An Open-label, Multicenter, Dose-escalation, Phase 1b/2 Study of the Safety, Efficacy, Pharmacodynamics, and Pharmacokinetics of RTA 408 in Combination With Ipilimumab or Nivolumab in the Treatment of Patients With Unresectable or Metastatic Melanoma
Phase: PHASE1
Conditions: Melanoma, Unresectable (Stage III) Melanoma, Metastatic (Stage IV) Melanoma
Sponsor: Biogen

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R T A 4 0 8  
 
4 0 8 -C -1 4 0 1  
 
A N O P E N -L A B E L, M U L TI C E N T E R, D O S E -
E S C A L A TI O N , P H A S E 1 B/ 2  S T U D Y O F T H E S A F E T Y, 
E F FI C A C Y , P H A R M A C O D Y N A MI C S, A N D 
P H A R M A C O KI N E TI C S O F R T A 4 0 8 I N C O M BI N A TI O N 
WI T H I PI LI M U M A B O R NI V O L U M A B I N T H E 
T R E A T M E N T O F P A TI E N T S WI T H U N R E S E C T A B L E 
O R M E T A S T A TI C M E L A N O M A   
 
V E R SI O N 5 . 0 –  2 9  N O V E M B E R 2 0 1 6  
N C T 0 2 2 5 9 2 3 1  
 
T he i nf or mati o n c o ntai ne d herei n is c o nfi de ntial a n d t he pr o prietar y pr o pert y of 
Reata P har ma ce uticals, I nc. a n d a n y u n a ut h orize d use or discl os ure of s uc h 
i nf or mati o n wit h o ut t he pri or writte n a ut h orizati o n of Reata P har mace uticals, 
I n c. is e x pressl y pr o hi bit e d. 

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S P O N S O R A P P R O V A L A N D SI G N A T U R E P A G E  
 
 
 
 
 
 
 
 
 
 
 
Date  
 
 
 
 
 
 
 
Date  
 
 
 
 
 
 
 
Date  
 
 

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I N V E S TI G A T O R’ S A G R E E M E N T 
 
I h a ve recei ve d a n d rea d t he I n v esti gat or’s Br oc h ure f or R T A 4 0 8 .  I ha ve rea d t he 4 0 8 -C -1 4 0 1  
cli nical st u d y pr ot oc ol  a n d a gree t o c o n d uct t he st u d y as o utli ne d .  I a gree t o mai ntai n t he 
c o nfi de ntialit y of all i nf or mati o n recei ve d or de v el o pe d i n c o n necti o n wit h t his pr ot oc ol.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pri nte d Na me of I n v esti gat or  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Si g nat ure of I n vesti gat or  
 
 
 
 
 
 
 
 
Date  

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P R O C E D U R E S I N C A S E O F E M E R G E N C Y  
 
T a ble 1 : 
E mer ge nc y C o nt act I nf or m ati o n  
R ole i n St u d y  
N a me  
A d dress a n d Tele p h o ne N u m ber  
 
 
 
  
 
 
 
 
 
 
   
 
  
  
 
  
 
 
 
 
 
 
 

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2.  
S Y N O P SI S  
N a me of S p o ns or/ co m p a n y:  
Reata P har mace uticals, I nc.  
N a me of in vesti g ati o n al p r o d ucts: 
R T A 4 0 8 Ca ps ules  
N a me of a cti ve in gre die nt:  
R T A 4 0 8  
Title of st u d y:  
A n O pe n -La bel, M ultice nter, D ose -Escalati o n , P hase 1 b/ 2  St u d y of t he Safet y, Efficac y, 
P har mac o d y na mics, a n d P har mac o ki netics of R T A 4 0 8 i n C o m bi nati o n w it h I pili m u ma b or 
Ni v ol u ma b i n t he Treat me nt of Patie nts w it h U nresecta ble or Metastatic Mela n o m a  
St u d y ce nter(s):  U p t o 1 5 st u d y  ce nters i n t he U nite d States  
St u die d peri o d ( ye ars): < 3  
Esti mate d date first patie nt e nr olle d : Se pte m ber 2 0 1 4  
Esti mate d date last patie nt c o m plete d: Marc h 2 0 1 8  
P h ase of de vel o p me nt:  
1 b/ 2  
O bjecti ves:  
Pri m ar y:  
•  
T o deter mi ne t he safet y of R T A 4 0 8 i n c o m bi nati o n wit h i pili m u ma b or ni v ol u ma b  
•  
T o e val uate t he efficac y of t he P hase 2 d ose of R T A 4 0 8 i n c o m bi nati o n wit h ni v ol u ma b 
usi n g o verall res p o nse rate ( O R R; c o m plete pl us partial res p o nses)  
E x pl or at or y:  
 
 
 
 
 
 
 
 
 
Met h o d ol o g y:  
I n t his o pe n-la bel, m ultice nter, d ose-escalati o n, P hase 1 b/ 2 st u d y, patie nts w h o q ualif y will recei ve 
R T A  4 0 8  at t he assi g ne d d ose le vel i n c o m bi nati o n wit h i pili m u ma b ( 3 m g/ k g) or ni v ol u ma b ( 2 4 0 
m g ).   
C o h orts 1 t o 3 : 
T wel ve patie nts will be e nr olle d at eac h d ose le vel, wit h si x patie nts a d mi nistere d R T A 4 0 8 + 
i pili m u ma b a n d t he re mai ni n g si x a d mi nistere d R T A 4 0 8 + ni v ol u ma b.  Selecti o n of t hera p y t o be 
use d i n c o m bi nati o n wit h R T A  4 0 8  (i.e., i pili m u ma b or ni v ol u ma b) s ho ul d be deter mi ne d b y t he 
i n vesti gat or as cli nicall y i n dicate d.   
C o h orts 4  t o 1 0 : 
T hree ( 3) t o si x ( 6) patie nts will be e nr olle d at eac h d ose le vel, a n d patie nts will recei ve R T A 4 0 8 + 
ni v ol u ma b.   
 

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Patie nts will recei ve R T A  4 0 8  m o n ot hera p y orall y o nce da il y d uri n g a r u n-i n peri o d f or 1 wee k pri or 
t o i nitiati o n of c o m bi nati o n t hera p y.  F or patie nts treate d wit h i pili m u ma b ( C o h orts 1 t o 3 o nl y) , t he 
r u n-i n peri o d will be f oll o we d b y R T A  4 0 8  orall y o nce dail y i n c o m bi nati o n wit h i pili m u ma b 
a d mi nistere d at Wee ks 1, 4, 7, a n d 1 0.  After Wee k 1 0, patie nts will recei ve mai nte na nce treat me nt 
wit h R T A  4 0 8  al o ne o nce dail y.  F or patie nts treate d wit h ni v ol u ma b t hera p y, t he r u n -i n peri o d will 
be f oll o we d b y R T A  4 0 8  orall y o nce dail y i n c o m bi nati o n wit h ni v ol u ma b a d mi nistere d e ver y t w o 
wee ks as cli nicall y i n dicate d.  After Wee k 2 4 ( patie nts treate d wit h R T A 4 0 8 + i pili m u ma b) or Wee k 
2 5 ( patie nts treate d wit h R T A 4 0 8 + ni v ol u ma b), patie nts will ret ur n f or st u d y visits e ver y 1 2 wee ks.  
Eac h patie nt will c o nti n ue at t he a ssi g ne d R T A  4 0 8  d ose le vel u ntil disease pr o gressi o n occ urs, 
t o xicit y re q uiri n g disc o nti n uati o n fr o m st u d y dr u g (i.e., R T A  4 0 8 ) is e x perie nce d, t he patie nt has 
c o m plete d 1 6 8  wee ks ( patie nts treate d wit h R T A  4 0 8  + i pili m u ma b) or 1 6 9  wee ks  ( patie nts treate d 
wit h R T A  4 0 8  + ni v ol u ma b) of treat me nt , t he patie nt is disc o nti n ue d fr o m t he st u d y dr u g f or a n ot her 
reas o n, t he patie nt wit h dra ws c o nse nt, or t he patie nt is eli gi ble f or d ose escalati o n (Secti o n  7. 4. 4 ).  
Patie nts will ret ur n 4  wee ks after R T A  4 0 8  treat me nt c o m pleti o n f or a f oll o w-u p visit.   
A tra diti o nal 3 + 3 d ose escalati o n desi g n will be i m ple me nte d f or t he P hase 1 b p orti o n of t he st u d y t o 
e val uate R T A 4 0 8 f or safet y a n d t olera bilit y wit hi n eac h c o h ort a n d select a tar get d ose f or t he 
P hase  2 p orti o n of t he st u d y.  D ose selecti o n i n t he P hase 1 b p orti o n of t he st u d y will be base d o n 
a vaila bl e safet y a n d  p har mac o d y na mic  data fr o m t his st u d y, as well as a d diti o nal d ata fr o m ot her 
st u dies wit h R T A 4 0 8 i n ot her patie nt p o p ulati o ns ( N C T 0 2 2 5 5 4 3 5 a n d N C T 0 2 2 5 5 4 2 2 ).  D ose 
escalati o n ma y  pr ocee d u ntil a ma xi m u m t olerate d d ose ( M T D) or ma xi m u m feasi ble 
p har mac o d y na mic  res p o nse has bee n reac he d.   
T he d ose -li miti n g t o xicit y ( D L T) o bser vati o n peri o d will last u ntil t he Wee k 7 visit f or patie nts 
recei vi n g R T A  4 0 8  i n c o m bi nati o n wit h i pili m u ma b, w hic h is 6 wee ks after i nitiati o n of i pili m u ma b 
t hera p y.  T he D L T o bser vati o n peri o d will last u ntil t he Wee k 5 visit f or patie nts recei vi n g R T A 4 0 8 
i n c o m bi nati o n wit h ni v ol u ma b, w hic h is 4  wee ks after i nitiati o n of ni v ol u ma b t hera p y.  D L T is 
defi ne d as a n y t o xicit y Gra de ≥ 3 ( usi n g C T C A E, versi o n 4. 0 3), e xce pt as n ote d i n pr ot oc ol Secti o n 
7. 4. 3  or  t o xicit y t hat re q uires i pili m u ma b or ni v ol u ma b dela y or disc o nti n uati o n as detaile d i n 
pr ot oc ol Secti o n  9. 1 . 
A fter t he first 3 patie nts ha ve c o m plete d t he D L T o bser vati o n peri o d, all a vaila ble safet y a n d 
p har mac o d y na mic i nf or mati o n f or all e nr olle d patie nts will be re vie we d b y t he pr ot oc ol safet y re vie w 
c o m mittee ( P S R C) t o ma ke a decisi o n re gar di n g escalati o n t o t he s u bse q ue nt R T A  4 0 8  d ose le vel or 
of t he nee d t o e val uate safet y data fr o m a d diti o nal patie nts treate d at t he c urre nt R T A  4 0 8 d ose le vel .  
If a d diti o nal safet y e val uati o n is nee de d as deter mi ne d b y t he r ules f or d ose escalati o n, a n ot her re vie w 
of t he dat a will occ ur o nce t he ne xt 3 patie nts (f or a t otal of 6 patie nts) ha ve c o m plete d t he D L T 
o bser vati o n peri o d.  T he P S R C ma y als o elect t o a d d 3 patie nts at t he d ose -le vel u n der re vie w t o gai n 
a d diti o nal p har mac o d y na mic data.  A d diti o nall y, t he P S R C ma y rec o m me n d e nr olli n g a c o h ort at a 
l o wer d ose le vel base d o n safet y data or re vie w of a vaila ble i n d uci ble nitric o xi de s y nt hase (i N O S) 
e x pressi o n c ha n ges o bser ve d i n e nr olle d patie nts s o t hat a p pr o priate d ose le vels are e nr olle d f or 
selecti o n of t he P hase 2 d ose.   
A P hase 2 d ose of R T A  4 0 8  will be selecte d base d o n safet y a n d p har mac o d y na mic data fr o m t he 
d ose -escalati o n c o h orts.  T he P hase 2 p orti o n of t he st u d y will  i ncl u de a se parate e x pa nsi o n c o h ort 
c o nsisti n g of patie nts w h o ha ve recei ve d pri or treat me nt w it h a nti -P D -1 or a nti -P D -L 1 t hera pies .  
Patie nts e nr olle d i n t he e x pa nsi o n c o h ort will be  treate d wit h t he selecte d P hase 2 d ose of R T A 4 0 8 i n 
c o m bi nati o n wit h ni v ol u ma b .  T he P hase 2 e x pa nsi o n c o h ort will i ncl u de a n a d diti o nal 2 4 or 
2 7  patie nts t o ac hie ve  a t otal of 3 0 patie nts at t hat R T A  4 0 8  d ose i n c o m bi nati o n wit h ni v ol u ma b.  
T u m or res p o nse will be assesse d at Wee k 1 3  a n d a p pr o xi matel y e ver y 1 2  wee ks t hereafter.  
N u m ber of p atie nts ( pl a n ne d):  
U p t o 1 0 2  patie nts are e x pecte d t o e nr oll i n t his st u d y.  

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Incl usi o n  criteri a:  
Patie nts m ust:  
1.  Pr o vi de writte n i nf or me d c o nse nt f or st u d y partici pati o n, a p pr o ve d b y t he a p pr o priate 
i nstit uti o nal re vie w b oar d 
2.  Be ≥ 1 8 years of a ge  
3.  Ha ve a d va nce d, u nresecta ble ( Sta ge I II) or metastatic ( Sta ge I V) mela n o ma 
4.  Be  eli gi ble f or c o m mercial recei pt of t hera p y t o be use d i n t his st u d y i n c o m bi nati o n  wit h 
R T A  4 0 8 (i.e., i pili m u ma b or ni v ol u ma b i n t he P hase 1 b c o h orts  a n d ni v ol u ma b o nl y i n t he 
P hase 2  c o h ort)  
5.  Ha ve recei ve d p ri or treat me nt wit h a nti-P D -1 or a nti -P D -L 1 t hera p y (i ncl u di n g e x peri me ntal 
t hera pies) if e nr olli n g i n t he P hase 2 p orti o n of t he st u d y.  T his criteria d oes n ot a p pl y t o 
patie nts e nr olli n g i n t he P hase 1 b p orti o n of t he st u d y .  S u bjects w h o are c urre ntl y ta ki n g 
ni v ol u ma b a n d ha ve sta ble disease ( S D) per i n vesti gat or assess me nt will be eli gi ble t o 
partici pate pr o vi de d S D has bee n  prese nt f or at least 3 m o nt hs  
6.  Ha ve > 5 % of t u m or cells fr o m t he scree ni n g bi o ps y stai ne d p ositi ve f or i N O S e x pressi o n i n 
a n i m m u n oc he mistr y assa y  
7.  Ha ve a n Easter n C o o perati ve O nc ol o g y Gr o u p perf or ma nce stat us ≤2  
8.  Ha ve a life e x pecta nc y of  ≥ 3 m o nt hs at t he ti me of scree ni n g i n t he i n ve sti gat or’s o pi ni o n   
9.  Ha ve disc o nti n ue d pre vi o us treat me nts f or ca ncer a n d rec o vere d fr o m all ac ute t o xic effects 
of pri or s yste mic t hera p y t o Gra de ≤1.  E xe m pte d are effects t hat are ofte n n o n -re versi ble or 
re q uire a pr ol o n ge d ti me f or re versal (e. g., al o pecia, h y p ot h yr oi dis m, ne ur o pat h y) 
1 0.  H a ve disc o nti n ue d pre vi o us e x peri me ntal t hera pies a n d c hec k p oi nt i n hi bit or a nti b o dies at 
least 2 8  da ys pri or t o t he Ra n d o mizati o n Visit .  T his d oes n ot a p pl y t o s u bjects f or P hase 2 
w h o are c urre ntl y recei vi n g ni v ol u ma b a n d ha ve S D  
1 1.  Ha ve a de q uate b o ne  marr o w  reser ve a n d or ga n f u ncti o n at t he Scree ni n g Visit as f oll o ws: 
a. He mat ol o gic:  A bs ol ute ne utr o p hil c o u nt > 1. 5 x 1 0 9/ L, platelets > 1 0 0 x 1 09/ L, 
he m o gl o bi n ≥9  g/ d L ( patie nts ma y recei ve er yt hr oc yte tra nsf usi o ns t o ac hie ve t his 
he m o gl o bi n le vel, at t he discreti o n of t he i n vesti gat or, b ut t he first d ose of st u d y dr u g 
m ust n ot be gi n u ntil 5 da ys after t he er yt hr oc yte tra nsf usi o n)  
b.  He patic:  T otal bilir u bi n ≤1. 5 X t he u p per li mit of n or mal ( U L N), ala ni ne 
a mi n otra nsferase a n d as partate a mi n otra nsferase ≤ 2. 5 X  U L N  f or patie nts wit h o ut 
li ver metastasis or ≤ 5 X  U L N f or patie nts wit h li ver metastasis  
c. Re nal:  Esti mate d gl o mer ular filtrati o n rate (e G F R) usi n g t he M o dificati o n of Diet i n 
Re nal Disease ( M D R D) f or m ula ≥6 0 m L/ mi n/ 1. 7 3 m 2 
1 2.  Be a ble t o s wall o w ca ps ules  
1 3.  Be willi n g a n d a ble t o c o o perate wit h all as pects of t he pr ot oc ol  
1 4.  Be willi n g t o practice t he f oll o wi n g me dicall y acce pta ble met h o ds of birt h c o ntr ol ( b ot h 
w o me n of c hil d beari n g p ote ntial a n d me n w h o ha ve part ners of c hil d beari n g p ote ntial) fr o m 
t he Scree ni n g Visit t hr ou g h 3 m o nt hs after ta ki n g t he fi nal d ose of R T A  4 0 8 :  s per mici de 
wit h d o u ble barrier, oral c o ntrace pti ve, va gi nal ri n g, i njecta ble or i m pla nta ble met h o d of 
c o ntrace pti o n, tra ns der mal c o ntrace pti ve, i ntra uteri ne de vice, s ur gical sterilizati o n of part ner, 
or  a bsti ne nce (f or n o n – se x uall y acti ve patie nts).  W o me n of c hil d beari n g p ote ntial i ncl u de all 
fe males w h o ha ve e x perie nce d me narc he a n d ha ve n ot e x perie nce d me n o pa use ( defi ne d as 
a me n orr hea f or > 1 2 c o nsec uti ve m o nt hs) or ha ve u n der g o ne  s uccessf ul s ur gical sterilizati o n 
( h ysterect o m y, bilateral t u bal li gati o n, or bilateral o o p h orect o m y) 
 

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1 5.  W o me n of c hil d beari n g p ote ntial m ust n ot be pre g na nt or lactati n g a n d m ust a gree t o ha ve 
pre g na nc y testi n g perf or me d at eac h visit e xce pt at Wee k 1 a n d Wee k 2 ( Visits 3 a n d 4) 
E x cl usi o n criteri a:  
Patie nts m ust n ot:  
1.  Ha ve oc ular mela n o ma   
2.  Ha ve pri or mali g na nc y acti ve wit hi n t he pre vi o us 2 years e xce pt f or l ocalize d ca ncers t hat are 
c o nsi dere d t o ha ve bee n c ure d a n d, i n t he o pi ni o n of t he i n vesti gat or, prese nt a l o w ris k f or 
rec urre nce (e. g., basal or s q ua m o us cell s ki n ca ncer, s u perficial bla d der ca ncer, or carci n o ma 
i n sit u of t he pr ostate, cer vi x, or breast ) 
3.  Ha ve a n y acti ve a ut oi m m u ne disease or a hist or y of k n o w n or s us pecte d a ut oi m m u ne disease, 
or hist or y of s y n dr o me t hat re q uire d s yste mic ster oi ds or i m m u n os u p pres si ve me dicati o ns, 
e xce pt f or patie nts wit h vitili g o or res ol ve d c hil d h o o d ast h ma/at o p y or ot her s y n dr o mes 
w hic h w o ul d n ot be e x pecte d t o rec ur i n t he a bse nce of a n e xter nal tri g ger.  Patie nts wit h t y pe 
1 dia betes mellit us are per mitte d t o e nr oll.  Diseases  t hat are c o nsi dere d a ut oi m m u ne relate d 
i ncl u de t he f oll o wi n g: 
a. I nfla m mat or y b o wel disease, i ncl u di n g ulcerati ve c olitis a n d Cr o h n’s disease 
b.  S y m pt o matic diseases (e. g., r he u mat oi d art hritis, s yste mic pr o gressi ve scler osis, 
syste mic lu p us er yt he mat os us, a uto i m m u ne vasc ulitis) 
c. M ot or ne ur o pat hies c o nsi dere d of a ut oi m m u ne ori gi n (e. g., G uillai n -Barr é sy n dr o me)  
4.  Ha ve ha d brai n metastases (scree ni n g n ot re q uire d), u nless t he y ha ve met all of t he f oll o wi n g 
criteria: 
a. Ha d a resecti o n a n d/ or c o m plete d a c o urse of cra n ial irra diati o n, a n d 
b.  Ha ve n o w orse ni n g ce ntral ner v o us s yste m s y m pt o ms, a n d  
c. Ha ve n o ma g netic res o na nce i ma gi n g ( M RI) e vi de nce of pr o gressi o n f or at least 
8  wee ks after treat me nt is c o m plete a n d wit hi n 2 8 da ys pri or t o first d ose of st u d y 
dr u g a d mi nistrati o n, a n d  
d.  Ha ve disc o nti n ue d all c ortic oster oi ds f or t hat i n dicati o n f or at least 2 wee ks  
5.  Ha ve t he f oll o wi n g car di o vasc ular a b n or malities:  
a. E vi de nce of p o or car di o vasc ular f u ncti o n, defi ne d as B -t y pe natri uretic pe pti de 
( B N P) > 2 0 0 p g/ m L or N T -pr o B N P > 2 X t he  u p per li mit of n or mal ( U L N)  
b.  Hist or y of c o n gesti ve heart fail ure, u nsta ble a n gi na, or u nc o ntr olle d h y perte nsi o n  
c. Cli nicall y si g nifica nt ve ntric ular arr h yt h mias at t he Scree ni n g Visit  
d.  M y ocar dial i nfarcti o n wit hi n 6 m o nt hs pri or t o t he Scree ni n g Visit  
e. C orrecte d  Q Tc i nter val o n electr ocar di o gra m ( E C G) at t he Scree ni n g Visit > 5 0 0 
msec  
6.  Ha ve k n o w n he patic i m pair me nt, i ncl u di n g cirr h osis  
7.  Ha ve k n o w n re nal i m pair me nt, i ncl u di n g gl o mer ul o ne p hritis  
8.  Ha ve se vere cere bral or peri p heral vasc ular disease  
9.  Ha ve pre -e xisti n g c hr o nic diarr hea C T C A E ( C o m m o n Ter mi n ol o g y Criteria f or A d verse 
E ve nts) Gra de ≥2 of a n y eti ol o g y (i ncl u di n g mala bs or pti o n dis or ders a n d s ur gical pr oce d ures 
t hat, i n t he o pi ni o n of t he i n vesti gat or, ma y affect a bs or pti o n of st u d y dr u g) 
1 0.  Ha ve k n o w n acti ve f u n gal , bacterial, a n d/ or viral i nfecti o n, i ncl u di n g h u ma n 
i m m u n o deficie nc y vir us ( HI V) or he patitis vir us ( A, B, or C) 

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1 1.  Ha ve ha d maj or s ur ger y wit hi n 2 1 da ys bef ore t he Ra n d o mizati o n Visit ( Da y 1 Visit)  
 
 
1 2.  Ha ve ta ke n a n y of t he f oll o wi n g dr u gs wit hi n 7 da ys bef ore t he Ra n d o mizati o n Visit ( Da y 1 
Visit):  
a. Se nsiti ve s u bstrates f or c yt oc hr o me P 4 5 0 2 C 8 or 3 A 4 (e. g., re pa gli ni de, mi daz ola m, 
sil de nafil) 
b.  S u bstrates f or p -gl yc o pr otei n tra ns p orter (e. g., a m brise nta n, di g o xi n), O C T 1 
tra ns p orter (e. g., metf or mi n), O A T 1 tra ns p orter (e. g., ca pt o pril, f ur ose mi de, 
met h otre xate), or O A T P 1 B 3 tra ns p orter (e. g., at or vastati n, r os u vastati n, valsarta n)  
c. C Y P 3 A i n hi bit ors a n d str o n g i n d ucers  
1 3.  Ha ve k n o w n or s us pecte d acti ve dr u g or alc o h ol a b use  
1 4.  Ha ve a n y a b n or mal la b orat or y test val ue or  seri o us pre-e xisti n g me dical c o n diti o n t hat, i n t he 
o pi ni o n of t he i n vesti gat or, w o ul d p ut t he patie nt at ris k b y trial e nr oll me nt  
1 5.  Be u na ble t o c o m pl y wit h t he re q uire me nts of t he st u d y pr ot oc ol or be u ns uita ble f or t he 
st u d y f or a n y reas o n, i n t he o pi ni on of t he i n vesti gat or  
I n vesti g ati o n al pr o d uct, d os a ge a n d m o de of a d mi nistr ati o n:  
R T A  4 0 8  ca ps ules will be a d mi nistere d orall y at t he starti n g d ose le vel a n d s u bse q ue nt d ose le vels 
defi ne d b y t he P S R C.  
D ur ati o n of tre at me nt:  
R T A  4 0 8  will be a d mi nistere d orall y o nce dail y f or u p t o 1 6 8  wee ks i n c o m bi nati o n wit h i pili m u ma b 
( 3 m g/ k g) gi ve n i ntra ve n o usl y at Wee ks 1, 4, 7, a n d 1 0 or u p t o 1 6 9  wee ks i n c o m bi nati o n wit h 
ni v ol u ma b ( 2 4 0 m g ) gi ve n i ntra ve n o usl y e ver y 2 wee ks f or 1 6 8  wee ks .  
R efere nce t her a p y, d os a ge , a n d m o de of a d mi nistr ati o n:  
N o ne.  
E n d p oi nts : 
Safet y :  Res ults of p h ysical e xa mi nati o ns, la b orat or y test res ults, E C Gs, vital si g n meas ure me nts, 
c o nc o mita nt me dicati o ns, a d verse e ve nts, a n d seri o us a d verse e ve nts  
Efficac y :  O R R, c o m plete res p o nse rate, partial res p o nse rate, pr o gressi o n -free s ur vi val, a n d perce nt 
re d ucti o n i n t u m or bi o ps y i N O S e x pressi o n 
P har mac o ki netic s:  R T A  4 0 8  plas ma c o nce ntrati o n -ti me data a n d p ossi ble meta b olite c o nce ntrati o n-
ti me data f or eac h a nal yte 
P har mac o d y na mic s:  C ha n ge fr o m baseli ne i n P B M C bi oc he mical mar kers, i n m yel oi d-deri ve d 
s u p press or cell ( M D S C) f u ncti o n, a n d i n t u m or bi o ps y bi o mar kers, i ncl u d i n g t he pr o p orti o n of i N O S-
p ositi ve t u m or cells  
St atistic al met h o ds:  
Sa m ple size :  T he sa m ple size ( n = u p t o 1 0 2 ) f or t his st u d y was selecte d t o ser ve 3 p ur p oses: ( 1) 
assess  t he safet y of R T A 4 0 8 c o m bi ne d wit h i pili m u ma b a n d R T A 4 0 8 c o m bi ne d wit h ni v ol u ma b , 
( 2) selecti o n of a P hase 2 d ose base d o n re vie w of safet y, efficac y, a n d p har mac o d y na mic  data,  a n d 
( 3) assess me nt of O R R  f or i N O S-p ositi ve mela n o ma patie nts i n c o m bi nati o n wit h ni v ol u ma b  at t he 
selecte d P hase 2 d ose of R T A 4 0 8.  T his sa m ple size  per mits  e nr oll me nt of 5 7  t o 7 8  patie nts i n d ose -
escalati o n c o h orts ( P hase 1 b) a n d 2 4 t o 2 7 patie nts i n t he e x pa nsi o n c o h ort ( P hase 2).    
T he P hase 1 b p orti o n of t he st u d y  all o ws f or assess me nt of safet y a n d selecti o n of a P hase 2 d ose.  
T he sa m ple size f or re vie wi n g safet y of R T A 4 0 8 c o m bi ne d wit h a n a d diti o nal t hera p y was selecte d 

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base d o n a tra diti o nal 3 + 3 desi g n f or a d ose -escalati o n st u d y wit h u p t o 6 patie nts o n eac h 
c o m bi nati o n t hera p y.  I n a d diti o n t o t he safet y pr ofile, selecti o n of a n a p pr o priate P hase 2 d ose is 
base d o n c ha n ges o bser ve d i n i N O S e x pressi o n meas ure d i n tu m or bi o psies at baseli ne a n d after 1 
wee k of m o n ot hera p y of R T A 4 0 8 (i.e., pri or t o starti n g c o m bi nati on t hera p y).   E val uati o n of t he 
descri pti ve s u m maries (i ncl u di n g 9 5 % c o nfi de nce i nter vals)  f or c ha n ge fr o m baseli ne i n perce nta ge 
of i N O S -p ositi ve t u m or cells  as well as ot her p har mac o d y na mic mar kers  fr o m t he P hase 1 b d ose-
escalati o n p orti o n of t he st u d y wi ll pr o vi de i nf or mati o n f or selecti n g t he P hase 2 e x pa nsi o n d ose.   
T he P hase 2 p orti o n of t he st u d y all o ws f or assess me nt of O R R at t he selecte d P hase 2 d ose of 
R T A  4 0 8  wit h ni v ol u ma b .  Si nce t he P hase 2 p orti o n will o nl y e nr oll patie nts pre vi o usl y treate d wit h 
a nti-P D -1 or a nti -P D -L 1 t hera p y (i ncl u di n g e x peri me ntal t hera pies), t he  O R R f or ni v ol u ma b 
m o n ot hera p y  is ass u me d t o be 0 %.  A sa m ple size of 2 4 patie nts f or t he e x pa nsi o n c o h ort  achie ves at 
least 8 0 % p o wer t o detect a n i m pr o ve me nt of 2 0 % i n O R R fr o m t he ass u me d ni v ol u ma b O R R as t he 
n ull h y p ot hesis  usi n g a 1 -si de d bi n o mial test at al p ha = 0. 1 0.   
Statistical a nal ysis :  A statistical a nal ysis pla n ( S A P) detaili n g t he a nal yses will be devel o pe d pri or t o 
t he data base l oc k.  T he S A P will i ncl u de a nal ysis of all safet y, p har mac o ki netic, p har mac o d y na mic, 
a n d res p o nse varia bles.  All statistical a nal yses a n d data  s u m maries will be perf or me d usi n g S A S ®  
( versi o n 9. 1 or hi g her) or ot her si milar s oft ware.  T he S A P will ser ve as t he fi nal ar biter of all 
statistical a nal yses.  Data will be s u m marize d o verall usi n g descri pti ve statistics.  C o nti n u o us data 
will be s u m marize d wit h n u m ber of patie nts ( n), mea n, me dia n, mi ni m u m, ma xi m u m, sta n dar d 
de viati o n, c oefficie nt of variati o n, a n d ge o metric mea n ( w here a p plica ble).  Cate g orical data will be 
s u m marize d usi n g fre q ue nc y c o u nts a n d perce nta ges. 
 

