Clinical trial NCT02259231
Conditions: Melanoma Unresectable (Stage III) Melanoma Metastatic (Stage IV) Melanoma
Keywords: RTA 408 RTA 408 Capsules Myeloid-derived suppressor cells (MDSDs) iNOS Melanoma Checkpoint inhibitor omaveloxolone
Sponsor: Biogen
Start date: 2014-10-31; Completion date: 2018-07-23
Enrollment: 41 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
Malignant melanoma is a leading cause of death from cutaneous malignancies, accounting for approximately three-fourths of all skin cancer deaths. For metastatic or unresectable melanomas, standard treatment options include immune checkpoint inhibitors (e.g., ipilimumab and nivolumab) and other therapies, however, approved therapies are rarely curative.

It is now well accepted that tumors are able to evade detection and eradication by the immune system, even though many tumor types, particularly melanoma, are capable of eliciting a strong immune response (Swann, 2007). Substantial mechanistic work in recent years has revealed the key role of myeloid-derived suppressor cells (MDSCs) in masking cancer cells from the immune system, promoting both tumor progression and resistance to cancer immunotherapy. The immune-suppressive effect of MDSCs is dependent on the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS). High levels of these reactive molecules and their by-products, such as nitrotyrosine, have been correlated with poor clinical outcomes in melanoma. Currently available melanoma therapies do not target MDSCs.

In animals, RTA 408 significantly reduces tumor nitrotyrosine burden, inhibits the activity of MDSCs, and augments T-cell anticancer activity at relevant doses. Thus, through inhibition of MDSC activity and suppression of tumor ROS/RNS, RTA 408 may work in combination with T-cell-activating therapeutics such as ipilimumab to enhance the natural immune anticancer response. RTA 408 also has direct anticancer effects via inhibition of NF-kappa B. Chronic activation of NF-kappa B is associated with tumor progression, metastasis, and resistance to therapy.

This proposed study is designed to assess the safety, efficacy, pharmacodynamics, and pharmacokinetics of omaveloxolone (RTA 408) in combination with ipilimumab or nivolumab in patients with unresectable or metastatic melanoma.

In this open-label, multicenter, dose-escalation, Phase 1b/2 study, patients who qualify will receive omaveloxolone (RTA 408) at the assigned dose level in combination with ipilimumab or nivolumab. Patients will receive omaveloxolone (RTA 408) orally once daily for 1 week prior to initiation of ipilimumab or nivolumab. For patients treated with ipilimumab , the run-in period will be followed by omaveloxolone (RTA 408) orally once daily in combination with ipilimumab administered at Weeks 1, 4, 7, and 10. After Week 10, patients will receive maintenance treatment with omaveloxolone (RTA 408) alone once daily. For patients treated with nivolumab, the run-in period will be followed by omaveloxolone (RTA 408) orally once daily in combination with nivolumab administered approximately every two weeks as clinically indicated. Each patient will continue at the assigned omaveloxolone (RTA 408) dose level until disease progression occurs, toxicity requiring discontinuation from study drug (i.e., RTA 408) is experienced, the patient has completed approximately 72 weeks of treatment, the patient is discontinued from the study drug for another reason, or the patient withdraws consent. Patients will return 4 weeks after omaveloxolone (RTA 408) treatment completion for a follow-up visit.

The starting omaveloxolone (RTA 408) dose level for the first dose-escalation cohort in this study has been selected based on available safety and pharmacodynamic data from a Phase 1 study of RTA 408 (NCT02029729). Subsequent cohorts will be enrolled at dose levels based on available safety and PD data from this study, but they will not be greater than 2-fold above the prior dose level.

Phase 1b (dose-escalation): In the phase 1b/2 portion of this study, 12 patients will be enrolled in each dose cohort, with six patients administered omaveloxolone (RTA 408) plus ipilimumab and the remaining six administered rTA 408 plus nivolumab. Subsequent cohorts will assess escalating the doses of omaveloxolone (RTA 408) administered in combination with ipilimumab or nivolumab. Dose escalation decisions will be based on ongoing review of all available safety information for enrolled patients.

Phase 2: The Phase 2 portion of the study may include separate expansion cohorts consisting of patients treated with either of the combination therapies. Each expansion cohort will include an additional 24 patients enrolled at the selected Phase 2 dose level to achieve a total of 30 patients at that omaveloxolone (RTA 408) dose in combination with ipilimumab or nivolumab.

Detailed description:

Arms: arm 1: Omaveloxolone (RTA 408) capsules, Dose1 taken orally once daily for 168 weeks, plus ipilimumab (3 mg/kg) administered at weeks 1, 4, 7, and 10. arm 2: Omaveloxolone (RTA 408) capsules, 10 mg taken orally once daily for 168 weeks, plus ipilimumab (3 mg/kg) administered at weeks 1, 4, 7, and 10. arm 3: Omaveloxolone (RTA 408) capsules, 5 mg taken orally once daily for 168 weeks, plus nivolumab (240 mg) administered every two weeks as clinically indicated. arm 4: Omaveloxolone (RTA 408) capsules, 10 mg taken orally once daily for 168 weeks, plus nivolumab (240 mg) administered every two weeks as clinically indicated. arm 5: Omaveloxolone (RTA 408) capsules, 20 mg taken orally once daily for 168 weeks, plus nivolumab (240 mg) administered every two weeks as clinically indicated. arm 6: Omaveloxolone (RTA 408) capsules, 100 mg taken orally once daily for 168 weeks, plus nivolumab (240 mg) administered every two weeks as clinically indicated. arm 7: Omaveloxolone (RTA 408) capsules, 150 mg taken orally once daily for 168 weeks, plus nivolumab (240 mg) administered every two weeks as clinically indicated.
Interventions: intervention 1: Omaveloxolone Capsules (2.5 mg/capsule) intervention 2: Ipilimumab (3 mg/kg) intervention 3: Nivolumab (240 mg) intervention 4: Omaveloxolone Capsules (10 mg/capsule) intervention 5: Omaveloxolone Capsules (50 mg/capsule)
Intervention descriptions: intervention 1: Capsules containing 2.5 mg of omaveloxolone per capsule to the dosage indicated in the Arm Label intervention 2: Sterile solution containing ipilimumab to be delivered intravenously at 3mg/kg intervention 3: Sterile solution containing nivolumab to be delivered intravenously at 240 mg intervention 4: Capsules containing 10 mg of omaveloxolone per capsule to the dosage indicated in the Arm Label intervention 5: Capsules containing 50 mg of omaveloxolone per capsule to the dosage indicated in the Arm Label

Protocol documents:
Prot_000.pdf: 
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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 
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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  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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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 
t y pe 2 dia betes. N E n gl J Me d 2 0 1 1; 3 6 5: 3 2 7-3 3 6.  
Place A E, S u h N, Willia ms C R, et al. T he n o vel s y nt hetic triter pe n oi d, C D D O-i mi daz oli de, 
i n hi bits i nfla m mat or y res p o nse a n d t u m or gr o wt h i n vi v o. Cli n Ca ncer Res 2 0 0 3; 9: 2 7 9 8-8 0 6.  
R o ma n o E a n d R o mer o P. T he t hera p e utic pr o mise of disr u pti n g t he P D -1/ P D -L 1 i m m u ne 
c hec k p oi nt i n ca n cer: u nl eas hi n g t he C D 8 T cell me diate d a nti -t u m or acti vit y res ults i n 
si g nifica nt, u n prece de nte d cli nical efficac y i n vari o us s oli d t u m ors . J I mm u n ot her Ca ncer 
2 0 1 5 ;3: 1 5 . 
S p or n M B a n d Li b y K T. N R F 2 a n d ca ncer: t he g o o d, t he ba d, a n d  t he i m p orta nce of c o nte xt. 
Nat  Re v Ca ncer 2 0 1 2; 1 2: 5 6 4 -7 1.  
S wa n n J B a n d S m yt h MJ. I m m u ne s ur veilla nce of t u m ors . J Cli n I n vest 2 0 0 7; 1 1 7: 1 1 3 7-4 6.  


Pr ot oc ol 4 0 8 -C -1 4 0 1                               Reata P har mace uticals                                  C o nfi de ntial  
Versi o n 5. 0                                                              7 9  
  
 
 
U S F o o d a n d Dr u g A d mi nistrati o n, G ui da nce f or I n d ustr y: Dr u g -i n d uce d li ver i nj ur y: 
Pre mar keti n g cli nical e v al uati o n, J ul y 2 0 0 9. A vaila ble at: 
h tt p:// w w w.f da. g o v/ d o w nl oa ds/ Dr u gs/.../ G ui da nces/ U C M 1 7 4 0 9 0. p df. Accesse d Marc h 1 0, 2 0 1 4. 
We ber J S, Mi n or D, D’ A n gel o S, et al. A p hase 3 ra n d o mize d, o pe n -la bel st u d y of ni v ol u ma b 
(a nti-P D -1; B M S -9 3 6 5 5 8, O N O -4 5 3 8) v ers us i n v esti gat or's c h oice c he m ot hera p y (I C C) i n 
patie nts wit h a d va nce d m ela n o ma aft er pri or a nti -C T L A 4 t hera p y .  A n n O nc ol 2 0 1 4 ;2 5 : 1-4 1.  
W olc h o k J D, H o os A, O’ Da y S, et al. G ui deli nes f or t he e val uati o n of i m m u ne t hera p y acti vit y 
i n s oli d t u m ors: I m m u ne-relate d res p o nse criteria. Cli n Ca ncer Res 2 0 0 9; 1 5: 7 4 1 2 – 2 0.  
W u K C, C ui J Y, Klaasse n C D. Be neficial r ole of Nrf 2 i n re g ulati n g N A D P H ge nerati o n a n d 
c o ns u m pti o n. T o xic ol Sci 2 0 1 1; 1 2 3: 5 9 0 -6 0 0.  
Yates M S, K wa k M K, E g ner P A, et al. P ote nt pr otecti o n a gai nst aflat o xi n-i n d uce d t u m ori ge nesis 
t hr o u g h i n d uctio n of Nrf 2 -re g ulate d p at h wa ys b y t he triter pe n oi d 1-[ 2-c ya n o-3 -, 1 2-di o x o olea n a -
1, 9( 1 1) -die n -2 8 -o yl]i mi daz ole. Ca ncer Res 2 0 0 6; 6 6: 2 4 8 8 -9 4.  


Pr ot oc ol 4 0 8 -C -1 4 0 1                               Reata P har mace uticals                                  C o nfi de ntial  
Versi o n 5. 0                                                              8 0  
  
 
 
A P P E N DI X A.  IPI LI M U M A B P A C K A G E  IN S E R T  
 
 
 
 
 


Pr ot oc ol 4 0 8 -C -1 4 0 1                               Reata P har mace uticals                                  C o nfi de ntial  
Versi o n 5. 0                                                              8 1  
  
 
 
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  
 
 
 

SAP_001.pdf: 
Reata P har mace uticals, I nc.  
 
P hase 1 b P orti o n of 4 0 8- C- 1 4 0 1 
Statistical A nal ysis Pla n Versi o n 1  
 
O C T 2 5, 2 0 1 9 
Pa g e 1 of 4 2  
 
R e at a C o nfi d e nti al  
 
 
S T A TI S TI C A L A N A L Y SI S P L A N  
P H A S E I  
N C T 0 2 2 5 9 2 3 1  
D A T E O F P L A N:  
2 5- Oct - 2 0 1 9 
 
B A S E D O N:  
Pr ot oc ol Versi o n 5. 0 ( N ove m ber 2 9, 2 0 1 6) 
S T U D Y D R U G:  
R T A 4 0 8 ( O M A V E L O X O L O N E)  
P R O T O C O L N U M B E R:  
4 0 8- C- 1 4 0 1 
S T U D Y TI T L E:  
A n O pe n- L a bel, M ultice nter, D ose - Esc al ati o n, P h ase 1 b/ 2 St u dy of t he S afety, Effic acy, 
P h ar m ac o dy n a mics, a n d P h ar m ac oki netics of R T A 4 0 8 i n C o m bi n ati o n wit h I pili m u m a b or 
Niv ol u m a b i n t he Tre at me nt of P atie nts wit h U nresect a ble or Met ast atic Mel a n o m a  
S P O N S O R:  
Re at a P h ar m ace utic als, I nc. 
2 8 0 1 G ate w ay Drive, S uite 1 5 0 
Irvi n g, Tex as 7 5 0 6 3- 2 6 4 8 
T his st u d y is bei n g c o n d ucte d i n c o m plia nce wit h g o o d cli nical practice, 
i ncl u di n g t he arc hi vi n g of esse ntial d oc u me nts. 
  
