A Randomized, Open-Label Study of Combinations of Standard and High Dose REGN2810 (Cemiplimab; Anti-PD-1 Antibody) and Ipilimumab (Anti-CTLA-4 Antibody) in the Second-Line Treatment of Patients With Advanced Non-Small Cell Lung Cancer
Phase: PHASE2
Conditions: Advanced Non-Small Cell Lung Carcinoma
Sponsor: Regeneron Pharmaceuticals



Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 2  of 1 2 9  
C O N FI D E N TI A L  
A M E N D M E N T HI S T O R Y  
A me n d me nt 2 Gl o b al  
T his gl o bal versi o n of t he pr ot oc ol i nc or p orates all of t he c ha n ges i m ple me nte d i n a me n d me nt 1  
V H P , w hic h was s u b mitte d o nl y t o V H P me m bers a n d was pri maril y de vel o pe d t o a d dress 
se parat e V H P re q uests.  T he f oll o wi n g ta ble o utli nes o nl y t he a d diti o nal c ha n ges ma de t o t he 
pr ot oc ol  after a me n d me nt 1 V H P was ma de .  T his gl o bal versi o n re places all pre vi o us versi o ns .  
C h a n ges  
Secti o ns C h a n ge d  
C ha n ge d t he st u d y p o p ulati o n e nr oll me nt 
criteria fr o m 
N S C L C patie nts wit h P D -L 1 e x pressi o n i n < 5 0 % of t u m or 
cells t o  i ncl u de t h ose wit h P D-L 1 e x pressi o n i n ≥5 0 % of 
t u m or cells.   
Rece nt data fr o m cli nical st u dies wit h ce mi pli ma b s h o w t hat 
ce mi pli ma b has p ote nt a nti -t u m or acti vit y a n d a n acce pta ble 
safet y pr ofile.  T hese i ncl u de  data fr o m a n N S C L C e x pa nsi o n 
c o h ort i n t he FI H st u d y (R 2 8 1 0 -O N C -1 4 2 3 ) i n w hic h s o me 
patie nts w h o were refract or y t o , or rela pse d after, at least 
first-li ne t hera p y i n t he rec urrent or metastatic disease setti n g 
ha d partial res p o nse or sta ble disease ( O R R was 2 8 % ( 6/ 2 1), 
per i n de pe n de nt ce ntral re vie w) .   
T he 
efficac y 
of a nti -P D -1/ P D -L 1 
bl oc ka de 
has 
bee n 
esta blis he d as sec o n d -li ne treat me nt i n patie nts wit h P D-L 1 
e x pressi o n i n ≥5 0 % of t u m or cells.  T o deter mi ne if 
ce mi pli ma b s h o ws si milar effic ac y t o ot her a nti -P D -1/ P D -L 1 
a ge nts i n t his patie nt p o p ulati o n, t his e nr oll me nt criteria  will 
be m o difie d t o i ncl u de  P D -L 1 e x pressi o n i n ≥5 0 % of t u m or 
cells, i n a d diti o n t o t h ose wit h P D-L 1  e x pressi o n i n < 5 0 % of 
t u m or cells. 
T he pri or versi o n of t his pr ot oc ol e xcl u de d patie nts w h ose 
t u m ors e x press P D-L 1 i n ≥5 0 % of t u m or cells .  T hese 
patie nts are n o w all o we d i nt o t he st u d y as well, as t he y ma y 
ac hie ve e ve n greater be nefit fr o m hi g her d ose or c o m bi nati o n 
t hera p y, wit h a n e x pl orat or y a nal ysis t o assess t he de gree of 
i m pr o ve me nt i n t heir res p o nse. 
Delete d refere nce t o ‘ T u m ors E x pressi n g P D-L 1 < 5 0 %’ i n 
t he title of t he pr ot oc ol a n d i n ot her areas t hr o u g h o ut t he 
pr ot oc ol .   
E x pa n de d t he patie nt p o p ulati o n i n t he sec o n dar y o bjecti ves 
a n d sec o n dar y e n d p oi nts t o i ncl u de all patie nts rat her t ha n 
j ust t h ose wit h P D-L 1 e x pressi o n i n < 5 0 % of t u m or cells.   
A d de d rati o nale f or a d diti o n 
of t he 
N S C L C 
patie nt 
p o p ulati o n wit h ≥5 0 % P D -L 1 e x pressi o n i n t u m or cells . 
Title pa ge  
Cli nical St u d y Pr ot oc ol S y n o psis : Title, 
O bjecti ves , P o p ulati o n  a n d E n d p oi nts  
Secti o n  1. 2   Ce mi pli ma b  
Secti o n  2. 2. 1   Sec o n dar y O bj ecti ves  
Secti o n  3. 2. 1   Rati o nale f or St u d y Desi g n  
Secti o n  3. 2. 3   Rati o nale f or C h oice of 
Patie nt P o p ulati o n   
Secti o n  4. 2. 2   Sec o n dar y E n d p oi nts  
Sect i o n 5. 1   St u d y Descri pti o n a n d 
D urati o n  
Secti o n  6. 2   St u d y P o p ulati o n  
Secti o n  6. 2. 1   I ncl usi o n Criteria # 4   
Secti o n  2 3   I n vesti gat or’s A gree me nt 
