An optional biopsy may be obtained at the time of disease 
progression, including from participants who respond and subsequently progress. Every attempt should be made for the on-treatment biopsies to be taken from the same lesion as 
the pre-treatment biopsy when feasible. 
k Stool will be collected at screening and during Cycle 2, if possible. Otherwise, any on-treatment stool sample will be acceptable. The stool sample may be collected at the clinic 
or at the participant’s home. 
l All SAEs will be collected from the time the participant signs informed consent. Prior to initiation of study intervention, only SAEs that are related to a protocol-mandated 
intervention, including those that occur prior to the assignment of study procedures should be reported. All AEs will be collected from the start of study intervention. All AEs 
and SAEs will be collected for at least 100 days after the last dose of study intervention. Refer to Section 8.3 of the core protocol for details regarding safety reporting for this 
study. 
m NKTR-214 will be administered at a dose of 0.006 mg/kg IV over 30 minutes Q3W on the same day as nivolumab and will continue for up to 2 years, unless the participant: is 
no longer clinically benefiting (as evidenced by symptomatic or radiographic disease progression and/or clinical deterioration); experiences any toxicity meeting specified 
discontinuation criteria (see Section 6.6) or unacceptable toxicity in the best clinical discretion of the treating physician; reaches the maximum duration of study intervention; or 
withdraws consent. A cycle is defined as 3 calendar weeks. 
n At least 1 liter of IV fluid will be administered prior to NKTR-214 administration on the day of each NKTR-214 dose. For the next 3 days after administration (ie, Days 2-4 of 
each cycle), participants are required to drink at least 2 liters per day of self-administered oral hydration (note: alcohol and caffeine intake should not be counted toward the daily 
hydration requirements). Advise participants to restrain from strenuous activity and avoid long hot showers and saunas for Days 1 to 5 of each cycle. Per clinical discretion, IV 
fluids may be administered at any time. The Investigator may decide to forego administering IV fluids to a participant if this is deemed in the best interest of the participant (eg, 
evidence of fluid overload). Advise participants with orthostatic symptoms to call their treating oncologist and consider increasing oral hydration (see Section 6.1.1). 
o Nivolumab will be administered at a dose of 360 mg IV over 30 minutes Q3W and will continue for up to 2 years, unless the participant: is no longer clinically benefiting (as 
evidenced by symptomatic or radiographic disease progression and/or clinical deterioration); experiences any toxicity meeting specified discontinuation criteria (see Section 6.6) 
or unacceptable toxicity in the best clinical discretion of the treating physician; reaches the maximum duration of study intervention; or withdraws consent. A cycle is defined as 
3 calendar weeks. The time between nivolumab doses should not be less than 18 days. 


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p Collection of information related to any post-study intervention alternate anticancer therapy. 
 


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2 
INTRODUCTION 
Refer to the core protocol. 
2.1 
STUDY RATIONALE 
Refer to the core protocol. 
2.2 
BACKGROUND 
Immunotherapy has changed the landscape of treatments for a number of malignancies, resulting 
in marked clinical benefit for patients with cancers including metastatic melanoma, non-small 
cell lung cancer (NSCLC) and renal cell carcinoma (RCC). Studies of immunotherapy in patients 
with advanced prostate cancer have failed to yield similar results. A phase 3 randomized, 
controlled trial of ipilimumab after docetaxel in patients with metastatic castration-resistant 
prostate cancer (mCRPC) failed to meet its primary endpoint of overall survival (OS; Kwon et 
al., 2014), and early phase studies of programmed cell death 1 (PD-1) blockade in advanced 
malignancies did not demonstrate clinical activity in advanced prostate cancer (Topalian et al., 
2012). However, emerging data suggest subsets of patients with prostate cancer, such as those 
with microsatellite instable tumors, which are enriched for neoantigens for T cells to respond to, 
may respond to anti-PD-1 immunotherapy (Graff et al., 2016). 
The prostate has historically been thought to be an immune-privileged site, with disease evidence 
of intratumoral natural killer (NK) cells, macrophages, and ‘low levels’ of both CD4+ and CD8+ 
T cells in prostate tumor tissue (Flammiger et al., 2012; Sfanos et al, 2009; De Marzo et al., 
2007; Massari et al., 2016). As a ‘cold’ tumor, the immunosuppressive microenvironment may 
contribute to the lack of clinical benefit to immunotherapy in prostate cancer, including low 
programmed cell death ligand 1 (PD-L1) expression (Martin et al., 2015), low mutational burden 
(Alexandrov et al., 2013), low abundance of intratumoral T cells (Flammiger et al., 2012), low 
cytolytic activity of NK cells (Pasero et al., 2016), and accumulation of regulatory T cells 
(Tregs) and myeloid-derived suppressor cells (MDSCs) in tumor bed (Miller et al., 2006; Lopez-
Bujanda and Drake, 2017). Treatment-based approaches that address these mechanisms of 
immune evasion or identify immune-responsive patient subsets may allow for more successful 
immunotherapy treatment approaches for this patient population with high unmet medical need.  
The T cell cytokine interleukin 2 (IL-2) is a potent antitumor cytokine, with a long clinical 
history as one of the first immunotherapeutic agents for the treatment of cancer. Aldesleukin 
(Proleukin®), which is approved by the United States (US) Food and Drug Administration 
(FDA) for metastatic melanoma and metastatic renal cell carcinoma, directly stimulates the 
immune system and has been shown to lead to durable responses in ~10% of people with 
metastatic melanoma and renal cancer (Payne et al., 2014). However, in addition to acting as a 


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stimulator of the immune system by activating tumor killing CD8+ T cells, aldesleukin also 
suppresses the immune system by activating Tregs (Boyman and Sprent, 2012).   
Despite favorable clinical outcomes associated with aldesleukin, it has several therapeutic 
limitations, including the need for inpatient hospital administration, 5 consecutive days of 
dosing, and the potential for serious toxicities, including capillary leak syndrome, hypotension, 
and pulmonary edema requiring medical management in the intensive care unit.  Nevertheless, a 
continued role for IL-2 in cancer immunotherapy exists, as patients treated with high dose IL-2 
have long lasting durable responses, including patients considered non-responders with stable 
disease (SD) (McDermott et al., 2015). These data underscore the relevance of cytokines and the 
need for improved cytokine therapies in the era of immune checkpoint inhibitors. 
2.2.1 
Background on Nivolumab (Bristol-Myers Squibb Company) 
Nivolumab is a human immunoglobulin G4 (IgG4) monoclonal antibody that binds to the PD-1 
receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated 
inhibition of the immune response, including the antitumor immune response. Opdivo® 
(nivolumab) is approved in the US for the treatment of several cancer types, including 
unresectable or metastatic melanoma (as monotherapy or in combination with ipilimumab) and 
as monotherapy in previously-treated metastatic NSCLC, advanced RCC, relapsed or refractory 
classical Hodgkin lymphoma (cHL), locally advanced or metastatic urothelial carcinoma (UC); 
recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN), microsatellite 
instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer 
(CRC), and hepatocellular carcinoma (HCC). In phase 1 investigation, nivolumab did not 
demonstrate clinical activity in 17 participants with mCRPC. This is consistent with mCRPC 
having a low level of immune cell infiltrate and tumor mutational burden (TMB). Treatment 
strategies to increase antigen presentation and immune infiltration and activation may improve 
the immune responsiveness of mCRPC to nivolumab. 
Refer to the Investigator’s Brochure (IB; Nivolumab Investigator’s Brochure, 2018) and 
approved US prescribing information (Opdivo [nivolumab] US Prescribing Information [USPI], 
2018) for detailed background information on nivolumab. 
2.2.2 
Background on NKTR-214 (Nektar Therapeutics) 
NKTR-214 is a novel cytokine with enhanced immune system activation. NKTR-214 consists of 
IL-2, which has the same amino acid sequence as aldesleukin (recombinant human IL-2 [rhIL-
2]), conjugated at a defined region within the protein to releasable polyethylene glycol (PEG) 
chains. In contrast to high-dose aldesleukin, which requires patients to be hospitalized for 
administration, NKTR-214 was designed as an outpatient therapy. In addition, NKTR-214 was 


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designed to mitigate the serious toxicities associated with rapid systemic immune activation seen 
with administration of high-dose IL-2 (NKTR-214 Investigator’s Brochure, 2018). 
NKTR-214 is a prodrug of a conjugated cancer immunotherapy cytokine that exerts its biological 
activity by binding to the IL-2 receptor and subsequent activation of effector T cells. The PEG 
chains of NKTR-214 render the molecule inactive. Upon intravenous (IV) administration, the 
PEG chains slowly release via hydrolysis to generate the active cytokine species (2-PEG-IL-2 
and 1-PEG-IL-2) that have a peak plasma concentration 26 to 30 hours after infusion. The slow 
generation of the 2-PEG-IL-2 and 1 PEG-IL-2 significantly mitigates the rapid-onset, systemic 
cytokine-related toxicities associated with high dose IL-2. Furthermore, the prodrug design of 
NKTR-214 with its antibody-like dosing, and the long half-life (13 to 19 hours) and sustained 
CD122 signaling of the active NKTR-214 moiety, obviate the need for 5-day courses of thrice 
daily infusions, or of daily subcutaneous injections. 
The polymer conjugation of NKTR-214 promotes biased signaling through the IL-2 receptor beta 
gamma (IL-2Rβγ). This unique feature preferentially increases the proliferation, activation and 
effector function of tumor antigen-specific CD8+ T cells and NK cells within the tumor 
microenvironment without expanding unwanted intra-tumoral Tregs that are activated through 
the IL-2 receptor alpha beta gamma (IL-2Rαβγ) (Charych et al., 2016a; Charych et al., 2016b). 
Specifically, the location of the NKTR-214 PEG chains interferes with the IL-2 alpha subunit 
responsible for the undesirable effect of activating Tregs in the tumor while continuing to permit 
binding to the IL-2Rβγ (CD122) receptor. 
NKTR-214 also correspondingly promotes expression of PD-1 on the surface of CD8+ T cells 
and induction of a Type II interferon gene signature in the tumor microenvironment, driving cell 
surface expression of PD-L1 on tumor cells (Diab et al., 2017a). The immunogenic properties of 
NKTR-214 with the induction of tumor infiltrating lymphocytes and upregulation of the 
PD-1/PD-L1 axis makes NKTR-214 a potentially promising combination therapy for use with 
checkpoint inhibitors that target and inhibit the PD-1/PD-L1 pathway. 
Multiple phase 1/2 clinical trials are currently underway in which NKTR-214 is administered 
either as monotherapy or in combination with immune checkpoint inhibitors, such as nivolumab, 
once every 2 or 3 weeks for the treatment of solid tumors (Charych et al., 2017). NKTR-214 has 
been generally well-tolerated in the clinical studies to date, with promising evidence of clinical 
efficacy in cancer patients, indicating a favorable benefit-risk profile. While no objective 
responses were observed in the single-agent study of NKTR-214 (Study 15-214-01 [EXCEL]), 9 
patients experienced tumor shrinkage between 1% and 30%, and 2 patients, after progressing on 
multiple prior therapies, had durable SD > 1 year. One patient with metastatic melanoma, who 
was previously treated with ipilimumab and a BRAF inhibitor, received 25 cycles of NKTR-214 
and had durable SD for 18 months. A second patient with metastatic RCC, who had progressed 