  
  
    
  
  
  
  
    
 
  
  
  
 
  
    
    
  
  
  
 
  
 
    
 
  
    
  
 
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 
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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. 




Reata P har mace uticals, I nc.  
 
P hase 1 b P orti o n of 4 0 8- C- 1 4 0 1 
Statistical A nal ysis Pla n Versi o n 1  
 
O C T 2 5, 2 0 1 9 
Pa g e 3 of 4 2  
 
R e at a C o nfi d e nti al  
T A B L E O F C O N T E N T S  
TI T L E P A G E  ................................................................................................................................... 1 
1.  
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 O F T E R M S  ................................. 6 
2.  
R E VI SI O N HI S T O R Y A N D R E L E V A N T D C O U M E N T S  ........................................ 8 
3.  
P U R P O S E O F T H E A N A L Y SI S P L A N  ...................................................................... 9 
4.  
S T U D Y O BJ E C TI V E S A N D E N D P OI N T S  .............................................................. 1 0 
4. 1.  
St u d y O bjecti ve(s) ...................................................................................................... 1 0  
4. 1. 1.  
Pri mar y O bjecti ves  ..................................................................................................... 1 0 
4. 1. 2.  
E x pl orat or y O bjecti ves ............................................................................................... 1 0  
4. 2.  
St u d y E n d p oi nt(s) ....................................................................................................... 1 0  
4. 2. 1.  
Efficac y E n d p oi nts ...................................................................................................... 1 0  
4. 2. 2.  
Safet y E n d p oi nts ......................................................................................................... 1 0  
4. 2. 3.  
P har mac o ki netic E n d p oi nts ........................................................................................ 1 0  
4. 2. 4.  
P har mac o d y na mic E n d p oi nts ..................................................................................... 1 0  
5.  
S T U D Y D E SI G N  ....................................................................................................... 1 1 
5. 1.  
O verall St u d y Desi g n .................................................................................................. 1 1  
5. 2.  
Ra n d o mizati o n a n d D osi n g ......................................................................................... 1 1  
5. 3.  
Assess me nts  ................................................................................................................ 1 2 
5. 3. 1.  
Efficac y Meas ure me nt a n d Varia bles  ......................................................................... 1 9 
5. 3. 2.  
P har mac o d y na mic M eas ure me nt a n d V aria bles  ......................................................... 1 9 
5. 3. 3.  
Safet y Meas ur e me nts a n d Varia bles  ........................................................................... 1 9 
5. 3. 4.  
P har mac o ki netics Meas ure me nts a n d V aria bles  ........................................................ 1 9 
6.  
S A M P L E SI Z E A N D P O W E R  .................................................................................. 2 0 
7.  
G E N E R A L C O N SI D E R A TI O N S  .............................................................................. 2 1 
7. 1.  
Deri ve d V aria bles  ....................................................................................................... 2 2 
7. 1. 1.  
A ge  .............................................................................................................................. 2 2 
7. 1. 2.  
St u d y Da y ................................................................................................................... 2 2  
7. 1. 3.  
O verall Res p o nse Rate  ................................................................................................ 2 2 
7. 1. 4.  
Electr ocar di o gra m Fri dericia C orrect e d Q T I nter v al  ................................................. 2 3 
7. 1. 5.  
T otal N u m ber of D os es ............................................................................................... 2 3  
7. 2.  
Baseli ne Val ues  .......................................................................................................... 2 3 
7. 2. 1.  
Hei g ht ......................................................................................................................... 2 3  


Reata P har mace uticals, I nc.  
 
P hase 1 b P orti o n of 4 0 8- C- 1 4 0 1 
Statistical A nal ysis Pla n Versi o n 1  
 
O C T 2 5, 2 0 1 9 
Pa g e 4 of 4 2  
 
R e at a C o nfi d e nti al  
7. 3.  
A nal ysis Wi n d o ws ...................................................................................................... 2 3  
7. 4.  
I n c o m plete Dia g n osis or Treat me nt D ate  ................................................................... 2 6 
8.  
A N A L Y SI S S E T S  ...................................................................................................... 2 7 
8. 1.  
Safet y A nal ysis Set  ..................................................................................................... 2 7 
8. 2.  
E va l ua ble A nal ysis Set ............................................................................................... 2 7 
8. 3.  
P har mac o ki netics A n al ysis Set  ................................................................................... 2 7 
9.  
S T U D Y P O P U L A TI O N  ............................................................................................. 2 8 
9. 1.  
Patie nt Dis p ositi o n  ...................................................................................................... 2 8 
9. 2.  
Pr ot oc ol De viati o ns .................................................................................................... 2 9  
9. 3.  
De m o gra p hics a n d Baseli ne C haract eristics  ............................................................... 2 9 
9. 4.  
Me dical Hist or y  .......................................................................................................... 2 9 
1 0.  
S T U D Y D R U G A N D O T H E R M E DI C A TI O N S  ...................................................... 3 0 
1 0. 1.  
Pri or a n d C o nc o mita nt Me dicati o ns ........................................................................... 3 0  
1 0. 2.  
D urati o n of St u d y Treat me nt a n d E x p os ure t o St u d y Dr u g ....................................... 3 0  
1 0. 3.  
C o m bi nati o n T hera p y E x p os ure ................................................................................. 3 1  
1 1.  
E F FI C A C Y A N A L Y S E S  ........................................................................................... 3 2 
1 1. 1.  
Pri mar y Efficac y A nal ysis  .......................................................................................... 3 2 
1 1. 1. 1.  
Re p orti n g Res ults ........................................................................................................ 3 2  
1 1. 2.  
A d diti o nal Efficac y A nal yses ..................................................................................... 3 2  
1 1. 2. 1.  
Ti me t o Res p o nse a n d D urati o n of Res p o nse ............................................................. 3 2  
1 1. 2. 2.  
Perce nt C ha n ge i n i N O S  ............................................................................................. 3 3 
1 1. 2. 3.  
E C O G Perf or ma n ce Stat us  ......................................................................................... 3 3 
1 1. 3.  
Se nsiti vit y A nal yses  .................................................................................................... 3 3 
1 1. 4.  
S u b gr o u ps A nal yses of Efficac y ................................................................................. 3 3  
1 2.  
S A F E T Y A N A L Y S E S  ............................................................................................... 3 5 
1 2. 1.  
A d verse E v e nts a n d Seri o us A d verse E v e nts ............................................................. 3 5  
1 2. 1. 1.  
Treat me nt E mer g e nt A d v erse E ve nts  ......................................................................... 3 5 
1 2. 1. 2.  
S u m mar y of Treat me nt - E mer ge nt A d verse E ve nts a n d Seri o us A d vers e 
E ve nts ......................................................................................................................... 3 6  
1 2. 1. 3.  
D ose -Li miti n g T o xicities  ............................................................................................ 3 7 
1 2. 2.  
Cli nical La b orat or y E val uati o n ................................................................................... 3 8  
1 2. 3.  
Vital Si g ns  .................................................................................................................. 3 9 
1 2. 4.  
B o d y Wei g ht ............................................................................................................... 3 9  


Reata P har mace uticals, I nc.  
 
P hase 1 b P orti o n of 4 0 8- C- 1 4 0 1 
Statistical A nal ysis Pla n Versi o n 1  
 
O C T 2 5, 2 0 1 9 
Pa g e 5 of 4 2  
 
R e at a C o nfi d e nti al  
1 2. 5.  
1 2- lea d E C G ............................................................................................................... 4 0 
1 2. 6.  
P h ysical E xa mi nati o n  ................................................................................................. 4 0 
1 3.  
P H A R M A C O KI N E TI C S A N A L Y SI S  ....................................................................... 4 1 
1 4.  
D E VI A TI O N F R O M T H E P R O T O C O L S P E CI FI E D A N A L Y SI S .......................... 4 2 
 
 
 
LI S T O F T A B L E S 
Ta ble  1: 
List of A b bre viati o ns a n d S pecial Ter ms ..................................................................... 6 
Ta ble  2: 
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 .................................................................................................................. 1 3 
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 + 
Ni v ol u ma b .................................................................................................................. 1 6  
Ta ble  4: 
A nal ysis Visit Wi n d o ws f or Patie nts Recei vi n g R T A 4 0 8 + I pili m u ma b  .................. 2 4 
Ta ble  5: 
A nal ysis Visit Wi n d o ws f or Patie nts Recei vi n g R T A 4 0 8 + Ni v ol u ma b .................. 2 5  
Ta ble  6: 
Pre -S pecifie d T hres h ol d Le vels f or L a b orat or y Para meters  ...................................... 3 8 
Ta ble  7: 
Pre -S pecifie d  U p per Li mit of N or mal ( U L N) Le vels f or La b orat or y 
Para meters  ................................................................................................................... 3 9 
Ta ble  8: 
Pre -S pecifie d T hres h ol d Le vels f or E C G Para met ers  ................................................ 4 0 
 
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  ......................................................................................... 1 2 
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 wit h Ni v ol u ma b i n Patie nts 
wit h Metastatic Mela n o ma  ......................................................................................... 1 2 
 
 


Reata P har mace uticals, I nc.  
 
P hase 1 b P orti o n of 4 0 8- C- 1 4 0 1 
Statistical A nal ysis Pla n Versi o n 1  
 
O C T 2 5, 2 0 1 9 
Pa g e 6 of 4 2  
 
R e at a C o nfi d e nti al  
1.  
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 O F T E R M S  
T he f oll o wi n g a b bre vi ati o ns a n d s pecial ter ms are use d i n t his statistical a nal ysis pla n.  
T a ble 1:  
List of A b bre vi ati o ns a n d S peci al Ter ms  
A b bre vi ati o n or 
S peci alist Ter m  
E x pl a n ati o n  
A E  
a d verse e ve nt  
A L T  
ala ni ne a mi n otra nsferas e  
A S T  
as partate a mi n otra nsferas e  
A T C  
A nat o mical/ T hera pe utic/ C he mical  
B MI  
b o d y mass i n de x  
C DI S C  
Cli nical Data I nterc ha n g e Sta n dar ds C o ns orti u m  
CI  
c o nfi de nce i nter val  
C M  
c o nc o mita nt me dicati o n  
C R  
c o m plete res p o nse  
C S R  
cli nical st u d y re p ort  
C T  
c o m p ute d t o m o gra p h y  
C T C A E  
C o m m o n Ter mi n ol o g y Criteria f or A d vers e E ve nts  
D L T  
d ose -li miti n g t o xicit y 
E A S  
e val ua ble a nal ysis set  
e C R F 
electr o nic case re p ort f or m  
E C G  
electr ocar di o gra m  
E C O G  
Easter n C o o perati ve O nc ol o g y Gr o u p  
F A S  
f ull a nal ysis set 
F D A  
F o o d a n d Dr u g A d mi nistrati o n ( U S)  
G G T  
ga m ma -gl uta m yl tra nsferase  
I C H 
I nter nati o nal C o nfere nce o n Har m o nizati o n 
i N O S 
i n d uci ble nitric o xi de s y nt hase 
I pi 
I pili m u ma b 
IN R  
I nter nati o nal N or m alize d Rati o 
L L D  
l o wer li mit of detecti o n 
M D S C  
m yel oi d -deri ve d s u p press or cell 
Me d D R A  
Me dical Dicti o nar y f or R e g ulat or y Acti vities  
Ni v o  
Ni v ol u ma b  
O R R  
o verall res p o ns e rate  
P B M Cs  
peri p her al bl o o d m o n o n uclear cells  
P K  
p har mac o ki netic  
P D -1  
Pr o gra m me d cell deat h pr otei n 1  
P D -L 1  
Pr o gra m me d deat h -li ga n d 1 
P F S  
Pr o gressi o n free s ur vi val  
P T  
preferre d t er m  
P R  
partial res p o nse  
Q Tc F  
Fri deri cia c orrecte d Q T i nter val  


Reata P har mace uticals, I nc.  
 
P hase 1 b P orti o n of 4 0 8- C- 1 4 0 1 
Statistical A nal ysis Pla n Versi o n 1  
 
O C T 2 5, 2 0 1 9 
Pa g e 7 of 4 2  
 
R e at a C o nfi d e nti al  
R E CI S T  
Res p o nse E val uati o n Criteria I n S oli d T u m o urs  
S A E  
seri o us a d vers e e v e nt 
S A P  
statistical a nal ysis pla n 
S D  
sta n dar d de viati o n 
S D T M  
St u d y Data Ta b ulati o n M o del  
SI  
I nter nati o nal S yste m of U nits 
S O C  
s yste m or ga n class 
T E A E  
treat me nt-e mer ge nt a d v erse e ve nt  
T B L  
t otal bilir u bi n 
U L N  
u p per li mit of n or mal  
W H O D D  
W orl d Healt h Or ga nizati o n Dr u g Dicti o nar y  
W O C B P  
w o me n of c hil d beari n g p ote ntial  


Reata P har mace uticals, I nc.  
 