Si g nat ure of S p o ns or’s Res p o nsi ble 
Officers  
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 3  of 1 2 9  
C O N FI D E N TI A L  
C h a n ges  
Secti o ns C h a n ge d  
U p date d t he pla n ne d patie nt e nr oll me nt n u m ber fr o m 
a p pr o xi matel y 2 0 1 t o a p pr o xi matel y 2 5 2.  
Cli nical St u d y Pr ot oc ol S y n o psis : 
P o p ulati o n  a n d Statistical Pla n  
Fi g ure  1   St u d y Fl o w Dia gra m  
Secti o n  6. 1   N u m ber of Patie nts Pla n ne d  
Secti o n  6. 2   St u d y P o p ulati o n  
Secti o n  1 0. 2   J ustificati o n of Sa m ple 
Size  
S pecifie d  t hat ser u m sa m ples c ollecte d f or ce mi pli ma b A D A 
assess me nt ma y be use d f or e val uati o n of i pili m u ma b A D A, 
if i n t he f ut ure it bec o mes necessar y t o e val uate i pili m u ma b 
A D A .  T his c ha n ge was i n res p o nse t o a n F D A re q uest .   
Secti o n  8. 2. 4. 2   A nti -Dr u g A nti b o d y 
Meas ure me nts a n d Sa m ples  
Secti o n  1 0. 4. 9   A nal ysis of A nti -Dr u g 
A nti b o d y Data  
A d de d i ncl usi o n of N S C L C patie nts wit h sta ge IIIc disease  
Secti o n  6. 2. 1   I ncl usi o n Criteria # 2   
Re m o ve d fr o m I ncl usi o n Criteria patie nts wit h ‘a ntici pate d 
life e x pecta nc y of at least 3 m o nt hs’ 
Secti o n  6. 2. 1  I ncl usi o n Criteria # 7 
( delete d) 
M o difie d e xcl usi o n criteria t o be defi ne d as occ urri n g ‘ pri or 
t o ra n d o mizati o n’ rat her t ha n ‘ pri or t o i nf or me d c o nse nt,’ 
‘ pri or t o e nr oll me nt,’ or pri or t o st u d y e ntr y.’ 
Secti o n  6. 2. 2   E xcl usi o n Criteria # 2   
Secti o n  6. 2. 2   E xcl usi o n Criteria # 4   
Secti o n  6. 2. 2   E xcl usi o n Criteria # 5   
Secti o n  6. 2. 2   E xcl usi o n Criteria # 1 0   
Secti o n  6. 2. 2   E xcl usi o n Criteria # 1 4   
(f or merl y # 1 3) 
Secti o n  6. 2. 2   E xcl usi o n Criteria # 1 5  
(f or merl y # 1 4) 
Secti o n  6. 2. 2   E xcl usi o n Criteria # 1 6   
(f or merl y # 1 5) 
A d de d a n e xcl usi o n criteri o n t o pr o hi bit 
enr oll me nt of 
patie nts wit h ‘ pri or treat me nt wit h a n a nti -C T L A -4 a nti b o d y 
or a nti -P D˗ 1/ P D˗ L 1 f or a d va nce d disease.’  
Secti o n  6. 2. 2   E xcl usi o n Criteria  # 9   
S pecifie d t hat patie nts w h o c o nti n ue treat me nt be y o n d t he 
i nitial deter mi nati o n of pr o gressi ve disease w o ul d be re q uire d 
t o re-c o nse nt usi n g a se parate I C F  
Secti o n  7. 8   Disease Pr o gressi o n W hile 
Recei vi n g Ce mi pli ma b  
C ha n ge d 
a n d 
u p date d  
stratificati o n 
of 
patie nts 
at 
ra n d o mizati o n b y P D-L 1 e x pressi o n i n t u m or cells fr o m 
‘ < 1 % vers us 1 % t o < 5 0 %’ t o ‘< 1 % vers us 1 % t o 4 9 % vers us 
≥5 0 % ’ f or c o nsiste nc y 
wit h t he c ha n ge i n t he patie nt 
p o p ulati o n t o i ncl u de all patie nts  
Cli nical St u d y Pr ot oc ol S y n o psis : St u d y 
Desi g n  
Secti o n  5. 1. 2   Treat me nt Peri o d  
Secti o n  7. 5   Met h o d of Treat me nt 
Assi g n me nt  
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Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 4  of 1 2 9  
C O N FI D E N TI A L  
C h a n ges  
Secti o ns C h a n ge d  
Re vise d te xt t o reflect t hat, at scree ni n g, tests of E G F R , A L K , 
a n d R O S-1  m utati o ns i n t u m or tiss ues will be perf or me d 
ce ntrall y f or all patie nts re gar dless of w het her patie nts ha d 
pri or test res ults.   
Secti o n  5. 1. 1   Scre e ni n g 
Secti o n  8. 2. 1   Pr oce d ures Perf or me d 
O nl y at t he Scree ni n g/ Baseli ne Visit  
Secti o n  8. 2. 5   Bi o mar ker Pr oce d ures  
T a ble  3   Sc he d ule of E ve nts:  Scree ni n g 
Visit Assess me nts a n d Pr oce d ures  
Re vise d sa m pli n g ti mes f or P K a n d 
A D A a nal yses t o 
mai ntai n c o nsiste nc y 
wit h t he u p date d o pti mal P D/ A D A 
sa m pli n g ti me p oi nts for st u dies i n N S C L C patie nts . 
Deleti o ns:  
 