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on high dose IL-2 and was refractory to single-agent OX40 and nivolumab, was treated with 19 
cycles of NKTR-214 and had durable SD for 14 months. Given the biological properties of 
NKTR-214 and nivolumab these observations further supported the rationale for combining 
these two agents. 
NKTR-214 has been safely administered in an out-patient setting supported by appropriate 
clinical monitoring. Hypotension is the most clinical significant adverse effect can be effectively 
mitigated by prevention and hydration guidelines. Hypotension due to capillary leak syndrome as 
has been observed with the use of IL-2 has not been observed in the hypotension associated with 
NKTR-214, which appears to be due to a vasodilatory effect of the cytokines released in 
response to NKTR-214. Other common adverse events (AEs) associated with NKTR-214 appear 
to be largely cytokine-driven, are generally mild or moderate in severity and self-limiting. 
Refer to the IB (NKTR-214 Investigator’s Brochure, 2018 and Addendum 1 to NKTR-214 
Investigator’s Brochure, 2018) for detailed background information on NKTR-214. 
2.2.3 
Rationale for NKRT-214 + Nivolumab Immunotherapy 
Combination 
Given the safety profile, modest antitumor activity, and observed pharmacodynamic effects of 
NKTR-214 on increasing PD-L1 expression and induction of interferon gene signature and T and 
NK lymphocytes in the tumor, a major focus of the development of NKTR-214 treatment is in 
combination with PD-1 checkpoint inhibitors. In an ongoing phase 1/2 study of NKTR-214 and 
nivolumab in immuno-oncology naive patients with locally advanced or metastatic solid tumor 
malignancies (Study 16-214-02 [PIVOT-02 study]), a total of 38 patients with melanoma, 
NSCLC, RCC were enrolled in the phase 1b dose-escalation cohort. Among these patients, 
clinical activity was observed in both PD-L1 negative and positive patients (Table 2). The 
recommended phase 2 dose for the combination is 0.006 mg/kg NKTR-214 and 360 mg 
nivolumab administered on the same day every 3 weeks (Q3W). 


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Table 2: 
Overall Tumor Response by Cancer Type: PIVOT-02 Dose-escalation Phase 
 
Melanoma 
(1L) 
(N = 11) 
RCC (1L) 
(N = 14) 
NSCLC (2L) 
(N = 4) 
NSCLC 
(1/2L) 
(N = 5) 
Best Overall Response (RECIST) 
 
 
 
 
ORR (CR + PR) 
  7 (64%) 
10 (71%) 
3 (75%) 
3 (60%) 
DCR (CR + PR + SD) 
10 (91%) 
11 (79%) 
3 (75%) 
4 (80%) 
ORR by PD-L1 Status 
 
 
 
 
PD-L1 (-) 
3/5 (60%) 
5/8 (63%) 
3/4 (75%) 
3/5 (60%) 
PD-L1 (+) 
4/6 (67%) 
4/5 (80%) 
0 
0 
PD-L1 Unknown 
0 
1/1 
0 
0 
Source: Diab et al., 2018 
1L = first-line; 2L = second-line; CR = complete response; DCR = disease control rate; NSCLC = non-small cell 
lung cancer; ORR = objective response rate; PD-L1 = programmed cell death ligand-1; PR = partial response; 
Q3W = every 3 weeks; RCC = renal cell carcinoma; RECIST = Response Evaluation Criteria in Solid Tumors; 
SD = stable disease 
Data included for the following doses studied:  NKTR-214 0.006 mg/kg Q3W + nivoloumab 240 mg QW; NKTR-
214 0.003 mg/kg Q2W + nivolumab 240 mg Q2W; 0.006 mg/kg Q2W + nivolumab 240 mg Q2W; 0.006 mg/kg 
Q3W + nivolumab 360 mg Q3W 
Data cut: 29 May 2018 
 
In the expansion cohort, 283 patients with melanoma, NSCLC, RCC, UC, or triple-negative 
breast cancer (TNBC) have been treated at the recommended phase 2 dose, including 18 first-
line (1L) patients from the dose-escalation cohort (7 melanoma and 11 RCC; Diab et al., 2018). 
Three of the phase 2 expansion cohorts have met the prespecified efficacy criteria as of the 29 
May 2018 data cutoff, supporting the evaluation of NKTR-214 and nivolumab in registrational 
trials (Table 3). Enrollment is ongoing for additional tumor types in immuno-oncology naive and 
refractory settings. 


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Table 3: 
Overall Tumor Response by Cancer Type: PIVOT-02 Expansion at 
Recommended Phase 2 Dose 
 
Melanoma Stage IV 
Naive 1L 
(N = 28) 
RCC Stage IV 
Naive 1L 
(N = 26) 
UC Stage IV 
Naive 1L 
(Cisplatin-
ineligible) 
(N = 10) 
Best Overall Response (RECIST) 
 
 
 
ORR (CR + PR) 
14 (50%) 
12 (46%) 
6 (60%) 
DCR (CR + PR + SD) 
20 (71%) 
20 (77%) 
7 (70%) 
ORR by PD-L1 Status 
 
 
 
PD-L1 (-) 
5/12 (42%) 
9/17 (53%) 
3/5 (60%) 
PD-L1 (+) 
8/13 (62%) 
2/7   (29%) 
3/5 (60%) 
PD-L1 Unknown 
1/3   (33%) 
1/5   (50%) 
0 
Source: Diab et al., 2018 
CR = complete response; DCR = disease control rate; 1L = first-line; ORR = objective response rate; 
PD-L1 = programmed cell death ligand-1; PR = partial response; RCC = renal cell carcinoma; RECIST = Response 
Evaluation Criteria in Solid Tumors; SD = stable disease; UC = urothelial carcinoma 
Recommended phase 2 dose: NKTR-214 0.006 mg/kg in combination with nivolumab 360 mg every 3 weeks 
Data cut: 29 May 2018 
 
The combination is safe and well-tolerated at the recommended phase 2 dose, with a low rate of 
≥ Grade 3 treatment-related AEs, including immune-mediated AEs (imAEs; Table 4). 
Cytokine-related toxicity is the most common toxicity observed in patients treated with 
NKTR-214 in combination with nivolumab. These toxicities, reported either as stand-alone 
clinical diagnoses or as the associated individual signs and symptoms, including flu-like 
symptoms, rash, pruritus, cytokine release syndrome, fatigue, and elevated hepatic 
transaminases, are generally mild or moderate in severity and are generally self-limiting. 


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Table 4: 
Safety: PIVOT-02 Expansion at Recommended Phase 2 Dose 
Preferred Term 
NKTR-214 0.006 mg/kg + 
Nivo 360 Q3W 
(N=283) 
Treatment-Related AE Grade 1-2 in > 15% 
 
Flu-like symptomsa 
166 (58.7%) 
Rashb 
126 (44.5%) 
Fatigue 
119 (42.0%) 
Pruritus 
89 (31.4%) 
Nausea 
62 (21.9%) 
Decreased appetite 
54 (19.1%) 
Diarrhea 
43 (15.2%) 
Treatment-Related AE Grade 3 or higher (≥ 1% listed below) 
40 (14.1%) 
Hypotension 
5 (1.8%) 
Syncope 
5 (1.8%) 
Increased lipase 
4 (1.4%) 
Rashb 
4 (1.4%) 
Dehydration 
3 (1.1%) 
Patients who discontinued due to a TRAE 
6 (2.1%) 
Any Immune-Mediated AE (≥ Grade 3) 
10 (3.5%) 
≥ Grade 3 Immune-Mediated AE Treated with Steroid / 
Immunomodulating Medication 
7 (2.5%) 
Pneumonitisc/dyspnea 
2 (0.7%) 
Skin adverse event 
2 (0.7%) 
Hepatitis 
1 (0.4%) 
Colitis 
1 (0.4%) 
Elevated lipase 
1 (0.4%) 
≥ Grade 3 Endocrinopathy 
3 (1.1%) 
Diabetes mellitus treated with insulin 
1 (0.4%) 
Hyperglycemia treated with insulin 
2 (0.7%) 
Source: Diab et al., 2018 
AE(s) = adverse event(s); MedDRA = Medical Dictionary for Regulatory Activities; Q3W = every 3 weeks; 
TRAE(s) = treatment-related adverse event(s) 
Data cut: 07 May 2018 
Patients are only counted once under each preferred term using highest grade 
a Flu-like symptoms includes the following MedDRA preferred terms: chills; influenza; influenza-like illness; 
pyrexia. 
b Rash includes the following MedDRA preferred terms: rash; rash erythematous; rash maculo-papular; rash 
pruritic; erythema; rash generalized; rash popular; rash pustular; rash macular 
c One treatment-related Grade 5 pneumonitis related to nivolumab in a patient with NSCLC pretreated with 
carboplatin/pemetrexed and history of brain metastases 
 


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Translational data from the PIVOT-02 study confirm the rationale for activation of the immune 
system in the tumor microenvironment, with a conversion of PD-L1 negative tumors to PD-L1 
positive on treatment in 9/17 (53%) of patients (Diab et al., 2018). 
Given that NKTR-214 administration results in increasing PD-L1 expression and induction of 
interferon gene signature and T and NK lymphocytes in the tumor, it may overcome some of the 
immune evasion mechanisms identified in mCRPC. NKTR-214 is a potentially promising 
immune-activating agent in combination therapy with checkpoint inhibitors targeting the 
PD-1/PD-L1 pathway, such as nivolumab. Moreover, the side effect profile of NKTR-214 does 
not overlap with that of checkpoint inhibitors, further supporting the use of NKTR-214 as a 
potentially complimentary combination partner with nivolumab. 
2.3 
BENEFIT/RISK ASSESSMENT 
Nivolumab 
Nivolumab has demonstrated durable responses exceeding 6 months as monotherapy in several 
tumor types, including NSCLC, melanoma, RCC, and SCCHN. In confirmatory trials, 
nivolumab demonstrated a statistically significant improvement in OS as compared with the 
current standard of care in subjects with advanced or metastatic NSCLC, unresectable or 
metastatic melanoma, advanced RCC, or SCCHN. 
For monotherapy, the safety profile is similar across tumor types. Most AEs were low-grade 
(Grade 1 to 2) with relatively few related high-grade (Grade 3 to 4) AEs. There is no pattern in 
the incidence, severity, or causality of AEs to nivolumab dose level. Clinically-relevant AEs 
typical of stimulation of the immune system were infrequent and manageable by delaying or 
stopping nivolumab treatment and timely immunosuppressive therapy or other supportive care 
(Nivolumab Investigator’s Brochure, 2018).  
In several ongoing clinical trials, the safety of nivolumab in combination with other therapeutics 
such as ipilimumab, cytotoxic chemotherapy, anti-angiogenics, and targeted therapies is being 
explored. Most studies are ongoing and, as such, the safety profile of nivolumab combinations 
continues to evolve. 
Overall, these findings support a favorable benefit-risk profile for nivolumab across various 
tumor types. More detailed information about the known and expected benefits and risks and 
reasonably expected AEs of nivolumab may be found in the prescribing information (Opdivo 
USPI, 2018). 