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3.  
T A B L E O F C O N T E N T S A N D LI S T S  O F T A B L E S  A N D FI G U R E S   
1.  
TI T L E P A G E  ................................................................................................................1  
2.  
S Y N O P SI S  ...................................................................................................................5  
3.  
T A B L E O F C O N T E N T S A N D LI S T S O F T A B L E S A N D FI G U R E S  .....................1 1  
4.  
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N S O F T E R M S .............................1 8  
5.  
I N T R O D U C TI O N ......................................................................................................2 1  
5. 1.  
Bac k gr o u n d o n R T A 4 0 8  ............................................................................................2 1  
5. 2.  
Rati o nale  .....................................................................................................................2 2  
6.  
T RI A L O BJ E C TI V E S A N D P U R P O S E  ....................................................................2 4  
6. 1.  
Pri mar y O bjecti ves  .....................................................................................................2 4  
6. 2.  
E x pl orat or y O bjecti ves  ...............................................................................................2 4  
7.  
I N V E S TI G A TI O N A L P L A N .....................................................................................2 5  
7. 1.  
O verall St u d y Desi g n  ..................................................................................................2 5  
7. 2.  
N u m ber of Patie nts  .....................................................................................................2 9  
7. 3.  
Treat me nt Assi g n me nt  ................................................................................................2 9  
7. 4.  
D ose Selecti o n a n d Escal ati o n Sc he me  ......................................................................2 9  
7. 4. 1.  
Selecti o n of Starti n g D ose  ..........................................................................................2 9  
7. 4. 2.  
D ose -Escalati o n Sc he me  ............................................................................................2 9  
7. 4. 3.  
Criteria f or D eter mi ni n g D ose -Li miti n g T o xicit y  ......................................................3 0  
7. 4. 4.  
I ntr a patie nt D ose Escalati o n .......................................................................................3 1  
7. 5.  
Criteria f or St u d y Ter mi nati o n  ...................................................................................3 1  
7. 6.  
Sc he d ule of Assess me nts  ............................................................................................3 1  
8.  
S E L E C TI O N A N D WI T H D R A W A L O F P A TI E N T S  ..............................................3 8  
8. 1.  
Patie nt I ncl usi o n Criteria  ............................................................................................3 8  
8. 2.  
Patie nt E xcl usi o n Criteria  ...........................................................................................3 9  
8. 3.  
Patie nt Rescree ni n g  ....................................................................................................4 0  
8. 4.  
Patie nt Wit h dra wal a n d Disc o nti n uati o n  ....................................................................4 1  
8. 4. 1.  
Patie nt Disc o nti n uati o n Criteria  .................................................................................4 1  
8. 4. 2.  
Patie nt Ter mi nati o n Criteria  .......................................................................................4 2  
9.  
T R E A T M E N T O F P A TI E N T S  ..................................................................................4 3  
9. 1.  
Descri pti o n of St u d y Dr u g, I pili m u ma b, a n d Ni v ol u ma b  ..........................................4 3  
9. 1. 1.  
St u d y Dr u g: R T A 4 0 8  .................................................................................................4 3  

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9. 1. 1. 1.  
St u d y Dr u g Treat me nt I nterr u pti o n  ............................................................................4 3  
9. 1. 2.  
I pili m u ma b ..................................................................................................................4 3  
9. 1. 2. 1.  
Dela y of I pili m u ma b  ...................................................................................................4 3  
9. 1. 2. 2.  
Restarti n g I pili m u ma b  ................................................................................................4 4  
9. 1. 2. 3.  
I pili m u ma b Disc o nti n uati o n .......................................................................................4 4  
9. 1. 2. 4.  
I m m u ne-Relate d A d v ers e E ve nts a n d Reacti o ns wit h I pili m u ma b  ............................4 6  
9. 1. 3.  
Ni v ol u ma b  ..................................................................................................................4 6  
9. 1. 3. 1.  
Dela y of Ni v ol u ma b  ...................................................................................................4 6  
9. 1. 3. 2.  
Restarti n g Ni v ol u ma b  .................................................................................................4 7  
9. 1. 3. 3.  
Ni v ol u ma b Disc o nti n uati o n  ........................................................................................4 7  
9. 1. 3. 4.  
I m m u ne-Relate d A d v ers e E ve nts a n d Reacti o ns wit h Ni v ol u ma b  .............................4 7  
9. 2.  
C o nc o mita nt Me dicati o ns  ...........................................................................................4 8  
9. 2. 1.  
E xcl u de d Me dic ati o ns  ................................................................................................4 8  
9. 2. 2.  
Per mitte d Me dicati o ns  ................................................................................................4 9  
9. 3.  
C o m plia nce wit h St u d y Dr u g  .....................................................................................4 9  
9. 4.  
Ra n d o mizati o n a n d Bli n di n g  ......................................................................................4 9  
9. 5.  
Pr ot oc ol Safet y Re vie w C o m mittee  ............................................................................4 9  
9. 6.  
U nsc he d ule d Visits  .....................................................................................................5 0  
9. 7.  
Pre g na nc y  ...................................................................................................................5 0  
9. 7. 1.  
W o me n of C hil d beari n g P ote ntial  ..............................................................................5 0  
9. 7. 2.  
Met h o ds of Birt h C o ntr ol ............................................................................................5 0  
9. 7. 3.  
S us pecte d Pre g na n c y  ..................................................................................................5 1  
9. 8.  
Seri o us T o xicities  .......................................................................................................5 1  
9. 9.  
St u d y Pr oce d ures  ........................................................................................................5 2  
9. 9. 1.  
I nf or me d C o nse nt .......................................................................................................5 2  
9. 9. 2.  
I n cl usi o n/ E xcl usi o n Criteria .......................................................................................5 2  
9. 9. 3.  
De m o gra p hics a n d Baseli ne Disease C haract eristics  .................................................5 3  
9. 9. 4.  
Pri or a n d C o nc o mita nt Me dicati o ns  ...........................................................................5 3  
9. 9. 5.  
Me dical Hist or y  ..........................................................................................................5 3  
9. 9. 6.  
E C O G Perf or ma n ce Stat us  .........................................................................................5 3  
9. 9. 7.  
Hei g ht  .........................................................................................................................5 3  
9. 9. 8.  
Wei g ht a n d B o d y Mass I n de x  .....................................................................................5 3  
9. 9. 9.  
Electr ocar di o gra m  .......................................................................................................5 4  

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9. 9. 1 0.  
Vital Si g n Meas ure me nts  ............................................................................................5 4  
9. 9. 1 1.  
P h ysical E xa mi nati o n  .................................................................................................5 4  
9. 9. 1 2.  
Pre g na nc y T est  ............................................................................................................5 4  
9. 9. 1 3.  
St u d y Dr u g Dis pe nsati o n  ............................................................................................5 4  
9. 9. 1 4.  
St u d y Dr u g Ret ur n/ Pill C o u nt  ....................................................................................5 4  
9. 9. 1 5.  
St u d y Dr u g A d mi nistrati o n .........................................................................................5 5  
9. 9. 1 6.  
I pili m u ma b A d mi nistrati o n ........................................................................................5 5  
9. 9. 1 7.  
Ni v ol u ma b A d mi nistrati o n  .........................................................................................5 5  
9. 9. 1 8.  
T u m or Bi o ps y  .............................................................................................................5 5  
9. 9. 1 9.  
T u m or B ur de n E val uati o n  ..........................................................................................5 5  
9. 9. 2 0.  
A d verse E v e nt C ollecti o n  ...........................................................................................5 6  
9. 9. 2 1.  
Cli nical C he mistr y  ......................................................................................................5 6  
9. 9. 2 2.  
He mat ol o g y  .................................................................................................................5 7  
9. 9. 2 3.  
C oa g ulati o n  .................................................................................................................5 8  
9. 9. 2 4.  
Vir us Ser ol o g y  ............................................................................................................5 8  
9. 9. 2 5 . 
Peri p heral Bl o o d M o n o n uclear Cell Bi o mar ker A nal ysis  ..........................................5 8  
9. 9. 2 6.  
Peri p heral Bl o o d M o n o n uclear Cell M yel oi d -Deri ve d S u p press or Cel l 
A nal ysis  ......................................................................................................................5 8  
9. 9. 2 7.  
P har mac o ki netic A n al ysis  ..........................................................................................5 9  
9. 9. 2 8.  
Uri nal ysis a n d Micr osc o p y  .........................................................................................5 9  
1 0.  
S T U D Y D R U G M A T E RI A L S A N D M A N A G E M E N T  ...........................................6 0  
1 0. 1.  
St u d y Dr u g  ..................................................................................................................6 0  
1 0. 2.  
St u d y Dr u g Pac ka gi n g a n d La beli n g  ..........................................................................6 0  
1 0. 3.  
St u d y Dr u g St ora ge  .....................................................................................................6 0  
1 0. 4.  
St u d y Dr u g A d mi nistrati o n .........................................................................................6 1  
1 0. 5.  
St u d y Dr u g Acc o u nta bilit y  .........................................................................................6 1  
1 0. 6.  
St u d y Dr u g Ha n dli n g a n d Dis p osal  ............................................................................6 1  
1 1.  
P H A R M A C O KI N E TI C, P H A R M A C O D Y N A MI C, A N D E F FI C A C Y 
A S S E S S M E N T S .........................................................................................................6 2  
1 1. 1.  
P har mac o ki netic Sa m ples  ...........................................................................................6 2  
1 1. 2.  
T u m or Bi o psies  ...........................................................................................................6 2  
1 1. 3.  
Peri p heral Bl o o d M o n o n uclear Cells  ..........................................................................6 2  
1 1. 4.  
T u m or B ur de n E val uati o n  ..........................................................................................6 2  

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1 2.  
S A F E T Y A S S E S S M E N T S  ........................................................................................6 3  
1 2. 1.  
Safet y Para met ers  .......................................................................................................6 3  
1 2. 2.  
A d verse a n d Seri o us A d verse E ve nts  .........................................................................6 3  
1 2. 2. 1.  
Defi niti o n of A d vers e E v e nts  .....................................................................................6 3  
1 2. 2. 1. 1.  
A d verse E v e nt  .............................................................................................................6 3  
1 2. 2. 1. 2.  
Seri o us A d verse E v e nt  ................................................................................................6 3  
1 2. 3.  
Eliciti n g A d verse E ve nt I nf or mati o n  ..........................................................................6 4  
1 2. 4.  
Assess me nt of Ca usalit y  .............................................................................................6 4  
1 2. 5.  
Assess me nt of Se verit y  ...............................................................................................6 5  
1 2. 6.  
Rec or di n g A d verse E ve nts  .........................................................................................6 5  
1 2. 7.  
Re p orti n g Seri o us A d verse E ve nts  .............................................................................6 6  
1 3.  
S T A TI S TI C S  ..............................................................................................................6 8  
1 3. 1.  
Sa m ple Size  ................................................................................................................6 8  
1 3. 2.  
St u d y Varia bles  ...........................................................................................................6 8  
1 3. 2. 1.  
P har mac o ki netic Varia bl es  .........................................................................................6 8  
1 3. 2. 2.  
P har mac o d y na mic V aria bles  ......................................................................................6 8  
1 3. 2. 3.  
Efficac y Varia bles  ......................................................................................................6 8  
1 3. 2. 4.  
Safet y Vari a bles  ..........................................................................................................6 9  
1 3. 3.  
Statistical A nal yses  .....................................................................................................6 9  
1 3. 3. 1.  
Pri mar y Efficac y A nal ys es  .........................................................................................6 9  
1 4.  
DI R E C T A C C E S S T O S O U R C E D A T A/ D O C U M E N T S .........................................7 0  
1 4. 1.  
St u d y M o nit ori n g  ........................................................................................................7 0  
1 4. 2.  
A u dits a n d I ns p ecti o ns  ................................................................................................7 0  
1 5.  
Q U A LI T Y C O N T R O L A N D Q U A LI T Y A S S U R A N C E  .........................................7 1  
1 5. 1.  
Q ualit y Ass ura nce  .......................................................................................................7 1  
1 5. 2 . 
Fi na ncial Discl os ur e  ...................................................................................................7 1  
1 5. 3.  
S p o ns or O bli gati o ns ....................................................................................................7 1  
1 5. 4.  
I n v esti gat or D oc u me nt ati o n ........................................................................................7 1  
1 5. 5.  
Cli nical St u d y I ns ura nce  .............................................................................................7 2  
1 5. 6.  
Use of I nf or mati o n  ......................................................................................................7 2  
1 6.  
E T HI C S  ......................................................................................................................7 3  
1 6. 1.  
I nstit uti o nal Re vie w B oar d Re vie w ............................................................................7 3  
1 6. 2.  
Et hical C o n d uct of t he St u d y  ......................................................................................7 3  

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1 6. 3.  
Writte n I nf or m e d C o nse nt  ..........................................................................................7 3  
1 6. 4.  
C o nfi de ntialit y  ............................................................................................................7 4  
1 6. 5.  
M o dificati o n of t he Pr ot oc ol  .......................................................................................7 4  
1 6. 6.  
Pr ot oc ol De viati o ns  ....................................................................................................7 4  
1 7.  
D A T A H A N D LI N G A N D R E C O R D K E E PI N G  .......................................................7 5  
1 7. 1.  
Rete nti o n of Rec or ds  ..................................................................................................7 5  
1 7 . 2. 
Case Re p ort F or ms  .....................................................................................................7 5  
1 8.  
P U B LI C A TI O N P O LI C Y  ..........................................................................................7 6  
1 9.  
LI S T O F R E F E R E N C E S  ............................................................................................7 7  
A P P E N D I X A. I PI LI M U M A B P A C K A G E I N S E R T ................................................................8 0  
A P P E N DI X B.  NI V O L U M A B P A C K A G E I N S E R T  ................................................................8 1  
 

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LI S T O F T A B L E S  
Ta ble 1:  
E mer ge nc y C o nta ct I nf or mati o n  ...................................................................................4  
Ta ble 2:  
List of A b bre viati o ns  ..................................................................................................1 8  
Ta ble 3:  
O verall Sc he d ule of Assess me nts f or Patie nts Recei vi n g R T A 4 0 8 + 
I pili m u ma b ..................................................................................................................3 2  
Ta ble 4:  
O verall Sc he d ule of Assess me nts f or Patie nts Recei vi n g R T A 4 0 8 + 
Ni v ol u ma b  ..................................................................................................................3 5  
Ta ble 5:  
R T A 4 0 8 Dr u g Pr o d uct I nf or mati o n  ...........................................................................4 3  
Ta ble 6:  
E C O G Perf or ma n ce Stat us  .........................................................................................5 3  
Ta ble 7:  
Cli nical C he mistr y Assess me nts .................................................................................5 7  
Ta ble 8:  
He mat ol o g y Assess me nts  ...........................................................................................5 8  
Ta ble 9:  
C oa g ulati o n Assess me nts  ...........................................................................................5 8  
Ta ble 1 0:  Uri nal ysis/ Micr osc o p y Assess me nts  ..........................................................................5 9  
Ta ble 1 1:  A E Se verit y Gra des  ....................................................................................................6 5  
Ta ble 1 2:  S A E Re p orti n g C o ntact I nf or mati o n  ..........................................................................6 6  
 

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LI S T O F FI G U R E S  
Fi g ure 1:  
Sc he ma f or St u d y of R T A 4 0 8 i n C o m bi nati o n wit h I pili m u ma b i n Patie nts 
wit h Metastatic Mela n o ma  .........................................................................................2 6  
Fi g ure 2:  
Sc he ma f or St u d y of R T A 4 0 8 i n C o m bi nati o n w it h Ni v ol u ma b i n Patie nts 
wit h Metastatic Mela n o ma  .........................................................................................2 6  
Fi g ure 3:  
R T A 4 0 8 D ose -Escalati o n a n d E x pa nsi o n Sc he ma  ....................................................2 8  
 
 

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5.  
I N T R O D U C TI O N 
5. 1.  
B ac k gr o u n d o n  R T A 4 0 8  
Nat ural triter pe n oi ds, s uc h as olea n olic aci d a n d urs olic aci d deri ve d fr o m pla nt e xtracts , ha v e 
bee n use d e xt e nsi vel y i n Asia n me dici ne f or t h eir a nti -i nfla m mat or y a n d a ntica ncer pr o perties 
(Li u, 1 9 9 5 ).  I n a n atte m pt t o i ncrease t he p ot e nc y of t hese c o m p o u n ds, Mi c hael S p or n a n d 
c ollea g ues t este d o v er 2 8 0 se mi -s y nt hetic olea na n e triter pe n oi ds for t h eir a bilit y t o i n hi bit t he 
i n d ucti o n of nitric o xi de ( N O) i n pri mar y m o us e macr o p ha g es treat e d wit h i nterfer o n-ga m ma 
(I F Nγ; H o n da, 1 9 9 9 ).  R T A  4 0 8  is a n o vel olea n a ne triter pe n oi d a n d is part of t his class of 
c o m p o u n ds .  S u bse q ue nt mec ha nistic st u dies  ha ve re veal e d t hat R T A  4 0 8  a n d t he se mi -s y nt hetic 
triter pe n oi ds are p ote nt i n hi bit ors of n uclear fact or ka p pa-li g ht-c h ai n-e n h a ncer of acti vate d B  
cells (N F -κ B ) a n d i nd ucers of n uclear fact or er yt hr oi d -deri ve d 2 -relate d fact or 2 ( Nrf 2), a n d t h us 
i n d uce a n a nti-infl a m mat or y a n d a nti o xi da nt p he n ot y pe.  
Acti vati o n of Nrf 2 i n d uces t he e x pressi o n of a batter y of c yt o pr otecti ve ge nes, i ncl u di n g t he 
pr ot ot y pical Nrf 2 tar get ge ne, N Q O 1 ( nic oti na mi de a de ni ne di n u cle oti de ( N A D( P) H) q ui n o n e 
o xi d ore d uctase 1), e nz y mes i n v ol ve d i n gl utat hi o ne s y nt hesis, a n d e nz y mes i n v ol ve d i n 
det o xificati o n ( W u, 2 0 1 1 ).  I n d ucti o n of t hese g e n es res ults i n a c o or di nat e d cell ular eff ort t o 
pr otect a gai nst o xi dati ve i ns ult, hi g hli g hte d b y i ncrease d a nti o xi dati ve ca p acit y, i n d ucti o n of 
gl uta t hi o ne s y nt hesis, a n d c o nj u gati o n of p ote ntiall y har mf ul m olec ules.  T he pr otecti ve r ole of 
t he Kea p 1-Nrf 2 pat h wa y i n carci n o ge n esis has bee n st u die d e xte nsi vel y a n d is t he s u bject of 
rece nt re vie w p a pers (S p or n, 2 0 1 2; Lee, 2 0 1 3 ).  B eca use of t he r ole Nrf 2 pl a ys i n cell ular 
pr otecti o n, Nrf 2 acti vati o n has m ulti ple p ote ntiall y be neficial effects i n ca n cer treat me nt.  
I m p ort a ntl y, se mi-s y nt hetic olea na ne triter pe n oi ds ha ve bee n s h o w n t o be hi g hl y effecti ve i n 
treati n g a wi de v ariet y of esta blis he d t u m ors i n multi ple m o dels ( Dee b, 2 0 0 9 ; H yer, 2 0 0 8 ; 
J ut o or u, 2 0 1 0; K o n o ple va, 2 0 0 6 ; Kress, 2 0 0 7 ; La pill o n ne, 2 0 0 3 ; Li n g, 2 0 0 7 ; Na garaj, 2 0 1 0 ; 
Place, 2 0 0 3 ).  As a class, t he se mi-s y nt hetic olea n a ne triter pe n oi ds ha ve als o bee n st u die d 
e xte nsi vel y i n n u mer o us m o dels of ca ncer pre ve nti o n, i ncl u di n g b ot h c he micall y a n d ge neticall y  
i n d uce d carci n o ge n esis.  I n t hes e st u dies, treat me nt wit h se mi-s y nt hetic olea na ne triter pe n oi ds 
e xte n de d lifes p a n a n d re d uce d t u m or b ur de n ( Ki m, 2 0 1 1 ; Lia o, 2 0 1 1 ; Li b y, 2 0 0 7 ; Li b y, 2 0 1 0 ; 
Yates, 2 0 0 6 ). 
O n t he basis of t hese d ata, R T A  4 0 8  is c urre ntl y bei n g e val uate d as a m o n ot hera p y i n a P hase 1 
st u d y i n patie nts wit h a d va nce d s oli d t u m ors ( St u d y 4 0 8-C -1 3 0 3).  St u d y 4 0 8 -C -1 3 0 3 is t he first-
i n-h u ma n st u d y wit h R T A  4 0 8  desi g ne d t o assess t he safet y, ma xi m u m t olerate d d os e, 
p har mac o d y n a mics , a n d p har mac o ki netics of R T A  4 0 8  i n patie nts wit h i nc ura ble n o n -s mall cell 
l u n g ca ncer (N S C L C ) or mela n o ma t hat is rela pse d, refract or y after sta n d ar d-of -care t h era p y, or 
f or w hic h sta n d ar d-of -care t hera p y i s n ot a p pr o priate .  A vaila ble data fr o m St u d y 4 0 8 -C -1 3 0 3 
will pr o vi de a d diti o nal cli nical  a n d safet y  i nf or mati o n f or t he c o n d uct of t h e pr o p ose d cli nical 
st u d y. 
Re gar di n g t he safet y pr ofile of R T A  4 0 8 , n o a d verse effects were o bser ve d i n t he safet y 
p har mac ol o g y st u dies .  T he ge n ot o xicit y p ote ntial of R T A  4 0 8  was i n vesti g ate d i n 2  i n vitr o 
ge netic t o xicit y tests a n d 2  i n viv o ge n ot o xicit y st u dies i n rats .  T he o verall  wei g ht of e vi de nce 
fr o m t he ge n ot o xicit y st u dies i n dicates t hat R T A  4 0 8  has a l o w ge n ot o xicit y ris k t o h u ma n 
s u bjects.  