C ycle 5, da y 1 - all ser u m/ plas ma sa m ples  
 
C ycle 6, da y 1 -all ser u m/ plas ma sa m ples  
 
C ycle 9, da y 1 - P K e n d -of -i nf usi o n o nl y 
 
C ycle 1 2, da y 1 - all ser u m/ plas ma sa m ples  
 
C ycle 1 5, da y 1 - all ser u m/ plas ma sa m ples  
 
C ycle 1 8, da y 1 - P K e n d -of -i nf usi o n o nl y  
 
C ycle 2 2, da y 1 - all ser u m/ plas ma sa m ples  
 
C ycle 2 6, da y 1 - P K a n d A D A e n d-of -i nf usi o n 
 
E n d of Treat me nt - all ser u m/ plas ma sa m ples  
A d diti o ns:  
 
F oll o w -u p visit 2 –  P K c ollect at visit  
 
F oll o w -u p visit 3 –  P K c ollect at visit  
 
At t he ti me of 
R E CI S T  1. 1 -defi ne d pr o gressi ve 
disease - A D A c ollect at visit  
A p pe n di x  4   Ce mi pli ma b 
P har mac o ki netic, I m m u n o ge nicit y, a n d 
Bi o mar ker Sa m pli n g Sc he d ule  
C ha n ge d t he defi niti o n of ac ute i nf usi o n reacti o ns wi n d o w 
fr o m ‘ wit hi n 2 h o urs after t he i nf usi o n’ t o ‘ wit hi n 1  da y after 
t he i nf usi o n’ 
Secti o n  9. 3. 4   I nf usi o n Reacti o ns 
C ha n ge d a d verse e ve nts re p orti n g re q uire me nt wi n d o w  fr o m 
‘ wit hi n 1 0 5 da ys after t he last st u d y treat me nt’ t o ‘ wit hi n 9 0 
da ys after t he last st u d y treat me nt’  
Secti o n  9. 4. 1   A d verse E ve nts  
Secti o n  9. 4. 2   Seri o us A d verse E ve nts  
Secti o n  9. 4. 6   F oll o w -u p  
Secti o n  1 0. 4. 6. 1   A d verse E ve nts  
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 5  of 1 2 9  
C O N FI D E N TI A L  
C h a n ges  
Secti o ns C h a n ge d  
Re m o ve d c ollecti o n of plas ma/ser u m c yt o ki ne sa m ples  
T a ble  4   Sc he d ule of E ve nts:  Treat me nt 
Peri o d Assess me nts a n d Pr oce d ures  
T a ble  5   Sc he d ule of E ve nts:  F oll o w -U p 
Peri o d Assess me nts a n d Pr oce d ures  
Re m o ve d 
P B M C sa m ple c ollecti o n 
1 
wee k after t he 
ra n d o mize d d ose 
T a ble  4   Sc he d ule of E ve nts:  Treat me nt 
Peri o d Assess me nts  
 