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NKTR-214 
NKTR-214 has been generally well-tolerated in the clinical studies to date, both as monotherapy 
as well as in combination with immune checkpoint inhibitors, such as nivolumab, with promising 
evidence of clinical efficacy indicating a favorable benefit-risk profile (NKTR-214 Investigator’s 
Brochure, 2018). NKTR-214 has been safely administered in an out-patient setting supported by 
appropriate clinical monitoring. 
The most clinically important risk, hypotension, can be effectively mitigated by prevention and 
hydration guidelines. Other common AEs associated with NKTR-214 appear to be largely 
cytokine-driven, are generally mild or moderate in severity and self-limiting. Importantly, 
although cases of hypothyroidism, thyroiditis, and vitiligo/hypopigmentation consistent with 
immune-mediated mechanism have been observed in participants receiving NKTR-214 plus 
nivolumab, there is no evidence that NKTR-214 increases the frequency or severity of imAEs 
associated with immune checkpoint inhibitors. The risk mitigation strategy and measures 
described for this immunotherapy combination are considered robust and adequate to safe guard 
participants from clinically significant toxicities. 
NKTR-214 and Nivolumab 
The safety profile of nivolumab is well characterized and manageable when administered alone 
or in combination, including regimens where it is administered in combination with additional 
immuno-oncology products. The risk of hypotension with NKTR-214 seen in the monotherapy 
study was mitigated by the implementation of a hydration protocol in the PIVOT-02 study and 
these guidelines will be used in the current study. The current aggregate safety data for patients 
treated with the combination appears similar to nivolumab monotherapy. Nonclinical data, as 
well as clinical experience with high dose IL-2 and checkpoint inhibitor combinations, indicate 
the potential for improvement in therapeutic response compared with either agent given alone. 
Thus, the potential benefit of this immunotherapy combination appears to outweigh the known 
risks of these agents and warrants clinical investigation. 
3 
OBJECTIVES AND ENDPOINTS 
The cohort-specific objectives and endpoints are listed in Table 5. 


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Table 5: 
Cohort-Specific Objectives and Corresponding Endpoints 
Objectives 
Endpoints 
Primary 
 
• To determine the safety of NKTR-214 + nivolumab 
in participants with mCRPC. 
Refer to the core protocol. 
Secondary 
 
• To determine the ORR of NKTR-214 + nivolumab 
in participants with measurable mCRPC. 
• To determine the DCR ≥ 9 months of NKTR-214 + 
nivolumab in participants with measurable mCRPC. 
• To evaluate the rPFS of NKTR-214 + nivolumab in 
participants with mCRPC. 
• To estimate the OS of NKTR-214 + nivolumab in 
participants with mCRPC. 
Refer to the core protocol. 
Exploratory 
 
• To evaluate the PK of NKTR-214 and/or nivolumab. 
• To evaluate the immunogenicity (ADA) of 
NKTR-214 and/or nivolumab. 
 
Refer to the core protocol for overall exploratory 
objective(s). 
• Sparse PK analysis. 
• Presence of ADA against NKTR-214 and/or 
nivolumab. 
 
Refer to the core protocol for overall exploratory 
endpoint(s). 
ADA = anti-drug antibodies; DCR = disease control rate; mCRPC = metastatic castration-resistant prostate cancer; 
ORR = objective response rate; OS = overall survival; PK = pharmacokinetics; rPFS = radiographic progression-free 
survival 
 
4 
STUDY DESIGN 
4.1 
OVERALL DESIGN 
In this study intervention cohort, NKTR-214 and nivolumab will be administered Q3W for up to 
2 years (Figure 1), unless the participant: is no longer clinically benefiting (as evidenced by 
symptomatic or radiographic disease progression and/or clinical deterioration); experiences any 
toxicity meeting specified discontinuation criteria (see Section 6.6) or unacceptable toxicity in 
the best clinical discretion of the treating physician; reaches the maximum duration of study 
intervention; or withdraws consent. 
Participants will be monitored for safety and response and will be followed on-study for up to 
2.5 years from the time of the initiation of study intervention. All participants will be followed 
for safety for at least 100 days after discontinuation of study intervention. Approximately 15 
participants, including a minimum of 7 with a non-bone metastatic lesion that can be biopsied, 
will be enrolled in Stage 1. An additional approximately 15 participants, including a minimum of 
7 with a non-bone metastatic lesion, will be enrolled in Stage 2, if the cohort is expanded. 


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A pre-treatment biopsy of a metastatic lesion is required for all participants, including those with 
bone only disease, if medically feasible. Participants must provide also consent for archival 
tissue from a prior biopsy or surgery for prostate cancer. An on-treatment biopsy is required, 
when medically feasible, usually after the second dose of study intervention. An optional biopsy 
may be obtained at the time of disease progression, including from participants who respond and 
subsequently progress following a response to treatment. The on-treatment biopsies should be 
taken from the same lesion as the pre-treatment biopsy when feasible. 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
The scientific rationale for this combination is provided in Section 2.2.3. 
4.3 
JUSTIFICATION FOR DOSE 
The doses of NKTR-214 and nivolumab proposed for this study have been established as being 
safe, resulting in pharmacodynamic activity and having antitumor activity in previous and 
ongoing clinical trials (Section 4.3.2 and Section 4.3.1.1, respectively). Further, the proposed 
doses are those currently under study as the recommended phase 2 dose in Study 16-214-02, the 
ongoing phase 1/2 study in subjects with locally advanced or metastatic solid tumor 
malignancies (Study 16-214-02 [PIVOT-02 study]; Diab et al., 2017b; Diab et al., 2018). 
Based on the safety profiles of the individual components, as well as the safety data from the use 
of the combination of NKTR-214 and nivolumab in other disease populations, there does not 
appear to be overlapping toxicities. Therefore, this combination at the doses proposed is 
considered warranted for the evaluation of safety and efficacy in this population. 
4.3.1 
Rationale for Nivolumab Dose and Schedule 
In the US, single-agent nivolumab was approved in 2014 at a dose of 3 mg/kg every 2 weeks 
(Q2W). Subsequently, population pharmacokinetics (PPK) and exposure response analyses were 
performed to support use of flat dosing regimens (ie, nivolumab 240 mg Q2W, 360 mg Q3W, 
and 480 mg every 4 weeks [Q4W]) in participants with cancer. A flat dose of nivolumab 240 mg 
Q2W was selected since it is identical to a dose of 3 mg/kg for participants weighing 80 kg, the 
observed median body weight in nivolumab-treated cancer patients, while the nivolumab 360 mg 
Q3W and 480 mg Q4W regimens allow flexibility of dosing with less frequent visits and in 
combination with other agents using alternative dosing schedules to Q2W, such as ipilimumab. 
Using a PPK model, the overall distributions of nivolumab exposures (average steady-state 
concentration [Cavgss], minimum steady-state plasma concentration [Cminss], maximum steady-
state plasma concentration [Cmaxss], and trough concentration after the first dose [Cmin1]) are 
comparable after treatment with either nivolumab 3 mg/kg or 240 mg Q2W (Nivolumab 
Investigator’s Brochure, 2018). The 240 mg Q2W dose was approved in the USPI in September 
2016 for use in metastatic melanoma, NSCLC, and RCC indications. In March 2018, the 480 mg 


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Q4W dose was approved in the USPI for use in metastatic melanoma, NSCLC, RCC, cHL, 
SCCHN, UC, and HCC indications (Opdivo USPI, 2018). 
4.3.1.1 
Nivolumab 360 mg Q3W Dosing Regimen 
Although not approved in the US, available data support the use of 360 mg Q3W. Following 
nivolumab 360 mg Q3W, Cavgss are expected to be similar to those following nivolumab 
3 mg/kg or 240 mg Q2W, while Cminss are predicted to be 6% lower and are not considered to 
be clinically relevant. Cmaxss are predicted to be approximately ~23% greater relative to that 
following nivolumab 3 mg/kg Q2W dosing. However, the range of nivolumab exposures 
(median and 90% prediction intervals) following administration of 240 mg flat Q2W, 360 mg 
Q3W, and 480 mg Q4W regimens across the 35 to 160 kg weight range are predicted to be 
maintained well below the corresponding exposures observed with the well tolerated 10 mg/kg 
nivolumab Q2W dosing regimen. This less frequent dosing regimen (ie, Q3W vs Q2W) is 
designed to afford greater convenience to the target patient population and allow combination of 
nivolumab with other agents (Nivolumab Investigator’s Brochure, 2018). 
4.3.2 
Rationale for NKTR-214 Dose and Schedule 
The clinical pharmacology profile of single-agent NKTR-214 was assessed in Study 15-214-01 
(Study 15-214-01 [EXCEL]). NKTR-214 was administered as a 15-minute intravenous infusion 
at dose levels of 0.003, 0.006, 0.009, and 0.012 mg/kg every 2 weeks (Q2W) or Q3W. The 
maximum tolerated dose (MTD) of NKTR-214, based on pre-defined dose limiting toxicity 
(DLT) criteria, was 0.009 mg/kg administered Q3W. Blood samples were analyzed for NKTR-
214 related cytokines (NKTR-214-RC), NKTR-214 active cytokines (NKTR-214-AC), 
unconjugated IL-2, and PEG to characterize the pharmacokinetics (PK) and metabolism of 
NKTR-214 (NKTR-214 Investigator’s Brochure, 2018). 
Maximal concentrations of NKTR-214-RC were achieved shortly after the end of the first 
infusion of NKTR-214 and declined monoexponentially thereafter, remaining detectable for 8 to 
11 days postdose and resulting in mean half-life values between 13 and 19 hours across dose 
levels. NKTR-214-RC maximum plasma concentrations (Cmax) and area under the curve (AUC) 
increased linearly with dose.  
NKTR-214-AC concentrations increased gradually after dosing, achieving a mean time to Cmax 
(Tmax) between 26 and 30 hours postdose. After reaching Cmax, NKTR-214-AC declined 
monoexponentially in parallel to the decline in NKTR-214-RC, and remained detectable for 8 
days postdose, resulting in mean half-life values between 13 and 23 hours.   
NKTR-214-RC and NKTR-214-AC exposure were similar across participants within a dose 
cohort and between cycles, without indication of accumulation with either the Q3W or Q2W 