P hase 1 b P orti o n of 4 0 8- C- 1 4 0 1 
Statistical A nal ysis Pla n Versi o n 1  
 
O C T 2 5, 2 0 1 9 
Pa g e 8 of 4 2  
 
R e at a C o nfi d e nti al  
2.  
R E VI SI O N HI S T O R Y A N D R E L E V A N T D C O U M E N T S  
Bel o w lists re visi o n s u m maries of t his statistical a nal ysis pla n.  
Versi o n  
Date  
D oc u me nt O w ner 
Re visi o n S u m mar y 
1. 0 
D D -O C T - 2 0 1 9 
Me ga n O’ Gra d y  
I nitial versi o n. 
 
T he a nal ysis pla n is base d o n t he i nf or mati o n fr o m t he f oll o wi n g d oc u me nt:  
Pr ot oc ol Versi o n 5. 0, 2 9 N o ve m ber 2 0 1 6.  


Reata P har mace uticals, I nc.  
 
P hase 1 b P orti o n of 4 0 8- C- 1 4 0 1 
Statistical A nal ysis Pla n Versi o n 1  
 
O C T 2 5, 2 0 1 9 
Pa g e 9 of 4 2  
 
R e at a C o nfi d e nti al  
3.  
P U R P O S E O F T H E A N A L Y SI S P L A N  
T he p ur p ose of t his statistical a nal ysis pla n ( S A P) is t o descri be t he r ules a n d c o n ve nti o ns t o be 
use d i n t he prese ntati o n a n d a nal ysis of efficac y a n d safet y data f or s u p p orti n g t he c o m pleti o n of 
t he cli nical st u d y re p ort ( C S R) of t he P hase 1 b p orti o n of Pr ot oc ol 4 0 8- C- 1 4 0 1 f or t he 
i n vesti gati o nal pr o d uct R T A 4 0 8.  T his S A P will be use d t o a nal yze t he safet y, t olera bilit y, a n d 
efficac y dat a c ollecte d d uri n g P hase 1 b p orti o n of t he st u d y.  A n y p har mac o ki netic a n d 
p har mac o d y n a mic a nal ys es n ot descri be d i n t his pla n will be descri b e d i n a se parat e a nal ysis 
pla n.   
Preli mi nar y safet y a n d efficac y res ults f or t he P has e 1 b p orti o n of t he st u d y will be perf or me d as 
a p pr o priate f or r eas o ns s uc h as, b ut n ot li mite d t o, re g ulat or y i nteracti o ns, scie ntific meeti n gs or 
p u blicati o ns, a n d cli nical de vel o p me nt pr o gra m s u p p ort.  T he fi nal a n al ysis f or t he P hase 1 b 
p orti o n will be perf or me d after d ata base l o c k f oll o wi n g t he last e nr olle d p atie nt ha vi n g 
c o m plete d t he st u d y.  T h e st u d y data base was l oc ke d o n A u g ust 2 0, 2 0 1 8.  T he S A P was 
fi nalize d after dat a base l oc k, b ut c ha n ges t o t he S A P after dat a base l oc k di d n ot mea ni n gf ull y 
affect saf et y or efficac y r es ults.  
T his pla n ma y be a me n d e d f or r eas o ns s uc h as, b ut n ot li mite d t o, pr ot oc ol a me n d me nts, i nteri m 
a nal ysis res ults, a n d i nter nal data re vi e ws t hat ta ke place of t he P has e 1 b p orti o n of t he st u d y.  
E x pl orat or y a nal ys es, w hic h are n ot defi ne d i n t his S A P, ma y be perf or m e d t o s u p p ort t he 
cli nical de vel o p me nt pr o gra m.  A n y p ost- h oc or u n pla n ne d a nal yses, w hic h are perf or m e d f or 
t he C S R, b ut n ot defi ne d i n t his S A P, will be clearl y i de ntifie d a n d d oc u me nte d i n t he C S R as 
will a n y c ha n ges fr o m t he pla n ne d a n al yses as stat e d i n t he st u d y pr ot oc ol. 




Reata P har mace uticals, I nc.  
 
P hase 1 b P orti o n of 4 0 8- C- 1 4 0 1 
Statistical A nal ysis Pla n Versi o n 1  
 
O C T 2 5, 2 0 1 9 
Pa g e 1 1  of 4 2  
 
R e at a C o nfi d e nti al  
5.  
S T U D Y D E SI G N  
5. 1.  
O ver all St u d y Desi g n  
I n t his ope 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 pili m u ma b ( 3 m g/ k g) or ni v ol u ma b ( 2 4 0 m g).  T he P has e 1 b p orti o n o f t he 
st u d y will e nr oll c o h orts of t hree t o si x patie nts at eac h d ose l e vel of R T A 4 0 8.  C o h orts 1 t o 3 
will be use d t o assess c o m bi nati o n t hera p y wit h i pili m u ma b se paratel y fr o m t he c o m bi nati o n 
wit h ni v ol u ma b.  C o h orts 4 t o 1 0 will o nl y be use d t o assess c o m bi nati o n t hera p y wit h 
ni v ol u ma b.  A P hase 2 d ose will be selecte d b ase d o n re vie w of s afet y, efficac y, a n d 
p har mac o d y n a mic data fr o m t he P hase 1 b p orti o n of t he st u d y. 
5. 2.  
R a n d o miz ati o n a n d D osi n g  
T he P hase 1 b p orti o n of t he st u d y will be o pe n- la b el wit h o ut ra n d o mizati o n.   
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 or all 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 nistere d at Wee ks 1, 4, 7, a n d 1 0 ( Fi g ure 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 patie 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 ( p atie 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 ).  Patie nts will ret ur n 
4 wee ks after R T A 4 0 8 tr eat 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. 








Reata P har mace uticals, I nc.  
 
P hase 1 b P orti o n of 4 0 8- C- 1 4 0 1 
Statistical A nal ysis Pla n Versi o n 1  
 
O C T 2 5, 2 0 1 9 
Pa g e 1 5  of 4 2  
 
 
R e at a C o nfi d e nti al  
g T h e Wee k 1 3 t u m or bi o ps y ma y be c ollecte d ± 1 wee k fr o m sc he d ule d visit.  Wee k 1 3 t u m or bi o ps y is o pti o nal f or patie nts e nr olle d i n t he P hase 2 p orti o n of t he st u d y.   
h I ma gi n g st u dies f or t u m or size/ b ur de n e val uati o n as a p pr o priate t o assess disease b ur de n or t u m or size.  T he assess me nt d o ne 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.  S piral C T wit h c o ntrast is a p pr o priate 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 perf 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.    
i  Res p o nse ( R E CI S T) assess me nt s h o ul d i ncl u de c hest a n d a b d o me n a n d a n y area t hat is bei n g m o nit ore d.   
j  Bl o o d sa m ples f or P B M C ( bi o mar ker a n d M D S C) a nal ysis s h o ul d be ta ke n pri or t o st u d y dr u g a d mi nistrati o n.  
k Bl o o d sa m ples f or P K a nal ysis s h o ul d be ta ke n pri or t o a n d 2 h o urs after d ose a d mi nistrati o n.  
l Wit h a p pr o v al of t he S p o ns or, or desi g nee, scree 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.  
 
A b bre viati o ns:  B MI = b o d y mass i n de x, C T =c o m p ute d t o m o gra p h y, E C O G = Easter n C o o perati ve O nc ol o g y Gr o u p, M D S C = m yel oi d -deri ve d s u p press or cell, P B M C = peri p heral bl o o d m o n o n uclear cell, 
P K = p har mac o ki netic, R E CI S T = Res p o nse E val uati o n Criteria I n S oli d T u m o urs, W O C B P = w o me n of c hil d beari n g p ote ntial.  
 
 
 
 






Reata P har mace uticals, I nc.  
 
P hase 1 b P orti o n of 4 0 8- C- 1 4 0 1 
Statistical A nal ysis Pla n Versi o n 1  
 
O C T 2 5, 2 0 1 9 
Pa g e 1 8  of 4 2  
 
 
R e at a C o nfi d e nti al  
 
a T h e Wee k 1 6 9 pr oce d ures s h o ul d be c o m plete d f or patie nts w h o ter mi nate partici pati o n i n t he st u d y earl y.  
b Da y 1 pr oce d ures s h o ul d be perf or me d wit hi n 1 h o ur pri or t o d ose a d mi nistrati o n.  
c W O C B P m ust h a ve ne gati ve ser u m pre g na nc y test res ults t o be eli gi ble f or t he st u d y.  
d W O C B P m ust ha ve ne gati ve uri ne pre g na nc y test res ults t o c o nti n ue i n t he st u d y.  
F o ot n otes c o nti n ue ne xt pa ge.  
e St u d y dr u g s h o ul d be a d mi nistere d i n t he prese nce of st u d y staff i n t he cli nic at Da y 1, Wee k 1, a n d Wee k 1 3 after t he pre d ose P K bl o o d c ollecti o n.  All ot her d oses ca n be a d mi nistere d at h o me.  
f Wee k 1 t u m or bi o ps y m ust be c ollecte d pri or t o first a d mi nistrati o n of ni v ol u ma b  b ut ma y be c ollecte d 1 da y pri or t o t he sc he d ule d visit.  Wee k 1 t u m or bi o ps y is o pti o nal f or patie nts e nr olle d i n t he 
P h ase 2 p orti o n of t he st u d y.  
g T h e Wee k 1 3 t u m or bi o ps y ma y be c ollecte d ± 1 wee k fr o m sc he d ule d visit.  Wee k 1 3 t u m or bi o ps y is o pti o nal f or patie nts e nr olle d i n t he P hase 2 p orti o n of t he st u d y.  
h I ma gi n g st u dies f or t u m or size/ b ur de n e val uati o n as a p pr o priate t o assess disease b ur de n or t u m or size.  T he assess me nt d o ne 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.  S piral C T wit h c o ntrast is a p pr o priate 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 m e n ts perf 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.   
i  Res p o nse ( R E CI S T) assess me nt s h o ul d i ncl u de c hest a n d a b d o me n a n d a n y area t hat is bei n g m o nit ore d.   
j  Bl o o d sa m ples f or P B M C ( bi o mar ker a n d M D S C) a nal ysis s h o ul d be  ta ke n pri or t o st u d y dr u g a d mi nistrati o n. 
k Bl o o d sa m ples f or P K a nal ysis s h o ul d be ta ke n pri or t o a n d 2 h o urs after d ose a d mi nistrati o n.  
l Wit h a p pr o v al of t he S p o ns or, or desi g nee, scree 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.  
m  Ni v ol u ma b s h o ul d c o nti n ue t o be a d mi nistere d e ver y 2 wee ks acc or di n g t o t he pac ka ge i nsert.  
 
A b bre viati o ns:  B MI = b o d y mass i n de x, C T =c o m p ute d t o m o gra p h y, E C O G = Easter n C o o perati ve O nc ol o g y Gr o u p, M D S C = m yel oi d -deri ve d s u p press or cell, P B M C = peri p heral bl o o d m o n o n uclear cell, 
P K = p har mac o ki netic, R E CI S T = Res p o nse E val uati o n Criteria I n S oli d T u m o urs, W O C B P = w o me n of c hil d beari n g p ote ntial.  
 
 


Reata P har mace uticals, I nc.  
 
P hase 1 b P orti o n of 4 0 8- C- 1 4 0 1 
Statistical A nal ysis Pla n Versi o n 1  
 
O C T 2 5, 2 0 1 9 
 
Pa g e 1 9  of 4 2   
 
R e at a C o nfi d e nti al  
5. 3. 1.  
Effic ac y Me as ure m e nt a n d V ari a bles  
O verall r es p o nse r ate ( O R R), defi ne d as t he pr o p orti o n of patie nts wit h c o m plete or partial t u m or 
size re d u cti o n acc or di n g t o R E CI S T 1. 1 criteria, will be s u m marize d.  Sta ble disease is n ot a 
c o m p o ne nt of O R R.   
Efficac y vari a bles ar e t u m or res p o nse r ates ( o v erall, c o m plete, a n d partial) acc or di n g t o R E CI S T 
1. 1 criteria, a n d per ce nt r e d ucti o n i n t u m or bi o ps y i N O S e x pressi o n. 
5. 3. 2.  
P h ar m ac o d y n a mi c Me as ure me nt a n d 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 eff ects 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 
ni 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. 
5. 3. 3.  
S afet y Me as ure m e nts a n d 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 r es ults (cli nical c he mistr y, hemat 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 d verse e ve nts ( A Es), a n d seri o us a d vers e e v e nts ( S A Es). 
5. 3. 4.  
P h ar m ac o ki netics Me as ure me nts a n d V ari a bles  
P har mac o ki netic ( P K) s a m ples will be c ollecte d o n Da y 1, Da y 8 ( ± 2 da ys), a n d Da y 9 2 ( ± 3 
da ys). Sa m ples will be c ollecte d pri or t o st u d y dr u g d osi n g ( pre- d ose), a n d 2 h o urs after d os e 
a d mi nistrati o n.  T he P K varia bles i ncl u de R T A 4 0 8  plas ma c o nce ntrati o n -ti me data, a n d 
esti mate d P K para met ers.  