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O verall, c o nsi deri n g t he lar ge b o d y of t o xicit y dat a ge nerate d t o date wit h R T A  4 0 8 , rats are 
m ore se nsiti ve t o t he t o xic ol o gic effects  of R T A  4 0 8  t ha n mice or m o n ke ys .  I n rats, t he hi g hest 
d os a ge teste d ( 3 0 m g/ k g/ da y) i n t he 2 8 -da y g o o d la b orat or y p ractice (G L P ) t o xicit y st u d y di d n ot 
pr o d uce se v ere t o xicit y; h o we ver, s e vere t o xicit y (i.e., m ortalit y, decrease i n wei g ht gai n, 
mar ke d re d ucti o n i n f o o d c o ns u m pti o n, a n d a d verse cli nical si g ns)  was o bser ve d at 
1 0 0  m g/ k g/ da y i n a n o n -G L P 1 4 -da y st u d y, s u g gesti n g t hat 3 0  m g/ k g/ da y ma y pr o vi de a 
c o nser vati ve esti mate of t he se verel y t o xic d osa ge  i n 1 0 % (S T D 1 0 ) of  rats.  I n m o n k e ys, t he 
hi g hest d os a ge teste d i n t he 2 8 -da y G L P st u d y was 1 0 0 m g/ k g/ da y, as hi g her d os a ges e val uate d 
i n a se parate p har m ac o ki netic ( P K) st u d y were n ot ass ociate d wit h i ncrease d e x p os ure .  
Alt h o u g h n o si g ns of t o xicit y were o bs er ve d wit h 1 0 0  m g/ k g/ da y i n m o n ke ys, t his d ose is 
c o nser vati vel y i de ntifie d as t he hi g hest n o n -se verel y t o xic d ose (H N S T D ) i n n o n-r o de nts. 
At d oses bel o w t h ose re q uire d t o pr o d uce s e vere t o xicit y, t he pri mar y s yste mic effects o bser ve d 
after oral a d mi nistrati o n of R T A  4 0 8  t o rats a n d, t o a m uc h lesser e xte nt, t o m o n ke ys were 
c o nsi dere d t o be m ostl y d ue t o t he k n o w n p har mac ol o gic acti vit y of R T A  4 0 8  i n a ni mal m o dels 
a n d li kel y d o n ot reflect off -tar g et t o xicit y.  T he rat was t he m ost se nsiti ve precli nical s pe cies, 
a n d t he n o -o bser ve d -a d v erse-effect le vel ( N O A E L ) i n t he G L P 2 8-da y st u d y wit h R T A  4 0 8  was 
3  m g/ k g / da y, base d o n a d verse li ver a n d ki d ne y fi n di n gs at t he hi g her d osa ges.  T he N O A E L i n 
rats decreas es wit h i ncrease d treat me nt d urati o n, a n d i n t he 6-m o nt h c hr o nic t o xic it y st u d y, 
a d verse fi n di n gs were n ote d i n t he l o west d os a ge gr o u p st u die d ( 0. 3 m g/ k g/ da y) .  I n c o ntr ast, a 
3 0 -m g/ k g/ da y d ose  i n m o n ke ys was n ot ass ociat e d wit h a d verse li ver or ki d ne y fi n di n gs 
re gar dl ess of t he treat me nt d urati o n.  T he a d verse li ver fi n di n gs i n rats were re ver si ble u p o n dr u g 
disc o nti n uati o n  a n d were ass ociate d wit h m o derate t o mar ke d i ncreas es i n ser u m ga m ma -
gl uta m yl tra ns pe pti dase ( G G T ), ala ni n e a mi n otra nsferas e ( A L T), as partate a mi n otra nsferase 
(A S T ), a n d t otal bilir u bi n.  Wit h s h ort treat me nt d urati o n (i.e., 1 4 da ys), t u b ular 
de ge nerati o n/re ge n erati o n i n rats was re v ersi ble wit h a 2 8 -da y treat me nt -free peri o d i n a n o n-
G L P st u d y.  Alt h o u g h  t he ki d ne y fi n di n gs i n rats after 2 8 da ys of treat me nt were n ot r e versi ble 
after a 4-wee k rec o ver y p eri o d, t he y were mil d, were n ot ass ociate d wit h e vi de nce of a n effect o n 
re nal f u n cti o n (i.e., n o i ncreas e i n bl o o d urea nitr o ge n [ B U N ] or ser u m creati ni ne) , a n d were n ot 
prese nt i n m o n ke ys at d oses u p t o 3 0  m g/ k g/ da y  after u p t o 9  m o nt hs of dail y a d mi n istrati o n.  
5. 2.  
R ati o n ale  
Mali g na nt mela n o ma is a lea di n g ca use of deat h fr o m c uta ne o us mali g na nci es, acc o u nti n g f or 
a p pr o xi matel y t hree -f o urt hs of all s ki n ca ncer deat hs (Hall, 1 9 9 9 ).  S ur gical e xcisi o n is t he 
sta n dar d treat me nt f or l o calize d mela n o m as, w hic h are hi g hl y c ura ble.  F or metastatic or 
u nresect a ble mela n o mas, sta n dar d treat me nt o pti o ns i ncl u de c hec k p oi nt i n hi bit ors 
(e.g ., i pili m u ma b), i nterle u ki n-2, si g nal tra ns d ucti o n i n hi bit ors, c he m ot hera p y, or palliati ve l ocal 
t hera p y (N C C N Mel a n o ma G ui deli nes, 2 0 1 4 ).  H o we ver, a p pr o ve d t h era pi es are rarel y c urati ve.  
It is n o w well acce pte d t hat t u m ors are a bl e t o e va de detecti o n a n d era dicati o n  b y t he i m m u ne 
s yste m, e ve n t h o u g h ma n y t u m or t y pes, partic ularl y  mela n o ma, are ca p a ble of eliciti n g a str o n g 
i m m u ne res p o nse (S wa n n , 2 0 0 7).  I pili m u ma b is a n a p pr o ve d m o n o cl o nal a nti b o d y t hat tar gets 
c yt ot o xic T-l y m p h oc yte-ass ociate d a nti ge n 4 ( C T L A -4) acti vit y.  C T L A -4 is a n i m m u ne 
c hec k p oi nt  m olec ule t hat pre ve nts a ut oi m m u nit y a n d e na bles t olera nce t o s elf-a nti ge ns b y 
d o w nre g ulati n g T -cell acti vati o n .  Ni v ol u ma b is a n ot her  a p pr o ve d t hera p y for metastatic 
mela n o ma  t hat tar gets t h e P D-1 pr otei n o n t he s urface of acti vate d T cells, w hic h re g ulates T -cell 

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acti vati o n a n d pr oliferati o n at t he t u m or site.  T h us t hr o u g h bl oc ka de of C T L A -4 or P D -1/ P D -L 1 
si g nali n g, i pili m u ma b a n d ni v ol u ma b ai m t o a m plif y T-cell-me diat e d i m m u nit y, w hic h 
t he oreticall y e n h a nces t h e patie nt’s ca pacit y t o m o u nt a n a ntit u m or i m m u ne res p o nse.  H o we v er, 
alt h o u g h treat me nt wit h i pili m u ma b or ni v ol u ma b has bee n s h o w n t o re d uce t he ris k of diseas e 
pr o gressi o n, res p o ns e t o t hera p y ma y b e f urt her a u g me nte d .  O nl y 6 % t o 1 1 % of mela n o ma 
patie nts treate d wit h i pili m u ma b ac hie ve d a partial or c o m plete res p o ns e, a n d me dia n o verall 
s ur vi val was o nl y 1 0 m o nt hs (H o di, 2 0 1 0 ).  W hile t he o verall res p o nse rat e f or ni v ol u ma b is 
hi g her t ha n f or i pili m u ma b, m ore t ha n half of pati e nts d o n’t res p o n d t o ni v ol u ma b 
(R o ma n o,  2 0 1 5 ; We ber, 2 0 1 4 ). 
S u bsta ntial mec ha nistic w or k i n rece nt years has re veal e d t he ke y r ole of m yel oi d -deri ve d 
s u p press or cells (M D S Cs ) i n mas ki n g t he t u m or e n vir o n me nt fr o m t he i m m u ne s yste m, w hic h i n 
t ur n c o ntri b utes t o b ot h t u m or pr o gressi o n a n d resista nce t o ca n cer i m m u n ot hera p y .  M D S Cs 
re pres e nt t he maj or p o p ulati o n of a nti ge n-pres e nti n g cells res p o nsi ble f or t he i n d ucti o n of 
a nti ge n-s pecifi c C D 8 + T -cell t olera n ce i n ca ncer ( Ga bril o vic h, 2 0 1 2 ).  T he i m m u ne -s u p pressi ve 
effect of M D S Cs is de pe n de nt o n t he pr o d ucti o n of reacti ve o x y ge n s pecies ( R O S) a n d reacti ve 
nitr o ge n s pecies ( R N S).  O ne mec h a nis m b y w hic h M D S Cs elicit T -cell t olera nce is t hr o u g h 
nitr os ylati o n of t yr osi ne resi d ues i n t he T-cell rece pt or -C D 8 c o m ple x, w hic h pre ve nts a nti ge n -
de pe n de nt T -cell acti vati o n ( Na garaj, 2 0 0 7 ).  As a res ult, i n hi biti o n of M D S C acti vit y a n d 
re d ucti o n of R O S a n d R N S le vels i n t he t u m or micr oe n vir o n me nt ha ve bee n s h o w n t o be 
effe cti ve i n rest ori n g i m m u ne rec o g niti o n of t u m or -s pecifi c a nti ge ns.  C o n versel y , t he fre q ue n c y 
of M D S Cs c orrelate wit h disease pr o gressi o n a n d decrease d o v erall s ur vi val i n Sta ge I V 
mela n o ma patie nts (J or d a n, 2 0 1 3), a n d increas e d t u m or le vels of i n d uci ble nitric o xi de s y nt hase 
(i N O S) a n d nitr ot yr osi ne e x pressi o n  ha v e  bee n c orrelate d wit h decrease d s ur vi val i n patie nts 
wit h metastatic  mela n o ma ( E k me kci o gl u, 2 0 0 0 ; E k me kci o gl u, 2 0 0 6 ).   
R T A  4 0 8  i n hi bits t u m or gr o wt h i n m o use t u m or xe n o graft m o dels a n d h as m ulti ple a ntica ncer 
effects, i ncl u di n g direct i n d ucti o n of a p o pt osis i n ca ncer cells  a n d s u p pressi o n of R O S 
pr o d ucti o n b y M D S Cs i n vitr o.  I n a d diti o n, R T A  4 0 8  si g nifica ntl y re d uces t u m or nitr ot yr osi ne 
b ur de n, i n hi bits t he acti vit y of M D S Cs, a n d a u g me nts T-cell a ntica n cer acti vit y  i n viv o.  T hese 
effects of R T A  4 0 8  are c o nsiste nt wit h t he i n hi biti o n of M D S Cs t hat has bee n o bser ve d wit h  
a n ot her se mi -s y nt hetic ol ea na n e triter pe n oi d, bar d o x ol o ne met h yl (Na garaj,  2 0 1 0 ).  S pecificall y, 
treat me nt wit h bar d o x ol o ne met h yl has bee n s h o w n t o a br o gate t he i m m u ne-s u p pressi ve effect of 
M D S Cs wit h a c orres p o n di n g i m pr o ve me nt i n i m m u ne res p o nse i n t u m or -beari n g mice a n d  i n 
patie nts wit h  ca ncer (N a garaj, 2 0 1 0 ).  T h us, t hr o u g h i n hi biti o n of M D S C acti vit y a n d 
s u p pressi o n of t u m or R O S/ R N S, R T A  4 0 8  ma y w or k i n c o m bi nati o n wit h T -cell-acti vati n g 
t hera pe utics s uc h as i pili m u ma b a n d ni v ol u ma b t o e n ha nce t he nat ur al i m m u ne a ntica ncer 
res p o nse.   
T h is st u d y is desi g ne d t o assess t he safet y, effi cac y , p har mac o d y n a mics , a n d p har mac o ki netics 
of R T A  4 0 8  i n c o m bi nati o n wit h i pili m u ma b or ni v ol u ma b i n patie nts wit h u nresect a ble or 
metastatic mela n o ma .  T he res ults of t his st u d y will hel p pr o vi de cli nical i nf o r mati o n f or t he 
desi g n a n d c o n d uct of f urt her cli nical st u dies wit h R T A  4 0 8  i n patie nts wit h ca ncer.  

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7.  
IN V E S TI G A TI O N A L P L A N  
7. 1.  
O ver all St u d y Desi g n  
I n this o pe n -la bel, m ultice nter, d ose-escalati o n, P hase 1 b/ 2 st u d y , patie nts wit h u nresecta bl e or 
metastatic mela n o ma w h o q ualif y  will recei v e R T A  4 0 8  at t he assi g ne d d ose le vel  i n 
c o m bi nati o n wit h i p ili m u ma b ( 3 m g/ k g)  or ni v ol u ma b ( 2 4 0 m g ).   
C o h orts 1 t o 3 : 
T wel ve patie nts will be e nr olle d at eac h d ose le vel, wit h si x patie nts a d mi nistere d R T A 4 0 8 + 
i pili m u ma b a n d t he re mai ni n g si x a d mi nistere d R T A 4 0 8 + ni v ol u ma b.  Selecti o n of t hera p y t o 
be use d i n c o m bi nati o n wit h R T A  4 0 8 (i.e.,  i pili m u ma b or ni v ol u ma b) s ho ul d be deter mi ne d b y 
t he i n vesti gat or as cli nicall y i n dicate d.  S u bse q ue nt c o h orts will assess escal ati n g d oses of 
R T A  4 0 8 a d mi nistere d i n c o m bi nati o n wit h i pili m u ma b or ni v ol u ma b.  A starti n g R T A  4 0 8 d ose 
le vel of 5 m g was selecte d f or t he first d ose -esc alati o n c o h ort i n t his st u d y base d o n a vaila bl e 
safet y a n d p h ar mac o d y n a mic data fr o m a s e parate P hase 1 st u d y of R T A  4 0 8 m o n ot hera p y i n 
patie nts wit h a d va nce d s oli d t u m ors ( St u d y 4 0 8 -C -1 3 0 3).   
C o h orts 4  t o 1 0 : 
T hree ( 3) t o si x ( 6) patie nts will be e nr olle d at eac h d ose le vel, a n d patie nts will recei ve 
R T A  4 0 8 + ni v ol u ma b.   
Patie nts  will start recei vi n g t heir assi g ne d d ose of R T A  4 0 8  orall y o n Da y 1.  Patie nts will 
recei v e R T A  4 0 8  m o n ot hera p y orall y o nce d ail y  d uri n g a r u n -i n peri o d f or 1 wee k pri or t o 
i nitiati o n of c o m bi nati o n t hera p y.  F or patie nts treate d wit h i pili m u ma b ( C o h orts 1 t o 3 o nl y) , t he 
r u n-i n peri o d will be f oll o we d b y R T A  4 0 8  orall y o nce dail y i n c o m bi nati o n wit h i pili m u ma b 
a d mi nist ere d at W ee ks 1, 4, 7, a n d 1 0  (Fi g ur e 1 ).  After Wee k 1 0, p atie nts will recei ve 
mai nte na nce tr eat me nt wit h R T A  4 0 8  al o ne o nce dail y .  F or patie nts treate d wit h ni v ol u ma b 
t hera p y, t he r u n -i n peri o d will be f oll o we d b y R T A  4 0 8  orall y o nce d ail y i n c o m bi nati o n wit h 
ni v ol u ma b a d mi nistere d e ver y t w o w ee ks  as cli nicall y i n dicate d  (Fi g ure 2 ).  After Wee k 2 4 
( patie nts treate d wit h R T A 4 0 8 + i pili m u ma b) or Wee k 2 5 ( p atie nts treat e d wit h R T A 4 0 8 + 
ni v ol u ma b), patie nts will ret ur n f or st u d y visits e v er y 1 2 wee ks.  Eac h p atie nt will c o nti n ue at t he 
assi g ne d  R T A  4 0 8  d ose l e vel  u ntil disease pr o gressi o n occ urs, t o xicit y re q uiri n g disc o nti n uati o n 
fr o m st u d y dr u g (i.e., R T A 4 0 8) is e x peri e nce d, t h e patie nt has c o m plete d 1 6 8  wee ks  ( patie nts 
treate d wit h R T A  4 0 8  + i pili m u ma b) or 1 6 9  wee ks (patie nts treate d wit h R T A  4 0 8 + ni v ol u ma b ) 
of treat me nt, t he p atie nt is disc o nti n ue d fr o m t he st u d y dr u g  f or a n ot her reas o n, t he patie nt 
wit h dra ws c o nse nt , or t h e patie nt is eli gi ble f or d ose escal ati o n ( Secti o n 7. 4. 4 ).  P atie nts will 
ret ur n 4 wee ks aft er R T A  4 0 8  treat me nt c o m pleti o n ( or earl y ter mi nati o n) f or a f oll o w-u p visit.    

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Criteria f or A d v erse E v e nts [ C T C A E], versi o n 4. 0 3) relate d t o R T A  4 0 8  tr eat me nt, e xce pt as 
n ote d i n pr ot oc ol Secti o n 7. 4. 3  or  t o xicit y t hat re q uires i pili m u ma b or ni v ol u ma b dela y or 
disc o nti n uati o n as detaile d i n pr ot oc ol Secti o n 9. 1 . 
A fter t he first 3 patie nts ha ve c o m plete d t h e D L T o bser vati o n peri o d , all a v aila ble safet y a n d 
p har mac o d y n a mic i nf or mati o n f or all e nr olle d patie nts will be re vie we d b y t he pr ot oc ol safet y 
re vie w c o m mittee ( P S R C ) t o ma ke a decisi o n re gar di n g escalati o n t o t he s u bse q ue nt R T A  4 0 8  
d ose le vel or of t he n ee d t o e val uate  safet y data fr o m a d diti o nal patie nts treate d at t he c urre nt 
R T A  4 0 8 d ose le vel.  If a d diti o nal safet y e val uati o n is nee de d as d eter mi ne d b y t he r ules f or d os e  
escalati o n , a n ot her re vi e w of t he data will occ ur o nce t he ne xt 3 p atie nts (f or a t otal of 6 patie nts) 
ha ve c o m plete d t h e D L T o bser vati o n peri o d .  T h e P S R C ma y als o elect t o a d d 3 patie nts at t he 
d ose  le vel u n der re vie w t o gai n a d diti o nal p har mac o d y na mic data.  A d diti o nall y, t he P S R C ma y 
rec o m me n d e nr olli n g a c o h ort at a l o wer d ose le vel base d o n safet y data or re vie w of a vaila ble 
i N O S e x pressi o n c ha n g es o bser ve d i n e nr olle d p atie nts s o t hat a p pr o priate d ose le vels are 
enr olle d f or s electi o n of t he P hase 2 d ose.   
A P hase 2 d ose of R T A  4 0 8  will be selecte d bas e d o n safet y a n d p h ar mac o d y na mic  data fr o m 
t he d ose-escalati o n c o h orts.  T he P hase 2 p orti o n of t he st u d y will i ncl u de a se parat e e x pa nsi o n 
c o h ort c o nsisti n g of pati e nts w h o ha ve recei ve d pri or treat me nt wit h a nti-P D -1 or a nti -P D -L 1 
t hera pies treate d wit h R T A 4 0 8 i n c o m bi nati o n wit h ni v ol u ma b.  T he P hase 2 e x pa nsi o n c o h ort 
will i ncl u de a n a d diti o nal 2 4 or 2 7 patie nts t o ac hi e ve a t otal of 3 0 p atie nts at t hat R T A  4 0 8 d ose 
i n c o m bi nati o n wit h ni v ol u ma b.  T u m or res p o nse will be assesse d at Wee k 1 3 a n d a p pr o xi matel y 
e ver y 1 2 w ee ks t hereafter.   
A d etaile d sc he d ul e of assess me nts f or t he st u d y is s h o w n i n Ta ble 3  (i pili m u ma b) a n d Ta bl e 4  
( ni v ol u ma b).  T he st u d y  c o nsists of u p t o a 2 1 -da y scree ni n g p eri o d, u p t o a p pr o xi matel y 
1 6 8  wee ks ( patie nts treat e d wit h R T A  4 0 8  + i pili m u ma b) or 1 6 9  wee ks ( patie nts treate d wit h 
R T A  4 0 8 + ni v ol u ma b) of R T A  4 0 8  treat me nt, w hic h i ncl u des 4 d oses of i pili m u ma b or 
i ntra ve n o us a d mi nistrati o n of ni v ol u ma b e ver y t w o wee ks, a n d a 4 -wee k p ost -treat me nt f oll o w-
u p .   

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7. 2.  
N u m ber  of P atie nt s 
U p t o 1 0 2  patie nts are e x pecte d t o e nr oll i n t his st u d y .  
7. 3.  
Tre at me nt  Assi g n me nt  
Patie nts w h o q ualif y f or t he st u d y will be assi g ne d t o t he d ose of R T A  4 0 8  o pe n f or e nr oll me nt 
i n t he d ose -escalati o n o r e x pa nsi o n c o h orts as d es cri be d i n Secti o n 7. 4. 2 . 
7. 4.  
D ose Selecti o n a n d Esc al ati o n Sc he me  
7. 4. 1.  
Selecti o n  of St arti n g D ose  
T he starti n g R T A  4 0 8  d ose le vel t hat will be c o m bi ne d wit h i pili m u ma b  or ni v ol u ma b  will be 
5  m g base d o n a vaila ble safet y a n d efficac y d ata fr o m an  o n g oi n g  P hase 1 st u d y of R T A  4 0 8  
m o n ot hera p y i n patie nts wit h a d va nce d s oli d t u m ors ( St u d y 4 0 8 -C -1 3 0 3).   
7. 4. 2.  
D ose -E sc al ati o n Sc he me  
A tra diti o nal 3 + 3 d ose es calati o n desi g n will be i m ple me nte d f or t he P has e 1 b p orti o n of t he 
st u d y t o e val uate R T A 4 0 8 f or safet y a n d t olera bilit y wit hi n eac h c o h ort a n d select a tar get d ose 
f or t he Phase 2 p orti o n of t he st u d y.   
A fter t he first 3 patie nts ha ve c o m plete d t h e D L T  o bser vati o n peri o d , all a v aila ble safet y a n d 
p har mac o d y n a mic i nf or mati o n f or all e nr olle d patie nts will be re vie we d b y t he P S R C t o ma ke a 
decisi o n re gar di n g escalati o n t o t he s u bse q ue nt R T A  4 0 8  d ose le vel or of t he nee d t o e val uate  
a d diti o nal patie nts at t he c urre nt R T A  4 0 8  d os e le vel.   T he P S R C ma y  i ncl u de t he 
i n vesti gat or(s), S p o ns or re prese nt ati ve(s), a n d i n d e pe n de nt p h ysicia n(s).  A n y P S R C decisi o n 
re q uires u na ni m o us a gree me nt a m o n g t he me m bers of t he P S R C.  A se parate c harter f or t he 
P S R C is n ot re q uire d f or t his st u d y .  If t here are n o ge neral s afet y c o ncer ns n ote d fr o m t he 
o verall assess me nt of s afet y  base d o n a v aila ble data fr o m all e nr olle d p atie nts , t he n the f oll o wi n g 
r ules f or a d diti o nal safet y e val uati o n or  d ose escalati o n will be a p plie d  wit hi n eac h c o m bi nati o n 
t hera p y t y pe bas e d o n as s ess me nt of D L Ts after c o m pleti n g t he s pecifie d D L T o bser vati o n 
peri o d : 
1.  If n o patie nts ( 0 of 3) e x p erie nce a D L T, t h e n d ose escalati o n ma y occ ur   
2.  If 1  patie nt ( 1  of 3) e x perie nces a D L T, t he n 3 a d diti o nal patie nts at t he sa me d ose le vel will 
be e val uat e d  after c o m pl eti n g t he D L T o bser vati o n peri o d  a n d t he f oll o wi n g r ules will be 
a p plie d:  
a. If n o ne of t he a d diti o nal patie nts e x perie n ce a D L T (i.e., 1  of 6 patie nts e x peri e nce a 
D L T at t he c urre nt d ose l e vel),  t he n R T A 4 0 8 d os e escal ati o n ma y occ ur   
b.  If ≥1  a d diti o nal patie nt s e x perie n ce a D L T (i .e., ≥2  of 6 patie nts e x peri e nce a D L T at 
t he c urre nt d ose le vel), t h e n d ose escalati o n will n ot occ ur.  T he P S R C ma y 
rec o m me n d d ose  re d ucti o n a n d e nr oll me nt of  a d diti o nal c o h ort s at a l o wer d ose 
bet wee n t he pre vi o usl y well-t olerate d d os e le vel a n d t he c urre nt d ose le vel .  T he 
P S R C ma y rec o m me n d n o f urt her patie nts b e e nr olle d at t he d ose u n der e val uati o n  
3.  If ≥2  patie nts ( ≥2  of 3 ) e x perie nce a D L T, t h e n d ose escal ati o n will n ot occ ur; h o we ver, t he 
P S R C  ma y rec o m me n d d ose re d ucti o n a n d e nr oll me nt of a d diti o nal c o h ort s at a l o wer d ose 

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bet wee n t he pre vi o usl y well -t olerate d d os e le vel a n d t he c urre nt d ose le vel .  T he P S R C ma y 
rec o m me n d n o f urt her patie nts be e nr olle d at t he d ose u n der e v al uati o n   
If all 6 patie nts ha ve c o m plete d t he D L T o bser vati o n peri o d  at t he c urre nt d ose le vel  a n d a 
decisi o n is n ot deter mi ne d b y t he a b o ve r ules, t h e n d ose escal ati o n will n ot occ ur; h o we v er,  t he 
P S R C ma y rec o m me n d d ose re d ucti o n a n d e nr oll me nt of a d diti o nal c o h orts at a l o wer d ose 
le vel.  
S u bse q ue nt c o h orts will be e nr olle d at d os e le vels  base d o n a vaila bl e safet y a n d 
p har mac o d y n a mic data fr o m t his st u d y, as well as a d diti o nal d ata fr o m ot her  st u dies wit h 
R T A  4 0 8 i n ot her patie nt p o p ulati o ns ( N C T 0 2 2 5 5 4 3 5 a n d N C T 0 2 2 5 5 4 2 2 ).  D ose escalati o n ma y  
pr ocee d u ntil a ma xi m u m t olerate d d ose ( M T D) or ma xi m u m feasi ble p har mac o d y na mic 
res p o nse has b ee n reac he d.   
7. 4. 3.  
Criteri a f or D eter mi ni n g D ose -Li miti n g T o xi cit y  
Beca use t he ti mec o urse of a n y p ote ntial R T A  4 0 8  D L T s are e x pecte d t o occ ur rel ati vel y s o o n 
after treat me nt i nitiati o n, t he D L T o bser vati o n peri o d f or patie nts recei vi n g R T A  4 0 8  i n 
c o m bi nati o n wit h i pili m u ma b will last t hr o u g h Wee k 7  (i.e., 6  wee ks fr o m i nitiati o n of 
i pili m u ma b t hera p y, as o p p ose d t o 1 2 wee ks).  T h e D L T o bser vati o n peri o d will last u ntil t he 
Wee k 5 visit f or patie nts recei vi n g R T A  4 0 8  i n c o m bi nati o n wit h ni v ol u ma b, w hic h is 4  wee ks 
after i nitiati o n of ni v ol u ma b  t hera p y.  F urt h er m ore, d uri n g safet y re vie w, t he P S R C will als o 
c o nsi der safet y data o btai ne d fr o m pri or c o h orts tr eate d at l o wer d oses of R T A  4 0 8  i n 
c o m bi nati o n wit h ipili m u ma b or ni v ol u ma b t o deter mi ne if late nt A Es o cc ur o utsi de of t he D L T 
o bser vati o n peri o d.  T h e C T C A E  (versi o n 4. 0 3) will be use d t o assess A Es  t hat ma y be 
c o nsi dere d a D L T , e x ce pt w here relate d t o tra ns a mi nase la b orat or y v al ues.  Nrf 2 acti vati o n b y 
R T A  4 0 8  a n d relate d a nal o gs has bee n s h o w n t o u pre g ulate t he pr o d ucti o n of tra nsa mi nases .  
T h e tra nsa mi nas e u pre g ulati o n is a p har mac ol o gic res p o nse relate d t o i ncrease d gl uc ose 
utilizati o n a n d has n ot bee n s h o w n t o be ass oci ate d wit h li ver t o xicit y i n a ni mal st u dies or 
cli nical st u dies wit h a rel ate d a nal o g ( H o n g, 2 0 1 2 ; Per g ola , 2 0 1 1 ).  T heref ore , t he deter mi nati o n 
of D L T will be defi n e d i n eac h p atie nt as all t o xicit y  Gra de ≥3  ( usi n g C T C A E, versi o n 4. 0 3) 
relate d t o R T A  4 0 8  treat me nt, e xce pt as n ote d b el o w: 
•  Na usea a n d v o miti n g  will be c o nsi dere d a D L T if Gra de 3 t o xicit y persists after o pti mal 
me dical t hera p y  
•  A n y he pat o biliar y d is or d ers of Gra de ≥2 (fr o m C T C A E , versi o n 4. 0 3, pa g es 2 4 -2 5)  will 
be c o nsi dere d a D L T .  N ote t hat la b orat or y meas ure me nts are i ncl u de d i n a se parat e 
secti o n of t he C T C A E 
•  C ha n ges i n A L T, A S T, a n d t otal bilir u bi n levels  m ust meet 1  of t he f oll o wi n g criteria t o 
be c o nsi dere d a D L T:  
o  A L T or A S T > 3 X U L N a n d  (t otal bilir u bi n > 2 X U L N or  i nter nati o nal 
n or malize d rati o [ I N R] > 1. 5)  
o  A L T or A S T > 3 X U L N wit h t he a p peara nce of fati g ue, na usea, v o miti n g, ri g ht 
u p per q ua dra nt pai n  or te n der ness, f e ver, ras h, a n d/ or e osi n o p hilia ( > 5 %)  
•  A n y t o xicit y liste d i n Secti o n 9. 1. 2. 1  or Secti o n 9. 1. 3. 1  t hat re q uires i pili m u ma b or 
ni v ol u ma b  dela y t hat is c o nsi dere d rel ate d t o R T A 4 0 8 treat me nt or a n y t o xicit y liste d i n 

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Secti o n 9. 1. 2. 3  or Secti o n  9. 1. 3. 3  t hat re q uires i pili m u ma b or n i v ol u ma b disc o nti n uati o n 
t hat is c o nsi dere d relate d t o R T A 4 0 8 treat me nt will be c o nsi dere d a D L T.  
7. 4. 4.  
I ntr a p atie nt D ose Esc al ati o n  
I ntr a patie nt d ose escal ati o n of t he select e d P hase 2 d ose (t o a hi g her d os e le vel t hat has pr o v e n 
t olera ble i n t he st u d y) wil l be all o we d at t he discreti o n of t he in vesti gat or o nce a p atie nt has 
c o m plete d Wee k 1 3 a ssess me nts.   
7. 5.  
Criteri a f or St u d y  Ter mi n ati o n  
Alt h o u g h t he S p o ns or i nte n ds t o c o m plete t he st u d y, t he  S p o ns or reser ves t he ri g ht t o 
disc o nti n ue t he st u d y at a n y ti me f or cli nical or a d mi nistrati ve reas o ns, or if re q uire d b y 
re g ulat or y a g e ncies.  If t he S p o ns or disc o nti n ues t he st u d y, all st u d y treat me nt will be 
disc o nti n ue d a n d t he i n vesti gat or will be re s p o nsi ble t o prescri be a n y a d diti o nal t hera p y t o be 
a d mi nistere d.  
7. 6.  
Sc he d ule of Assess me nts  
Ta ble 3  a n d T a ble 4  list t he sc he d ule of assess me nts f or patie nts recei vi n g R T A  4 0 8  a n d 
i pili m u ma b or ni v ol u ma b, res pecti vel y.   