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administration schedules, as expected based on the half-life. NKTR-214-AC and NKTR-214-RC 
exposure increased linearly with dose over the dose range studied. 
Unconjugated IL-2 was only sporadically detected, and when detected, was present only at low 
concentrations (0.5 to 7.1 ng/mL, with the majority near the quantitation limit of 0.5 ng/mL) 
indicating that unconjugated IL-2 does not contribute to plasma NKTR-214 exposure. Analysis 
of PEG is ongoing. 
The effect of nivolumab on NKTR-214 PK was assessed in Study 16-214-02 (PIVOT-02), based 
on NKTR-214-RC exposure. Pharmacokinetics of NKTR-214-RC in combination with 
nivolumab appear similar to those after NKTR-214 monotherapy, suggesting no drug-drug 
interaction between NKTR-214 and nivolumab (NKTR-214 Investigator’s Brochure, 2018). 
4.4 
TREATMENT BEYOND DISEASE PROGRESSION 
Refer to the core protocol. 
4.5 
END OF STUDY DEFINITION 
Refer to the core protocol for the end of study definition. 
The total length of this study cohort, from screening of the first participant to the end of the 
cohort, is expected to be approximately 3 years, 9 months. 
5 
STUDY POPULATION 
Prospective requests for approval of protocol deviations to recruitment and enrollment criteria, 
also known as waivers or exemptions, is not allowed. 
5.1 
INCLUSION CRITERIA 
Participants are eligible to be included in the study only if all the following criteria apply: 
5.1.1 
Common Inclusion Criteria 
1. Participant must be ≥ 18 years of age at the time the informed consent is signed. 
2. Participants must agree to use an adequate method of contraception as outlined in 
Appendix 6 of the core protocol starting with the first dose of study intervention and for 
at least 7 months after the last dose of study intervention and refrain from donating sperm 
during this period. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for 
the participant. 
3. Participants must be able and willing to comply with the study visit schedule and study 
procedures. 
4. Histologically documented adenocarcinoma of the prostate. 


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5. Metastatic castration resistant prostate cancer with castrate-level testosterone 
(< 50 ng/dL) at screening. 
6. Have received and progressed on prior secondary androgen receptor signaling inhibitor 
therapy (eg, abiraterone, enzalutamide, apalutamide). Progression is defined by one or 
more of the following 3 criteria: 
a. Prostate-specific antigen (PSA) ≥ 1.0 ng/mL and rising PSA by at least 2 
consecutive measurements a minimum of 1-week apart. 
b. Soft tissue progression as defined by Response Evaluation Criteria in Solid 
Tumors (RECIST) version 1.1 (Eisenhauer et al., 2009). 
c. Bone disease progression as defined by 2 new bone lesions (as per Prostate 
Cancer Clinical Trials Working Group 3 [PCWG3; Scher et al., 2016]).  
7. Have measurable disease or non-measurable disease based on PCWG3-modified 
RECIST 1.1. 
8. Provide fresh pre-treatment core needle or incisional biopsy of a metastatic tumor lesion 
not previously irradiated. Fine needle aspiration is not acceptable. 
a. Additionally, if a pre-treatment biopsy is not medically feasible for participants 
with bone only disease, formalin-fixed paraffin-embedded (FFPE) tumor 
specimen in a paraffin block (preferred) or at least 10 slides containing unstained, 
freshly cut, serial sections must be provided. 
b. For all participants, in addition to fresh pre-treatment biopsy, consent for archival 
tissue is required. 
9. Must be willing to undergo tumor biopsy(ies) on treatment, if medically feasible. 
10. Participants must discontinue antiandrogen therapy (ie, bicalutamide, flutamide, 
nilutamide) at least 4-6 weeks prior to registration with no evidence of PSA decline after 
washout. 
a. Bicalutamide: Washout period at least 6 weeks 
b. Flutamide and nilutamide: Washout period at least 4 weeks 
11. Participants must discontinue therapies for mCRPC for 5 half-lives or 28 days, whichever 
is shorter. 
a. Participants will remain on gonadotropin-releasing hormone (GnRH) agents 
throughout this study. 
b. Prior chemotherapy is allowed if no progression of disease on chemotherapy as 
defined by PCWG3-modified RECIST 1.1.  
c. Prior treatment with sipuleucel-T, radium-223, or poly adenosine diphosphate 
(ADP)-ribose polymerase (PARP) inhibitor (eg, olaparib) is allowed. 
d. Tissue biopsy may be performed during washout period. 
12. Participants with prior or concurrent malignancies are permitted if any one of the 
following applies: 


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a. Previously treated malignancy for which all treatment of that malignancy was 
completed at least 2 years before enrollment and no evidence of disease exists, or 
b. With agreement from the Medical Monitor and Principal Investigator (PI), 
participants who have a concurrent malignancy that is clinically stable and does 
not require tumor-directed treatment are eligible to participate if the risk of the 
prior malignancy interfering with either safety or efficacy endpoints is very low, 
or 
c. With agreement from the Medical Monitor and PI, other malignancies may be 
permitted if the risk of the prior malignancy interfering with either safety or 
efficacy end points is very low. 
13. Have a performance status of 0 or 1 according to the Eastern Cooperative Oncology 
Group (ECOG) scale. 
14. Demonstrate adequate organ function on screening laboratory tests performed within 
14 days of treatment initiation and as evidenced by: 
a. Hemoglobin ≥ 9.0 g/dL or ≥ 5.6 mmol/L without transfusion or erythropoietin 
(EPO) dependency (within ≤ 7 days of assessment) 
b. Absolute neutrophil count ≥ 1,500/mm3 without growth factor support (within 
< 28 days of assessment) 
c. Platelet count ≥ 100,000/mm3 
d. Estimated glomerular filtration rate (GFR) ≥ 45 mL/min using the Cockcroft-
Gault formula 
e. Serum total bilirubin < 1.5 x upper limit of normal (ULN) or ≤ 2.0 x ULN for 
participants with liver metastases 
i. Participants with Gilbert's syndrome must have ≤ 3 x ULN and no liver 
lesions 
f. Aspartate aminotransferase (AST) (SGOT) and alanine aminotransferase (ALT) 
(SGPT) ≤ 3.0 x ULN or ≤ 5.0 x ULN for participants with liver metastases. 
g. Albumin ≥ 2.5 mg/dL. 
h. International normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 x ULN 
unless participant is receiving anticoagulant therapy, as long as PT is within 
therapeutic range of intended use of anticoagulants. 
i. Activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN unless participant is 
receiving anticoagulant therapy, as long as PTT is within therapeutic range of 
intended use of anticoagulants. 


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15. Willing and capable of giving signed informed consent as described in Appendix 1 of the 
core protocol, which includes compliance with the requirements and restrictions listed in 
the informed consent form (ICF) and in this protocol. 
 
5.1.2 
Combination-specific Inclusion Criteria 
1. A documented left ventricular ejection fraction (LVEF) > 45% using standard 
echocardiogram (ECHO) or multigated acquisition (MUGA) scan test within 60 days 
prior to Cycle 1 Day 1. 
2. Oxygen saturation ≥ 92% on room air. 
 
5.2 
EXCLUSION CRITERIA 
Participants are excluded from the study if any of the following criteria apply: 
5.2.1 
Common Exclusion Criteria 
1. Is currently participating and receiving study therapy or has participated in a study of an 
investigational agent and received study therapy or used an investigational device within 
4 weeks of the first dose of treatment. 
a. Recent or concurrent non-therapeutic investigational agents that are not 
anticipated to interfere with study intervention, such as certain investigational 
imaging tracers, may be permitted with written agreement from the Medical 
Monitor. 
2. Has a diagnosis of immunodeficiency or conditions that need systemic corticosteroid 
replacement therapy > 10 mg/day prednisone (or equivalent) or other immunosuppressive 
medications within 28 days prior to the first dose of study intervention. Inhaled steroids 
are permitted if necessary. 
3. Has any active known or suspected autoimmune disease. Participants with vitiligo, type I 
diabetes mellitus, controlled autoimmune hypothyroidism, psoriasis not requiring 
systemic treatment, or other conditions under control are permitted to enroll. 
Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement 
therapy ≤ 10 mg of prednisone/day for adrenal or pituitary insufficiency, etc.) is not 
considered a form of systemic treatment.  
4. Has a known history of active TB (Bacillus Tuberculosis). 
5. Has known history of, or any evidence of active, non-infectious pneumonitis. 
6. Has an active infection requiring systemic therapy. 
7. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the participant’s participation 
for the full duration of the trial, or is not in the best interest of the participant to 
participate, in the opinion of the treating Investigator. 


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8. Has known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the trial. 
9. Is expecting to father children within the projected duration of the trial, starting with the 
pre-screening or screening visit through 7 months after the last dose of study intervention. 
10. Known history of testing positive for human immunodeficiency virus (HIV), known 
acquired immunodeficiency syndrome (AIDS), or any positive test for hepatitis B or 
hepatitis C virus representing acute or chronic disease. 
11. Has received a live vaccine within 30 days of planned start of study intervention. 
Note:  Seasonal influenza vaccines for injection are generally inactivated flu vaccines and 
are allowed; however intranasal influenza vaccines (eg, Flu-Mist®) are live attenuated 
vaccines, and are not allowed. 
12. Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis. Participants with previously treated brain metastases may participate provided 
they are stable (without evidence of progression by imaging for at least 4 weeks prior to 
the first dose of study intervention and any neurologic symptoms have returned to 
baseline), have no evidence of new or enlarging brain metastases, and are not using 
steroids for at least 7 days prior to study intervention.  This exception does not include 
carcinomatous meningitis which is excluded regardless of clinical stability.   
13. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study 
Day 1 or who has not recovered (ie, ≤ Grade 1 or at baseline) from AEs due to agents 
administered more than 4 weeks earlier. 
a. Participants with controlled autoimmune disease as described in exclusion 
criterion #3 are permitted to enroll. 
14. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 
2 weeks prior to study Day 1 or who has not recovered (ie, ≤ Grade 1 or at baseline) from 
AEs due to a previously administered agent. 
a. Note:  Participants with ≤ Grade 2 neuropathy and/or hearing loss are an 
exception to this criterion and may qualify for the study. 
b. Note:  If a participant received major surgery, he must have recovered adequately 
from the toxicity and/or complications from the intervention prior to starting 
therapy.   
15. History of allergy to any of the study intervention components. 
 
5.2.2 
Combination-specific Exclusion Criteria 
1. Participants must not have received prior IL-2 therapy. 
2. Has had prior therapy with any anti-PD-1 or anti-PD-L1 antibody (prior therapy with an 
anti-cytotoxic T-lymphocyte-associated protein 4 [CTLA-4] antibody is permitted). 
3. Prolonged Fridericia’s corrected QT interval (QTcF) > 450 ms at screening. 


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4. History of unstable or deteriorating cardiac disease within the previous 6 months prior to 
screening including but not limited to the following: 
a. Unstable angina or myocardial infarction 
b. Congestive heart failure (New York Heart Association [NYHA] Class III or IV) 
c. Uncontrolled clinically significant arrhythmias 
5. Need for > 2 antihypertensive medications for management of hypertension (including 
diuretics). 
 