Reata P har mace uticals, I nc.  
 
P hase 1 b P orti o n of 4 0 8- C- 1 4 0 1 
Statistical A nal ysis Pla n Versi o n 1  
 
O C T 2 5, 2 0 1 9 
 
Pa g e 2 0  of 4 2   
 
R e at a C o nfi d e nti al  
6.  
S A M P L E SI Z E A N D P O W E R  
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 v e 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) 
select P hase 2 d ose b ase d o n re vie w of s afet y, effi cac y, a n d p har mac o d y na mic data, a n d ( 3) 
assess 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 s electi 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 select e d base d o n a tra diti o nal 3 + 3 desi g n f or a d ose- es calatio 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 her a 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 w ee 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 st 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.   
 


Reata P har mace uticals, I nc.  
 
P hase 1 b P orti o n of 4 0 8- C- 1 4 0 1 
Statistical A nal ysis Pla n Versi o n 1  
 
O C T 2 5, 2 0 1 9 
 
Pa g e 2 1  of 4 2   
 
R e at a C o nfi d e nti al  
7.  
G E N E R A L C O N SI D E R A TI O N S  
T he a nal ysis sets, as defi ne d i n Secti o n  8 , will be use d f or efficac y, safet y, a n d t olera bilit y.  
Patie nt listi n gs of all a nal ysis data t hat s u p p ort s u m mar y ta bles a n d/ or fi g ures will be pr o vi de d 
al o n g wit h t heir s o urce d ata fr o m t he e lectr o nic case re p ort f or ms (e C R Fs).  Meas ure me nts fr o m 
patie nts e xcl u de d fr o m t he pre- d efi ne d a nal ysis sets or e xtra meas ure me nts (s uc h as u nsc h e d ule d 
or re peat assess me nts) will n ot be i ncl u de d i n s u m mar y ta bles u nless s pecifie d ot her wise b ut will 
be i ncl u de d i n t he patie nt listi n gs.  Missi n g data will n ot be i m p ute d, u nless ot her wise s pecifie d.  
I n g e ner al, patie nt listi n gs will be s orte d b y patie nt n u m ber a n d assess me nt date (ti me a n d 
para meter, as a p plica ble).   
U nless ot her wise s pecifie d, descri pti ve statistics f or c o nti n u o us varia bles will i ncl u de t he n u m ber 
of patie nts wit h data ( N), mea n, sta n dar d d e viati o n ( S D), me dia n, mi ni m u m, a n d ma xi m u m.  F or 
all a nal yses e x ce pt cli nical c he mistr y, he mat ol o g y, a n d uri nal ysis data, t he sa me n u m ber of 
deci mal pla ces as i n t he o bser ve d val u e will be prese nte d w he n re p orti n g mi ni m u m a n d 
ma xi m u m; 1 m ore deci mal place t ha n i n t he o bs er ve d val ue will be prese nt e d w he n re p orti n g 
mea n a n d me dia n; a n d 2 m ore deci mal places t ha n i n t he o bser ve d val u e will be prese nte d w h e n  
re p orti n g S D. Cli nical c he mistr y, he mat ol o g y, a n d uri nal ysis data m ust be c o n verte d t o 
c o n ve nti o nal u nits bef ore a n y a nal yses are p erf or me d. F or cli nical c he mistr y, he mat ol o g y, a n d 
uri nal ysis data, t he sa me n u m ber of deci mal places as i n t he val ue i n SI u nits will be prese nte d 
w he n re p orti n g mi ni m u m a n d ma xi m u m; 1 m ore deci mal place t h a n t he val ue i n SI u nits will be 
prese nte d w h e n re p orti n g mea n a n d me dia n; a n d 2 m ore deci mal places t ha n t he val ue i n SI u nits 
will be prese nte d w h e n r e p orti n g S D. 
Cli nical c he mistr y, he mat ol o g y, a n d uri nal ysis data m ust be c o n vert e d t o I nter nati o nal S yste m of 
U nits ( SI u nits) bef ore a n y a nal yses ar e perf or me d.  
All cate g orical/ q ualitati ve data will be prese nte d usi n g fre q ue nc y c o u nts a n d perce nt a ges.  All 
perce nt a ges will be pr ese nte d t o 1 deci mal place, u nless ot her wise s pecifie d.  Perce nta g es e q ual 
t o 1 0 0 will be prese nte d as 1 0 0 % a n d n o perce nta ges will be prese nte d f or zer o fre q ue n cies.  
W here i n di vi d ual varia bl e val ues are missi n g, cate g orical data will be s u m marize d bas e d o n 
re d uce d d e n o mi nat ors (i. e., o nl y patie nts wit h a vaila ble data will be i ncl u d e d i n t he 
de n o mi nat ors).  F or s u m maries of A Es a n d c o nc o mita nt me dicati o ns ( C M), t he perce nta ges will 
be base d o n t he n u m ber of patie nts w h o recei ve d st u d y dr u g. 
T he f oll o wi n g data c ollecte d fr o m patie nts e nr olle d i n t he R T A 4 0 8 + i pili m u ma b c o h orts will be 
s u m marize d se paratel y fr o m data c ollecte d fr o m p atie nts e nr olle d i n t he R T A 4 0 8 + ni v ol u ma b 
c o h orts:  
•  De m o gra p hics a n d Baseli ne C haract eristics  
•  Efficac y s u m maries ( Secti o n  1 1 ) 
•  Treat me nt -e mer ge nt a d v erse e v e nts ( Secti o n  1 2 ) 
 
 


Reata P har mace uticals, I nc.  
 
P hase 1 b P orti o n of 4 0 8- C- 1 4 0 1 
Statistical A nal ysis Pla n Versi o n 1  
 
O C T 2 5, 2 0 1 9 
 
Pa g e 2 2  of 4 2   
 
R e at a C o nfi d e nti al  
•  La b orat or y v al ues of i nterest, i ncl u di n g: 
− Ala ni ne tra nsa mi nas e ( A L T)  
− As partate tr a nsa mi nase ( A S T)  
− Al kali ne p h os p hatase 
− Ferriti n  
− Ga m ma -gl uta m yl tra nsferase ( G G T)  
− T otal bilir u bi n  
Res ults of statistical a nal yses will be re p orte d usi n g s u m mar y ta bles, l isti n gs, a n d fi g ures ( T L Fs).  
T he I C H n u m beri n g c o n ve nti o n will be use d f or all T L Fs.  T he f oll o wi n g c o n ve nti o ns will be 
f oll o we d: 
•  U nless ot her wise n ote d, all statistical testi n g will be t w o -si de d a n d will be perf or me d 
at t he 0. 0 5 si g nifica nce le vel 
•  Tests will be declar e d statisticall y si g nifica nt if t he calc ul ate d p -val u e is < 0. 0 5  
All a nal yses a n d s u m maries will be pr o d uce d usi n g S A S ® versi o n 9. 3 ( or hi g her). 
7. 1.  
Deri ve d V ari a bles  
7. 1. 1.  
A ge  
A ge ( years) will be calc ulate d as t he n u m ber of years bet wee n date of birt h a n d date of i nf or me d 
c o nse nt, e x pr esse d as a n i nte ger. 
7. 1. 2.  
St u d y D a y  
St u d y Da y will f oll o w t he Cli nical Data I nterc ha n ge Sta n dar ds C o ns orti u m ( C DI S C) St u d y Data 
Ta b ulati o n M o del ( S D T M) sta n dar d a n d is d efi ne d as f oll o ws: 
•  assess me nt date – dat e of first s t u d y dr u g d osi n g + 1, w here t he assess me nt date is o n 
or after t h e date of first st u d y dr u g d osi n g 
•  assess me nt date – dat e of first st u d y dr u g d osi n g, w here t he assess me nt dat e is bef ore 
t he date of first st u d y dr u g d osi n g  
7. 1. 3.  
O ver all Res p o nse R ate  
Best o verall res p o nse rat e ( O R R) is defi ne d as t he pr o p orti o n of e val ua bl e patie nts wit h t he best 
re p orte d t u m or r es p o nse of c o m plete r es p o nse ( C R) or partial res p o ns e ( P R) acc or di n g t o 
R E CI S T versi o n 1. 1 criteria. T he first occ urre nce of a res p o ns e is c o nsi dere d a n u nc o nfir me d 


Reata P har mace uticals, I nc.  
 
P hase 1 b P orti o n of 4 0 8- C- 1 4 0 1 
Statistical A nal ysis Pla n Versi o n 1  
 
O C T 2 5, 2 0 1 9 
 
Pa g e 2 3  of 4 2   
 
R e at a C o nfi d e nti al  
res p o nse.  A C R or P R w hic h persists t o t he ne xt t u m or b ur de n assess me nt is t he n c o nsi dere d a 
c o nfir me d r es p o nse. 
7. 1. 4.  
Electr oc a r di o gr a m Fri derici a C orrecte d Q T I nter v al  
Electr ocar di o gra m i nter v als, i ncl u di n g Fri derici a c orrect e d Q T i nter v al ( Q T c F), will be assesse d 
l ocall y at eac h site.  I n t he e ve nt t hat Q T c F i nter val is n ot pr o vi de d, it ca n be calc ul ate d fr o m Q T 
a n d R R i nter vals usi n g t he f oll o wi n g f or m ula:  
•  𝑄𝑄𝑄𝑄𝑄𝑄𝑄𝑄=  𝑄𝑄𝑄𝑄/ √𝑅𝑅𝑅𝑅
3
 
W here R R = 6 0 / ( Heart Rate).  
7. 1. 5.  
T ot al N u m ber of D oses 
T otal n u m ber of d oses r ecei ve d will be calc ulate d fr o m i nf or mati o n o n t he e C R F of St u d y Dr u g 
Ret ur n a n d St u d y Dr u g Dis pe nsati o n, as t he t otal n u m ber of d oses dis pe ns e d – t otal n u m ber of 
d oses ret ur ne d.  T he t otal d ose ( m g) recei ve d ca n be calc ul ate d i n si milar wa y.  T he a v era ge 
dail y d ose ( m g) will be calc ulate d as t otal d ose ( m g) / (t otal n u m ber of da ys of e x p os ure – t h e 
wit h dra wal peri o ds).  St u d y dr u g c o m plia nce ( %) will be calc ulate d as 1 0 0 × t otal n u m ber of 
d oses recei ve d / t otal n u m ber of d oses dis pe nse d. 
7. 2.  
B aseli ne V al ues  
Baseli ne val ues are defi ne d as t he last n o n - missi n g assess me nt pri or t o t he first st u d y dr u g 
d osi n g, u nless ot her wise s pecifie d bel o w.   
7. 2. 1.  
Hei g ht  
Baseli ne hei g ht is t he last n o n - missi n g assess me nt pri or t o t he first st u d y dr u g d osi n g re gar dless 
of st u d y da y pri or t o date of first d ose. 
7. 3.  
A n al ysis Wi n d o ws  
Beca use cli nical visits ma y occ ur o utsi de pr ot oc o l s pecifie d wi n d o ws, i nstea d of rel yi n g s olel y 
o n visit la bels i n t he cli nical data b ase, a n al ysis visits a n d t heir wi n d o ws are defi ne d usi n g St u d y 
Da y ( Secti o n  7. 1. 2 ).  F or t he p ur p oses of dat a a nal ysis a n d s u m mar y, o n-treat me nt assess me nts 
a n d/ or meas ur e me nts will be fla g ge d bas e d o n t he c ollecti o n date/ti me t hat is cl osest t o t he 
pr ot oc ol sc he d ule d ti me p oi nt ( or tar get St u d y Da y).  Off- treat me nt ass ess me nts will be fla g ge d 
base d o n da ys si nce last d ose of R T A 4 0 8.  A nal ysis visit wi n d o ws are prese nte d i n Ta ble  4 b y 
t y pe of assess me nts a n d/ or meas ure m e nts.   
 
 


Reata P har mace uticals, I nc.  
 