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f W e ek 1 t u m or bi o psy m ust b e c oll ect e d pri or t o first a d mi nistr ati o n of i pili m u m a b b ut m a y b e c oll ect e d 1 d a y  pri or t o t h e  sc h e d ul e d visit.  W e ek 1 t u m or bi o psy is o pti o n al f or p ati e nts e nr oll e d i n 
t h e P h as e 2 p orti o n of  t h e st u dy. 
g  T h e  W e ek 1 3 t u m or bi o psy m a y b e c oll ect e d ± 1 w e ek fr o m sc h e d ul e d visit .  W e ek 1 3 t u m or bi o psy is o pti o n al f or p ati e nts e nr oll e d i n t h e P h as e 2 p orti o n of t h e st u dy.  
h  I m a gi n g st u di es f or t u m or siz e/ b ur d e n ev al u ati o n as a p pr o pri at e t o ass ess dis e as e b ur d e n or t u m or siz e.  T h e ass ess m e nt d o n e at t h e Scr e e ni n g Visit s h o ul d b e t h e s a m e m et h o d us e d t hr o u g h o ut 
t h e st u dy.  S pir al C T wit h c o ntr ast is a p pr o pri at e u nl ess ot h er wise s p ecifi e d by t h e pri nci p al i n v esti g at or or d esi g n e e.  Ass ess m e nts p erf or m e d wit hi n 2 8 d a ys pr ec e di n g a d mi nistr ati o n of t h e first 
d os e m a y b e us e d.   
i  R es p o ns e ( R E CI S T) ass ess m e nt s h o ul d i ncl u d e c h est a n d a b d o m e n a n d a n y ar e a t h at is b ei n g m o nit or e d.   
j  Bl o o d s a m pl es f or P B M C ( bi o m ark er a n d M D S C) a n alysis s h o ul d b e t a k e n pri or t o st u dy dr u g a d mi nistr ati o n.  
k  Bl o o d s a m pl es f or P K a n alysis s h o ul d b e t a k e n pri or t o a n d 2 h o urs aft er d os e a d mi nistr ati o n.  
l W it h a p pr ov al of t h e S p o ns or , or d esi g n e e, scr e e ni n g m a y b e i ncr e as e d t o 2 8 d a ys o n a n i n divi d u al p ati e nt b asis . 
 
A b br evi ati o ns:  B MI = b o d y m ass i n d ex, C T =c o m p ut e d t o m o gr a p h y, E C O G = E ast er n C o o p er ativ e O nc ol o g y Gr o u p, M D S C = m y el oi d -d eriv e d s u p pr ess or c ell, P B M C = p eri p h er al bl o o d m o n o n ucl e ar c ell, 
P K = p h ar m ac oki n etic, R E CI S T =  R es p o ns e E v al u ati o n Crit eri a I n S oli d T u m o u rs, W O C B P = w o m e n of c hil d b e ari n g p ot e nti al.

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f W e ek 1 t u m or bi o psy m ust b e c oll ect e d pri or t o first a d mi nistr ati o n of  niv ol u m a b  b ut m a y b e c oll ect e d 1 d a y  pri or t o t h e  sc h e d ul e d visit.  W e ek 1 t u m or bi o psy is o pti o n al f or p ati e nts e nr oll e d i n 
t h e P h as e 2 p orti o n of t h e st u dy.  
g  T h e  W e ek 1 3 t u m or bi o psy m a y b e c oll ect e d ± 1 w e ek fr o m sc h e d ul e d visit .  W e ek 1 3 t u m or bi o psy is o pti o n al f or p ati e nts e nr oll e d i n t h e P h as e 2 p orti o n of t h e st u dy . 
h  I m a gi n g st u di es f or t u m or siz e/ b ur d e n ev al u ati o n as a p pr o pri at e t o ass ess dis e as e b ur d e n or t u m or siz e.  T h e ass ess m e nt d o n e at t h e Scr e e ni n g Visit s h o ul d b e t h e s a m e m et h o d us e d t hr o u g h o ut 
t h e st u dy.  S pir al C T wit h c o ntr ast is a p pr o pri at e u nl ess ot h er wise s p ecifi e d by t h e pri nci p al i n v esti g at or or d esi g n e e.  Ass ess m e nts p erf or m e d wit hi n 2 8 d a ys pr ec e di n g a d mi nistr ati o n of t h e first 
d os e m a y b e us e d.   
i  R es p o ns e ( R E CI S T) ass ess m e nt s h o ul d i ncl u d e c h est a n d a b d o m e n a n d a n y ar e a t h at is b ei n g m o nit or e d.   
j  Bl o o d s a m pl es f or P B M C ( bi o m ark er a n d M D S C) a n alysis s h o ul d b e t a k e n pri or t o st u dy dr u g a d mi nistr ati o n.  
k  Bl o o d s a m pl es f or P K a n alysis s h o ul d b e t a k e n pri or t o a n d 2 h o urs aft er d os e a d mi nistr ati o n.  
l W it h a p pr ov al of t h e S p o ns or , or d esi g n e e, scr e e n i n g m a y b e i ncr e as e d t o 2 8 d a ys o n a n i n divi d u al p ati e nt b asis. 
m  Niv ol u m a b s h o ul d c o nti n u e t o b e a d mi nist er e d ev ery 2 w e eks acc or di n g t o t h e p ack a g e i ns ert.  
 
A b br evi ati o ns:  B MI = b o d y m ass i n d ex, C T =c o m p ut e d t o m o gr a p h y, E C O G = E ast er n C o o p er ativ e O nc ol o g y Gr o u p, M D S C = m y el oi d -d eriv e d s u p pr ess or c ell, P B M C = p eri p h er al bl o o d m o n o n ucl e ar c ell, 
P K = p h ar m ac oki n etic, R E CI S T =  R es p o ns e E v al u ati o n Crit eri a I n S oli d T u m o u rs, W O C B P = w o m e n of c hil d b e ari n g p ot e nti al.

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8.  
S E L E C TI O N A N D WI T H D R A W A L O F P A TI E N T S  
8. 1.  
P atie nt  I ncl usi o n Criteri a 
All patie nts m ust meet all of t he f oll o wi n g criteria t o be i ncl u de d i n t he st u d y:  
1.  Pr o vi de writte n i nf or me d  c o nse nt f or st u d y partici pati o n, a p pr o ve d b y t he a p pr o priate 
instit uti o nal re vie w b oar d  (I R B) 
2.  Be ≥1 8 years of a ge  
3.  Ha ve a d v a nce d, u nres ect a ble ( Sta ge III) or metast atic ( Sta ge I V) mela n o m a  
4.  Be eli gi ble f or c o m mercial recei pt of t hera p y t o b e use d i n t his st u d y i n c o m bi nati o n wit h 
R T A  4 0 8  (i.e., i pili m u ma b or ni v ol u ma b i n t he P hase 1 b p orti o n a n d ni v ol u ma b o nl y i n t he 
P hase 2 p orti o n ) 
5.  Ha ve recei v e d pri or tr eat me nt wit h a nti-P D -1 or a nti -P D -L 1 t hera p y (i ncl u di n g e x peri me ntal 
t hera pies) if e nr olli n g i n t he P hase 2 p orti o n of t he st u d y.  T his criteria d oes n ot a p pl y t o 
patie nts e nr olli n g i n t he P hase 1 b p orti o n of t he st u d y.   S u bjects w h o are c urre ntl y ta ki n g 
ni v ol u ma b a n d ha ve sta ble disease ( S D) p er i n vesti gat or assess me nt will be eli gi ble t o 
partici pate pr o vi d e d S D has bee n prese nt f or at least 3 m o nt hs  
6.  Ha ve > 5 % of t u m or cells fr o m t he scree ni n g bi o ps y stai ne d p ositi ve f or i N O S e x pressi o n i n 
a n i m m u n oc he mistr y assa y  
7.  Ha ve a n E aster 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 ≤2  
8.  Ha ve a life e x pecta nc y of ≥ 3 m o nt hs at t he ti me of scree ni n g i n t he i n vesti gat or’s o pi ni o n  
9.  Ha ve disc o nti n ue d pre vi o us treat me nts f or ca ncer a n d rec o v ere d fr o m all ac ute t o xic effects 
of pri or s yste mic t hera p y t o Gra de ≤1.  E xe m pte d are effects t hat are ofte n n o n -re versi ble or 
re q uire a pr ol o n ge d ti me f or re v ersal ( e. g., al o peci a, h y p ot h yr oi dis m , ne ur o pat h y) 
1 0.  Ha ve disc o nti n ue d pre vi o us e x peri me ntal t hera pi es a n d c hec k p oi nt i n hi bit or a nti b o dies at 
least 2 8 da ys pri or t o t he Ra n d o mizati o n Visit .  T his d oes not a p pl y t o s u bjects w h o are 
c urre ntl y recei vi n g ni v ol u ma b a n d ha ve S D  
1 1.  Ha ve a d e q uate b o n e marr o w res er ve a n d or ga n f u ncti o n at t he Scree ni n g Visit as f oll o ws: 
a. He mat ol o gic:  A bs ol ute ne utr o p hil c o u nt > 1. 5 x 1 0 9/ L, platelets > 1 0 0 x 1 09/ L, 
he m o gl o bi n ≥9 g/ d L  ( patie nts ma y recei ve er yt hr oc yte tra nsf usi o ns t o ac hi e ve t his 
he m o gl o bi n le vel, at t he discreti o n of t he i n vesti g at or , b ut the first d ose of st u d y dr u g 
m ust n ot be gi n u ntil 5 da ys after t he er yt hr oc yt e tr a nsf usi o n)  
b.  He patic:  T otal bilir u bi n ≤1. 5 X U L N, A L T a n d A S T ≤ 2. 5 X  U L N  f or patie nts wit h o ut 
li ver metastasis or ≤ 5 X  U L N f or patie nts wit h li ver metastasis  
c. Re nal:  E sti mate d gl o mer ular filtrati o n rate (e G F R) usi n g t he M o dificati o n of D iet i n 
R e nal D isease ( M D R D) f or m ula ≥6 0 m L/ mi n / 1. 7 3 m2 
1 2.  Be a ble t o s wall o w ca ps ules 
1 3.  Be willi n g a n d a ble t o c o o perate wit h all as p ects of t he pr ot oc ol  

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1 4.  Be willi n g t o practice t he f oll o wi n g me dicall y acce pta ble met h o ds of birt h c o ntr ol ( b ot h 
w o me n of c hil d beari n g p ote ntial ( W O C B P) a n d me n w h o ha ve p art ners of c hil d beari n g 
p o te ntial) fr o m t he Scree ni n g  Visit  t hr o u g h 3 m o nt hs after ta ki n g t he fi n al d ose of R T A  4 0 8 :  
s per mici de wit h d o u ble  b arrier, oral c o ntrace pti ve, va gi nal ri n g, i njecta ble or i m pla nta ble 
met h o d of c o ntrace pti o n, tra ns der mal c o ntrace pti ve, i ntra uteri ne de vice,  s ur gical sterilizati o n 
of part ner, or a bsti ne nce (f or n o n – se x u all y acti ve patie nts).  WO C B P  i ncl u de all fe males w h o 
ha ve e x p erie nce d me narc he a n d ha v e n ot e x peri e n ce d me n o pa us e ( defi ne d as a me n orr hea f or 
> 1 2 c o nsec uti ve m o nt hs) or ha ve u n der g o ne s u ccessf u l s ur gical sterilizati o n ( h ysterect o m y, 
bilateral t u bal li gati o n, or bilateral o o p h orect o m y)  
1 5.  W O C B P  m ust n ot be pre g na nt or lactati n g a n d m ust a gree t o ha ve pre g n a nc y testi n g 
perf or me d at eac h visit  e xce pt at Wee k 1  a n d Wee k 2  ( Visits 3 a n d 4)   
8. 2.  
P atie nt  E xcl usi o n  Criteri a  
All patie nts wit h a n y of t he f oll o wi n g c o n diti o ns or c haracteristics m ust be e xcl u de d fr o m t he 
st u d y: 
1.  Ha ve oc ul ar mela n o ma  
2.  Ha ve p ri or m ali g na nc y acti ve wit hi n t he pre vi o us 2 years e x ce pt f or l ocalize d ca n cers t hat 
are c o nsi d ere d t o ha v e bee n c ure d a n d, i n t he o pi ni o n of t he i n vesti gat or, prese nt a l o w ris k 
f or rec urre nce (e. g., b asal or s q ua m o us cell s ki n ca ncer, s u perficial bla d d er ca ncer, or 
carci n o ma i n sit u of t he pr ostate, cer vi x, or breast)   
3.  Ha ve a n y acti ve a ut oi m m u ne disease or a hist or y of k n o w n or s us pect e d a ut oi m m u ne 
disease, or hist or y of s y n dr o me t hat re q uir e d s yste mic ster oi ds or i m m u n os u p pressi ve 
me dicati o ns, e xce pt f or p atie nts  wit h vitili g o or res ol ve d c hil d h o o d ast h ma/at o p y or ot her 
s y n dro mes w hic h w o ul d n ot be e x pect e d t o rec ur i n t he a bse nce of a n e xter nal tri g ger.   
Patie nts wit h t y pe 1 dia betes mellit us are per mitte d t o e nr oll.  Diseases t hat are c o nsi d ere d 
a ut oi m m u ne relate d i ncl u de t he f oll o wi n g:  
a. I nfla m mat or y b o wel disease, i ncl u di n g ulcerati ve c olitis a n d Cr o h n’s disease  
b.  
S y m pt o matic diseases (e. g., r he u mat oi d art hritis, s yste mic pr o gressi ve scl er osis, 
syste mic lu p us er yt he mat os us, a utoi m m u ne vasc ulitis)  
c. M ot or ne ur o pat hies c o nsi dere d of  a ut oi m m u ne ori gi n (e. g., G uillai n -Barr é sy n dr o me )  
4.  Ha ve ha d brai n metastas es (scree ni n g n ot re q uir e d) u nless t he y ha ve met all of t he f oll o wi n g 
criteria:  
a. Ha d a resecti o n a n d/ or c o m plete d a c o urse of cra ni al irra diati o n, a n d  
b.  Ha ve n o w orse ni n g ce ntral ner v o us s yste m s y m pt o ms, a n d  
c. Ha ve n o ma g n etic res o n a nce i ma gi n g ( M RI) e vi d e nce of pr o gressi o n f or at least 
8  wee ks after treat me nt is c o m plete a n d wit hi n 2 8 da ys pri or t o first d ose of st u d y 
dr u g a d mi nistrati o n,  a n d 
d.  Ha ve disc o nti n ue d all c ortic oster oi ds f or t hat i n di cati o n f or at least 2 wee ks  

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5.  Ha ve t h e f oll o wi n g car di o vasc ular a b n or malities:  
a. E vi de nce of p o or car di o v asc ular f u ncti o n, defi ne d as B -t y pe natri uretic p e pti de 
( B N P) >2 0 0 p g/ m L  or N T -pr o B N P > 2 X  t he u p per li mit of n or mal ( U L N)  
b.  Hist or y of c o n gesti ve heart fail ure, u nst a ble a n gi n a, or u nc o ntr ol le d h y pert e nsi o n 
c. Cli nicall y si g nifica nt ve ntric ular arr h yt h mias at t he Scree ni n g Visit  
d.  M y ocar dial i nfarcti o n wit hi n 6 m o nt hs pri or t o t he Scree ni n g Visit  
e. C or recte d Q T i nter val (Q Tc ) o n electr ocar di o gra m ( E C G) at t he Scree ni n g Visit 
> 5 0 0  msec  
6.  Ha ve k n o w n h e p atic i m p air me nt , i ncl u di n g cirr h osis 
7.  Ha ve  k n o w n re nal i m pair me nt , i ncl u di n g gl o mer ul o ne p hritis 
8.  Ha ve se v ere cere bral or p eri p heral vasc ular diseas e 
9.  Ha ve pre -e xisti n g c hr o ni c diarr hea C T C A E Gra de ≥2 of a n y eti ol o g y (i ncl u di n g 
mala bs or pti o n dis or ders a n d s ur gical pr o ce d ures t hat, i n t he o pi ni o n of t he i n vesti gat or, ma y 
affect a bs or pti o n of st u d y dr u g)  
1 0.  Ha ve k n o w n acti ve f u n gal, bacteri al, a n d/ or viral i nfecti o n , i ncl u di n g h u ma n 
i m m u n o deficie nc y vir us  ( HI V) or he patitis vir us  ( A, B, or C) 
1 1.  Ha ve ha d m aj or s ur ger y wit hi n 2 1 da ys bef ore t he Ra n d o mizati o n Visit ( Da y 1 Visit ) 
1 2.  Ha ve ta ke n a n y of t he f oll o wi n g dr u gs wit hi n 7 da ys bef ore t he R a n d o mizati o n Visit ( Da y  1 
Visit ): 
a. Se nsiti ve s u bstrates f or c yt oc hr o me P 4 5 0 2 C 8 or 3 A 4 (e .g ., re pa gli ni de, mi daz ola m, 
sil de nafil) 
b.  S u bstrates f or p -gl yc o pr otei n tra ns p orter (e .g ., a m brise nta n, di g o xi n), O C T 1 
tra ns p orter (e.g ., metf or mi n), O A T 1 tra ns p orter (e.g ., ca pt o pril, f ur os e mi de, 
met h otre xate), or O A T P 1 B 3 tra ns p orter (e .g ., at or vastati n, r os u vastati n, valsartan)  
c. C Y P 3 A i n hi bit or s a n d str o n g i n d ucers 
1 3.  Ha ve k n o w n or s us pecte d acti ve dr u g or alc o h ol a b use  
1 4.  Ha ve a n y a b n or mal la b orat or y test val ue or s eri o us pre -e xisti n g me dical c o n diti o n t hat, i n t he 
o pi ni o n of t he i n vesti gat or, w o ul d p ut t he patie nt at ris k b y trial e nr oll me nt  
1 5.  Be u na ble t o c o m pl y wit h t he re q uire m e nts of t he st u d y pr ot oc ol or be u ns uita ble f or t he 
st u d y f or a n y reas o n, i n t he o pi ni o n of t he i n vesti gat or 
8. 3.  
P at ie nt R escree ni n g  
Patie nts ma y re peat t he s cree ni n g pr oce d ures t o q ualif y f or t he st u d y  wit h a p pr o val fr o m t he 
me dical m o nit or .  

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8. 4.  
P atie nt  Wit h dr a w al  a n d Disc o nti n u ati o n  
Patie nts ha ve t he ri g ht t o wit h dra w fr o m t he st u d y at a n y ti me f or a n y reas o n, wit h o ut prej u dice 
t o t heir me dical care.  F urt her m ore, t he i n v esti gat or ma y disc o nti n ue a pati e n t fr o m st u d y dr u g or 
ter mi nate t he patie nt fr o m t he st u d y.  T he reas o n f or a patie nt’s wit h dra wal or disc o nti n uati o n 
fr o m t he st u d y will be rec or de d i n t he case re p ort f or m ( C R F).  
8. 4. 1.  
P atie nt Disc o nti n u ati o n  Criteri a  
Disc o nti n uati o n refers t o a patie nt st o p pi n g a d mi nistrati o n of st u d y dr u g  (R T A  4 0 8  o nl y) .  
Reas o ns f or st u d y dr u g disc o nti n uati o n i ncl u de t he f oll o wi n g:  
•  Disease pr o gressi o n  
•  D L T  
•  Occ urre nce of a n A E or c ha n ge i n me dical stat us t hat lea ds t he i n vesti gat or t o be 
c o ncer ne d a b o ut t he p atie nt’s welfare  
•  N o nc o m plia nce wit h st u d y pr oce d ures  
•  Pre g na nc y d uri n g t he st u d y  
S u bjects wit h R E CI S T pr o gressi ve diseas e  ma y c o nti n ue o n st u d y at t he discreti o n of t he 
In v esti gat or if pse u d o -pr o gressi o n is s us pecte d  a n d t he patie nt c o nse nts t o c o nti n ue d treat me nt .  
Pse u d o -pr o gressi o n is defi ne d as a p p are nt disease pr o gressi o n t hat m a y be d ue t o T -cell 
i nfiltrati o n of t he t u m or site, w hic h c o ul d ca us e a n i ncreas e i n t u m or size or ne w lesi o ns t o 
a p pear u p o n i ma gi n g .  W he n pse u d o -pr o gressi o n is s us pecte d, patie nts ma y c o nti n ue t o 
partici pate i n t he st u d y a n d c o nti n ue t o recei ve pr ot oc ol -s pecifie d tr eat me nt if t he f oll o wi n g 
criteria are met:  
•  A bse nce of cli nical s y m pt o ms or si g ns i n dicati n g cli nicall y si g nifica nt disease 
p r o gressi o n 
•  N o decli ne i n W H O/ E C O G perf or ma nce stat us 
•  A bse nce of ra pi d disease pr o gressi o n or t hreat t o vital or ga ns or critic al a nat o mical sites 
(e. g., C N S metastasis, res pirat or y fail ure d u e t o t u m or c o m pressi o n, s pi nal c or d 
c o m pressi o n) re q uiri n g ur ge nt alter nati ve me dical i nter ve nti o n 
•  N o si g nifica nt, u nacce pta ble or irre v ersi ble t o xicities relate d t o pr ot o c ol -s pecifie d 
treat me nt 
S u bjects wit h s u bse q ue nt re d ucti o n i n t u m or dia meter will ha ve C T res ults c o m pare d t o bas eli ne 
f or cal c ulati o n of R E CI S T res p o nse.   Patie nts w h o are disc o nti n ue d fr o m st u d y dr u g s h o ul d still  
c o nti n ue t o recei ve i pili m u ma b  or ni v ol u ma b  as i n dicate d (acc or di n g t o i pili m u ma b  or 
ni v ol u ma b  prescri bi n g i nf or mati o n),  atte n d all st u d y visits , a n d u n der g o all st u d y assess m e nts, if 
p ossi ble.   Patie nts w h o are disc o nti n ue d pri or t o t he assess me nt of p ote ntial t o xicit y ma y be 
re place d, e xce pt w he n t h e disc o nti n uati o n is d ue t o a patie nt e x perie nci n g a D L T. 

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8. 4. 2.  
P atie nt Ter mi n ati o n Criteri a  
Ter mi nati o n refers t o a p atie nt st o p pi n g s t u d y dr u g a n d all st u d y assess me nts a n d visits.  Reas o ns 
f or st u d y ter mi nati o n i ncl u de t he f oll o wi n g: 
•  Fail ure t o r et ur n f or f oll o w -u p  
•  A d verse eve nt, w hic h res ults i n d eat h 
•  Wit h dra wal of c o nse nt  
Patie nts w h o ter mi nate R T A  4 0 8  f or a n y reas o n m a y n ot re-i nitiate R T A  4 0 8  at a n y ti me.   