5.3 
LIFESTYLE CONSIDERATIONS 
5.3.1 
Meals and Dietary Restrictions 
Complete hydration guidelines are provided in Section 6.1.1. For all cycles, at least 2 liters per 
day of self-administered oral hydration on Days 2 to 5 are recommended. 
5.3.2 
Activity 
As part of the protocol hydration guidelines, participants should be advised to restrain from 
strenuous activity and avoid long hot showers and saunas for Days 1 to 5 of every cycle.   
5.4 
SCREEN FAILURES 
Refer to the core protocol. 
6 
STUDY INTERVENTION 
Study intervention is defined as any investigational intervention(s), marketed product(s) or 
placebo intended to be administered to a study participant according to the study protocol. 
6.1 
STUDY INTERVENTION(S) ADMINISTERED 
The study interventions to be administered in this study are summarized in Table 6. 
Table 6: 
Study Intervention 
Study 
Intervention 
Name 
Dosage Formulation 
Unit Dose 
Strength(s) 
Dosage 
Level(s) 
Route of 
Administration 
Sourcing 
NKTR-214 
Sterile lyophilized powder to be 
reconstituted with sterile water 
for injection and diluted with 
commercially available dextrose 
5% or normal saline 
1.0 mg/mL 
of IL-2 
0.006 mg/kg 
IV infusion 
Nektar 
Therapeutics 
Nivolumab 
Aqueous solution 
10 mg/mL 
360 mg 
IV infusion 
Bristol-Myers 
Squibb 
IV = intravenous 
 


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NKTR-214 0.006 mg/kg will be administered as an IV infusion over approximately 30 minutes 
(± 5 minutes) (see Section 4.3.2), followed approximately 30 minutes later by nivolumab 360 
mg, administered as an IV infusion over approximately 30 minutes (see Section 4.3.1.1). Study 
intervention will be administered Q3W for up to 2 years, unless the participant: is no longer 
clinically benefiting (as evidenced by symptomatic or radiographic disease progression and/or 
clinical deterioration); experiences any toxicity meeting specified discontinuation criteria (see 
Section 6.6) or unacceptable toxicity in the best clinical discretion of the treating physician; 
reaches the maximum duration of study intervention; or withdraws consent. A cycle is defined as 
3 calendar weeks. 
The NKTR-214 dose will be determined by the participant’s weight in kilograms, which will be 
determined before the start of each 3-week cycle. If the participant’s weight is within 10% of the 
participant’s weight on Day 1 of Cycle 1, the study drug dose does not need to be recalculated, 
depending on institutional guidelines/preference. 
Administration of study intervention will be performed in a monitored setting in which there is 
immediate access to trained personnel and adequate equipment and medicine to manage 
potentially serious reactions. 
6.1.1 
Hydration Guidelines for NKTR-214 
Important safety information and hydration instructions are to be provided to participants. 
For those participants enrolled in this cohort, at least 1 liter of IV fluid on will be administered 
prior to NKTR-214 administration on the day of each NKTR-214 dose. For the next 3 days after 
administration (ie, Days 2 – 4 of each cycle), participants should be instructed that they are 
required to drink at least 2 liters per day of self-administered oral hydration (note: alcohol and 
caffeine intake should not be counted toward the daily hydration requirements). Participants 
should be advised to restrain from strenuous activity and avoid long hot showers and saunas for 
Day 1 to Day 5 of each cycle of NKTR-214 administration. Per clinical discretion, IV fluids may 
be administered at any time. The Investigator may decide to forego administering IV fluids to a 
participant if this is deemed to be in the best interest of the participant (eg, evidence of fluid 
overload). 
Participants should be advised to call their treating oncologist if they experience orthostatic 
symptoms and consider increasing oral hydration. 
To mitigate the event of hypotension, consideration should be given to withholding 
antihypertensive medications, including diuretics, as well as other drugs with hypotensive 
properties as described Section 6.5.2. 


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6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
Refer to the core protocol for general guidance on handling, storage, and accountability. 
NKTR-214 drug product should be stored in a secure, locked area with temperature at monitored 
-20 °C (± 5 °C), as specified on the drug label. 
Nivolumab must be stored at 2°-8°C and protected from light and freezing.  
The instructions for reconstitution and administration of the study intervention are described in 
the Pharmacy Manual(s). 
6.3 
RANDOMIZATION AND BLINDING 
This is not a randomized study, and study intervention will be administered in an open-label 
fashion. 
6.4 
STUDY INTERVENTION COMPLIANCE 
Study intervention will be administered by authorized site personnel and tracked using drug 
accountability records. No additional measures of compliance will be instituted. 
6.5 
CONCOMITANT THERAPY 
Refer to the core protocol. 
6.5.1 
Permitted Therapy 
Refer to the core protocol. 
6.5.2 
Prohibited Therapy 
Refer to the core protocol. 
In addition to the prohibited therapy described in the core protocol, based on clinical evidence, 
the Investigator may decide to withhold antihypertensive medications, including diuretics, as 
well as other drugs with hypotensive properties (eg, alpha blockers for benign prostatic 
hypertrophy) prior to each dose of NKTR-214, particularly when therapy involves multiple anti-
hypertensive drugs and classes other than thiazide diuretics. If discontinuing antihypertensive 
medications, discontinue no less than 12 hours and no more than 48 hours prior to each dose of 
NKTR-214. Antihypertensive medications may be reinstituted in between doses of NKTR-214 if 
the diastolic pressure exceeds 90 mm Hg and/or the systolic pressure exceeds 160 mm Hg. 
6.6 
DOSE MODIFICATIONS 
6.6.1 
Dose Modifications for the Combination of Nivolumab and 
NKTR-214 
Study participants may not have any dose escalation or dose reduction of nivolumab in this 
study; dose reduction, but not dose escalation, of NKTR-214 is allowed. 


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Participants who experience an AE described in Table 7 will be permanently discontinued from 
all study intervention and should continue follow-up assessments as outlined in the SOA 
(Section 1.3). 
Grade 3 and 4 toxicities are observed in all trials of nivolumab in multiple tumor types. As such 
toxicities are anticipated; however, given the unique nature of this protocol, monitoring for AEs 
described in Table 7 will continue throughout the study. 
The Investigator may attribute each AE to the combination or any individual component of the 
study intervention. Holding of 1 agent and not the other agents is appropriate if, in the opinion of 
the Investigator, the toxicity is clearly related to 1 of the study interventions. If an Investigator 
believes a toxicity is uniquely related to one agent, then appropriate documentation is required 
regarding the drug to which the Investigator is attributing the AE. If, in the opinion of the 
Investigator, the toxicity is related to the combination of nivolumab and NKTR-214 then all 
drugs should be held according to recommended dose modifications. If toxicity does not resolve 
or the criteria for resuming study intervention are not met within 6 weeks after the last dose, the 
participant must be discontinued from the combination therapy, unless written approval to restart 
therapy is provided by the Medical Monitor. 
The anticipated important safety risks associated with the administration of nivolumab and 
NKTR-214, as well as the measures to be taken, are outlined in the following sections. The 
combined effect of NKTR-214 and nivolumab on the AE or immune-related AE (irAE) profiles 
of these agents continues to evolve. Guidance with respect to the individual agents is provided in 
Section 6.6.2 and Section 6.6.3. Refer to the USPI for nivolumab (Opdivo USPI, 2018) and the 
Investigator’s Brochures for nivolumab and NKTR-214 for complete summaries of safety 
information. 


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Table 7: 
Toxicity Criteria Requiring Permanent Treatment Discontinuation 
Participants should be monitored for the occurrence of any of the following AEs that are considered by the 
Investigator to be possibly, probably, or definitely related to nivolumab, NKTR-214, or the immunotherapy 
combination. Treatment with all study intervention should be permanently discontinued for the following: 
• 
Grade 4 non-hematological toxicity (not laboratory) 
• 
Grade 4 hematologic toxicity lasting ≥ 7 days or that is clinically significant 
• 
Grade 3 thrombocytopenia in the presence of clinically significant active bleeding (eg, requiring 
transfusion or hospitalization) 
• 
Any non-hematologic toxicity ≥ Grade 3 in severity, with the following exceptions: 
o 
Endocrinopathy AEs, such as adrenal insufficiency, adrenocorticotropic hormone (ACTH) deficiency, 
hyper- or hypothyroidism, that resolve or are adequately controlled with physiologic hormone 
replacement (corticosteroids, thyroid hormones) or glucose intolerance managed with glucose-
controlling agents 
o 
Amylase or lipase elevations that last ≤ 7 days 
o 
Electrolyte imbalances/abnormalities that are not associated with clinical sequelae and are corrected 
with supplementation/appropriate management within 72 hours of their onset 
o 
Tumor flare defined as local pain, irritation, or rash localized at sites of known or suspected tumor 
o 
Grade 3 nausea, vomiting, or diarrhea that can be medically managed to ≤ Grade 2 within 72 hours 
o 
Grade 3 hypotension during Cycles 1 or 2 that lasts ≤ 48 hours post-dose 
o 
Fatigue that improves to ≤ Grade 2 with 7 days 
o 
Grade 3 rash without use of corticosteroids or anti-inflammatory agents per standard of care 
• 
Any new Grade 3 or Grade 4 non-hematologic laboratory abnormality, if 
o 
the abnormality leads to hospitalization, or 
o 
the abnormality persists for > 1 week and is believed to be clinically significant. For example, 
exceptions would include asymptomatic pancreatitis. 
• 
Febrile neutropenia Grade 3 or Grade 4 
• 
Any elevated AST or ALT laboratory value that is ≥ 3 × ULN and an elevated total bilirubin lab value that 
is ≥ 2 × ULN and an alkaline phosphatase lab value that is < 2 × ULN, in which no alternative reasons can 
be found to explain the combination of increased AST/ALT and total bilirubin, such as viral hepatitis A, B 
or C, preexisting or acute liver diseases, pre-existing known liver metastases, or another drug capable of 
causing the observed injury 
• 
Grade 5 toxicity 
ACTH = adrenocorticotropic hormone; AE(s) = adverse event(s); ALT = alanine aminotransferase; AST = aspartate 
aminotransferase; ULN = upper limit of normal 
 
 
6.6.1.1 
Potential for Overlapping Toxicities with Nivolumab and 
NKTR-214 
Based on the safety profile observed with ongoing use of this combination, the toxicities 
associated with the monotherapy administration of nivolumab and NKTR-214 do not overlap 
when administered in combination. 
The safety data for nivolumab are described in the USPI (Opdivo USPI, 2018). Nivolumab 
therapy is associated with immune-mediated adverse reactions, which can be severe and fatal in 
some cases. With appropriate medical therapy, immune-related adverse reactions resolved in 
most cases. Immune-mediated adverse reactions may involve any organ system; however, the 