A d de d f o ot n ote b  s pecif yi n g t hat sa m ples ma y be c ollecte d 
f or u p t o 1 0 da ys after t he st u d y visit 
A p pe n di x  4   Ce mi pli ma b 
P har mac o ki netic, I m m u n o ge nicit y, a n d 
Bi o mar ke r Sa m pli n g Sc he d ule 
A d de d t o t he defi niti o n of prei nf usi o n as t hat occ urri n g a n y 
ti me bef ore t he start of i nf usi o n o n t he da y of i nf usi o n.  
A d de d t o t he e n d of i nf usi o n defi niti o n as t hat occ urri n g 
wit hi n 1 0 mi n utes after i nf usi o n has c o m plete d.  
A p pe n di x  4  Ce mi pli ma b 
P har mac o ki netic, I m m u n o ge nicit y, a n d 
Bi o mar ker Sa m pli n g Sc he d ule : 
F o ot n ote  a 
Re m o ve d s pecificati o n t o ha ve  ne gati ve uri ne pre g na nc y test  
e ver y 6 wee ks ( Q 6 W)   
T a ble  4   Sc he d ule of E ve nts:  Treat me nt 
Peri o d Assess me nts  
Secti o n  8. 2. 3. 6   La b orat or y 
T esti n g -Pre g na nc y T est i n g  
A d de d t o t he defi niti o n of f urt her pr o gressi ve disease t o 
i ncl u de ‘t he e mer ge nce of s y m pt o matic pr o gressi o n’ 
Cli nical St u d y Pr ot oc ol S y n o psis: St u d y 
Desi g n  
Secti o n  5. 1. 2   Treat me nt Peri o d  
Re m o ve d s pecificati o n t hat h eart rate will be rec or de d fr o m 
t he ve ntric ular rate, a n d t he P R, Q R S, R R, Q T, a n d Q T will 
be c orrecte d f or Bazett’s f or m ula i nter vals.  
Secti o n  8. 2. 3. 5 .  1 2 -Lea d 
Electr ocar di o gra m  
Re na me d t he cate g ories of Ot her Sec o n dar y O bj ecti ves a n d 
Ot her Sec o n dar y E n d p oi nts t o E x pl orat or y O bjecti ves a n d 
E x pl orat or y E n d p oi nts, res pecti vel y  
Secti o n  2. 2. 2   E x pl orat or y O bjecti ves 
(f or merl y Ot her Sec o n dar y O bjecti ves)  
Secti o n  4. 2. 3   E x pl or at or y E n d p oi nts 
(f or merl y Ot her Sec o n dar y E n d p oi nts) 
T o ali g n t he pri mar y e n d p oi nt wit h t he pri mar y o bjecti ve, 
ad de d te xt s pecif yi n g t he pri mar y e n d p oi nt a p plies t o patie nts 
w h ose t u m ors e x press P D -L 1 i n < 5 0 % of t u m or cells  
Cli nical St u d y Pr ot oc ol S y n o psis : 
E n d p oi nts  
Secti o n  4. 2. 1   Pri mar y E n d p oi nt  
A d de d a sec o n dar y o bj ecti ve t o co m pare t he O R R i n patie nts 
wit h P D -L 1 i n ≥5 0 % of t u m or cells a n d i n all patie nts a n d a 
c orres p o n di n g sec o n dar y e n d p oi nt t o e val uate O R R i n all 
patie nts  
Cli nical St u d y Pr ot oc ol S y n o psis : 
O bjecti ves  a n d E n d p oi nts  
Secti o n  2. 2. 1   Sec o n dar y O bj ecti ves  
Secti o n  4. 2. 2   Sec o n dar y E n d p oi nts   
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 6  of 1 2 9  
C O N FI D E N TI A L  
C h a n ges  
Secti o ns C h a n ge d  
M o ve d 
t he Sec o n dar y O bjecti ves i n v ol vi n g assess me nts of 
O S at 1 2 m o nt hs a n d 1 8 m o nt hs, Q O L, A D A, a n d P K t o 
E x pl orat or y O bj ecti ves  
Cli nical St u d y Pr ot o c ol S y n o psis : 
O bjecti ves  
Secti o n  2. 2. 1   Sec o n dar y O bj ecti ves  
Secti o n  2. 2. 2   E x pl orat or y O bjecti ves 
(f or merl y Ot her Sec o n dar y O bjecti ves) 
C ha n ge d R E G N 2 8 1 0 t o t he ge neric na me, ce mi pli ma b  
T hr o u g h o ut t he pr ot oc ol  
A d de d te xt t o s pecif y testi n g of ge ne 
m utati o ns will be 
perf or me d b y t he ce ntral la b  
Secti o n  6. 2. 2   E xcl usi o n Criteria # 3   
Secti o n  8. 2. 5   Bi o mar ker Pr oce d ures  
C orrecte d err or i n t he P h ysical E xa mi nati o n pr oce d ures  
Secti o n  8. 2. 3. 1   P h ysical E xa mi nati o n  
C orrecte d err ors fr o m pri or versi o ns of t he pr ot oc ol.  
C o nti n uati o n of r a di o gra p hic assess me nts f or patie nts wit h o ut 
R E CI S T -1. 1 -defi ne d pr o gressi ve disease was  c orrecte d fr o m 
‘e ver y 9 wee ks’ t o ‘e ver y 1 2 wee ks’.   
A d de d ‘ as cli nicall y i n dicate d’ f or c oa g ulati o n test t o c orrect 
a n err or fr o m t he pri or versi o ns of t he pr ot oc ol  
T a ble  5   Sc he d ule of E ve nts: F oll o w -U p 
Peri o d A ssess me nts a n d Pr oce d ures 
A d de d te xt t o anal ysis sets t o s pecif y t hat pri mar y a nal ysis  of 
t he efficac y e n d p oi nt  will be a nal yze d wit h t he strat u m of 
patie nts i n t he F A S w h o ha ve P D -L 1 e x pressi o n i n < 5 0 % of 
t u m or cells 