P hase 1 b P orti o n of 4 0 8- C- 1 4 0 1 
Statistical A nal ysis Pla n Versi o n 1  
 
O C T 2 5, 2 0 1 9 
 
Pa g e 2 4  of 4 2   
 
R e at a C o nfi d e nti al  
T a ble 4:  
A n al ysis Visit Wi n d o ws f or P atie nts R ecei vi n g R T A 4 0 8 + I pili m u m a b 
Pr ot oc ol Sc he d ule d  Ti me P oi nt  
T ar get St u d y D a y  
A n al ysis Visit Wi n d o ws  
Scree ni n g  
- 1 
All pre -d ose val ue  
Da y 1  
1  
1  
Wee k 1  
8  
2 t o 1 1  
Wee k 2  
1 5  
1 2 t o 2 2  
Wee k 4  
2 9  
2 3 t o 3 5  
Wee k 7  
5 0  
3 6 t o 5 7  
Wee k 1 0  
7 1  
5 8 t o 7 8  
Wee k 1 3  
9 2  
7 9 t o 9 9  
Wee k 1 5  
1 0 6  
1 0 0 t o 1 1 3  
Wee k 1 8  
1 2 7  
1 1 4 t o 1 3 4  
Wee k 2 1  
1 4 8  
1 3 5 t o 1 5 5  
Wee k 2 4  
1 6 9  
1 5 6 t o 1 7 6  
Wee k 3 6  
2 5 3  
1 7 7 t o 2 6 0  
Wee k 4 8  
3 3 7  
2 6 1 t o 3 4 3  
Wee k 6 0  
4 2 1  
3 4 4 t o 4 2 8  
Wee k 7 2  
5 0 5  
4 2 9 t o 5 1 2  
Wee k 8 4  
5 8 9  
5 1 3 t o 5 9 6  
Wee k 9 6  
6 7 3  
5 9 7 t o 6 8 0  
Wee k 1 0 8  
7 5 7  
6 8 1 t o 7 6 4  
Wee k 1 2 0  
8 4 1  
7 6 5 t o 8 4 8  
Wee k 1 3 2  
9 2 5  
8 4 9 t o 9 3 4  
Wee k 1 4 4  
1 0 0 9  
9 3 5 t o 1 0 1 6  
Wee k 1 5 6  
1 0 9 3  
1 0 1 7 t o 1 1 0 0  
Wee k 1 6 8  
1 1 7 7  
1 1 0 1 t o 1 1 8 4  
Wee k 1 7 2  
1 2 0 5  
> 1 1 8 5  
F oll o w- u p 
2 8 da ys after last d ose  
1 4 ≤ d a ys after last d ose ≤ 3 5  
 


Reata P har mace uticals, I nc.  
 
P hase 1 b P orti o n of 4 0 8- C- 1 4 0 1 
Statistical A nal ysis Pla n Versi o n 1  
 
O C T 2 5, 2 0 1 9 
 
Pa g e 2 5  of 4 2   
 
R e at a C o nfi d e nti al  
T a ble 5:  
A n al ysis Visit Wi n d o ws f or P atie nts R ecei vi n g R T A 4 0 8 + Ni v ol u m a b 
Pr ot oc ol Sc he d ule d Ti me P oi nt  
T ar get St u d y D a y  
A n al ysis Visit Wi n d o ws  
Scree ni n g  
St u d y Da y 
All pre -d ose val ues  
Da y 1  
1  
1  
Wee k 1  
8  
2 t o 1 1  
Wee k 2  
1 5  
1 2 t o 1 8 
Wee k 3  
2 2 
1 9 t o 2 8 
Wee k 5  
3 6 
2 9 t o 4 2 
Wee k 7  
5 0 
4 3 t o 5 6 
Wee k 9  
6 4 
5 7 t o 7 0 
Wee k 1 1  
7 8 
7 1 t o 8 4 
Wee k 1 3  
9 2 
8 5 t o 9 9 
Wee k 1 5  
1 0 6 
1 0 0 t o 1 1 3  
Wee k 1 7  
1 2 0 
1 1 4 t o 1 2 6  
Wee k 1 9  
1 3 4 
1 2 7 t o 1 4 0  
Wee k 2 1  
1 4 8 
1 4 1 t o 1 5 4  
Wee k 2 3  
1 6 2 
1 5 5 t o 1 6 8  
Wee k 2 5  
1 7 6 
1 6 9 t o 1 8 2  
Wee k 3 7  
2 6 0 
1 8 3 t o 2 6 6  
Wee k 4 9  
3 4 4 
2 6 7 t o 3 5 0  
Wee k 6 1  
4 2 8 
3 5 1 t o 4 3 4  
Wee k 7 3  
5 1 2 
4 3 5 t o 5 1 8  
Wee k 8 5  
5 9 6 
5 1 9 t o 6 0 2  
Wee k 9 7  
6 8 0 
6 0 3 t o 6 8 6  
Wee k 1 0 9  
7 6 4 
6 8 7 t o 7 7 0  
Wee k 1 2 1  
8 4 8 
7 7 1 t o 8 5 4  
Wee k 1 3 3  
9 3 2 
8 5 5 t o 9 3 8  
Wee k 1 4 5  
1 0 1 6 
9 3 9 t o 1 0 2 2  
Wee k 1 5 7  
1 1 0 0 
1 0 2 3 t o 1 1 0 6 
Wee k 1 6 9  
1 1 8 4 
1 1 0 7 t o 1 1 9 0 
Wee k 1 7 3  
1 2 1 2 
> 1 1 9 0 
F oll o w- u p  
2 8 da ys after last d ose  
1 4 ≤ Da ys after last d ose ≤ 3 5  


Reata P har mace uticals, I nc.  
 
P hase 1 b P orti o n of 4 0 8- C- 1 4 0 1 
Statistical A nal ysis Pla n Versi o n 1  
 
O C T 2 5, 2 0 1 9 
 
Pa g e 2 6  of 4 2   
 
R e at a C o nfi d e nti al  
N ote: St u d y Da y is relati ve t o t he first date of st u d y dr u g a d mi nistrati o n ( St u d y Da y 1).  Pr ot oc ol 
Sc he d ule d Ti me P oi nt = A nal ysis Visit ( A VI SI T), after a p pl yi n g t he a nal ysis wi n d o ws descri be d 
a b o ve.  T he Wee k 1 7 2 ( R T A 4 0 8 + i pili m u ma b) a n d Wee k 1 7 3 ( R T A 4 0 8 + ni v ol u ma b) visits 
ha ve t he a d diti o nal r estricti o n t hat assess me nts m ust be c ollecte d after fi n al d ose of R T A 4 0 8 
d uri n g t he 4- wee k f oll o w- u p visit.  F or patie nts w h o ter mi nate d treat me nt pri or t o Wee k 1 6 8  
( R T A 4 0 8 + i pili m u ma b) or Wee k 1 6 9 ( R T A 4 0 8 + ni v ol u ma b), use Wee k 1 7 2  ( R T A 4 0 8 + 
i pili m u ma b) or Wee k 1 7 3 ( R T A 4 0 8 + ni v ol u ma b) as f oll o w- u p visit, ot her wise Wee k 1 7 2  
( R T A 4 0 8 + i pili m u ma b) or Wee k 1 7 3 ( R T A 4 0 8 + ni v ol u ma b). 
T he f oll o w- u p is base d o n da ys si nce last d ose.  If m ore t ha n o ne ass ess me nt e xists d uri n g t he 
f oll o w- u p after last d ose, t he o ne cl osest t o 2 8 da ys f oll o wi n g t he date of t h e last st u d y dr u g 
a d mi nistrati o n is use d f or a nal ysis a n d s u m mar y. 
If m ore t ha n o n e meas ure me nt is c ollecte d e q ui dista nt t o t he tar get St u d y Da y a n d o n differe nt 
c ollecti o n date, t he first meas ure me nt will be fl a g ge d f or a n al ysis a n d s u m mar y.  If m ore t ha n 
o ne meas ur e me nt is cl osest t o t he tar get St u d y Da y a n d c ollecte d o n t h e sa me date, t he a v era g e 
of t h ose meas ur e me nts will be use d f or a nal ysis a n d s u m mar y.  If m ulti ple n o mi nal st u d y visit 
assess me nts fall wit hi n t he sa me a n al ysis visit, t he assess me nt cl osest t o t h e tar get visit da y 
s pecifie d i n t he pr ot oc ol st u d y pr oce d ures will be use d.   
7. 4.  
Inc o m plete Di a g n osis or Tre at me nt D ate  
I n c o m plete dia g n osis a n d treat me nt dates are i m p ute d as f oll o ws: 
•  If da y is missi n g, da y will be set t o 1 5t h of t he m o nt h 
•  If m o nt h a n d da y are missi n g, m o nt h a n d da y will be set t o J ul y 1st  
•  If year, m o nt h, a n d da y are missi n g, date will be set t o missi n g  
If treat me nt d ates occ ur after st u d y c o m pleti o n or t er mi nati o n, t he n t he treat me nt dates are 
i m p ute d as t he date of st u d y c o m pleti o n or ter mi nati o n. 


Reata P har mace uticals, I nc.  
 
P hase 1 b P orti o n of 4 0 8- C- 1 4 0 1 
Statistical A nal ysis Pla n Versi o n 1  
 
O C T 2 5, 2 0 1 9 
 
Pa g e 2 7  of 4 2   
 
R e at a C o nfi d e nti al  
8.  
A N A L Y SI S S E T S 
8. 1.  
S afet y A n al ysis Set  
Safet y a nal ysis set is defi ne d as all patie nts w h o recei ve d a n y a m o u nt of st u d y dr u g.  T he safet y 
a nal ysis set will be use d f or e val u ati o n of safet y v aria bles.  
8. 2.  
E v al u a ble A n al ysis Set  
E val ua ble a n al ysis set ( E A S) is defi ne d as all e nr olle d patie nts ha vi n g recei ve d at least t w o 
wee ks of st u d y dr u g b ef ore disease pr o gressi o n a n d e xcl u des patie nts w h o disc o nti n ue d fr o m 
st u d y f or reas o ns ot her t h a n a n a d v erse e ve nt pri or t o first t u m or resta gi n g.  T he E A S will be 
use d f or e v al uati o n of all efficac y para meters . 
8. 3.  
P h ar m ac o ki netics A n al ysis Set  
P har mac o ki netics  ( P K) a nal ysis set is defi ne d as all patie nts w h o recei v e d a n y a m o u nt of st u d y 
dr u g a n d ha d at least o ne R T A 4 0 8 plas ma c o nce ntrati o n meas ure m e nt.  T he P K a nal ysis set will 
be use d f or e val uati o n of p har mac o ki netics. 
 


Reata P har mace uticals, I nc.  
 
P hase 1 b P orti o n of 4 0 8- C- 1 4 0 1 
Statistical A nal ysis Pla n Versi o n 1  
 
O C T 2 5, 2 0 1 9 
 
Pa g e 2 8  of 4 2   
 
R e at a C o nfi d e nti al  
9.  
S T U D Y P O P U L A TI O N  
9. 1.  
P atie nt Dis p ositi o n  
E nr oll me nt a n d dis p ositi o n will be s u m marize d.  A patie nt will be defi ne d as e nr olle d if t he y 
si g n t he i nf or me d c o nse nt f or m.  T he patie nt dis p ositi o n s u m mar y will i ncl u de t he n u m ber of 
patie nts w h o: 
•  e nr olle d i n t he st u d y  
•  are i n t he safet y a n al ysis set  
•  are i n t he e v al ua ble a nal ysis set  
•  are i n t he p har mac o ki n etics a nal ysis set  
•  c o m plete d t he Wee k 1 3 treat me nt peri o d ( R T A 4 0 8 + i pili m u ma b patients) 
•  c o m plete d t he Wee k 1 3  treat me nt peri o d ( R T A 4 0 8 + ni v ol u ma b patie nts) 
•  c o m plete d t he Wee k 2 4 treat me nt peri o d ( R T A 4 0 8 + i pili m u ma b patie nts) 
•  c o m plete d t he Wee k 2 5  treat me nt peri o d ( R T A 4 0 8 + ni v ol u ma b patie nts) 
•  c o m plete d t he Wee k 3 6 treat me nt peri o d ( R T A 4 0 8 + i pili m u ma b patie nts)  
•  c o m plete d t he Wee k 3 7  treat me nt peri o d ( R T A 4 0 8 + ni v ol u ma b patie nts) 
•  c o m plete d t he Wee k 4 8 treat me nt peri o d ( R T A 4 0 8 + i pili m u ma b patie nts) 
•  c o m plete d t he Wee k 4 9  treat me nt peri o d ( R T A 4 0 8 + ni v ol u ma b patie nts) 
•  c o m plete d t he Wee k 6 0 treat me nt peri o d ( R T A 4 0 8 + i pili m u ma b patie nts) 
•  c o m plete d t he Wee k 6 1 treat me nt peri o d ( R T A 4 0 8 + ni v ol u ma b patie nts) 
•  per ma ne ntl y disc o nti n ue d fr o m t he st u d y 
•  c o m plete d t he st u d y 
T he dis p ositi o n s u m mar y will als o i ncl u de t he pri mar y reas o n f or wit h dra wal fr o m t he st u d y.  
Patie nts w h o recei v e d st u d y dr u g f or e ntire st u die d peri o d are defi ne d as t h ose w h o recei ve d 
st u d y dr u g t hr o u g h Wee k 1 0 8 i n t he R T A 4 0 8 + I pili m u ma b c o h orts or recei ve d st u d y dr u g 
t hr o u g h Wee k 1 0 9 i n t he R T A 4 0 8 + Ni v ol u ma b c o h orts.  A listi n g of dis p ositi o n will be 
pr o vi de d f or all e nr olle d patie nts.   
 