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most common severe immune-mediated adverse reactions are enterocolitis, endocrinopathies, 
hepatitis, dermatitis (including toxic epidermal necrolysis and Stevens-Johnson syndrome), and 
neuropathy. The safety profile of nivolumab combination therapy varies with the agent combined 
with nivolumab but is generally consistent with the safety profiles observed with either agent 
alone and, in some cases, both frequency and severity of AEs were greater than that observed 
with either agent alone. 
Cytokine-related toxicity is the most common toxicity observed in patients treated with 
NKTR-214 monotherapy and NKTR-214 in combination with nivolumab. These toxicities, 
reported either as stand-alone clinical diagnoses or as the associated individual signs and 
symptoms, including flu-like symptoms, rash, pruritus, cytokine release syndrome, fatigue, and 
elevated hepatic transaminases are generally mild or moderate in severity, and are self-limiting. 
Thyroid dysfunction, reported as hypothyroidism, thyroiditis (may be characterized by initial 
hyperthyroidism followed by hypothyroidism), or hyperthyroidism, occurred primarily in 
patients receiving combination therapy with NKTR-214 and nivolumab. Most of the cases were 
mild or moderate in severity, asymptomatic, and managed by hormone replacement therapy 
without corticosteroids. 
Frequent and significant eosinophilia has been observed in patients receiving both single agent 
NKTR-214 and NKTR-214 plus nivolumab, primarily starting at Cycle 2 or later, consistent with 
a known effect of IL-2 therapy. The frequency of selected AEs (primarily Grade 1 or 2 in 
severity) such as rash, pruritus, edema, nausea, vomiting, diarrhea and dizziness increased with 
level of eosinophilia. Isolated cases of suspected hypereosinophilic syndrome have been 
reported. Absolute eosinophil count should be closely monitored per protocol. 
6.6.1.2 
Dose Modifications and Toxicity Management for Adverse Events 
Associated with Nivolumab and NKTR-214 
Immuno-oncology agents are associated with AEs that can differ in severity and duration from 
AEs caused by other therapeutic classes. Early recognition and management of AEs associated 
with immuno-oncology agents may mitigate severe toxicity. Management algorithms (Appendix 
A-1) have been developed to assist Investigators in assessing and managing the following drug-
related AEs. 
• Immune-mediated colitis 
• Immune-mediated nephritis and renal dysfunction 
• Immune-mediated pneumonitis 
• Immune-mediated hepatitis 


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• Immune-mediated endocrinopathies (hypophysitis, adrenal insufficiency, hypothyroidism 
and hyperthyroidism, Type 1 diabetes mellitus) 
• Immune-mediated skin adverse reactions 
• Immune-mediated encephalitis 
 
6.6.1.3 
Dose Modifications and Toxicity Management for Infusion-
related Reactions Associated with the Administration of 
NKTR-214 and/or Nivolumab 
Interrupt or slow the rate of infusion in participants with mild or moderate infusion reactions. 
Discontinue the immunotherapy combination in participants with severe or life-threatening 
infusion reactions. 
All Grade 3 or 4 infusion reactions should be reported within 24 hours to the study Medical 
Monitor and reported as a serious adverse event (SAE) if it meets the criteria. Infusion reactions 
should be graded as described in Section 10.5.3 of the core protocol. 
Dose modification and toxicity management guidelines for infusion-related reactions are 
provided in Table 8.  
 


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Table 8:  
Dose Modification and Toxicity Management Guidelines for Infusion-related Reactions Associated with the 
administration of NKTR-214 and/or Nivolumab 
Grade 
(NCI CTCAE v 5.0) 
 
Treatment 
Premedication at 
Subsequent Dosing 
Grade 1 
Mild reaction; infusion interruption not indicated; 
intervention not indicated 
Increase monitoring of vital signs as medically indicated until the participant is 
deemed medically stable in the opinion of the Investigator 
None 
Grade 2 
Requires therapy or infusion interruption but responds 
promptly to symptomatic treatment (eg, antihistamines, 
NSAIDs, narcotics, IV fluids); prophylactic medications 
indicated for ≤ 24 hours 
Stop Infusion 
Additional appropriate medical therapy may include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDs 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically indicated until the participant is 
deemed medically stable in the opinion of the Investigator 
If symptoms resolve within 1 hour of stopping drug infusion, the infusion may 
be restarted at 50% of the original infusion rate (eg, from 100 mL/h to 50 mL/h).  
Otherwise dosing will be held until symptoms resolve and the participant should 
be premedicated for the next scheduled dose 
Participants who develop Grade 2 toxicity despite adequate premedication 
should be permanently discontinued from further study intervention 
Participant may be premedicated 
according to local treatment 
guidelines 
Grades 3 or 4 
Grade 3: 
Prolonged (ie, not rapidly responsive to symptomatic 
medication and/or brief interruption of infusion); 
recurrence of symptoms following initial improvement; 
hospitalization indicated for other clinical sequelae (eg, 
renal impairment, pulmonary infiltrates) 
Grade 4: 
Life-threatening; pressor or ventilatory support indicated 
Stop Infusion 
Administer urgent medical therapy as appropriate/clinically indicated 
Increase monitoring of vital signs as medically indicated until the participant is 
deemed medically stable in the opinion of the Investigator 
Hospitalization may be indicated 
**In cases of anaphylaxis, epinephrine should be used immediately 
Participant is permanently discontinued from further study intervention 
No subsequent dosing 
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of drug administration. 
For further information, please refer to the Common Terminology Criteria for Adverse Events v5.0 (CTCAE) at http://ctep.cancer.gov 
CTCAE = Common Terminology Criteria for Adverse Events; NCI = National Cancer Institute; NSAIDs = nonsteroidal anti-inflammatory drugs; IV = intravenous 
 


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6.6.1.4 
Dose Delays and Interruptions of NKTR-214 + Nivolumab 
Combination Immunotherapy 
Dose delays and interruptions are permitted for toxicity reasons (see Section 6.6.2 and 
Section 6.6.3). 
The Investigator may attribute each AE to the combination or to either individual intervention. 
• If, in the opinion of the Investigator, the toxicity is related to the combination of the 
agents, then all drugs should be held according to recommended dose modifications. 
• If the toxicity is considered clearly related to 1 agent, but not the others, then the other 
agents can continue unless toxicity related to that study intervention would warrant a 
dose delay. 
 
Appropriate documentation is required regarding the drug to which the Investigator is attributing 
the AE. If toxicity does not resolve or the criteria for resuming study intervention are not met 
within 6 weeks after the last dose, the participant must be discontinued from the combination 
therapy. 
Dose delays and interruptions for reasons other than toxicity, such as surgical procedures, may 
be allowed with Medical Monitor approval. The acceptable length of interruption will depend on 
agreement between Investigator and Medical Monitor. 
6.6.2 
Dose Modifications for Nivolumab 
This study will include set dosing for nivolumab (360 mg Q3W). Dose escalation or reduction of 
nivolumab will not be allowed. If toxicity does not resolve or the criteria for resuming study 
intervention are not met within 6 weeks after the last dose, the participant must discontinue study 
intervention, unless written approval to restart therapy is provided by the Medical Monitor. 
Specific anticipated or potential toxicities associated with the administration of nivolumab, as 
well as the measures to be taken to avoid or minimize such toxicity in this trial, are described in 
Table 9. 
AEs associated with nivolumab exposure may represent an immunologic etiology. These irAEs 
may occur shortly after the first dose or several months after the last dose of treatment and may 
affect more than one body system simultaneously. Therefore, early recognition and initiation of 
treatment is critical to reduce complications. Based on existing clinical study data, drug-related 
AEs have included pulmonary toxicity, renal toxicity (including acute renal failure), endocrine 
abnormalities, gastrointestinal toxicity, dermatologic toxicity (including rash), and 
hepatotoxicity. For nivolumab monotherapy, as well as when administered in combination, the 
majority of these AEs have been managed successfully with supportive care and, in more severe 
cases, a combination of dose delay, permanent discontinuation, and/or use of corticosteroids or 


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hormone replacement therapy (endocrinopathies). For suspected irAEs, ensure adequate 
evaluation to confirm etiology or exclude other causes. Additional procedures or tests such as 
bronchoscopy, endoscopy, and skin biopsy may be included as part of the evaluation. 
Dose modification and toxicity management guidelines for irAEs associated with nivolumab are 
provided in Table 9. 
Table 9: 
Dose Modification and Toxicity Management Guidelines for Adverse Events 
Associated with Nivolumab 
Adverse Reaction 
Severitya 
Dose Modifications 
Colitis 
Grade 2 diarrhea or colitis 
Withhold doseb 
Grade 3 diarrhea or colitis 
Withhold doseb  
Grade 4 diarrhea or colitis 
Permanently discontinue 
Pneumonitis 
Grade 2 pneumonitis 
Withhold doseb 
Grade 3 or 4 pneumonitis 
Permanently discontinue 
Hepatitis/non-HCC 
Aspartate aminotransferase (AST) or alanine 
aminotransferase (ALT) more than 3 and up 
to 5 times the upper limit of normal (ULN) 
or total bilirubin more than 1.5 and up to 3 
times the ULN 
Withhold doseb 
AST or ALT more than 5 times the ULN or 
total bilirubin more than 3 times the ULN 
Permanently discontinue 
Hepatitis/HCC 
• If AST/ALT is within normal limits at 
baseline and increases to more than 3 and 
up to 5 times the ULN 
• If AST/ALT is more than 1 and up to 3 
times ULN at baseline and increases to 
more than 5 and up to 10 times the ULN 
• If AST/ALT is more than 3 and up to 5 
times ULN at baseline and increases to 
more than 8 and up to 10 times the ULN 
Withhold dosec 
If AST or ALT increases to more than 10 
times the ULN or total bilirubin increases to 
more than 3 times the ULN 
Permanently discontinue 
Hypophysitis 
Grade 2 or 3 hypophysitis 
Withhold doseb 
Grade 4 hypophysitis 
Permanently discontinue 
Adrenal insufficiency 
Grade 2 adrenal insufficiency 
Withhold doseb 
Grade 3 or 4 adrenal insufficiency 
Permanently discontinue 
Type 1 diabetes mellitus 
Grade 3 hyperglycemia 
Withhold doseb 
Grade 4 hyperglycemia 
Permanently discontinue 
Nephritis and renal 
dysfunction 
Serum creatinine more than 1.5 and up to 6 
times the ULN 
Withhold doseb 
Serum creatinine more than 6 times the 
ULN 
Permanently discontinue 


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Adverse Reaction 
Severitya 
Dose Modifications 
Skin 
Grade 3 rash or suspected Stevens-Johnson 
syndrome (SJS) or toxic epidermal 
necrolysis (TEN) 
Withhold doseb 
Grade 4 rash or confirmed SJS or TEN 
Permanently discontinue 
Encephalitis 
New onset moderate or severe neurologic 
signs or symptoms 
Withhold doseb 
Immune-mediated encephalitis 
Permanently discontinue 
Other 
Other Grade 3 adverse reaction 
• First occurrence 
• Recurrence of the same Grade 3 adverse 
reaction 
 
Withhold doseb 
Permanently discontinue 
Life-threatening or Grade 4 adverse reaction 
Permanently discontinue 
Grade 3 myocarditis 
Permanently discontinue 
Requirement for 10 mg per day or greater 
prednisone or equivalent for more than 12 
weeks 
Permanently discontinue 
Persistent Grade 2 or 3 adverse reactions 
lasting 12 weeks or longer 
Permanently discontinue 
Source: Opdivo USPI, 2018  
ALT = alanine aminotransferase; AST = aspartate aminotransferase; HCC = hepatocellular carcinoma; 
SJS = Stevens-Johnson syndrome; TEN = toxic epidermal necrolysis; ULN = upper limit of normal 
a Guidelines based on toxicity graded per National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI CTCAE), where applicable. 
b Resume treatment when adverse reaction improves to Grade 0 or 1. 
c Resume treatment when AST/ALT return(s) to baseline. 
 