Secti o n  1 0. 3. 1   Efficac y A nal ysis Sets  
S pecifie d t hat O R R will be a nal yze d usi n g t he sa me met h o d 
as t hat use d f or a nal ysis of t he pri mar y e n d p oi nt .  Re vise d 
hea di n g fr o m ‘ Sec o n dar y 
A nal ysis’ t o ‘ Sec o n dar y a n d 
E x pl orat or y 
A nal ysis’ f or c o nsiste nc y 
wit h c ha n ge fr o m 
Ot her Sec o n dar y E n d p oi nts t o E x pl orat or y E n d p oi nts  
Secti o n  1 0. 4. 5. 2   Sec o n dar y a n d 
E x pl orat or y A nal ysis (f or merl y 
Sec o n dar y A nal ysis)  
A d de d a h y p ot hesis t hat hi g h -d ose ce mi pli ma b or ce mi pli ma b 
pl us i pi li m u ma b 
will i m pr o ve t he o verall s ur vi val a n d 
pr o gressi o n -free s ur vi val i n all patie nts 
Secti o n  3. 1   H y p ot hesis  
M o ve d te xt s pecif yi n g P K a n d A D A c ollecti o n ti mes i n t he 
Sc he d ule of 
E ve nts Treat me nt Peri o d t o 
A p pe n di x 4.  
Re m o ve d acc o m pa n yi n g f o ot n otes.  
T a ble  4   Sc he d ule of E ve nts: Treat me nt 
Peri o d Assess me nts  
Secti o n  8. 1. 1  F o ot n otes f or t he Sc he d ule 
of E ve nts Ta ble 4 (re m o ve d)  
Re vise d , a d de d, or  re m o ve d te xt, i ncl u di n g re d u n da nt te xt, 
f or clarit y.   
Cli nical St u d y Pr ot oc ol S y n o psis : 
O bjecti ves ; St u d y Desi g n ; E n d of St u d y 
Defi niti o n ; P o p ulati o n ; E n d p oi nts ; 
Pr oce d ures a n d Assess me nts ; a n d 
Statistical Pla n  
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 7  of 1 2 9  
C O N FI D E N TI A L  
C h a n ges  
Secti o ns C h a n ge d  
Secti o n  1. 1   I m m u n ot hera p y A ge nts f or 
N o n -S mall Cell L u n g Ca ncer  (a d diti o n) 
Secti o n  1. 2  Ce mi pli ma b  (a d diti o n) 
Secti o n  2. 1   Pri mar y O bj ecti ve  
Secti o n  2. 2. 1   Sec o n dar y O bj ecti ves  
Secti o n  2. 2. 2     E x pl orat or y O bj ecti ves 
(f or merl y Ot her Sec o n dar y O bjecti ves) 
Secti o n  3. 1  H y p ot hesis  
Secti o n  3. 2. 2  Rati o nale f or E n d p oi nts 
a n d O bjecti ves 
Secti o n  3. 2. 3   Rati o nale f or C h oice of 
Patie nt P o p ulati o n  
Secti o n  3. 2. 4   Rati o nale f or C o m bi nati o n 
of Ce mi pli ma b  
Secti o n  3. 2. 5   Rati o nale f or Sta n dar d 
D ose Ce mi pli ma b D ose Selecti o n  
Secti o n  4. 2. 3   E x pl orat or y E n d p oi nts 
(f or merl y Ot her Sec o n dar y E n d p oi nts) 
Secti o n  5. 1   St u d y Desc ri pti o n a n d 
D urati o n  
Secti o n  5. 1. 2   Treat me nt Peri o d  
Secti o n  5. 1. 3   F oll o w -u p Peri o d  
Secti o n  5. 1. 4   E n d of St u d y Defi niti o n  
Secti o n  6. 2. 1   I ncl usi o n Criteria # 2   
Secti o n  6. 2. 1   I ncl usi o n Criteria # 7. h   
Secti o n  6. 2. 2   E xcl usi o n Criteria # 1 1   
(f or merl y # 1 0)  
Secti o n  7. 1. 1   Ce mi pli ma b ( R E G N 2 8 1 0)  
Secti o n  7. 2   Pre -Treat me nts   
Secti o n  7. 3. 1. 1   D osi n g Dela y R ules  
Secti o n  7. 3. 1. 3   D osi n g Disc o nti n uati o n 
R ules  
Secti o n  7. 3. 2   Ce mi pli ma b Al o ne  
Secti o n  7. 5   Met h o d of Treat me nt 
Assi g n me nt  
Secti o n  7. 6. 1   Pac ka gi n g, L a beli n g, a n d 
St ora ge  
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 8  of 1 2 9  
C O N FI D E N TI A L  
C h a n ges  
Secti o ns C h a n ge d  
Secti o n  7. 8   Disease Pr o gressi o n W hile 
Recei vi n g Ce mi pli ma b  
Secti o n  8. 1. 1  Earl y Ter mi nati o n Visit  
Secti o n  8. 2. 2. 5   Hair Pi g me ntati o n 
Assess me nt  
Secti o n  8. 2. 5 .  Bi o mar ker Pr oce d ures  
Secti o n  1 0. 5   M ulti plicit y C o nsi derati o ns  
T a ble  1   Ce mi pli ma b G ui deli nes f or 
T e m p orar y a n d Per ma ne nt 
Disc o nti n uati o n f or T o xicit y  
T a ble  4   Sc he d ule of E ve nts:  Treat me nt 
Peri o d Assess me nts  
T a ble  5   Sc he d ule of E ve nts:  F oll o w -u p 
Peri o d Assess me nts   
A p pe n di x  2   Res p o nse E val uati o n 
Criteria i n S oli d T u m ors:  R E CI S T 
G ui deli ne ( Versi o n 1. 1)  
A p pe n di x  3 .  Rec o m me n de d D ose 
M o dificati o n or Disc o nti n uati o n a n d 
S u p p orti ve Care G ui deli nes f or S pecific 
Ce mi pli ma b Dr u g -Relate d A d verse 
E ve nts  
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 9  of 1 2 9  
C O N FI D E N TI A L  
A me n d me nt 1  V H P  
C h a n ges  
Secti o ns C h a n ge d  
T he c urre nt te xt of sec o n dar y e n d p oi nt “ A patie nt w h o 