Reata P har mace uticals, I nc.  
 
P hase 1 b P orti o n of 4 0 8- C- 1 4 0 1 
Statistical A nal ysis Pla n Versi o n 1  
 
O C T 2 5, 2 0 1 9 
 
Pa g e 2 9  of 4 2   
 
R e at a C o nfi d e nti al  
9. 2.  
Pr ot oc ol De vi ati o ns  
W here a vaila ble, pr ot oc ol de viati o ns i n t he Safet y A nal ysis Set will be liste d b y de viati o n 
cate g or y (e. g., eli gi bilit y criteria, o ut of wi n d o w visit, seri o us a d verse e ve nt ( S A E) re p orti n g, 
st u d y pr oce d ur es, treat m e nt pr oce d ures).  All de vi ati o ns, i ncl u di n g maj or pr ot oc ol de viati o ns t hat 
c o ul d p ote ntiall y affect t he effi cac y or safet y c o n cl usi o ns of t he st u d y, will be i de ntifie d pri or t o 
data base l oc k.  Pr ot o c o l de viati o ns will be liste d i n a data listi n g a n d s u m marize d b y de vi ati o n 
cate g or y.   
9. 3.  
De m o gr a p hics a n d B aseli ne C h ar acteristics  
De m o gra p hics a n d baseli ne c har acteristics will be s u m marize d f or t h e S afet y A nal ysis S et.  
De m o gra p hic c har acteristics will i ncl u de a ge, ge n der, race, a n d et h nicit y.  T he baseli ne 
c haracteristics i ncl u de: b aseli ne wei g ht, hei g ht, a n d b o d y mass i n de x ( B MI), i N O S stai ni n g ( %); 
E C O G perf or ma nce stat us, Mela n o ma relat e d i nf or mati o n — mela n o ma hist or y, c urre nt dis ease 
sta ge, a n d pri or c hec k p oi nt i n hi bit or t hera p y use. De m o gra p hics a n d Baseli ne C haract eristics 
will be liste d.  
9. 4.  
Me dic al Hist or y  
Me dical hist or y will be ma p pe d t o pref erre d ter ms ( P T) a n d s yste m or ga n classes ( S O C) usi n g 
t he Me dical Dicti o nar y f or Re g ulat or y Acti vities ( Me d D R A ®) Dicti o nar y ( versi o n 1 4. 1).  
Me dical hist or y ite ms will be s u m marize d b y Me d D R A S O C a n d P T a n d patie nt listi n g will be 
pr o vi de d f or t he Safet y A nal ysis Set.   


Reata P har mace uticals, I nc.  
 
P hase 1 b P orti o n of 4 0 8- C- 1 4 0 1 
Statistical A nal ysis Pla n Versi o n 1  
 
O C T 2 5, 2 0 1 9 
 
Pa g e 3 0  of 4 2   
 
R e at a C o nfi d e nti al  
1 0.  
S T U D Y D R U G A N D O T H E R M E DI C A TI O N S  
1 0. 1.  
Pri or a n d C o nc o mit a nt Me dic ati o ns  
Pri or a n d c o nc o mita nt m e dicati o n ver b ati m ter ms o n e C R Fs will be ma p pe d t o 
A nat o mical/ T hera pe utic/ C he mical ( A T C) class a n d preferre d n a mes usi n g t he W orl d Healt h 
Or ga nizati o n Dr u g Dicti o nar y ( W H O D D) E n ha n ce d versi o n, Se pte m b er 2 0 1 1, B 2 f or mat. 
A pri or me dicati o n is a n y me dicati o n t hat is ta ke n a n d st o p pe d pri or t o t he first d ose of st u d y 
dr u g.  Me dicati o ns t hat are st o p pe d o n t he dat e of first st u d y dr u g a d mi nistrati o n are pri or 
me dicati o ns.  A c o nc o mita nt me dicati o n is a n y me dicati o n ta ke n at t he ti m e of first st u d y 
treat me nt or a me dicati o n t hat was starte d after t h e start of st u d y dr u g d osi n g.  S pecificall y, 
c o nc o mita nt me dicati o ns are me dicati o ns t hat are c o nti n ue d fr o m scree ni n g a n d c o nti n ue d aft er 
t he first st u d y dr u g d osi n g, or t hat ha ve start d ates or st o p dates wit hi n t he treat me nt peri o d.  
Pri or a n d c o nc o mita nt m e dicati o ns will be s u m marize d f or eac h treat me nt gr o u p b y W H O D D 
A T C class a n d pr eferre d na me.  T hese s u m maries will prese nt t he n u m ber a n d perce nt a ge of 
patie nts usi n g eac h me di cati o n.  Patie nts ma y ha v e m ore t ha n o ne m e dicati o n per A T C class a n d 
preferre d n a me.  At eac h le vel of patie nt s u m marizati o n, a patie nt is c o u nte d o nce if he/s he 
re p orte d o n e or m ore m e dicati o ns at t hat le vel.  E ac h s u m mar y will be or d ere d b y des ce n di n g 
or der of i nci d e nce of A T C class a n d preferre d na me wit hi n eac h A T C cl ass.  
I n a d diti o n, patie nts w h o ta ke e xcl u d e d me dicati o ns ( defi ne d i n t he Pr ot oc ol Secti o n 9. 2. 1 ) 
d uri n g t he st u d y will be liste d. 
1 0. 2.  
D ur ati o n of St u d y Tre at me nt a n d E x p os ure t o St u d y Dr u g  
T he d urati o n of st u d y dr u g e x p os ure is defi n e d as t he n u m ber of d a ys o n treat me nt fr o m t he first 
d ose of st u d y dr u g u ntil t he last d ose of st u d y dr u g (last d ose – first d ose + 1).  St u d y dr u g 
e x p os ure will be s u m marize d b y descri pti ve statistics.  S u m maries will i ncl u de t he n u m ber of 
d oses recei ve d ( or dis pe nse d), t otal d ose ( m g) recei ve d ( or dis pe nse d), a vera ge dail y d ose ( m g), 
st u d y dr u g c o m plia nce, a n d d urati o n ( da ys) of e x p os ure d uri n g t he st u d y treat me nt peri o d.   
T otal n u m ber of d oses dis pe nse d a n d t otal d ose ( m g) dis pe nse d will be cal c ulate d fr o m t otal 
n u m ber of kits ( b ottles) r ec or de d o n t h e St u d y Dr u g Dis pe nsati o n e C R F.   
T he Safet y A n al ysis Set is use d t o s u m marize t he d urati o n of st u d y treat me nt a n d e x p os ure t o 
st u d y dr u g. 
Patie nts will ret ur n all u n use d pills at ea c 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 nc o m plia nt wit h d osi n g.  Patie nts will n ot 
be disc 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 d e d f or d osi n g n o n c o m plia nce. 
All st u d y dr u g dis pe nse, a n d acc o u nta bilit y data will be liste d i n patie nt listi n g.  


Reata P har mace uticals, I nc.  
 
P hase 1 b P orti o n of 4 0 8- C- 1 4 0 1 
Statistical A nal ysis Pla n Versi o n 1  
 
O C T 2 5, 2 0 1 9 
 
Pa g e 3 1  of 4 2   
 
R e at a C o nfi d e nti al  
1 0. 3.  
C o m bi n ati o n T her a p y E x p os ure  
Patie nts e nr olle d i n t he st u d y will a d mi nister R T A 4 0 8 i n c o m bi nati o n wit h eit her i pili m u ma b 
(I pi) or ni v ol u ma b ( Ni v o), acc or di n g t o t he pac k a ge i nsert (I pi x 4 d oses or Ni v o q 2 wee ks (a n d 
2 4 0 m g after 2 0 1 7)): 
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 
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 
T he d urati o n of c o m bi nati o n t hera p y e x p os ure is defi ne d as t he n u m b er of d a ys fr o m t he first 
a d mi nistrati o n u ntil t he last a d mi nistrati o n (last a d mi nistrati o n – first a d mi nistrati o n + 1).  
C o m bi nati o n t hera p y e x p os ure will be s u m marize d b y descri pti ve stat istics.  S u m maries will 
i ncl u de t he n u m ber of d oses a d mi nistere d d ose ( m g).   
T he pac k a ge i nsert f or I pi i n dicates f o ur d oses s h o ul d be a d mi nistere d.  F or patie nts recei vi n g 
I pi, t he pr o p orti o n of pati e nts recei vi n g all f o ur of t he e x pect e d d oses will be su m marize d.   
T he pac k a ge i nsert f or Ni v o i n dicates d oses s h o ul d be a d mi nistere d e v er y t w o wee ks, u nless a 
dela y is necess ar y ( e. g., s ki n relate d A E, i m m u ne relate d A E, la b a b n or malit y).  F or patie nts 
recei vi n g Ni v o, t he pr o p orti o n of patie nts wit h a dela yed treat me nt will be ta b ulate d.  
All c o m bi nati o n t hera p y a d mi nistrati o n data will be liste d i n patie nt listi n g.  


Reata P har mace uticals, I nc.  
 
P hase 1 b P orti o n of 4 0 8- C- 1 4 0 1 
Statistical A nal ysis Pla n Versi o n 1  
 
O C T 2 5, 2 0 1 9 
 
Pa g e 3 2  of 4 2   
 
R e at a C o nfi d e nti al  
1 1.  
E F FI C A C Y A N A L Y S E S  
1 1. 1.  
Pri m ar y Effic ac y A n al ysis  
Wit h o nl y 3 t o 6 patie nts per d ose, t he P has e 1 b p orti o n of t he st u d y is n ot p o were d f or efficac y.  
T h e p hase 1 b p orti o n of t he st u d y is i nte n de d t o i de ntif y a n o pti mal d ose f or p hase 2.  C o m plete 
a n d partial t u m or res p o ns es will be e val uate d b y ra di o gra p hic assess me nt usi n g t he sta n dar dize d 
res p o nse criteria de v el o p e d b y t he R E CI S T ( Res p o nse E val uati o n Criteria I n S oli d T u m o urs ) 
W or ki n g Gr o u p, versi o n 1. 1.  O verall r es p o nse rate ( O R R), defi n e d i n Secti o n 5. 1. 3 , as well as 
t he n u m ber a n d pr o p orti o n of partial a n d c o m plete res p o nses, will be s u m marize d d escri pti vel y 
wit hi n eac h d ose a n d o v erall.  O R R will be s u m marize d as c o nfir m e d, u nc o nfir me d, a n d 
c o nfir me d + u n c o nfir me d.  S u m maries of O R R, C R a n d P R will be ta b ulate d b y d ose a n d f or all 
d oses wit hi n eac h 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).   
1 1. 1. 1.  
Re p orti n g Res ults  
Ta bles will s u m marize t h e n u m ber a n d p erce nt of patie nts wit h c o m plete res p o nse, partial 
res p o nse, a n d disease pr o gressi o n b y: 
•  O verall ( all patie nts i n e val ua ble a n al ysis set)  
•  Patie nts wit h R T A 4 0 8 + i pili m u ma b treat me nt (all R T A 4 0 8 d oses i n e val ua ble 
a nal ysis set)  
•  Patie nts wit h R T A 4 0 8 + ni v ol u ma b treat me nt (all R T A 4 0 8 d oses i n e val u a ble 
a nal ysis set)  
•  Patie nts wit h R T A 4 0 8 + i pili m u ma b treat me nt ( b y R T A 4 0 8 d ose i n e val u a ble 
a nal ysis set)  
•  Patie nts wit h R T A 4 0 8 + ni v ol u ma b treat me nt ( b y R T A 4 0 8 d ose i n e val ua ble 
a nal ysis set)  
•  B y pri or t hera p y wit hi n R T A 4 0 8 + i pili m u ma b patie nts: CI -n aï ve, CI -refract or y, P D-
1/ P D- L 1 refr act or y  i n e v al ua ble a n al ysis set 
•  B y pri or t hera p y wit hi n R T A 4 0 8 + ni v ol u ma b patie nts : CI-n aï ve, CI -refract or y, P D-
1/ P D- L 1 refr act or y  i n e v al ua ble a n al ysis set 
1 1. 2.  
A d diti o n al Effic ac y A n al yses  
1 1. 2. 1.  
Ti m e t o Res p o nse a n d D ur ati o n of Res p o nse  
A listi n g of patie nts ha vi n g re p orte d a P R d uri n g t he st u d y will be pr o vi de d w hic h i ncl u des 
patie nt I D; st u d y treat me nt a n d c o m bi nati o n t hera p y; st u d y wee k ( da y) of P R; st u d y wee k ( da y) 
of C R ; a n d d urati o n of res p o nse ( wee ks).  