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•  A n y G ra d e ≥2 n o n ‒ s ki n-relate d A E  (i ncl u di n g i m m u ne-relat e d a d verse reacti o ns), e xce pt 
f or easil y c orrect e d la b orat or y a b n or malities t hat d o n ot reflect u n d erl yi n g or ga n 
pat h ol o g y  
•  A n y G ra d e ≥3 la b orat or y a b n or malit y  
•  A n y A E  or  la b orat or y a b n or malit y t hat, i n t he j u d g me nt of t he i n vesti gat or, prese nts a 
s u bsta ntial cli nical ris k t o t he patie nt  wit h c o nti n ue d d osi n g  
•  It ma y b e necessar y t o h ol d st u d y dr u g t o e val uate G ra de 1 e ve nts t hat s u g g est o n g oi n g or 
i nci pie nt a ut oi mm u ne disease , i ncl u di n g gastr oi ntesti nal  ( GI) t o xicit y, diarr hea, 
pa ncreatitis, h e patitis, pit uitar y i ns ufficie nc y, earl y e vi de nce of ne ur ol o gic e ve nts, a n d 
s ki n t o xicit y, u ntil dia g n osis a n d pr o gressi o n are deter mi ne d  
9. 1. 2. 2.  
Rest arti n g  I pili m u m a b 
I pili m u ma b ma y be restarte d if/ w he n t he A E (s) res ol ve(s) or  ret ur ns t o bas eli ne se verit y wit hi n 
2  wee ks of last d ose a d mi nistrati o n . 
If t he A E  has b ee n d eter mi ne d n ot be relate d t o i pili m u ma b or is n ot a n 
a ut oi m m u ne/i nfla m mat or y e ve nt.  If > 1 d ose is t o be hel d or > 2-we e k dela y is e x pecte d d ue t o 
c urre nt e ve nts n ot relat e d t o st u d y , t he d osi n g sc he d ule m o dificati o ns m ust be disc usse d wit h t he 
pri nci pal i n vesti gat or pri or t o i m ple me ntati o n .  
If t he A E  has res ol ve d t o  G ra de ≤1 , i pili m u ma b d osi n g ma y be restart e d at t he ne xt sc he d ule d 
ti me p oi nt per pr ot oc ol.  Please f oll o w g ui deli nes f or s pecifi c e ve nts.  Pleas e n ote t hat re -
i nitiati n g treat me nt ma y be ass ociate d wit h rec urre nce or e xacer bati o n of a ut oi m m u ne or 
i nfla m mat or y e ve nts.  I n s o me i nsta nces, cli nical r es ol uti o n of e ve nts s uc h as c olitis ma y be 
ass ociate d wit h resi d u al pat h ol o gic c ha n ges a n d s h o ul d re q uire e v al uati o n of c o m plete res ol uti o n 
pri or t o restarti n g t hera p y . 
E ve nts t hat re q uire i nter ve nti o n wit h i m m u n os u p pressa nt t hera p y, ster oi ds, s ur ger y, or h or m o ne 
re place me nt ge nerall y re q uire per ma n entl y disc o nti n uati o n of ipili m u ma b . 
A ut oi m m u ne/i nfla m mat or y e ve nts are pres u ma bl y relate d t o t he mec ha nis ms of acti o n of 
i pili m u ma b a n d p ote ntiall y t o a t hera pe utic effect.  T he inci de nce a n d se v erit y of t hese e ve nts 
ma y be d ose relate d, b ut o nce i nitiate d, t here is n o e vi de nce t h at l o were d d oses ca n be 
a d mi nistere d wit h o ut c o nti n ue d a ut oi m m u ne acti vit y a n d t here has s o far bee n n o de m o nstra ble 
be nefit t o c o nti n ui n g i pili m u ma b afte r a n a ut oi m m u ne e ve nt d uri n g t he i nitial treat me nt.  As 
s uc h, n o d ose m o dificati o n is use d f or i pili m u ma b.  
9. 1. 2. 3.  
I pili m u m a b Disc o nti n u ati o n  
Patie nts  m ust be disc o nti n ue d fr o m i pili m u ma b t hera p y a n d dis c o nti n ue d  fr o m st u d y dr u g  f or t he 
f oll o wi n g reas o ns: 
•  Persist e nt a d verse reacti o ns t hat re q uire h ol di n g m ore t ha n 2 treat me nt d oses   
•  A n y m ot or ne ur ol o gic t o xicit y G ra de ≥3 re gar dl ess of ca usalit y  
•  A n y G ra d e ≥3 treat me nt -relate d se ns or y ne ur ol o gi c t o xicit y 
•  Ot he r G ra de 3 or 4 e ve nt s, i ncl u di n g t he f oll o wi n g: 

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o  A n y e ve nt t hat re q uires s yste mic ster oi ds or i m m u n os u p pressi ve treat me nt 
o  Se vere or lif e -t hreate ni n g a d verse reacti o ns, i ncl u di n g a n y of t he f oll o wi n g: 
o  C olitis wit h a b d o mi nal pai n, fe ver, ile us, or perit o neal si g ns; i ncreas e i n st o ol 
fre q ue nc y ( 7 or m ore per da y o ver bas eli ne), st o ol i nc o nti ne nce, nee d f or 
i ntra ve n o us (I V) h y drati o n f or m ore t ha n 2 4 h o urs, GI  he m orr h a ge, or  GI  
perf orati o n  
o  A S T or A L T > 5 X U L N  or t otal bilir u bi n > 3 X U L N  
o  Ste ve ns -J o h ns o n s y n dr o me, t o xic e pi der mal necr ol ysis, or ras h c o m plicate d b y 
f ull t hic k ness der mal ulcerati o n, or necr otic, b ull o us, or he m orr ha gi c 
ma nifestati o ns  
o  Se vere m ot or or s e ns or y ne ur o pat h y, G uillai n -Barré s y n dr o me, or m y ast he nia 
gra vis  
o  Se vere i m m u ne-relate d reacti o ns i n v ol vi n g a n y or ga n s yste m (e.g ., ne p hritis, 
p ne u m o nitis, pa ncreatitis, n o n -i nfecti o us m y ocar ditis) 
o  I m m u ne-relat e d oc ular disease t hat is u nres p o nsi v e t o t o pical i m m u n os u p pressi ve 
t hera p y 
o  A n y A E  or  la b orat or y a b n or malit y t hat, i n t he j u d g me nt of t he i n vesti gat or, 
prese nts or ga n s p ecific i nj ur y a n d/ or a  s u bsta ntial cli nical ris k t o t he patie nt wit h 
c o nti n ue d d osi n g  
E xce pti o ns t o  i pili m u ma b disc o nti n uati o n i ncl u de: 
•  P ote ntiall y re versi ble i nfla m mati o n ( G ra d e < 4), attri b uta ble t o a l ocal a ntit u m or r eacti o n 
a n d a p ote ntial t hera pe uti c res p o nse.  T his i ncl u des i nfla m mat or y reacti o ns at sites of 
t u m or resecti o ns or i n drai ni n g l y m p h n o des, or at sites s us pici o us f or b ut n ot dia g n ostic 
of metastasis  
•  H os pitalizati o n f or  G ra de ≤2 A E s w here t h e pri mar y reas o n f or h os pitalizati o n is t o 
e x pe dite t he cli nical w or k -u p  
•  T he f oll o wi n g c o n diti o ns w here , i n t he i n vesti gat or’s o pi ni o n, c o nti n ui n g st u d y dr u g 
a d mi nistrati o n is j ustifie d  base d o n t he p ote ntial f or c o nti n ue d cli nical be nefit:  
o  T reatme nt  wit h s yste mic ster oi ds f or < 2 wee ks wit h o ut e vi de nce of a ut oi m m u ne 
disease re q uiri n g ster oi d treat me nt  
o  Gra de 2 s ki n ras h treate d wit h t o pical ster oi ds f or < 4 wee ks  
o  Gra de 2 o c ular t o xicit y t hat has c o m pletel y res p o n de d t o t o pical t hera p y wit hi n  
4  wee ks  
o  E n d ocri n o pat hies w here cli nical s y m pt o ms are c o ntr olle d wit h a p pr o priate 
h or m o ne re pla ce me nt t hera p y.  N ote:  I pili m u ma b ma y n ot be restart e d w hile t he 
patie nt is bei n g treate d wit h s yste mic c ortic oster oi ds e xce pt f or patie nts o n sta ble 
d oses of h or m o ne re place me nt  t hera p y, s u c h as h y dr oc ortis o ne 

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9. 1. 2. 4.  
I m m u ne-Re late d A d verse E ve nts a n d Re acti o ns w it h I pili m u m a b  
Im m u ne -relat e d A E s or reacti o n s are defi n e d as a d verse reacti o n s of u n k n o w n eti ol o g y 
ass ociate d wit h i pili m u ma b e x p os ure a n d c o nsiste nt wit h a n i m m u ne p he n o me n o n.   Eff orts 
s h o ul d be ma de t o r ule o ut ne o plastic, i nfecti o us, meta b olic, t o xi n, or ot her eti ol o gic ca uses pri or 
t o la beli n g a n e ve nt a n im m u ne -relate d A E .  Ser ol o gic, i m m u n ol o gic, a n d hist ol o gic ( bi o ps y) 
data s h o ul d be use d t o s u p p ort t he dia g n osis of a n i m m u ne -relate d t o xicit y.  S us pecte d i m m u ne -
relate d a d v erse reacti o ns m ust be d oc u me nte d o n a n A E or seri o us a d v erse e ve nt (S A E ) f or m.  
Patie nts s h o ul d be i nf or me d of a n d caref ull y m o nit ore d f or e vi de nce of cli nicall y si g nifica nt 
s yste mic i m m u ne-relate d a d verse reacti o ns (e .g ., s yste mic l u p us er yt he mat os us-li ke diseases) or 
or ga n -s pecific i m m u ne-relate d a d v erse reacti o n  (e.g ., ras h, c olitis, u veitis, he patitis, or t h yr oi d 
disease).  If a n i m m u ne-relate d a d v erse reacti o n is n ote d, a p pr o priat e w or k -u p (i ncl u di n g bi o ps y , 
if p ossi ble) s h o ul d be perf or me d, a n d ster oi d t hera p y ma y be c o nsi dere d if cli nicall y necessar y.   
It is u n k n o w n if s yste mic c ortic oster oi d t hera p y has a n atte n uati n g effect o n i pili m u ma b acti vit y.   
H o we ver, cli nical a ntit u m or res p o nses ha v e bee n mai ntai ne d i n patie nts treate d wit h 
c ortic oster oi ds a n d disc o nti n ue d fr o m i pili m u ma b.  If utilize d, c ortic oster oi d t hera p y s h o ul d be 
i n di vi d ualize d f or eac h p atie nt.   
G ui deli nes f or treat me nt a n d m o nit ori n g of s pecifi c i m m u ne-relate d a d verse reacti o ns  s h o ul d 
f oll o w t he i pili m u ma b pac ka ge i nsert (A p pe n di x A ).  T hese rec o m me n d ati o ns s h o ul d be utilize d 
as cli nicall y a p pr o pri ate  f or t he treat me nt of i n di vi d ual patie nts.   
9. 1. 3.  
Ni v ol u m a b  
Ni v ol u ma b will be a d mi nistere d acc or di n g t o t he pac ka g e i nsert ( A p pe n di x B ) t o t he patie nt 
i ntra ve n o usl y.  T he f oll o wi n g g ui deli nes will be a p plie d re gar di n g d ela y of d ose a d mi nistrati o n 
or disc o nti n uati o n of ni v ol u ma b t hera p y.  M o dificati o ns t o ni v ol u ma b t hera p y d uri n g t he st u d y 
d o n ot i m pact patie nt partici pati o n i n t he st u d y, e xce pt w here s pecificall y n ote d bel o w.  
Decisi o ns t o dela y  a n ni v ol u ma b  d ose m ust be ma de o n s pecifie d s afet y criteria.  Treat me nt wit h 
ni v ol u ma b  will be d ela ye d or disc o nti n ue d if t he p atie nt  e x perie n ces at least 1 A E , s pecifie d 
bel o w, c o nsi dere d b y t he i n vesti gat or t o be “pr o ba bl y” or “ defi nitel y” relat e d t o ni v ol u ma b  
treat me nt.  Decisi o ns t o dela y or disc o nti n ue ni v ol u ma b d ue t o tra nsa mi nase ele vati o ns s h o ul d be 
disc usse d wit h t he me dical m o nit or . 
9. 1. 3. 1.  
Del a y of Ni v ol u m a b  
T he f oll o wi n g criteri a will be use d t o deter mi ne d ose dela y  of ni v ol u ma b:  
•  A n y Gra d e 2 p ne u m o nitis  
•  Gra de 2 or 3 c olitis  
•  A L T or A S T > 3 X  U L N ( or A L T or A S T > 8 X U L N i n patie nts ta ki n g li ver me dicati o ns 
at baseli ne) a n d u p t o 5 X  U L N or t otal bilir u bi n > 1. 5 X  U L N a n d u p t o 3 X  U L N  
•  Creati ni ne > 1. 5 X  a n d u p t o 6 X  U L N or greater t h a n 1. 5 X  baseli ne  
•  A n y ot her se vere or G ra d e ≥3 a d verse reacti o n attri b ut e d t o ni v ol u ma b a d mi nistrati o n  

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•  A n y A E or  la b orat or y a b n or malit y attri b ute d t o ni v ol u ma b t hat, i n t he j u d g me nt of t he 
i n vesti gat or, prese nts a s u bsta ntial cli nical ris k t o t he patie nt  wit h c o nti n ue d d osi n g  
9. 1. 3. 2.  
Rest arti n g Ni v ol u m a b  
Patie nts ma y res u me treat me nt wit h ni v ol u ma b u nless t he criteria f or per ma ne nt disc o nti n uati o n 
are met (Secti o n 9. 1. 3. 3 ).  Ni v ol u ma b ma y be rest arte d i n patie nts w h ose a d verse reacti o ns 
rec o ver t o Gra d e 0 t o 1.  If t he A E has res ol ve d t o  Gra de  ≤1 , ni v ol u ma b d osi n g ma y be restart e d 
at t he ne xt sc he d ule d ti m e  p oi nt per pr ot oc ol.  Please n ote t hat r e -i nitiati n g treat me nt ma y be 
ass ociate d wit h rec urre nce or e xacer bati o n of a ut oi m m u ne or i nfla m mat or y e ve nts.   
If > 1 d ose is t o be h el d or > 2-w ee k del a y is e x pecte d d ue t o c urre nt e ve nts n ot relate d t o st u d y, 
t he d osi n g sc he d ule m o dificati o ns m ust be disc usse d wit h t he Me dical M o nit or pri or t o 
i m ple me ntati o n.  
9. 1. 3. 3.  
Ni v ol u m a b Disc o nti n u ati o n  
Patie nts m ust be disc o nti n ue d fr o m ni v ol u ma b t hera p y a n d  disc o nti n ue d  fr o m st u d y dr u g  f or t he 
f oll o wi n g reas o ns: 
•  Persiste nt a d verse reacti o ns t hat re q uire h ol di n g m ore t ha n 2 treat me nt d oses  of 
ni v ol u ma b    
•  A n y life -th reate ni n g or Gra de 4 a d v erse reacti o n  
•  Gra de 3 or 4 p ne u m o nitis  
•  Gra de 4 c olitis  
•  A S T or A L T > 5 X  U L N or t otal bilir u bi n > 3 X  U L N  
•  Creati ni ne greater t ha n 6 X  U L N  
•  A n y Gra d e ≥ 3 br o nc h os pas m, h y perse n siti vit y reacti o n, or i nf usi o n reacti o n 
•  A n y se vere or Gra de ≥ 3 a d verse reacti o n relate d t o n i v ol u ma b treat me nt t hat rec urs 
•  Persiste nt Gra de 2 or 3 treat me nt -relate d a d v erse reacti o ns t hat d o n ot rec o ver t o Gra d e 1 
or res ol ve wit hi n 1 2 wee ks after last d ose of ni v ol u ma b  
•  I n a bilit y t o re d uce c ortic oster oi d d ose t o 1 0 m g or less of pre d nis o ne or e q uivale nt per 
da y wit hi n 1 2 wee ks  
•  A n y A E or  la b orat or y a b n or malit y t hat, i n t he j u d g me nt of t he i n vesti gat or, prese nts 
or ga n s pecifi c i nj ur y a n d/ or a  s u bsta ntial cli nical ris k t o t he patie nt wit h c o nti n ue d d osi n g  
9. 1. 3. 4.  
I m m u ne-Rel ate d A d verse E ve nts a n d Re acti o ns w it h Ni v ol u m a b  
Im m u ne -relat e d A Es or reacti o ns are  defi n e d as a d verse reacti o n s of u n k n o w n eti ol o g y 
ass ociate d wit h ni v ol u ma b  e x p os ure a n d c o nsiste nt wit h a n i m m u ne p he n o me n o n.  Eff orts 
s h o ul d be ma de t o r ule o ut ne o plastic, i nfecti o us, meta b olic, t o xi n, o r ot her eti ol o gic ca uses pri or 
t o la beli n g a n e ve nt a n im m u ne -relate d A E.  S us pecte d i m m u ne-relate d a d verse reacti o ns m ust 
be d oc u me nte d o n a n A E or S A E f or m.  

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Patie nts s h o ul d be i nf or me d of a n d caref ull y m o nit ore d f or e vi de nce of cli nicall y si g nifica nt 
s yste mic i m m u ne-relate d a d verse reacti o ns (e .g ., s yste mic l u p us er yt he mat os us-li ke diseases) or 
or ga n -s pecific i m m u ne-relate d a d v erse reacti o n  (e.g ., p ne u m o nitis , c olitis, he patitis).  If a n 
i m m u ne-relate d a d vers e reacti o n is n ote d, a p pr o priate w or k -u p s h o ul d b e perf or me d, a n d st er oi d 
t hera p y ma y be c o nsi dere d if cli nicall y necessar y.   
G ui deli nes f or treat me nt a n d m o nit ori n g of s pecifi c i m m u ne-relate d a d verse reacti o ns  s h o ul d 
f oll o w t he ni v ol u ma b pac ka ge i nsert (A p pe n di x B ).  T hese rec o m me n dati o ns s h o ul d be utilize d 
as cli nicall y a p pr o pri ate  f or t he treat me nt of i ndi vi d ual patie nts.    
9. 2.  
C o nc o mit a nt  Me dic ati o ns  
9. 2. 1.  
E xcl u de d M e dic ati o ns 
Patie nts w h o ha ve ta ke n a n y of t he f oll o wi n g dr u gs wit hi n 7 da ys pri or t o t he Ra n d o mizati o n 
Visit ( Da y 1 Visit) will be  e xcl u de d fr o m t he st u d y:  
•  Se nsiti ve s u bstrates f or c yt oc hr o me P 4 5 0 2 C 8 or 3 A 4 (e .g ., re pa gli ni de, mi daz ola m, 
sil de nafil) 
•  S u bstrates f or p -gl yc o pr otei n tra ns p orter (e .g ., a m brise nta n, di g o xi n), O C T 1 tra ns p orter 
(e.g ., metf or mi n), O A T 1 tra ns p orter (e.g ., ca pt o pril, f ur ose mi de, met h otre x ate), a n d 
O A T P 1 B 3 tra ns p orter (e .g ., at or vastati n, r os u vastati n, valsarta n)  
Please refer t o t he la b el of eac h m e dicati o n f or s u bstrate i nf or mati o n.   
A d mi nistrati o n of t hese me dicati o ns will n ot be c o nsi dere d pr ot oc ol de vi ati o ns:  
•  S i n gle d ose a d mi nistrati o n of a nal gesics, a nest heti cs, or a n xiol ytics re q uir e d f or st u d y -
relate d bi o psies  
•  L o pera mi de (I m o di u m ® ) t o treat ca n cer treat me nt-i n d uce d diarr hea 
T he f oll o wi n g me dicati o ns a n d me dicati o n classes are n ot per mitte d d uri n g  t his st u d y, e xce pt as 
n ote d i n Secti o n  9. 2. 2 .  T h us, p atie nts ta ki n g t hese me dicati o ns or treat me nts will be i neli gi ble 
f or c o nti n uati o n i n t he st u d y: 
•  A n y ot her i n vesti gati o nal dr u g  
•  A n y ot her a ge nt i nte n de d f or t he treat me nt of ca ncer 
•  Her bal pr e parati o ns  or o ver -t he-c o u nter m e dicati o n, e xce pt as i de ntifi e d i n Secti o n  9. 2. 2  
•  Gra n ul oc yte -sti m ulati n g fact ors, e x ce pt f or i nter mitte nt treat me nt of ne utr o pe nia 
•  Se nsiti ve s u bstrates f or c yt oc hr o me P 4 5 0 2 C 8 or 3 A 4 (e .g ., re pa gli ni de, mi daz ola m, 
sil de nafil) 
•  S u bstrates f or p -gl yc o pr otei n tra ns p orter (e .g ., a m brise nta n, di g o xi n), O C T 1 tra ns p orter 
(e.g ., metf or mi n), O A T 1 tra nsp orter (e .g ., ca pt o pril, f ur ose mi de, met h otre x ate), a n d 
O A T P 1 B 3 tra ns p orter (e .g ., at or vastati n, r os u vastati n, valsarta n) 

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9. 2. 2.  
Per mitte d  M e dic ati o ns  
Pr o p h ylactic a nti e metics will be all o we d, at t he discreti o n of t he treati n g p h ysicia n.   T he 
f oll o wi n g c o nc o mita nt me dicati o ns are per mitte d , as a ut h orize d b y t h e treati n g p h ysicia n:  
•  A nti bi otics , e xce pt as n ot e d a b o ve ( Secti o n 9. 2. 1 ) 
•  Dail y m ulti vita mi n s 
•  Dail y s u p ple me nts , vita mi ns , a n d mi nerals (e.g ., calci u m, ma g nesi u m, vita mi n D, B -
c o m ple x vita mi ns, vita mi n E, etc.)  
•  Pai n me dicati o n , e xce pt as n ote d a b o ve ( Secti o n  9. 2. 1 ) 
•  Ot her me dicati o ns i nte n d e d t o ma na ge c o nc urre nt diseases, e xce pt as n ote d a b o ve 
(Secti o n  9. 2. 1 ) 
•  Oral, i m pla nta bl e, or i njecta ble c o ntr ace pti ves  
Patie nts ta ki n g me dicati o n c hr o nicall y s h o ul d be mai ntai ne d o n t h ose sa m e d oses a n d d ose 
sc he d ules t hr o u g h o ut t he st u d y peri o d, as me dicall y feasi ble .  Patie nts ta ki n g me dicati o ns wit h 
i nter mitte nt or as -nee d e d sc he d ules s h o ul d tr y t o a v oi d ta ki n g t he c o nc o mita nt me dicati o n o n 
da ys w he n P K sa m ples will be c ollecte d ( i.e., Visits 2 , 3, a n d 8), as me dicall y feasi ble. 
9. 3.  
C o m pli a nce  w it h St ud y Dr u g  
T he i n vesti gat or or desi g nee w ill o nl y dis pe nse  st u d y dr u g (R T A  4 0 8 ) t o p atie nt s e nr olle d i n t he 
st u d y i n acc or da n ce wit h t he pr ot oc ol.  T he st u d y dr u g m ust n ot be use d f or reas o ns ot her t ha n 
t hat descri be d i n t he pr ot oc ol. 
Be gi n ni n g wit h t he Wee k 4  Visit  ( Visit 5 ), patie nts will ret ur n all u n use d pills at eac h visit a n d 
will be dis pe nse d a ne w b ottle of pills t o ta ke u ntil t he ne xt visit.  C o m plia nce will be meas ure d 
b y  c o u nti n g pills t o deter mi ne t he n u m ber of misse d d oses fr o m o ne visit t o t he ne xt.   T o be 
c o nsi dere d c o m plia nt wit h st u d y dr u g, patie nts ca n miss n o m ore t ha n 2 5 % of t he t otal pla n ne d 
d oses  d uri n g t he st u d y.  Patie nts w h o e xcee d t h e n u m ber of all o we d misse d d oses will be 
c o nsi dere d n o n c o m plia nt wit h d osi n g.  Patie nts will n ot be di sc o nti n ue d fr o m t he st u d y f or 
treat me nt n o nc o m plia nce, b ut pr ot oc ol de viati o ns s h o ul d be rec or de d f or d osi n g n o nc o m plia nce. 
9. 4.  
R a n d o miz ati o n  a n d Bli n di n g  
N o bli n di n g or ra n d o mizati o n pr oce d ures will be e m pl o ye d  i n t his o pe n-la bel st u d y. 
9. 5.  
Pr ot oc ol  S afet y Re vie w  C o m mittee  
As detaile d i n Secti o n  7. 4. 2 , f or eac h c o m bi nati o n t hera p y (i.e., R T A  4 0 8  + i pili m u ma b or 
R T A  4 0 8 + ni v ol u ma b), after t he first 3 patie nts h a ve c o m plete d t he D L T o bser vati o n peri o d , all 
a vaila ble safet y  a n d p h ar mac o d y na mic  i nf or m ati o n will be re vie we d b y t h e P S R C t o ma ke a 
decisi o n re gar di n g escalati o n t o t he s u bse q ue nt R T A  4 0 8  d ose le vel or of t he nee d t o e val uate  
a d diti o nal pati e nts at t he c urre nt R T A  4 0 8  d os e le vel  i n c o m bi nati o n wit h i pili m u ma b or 
ni v ol u ma b .  T he P S R C will i ncl u de at a mi ni m u m a S p o ns or re pres e ntati ve, a n o nc ol o gist,  a n d a 
statisticia n.  S h o ul d iss ues arise re q uiri n g e x pertis e n ot re prese nte d b y t he c urre nt me m b ers, t he 
P S R C  ma y a p p oi nt a d diti o nal cli nical s pecialists.  

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Base d o n t he n u m ber of e val ua ble p atie nts a n d n u m ber of D L Ts e x perie n ce d o utli ne d i n 
Secti o n  7. 4. 2 , t he P S R C will rec o m me n d o ne of t he f oll o wi n g: ( 1) patie nts e nr olle d i n t he 
s u bse q ue nt c o h ort ma y b e treate d at t he ne xt hi g h er d ose le vel; ( 2) safet y e val uati o n after 
3  a d diti o nal patie nts ha ve c o m plete d t he D L T o bser vati o n peri o d  at t he c urre nt  d ose le vel ; 
( 3) d o se es calati o n will n ot occ ur; or ( 4) patie nts e nr olle d i n t he s u bse q ue nt c o h ort ma y be 
treate d at a l o wer d os e bet wee n a  pre vi o usl y well -t olerate d d ose le vel a n d t h e c urre nt d ose le vel.   
T he P S R C will als o rec o m me n d o ne of t he f oll o wi n g: ( 1) e nr oll me nt wil l c o nti n ue at t he c urre nt 
d ose le vel t o a ma xi m u m of 6  patie nts ; or ( 2) e nr oll me nt will n ot c o nti n ue at t he c urre nt d ose 
le vel. 
A d diti o nall y, t he P S R C will als o e val uate data f or si g ns of p har mac o d y na mic acti vit y a n d 
effic ac y t o rec o m me n d a P hase 2 d ose.   
9. 6.  
U nsc he d ule d V isits 
U nsc he d ule d visits are all o we d f or t he f oll o wi n g reas o ns:  
•  Patie nt rescree ni n g  
•  M a na ge me nt of a n A E  or  S A E  
•  Perf or ma nce of a d diti o nal la b orat or y tests f or cli nicall y a b n or mal test val ues or t o 
c o nfir m a p ossi ble pre g n a nc y  
•  I ma gi n g st u dies for t u m or size/ b ur de n e val uati o n as a p pr o priat e t o assess disease b ur de n 
or t u m or size i n patie nts wit h pse u d o -pr o gressi o n  
•  A n y ti me t he i n vesti gat or feels t hat it is cli nicall y a p pr o priate f or patie nt safet y  
9. 7.  
Pre g n a nc y  
9. 7. 1.  
W o me n of C hil d be ari n g  P ote nti al  
W O C B P are fe m ale patie nts w h o are n ot s ur gicall y sterile ( n o hist or y of bilateral t u bal li gati o n, 
h ysterect o m y, or bilateral sal pi n g o -o o p h orect o m y) , d o n ot ha ve fall o pia n i nserts wit h c o nfir me d 
bl oc ka ge , ha v e n ot ha d re pr o d ucti ve p ote ntial ter minate d b y ra diati o n, a n d are n ot 
p ost me n o pa usal f or at least 1 year.  
9. 7. 2.  
Met h o ds  of Birt h C o ntr ol  
Fr o m  t he Scree ni n g  Visit , w hile ta ki n g st u d y dr u g, a n d u ntil 3 m o nt hs after ta ki n g t he fi nal d ose 
of st u d y dr u g , W O C B P m ust a gree t o practice o n e of t he f oll o wi n g met h o ds of birt h c o ntr ol:  
•  Use of a d o u ble -barrier c o ntrace pti o n met h o d , defi ne d as male use of a c o n d o m a n d 
fe male use of a barrier met h o d  
•  Use of h or m o nal c o ntrace pti ves ( oral, pare nteral, va gi nal , or tra ns der mal) f or at least 
3  m o nt hs pri or t o st u d y dr u g a d mi nistrati o n  
•  Use of a n i ntra uteri ne d e vice  
•  C o m plete a bsti n ence  fr om se x ual i nterc o urse  