has n ot die d will be ce ns ore d at t he last k n o w n d ate of 
t hat patie nt bei n g ali ve” has bee n re vise d t o “A patie nt 
w h o is l ost t o f oll o w -u p will be ce ns ore d at t he last date 
t hat t he patie nt was k n o w n t o be ali ve” as re q ueste d 
f oll o wi n g E U re g ulat or y re vie w. 
Secti o n  4. 2. 2  Se co n dar y E n d p oi nts  
Re vise d t he e x cl usi o n criteria c o ncer ni n g h u ma n 
i m m u n o deficie nc y vir us (HI V), h e patitis B vir us 
( H B V) a n d h e patitis C vir us ( H C V) t o clarif y t hat 
patie nts wit h u nc o ntr olle d i nfecti o n are e x cl u de d, b ut 
patie nts wit h c o ntr olle d i nfecti o n are per mitte d, as 
re q ueste d f oll o wi n g E U re g ul at or y re vi e w. 
Secti o n  6. 2. 2  E xcl usi o n Criteria  # 1 0  
A d de d t u berc ul osis scree ni n g, as r e q ueste d f oll o wi n g 
E U re g ulat or y re vie w.  
Secti o n  6. 2. 2  E xcl usi o n Criteria # 2 2  
T a ble  3  Sc he d ule of E ve nts: Scree ni n g 
Visit Assess me nts a n d Pr oce d ures  
Secti o n  8. 2. 1  Pr oce d u res Perf or me d O nl y 
at t he Scree ni n g/ Baseli ne Visit  
Secti o n  8. 2. 3. 6  La b orat or y T esti n g  
A d de d testi n g f or a m ylas e a n d li pase, as re q uest e d 
f oll o wi n g E U re g ulat or y re vie w.  
T a ble  3  Sc he d ule of E ve nts: Scree ni n g 
Visit Assess me nts a n d Pr oce d ures  
T a ble  4  Sc he d ule of E ve nts: Treat me nt 
Peri o d Assess me nts a n d Pr oce d ures  
Secti o n  8. 2. 3. 6  La b orat or y T esti n g  
T he c urre nt te xt : “ Eac h vial will c o ntai n a 
wit h dra wa ble v ol u me of 5 or 7 m L of ce mi pli ma b  at a 
c o nce ntr ati o n of 5 0  m g/ m L” re vise d t o “ E ac h vial will 
c o ntai n wit h dra wa bl e ce mi pli ma b  at a c o nce ntr ati o n of 
5 0  m g/ m L. ” as r e q ueste d f oll o wi n g E U re g ulat or y 
re vie w. 
Secti o n  7. 1. 1   Ce mi pli ma b  
Secti o n  7. 6. 1  Pac ka gi n g, La beli n g, a n d 
St ora ge  
Re vise d t he pr ot oc ol t o i ncl u de re g ular t h yr oi d f u ncti o n 
testi n g:  
F or Ar m A ( ce mi pli ma b  3 5 0  m g, Q 3 W f or 1 0 8  wee ks ) 
a n d Ar m C (ce mi pli ma b  1 0 5 0 m g, Q 3 W f or 
1 0 8  wee ks)  T S H (a n d free T 4 if T S H is a b n or mal) will 
be teste d at scree ni n g a n d Q 9 W as re q ueste d f oll o wi n g 
T a ble  4  Sc he d ule of E ve nts:  Treat me nt 
Peri o d Assess me nts a n d Pr oce d ures  
Secti o n  8. 2. 3. 6  La b orat or y T esti n g  
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 1 0  of 1 2 9  
C O N FI D E N TI A L  
E U re g ulat or y re vie w.  
F or Ar m B ( ce mi pli ma b  3 5 0 m g Q 3 W f or 1 0 8  wee ks 
pl us i pili m u ma b) clarifie d t hat free T 4 will be teste d if 
T S H is o ut of t he n or mal ra n ge at s cree ni n g, b ef ore 
eac h i pili m u ma b d ose  ( Q 6 W) a n d t hereafter Q 9 W  as 
re q ueste d f oll o wi n g E U re g ul at or y re vi e w. 
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 1 1  of 1 2 9  
C O N FI D E N TI A L  
C LI NI C A L S T U D Y P R O T O C O L S Y N O P SI S  
Title  
A Ra n d o mize d, O pe n -La bel St u d y of C o m bi nati o ns of St a n dar d a n d Hi g h 
D ose 
R E G N 2 8 1 0 ( Ce mi pli ma b; 
A nti -P D -1 
A nti b o d y) a n d I pili m u ma b 
( A nti-C T L A -4 A nti b o d y) i n t he Sec o n d -Li ne Treat me nt of P atie nts wit h 
A d va nce d  N o n -S mall Cell L u n g Ca ncer  
Site L oc ati o ns  
P atie nts will be ra n d o mize d at a p pr o xi matel y 8 0  gl o bal st u d y sites .   
O bjecti ves  
Pri m ar y O bjecti ve:  
T he pri mar y o bj ecti ve of t he st u d y is t o c o m pare t he o bj ecti ve res p o nse rate 
( O R R) of hi g h d ose ce mi pli ma b  (“ H D R E G N 2 8 1 0”) a n d sta n dar d d ose 
ce mi pli ma b  pl us i pili m u ma b c o m bi nati o n t hera p y (“ S D R E G N 2 8 1 0/i pi”) t o 
t he O R R of sta n dar d d ose ce mi pli ma b  (“ S D R E G N 2 8 1 0”) i n t he sec o n d-li ne 
treat me nt of patie nts wit h a d va nce d s q ua m o us or n o n-s q ua m o us n o n-s mall 
cell l u n g ca ncer ( N S C L C), i n patie nts w h ose t u m ors e x pre ss pr o gra m me d 
cell deat h li ga n d 1 ( P D -L 1) i n < 5 0 % of t u m or cells.  
Sec o n d ar y O bjecti ves:  
T he sec o n dar y o bj ecti ves of t he st u d y are t he f oll o wi n g:  
 