Reata P har mace uticals, I nc.  
 
P hase 1 b P orti o n of 4 0 8- C- 1 4 0 1 
Statistical A nal ysis Pla n Versi o n 1  
 
O C T 2 5, 2 0 1 9 
 
Pa g e 3 3  of 4 2   
 
R e at a C o nfi d e nti al  
T he listi n g s h o ul d be s u m marize d b y: 
•  Patie nts wit h R T A 4 0 8 + i pili m u ma b treat me nt ( b y R T A 4 0 8 d ose i n e val u a ble 
a nal ysis set)  
•  Patie nts wit h R T A 4 0 8 + ni v ol u ma b treat me nt ( b y R T A 4 0 8 d ose i n e val ua ble 
a nal ysis set)  
1 1. 2. 2.  
Perce nt C h a n ge i n i N O S  
A listi n g of all patie nts will i ncl u de i N O S e x pressi o n at baseli ne, Da y 8, a n d Wee k 1 3.  T h e 
listi n g s h o ul d be ta b ulate d b y R T A 4 0 8 d ose gr o u p a n d c o h ort ( 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).  T he a nal ysis visits use d f or t he O ve rall s u m maries are baseli ne, Da y 8, a n d 
Wee k 1 3 a nal ysis visits p o ole d.  T he listi n g s h o ul d be s u m marize d b y: 
•  O verall ( all patie nts i n e val ua ble a n al ysis set)  
•  Patie nts wit h R T A 4 0 8 + i pili m u ma b treat me nt (all R T A 4 0 8 d oses i n e val ua ble 
a nal ysis set)  
•  Patie nts wit h R T A 4 0 8 + ni v ol u ma b treat me nt (all R T A 4 0 8 d oses i n e val u a ble 
a nal ysis set)  
1 1. 2. 3.  
E C O G Perf or m a nce St at us  
T he E C O G perf or ma n ce stat us will be s u m marize d usi n g descri pti ve statistics, i ncl u di n g 9 5 % CI 
f or c ha n g e fr o m b aseli ne.  T he ta bles a n d listi n gs s h o ul d be s u m marize d b y: 
•  Patie nts wit h R T A 4 0 8 + i pili m u ma b treat me nt (all R T A 4 0 8 d oses i n e val ua ble 
a nal ysis set)  
•  Patie nts wit h R T A 4 0 8 + ni v ol u ma b treat me nt (all R T A 4 0 8 d oses i n e val u a ble 
a nal ysis set)  
1 1. 3.  
Se nsiti vit y A n al yses  
T here is n o pr e- pla n ne d s e nsiti vit y a nal ysis f or t he pri mar y efficac y varia bl e f or t he P has e 1 b 
p orti o n of t he st u d y. 
1 1. 4.  
S u b gr o u ps A n al yses of Effic ac y  
T he effi cac y v aria bles will be s u m marize d usi n g descri pti ve statistics, i ncl u di n g 9 5 % CI f or 
c ha n ge fr o m baseli ne, will be re p orte d f or eac h s u b gr o u p of i nterest liste d bel o w: 
•  C hec k p oi nt i n hi bit or naï ve, pri or c h ec k p oi nt i n hi bit or treat me nt 
− A s u bject is c o nsi dere d ' CI- Nai ve' if h e or s he h as n o pri or hist or y of treat me nt 
wit h I pili m u ma b, Ni v ol u ma b, or Pe m br oliz u ma b. 


Reata P har mace uticals, I nc.  
 
P hase 1 b P orti o n of 4 0 8- C- 1 4 0 1 
Statistical A nal ysis Pla n Versi o n 1  
 
O C T 2 5, 2 0 1 9 
 
Pa g e 3 4  of 4 2   
 
R e at a C o nfi d e nti al  
− A s u bject is c o nsi de re d ' P D- 1/ P D-L 1 Refract or y' if he or s he has e ver bee n treate d 
wit h Ni v ol u ma b or Pe m br oliz u ma b. 
− A s u bject is c o nsi dere d ' CI- Refract or y' if he or s h e has e ver bee n treat e d wit h 
I pili m u ma b, Ni v ol u ma b, or Pe m br oliz u ma b. 
F or t he P hase 1 b p orti o n of t he st u d y, n o statistical testi n g will be perf or me d f or s u b gr o u ps. 


Reata P har mace uticals, I nc.  
 
P hase 1 b P orti o n of 4 0 8- C- 1 4 0 1 
Statistical A nal ysis Pla n Versi o n 1  
 
O C T 2 5, 2 0 1 9 
 
Pa g e 3 5  of 4 2   
 
R e at a C o nfi d e nti al  
1 2.  
S A F E T Y  AN A L Y S E S  
Safet y a n d t oler a bilit y are e val uat e d b y A Es, S A Es, cli nical la b orat or y test res ults, b o d y wei g ht, 
vital si g ns, 1 2-lea d E C G fi n di n gs, a n d p h ysical e x a mi nati o n.  All a nal yses of t he safet y d ata will 
be perf or me d usi n g t he s afet y a n al ysis set.  Descri pti ve s tatistics ( descri be d i n Secti o n 7 ) will be 
prese nte d b y tr eat me nt gr o u p assi g n me nt i n t he safet y a nal ysis set. 
Ta bles will s u m marize t h e safet y r es ults b y:  
•  Patie nts wit h R T A 4 0 8 + i pili m u ma b treat me nt (all R T A 4 0 8 d oses i n e val ua ble 
a nal ysis set)  
•  Patie nts  wit h R T A 4 0 8 + ni v ol u ma b treat me nt (all R T A 4 0 8 d oses i n e val u a ble 
a nal ysis set)  
•  Patie nts wit h R T A 4 0 8 + i pili m u ma b treat me nt ( b y R T A 4 0 8 d ose i n e val u a ble 
a nal ysis set)  
•  Patie nts wit h R T A 4 0 8 + ni v ol u ma b treat me nt ( b y R T A 4 0 8 d ose i n e val ua ble 
a nal ysis set) 
1 2. 1.  
A d verse E ve nts a n d Seri o us A d verse E ve nts  
All a d verse e ve nt ver b ati m ter ms o n electr o nic cas e re p ort f or ms (e C R Fs) will be ma p pe d t o 
preferre d t er ms a n d s yste m or ga n classes usi n g t he Me dical Dicti o nar y f or Re g ulat or y Acti vities 
( Me d D R A® ) Dicti o nar y ( versi o n 1 4. 1). 
1 2. 1. 1.  
Tre at m e nt E m er ge nt A d verse E ve nts  
Treat me nt - e mer ge nt A Es ( T E A Es) are defi ne d as a n y A Es, re g ar dless of relati o ns hi p t o st u d y 
dr u g, t hat ha ve a n o ns et or w orse n i n se v erit y o n or after t h e first d ose of st u d y dr u g.  Treat me nt -
e mer ge nt a d v erse e ve nts are e v e nts t hat eit her:  
•  Date of o nset o n or after t he date of first d ose a n d n ot m ore t ha n 3 0 da ys aft er t he date 
of t he last d ose of st u d y dr u g, or  
•  Ha d n o rec or de d d ate of o nset wit h a st o p date aft er t he first d ose of st u d y dr u g, or 
•  Ha d n o rec or de d d ate of o nset or st o p date 
If it ca n n ot be d eter mi ne d w het her t he A E is treat me nt-e mer g e nt d ue t o a p artial o nset date, t he n 
it will be c o u nte d as a T E A E.  A d vers e e ve nts wit h i nc o m plete start dates will be c o nsi dere d 
T E A Es, i f: 
•  O nset ti me is missi n g b ut t he o nset date is o n St u d y Da y 1 


Reata P har mace uticals, I nc.  
 
P hase 1 b P orti o n of 4 0 8- C- 1 4 0 1 
Statistical A nal ysis Pla n Versi o n 1  
 
O C T 2 5, 2 0 1 9 
 
Pa g e 3 6  of 4 2   
 
R e at a C o nfi d e nti al  
•  Da y a n d m o nt h ar e missi n g a n d t he year is e q ual t o or after t h e year of t he first date 
of st u d y dr u g d osi n g 
•  Da y is missi n g a n d t he year is aft er t he y ear of t he first date of st u d y dr u g d osi n g  
•  Da y is missi n g a n d t he year is e q u al t o t he year of t he first date of st u d y dr u g d osi n g 
a n d t he m o nt h is e q ual t o or after t h e m o nt h of t he first date of st u d y dr u g d osi n g; or 
•  Year is missi n g  
Relate d A Es ar e t h ose wit h relati o ns hi p t o st u d y dr u g re p orte d as “ p ossi bl y relate d”, “ pr o b a bl y 
relate d”, or “ d efi nitel y relate d”.  If s e verit y (relati o ns hi p) of a n A E t o st u d y dr u g is n ot rec or d e d, 
t he se verit y (r elati o ns hi p) will be i m p ute d as ‘se v ere’ (‘ defi nitel y relate d’). 
All re p orte d A Es (i ncl u di n g n o n- T E A Es), S A E, a n d deat hs will be liste d i n se parat e patie nt 
listi n gs. 
1 2. 1. 2.  
S u m m ar y of Tre at m e nt -E mer ge nt A d verse E ve nts a n d Seri o us A d verse E ve nts  
All T E A E s u m mar y ta bles will i ncl u de t he n u m ber a n d perce nta ges of p atie nts re p orti n g T E A Es.  
A s u m mar y of T E A Es b y se verit y, seri o us ness, a n d relati o n t o st u d y dr u g will be ta b ulate d.  I n 
a d diti o n, T E A Es will be s u m marize d b y Me d D R A s yste m or ga n class a n d preferre d t er m.  
Patie nts ca n ha ve m or e t ha n o ne T E A E p er s yste m or ga n class a n d preferre d ter m.  T hese 
s u m maries will i nclu de t he f oll o wi n g: 
•  All T E A Es  
•  T E A Es b y w orst se verit y 
•  Relate d T E A Es  
•  T E A Es lea di n g t o st u d y dr u g i nterr u pti o n (if a n y) 
•  T E A Es lea di n g t o st u d y dr u g disc o nti n uati o n (if a n y) 
•  All treat me nt -e mer ge nt S A Es  
•  Treat me nt - e mer ge nt S A Es b y w orst se verit y 
•  Relate d treat me n t-e mer g e nt S A Es  
At eac h le v el of patie nt s u m marizati o n, a patie nt is c o u nte d o nce if h e/s he re p orte d o ne or m ore 
T E A E at t hat le vel.  If a patie nt re p orte d t h e sa me T E A E o n m ulti ple occasi o ns, t he hi g hest 
se verit y (se v ere > m o der ate > mil d) or st u d y dr u g relati o ns hi p (relat e d > pr o ba ble > p ossi ble > 
u nli kel y > u nrelate d) rec or de d f or t he e ve nt will b e s u m marize d.  E ac h s u m mar y will be or dere d 
b y desce n di n g or d er of i n ci de nce of s yste m or ga n class a n d preferre d ter m wit hi n eac h s yste m 
or ga n class.  


Reata P har mace uticals, I nc.  
 