6.6.3 
Dose Modifications for NKTR-214 
Dose delays and reductions are permitted for NKTR-214. Per recommendation of the 
Investigator and approval of the Sponsor’s Medical Monitor, NKTR-214 dose may be delayed or 
reduced to 0.003 mg/kg based on observed drug-related toxicities. If the NKTR-214 dose is 
reduced to 0.003 mg/kg, the dose should remain at this level throughout the remainder of the 
study.  
NKTR-214 may be delayed or reduced for the following reasons (considered to be related to 
NKTR-214): 
• Grade 1 or 2 toxicity:  No requirement for dose delay or dose reduction.  If the toxicity 
persists at Grade 2 following completion of Cycle 1, a dose delay or dose reduction may 
be implemented at the discretion of the Investigator with the approval of the Medical 
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• Grade 3 toxicity:  NKTR-214 may be withheld if toxicity cannot be managed by adequate 
medical intervention. NKTR-214 dosing may resume at the same NKTR-214 dose or at a 
lower NKTR-214 dose level when toxicity resolves to Grade 1 or returns to baseline, 
except for instances where the potential recurrence of the event poses an undue risk for 
the participant. 
If NKTR-214 is delayed, nivolumab administration can continue unless toxicity related to 
nivolumab would warrant a dose delay.   
Participants will be permitted to resume study drug(s) at the same dose level(s) following 
resolution of an AE to ≤ Grade 1 or to baseline within 6 weeks after the last dose, with the 
exception of participants who meet criteria for permanent discontinuation as specified in 
Section 6.6.3.1. Participants who meet criteria for permanent discontinuation of NKTR-214 must 
permanently discontinue all study intervention. 
If the decision is made to resume study drug(s) dosing, the participant should restart treatment on 
the next regularly scheduled study drug(s) dosing visit.  Skipped doses are not to be replaced. 
Participants may resume treatment when the drug-related AE(s) resolve(s) to ≤ Grade 1 or 
baseline, with the following exceptions: 
• Participants may resume treatment in the presence of Grade 2 fatigue. 
• Participants with baseline Grade 1 AST/ALT or total bilirubin who require dose delays 
for reasons other than a 2-grade shift in AST/ALT or total bilirubin may resume 
treatment in the presence of Grade 2 AST/ALT or total bilirubin. 
• Participants with combined Grade 2 AST/ALT and total bilirubin values meeting 
discontinuation parameters (see Section 6.6.3.1) should have treatment permanently 
discontinued. 
• Drug-related pulmonary toxicity, diarrhea, or colitis must have resolved to baseline 
before treatment is resumed. Participants with persistent Grade 1 pneumonitis after 
completion of a steroid taper over at least 1 month may be eligible to resume study 
drug(s) treatment if discussed with and approved by the Medical Monitor. 
• Drug-related endocrinopathies adequately controlled with only physiologic hormone 
replacement may resume treatment after consultation with the Medical Monitor. 
 
Dose delay of NKTR-214 that results in treatment delay of > 6 weeks requires treatment 
discontinuation, with exceptions as noted in Section 6.6.3.1. However, if the toxicity resolves to 
≤ Grade 1 or baseline > 6 weeks after the last dose, but the participant does not otherwise meet 


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the criteria for permanent discontinuation (see Section 6.6.3.1), and the Investigator believes that 
the participant is deriving clinical benefit, then the participant may be eligible to resume 
treatment with NKTR-214.  
6.6.3.1 
Permanent Treatment Discontinuation Criteria 
Participants meeting any of the following criteria attributed to NKTR-214 will be required to 
permanently discontinue all treatment with NKTR-214. However, with Medical Monitor 
approval, NKTR-214 treatment may continue if the toxicities listed below are considered related 
to nivolumab only, provided the event does not meet criteria for delaying or discontinuation of 
nivolumab (see Section 6.6.2).  
• Disease progression in the absence of clinical benefit (see details regarding continuing 
treatment beyond initial assessment of progression per PCWG3-modified RECIST 1.1 in 
Section 4.4 of the core protocol). 
• Clinical deterioration, as assessed by the Investigator. 
• Any Grade 2 drug-related uveitis, eye pain, or blurred vision that does not respond to 
topical therapy and does not improve to Grade 1 severity within 6 weeks or requires 
systemic treatment. 
• Any ≥ Grade 2 drug-related pneumonitis or interstitial lung disease that does not resolve 
following dose delay and systemic steroids (also see Pulmonary Adverse Event 
Management Algorithm in Appendix A-1). 
• Any Grade 3 nonskin, drug-related AE lasting > 7 days, with the following exceptions for 
uveitis, pneumonitis, bronchospasm, diarrhea, colitis, neurologic toxicity, 
hypersensitivity reactions, infusion reactions, endocrinopathies, and laboratory 
abnormalities: 
o Grade 3 drug-related uveitis, pneumonitis, bronchospasm, diarrhea, colitis, neurologic 
toxicity, hypersensitivity reaction, or infusion reaction of any duration requires 
discontinuation. 
o Grade 3 drug-related endocrinopathies adequately controlled with only physiologic 
hormone replacement do not require discontinuation. 
o Grade 3 drug-related laboratory abnormalities do not require treatment 
discontinuation except: 
 Grade 3 drug-related thrombocytopenia > 7 days associated with clinically 
significant bleeding requires discontinuation. 


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 Any drug-related liver function test abnormality that meets the following criteria 
require discontinuation (also see Hepatic Adverse Event Management Algorithm 
in Appendix A-1): 
­ AST or ALT > 5 × to 10 × ULN for > 2 weeks 
­ AST or ALT > 10 × ULN 
­ Total bilirubin > 5 × ULN 
­ Concurrent AST or ALT > 3 × ULN and total bilirubin > 2 × ULN 
• Any Grade 4 drug-related AE or laboratory abnormality, except for the following events, 
which do not require discontinuation: 
o Grade 4 neutropenia ≤ 7 days 
o Grade 4 lymphopenia or leukopenia ≤ 14 days in duration 
o Isolated Grade 4 amylase or lipase abnormalities that are not associated with 
symptoms or clinical manifestations of pancreatitis and decrease to < Grade 4 or 
return to baseline within 7 days. 
o Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with 
clinical sequelae and are corrected with supplementation/appropriate management 
within 72 hours of their onset 
o Grade 4 drug-related endocrinopathy AEs such as adrenal insufficiency, 
adrenocorticotropic hormone deficiency, hyper- or hypothyroidism, or glucose 
intolerance, that resolve or are adequately controlled with physiologic hormone 
replacement (corticosteroids at ≤ 10 mg of prednisone or equivalent per day, thyroid 
hormones) or glucose-controlling agents, respectively, may not require 
discontinuation after discussion with and approval from the Medical Monitor. 
• Any AE, laboratory abnormality, or intercurrent illness that, in the judgment of the 
Investigator, presents a substantial clinical risk to the participant with continued 
treatment. 
• Any dosing delay lasting > 6 weeks after the last dose, with the following exceptions: 
o Dosing delays to allow for prolonged steroid tapers to manage drug-related AEs are 
allowed. Prior to re-initiating treatment in a participant with a dosing delay lasting 
> 6 weeks after the last dose and with no more than 3 missed doses, the Medical 
Monitor must be consulted.  Tumor assessments should continue as per protocol even 
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o Dosing delays > 6 weeks after the last dose that occur for nondrug-related reasons, 
may be allowed if approved by the Medical Monitor. Prior to re-initiating treatment in 
a participant with a dosing delay lasting > 6 weeks after the last dose and with no 
more than 3 missed doses, the Medical Monitor must be consulted. Tumor 
assessments should continue as per protocol even if dosing is delayed, and 
participants must otherwise meet the criteria for continued treatment at the time re-
initiation of study intervention is considered. 
 
7 
DISCONTINUATIONS OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1 
DISCONTINUATION OF STUDY INTERVENTION 
Refer to the core protocol. 
In addition to the discontinuation criteria described in the core protocol, refer to Table 7, 
Section 6.6.2, and Section 6.6.3 for toxicities requiring permanent discontinuation of nivolumab 
and/or NKTR-214. 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM 
STUDY 
Refer to the core protocol. 
7.3 
LOST TO FOLLOW-UP 
Refer to the core protocol. 
8 
STUDY ASSESSMENTS AND PROCEDURES 
Refer to the core protocol. Any combination-specific supplementary information or 
modifications from the core protocol are described in the following sections. 
In this study cohort, the time between doses must not be less than 18 days. 
8.1 
EFFICACY ASSESSMENTS 
Refer to the core protocol. 
8.1.1 
Laboratory Assessments of Clinical Activity 
Samples for the laboratory assessments of clinical activity and hormone levels in Table 10 will 
be sent to the study site’s local laboratory for analysis: 


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Table 10: 
Laboratory Tests Sent to the Study Site’s Local Laboratory for Analysis of 
Disease-related Endpoints 
Profile 
Laboratory Test 
Clinical activity 
PSA 
Hormone levels 
testosterone 
PSA = prostate-specific antigen 
 