T o c o m pare t he O R R  of H D R E G N 2 8 1 0 a n d S D R E G N 2 8 1 0/i pi t o 
t he O R R of S D R E G N 2 8 1 0 i n t he sec o n d-li ne treat me nt of patie nts 
wit h a d va nce d s q ua m o us or n o n -s q ua m o us N S C L C i n all patie nts  
 
T o c o m pare t he O S  of H D R E G N 2 8 1 0 , a n d S D R E G N 2 8 1 0/i pi 
c o m bi nati o n t hera p y c o m pare d t o  S D R E G N 2 8 1 0 i n t he sec o n d -li ne 
treat me nt of patie nts wit h a d va nce d s q ua m o us or n o n-s q ua m o us 
N S C L C i n patie nts wit h  P D -L 1 i n < 5 0 % of t u m or cells  a n d i n all 
patie nts . 
 
T o c o m pare  t he P F S  of H D R E G N 2 8 1 0 a n d S D R E G N 2 8 1 0/i pi 
c o m bi nati o n t hera p y t o t he P F S  of 
S D R E G N 2 8 1 0 i n t he 
sec o n d-li ne treat me nt of patie nts 
wit h a d va nce d s q ua m o us or 
n o n -s q ua m o us N S C L C i n patie nts wit h P D -L 1 i n < 5 0 % of t u m or 
cells a n d i n all patie nts.  
 