P hase 1 b P orti o n of 4 0 8- C- 1 4 0 1 
Statistical A nal ysis Pla n Versi o n 1  
 
O C T 2 5, 2 0 1 9 
 
Pa g e 3 7  of 4 2   
 
R e at a C o nfi d e nti al  
T E A E list i n gs s h o ul d be s u m marize d b y: 
•  Safet y a nal ysis set  
•  Patie nts treate d wit h R T A 4 0 8 + i pil im u ma b i n safet y a n al ysis set (all d oses)  
•  Patie nts treate d wit h R T A 4 0 8 + ni v ol u ma b i n safet y a nal ysis set (all d oses) 
1 2. 1. 3.  
D ose -Li miti n g T o xicities  
A listi n g of p ote ntial d ose- li miti n g t o xicities ( D L Ts) will dis pla y all e ve nts meeti n g t he 
f oll o wi n g pr ot oc ol-defi n e d D L T criteria:  
T he deter mi nati o n of D L T will be defi ne d i n eac h patie nt as all t o xicit y Gra de ≥3 ( usi n g 
C o m m o n Ter mi n ol o g y Criteria f or A d vers e E ve nts [ 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 bel o w: 
•  Na usea a n d v o miti n g will be c o nsi dere d a D L T if t he a d vers e e ve nts are se vere or s eri o us 
a n d t he d urati o n is greater t ha n 4 8 h o urs 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 a n d 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 after o pti mal me dical t hera p y 
•  A n y he pat o biliar y dis 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 der e 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 le vels m ust meet 1 of t he f oll o wi n g criteria t o 
be c o nsi der e 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 m alize 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 dr a nt pai n or te n der ness, fe 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 pr ot oc ol Secti o n 9. 1. 2. 1  or pr ot oc ol 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 relate d t o R T A 4 0 8 treat me nt or a n y 
t o xicit y liste d i n 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 ni v ol u ma b 
disc o nti n uati o n t hat is c o nsi dere d rel ate d t o R T A 4 0 8 treat me nt will be c o nsi dere d a D L T 
T he fi nal deter mi nati o n of a D L T is bas e d o n t he e ve nt ti mi n g.  Beca use t he ti me c o urse of a n y 
p ote ntial R T A  4 0 8 D L Ts are e x p ect e d t o o cc 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 w ee 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 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.  T heref ore, 
i n a d diti o n t o e ve nt i nf or mati o n, t he D L T listi n g will als o i ncl u de e ve nt start wee k. 


Reata P har mace uticals, I nc.  
 
P hase 1 b P orti o n of 4 0 8- C- 1 4 0 1 
Statistical A nal ysis Pla n Versi o n 1  
 
O C T 2 5, 2 0 1 9 
 
Pa g e 3 8  of 4 2   
 
R e at a C o nfi d e nti al  
1 2. 2.  
Cli nic al L a b or at or y E v al u ati o n  
Cli nical la b orat or y tests are s pecifie d i n t he pr ot o c ol: cli nical c he mistr y  i n Secti o n 9. 9. 2 1, 
he mat ol o g y  i n Secti o n 9. 9. 2 2, c oa g ulati o n  i n Secti o n 9. 9. 2 3, vir us ser ol o g y  i n Secti o n 9. 9. 2 3, 
a n d uri nal ysis  i n Secti o n 9. 9. 2 8.  Sa m ples will be a nal yze d at t he l ocal la b orat or y a n d rec or de d 
i n t he e C R F usi n g l ocal r a n ges a n d u nits.   La b orat or y res ults t hat are a b o v e or bel o w n or m al 
li mits will be fla g ge d i n t he listi n gs.  All la b orat or y res ults (i ncl u di n g pre g na nc y test res ults) will 
be prese nt e d i n data listi n gs, b ut descri pti ve s u m maries will be li mite d t o cli nical c he mistr y a n d  
he mat ol o g y res ults.  L ocal la b data will be c o n v erte d t o sta n dar d u nits f or a nal ysis.  Cli nical 
c he mistr y, he mat ol o g y, a n d uri nal ysis data m ust be c o n vert e d t o I nter n ati o nal S yste m of U nits 
( SI u nits) bef ore a n y a n al yses are p erf or me d.  T he sta n dar dize d v al ues will be s u m marize d usi n g 
descri pti ve statistics at eac h sc he d ule d ti me p oi nt.  P ost - baseli ne la b orat or y assess me nts missi n g 
or bel o w t he l o wer li mit of detecti o n ( L L D) will be i m p ute d usi n g t he L L D val ues mi n us o ne 
or der of ma g nit u de i n t he first t w o deci mal places .  F or i nsta nce, a L L D v al ue of 2 0 are i m p ute d  
as 1 9. 9 0 a n d a L L D val u e < 1 is i m p ute d as 0. 9 9.  C ha n ges fr o m bas eli ne will als o be 
s u m marize d b y ti me p oi nt. 
Listi n gs f or la b orat or y para meters of i nterest i ncl u de t he f oll o wi n g ite ms:  
•  Ala ni ne tra nsa mi nas e ( A L T)  
•  As partate tr a nsa mi nase ( A S T)  
•  Al kali ne p h os p hatase 
•  Ferriti n  
•  Ga m ma -gl uta m yl tra nsf erase ( G G T)  
•  T otal bilir u bi n  
Listi n gs f or la b orat or y para meters of i nterest will be s u m marize d b y:  
•  Patie nts wit h R T A 4 0 8 + i pili m u ma b treat me nt ( b y R T A 4 0 8 d ose i n safet y a nal ysis 
set) 
•  Patie nts wit h R T A 4 0 8 + ni v ol u ma b treat me nt ( b y R T A 4 0 8 d ose i n safet y a nal ysis 
set) 
I n a d diti o n, a s u m mar y ta ble will be pr o vi de d f or n u m ber a n d perce nt a ge of patie nts meeti n g t he 
f oll o wi n g pre-s pecifie d t hres h ol d le vel at a n y ti m e d uri n g t he st u d y. 
T a ble 6: 
Pre -S pecifie d T hres h ol d Le vels f or L a b or at or y P ar a meters  
L a b P ar a meter 
Pre -S pecifie d Le vel  
B N P  
> 2 0 0 p g/ m L 
A L T, A S T  
> 3 × u p per li mit of n or mal ( U L N)  


Reata P har mace uticals, I nc.  
 
P hase 1 b P orti o n of 4 0 8- C- 1 4 0 1 
Statistical A nal ysis Pla n Versi o n 1  
 
O C T 2 5, 2 0 1 9 
 
Pa g e 3 9  of 4 2   
 
R e at a C o nfi d e nti al  
L a b P ar a meter 
Pre -S pecifie d Le vel  
A L T, A S T  
> 8 × U L N  
A L T, A S T  
> 5 × U L N f or m ore t ha n 2 wee ks 
A L T, A S T, T B L, I N R  
> 3 × U L N a n d ( T B L > 2 × U L N or I N R > 1. 5 × U L N) 
 
Cate g orical la b or at or y s u m maries usi n g U L N t hres h ol ds i n Ta ble 6 will use t he f oll o wi n g li mits:  
T a ble 7: 
Pre -S pecifie d U p per Li mit of N or m al ( U L N) Le vels f or L a b or at o r y 
P ar a m eters  
L a b P ar a meter 
Se x  
A ge  
U L N  
A L T  
Fe male  
All  
3 4 U/ L 
Male  
All  
4 3 U/ L 
A S T  
Fe male  
< 1 8 
4 0 U/ L 
≥ 1 8  
3 4 U/ L 
Male  
< 1 8 
4 0 U/ L 
≥ 1 8  
3 6 U/ L 
T B L  
 
 
Ce ntral la b U L N  
I N R 
 
 
Ce ntral la b U L N  
 
Uri nal ysis res ults ( ot her t ha n p H a n d s pecific gra vit y) of ket o nes, pr otei n, bl o o d, gl uc ose, clarit y, 
c ol or, le u k oc ytes, nitrite, bilir u bi n, a n d micr osc o pic e xa mi nati o ns (if i n dicat e d base d o n 
la b orat or y r es ults), uri ne micr osc o pic fi n di n gs, a n d pre g na nc y t est res ults will n ot be 
s u m marize d.   
La b orat or y res ults t hat ar e a b o ve or b el o w n or mal li mits will be fla g ge d i n t he listi n gs.   
1 2. 3.  
Vit al Si g ns  
Descri pti ve statistics f or bl o o d press ure, heart rate, a n d te m perat ure i ncl u di n g baseli ne val ues 
a n d c ha n g e fr o m bas eli ne val ues, will be s u m marize d b y ti me p oi nt.  All vital si g ns para meters 
will be liste d.   
1 2. 4.  
B o d y Wei g ht  
Descri pti ve statistics f or b o d y wei g ht t hat are c ollecte d o n t he e C R F a n d c ha n ge fr o m b aseli ne 
val ues will be s u m marize d a n d liste d b y ti me p oi nt.  I n a d diti o n, n u m ber a n d perce nt a ge of 
patie nts w h o e x peri e nce a fi ve p o u n d ( 2. 3 k g) or greater i ncrease i n w ei g ht vers us baseli ne will 
be s u m marize d b y ti me p oi nt.  


Reata P har mace uticals, I nc.  
 
P hase 1 b P orti o n of 4 0 8- C- 1 4 0 1 
Statistical A nal ysis Pla n Versi o n 1  
 
O C T 2 5, 2 0 1 9 
 
Pa g e 4 0  of 4 2   
 
R e at a C o nfi d e nti al  
1 2. 5.  
1 2 -le a d E C G 
Electr ocar di o gra m ( E C G) data, s uc h as cli nical i nter pret ati o n of E C Gs, ve ntric ular rat e a n d 
i nter val assess me nts of P R, Q R S, a n d Q T, will be c ollecte d o n t he e C R F.  Q T will be c orrecte d 
t o Q Tc F as descri b e d i n Secti o n 7. 4. 1 . Q Tc F will be i ncl u de d i n data s u m maries, w hile Q T will 
o nl y be liste d.  Descri pti ve statistics f or o bser ve d val ues a n d c h a n ge fr o m baseli ne at eac h ti me 
p oi nt will be prese nte d f or t hese 1 2-lea d E C G i nter val assess me nts.  I n a d diti o n, n u m ber a n d 
perce nt a g e of p atie nts wit h a n y a b n or mal val ues (i.e., a b o ve a pre-s pecifi e d t hres h ol d) will be 
s u m marize d b y ti me p oi nt a n d o verall w hile o n st u d y dr u g.  T he pre-s pecifie d le vels of E C G 
Q Tc t hres h ol ds are c o nsiste nt wit h F D A g ui da nce ( See Ta ble 8 b el o w).   
T a ble 8: 
Pre -S pecifie d T hres h ol d Le vels f or E C G P ar a meters  
E C G P ar a meter  
Pre -S pecifie d  Le vel  
P R  
> 2 0 0 msec  
Q Tc F  
> 4 5 0, > 4 8 0 or > 5 0 0 msec, > 3 0 or > 6 0 msec i ncrease fr o m baseli ne 
Heart Rate  
< 4 0, > 1 0 0 beats/ mi n 
 
All E C G para meters will be liste d.  A n y res ults t hat e xcee d t h e a b o ve le v els ( pr o vi de d i n t he 
a b o ve ta ble) will be fla g g e d i n t he listi n g.  
1 2. 6.  
P h ysic al E x a mi n ati o n  
A b n or mal cli nicall y si g nifica nt fi n di n gs will be re p orte d as Me dical Hist or y or A d vers e E ve nts 
de pe n di n g o n da y of o ns et.  A b n or mal n o n- cli nicall y si g nifica nt fi n di n gs fr o m p h ysical 
e xa mi nati o ns will be liste d.  
 


Reata P har mace uticals, I nc.  
 
P hase 1 b P orti o n of 4 0 8- C- 1 4 0 1 
Statistical A nal ysis Pla n Versi o n 1  
 
O C T 2 5, 2 0 1 9 
 
Pa g e 4 1  of 4 2   
 
R e at a C o nfi d e nti al  
1 3.  
P H A R M A C O KI N E TI C S A N A L Y SI S  
Bl o o d sa m ples f or deter mi nati o n of plas ma R T A 4 0 8 a n d p ote ntial meta b olite c o nce ntrati o ns 
will be dra w n as s h o w n i n Ta ble  3.  T he P K pr ofile of R T A 4 0 8 will be e val uate d fr o m plas ma 
c o nce ntr ati o n data fr o m i n di vi d ual patie nts.   


Reata P har mace uticals, I nc.  
 
P hase 1 b P orti o n of 4 0 8- C- 1 4 0 1 
Statistical A nal ysis Pla n Versi o n 1  
 
O C T 2 5, 2 0 1 9 
 
Pa g e 4 2  of 4 2   
 
R e at a C o nfi d e nti al  
1 4.  
D E VI A TI O N F R O M T H E P R O T O C O L S P E CI FI E D A N A L Y SI S  
Pr o gressi o n free s ur vi val ( P F S) is liste d i n t he pr ot oc ol as w o ul d be assess e d, h o we ver, t his 
e n d p oi nt will n ot be calc ulate d or a nal y ze d f or t he p hase 1 b p orti o n of t he st u d y.