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Fr o m t he S cree ni n g  Visit , w hile ta ki n g st u d y dr u g, a n d u ntil 3 m o nt hs after ta ki n g t he fi nal d ose 
of st u d y d r u g, males w h o ha ve fe m ale part ners of c hil d beari n g p ote ntial m ust a gree t o practice 
o ne of t he f oll o wi n g met h o ds of birt h c o ntr ol:  
•  Ha ve ha d a vasect o m y (at least 6 m o nt hs earlier)  
•  Use of a d o u ble -barrier c o ntrace pti o n  met h o d , defi ne d as male use of a c o n d o m a n d 
fe male use of a barrier met h o d  
•  Part ner use of h or m o nal c o ntrace pti ves ( oral, pare nteral, va gi nal or tra ns der mal) f or at 
least 3 m o nt hs pri or t o st u d y dr u g a d mi nistrati o n 
•  P art ner use of a n i ntra uteri ne de vice  
•  C o m plete a bst i nence  fr o m se x ual i nterc o urse 
9. 7. 3.  
S us pecte d Pre g n a nc y  
D uri n g t he st u d y, all W O C B P m ust be i nstr ucte d t o c o ntact t he i n vesti gat or i m me diatel y if t he y 
s us pect t he y mi g ht be pre g na nt (e.g ., late or misse d me nstr ual peri o d).  Mal e patie nts m ust be 
i nstr ucte d t o c o ntact t he i n vesti gat or if a se x u al part ner s us pects s he m a y be pre g na nt. 
If a patie nt or i n v esti gat or s us pects t hat t he patie nt ma y be pre g n a nt, t he st u d y dr u g m ust be 
wit h hel d u ntil t he res ults of a ser u m pre g na n c y test are a v aila ble .  If pre g na nc y is c o nfir med  wit h 
a ser u m pre g n a nc y test , t he patie nt m ust disc o nti n ue ta ki n g st u d y dr u g b ut c o nti n ue t o atte n d all 
st u d y visits a n d u n der g o all st u d y assess me nts.  T he patie nt s h o ul d als o f oll o w t he g ui da nce o n 
t he i pili m u ma b or ni v ol u ma b prescri bi n g i nf or m ati o n re g ar di n g c o nti n uati o n of i pili m u ma b  or 
n iv ol u ma b .  T he i n vesti gat or m ust i m me diatel y re p ort a pre g n a nc y ass o ciat e d wit h st u d y dr u g 
e x p os ure a n d rec or d t he e ve nt .   
Pre g na nc y is n ot c o nsi dere d a n A E;  h o we ver, t he i n vesti gat or m ust f oll o w a pre g na nt p atie nt or  
t he pre g na nt f e male part ner of a m ale patie nt (if c o nse nti n g), a n d re p ort f oll o w-u p i nf or mati o n 
re gar di n g t he c o urse of t he pre g na n c y, i ncl u di n g peri natal a n d n e o natal o utc o me.  I nfa nts 
res ulti n g fr o m s uc h pre g na ncies s h o ul d be f oll o we d f or a mi ni m u m of 8 wee ks .  Reata 
P har mace uticals or its desi g nee ma y c o ntact t he i n vesti gat or t o re q uest a d diti o nal i nf or mati o n 
t hr o u g h o ut t he c o urse of t he pre g na n c y. 
T he f oll o wi n g pre g na n c y o utc o mes m ust be c o nsi dere d S A E s a n d will re q uire a d diti o nal 
re p orti n g i n t he ele ctr o nic C R F  a n d o n a n S A E  f or m: 
•  C o n ge nital a n o mal y/ birt h defect  
•  Still birt h  
•  S p o nta ne o us miscarria g e  
9. 8.  
Seri o us  T o xicities  
I n t he cas e of seri o us t o xicities t hat d o n ot meet t he defi niti o n of a D L T (Secti o n 7. 4. 3 ), t he 
i n vesti gat or ma y c h o ose t o i nterr u pt treat me nt wit h R T A  4 0 8 .  R T A  4 0 8  treat me nt ma y be 
restarte d wit h a p pr o val fr o m t he me dical m o nit or .  D ose re d u cti o ns are n ot per mitte d.  As state d 
in Secti o n  9. 3 , if a patie nt misses m ore t ha n 2 5 % of t he t otal pla n ne d d oses d uri n g t he st u d y, 
pr ot oc ol de viati o ns s h o ul d be rec or de d i n t he C R F .  R ec o m me n de d g ui deli nes f or treat me nt a n d 

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m o nit ori n g of s pecific i m m u ne -relat e d a d verse reacti o ns are i ncl u de d i n t he i pili m u ma b pac ka ge 
i nsert (A p pe n di x A ) a n d t he ni v ol u ma b pac ka g e i nsert ( A p pe n di x B ), a n d s pecifie d safet y 
criteria d etai le d i n Secti o n s 9. 1. 1. 1  a n d 9. 1. 3  will be use d t o deter mi ne d os e dela y, restarti n g 
d oses, or disc o nti n u ati o n of  i pili m u ma b a n d ni v ol u ma b t hera p y, res pecti vel y. 
Pre vi o us cli nical e x peri e nce i n o nc ol o g y patie nts wit h a relate d c o m p o u n d , bar d o x ol o ne met h yl, 
s u g gests t hat tra nsie nt ele vati o ns i n tra nsa mi nase ( A L T or A S T) a n d G G T le vels ma y occ ur a n d 
t he n s p o nta ne o usl y res ol ve w hile c o nti n ui n g treat me nt wit h R T A  4 0 8 .  F urt her m ore, t he D L T f or 
bar d o x ol o ne met h yl i n o nc ol o g y patie nts was  transa mi nase ele vati o ns ( H o n g, 2 0 1 2 ).  
A n y i ncreas e i n tra nsa mi nase ( A L T or A S T) le vels t o > 3 X U L N s h o ul d be f oll o we d b y re p eat 
testi n g of A L T, A S T, a n d t otal bilir u bi n wit hi n 4 8 t o 7 2 h o urs.  If t he ele vati o ns persist a b o ve 3 X 
U L N, t he tra ns a mi nase a n d t otal  bilir u bi n tests s h o ul d be re peate d 2 t o 3 ti mes wee kl y .  P atie nts 
m ust be disc o nti n ue d fr o m t he st u d y dr u g if t he y meet a n y of t he f oll o wi n g criteria : 
•  A L T or A S T > 3 X U L N a n d  (t otal bilir u bi n > 2 X U L N or  I N R > 1. 5) 
•  A L T or A S T > 3 X U L N wit h t he a p peara nce of fati g ue, na usea, v o miti n g, ri g ht u p per 
q ua dra nt pai n or t e n der ness, fe ver, ras h, a n d/ or e osi n o p hilia (> 5 %)  
If a patie nt is disc o nti n ue d fr o m st u d y dr u g  d ue t o o ne of t he a b o v e criteri a, t he he pat o biliar y tree 
m ust be vis ualize d (e .g ., ultras o u n d) a n d ass esse d.  A d diti o nal tests or st u dies ma y be warra nt e d 
de pe n di n g o n t he cli nical prese ntati o n.  
9. 9.  
St u d y Pr oce d ures   
•  T o a v oi d i nter o bser ver varia bilit y, e ver y eff ort s h o ul d be ma de t o e ns ure t hat t he sa me 
i n di vi d ual w h o ma de t he i nitial baseli ne deter mi nati o n c o m pletes all s u bse q ue nt 
assess me nts.  
•  Wit h a p pr o val of t he S p o ns or, or desi g nee, s cree ni n g ma y be i ncrease d t o 2 8 da ys o n a n 
i n di vi d ual patie nt basis. 
9. 9. 1.  
I nf or me d C o nse nt  
Writte n i nf or me d c o ns e nt  (Secti o n  1 6. 3 ) m ust be o btai ne d fr o m t he patie nt bef ore a n y 
st u d y-relate d pr oce d ures are perf or m e d, a n d if t here is a c h a n g e i n t he st u d y pr oce d ures t hat 
co ul d affect t he patie nt’s willi n g ness t o partici pate.   I nf or me d c o nse nt m ust als o be o btai ne d 
fr o m t he patie nt if R E CI S T pr o gressi ve diseas e  is o bser ve d t hat t he I n v esti gat or s us pects is d ue 
t o pse u d o-pr o gressi o n a n d t he patie nt wis hes t o c o nti n ue pr ot oc ol -s pecifi e d treatme nt 
(Secti o n  8. 4. 1 ). 
9. 9. 2.  
I ncl usi o n/ E xcl usi o n Criteri a  
I n cl usi o n a n d e xcl usi o n criteria s h o ul d be re vie we d at t he ti mes i n dicate d i n Ta ble 3  a n d T a ble 4 .  
Patie nts m ust meet all of t he i ncl usi o n criteria a n d n o ne of t he e x cl usi o n criteria f or e ntr y i nt o t he 
st u d y.  

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9. 9. 9.  
Electr oc a r di o gr a m  
A 1 2 -lea d E C G will be rec or de d at t he ti mes i n dicate d i n Ta ble 3  a n d Ta bl e 4  after t he patie nt 
has reste d f or a p pr o xi mat el y 1 0 mi n utes i n a s u pi ne p ositi o n.  T he heart rate fr o m t he E C G 
mac hi ne s h o ul d n ot be us e d as part of t h e vital si g n meas ure me nts.  
9. 9. 1 0.  
Vit al  Si g n Me as ure me nts  
Vital si g n meas ure me nts s h o ul d be ta ke n at t he ti mes i n dicate d i n Ta ble 3  a n d Ta ble 4  a n d 
i ncl u de t he patie nt’s heart rate ( beats/ mi n ute), bl o o d press ure ( m m Hg), a n d b o d y 
te m perat ur e (° C).  Bl o o d press ure s h o ul d be t a ke n after t he p atie nt has rest e d i n a sitti n g p ositi o n 
f or a p pr o xi matel y 5 mi n utes.  T he sa me ar m ( us u all y t he n o n-d o mi na nt ar m) a n d t he a p pr o priate 
size c uff s h o ul d b e use d f or eac h m eas ure me nt.   
9. 9. 1 1.  
P h ysic al  E x a mi n ati o n  
A c o m pre he nsi v e p h ysical e xa mi nati o n m ust be perf or me d b y a p h ysicia n, p h ysicia n assista nt, or 
re gistere d n urse practiti o ner at t he ti mes i n dicate d i n Ta ble 3  a n d Ta bl e 4 .  If p ossi ble, t he sa me 
i n di vi d ual s h o ul d perf or m eac h p h ysical e xa m o n a patie nt d uri n g t he st u d y.  T he e xa mi nati o n 
m ust i ncl u de t he f oll o wi n g or ga n or b o d y s yste m assess me nts:  hea d, e y es, ears, n ose, t hr o at, 
m usc ul os keletal, car di o v asc ular, l y m p hatic, res pir at or y, a b d o me n, s ki n, e xtre mities, a n d 
ne ur ol o gical.  Assess me nts of a n y s pecific si g ns or s y m pt o ms re p orte d b y t he patie nt m ust als o 
be perf or me d a n d d o c u me nte d al o n g wit h a n y ot h er fi n di n gs of n ote.  Fi n di n gs at t he Scree ni n g  
Visit m ust be c haracterize d as eit her n or mal or a b n or mal, a n d , if a b n or m al, a descri pti o n of t he 
a b n or malit y m ust be pr o vi de d.  F oll o wi n g t he e xa mi nati o n at t he Scree ni n g Visit,  t he 
assess me nts m ust be classifie d as u nc ha n g e d, ne w, w orse ne d, or i m pr o ve d fr o m t he last ti me t he 
b o d y s yste m was assesse d.  
9. 9. 1 2.  
Pre g n a nc y Test  
W O C B P  (Secti o n  9. 7. 1 ) will pr o vi de a bl o o d or uri ne sa m ple f or a pre g n a n c y test  at t he ti mes 
i n dicate d i n Ta ble 3  a n d Ta ble 4 .  Ne g ati ve ser u m test res ults are re q uire d at t he Ra n d o mizati o n 
Visit ( Da y 1  Visit)  bef ore st u d y dr u g a d mi nistrati o n, a n d ne gati ve uri n e test res ults are re q uire d 
at all ot her ti mes i n dicate d i n Ta ble 3  a n d Ta bl e 4  f or c o nti n ue d participati o n i n t he st u d y .  A n y 
patie nt w h o bec o mes pre g na nt d uri n g t he st u d y m ust disc o nti n ue ta ki n g st u d y dr u g i m me diatel y .  
See Secti o n  9. 7. 3  f or a d escri pti o n of pr oce d ures t o be f oll o we d i n cas e of pre g na nc y.  
9. 9. 1 3.  
St u d y Dr u g Dis pe ns ati o n   
A de q uate q u a ntities  of R T A  4 0 8  ca ps ules will be dis pe nse d t o t he patie nt at t he ti mes i n dicate d 
i n Ta ble 3  a n d Ta bl e 4  t o last t he patie nt  u ntil t he ne xt visit , al o n g wit h i nstr ucti o ns f or use.  
9. 9. 1 4.  
St u d y Dr u g Ret ur n/ Pill C o u nt   
Ca ps ules ret ur ne d b y t he patie nt will be c o u nte d b y t he st u d y d oct or or t he st u d y staff at t he 
ti mes i n dicate d i n Ta ble 3  a n d Ta ble 4  t o deter mi ne treat me nt c o m plia n ce.  Criteria f or 
n o nc o m plia nce a n d i nstr ucti o ns f or rec or di n g c o m plia nce o n t he C R F are i ncl u de d i n 
Secti o n  9. 3 .  

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9. 9. 1 5.  
St u d y Dr u g  A d mi nistr ati o n  
Patie nts s h o ul d self -a d mi nister t he assi g ne d n u m b er of R T A  4 0 8  C a ps ules orall y o nce da ily i n 
t he m or ni n g o n a n e m pt y st o mac h (a p pr o xi matel y 1 h o ur bef ore or 2 h o urs after eati n g) wit h 
water at t he ti mes i n dicat e d i n  Ta ble 3  a n d T a ble 4 , e xce pt o n da ys w he n P K sa m ples are 
c ollecte d (D a y 1, Wee k 1, a n d Wee k 1 3 [ Visits 2 , 3, a n d 8]), at w hi c h ti me st u d y staff will 
a d mi nister R T A  4 0 8  at t he cli nic f oll o wi n g c ollecti o n  of t he first ( pre d os e) P K sa m ple.   
A v o mite d d ose s h o ul d n ot be re place d.  Misse d d oses ma y be ta ke n i n t he after n o o n or e ve ni n g 
of t he sa me da y a p pr o xi matel y 1 h o ur bef ore or 2 h o urs after a meal.  A d o u ble d ose 
(e.g ., misse d d ose fr o m pre vi o us da y a n d d os e f or c urre nt d a y) s h o ul d n ot be ta ke n.  
9. 9. 1 6.  
I pili m u m a b A d mi nistr ati o n  
I pili m u ma b 3 m g/ k g will be a d mi nistere d t o t he p atie nt i ntra ve n o usl y at t he ti mes i n dicate d i n 
Ta ble 3  acc or di n g t o t he pac ka g e i nsert (A p pe n di x A ). 
9. 9. 1 7.  
Ni v ol u m a b A d mi nistr ati o n  
Ni v ol u ma b 2 4 0 m g will be a d mi nistere d  t o t he patie nt i ntra ve n o usl y at t he ti mes i n dicate d i n 
Ta ble 4  acc or di n g t o t he pac ka g e i nsert ( A p pe n di x B ). 
9. 9. 1 8.  
T u m or  Bi o ps y  
T hree tu m or bi o psies wil l be c ollecte d at t he Scree ni n g  Visit , at Wee k 1, a n d at Wee k  1 3  
(Ta ble 3  a n d T a ble 4 ) f or a nal ysis of t he f oll o wi n g bi o mar kers: N F -κ B, i N O S, nitr ot yr osi ne, 
ar gi nase, a n d ot her mar kers of i m m u ne stat us a n d i nfla m mati o n.  All t u m or bi o psies are 
ma n dat or y f or patie nts e nr olli n g i n t he P hase 1 b d ose -escalati o n p orti o n of t he st u d y.  T he 
Scree ni n g visit t u m or bi o ps y is ma n dat or y f or pati e nts e nr olli n g i n t he P hase 2 p orti o n of t he 
st u d y, b ut t he Wee k 1 a n d Wee k 1 3 t u m or bi o psies are o pti o nal f or t h ese p atie nts.  A d diti o nall y, 
i m m u no hist oc he mical stai ni n g will be use d t o q ua ntif y t u m or cell p o p ulati o ns (e. g., t u m or 
i nfiltrati n g l y m p h oc ytes a n d M D S Cs).  T hese bi o psies s h o ul d i ncl u de a de q uate tiss ue f or sa m ple 
a nal ysis , as detaile d i n t h e st u d y ma n ual.  Detaile d pr ocessi n g i nstr ucti o ns will be pr o vi de d f or 
is olati o n, st ora ge, a n d s hi p me nt of t u m or bi o ps y sa m ples. 
T he date a n d ti me of c ollecti o n of all t u m or bi o ps y sa m ples s h o ul d be rec or de d; h o we ver, a n y 
de viati o ns fr o m t he pr ot o c ol -s pecifie d s a m pli n g ti mes will n ot be c o nsidere d pr ot oc ol de viati o ns.  
Sa m ple ti me de viati o ns will be s u m marize d i n t he st u d y re p ort.   
9. 9. 1 9.  
T u m or  B ur de n E v al u ati o n  
C o m plete a n d partial t u m or r es p o nses will be e val uate d b y ra di o gr a p hic ass ess me nt at t he ti mes 
i n dicate d i n Ta ble 3  a n d Ta ble 4  usi n g t he sta n dar dize d res p o ns e criteri a de vel o pe d b y the 
R E CI S T  ( Res p o nse E v al uati o n Criteria I n S oli d T u m ou rs) W or ki n g Gr o u p, v ersi o n 1. 1 
(Eise n ha uer,  2 0 0 9 ), w hic h will be pr o vi de d t o t he i n vesti gat or.  S piral c o m p ute d t o m o gra p h y 
(C T ) wit h c o ntrast is preferre d  u nl ess ot her wise s p ecifie d b y t he pri nci pal i n vesti gat or or 
desi g nee.  Assess me nts p erf or me d wit hi n 2 8 da ys prece di n g a d mi nistrati o n of t he first d ose ma y 
be use d  f or b aseli ne t u m or b ur de n  e v al uati o n .  If t u m or assess me nts are perf or me d f or a n y 
reas o n pri or t o Wee k 1 3, in vesti gat ors s h o ul d c o nsi der t hat tra nsie nt i ncreas e of t u m or b ur de n o n 

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ra di o gra p hic assess me nts has bee n re p orte d wit h i pili m u ma b t hat ma y s u bse q ue ntl y res ol ve o n 
c o nti n ue d t hera p y, a n d disc o nti n uati o n of pr ot oc ol t hera p y is n ot re q uir e d b ase d o n s uc h res ults. 
9. 9. 2 0.  
A d verse  E ve nt C ollecti o n  
Patie nts s h o ul d be o bser ve d  f or ge n eral a p peara n ce, prese n ce of ill ness or i nj ur y, or si g ns 
i n dicati ve of a c o n c urre nt ill ness at t he ti mes i n dicate d i n  Ta ble 3  a n d Ta ble 4 .  P atie nts s h o ul d 
be i nstr ucte d t o v ol u nteer a n y i nf or mati o n re g ar di n g A Es at a n y ti me d uri n g t he st u d y.  T he 
st u d y d oct or or t he st u d y staff s h o ul d als o q uer y patie nts wit h a n o pe n q uesti o n re gar di n g a n y 
A Es t he y ma y be e x p erie nci n g (e .g ., “ H o w d o y o u feel?”  or “ H o w ha v e y o u bee n feeli n g si nce 
y o ur last visit?”) .  A n y  fi n di n gs are t o be d oc u m e nte d  a n d will be e val u ate d b y t he i n vesti gat or 
or desi g nee acc or di n g t o t he C T C A E criteria p er Secti o n  1 2. 5 . 
9. 9. 2 1.  
Cli nic al  C he mistr y  
Bl o o d s a m ples will be c ollecte d f or cli nical c he mistr y a nal yses at t he ti mes i n dicate d i n Ta ble 3  
a n d Ta ble 4 .  Cli nical c h e mistr y a nal yses are liste d i n  Ta ble 7 .  F or calc ul ati o n of t he e G F R, t he 
4 -varia ble M D R D e q uati o n m ust be use d.  T he e q uati o n is  as f oll o ws : 
e G F R = 1 7 5 x sta n dar dize d ser u m creati ni ne – 1 1 5 4 x a ge – 0 2 0 3 x 1. 2 1 2 [if blac k] x 0. 7 4 2 [if fe male]  
 
 

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1 0.  
S T U D Y D R U G M A T E RI A L S A N D M A N A G E M E N T  
1 0. 1.  
St u d y Dr u g  
R T A  4 0 8  ca ps ules , i n 2. 5 -m g , 1 0 -m g , a n d/or 5 0 -m g stre n gt hs, will be use d i n t his st u d y.  
1 0. 2.  
St u d y Dr u g P ac k a gi n g a n d L a beli n g  
R T A  4 0 8  will be s u p plie d i n 7 5 -cc w hite hi g h -d e nsit y p ol yet h yle ne ( H D P E) b ottles wit h f oil 
i n d ucti o n-seal li ners a n d a c hil d-resista nt cl os ur e.  Eac h b ottle of st u d y dr u g will c o ntai n 
3 0  ca ps ules a n d eac h ca ps ule will c o ntai n 2. 5 m g , 1 0  m g , or 5 0 m g of R T A  4 0 8 .  Eac h b ottle will 
als o c o ntai n a desic ca nt i nsert t hat m ust n ot be  i n geste d.  T he la bel o n eac h b ottle will c o ntai n 
t he f oll o wi n g i nf or mati o n: 
•  Pr ot oc ol 4 0 8 -C -1 4 0 1  
•  L ot n u m ber  
•  D ose stre n gt h  ( o ne of t he f oll o wi n g): 
o  R T A  4 0 8  Ca ps ules, 2. 5 m g   
o  R T A  4 0 8  Ca ps ules, 1 0 m g   
o  R T A  4 0 8 Ca ps ules, 5 0 m g   
•  C o nte nts: 3 0 ca ps ules.  B ottle als o c o ntai ns o ne desicca nt i nsert; d o n ot i n gest t he 
desicca nt i nsert.  
•  Directi o n f or us e:  Ta ke ca ps ule(s) as directe d orall y o nce a da y i n t he m or ni n g o n a n 
e m pt y st o mac h ( 1 h o ur bef ore or 2 h o urs after eati n g) wit h water  
•  C a uti o n State me nt: Ne w Dr u g –  Li mite d b y Fe d eral La w t o I n vesti gati o nal Use   
•  F O R O R A L U S E O N L Y  
•  St ora ge: St ore at 2 0° C t o 2 5° C  ( 6 8° F - 7 7° F) , e x c ursi o ns all o we d t o 1 5° C t o 3 0° C ( 5 9° F - 
8 6° F) .  
•  Reata P har ma ce uticals, I nc., Ir vi n g, T X  
T o acc o m m o date m ulti ple d ose le vels, t he st u d y dr u g will be pr o vi de d t o t he site p har mac y .  T he 
p har macist will pr o vi de a n a de q uate  n u m b er  of b ottles  t o eac h patie nt wit h clear i nstr ucti o ns o n 
t he n u m ber a n d t y pe of ca ps ules t o be ta ke n eac h da y.  
1 0. 3.  
St u d y Dr u g  St or a ge  
T he sta bilit y of t he dr u g pr o d uct is bei n g e val uat e d i n o n g oi n g st u dies. 
I n v esti gati ve sites m ust st ore t he i n vesti gati o nal pr o d uct i n a sec ure l ocati o n wit h r o o m 
te m perat ur e c o n diti o ns of 2 0°C  t o 2 5° C ( 6 8° F  - 7 7° F) , e x c ursi o ns all o we d t o 1 5° C t o 3 0° C 
( 5 9° F - 8 6° F) . 

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1 0. 4.  
St u d y Dr u g A d mi nistr ati o n  
Please refer t o Secti o n  9. 9. 1 5  f or details o n st u d y dr u g a d mi nistrati o n.  A n a p pr o priate n u m b er of 
ca ps ules  a n d/ or b ottles will be pr o vi de d t o eac h p atie nt base d o n t he n u m ber of ca ps ules re q uir e d 
f or eac h d ose le v el.  Clear i nstr ucti o ns will be pr o vi de d t o t he patie nt re gar di n g t he n u m ber a n d 
t y pe of ca ps ules t o be i n g este d at eac h st u d y dr u g a d mi nistrati o n ti me p oi nt liste d i n Ta ble 3  a n d 
Ta ble 4 .   
1 0. 5.  
St u d y  Dr u g Acc o u nt a bilit y  
T he i n vesti gat or or desi g nee will mai ntai n a  rec or d of all st u d y dr u g recei v e d, dis pe nse d, a n d 
ret ur ne d t o t he S p o ns or or its desi g nee.  N o st u d y dr u g s hall be destr o ye d b y t he cli nical site 
u nless directe d t o d o s o b y t he S p o ns or or its desi g nee.   St u d y dr u g b ottles a n d a n y u n use d 
ca ps ules s h o ul d b e ret ur n e d b y t he patie nt t o t he st u d y staff. 
1 0. 6.  
St u d y  Dr u g H a n dli n g a n d Dis p os al  
At t he c o ncl usi o n of t he st u d y, t he S p o ns or or its desi g nee will direct t he site re gar di n g t he fi nal 
dis p ositi o n of a n y re mai ni n g st u d y dr u g.  

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1 1.  
P H A R M A C O KI N E TI C, P H A R M A C O D Y N A MI C, A N D 
E F FI C A C Y A S S E S S M E N T S  
1 1. 1.  
P h ar m ac o ki netic S a m ples  
P K  sa m ples will be a nal y ze d f or R T A  4 0 8  usi n g a vali date d a nal ytical met h o d .  Sa m ples ma y be 
a nal yze d f or p ote ntial meta b olites of R T A  4 0 8  usi n g n o n vali date d a nal ytical met h o ds.  
1 1. 2.  
T u m or Bi o psies  
T u m or bi o psies will be a nal yze d f or bi o mar kers of N F -κ B a n d t o deter mi ne t he i m m u ne stat us of 
t u m ors.  T hese bi o mar kers i ncl u de, b ut are n ot li mite d t o, t he f oll o wi n g para meters: N F-κ B, 
i N O S, nitr ot yr osi ne, ar gi nase, a n d ot her mar kers of i m m u ne stat us a n d i nfla m mati o n.  
A d diti o nall y, i m m u n o hist oc he mical stai ni n g will be use d t o q ua ntif y t u m or cell p o p ulati o ns 
(e.g ., t u m or i nfiltrati n g l y m p h oc ytes a n d M D S Cs).   
1 1. 3.  
Peri p her al Bl o o d M o n o n ucle ar  Cells  
P B M C sa m ples will be a nal yze d f or bi o mar kers of Nrf 2 a n d N F -κ B p har m ac ol o g y usi n g 
n o n vali date d a nal ytical met h o ds .  A d diti o nal  bi o mar kers i ncl u de, b ut are n ot li mite d t o , t he 
f oll o wi n g ge nes : N QO 1, S R X N 1, G C L C, G S R, G L R X, P R D X 1, T X N, T X N R D 1, P G D, a n d 
G 6 P D.  
P B M C  sa m ples will als o be c ollecte d f or M D S C a nal ysis .  M ulti ple tests will be perf or me d , 
i ncl u di n g a nal ysis of R O S a n d per o x y nitrite le vels i n m yel oi d cells, a nal ysis of t he f u ncti o nal 
acti vit y of M D S Cs, a n d assessi n g t he res p o nse of m o n o n uclear cells t o sti m ulati o n wit h recall 
a nti ge n (teta n us t o x oi d).  Beca use R T A  4 0 8  i nfl ue nces t he tra ns cri pti o n of ge nes t hat res ult i n 
re d uce d p er o x y nitrite le v els, M D S Cs rec o vere d fr o m t he bl o o d of patie nts treate d wit h R T A  4 0 8  
are e x p ecte d t o h a ve re d u ce d f u ncti o nal ca pacit y.  
1 1. 4.  
T u m or  B ur de n E v al u ati o n  
S piral C T wit h c o ntrast is preferre d t o e val uate t u m or b ur de n u nless ot her wise s pecifie d b y t he 
pri nci pal i n vesti gat or or desi g nee.  Assess me nts p erf or me d wit hi n 2 8 da ys prece di n g 
a d mi nistrati o n of t he first d ose ma y be use d  t o ass ess baseli ne t u m or b ur de n.  T he assess me nt 
perf or me d  at t he Scree ni n g Visit s h o ul d  be t he sa me met h o d use d t hr o u g h o ut t he st u d y.   
C o m plete a n d partial r es p o nse s t o R T A  4 0 8  a n d i pili m u ma b  or R T A  4 0 8  a n d n i v ol u ma b will be 
e val uate d usi n g t he sta n d ar dize d res p o nse criteria de vel o pe d b y T he R E CI S T W or ki n g Gr o u p, 
v ersi o n 1. 1 (Eise n ha u er, 2 0 0 9 ), w hic h will be pr o vi de d t o t he i n vesti gat or.   
 