 
8.2 
SAFETY ASSESSMENTS 
Refer to the core protocol for a description of the assessments for medical history and 
demographic data, physical examinations, vital signs, and electrocardiograms. 
Descriptions of additional combination-specific assessments are provided in the following 
sections.  
8.2.1 
Increased Monitoring and Vital Sign Guidelines for Infusion-
related Reaction or Hypotension 
If the participant experiences a ≥ Grade 2 infusion-related reaction or hypotension during the 
days after NKTR-214 and/or nivolumab administration, the participant may be monitored 
overnight at the discretion of the Investigator. Longer periods of monitoring may be 
implemented at the discretion of the Investigator. 
8.2.2 
Echocardiograms 
Standard ECHO will be performed to assess cardiac function and LVEF according to the SOA 
(Section 1.3). In the event of an abnormal ECHO, the Investigator may perform a stress ECHO 
(either exercise or nuclear). A MUGA scan can be performed to assess cardiac function and 
LVEF if a standard echocardiogram cannot be performed. The same assessment method should 
be used for the same participant throughout the study. 
8.2.3 
Clinical Safety Laboratory Assessments 
8.2.3.1 
Local Laboratory Assessments 
Samples for the laboratory tests in Table 11 will be sent to the study site’s local laboratory for 
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Table 11: 
Laboratory Tests Sent to the Study Site’s Local Laboratory for Analysis of 
Safety 
Profile 
Laboratory Test 
Hematology 
RBC count 
hemoglobin 
hematocrit 
WBC count with automated differential (neutrophils, eosinophils, basophils, 
monocytes, lymphocytes, other cells) 
platelet count 
manual differential, if clinically indicated 
Clinical Chemistry 
(Serum or Plasma) 
sodium 
potassium 
chloride 
bicarbonate 
glucose 
BUN or urea 
creatinine 
total protein 
albumin 
calcium 
total bilirubin 
alkaline phosphatase 
ALT 
AST 
LDH 
TSH (T3 and FT4 should be checked if TSH is outside the normal range) 
coagulation assessments (PT, PTT, INR)a 
Urinalysis 
 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; 
INR = international normalized ratio; LDH = lactate dehydrogenase; PT = prothrombin time; PTT = partial 
thromboplastin time; RBC = red blood cell; TSH = thyroid stimulating hormone; WBC = white blood cell 
a Coagulation assessment not required during treatment phase unless indicated 
 
 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
Refer to the core protocol for the SAE and AE collection periods and for details regarding safety 
reporting. 
8.3.4 
Regulatory Reporting Requirements for SAEs 
Refer to the core protocol for the regulatory reporting requirements for SAEs. 
For this cohort, the Parker Institute for Cancer Immunotherapy Pharmacovigilance Group will 
report SAEs to regulatory authorities, the overall PI, Bristol-Myers Squibb, Nektar Therapeutics, 
and the Institutional Review Board/Independent Ethics Committee (IRB/IEC), as appropriate. 


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The process for such reporting, including contact information and specific instructions for 
reporting to each of these organizations, is described in the Safety Monitoring Plan. 
8.3.7 
Adverse Events of Special Interest 
There are no identified adverse events of special interest for this immunotherapy combination. 
8.4 
TREATMENT OF OVERDOSE 
Refer to the core protocol. 
8.5 
PHARMACOKINETICS 
Sparse PK blood sampling will be collected according to the SOA to assess the PK of 
NKTR-214 and/or nivolumab. 
PK profiles for NKTR-214 and/or nivolumab may be performed using a validated assay method 
under the supervision of the Sponsor’s designee. 
8.6 
ANTI-DRUG ANTIBODIES 
Immunogenicity samples will be collected according to the SOA to enable evaluation of anti-
drug antibodies (ADA) to either NKTR-214 and/or nivolumab. Additionally, blood samples 
should also be collected at the final visit from participants who discontinued study intervention 
or were withdrawn from the study. These samples may be tested by the Sponsor's designee. 
The detection and characterization of antibodies to NKTR-214 and/or nivolumab may be 
performed using a validated assay method under the supervision of the Sponsor’s designee. 
8.7 
BIOMARKERS 
Refer to the core protocol. 
8.8 
MEDICAL RESOURCE UTILIZATION AND HEALTH 
ECONOMICS 
Refer to the core protocol. 
9 
STATISTICAL CONSIDERATIONS 
Refer to the core protocol. 
9.5.1 
Interim Safety Monitoring 
Refer to the core protocol for details related to the Safety Assessment Committee (SAC), the 
committee charged with safety review for this study. 


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10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
Refer to the core protocol for the following appendices: 
Appendix 1: Regulatory, Ethical and Study Oversight Considerations 
Appendix 2: Eastern Cooperative Oncology Group (ECOG) Performance Status 
Appendix 3: RECIST Criteria (Version 1.1) with Modifications as Recommended by 
PCWG3 
Appendix 4: Clinical Laboratory Tests 
Appendix 5: Adverse Events: Definitions and Procedures for Recording, Evaluating, Follow-
up, and Reporting 
Appendix 6: Contraceptive Guidance and Collection of Pregnancy Information 
Appendix 7: Genetics 


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10.1 
APPENDIX A-1: MANAGEMENT ALGORITHMS 
Management algorithms have been developed to provide guidance for Investigators in assessing 
and managing immune-mediated events in participants receiving nivolumab. Section 6.6.2 
describes the criteria for dose delay and discontinuation to be followed for nivolumab in this 
cohort. These algorithms are intended to provide clinical recommendations. In cases in which the 
modification criteria in Section 6.6.2 and the algorithms differ, the criteria in Section 6.6.2 
should take precedence. 
The management algorithms are provided for the following groups of drug-related AEs: 
• Immune-mediated gastrointestinal adverse events (diarrhea, colitis) 
• Immune-mediated renal adverse events (nephritis and renal dysfunction) 
• Immune-mediated pulmonary adverse events (pneumonitis) 
• Immune-mediated hepatic adverse events (hepatitis) 
• Immune-mediated endocrinopathy adverse events (hypophysitis, adrenal insufficiency, 
hypothyroidism and hyperthyroidism, Type 1 diabetes mellitus) 
• Immune-mediated skin adverse events 
• Immune-mediated neurologic adverse events (encephalitis) 
 
 


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10.2 
APPENDIX A-2: LISTS OF TERMINOLOGY AND 
ABBREVIATIONS 
10.2.1 
List of Terminology 
Terminology 
Description 
Cohort 
A group of participants receiving the same immunotherapy 
combination. 
Cohort appendix 
A document that guides the treatment of participants in a given 
cohort. The cohort appendices are identified using a letter 
designation (eg, Appendix Cohort A).  
Core protocol 
The master document that provides the elements common 
across the study and among all cohorts, unless otherwise 
specified. 
Immunotherapy combination 
Two or more study interventions administered to a cohort of 
participants. 
 
10.2.2 
List of Abbreviations 
Abbreviation 
Definition 
1L 
first-line 
2L 
second-line 
ACTH 
adrenocorticotropic hormone 
ADA 
anti-drug antibody(ies) 
ADP 
adenosine diphosphate 
AE(s) 
adverse event(s) 
AIDS 
acquired immunodeficiency syndrome 
ALT 
alanine aminotransferase 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
BUN 
blood urea nitrogen 
C 
cycle 
Cavgss 
average steady-state concentration 
cfDNA 
cell-free deoxyribonucleic acid 
cHL 
classical Hodgkin lymphoma 
Cmax 
maximum observed drug concentration 
Cmaxss 
maximum steady-state plasma concentration 
Cminss 
minimum steady-state plasma concentration 
Cmin1 
trough concentration after the first dose 
CNS 
central nervous system 


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Abbreviation 
Definition 
CR 
complete response 
CRC 
colorectal cancer 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA-4 
cytotoxic T-lymphocyte-associated protein 4 
DCR 
disease control rate 
DLT 
dose limiting toxicity 
dMMR 
mismatch repair deficient 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EOT 
end of treatment 
EPO 
erythropoietin 
FDA 
Food and Drug Administration 
FFPE 
formalin-fixed paraffin-embedded 
GCP 
Good Clinical Practice 
GFR 
glomerular filtration rate 
GnRH 
gonadotropin-releasing hormone 
HCC 
hepatocellular carcinoma 
HIV 
human immunodeficiency virus 
I/E 
inclusion/exclusion 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
IgG4 
immunoglobulin G4 
IL-2 
interleukin 2 
IL-2Rαβγ 
IL-2 receptor alpha beta gamma 
IL-2Rβγ 
IL-2 receptor beta gamma 
imAE(s) 
immune-mediated AE(s) 
INR 
international normalized ratio 
irAE(s) 
immune-related AE(s) 
IRB/IEC 
Institutional Review Board/Independent Ethics Committee 
IV 
intravenous(ly) 
LDH 
lactate dehydrogenase 
LVEF 
left ventricular ejection fraction 
mAb 
monoclonal antibody 
mCRPC 
metastatic castration-resistant prostate cancer 
MDSC(s) 
myeloid-derived suppressor cell(s) 
MedDRA 
Medical Dictionary for Regulatory Activities 
MSI-H 
microsatellite instability-high 


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Abbreviation 
Definition 
MTD 
maximum tolerated dose 
MUGA 
multigated acquisition 
NCI 
National Cancer Institute 
NK 
natural killer 
NKTR-214-AC 
NKTR-214 active cytokines 
NKTR-214-RC 
NKTR-214 related cytokines 
NSAIDs 
nonsteroidal anti-inflammatory drugs 
NSCLC 
non–small-cell lung cancer 
NYHA 
New York Heart Association 
ORR 
objective response rate 
OS 
overall survival 
PARP 
poly ADP ribose polymerase 
PCWG3 
Prostate Cancer Clinical Trials Working Group 3 
PD 
progressive disease 
PD-1 
programmed cell death 1 
PD-L1 
programed cell death ligand 1 
PEG 
polyethylene glycol 
PI 
Principal Investigator 
PK 
pharmacokinetics 
PORTER 
Prostate Researching Translational Endpoints Correlated to Response 
PPK 
population pharmacokinetics 
PR 
partial response 
PSA 
prostate-specific antigen 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
Q2W 
every 2 weeks 
Q3M 
every 3 months 
Q3W 
every 3 weeks 
Q4W 
every 4 weeks 
QTcF 
Fridericia’s corrected QT interval 
RBC 
red blood cell 
RCC 
renal cell carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
rhIL-2 
recombinant human interleukin-2 
rPFS 
radiographic progression-free survival 
S 
screening 
SAC 
Safety Assessment Committee 
SAE(s) 
serious adverse event(s) 


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Abbreviation 
Definition 
SCCHN 
squamous cell carcinoma of the head and neck 
SD 
stable disease 
SGOT 
serum glutamic-oxaloacetic transaminase 
SGPT 
serum glutamic-pyruvic transaminase 
SJS 
Stevens-Johnson syndrome 
SOA 
Schedule of Activities 
TB 
tuberculosis 
TEN 
toxic epidermal necrolysis 
Tmax 
mean time to maximum serum concentration 
TMB 
tumor mutational burden 
TNBC 
triple-negative breast cancer 
TRAE(s) 
treatment-related adverse event(s) 
Treg(s) 
regulatory tumor cell(s) 
TSH 
thyroid stimulating hormone 
UC 
urothelial carcinoma 
ULN 
upper limit of normal 
US 
United States 
USPI 
US Prescribing Information 
WBC 
white blood cell 
 


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10.3 
APPENDIX A-3: APPENDIX COHORT A AMENDMENT 
HISTORY 
 
DOCUMENT HISTORY 
Documents 
Date of Issue 
Amendment 1 
24 Jan 2019 
Original Appendix Cohort A 
07 Dec 2018 
 
 
 


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11 
REFERENCES 
Addendum 1 to NKTR-214 Investigator’s Brochure version 5.0, dated 03-Jul-2018. Nektar 
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