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1 2.  
S A F E T Y A S S E S S M E N T S  
1 2. 1.  
S afet y  P ar a meters  
Safet y para meters i ncl u d e wei g ht, B MI, E C G, vital si g n meas ure me nts, p h ysical e xa m i nati o n, 
A E s, S A E s, a n d la b orat or y tests (cli nical c he mistr y , he mat ol o g y , uri nal ysis , a n d micr osc o p y ).  
1 2. 2.  
A d verse  a n d Seri o us A d verse E ve nts  
1 2. 2. 1.  
Defi niti o n  of A d verse E ve nts  
1 2. 2. 1. 1.  A d verse  E ve nt  
A n A E is defi ne d as a n y u nt o war d me dical o cc urre nce i n a p atie nt  re g ar dless of its ca usal 
relati o ns hi p t o st u d y treat me nt.  A n A E ca n b e a n y u nfa v o ra bl e a n d u ni nte n de d si g n (i ncl u di n g 
a n y cli nicall y si g nifica nt a b n or mal la b orat or y test res ult), s y m pt o m, or disease te m p orall y 
ass ociate d wit h t he use of t he st u d y dr u g, w het her or n ot it is c o nsi dere d t o be relate d  t o 
R T A  4 0 8 or i pili m u ma b  or ni v ol u ma b .  I n cl u de d in t his defi niti o n are a n y ne wl y occ urri n g 
e ve nts or pre vi o us c o n diti o n t hat has i ncreas e d i n se verit y or fre q ue n c y si nce t he a d mi nistrati o n 
of st u d y dr u g.   Disease pr o gressi o n is a st u d y e n d p oi nt a n d c o nse q ue ntl y, disease pr o gressi o n 
s h o ul d n ot be re p orte d as a n A E .  H o we ver, w h e n a patie nt  dies fr o m disease pr o gressi o n wit h n o 
ot her i m me diate ca us es, “ disease pr o gressi o n” s h o ul d be re p orte d as a n  S A E  (Secti o n  1 2. 2. 1. 2 ).  
A d diti o nall y, si g ns a n d s y m pt o ms t hat ma y be relate d t o disease pr o gressi o n or t he u n derl yi n g 
disease (re gar dl ess of dis ease pr o gressi o n) s h o ul d be re p ort e d as a n A E  or as a n S A E if it mee ts 
t he defi niti o n of a n S A E i n Secti o n  1 2. 2. 1. 2 . 
All A Es t hat are o bser ve d or re p orte d b y t he patie nt  d uri n g t he st u d y ( fr o m t he ti me of t he first 
d o se of st u d y dr u g u ntil t he fi nal visit) m ust be re p orte d, re g ar dless of t heir relati o ns hi p t o st u d y 
dr u g or t heir cli nical si g nifica nce.  
1 2. 2. 1. 2.  Seri o us  A d verse E ve nt  
A n  S A E is a n y A E occ urri n g at a n y d ose a n d re gar dless of ca us alit y t hat:  
•  Res ults i n deat h  
•  Is life-t hreate ni n g 
•  Re q uires i n patie nt h os pitalizati o n or pr ol o n gat i o n of e xisti n g h os pitalizati o n 
•  Res ults i n persiste nt or si g nifica nt i nca pacit y or s u bsta ntial disr u pti o n of t he a bilit y t o 
c o n d uct n or mal life f u ncti o ns  
•  Is a c o n ge nital a n o mal y or birt h defect i n a n offs pri n g of a patie nt  ta ki n g st u d y dr u g 
•  Is a n i m p orta nt me dical e ve nt  
T he ter m "life -t hr eate ni n g" refers t o a n e ve nt i n w hic h t he patie nt  was at i m me diate ris k of deat h 
at t he ti me of t he e ve nt .  It d oes n ot refer t o a n e v e nt t hat h y p ot heticall y mi g ht ha ve ca us e d deat h 
if it were m ore s e vere. 
I m p ort a nt me dical e v e nts are t h ose t hat ma y n ot m eet a n y of t he criteri a defi ne d a b o ve; h o we v er, 
t he y ma y be c o nsi dere d s eri o us w he n, bas e d u p o n a p pr o priate m e dical j u d g me nt, t he y ma y 

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je o par dize t h e patie nt  an d ma y re q uire m e dical or s ur gical i nter ve nti o n t o pre ve nt o ne of t he 
ot her o utc o mes liste d i n t he S A E defi niti o n.  
Pre g na nc y is n ot c o nsi dere d a n A E; h o w e ver, i nf or mati o n will be c ollecte d f or a n y pre g na nci es 
t hat occ ur d uri n g t he st u d y (fr o m t he ti me of  first d ose of st u d y dr u g u ntil t he fi nal visit).  Certai n 
pre g na nc y o ut c o mes will re q uire s u b missi o n as a n S A E ( Secti o n  9. 7. 3 ). 
T he i n vesti gat or is r es p o nsi ble f or re p orti n g t o Reata P har mace uticals or its desi g nee all A Es a n d 
S A Es t hat are o bser ve d or re p orte d b y t h e patie nt  d uri n g t he st u d y (fr o m t he ti me of  first d ose of 
st u d y dr u g u ntil t he fi nal visit ) acc or di n g t o desi g n ate d S ta n dar d O p erati n g P r oce d ures, 
re gar dl ess of t heir relati o ns hi p t o st u d y dr u g or t heir cli nical si g nifica n ce.  All S A Es re p orte d or 
o bser ve d d uri n g t he st u d y m ust be f oll o we d t o res ol uti o n or u ntil t he i n vesti gat or dee ms t he 
e ve nt t o be c hr o ni c or t he patie nt  t o be sta ble.  Reata  P har mace uticals  or its desi g nee ma y c o nt act 
t he i n vesti gat or t o o btai n a d diti o nal i nf or mati o n o n a n y S A E t hat has n ot res ol ve d at t he ti me t he 
patie nt  c o m pletes t he st u d y.  
1 2. 3.  
Eliciti n g  A d verse E ve nt I nf or m ati o n  
At e ver y st u d y visit, patie nt s m ust be as ke d a sta n dar d, n o n-directe d q uesti o n, s uc h as,  “ H o w d o 
y o u feel? ” or  “ H o w ha v e y o u bee n feeli n g si nce y o ur last visit?” t o elicit a n y me dicall y relate d 
c ha n ges i n t heir well -bei n g .  T he y  ma y  als o be as ke d if t he y ha ve b ee n h os pitalize d, ha d a n y 
acci de nts, use d a n y ne w me dicati o ns, or c ha n g e d c o nc o mita nt me dicati o n re gi me ns ( i ncl u di n g 
prescri pti o n dr u gs, o ver -t he-c o u nter me dicati o ns , vita mi ns, her bal pr o d ucts, a n d mi nerals).  
Res p o nses s h o ul d be rec or de d i n t he s o urce  d oc u me nts.  
I n a d diti o n t o patie nt  o bser vati o ns, A Es m ust be d oc u me nte d f or a n y cli nicall y si g nifica nt 
dia g n osis res ulti n g fr o m a b n or mal la b orat or y test val ues, p h ysical e xa mi nati o n fi n di n gs, E C G 
a b n or malities, or ot her d oc u me n ts t hat are rele va nt t o patie nt  safet y. 
1 2. 4.  
Assess me nt  of C a us alit y  
T he i n vesti gat or m ust use t he f oll o wi n g classificati o ns a n d criteria t o c haracterize t h e 
relati o ns hi p or ass ociati o n of R T A  4 0 8  or i pili m u ma b  or ni v ol u ma b , i n ca usi n g or c o ntri b uti n g t o 
t he AE:  
U nrelate d :  T his r elati o ns hi p s u g gests t hat t here is n o ass ociati o n bet wee n t he st u d y dr u g a n d t he 
re p orte d e ve nt. 
U nli kel y :  T his relati o ns hi p s u g gests t hat t he te m p oral se q ue n ce of t he e ve nt wit h st u d y dr u g 
a d mi nistrati o n ma kes a ca usal relati o ns hi p i m pr o b a ble a n d/ or ot her fact ors als o pr o vi de pla usi ble 
e x pla nati o ns.  
P ossi ble :  T his relati o ns hi p s u g gests t hat treat me nt wit h t he st u d y dr u g ca us e d or c o ntri b ute d t o 
t he A E.  T hat is, t he e ve nt f oll o ws a reas o n a ble te m p oral se q ue nce fr o m t h e ti me of st u d y dr u g 
a d mi nistrati o n, a n d/ or, f oll o ws a k n o w n res p o nse patter n t o t he st u d y dr u g, b ut c o ul d ha ve bee n 
pr o d uce d b y ot her fact ors.  
Pr o ba ble :  T his relati o ns hi p s u g gests t hat a reas o n a ble te m p oral se q u e nce of t he e ve nt wit h st u d y 
dr u g a d mi nistrat i o n e xists a n d, base d u p o n t he k n o w n p har mac ol o gical acti o n of t he dr u g, 
k n o w n or pre vi o usl y re p orte d a d verse reacti o ns t o t he dr u g or class of dr u gs, or j u d g me nt base d 

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o n t he i n vesti gat or’s cli nical e x perie nce, t he ass oci ati o n of t he e ve nt wit h st u d y dr u g  
a d mi nistrati o n see ms li kel y.  
1 2. 5.  
Assess me nt of Se verit y  
T he i n vesti gat or will gra de t he se verit y of t he A Es as Gra d es 1, 2, 3, 4, or 5 base d o n t he 
Nati o nal Ca ncer I nstit ute ( N CI) C T C A E, versi o n 4. 0 3 .  If t he criteria i n t he C T C A E versi o n 4. 0 3  
d o n ot a p pl y, s e verit y s h o ul d be defi ne d as s h o w n i n Ta ble 1 1 . 
T a ble 1 1 : 
A E  Se verit y Gr a des  
Gr a de  
Descri pti o n  
1  
Mil d; as y m pt o matic or mil d s y m pt o ms; cli nical or dia g n ostic o bser vati o ns o nl y; i nter ve nti o n  
n ot i n dicate d  
2  
M o derate; mi ni mal, l ocal or n o ni n vasi ve i nter ve nti o n i n dicate d; li miti n g a ge -a p pr o priate 
i nstr u me ntal acti vities of dail y li vi n g  
3  
Se vere or me dicall y si g nifica nt b ut n ot i m me diatel y life -t hreate ni n g; h os pitalizati o n or 
pr ol o n gati o n of h os pitalizati o n i n dicate d; disa bli n g; li miti n g self-care  acti vities of dail y 
li vi n g 
4  
Life -t hreate ni n g c o nse q ue nces; ur ge nt  i nter ve nti o n i n dicate d 
5  
Deat h relate d t o A E  
T he N CI C T C A E, versi o n 4. 0 3  will be pr o vi de d t o t he i n vesti gat or.  
1 2. 6.  
Rec or di n g  A d verse E ve nts  
All c o n diti o ns prese nt pri or t o t he first d ose of st u d y dr u g s h o ul d be d oc u m e nte d as me dical 
hist or y .  All dr u g -relate d (c haracterize d as p ossi b ly  or p r o ba bly relate d ; Secti o n 1 2. 4 ) A Es a n d 
a b n or mal la b orat or y test res ults re p orte d or o bser ve d d uri n g t he st u d y m ust be f oll o we d t o 
res ol uti o n (eit her ret ur n t o baseli ne or wit hi n n or mal li mits).  All ot her A Es will be f oll o we d 
t hr o u g h t he fi nal visit (i.e., e n d of st u d y or earl y ter mi nati o n) .  I nf or mati o n t o be c ollecte d 
i ncl u des t y pe of e v e nt, date of o nset, dat e of res ol uti o n, i n vesti gat or-s pecifie d assess me nt of 
se verit y a n d relati o ns hi p t o st u d y dr u g, seri o us ness, as well as a n y acti o n ta ke n.  
W hile a n A E is o n g oi n g, c ha n ges i n t he se v erit y (e .g ., w orse ni n g or  i m pr o vi n g) s h o ul d be n ote d 
i n t he s o urce d oc u m e nts b ut w he n d oc u me nti n g t he A E, o nly t he t otal d urati o n a n d greatest 
se verit y s h o ul d be rec or de d i n t he C R F .  A Es c haracterize d as i nter mitte nt r e q uire d oc u me nt ati o n 
of o nset a n d d urati o n.  
A Es res ulti n g fr o m c o nc urre nt ill nesses, reacti o ns t o c o nc urre nt ill nesses, or reacti o ns t o 
c o nc urre nt  me dicati o ns  m ust als o be re p orte d .  W orse ni n g or c o m plicati o n of s uc h a c o n c urre nt 
c o n diti o n s h o ul d als o be rec or de d as a n A E.  I n v esti gat ors s h o ul d e ns ure t hat t he A E ter m 
rec or de d ca pt ures t he c ha n ge i n t he c o n diti o n (e. g., “ w orse ni n g of … ”).  Pre -e xisti n g c o n diti o ns 
( prese nt bef ore t h e start of t he A E c ollecti o n peri o d) are c o nsi dere d c o nc urre nt me dical 
c o n diti o ns a n d s h o ul d N O T be rec or de d as A Es .  Disease pr o gressi o n is a st u d y e n d p oi nt a n d 
c o nse q ue ntl y, disease pr o gressi o n s h o ul d n ot be re p orte d as a n A E or S A E.  H o we ver, w he n a 
s u bject dies fr o m diseas e pr o gressi o n wit h n o ot her i m me diate ca uses, “ dise ase pr o gressi o n” 
s h o ul d be re p orte d as a n S A E.  A d diti o nall y, si g ns a n d s y m pt o ms t hat ma y be relate d t o disease 

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pr o gressi o n or t he u n d erl yi n g disease (re gar dless of disease pr o gressi o n) s h o ul d be re p orte d as 
a n A E or as a n S A E if it meets t he defi niti o n of a n S A E i n Secti o n  1 2. 2. 1. 2 . 
Eac h A E s h o ul d be rec or de d t o re prese nt a si n gle dia g n osis .  Acc o m pa n yi n g si g ns (i ncl u di n g 
a b n or mal la b orat or y test val ues or E C G fi n di n gs) or s y m pt o ms s h o ul d N O T be rec or de d as 
a d diti o nal A Es .  If a dia g n osis is u n k n o w n, si g n(s) or s y m pt o m(s) s h o ul d be rec or de d as a n 
A E(s) .  C ha n ges i n la b orat or y test val u es or E C G para meters are o nl y c o nsi dere d t o be A Es if 
t he y are j u d ge d t o b e cli nicall y si g nifica nt (i.e., if s o me acti o n or i nter ve nti o n is re q uire d or if t he 
i n vesti gat or j u d ges t he c ha n ge t o be be y o n d t h e ra n ge of n or m al p h ysi ol o gical fl uct uati o n).  If 
ab n or mal la b orat or y test val ues or E C G fi n di n gs are t he res ult of pat h ol o g y f or w hic h t here is a n 
o verall dia g n osis (e .g ., i n creas e d creati ni ne le v els i n re nal fail ure), o nl y t he dia g n osis s h o ul d be 
re p orte d as a n A E. 
Electi ve pr oce d ures (s ur g eries or t hera pies) t h at w ere sc h e d ule d pri or t o t he start of A E 
c ollecti o n are n ot c o nsi dere d A Es .  T h ese electi ve pr oce d ures s h o ul d n ot be rec or de d as A Es b ut 
s h o ul d be d oc u me nte d i n t he patie nt ’s s o urce d oc u me nts as electi ve (e.g ., el ecti ve peri o d ontal 
s ur ger y).  H o we ver, if a pre pla n ne d pr oce d ure is perf or me d earl y ( e.g ., as a n e mer g e nc y) 
beca use of a w orse ni n g of t he pre -e xisti n g c o n diti o n, t he w orse ni n g of t he c o n diti o n s h o ul d be 
ca pt ure d as a n A E.  
1 2. 7.  
Re p orti n g  Seri o us A d verse E ve nts  
A n y A E t h at meets t he criteria of seri o us acc or di n g t o t he pre vi o usl y descri be d criteri a m ust be 
re p orte d wit hi n 2 4 h o urs fr o m t he ti me w he n site pers o n nel first lear n a b o ut t he e ve nt.  T o re p ort 
t he S A E, fa x t he c o m plet e d S A E f or m t o Me d pace (fa x n u m ber liste d b el o w i n Ta ble 1 2 ) wit hi n 
2 4 h o urs of a w are n ess.  
 
 
 
 
 
 
 
 
 
 
  
  
 
T he i n vesti gat or m ust c o nti n ue t o f oll o w t he patie nt u ntil t he S A E has s u bsi de d or u ntil t he 
c o n diti o n bec o mes c hr o nic i n nat ure, sta bilizes (i n t he case of persiste nt i m pair me nt), or t he 
patie nt  dies.  Wit hi n 2 4 h o urs of recei pt of ne w i nf or mati o n, t he u p date d f oll o w -u p S A E f or m, 
al o n g wit h a n y s u p p orti n g d oc u me ntati o n (e .g ., patie nt  disc har ge s u m mar y or a ut o ps y re p orts), 
s h o ul d be fa xe d t o Me d p ace Cli nical Safet y  (Ta bl e 1 2 ). 

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Reata P har mace uticals or its desi g nee will n otif y re g ulat or y a ge n cies of a n y fatal or life -
t hreate ni n g u ne x p ecte d e ve nts ass ociate d wit h t he use of t he st u d y dr u g as s o o n as p ossi ble b ut 
n o later t ha n 7 cale n dar da ys after t h e i nitial recei pt of t he i nf or mati o n .  I nitial n otificati o n will 
be f oll o we d b y a writte n re p ort wit hi n t he ti mefra me esta blis he d b y t he  a p pr o priate re g ulat or y 
a ge nc y.  F or ot her S A Es t hat d o n ot meet t he fatal or life -t hreate ni n g u ne x p ecte d criteria, b ut are 
re p orte d t o be ass ociate d wit h t he use of t he st u d y dr u g (t hat is, “ p ossi ble” or “ pr o ba bl e” i n 
ca usalit y assess me nt) , Reata P har mace uticals or its desi g nee will n otif y t he a p pr o priate 
re g ulat or y a g e ncies i n writi n g wit hi n t he ti mefra m e esta blis he d b y t h ose re g ulat or y a ge nci es.  
Reata  P har mace uticals  or its desi g nee will pr o vi de c o pies of a n y re p orts t o r e g ulat or y a ge n cies 
re gar di n g seri o us a n d u n e x pecte d S A Es t o t he i n v esti gat ors f or t heir i nf or mati o n a n d s u b missi o n 
t o t heir I R B, as a p pr o priate.  
Pri nci pal i n vesti gat ors are res p o nsi ble f or i nf or mi n g t heir I R B of a n y S A Es at t heir site , as 
a p pr o priate.  S A E c orres p o n de nce wit h r e g ulat or y a ut h orities or I R Bs m ust be s u b mitte d t o 
Reata P har mace uticals or its desi g nee f or rec or di n g i n t he st u d y file.  

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1 3.  
S T A TI S TI C S  
1 3. 1.  
S a m ple  Size  
T he sa m ple size ( n = u p t o 1 0 2 ) f or t his st u d y was selecte d t o ser ve 3 p ur p oses: ( 1) assess t he 
safet y of R T A 4 0 8 c o m bi ne d wit h i pili m u ma b a n d R T A 4 0 8 c o m bi ne d with ni v ol u ma b, 
( 2) selecti o n of a P hase 2 d ose base d o n re vie w of safet y, efficac y, a n d p h ar mac o d y na mic dat a, 
a n d ( 3) ass ess me nt of O R R  f or i N O S-p ositi ve mela n o ma patie nts i n c o m bi nati o n wit h ni v ol u ma b  
at t he selecte d P has e 2 d ose of R T A 4 0 8.  T his sa m ple size per mits e nr oll me nt of 5 7  t o 
7 8  patie nts i n d ose -escalati o n c o h orts ( P hase 1 b) a n d 2 4 t o 2 7 patie nts i n t he e x pa nsi o n c o h ort 
( P hase 2).    
T he P hase 1 b p orti o n of t he st u d y all o ws f or assess me nt of safet y a n d s electi o n of a P hase 2 
d ose.  T he sa m ple siz e f or re vie wi n g safet y of R T A 4 0 8 c o m bi ne d wit h a n a d diti o nal t hera p y 
was select e d base d o n a tra diti o nal 3 + 3 desi g n f or a d ose -es calati o n st u d y wit h u p t o 6 patie nts 
o n eac h c o m bi nati o n t hera p y.  I n a d diti o n t o t he safet y pr ofile, sel ecti o n of a n a p pr o pri ate 
P hase  2 d ose is base d o n c ha n ges o bser ve d i n i N O S e x pressi o n meas ure d i n t u m or bi o psies at 
baseli ne a n d after 1 wee k of m o n ot hera p y of R T A 4 0 8 (i.e., pri or t o starti n g c o m bi nati o n 
t hera p y).  E v al uati o n of t he descri pti ve s u m mari es (i ncl u di n g 9 5 % c o nfi de n ce i nter vals) f or 
c ha n ge fr o m baseli ne i n perce nt a ge of i N O S -p ositi ve t u m or cells fr o m t he P hase 1 b d ose -
escalati o n p orti o n of t he s t u d y will pr o vi de i nf or mati o n f or selecti n g t he P hase 2 e x pa nsi o n d ose.   
T he P hase 2 p orti o n of t h e st u d y all o ws f or assess me nt of O R R at t he selecte d P hase 2 d ose of 
R T A  4 0 8 wit h ni v ol u ma b.  Si nce t he P hase 2 p orti o n will o nl y e nr oll patie nts pre vi o usl y treate d 
wit h a nti -P D -1 or a nti -P D -L 1 t hera p y (i ncl u di n g e x peri me ntal t hera pies), t he O R R f or 
ni v ol u ma b m o n ot hera p y is ass u me d t o be 0 %.  A sa m ple size of 2 4 patie nts f or t he e x pa nsi o n 
c o h ort ac hie v es a p pr o xi matel y 8 0 % p o wer t o d etect a n i m pr o ve me nt of 2 0 % i n O R R fr o m t he 
ass u me d ni v ol u ma b O R R as t he n ull h y p ot hesis usi n g a 1 -si de d bi n o mial test at al p ha = 0. 1 0.   
1 3. 2.  
St u d y  V ari a bles  
1 3. 2. 1.  
P h ar m ac o ki netic  V ari a bles  
T he P K  varia bles i ncl u d e R T A  4 0 8  plas ma c o nce ntrati o n -ti me data a n d met a b olite 
c o nce ntr ati o n -ti me data (if a vaila ble) f or eac h a n al yte. 
1 3. 2. 2.  
P h ar m ac o d y n a mic  V ari a bles  
T he p har mac o d y na mic v aria bles i ncl u de  t u m or bi o ps y bi o mar kers a n d P B M C  assess me nts.   
A u g me nte d i m m u ne -me diate d effects wit h c o m bi ne d R T A  4 0 8  a n d i pili m u ma b or R T A  4 0 8  a n d 
n i v ol u ma b treat me nt, as assesse d b y t u m or bi o ps y a n d P B M C para meters, are e x p ecte d t o 
c orrel ate wit h decreas e d i N O S e x pressi o n i n t u m ors.  
1 3. 2. 3.  
Effic ac y  V ari a bles  
Efficac y vari a bles ar e t u m or res p o nse rates ( o verall, c o m plete, a n d partial) acc or di n g t o  R E CI S T 
1. 1 criteria , pr o gressi o n-free s ur vi val, a n d perce nt re d ucti o n i n t u m or bi o ps y i N O S e x pressi o n . 

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1 3. 2. 4.  
S afet y V ari a bles  
T he safet y v aria bles i ncl u de E C Gs , vital si g n meas ure me nts, res ults of p h ysical e xa mi nati o ns, 
la b orat or y test res ults (cli nical c he mistr y, he mat ol o g y, a n d uri nal ysis  a n d micr osc o p y ), 
c o nc o mita nt me dicati o ns, A E s, a n d S A Es . 
1 3. 3.  
St atistic al A n al yses  
A statistical a nal ysis pla n ( S A P) detaili n g t he a nal yses will be de vel o pe d pri or t o t he data base 
l oc k.  T he S A P will i ncl u de a nal ysis of all safet y, P K , p har mac o d y n a mic ( P D ), a n d res p o nse 
varia bles .  All statistical a nal yses a n d d ata s u m maries will be perf or me d usi n g S A S ®  (v ersi o n 9. 1 
or hi g her) or o t h er si milar s oft ware.  T he S A P will ser ve as t he fi nal ar biter of all statistical 
a nal yses.  Dat a will be s u m marize d o verall usi n g descri pti ve statistics .  C o nti n u o us data will be 
s u m marize d wit h n u m ber of patie nts  ( n), mea n, me dia n, mi ni m u m, ma xi m u m, stan dar d 
de viati o n, c oefficie nt of variati o n, a n d ge o metric mea n ( w here a p plica ble) .  Cate g orical data will 
be s u m marize d usi n g fre q ue nc y c o u nts a n d p erce nta ges.   Patie nts  will be p o ole d fr o m t he 
P hase  1 b d ose -es calati o n c o h orts wit h t he P hase 2 e x pa nsi o n c o h ort b y R T A  4 0 8  d ose le vel f or 
data a nal yses.  
1 3. 3. 1.  
Pri m ar y  Effic ac y A n al yses  
T he O R R f or t he P hase 2 d ose will be c o m pare d t o t he n ull h y p ot hesis of 0 % f or ni v ol u ma b  
m o n ot hera p y usi n g a 1 -si de d bi n o mial test.   
 

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1 4.  
DI R E C T A C C E S S T O S O U R C E D A T A/ D O C U M E N T S  
1 4. 1.  
St u d y  M o nit ori n g  
T he st u d y m o nit or, as a re prese nt ati ve of t he S p o ns or, has t he o bli gati o n t o f oll o w t he st u d y 
c o n d uct cl osel y .  I n d oi n g s o, t he m o nit or will visit t he pri nci pal i n vesti gat or a n d st u d y facilities 
peri o dicall y, i n a d diti o n t o mai ntai ni n g necessa r y t ele p h o ne a n d l etter c o ntact.  T he m o nit or will 
mai ntai n c urre nt k n o wl e d ge of t he st u d y acti vit y of t he i n vesti gat or a n d his/ her staff t hr o u g h 
o bser vati o n, re vie w of st u d y rec or ds a n d s o urce d oc u me ntati o n, a n d disc ussi o n of t he c o n d uct of 
t he st u d y wit h t he i n vesti gat ors a n d staff. 
T he S p o ns or or its desi g nee will m o nit or all as pects of t he st u d y f or c o m plia nce wit h a p plica ble 
g o ver n me nt re g ul ati o n wit h res pect t o t he I nter nati o nal C o nfere nce o n H ar m o nisati o n  
Har m o nise d Tri partite G ui deli ne f or G o o d C li nical P ractice ( G C P) E 6( R 1), a b bre vi ate d as I C H 
E 6( R 1), a n d c urre nt sta n dar d o perati n g pr oce d ures.  
Eac h pri nci p al i n vesti gat or is e x pecte d t o ma ke a reas o na bl e eff ort t o acc o m m o date t he m o nit or 
w he n m o nit ori n g visits are necessar y a n d t o be a v aila ble d uri n g  t he site visit.  F urt her m ore, t h e 
m o nit or s h o ul d be pr o vi de d direct a ccess t o s o urce data a n d d oc u m e nts f or trial -relat e d 
m o nit ori n g a n d t o t he i nter net d uri n g t he visit. 
1 4. 2.  
A u dits  a n d I ns pecti o ns  
Pri nci pal i n vesti gat ors a n d i nstit uti o ns i n v ol ve d i n t he st u d y will per mit st u d y -relate d 
m o nit ori n g, a u dits, I R B re vie w, a n d re g ulat or y i ns pecti o n(s), b y pr o vi di n g direct access t o all 
st u d y rec or ds.  I n t h e e ve nt of a n a u dit, t he pri nci p al i n vesti gat or a grees t o all o w t he S p o ns or, 
re pres e ntati ves of t he S p o ns or, t he F D A, or ot her rele va nt r e g ulat or y a ut h orities access t o all 
st u d y rec or ds. 
T he pri nci pal i n vesti gat or or desi g nee s h o ul d pr o m ptl y n otif y t he S p o ns or or desi g nee of a n y 
a u dits sc he d ule d b y a n y re g ulat or y a ut h orities a n d pr o m ptl y f or war d c o pies of a n y a u dit re p orts 
recei v e d t o t he S p o ns or or its desi g nee . 
 
 

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1 5.  
Q U A LI T Y C O N T R O L  A N D Q U A LI T Y A S S U R A N C E  
1 5. 1.  
Q u alit y Ass ur a nce  
T o e ns u re c o m plia n ce wit h G C P a n d all a p plica ble re g ulat or y re q uir e me nts, Reata 
P har mace uticals ma y c o n d uct a q ualit y ass ura n ce a u dit .  Please see Secti o n 1 4. 2  f or m ore d etails 
re gar di n g t he a u dit pr ocess. 
1 5. 2.  
Fi n a nci al Discl os ure   
Pri nci pal i n vesti gat ors a n d s u b -i n vesti gat ors are re q uire d t o pr o vi de fi na n cial discl os ure 
i nf or mati o n pri or t o starti n g t he st u d y.  I n a d diti o n, t he pri nci pal i n vesti gat or a n d s u b-
i nvesti gat ors m ust pr o vi de t he S p o ns or or its desi g nee wit h u p date d i nf or mati o n, if a n y rele va nt 
c ha n ges occ ur d uri n g t he c o urse of t he i n v esti gati o n a n d f or 1  year f oll o wi n g t he c o m pleti o n of 
t he st u d y. 
A n y p ote ntial i n vesti gat or w h o has a v este d fi na ncial i nterest i n t he s uccess of t his st u d y ma y n ot 
partici pate i n t his st u d y.  
1 5. 3.  
S p o ns or O bli g ati o ns   
T he S p o ns or or its desi g nee is n ot fi na nciall y r es p o nsi ble f or f urt her testi n g/treat me nt of a n y 
me dical c o n diti o n t hat ma y be dete cte d d uri n g t he scree ni n g pr o ces s.  I n a d diti o n, i n t he a bse nce 
of s pecific arra n ge me nts, t he S p o ns or or its desi g nee is n ot fi na nciall y r es p o nsi ble f or treat me nt 
of  n o n -st u d y-rel ate d fat alities, p h ysical i nj uries, or da ma ge t o healt h t hat ma y occ ur d uri n g t he 
cli nical st u d y , as well as  the patie nt’s u n derl yi n g disease.  
1 5. 4.  
I n vesti g at or D oc u me nt ati o n  
Bef ore be gi n ni n g t he st u d y, t he pri nci pal i n vesti gat or will be as ke d t o c o m pl y wit h I C H E 6( R 1) , 
Secti o n 8. 2 a n d Title 2 1 of t he U nite d S tates ( U S) C o de of Fe d eral Re g ulati o ns ( C F R ), 
a b bre viate d as U S  C F R Title 2 1,  b y pr o vi di n g t he esse ntial d oc u me nts t o t he S p o ns or or its 
desi g nee, w hic h i ncl u d e b ut are n ot li mite d t o t he f oll o wi n g:  
•  A n ori gi nal i n vesti gat or -si g ne d i n vesti gat or a gree me nt pa ge of t he pr ot oc ol 
•  T he I R B a p pr o val of t h e pr o t oc ol 
•  T he I R B -a p pr o ve d i nf or me d c o nse nt, sa m ples of site a d vertise me nts f or recr uit me nt f or 
t his st u d y, a n d a n y ot her writte n i nf or mati o n re g ar di n g t his st u d y t hat is t o be pr o vi de d t o 
t he patie nt or le gal g uar dia ns 
•  A F or m F D A 1 5 7 2, f ull y e xec ute d, a n d all u p dates o n a n e w f ull y e x ec ute d F or m F D A 
1 5 7 2  
•  C urric ul u m  vitae f or t he pri nci pal i n vesti gat or a n d eac h s u b -i n v esti gat or liste d o n F or m 
F D A 1 5 7 2.   A c urric ul u m  vita a n d c urre nt lice ns ure , as a p plica ble, m ust be pr o vi de d.   
T he c urr i c ul u m vi tae m ust ha ve bee n si g ne d a n d date d b y t he pri nci pal i n v esti gat ors a n d 
s u b-i n vesti gat ors wit hi n 2 years bef ore st u d y start-u p t o i n dicate t he d oc u m e nts are 
acc urate a n d c urre nt  

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•  C o m plete d fi na ncial discl os ure f or ms ( Secti o n 1 5. 2 ) t o all o w t he S p o ns or or its desi g nee 
t o s u b mit c o m plete a n d acc urat e certificati o n or discl os ure state me nts re q uire d u n der U S 
C F R Title 2 1 , Part 5 4.  I n a d diti o n, t he i n vesti gat ors m ust pr o vi de t o t he S p o ns or or its 
desi g nee a c o m mit me nt t o u p date t his i nf or mati o n pr o m ptl y if a n y rele va nt c ha n ges occ ur 
d uri n g t he c o urse of t he i n vesti gati o n a n d f or 1 year f oll o w i n g t he c o m pleti o n of t he 
st u d y 
•  La b orat or y certificati o ns a n d n or mal  ra n g es f or a n y la b orat ories use d b y t h e site f or t he 
c o n d uct of t his st u d y  
1 5. 5.  
Cli nic al St u d y  I ns ur a nce 
I n acc or da n ce wit h t he res pecti ve nati o nal dr u g la ws, t he S p o ns or has ta ke n o ut patie nt lia bilit y 
i ns ura nce f or all patie nts w h o gi ve t heir c o nse nt a n d e nr oll i n t his st u d y .  T his i ns ura nce c o v ers 
p ote ntial st u d y-relate d fatalities, p h ysical i nj uries, or da ma ge t o healt h t hat ma y occ ur d uri n g t he 
cli nical st u d y.  
1 5. 6.  
Use of I nf or m ati o n  
All i nf or mati o n re gar di n g R T A  4 0 8  s u p plie d b y t he S p o ns or t o t he in vesti ga t or is pri vile ge d a n d 
c o nfi de ntial .  T he i n vesti gat or  a grees t o use t his i nf or mati o n t o acc o m plis h t he st u d y a n d will n ot 
use it f or ot her p ur p os es wit h o ut c o nse nt fr o m t he S p o ns or.  F urt her m ore, t he i n vesti gat or is 
o bli gate d t o pr o vi de t he S p o ns or wit h c o m plete data o btai ne d d uri n g t he st u d y .  T he i nf or mati o n 
o btai ne d fr o m t he cli nical st u d y will be use d t o war ds t he de vel o p me nt of R T A  4 0 8  Ca ps ules a n d 
ma y be discl ose d t o re g ul at or y a ut h orit y(ies), ot her i n vesti gat ors, c or p orate part ners, or 
c o ns ulta nts , as re q uire d. 
 

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1 6.  
E T HI C S  
1 6. 1.  
I nstit uti o n al Re vie w B o ar d Re vie w  
T he pr ot oc ol a n d t he pr o p ose d i nf or me d c o ns e nt f or m  (I C F) m ust be re vie we d a n d a p pr o ve d b y 
a pr o perl y c o nstit ute d I R B bef ore st u d y start .  Eac h site m ust pr o vi de t he S p o ns or or its desi g nee 
a si g ne d a n d date d st ate me nt t hat t he pr ot oc ol a n d i nf or me d c o nse nt ha ve bee n a p pr o ve d b y t he 
I R B bef ore c o nse nti n g patie nts.  Pri or t o st u d y i nitiati o n, t he i n vesti gat or is re q uire d t o si g n a 
pr ot oc ol si g nat ure pa g e c o nfir mi n g a gree m e nt t o c o n d uct t he st u d y i n acc or da nce wit h t his 
pr ot oc ol a n d t o gi ve access t o all rele va nt data a n d rec or ds t o t he S p o ns or, its desi g nee, a n d 
re g ulat or y a ut h orities, as re q uire d.  
T he I R B c hair pers o n or d esi g nee m ust si g n all I R B a p pr o vals a n d m ust i de ntif y t he I R B b y na me 
a n d a d dress, t h e  cli nical pr ot oc ol, a n d t he date a p pr o val a n d/ or fa v ora bl e o pi ni o n was gra nte d.  
T he pri nci pal i n vesti gat or is res p o nsi ble f or o btai ni n g re vie ws of t he cli nical researc h at i nter v als 
s pecifie d b y t he I R B, b ut n ot e xcee di n g 1 y ear.  T he pri nci pal i n vesti gat o r m ust s u p pl y t he 
S p o ns or or its desi g nee wit h writte n d oc u me ntati o n of re vie ws of t he cli ni cal res earc h.  
1 6. 2.  
Et hic al  C o n d uct of t he St u d y  
T his cli nical st u d y was desi g ne d a n d s hall be i m pl e me nte d a n d re p orte d i n acc or da nce wit h t he 
I C H E 6( R 1) , wit h a p plic a ble l ocal r e g ulati o ns (e.g ., U S C F R Title 2 1), a n d wit h t he et hical 
pri nci ples of  t he Declarati o n of Helsi n ki.  
T he pri nci pal i n vesti gat or a grees t o c o n d uct t he st u d y i n acc or da nce wit h t he I C H E 6( R 1) a n d 
t he pri nci ples of t he Decl arati o n of H elsi n ki.  T he pri nci pal i n vesti gat or m ust c o n d uct all as pects 
of t his st u d y i n acc or da n ce wit h all nati o nal, state, a n d l ocal  la ws or re g ulati o ns. 
1 6. 3.  
Writte n I nf or me d C o nse nt  
Beca use t he st u d y will be c o n d ucte d u n der a U S I n vesti gati o nal Ne w Dr u g A p plicati o n, a si g ne d 
I C F, i n c o m plia nce wit h U S  C F R Title 2 1, Part 5 0,  will be o btai ne d fr o m eac h patie nt bef ore t he 
patie nt e nters t he st u d y.  A n i nf or me d c o ns e nt te m plate ma y be pr o vi de d b y t he S p o ns or or its 
desi g nee t o t he i n vesti gat ors .  T he c o nse nt m ust be re vie we d b y t h e S p o ns or or its desi g nee 
bef ore I R B s u b missi o n .  O nce re vie we d, t h e c o ns e nt will be s u b mitte d b y t he pri nci pal 
i n vesti gat or t o his or her I R B f or re vie w a n d a p pr o val bef ore t he start of t h e st u d y .  If t he I C F is 
re vise d d uri n g t he c o urse of t he st u d y, all partici pa nts affect e d b y t he re visi o n m ust si g n t he 
re vise d I R B-a p pr o ve d c o nse nt f or m.  
Bef ore e nr oll me nt, eac h pr o s pecti ve patie nt will b e gi ve n a f ull e x pla nati o n of t he st u d y a n d be 
all o we d t o rea d t h e a p pr o ve d I C F.  O n ce t he pri nci pal i n vesti gat or or desi g n ee is ass ure d t h at t he 
patie nt u n dersta n ds t he i m plicati o ns of partici pati n g i n t he st u d y, t he patie nt will be  as ke d t o gi ve 
c o nse nt t o partici pate i n t he st u d y b y si g ni n g t he I C F.  
Eli gi ble patie nts ma y o nl y be i ncl u de d i n t he st u d y after pr o vi di n g writte n ( wit nesse d, w here 
re q uire d b y la w or re g ulati o n), I R B-a p pr o ve d i nf or me d c o nse nt .  I nf or me d c o nse nt m ust be 
o btai ne d bef ore c o n d u cti n g a n y st u d y -s pecific pr oce d ures (i.e., all of t he pr oce d ures d escri b e d i n 
t he pr ot oc ol).  T he pr ocess of o btai ni n g i nf or me d c o nse nt m ust be d oc u me nte d i n t he patie nt 
s o urce d oc u m e nts. 

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A n y c ha n ges t o t he pr o p ose d c o nse nt f or m s u g g est e d b y t he i n vesti gat or m ust be a gree d t o b y 
t he S p o ns or bef ore s u b missi o n t o t he I R B, a n d a c o p y of t he a p pr o ve d versi o n a n d t he n otice of 
a p pr o val m ust be pr o vi de d t o t he S p o ns or’s desi g nate d m o nit or after I R B a p pr o val.  
T he pri nci pal i n vesti gat or or desi g nee will pr o vi de a c o p y of t h e I C F (si g ne d c o p y t o be pr o vi de d 
per a p plica bl e la w) t o t he patie nt a n d/ or le gal g uar dia n .  T he ori gi nal f or m will be mai ntai ne d i n 
t he patie nt’s me dical r ec or ds at t he site. 
1 6. 4.  
C o nfi de nti alit y  
All la b orat or y s peci me ns, e val uati o n f or ms, r e p orts, a n d ot her rec or ds will be i de ntifie d i n a 
ma n ner desi g ne d t o mai ntai n patie nt c o nfi de ntialit y .  All rec or ds will be ke pt i n a sec ure st or a ge 
area wit h li mite d access .  Cli nical i nf or mati o n will n ot be releas e d wit h o ut t he writte n 
per missi o n of t he patie nt ( or t he patie nt’s g u ar dia n), e xce pt as necessar y f or m o nit ori n g a n d 
a u diti n g b y t he S p o ns or, its desi g nee, t he F D A or a p plica ble re g ulat or y a ut h orities, or t he I R B.  
T he pri nci pal i n vesti gat or a n d all e m pl o yees a n d c o w or kers i n v ol ve d wit h t his st u d y ma y n ot 
discl ose or use f or a n y p ur p ose ot her t ha n perf or ma nce of t he st u d y, a n y data, rec or d, or ot her 
u n p u blis he d c o nfi de ntial i nf or mati o n discl ose d t o t he m f or t he p ur p ose of t he st u d y .  Pri or 
writte n a gree me nt fr o m t he S p o ns or or its desi g ne e m ust be o btai ne d f or t h e discl os ure of a n y 
sai d c o nfi de ntial i nf or mati o n t o ot her parties. 
1 6. 5.  
M o dific ati o n  of t he Pr ot oc ol  
A n y c ha n ges t h at arise after t he a p pr o val of t he pr ot oc ol m ust be d oc u me nte d as pr ot oc ol 
a me n d me nts .  F D A m ust be n otifie d of pr ot oc ol a me n d me nts .  T he c ha n g es will bec o me 
effecti ve o nl y after a p pr o val of t he S p o ns or, t he pri nci pal i n vesti gat or, a n d t he I R B.  I n cas es 
w he re t he pr ot oc ol is m o difie d t o e n ha nce patie nt safet y, c ha n ges ma y be i m ple me nte d a n d t he 
a me n d me nt m ust be i m me diatel y s u b mitte d t o t he I R B.  
T he pri nci pal i n vesti gat or is res p o nsi ble f or i nf or mi n g t he I R B of all pr o bl e ms i n v ol vi n g ris ks t o 
patie n ts acc or di n g t o nati o nal le gislati o n.  I n case of ur ge nt safet y meas ures, t he S p o ns or will 
i m me diatel y n otif y F D A i n acc or d wit h U S C F R  Title 2 1 , Part 3 1 2 , Secti o n 3 2 . 
1 6. 6.  
Pr ot oc ol  De vi ati o ns  
T he pri nci pal i n vesti gat or or desi g nee m ust d oc u me nt a n y pr ot oc ol de viati o n .  T he I R B m ust be 
n otifie d of all pr ot oc ol de viati o ns  i n a ti mel y ma n ner b y t he i n vesti gat or as a p pr o priate.  Pr ot oc ol 
de viati o ns will  als o be d oc u me nte d b y t he res p o nsi ble m o nit or d uri n g m o nit ori n g visits, a n d 
t h ose o bser vati o ns will be c o m m u nicate d t o t he i n vesti gat or.  
If t here is a n i m me diate hazar d t o a patie nt, t he pri nci pal i n vesti gat or ma y de viate fr o m t he 
pr ot oc ol wit h o ut pri or S p o ns or a n d I R B a p pr o val .  T he S p o ns or a n d I R B m ust be n otifie d of t he 
de viati o n.  

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1 7.  
D A T A  H A N D LI N G A N D R E C O R D K E E PI N G  
1 7. 1.  
R ete nti o n  of Rec or ds  
T he i n vesti gat or will mai ntai n all st u d y rec or ds acc or di n g t o I C H  E 6( R 1)  a n d a p plica ble 
re g ulat or y re q uire me nt(s).  Rec or ds will be retai n e d f or at least 2 years aft er t he last mar k eti n g 
a p plicati o n is a p pr o ve d or 2 years after f or mal dis c o nti n uati o n of t he cli nical de vel o p me nt of t he 
i n vesti gati o nal pr o d uct.  If t he i n vesti gat or wit h dra ws fr o m t he res p o nsi bilit y of kee pi n g t he 
st u d y rec or ds, c ust o d y m ust be tra nsferre d t o a pers o n willi n g t o acce pt t he res p o nsi bilit y .  T he 
S p o ns or m ust be n otifie d i n writi n g if a c ust o dial c ha n ge o cc urs.  
1 7. 2.  
C ase Re p ort F or ms  
All C R F  data will be e nt ere d i n electr o nic f or ms at t he i n vesti gati o nal site .  T he  electr o nic d ata 
ca pt ure ( E D C) s yste m us e d t o ca pt ure d ata el ectr o nicall y f or all ra n d o mize d patie nts will be U S 
C F R  Title 2 1,  Part 1 1 c o m plia nt . 

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1 8.  
P U B LI C A TI O N  P O LI C Y  
Reata P har mace uticals reser ves t he ri g ht t o re vi e w all pla n ne d c o m m u nicati o ns a n d ma n uscri pts 
base d o n t he res ults of t his st u d y .  T his reser vati o n of t he ri g ht is n ot  i nte n de d t o restrict or 
hi n der p u blicati o n or a n y ot her disse mi nati o n of st u d y res ults, b ut t o all o w t he S p o ns or t o 
c o nfir m t he acc urac y of t he data, t o pr otect pr o pri etar y i nf or mati o n, a n d t o pr o vi de c o m me nts 
base d o n i nf or mati o n t hat ma y n ot yet be a vai la bl e t o t he st u d y i n vesti gat ors.  Reata 
P har mace uticals s u p p orts c o m m u nicati o n a n d p u blicati o n of st u d y res ults w hate ver t he fi n di n gs 
of t he st u d y .  Reata P har mace uticals als o e nc o ura ges discl os ure of a n y c o nflict of i nterest fr o m 
all a ut h ors or i n vesti ga t ors w he n ma n uscri pts are s u b mitte d f or p u blicati o n.  
T h ose i n di vi d uals w h o ha ve c o ntri b ute d greatl y t o t his st u d y, as deter mi ne d b y Reata  
P har mace uticals , will ser ve o n a n y p u blicati o ns c o m mittee f or t he st u d y.  

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1 9.  
LI S T O F R E F E R E N C E S  
Dee b D, Ga o X, Jia n g H, et al. Olea n a ne triter pe n oi d C D D O-Me i n hi bits gr o wt h a n d i n d uces 
a p o pt osis i n pr ostate ca n cer cells b y i n de pe n de ntl y tar geti n g pr o -s ur vi val A kt a n d m T O R. 
Pr ostate 2 0 0 9; 6 9: 8 5 1 -6 0.  
E k me kci o gl u S, Eller h orst J A, Priet o V G, et al.  T u m or  i N O S pre dicts p o or s ur vi val f or sta ge III 
mela n o ma patie nts. I nt J Ca ncer 2 0 0 6; 1 1 9: 8 6 1 -6.  
E k me kci o gl u S, Eller h orst J, S mi d C M, et al.  I n d uci ble nitric o xi de s y nt hase a n d nitr ot yr osi ne i n 
h u ma n metastatic mela n o ma t u m ors c orrel ate wit h p o or s ur vi val. Cli n  Ca ncer Res 2 0 0 0; 6: 4 7 6 8 -
7 5.  
Eise n ha uer E A, T herasse P, B o gaerts J, et al. Ne w res p o nse e v al uati o n criteria i n s oli d t u m o u rs: 
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 8 -4 7.  
Ga bril o vic h DI, Ostr a n g -R ose n ber g S, Br o nte V. C o or di nate d re g ulati o n of m yel oi d cells b y 
t u m o urs. Nat Re v I m m u n ol 2 0 1 2; 1 2: 2 5 3-6 8.  
Hall HI, Miller D R, R o gers J D, et al. U p date o n t he i nci de nce a n d m ortalit y fr o m mela n o ma i n 
t he U nite d States. J A m Aca d D er mat ol 1 9 9 9; 4 0: 3 5-4 2.  
H o di F S, O’ Da y SJ, Mc Der m ott D F, et al. I m pr o ve d s ur vi val wit h i pili m u ma b i n patie nts wit h 
metastatic mela n o ma. N E n gl J Me d 2 0 1 0; 3 6 3: 7 1 1 -2 3.  
H o n da T, R o u n ds B V, B ore L, et al. N o vel s y nt hetic olea na ne triter pe n oi ds: a series of hi g hl y 
acti ve i n hi bit ors of nitric o xi de pr o d ucti o n i n m o use macr o p h a ges. Bi o or g Me d C he m Lett  
1 9 9 9; 9: 3 4 2 9 -3 4.  
H o n g D S, K urzr oc k R, S u p k o J G, et al. A P hase I first -i n-h u ma n trial of bar d o x ol o ne met h yl i n 
patie nts wit h a d va nce d s oli d t u m ors a n d l y m p h o mas. Cli n Ca ncer Res 2 0 1 2; 1 8: 3 3 9 6 -4 0 6.  
H yer M L, S hi R, Kraje ws ka M, et al. A p o pt otic acti vit y a n d mec ha nis m of 2-c ya n o -3, 1 2 -
di o x o olea n -1, 9 -die n -2 8 -oic -aci d a n d relate d s y nt hetic triter pe n oi ds i n pr ostate ca ncer. Ca n cer 
Res 2 0 0 8; 6 8: 2 9 2 7 -3 3.  
J or da n K R, A maria R N, Ra mirez O, et al. M yel oi d -deri ve d s u p press or cells are ass o ciate d wit h 
disease pr o gressi o n a n d decrease d o v erall s ur vi val i n a d va nce d -st a ge mela n o ma patie nts. Ca ncer 
I m m u n ol I m m u n ot her 2 0 1 3; 6 2: 1 7 1 1-2 2.  
J ut o or u I, C ha d ala pa k a G, A b delra hi m M, et al. M et h yl 2-c ya n o-3, 1 2 -di o x o olea na -1, 9 -die n -2 8 -
oate decreas es s pe cifi cit y pr otei n tra nscri pti o n fact ors a n d i n hi bits pa ncreatic t u m or gr o wt h: r ole 
of micr o R N A -2 7a. M ol P har mac ol 2 0 1 0; 7 8: 2 2 6 -3 6.  
Ki m E H, De n g C X, S p or n M B, et al. C D D O-i mi daz oli de i n d uces D N A da ma ge, G 2/ M arrest 
a n d a p o pt osis i n B R C A 1 -m utate d breast ca ncer  cells. Ca ncer Pre v Res 2 0 1 1; 4: 4 2 5 -3 4.  
K o n o ple va M, Z ha n g W, S hi Y X, et al. S y nt hetic triter pe n oi d 2-c y a n o-3, 1 2 -di o x o olea na -1, 9 -
die n -2 8 -oic aci d i n d uces gr o wt h arrest i n H E R 2 -o vere x pressi n g breast ca n cer cells. M ol Ca ncer 
T her 2 0 0 6; 5: 3 1 7 -2 8.  
Kress C L, K o n o ple va M, Marti nez -G arcia V, et al. Triter pe n oi ds dis pla y si n gle a ge nt a nti-t u m or 
acti vit y i n a tra ns ge nic m o use m o del of c hr o nic l y m p h oc ytic le u ke mia a n d s mall B cell 
l y m p h o ma. P L o S O ne 2 0 0 7; 2:e 5 5 9. 

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La pill o n ne H, K o n o ple va M, Tsa o T, et al. Acti vati o n of per o xis o me pr oliferat or -acti vate d 
rece pt or ga m ma b y a n o v el s y nt hetic triter pe n oi d 2-c ya n o-3, 1 2 -di o x o olea n a -1, 9 -die n -2 8 -oic aci d 
i n d uces gr o wt h arrest a n d a p o pt osis i n breast ca n cer cells. Ca ncer Res 2 0 0 3; 6 3: 5 9 2 6-3 9.  
Lee J H, K h or T O, S h u L, et al. Dietar y ph yt oc he micals a n d ca n cer pre v e nti o n: Nrf 2 si g nali n g, 
e pi ge netics, a n d cell deat h mec ha nis ms i n bl oc ki n g ca ncer i nitiati o n a n d pr o gressi o n. P har mac ol 
T her 2 0 1 3; 1 3 7: 1 5 3 -7 1.  
Lia o D, Li u Z, Wrasi dl o WJ, et al. Tar gete d t hera pe utic re m o deli n g of t he t u m or 
micr o e n vir o n me nt i m pr o ves a n d H E R -2 D N A vacci ne a n d pre ve nts rec urre nce i n a m uri ne 
breast c a ncer m o del. Ca n cer Res 2 0 1 1; 7 1: 5 6 8 8 -9 6.  
Li b y K, R o yce D B, Willia ms C R, et al. T he s y nt hetic triter pe n oi ds C D D O-met h yl ester a n d 
C D D O -et h yl a mi de pre v e nt l u n g ca ncer i n d uce d b y vi n yl car ba mate i n A/J mice. Ca ncer R es 
2 0 0 7; 6 7: 2 4 1 4 -1 9.  
Li b y K T, R o yce D B, Risi n gs o n g B, et al. S y nt hetic triter pe n oi ds pr ol o n g s ur vi val i n a tra ns ge nic 
m o use m o del of pa ncreatic ca ncer. Ca n cer Pre v Res 2 0 1 0; 3: 1 4 2 7 -3 4.  
Li n g X, K o n o ple va M, Z e n g Z,  et al. T he n o v el triter pe n oi d C-2 8 met h yl ester of 2 -c y a n o-3, 1 2 - 
di o x o ole n -1, 9 -die n -2 8 -oic aci d i n hi bits metastatic m uri ne breast t u m or gr o wt h t hr o u g h 
i nacti vati o n of S T A T 3 si g nali n g. Ca ncer Res 2 0 0 7; 6 7: 4 2 1 0-8.  
Li u J. P har mac ol o g y of olea n olic aci d a n d urs olic aci d. J Et h n o p har mac ol 1 9 9 5; 4 9: 5 7 -6 8.  
Na garaj S, G u pta K, Pisare v V, et al. Altere d rec o g niti o n of a nti ge n is a mec ha nis m of C D 8 + T 
cell t olera nce i n ca n cer. Nat Me d 2 0 0 7; 1 3: 8 2 8 -3 5.  
Na garaj S, Y o u n JI, We b er H, et al. A nti -i nfl a m mat or y triter pe n oi d bl oc ks i m m u ne s u p pressi ve 
f u ncti o n of m yel oi d-deri ve d s u p press or cells a n d i m pr o ves i m m u ne res p o nse i n ca ncer. Cli n 
Ca ncer Res 2 0 1 0; 1 6: 1 8 1 2 -2 3.  
Nati o nal C o m pre he nsi ve Ca ncer Net w or k, Cli nical Practice G ui deli nes i n Mela n o ma. Versi o n 
3. 2 0 1 4. A vaila ble at: htt p:// w w w. ncc n. or g/ pr ofessi o nals/ p h ysicia n _ gls/ p df/ mela n o ma. p df. 
Access e d Marc h 1 0, 2 0 1 4.  
O ke n M M, Creec h R H, T or me y D C, et al. T o xicit y a n d res p o nse criteria of t he Easter n 
C o o perati ve O nc ol o g y Gr o u p. A m J Cli n O nc ol 1 9 8 2; 5: 6 4 9 -5 5.  
Per g ola P E, Ras ki n P, T ot o R D, et al. Bar d o x ol o ne met h yl a n d ki d ne y f u ncti o n i n C K D wit h 
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