T o e val uate t he safet y a n d t olera bilit y of H D R E G N 2 8 1 0  a n d 
S D R E G N 2 8 1 0/i pi c o m pare d t o t h ose  of S D R E G N 2 8 1 0 t hera p y  
St u d y Desi g n  
T his is a p hase 2, ra n d o mi ze d, o pe n -la bel st u d y of H D R E G N 2 8 1 0 a n d 
S D R E G N 2 8 1 0/i pi 
vers us 
S D R E G N 2 8 1 0 t hera p y i n t he 
sec o n d-li ne 
treat me nt of patie nts wit h a d va nce d s q ua m o us or n o n-s q ua m o us N S C L C ≥ 
T he st u d y will c o nsist of t he f oll o wi n g 3  peri o ds:  sc ree ni n g, treat me nt, a n d 
f oll o w-u p.  
P atie nts will u n der g o a scree ni n g e val uati o n t o deter mi ne t heir eli gi bilit y 
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 1 2  of 1 2 9  
C O N FI D E N TI A L  
wit hi n 2 8  da ys pri or t o  ra n d o mizati o n.   
Eli gi ble patie nts will be ra n d o mize d  1: 1: 1  t o recei ve o ne of t he f oll o wi n g 
treat me nt re gi me ns:   
 
Treat me nt Ar m A:  Ce mi pli ma b  3 5 0 m g e ver y 3 wee ks ( Q 3 W) f or 
1 0 8  wee ks (referre d t o as “ S D R E G N 2 8 1 0” herei nafter)  
 
Treat me nt Ar m B:  Ce mi pli ma b  3 5 0 m g Q 3 W f or 1 0 8  wee ks pl us 
i pili m u ma b 5 0 m g e ver y 6 we e ks ( Q 6 W) f or u p t o 4  d oses (referre d 
t o as “ S D R E G N 2 8 1 0/i pi” herei nafter) 
 
Treat me nt Ar m C: Ce mi pli ma b  1 0 5 0 
m g Q 3 W f or 1 0 8  wee ks 
(referre d t o as “ H D R E G N 2 8 1 0” herei nafter) 
At ra n d o mizati o n, patie nts will be stratifie d b y hist ol o g y (s q ua m o us vers us 
n o n -s q ua m o us) a n d P D -L 1 e x pressi o n le vel ( < 1 % vers us 1 % t o 4 9 % vers u s 
≥5 0 %).  
P atie nts will recei ve t heir assi g ne d treat me nt f or t he treat me nt peri o d (as 
n ote d a b o ve) .  Treat me nt 
ma y be disc o nti n ue d earl y d ue t o Res p o ns e 
E val uati o n Criteria i n S oli d T u m ors 
Versi o n  1. 1 ( R E CI S T  1. 1) -defi ne d 
pr o gressi ve disease, u nacce pta ble t o xicit y, wit h dra wal of c o nse nt, deat h, 
i nitiati o n of a n ot her a nti-ca ncer treat me nt, or i n s pecific i nsta nces of 
c o nfir me d c o m plete res p o nse ( C R) , partial res p o nse ( P R)  or sta ble disease 
( S D).  P atie nts w h o e x perie nce R E CI S T  1. 1 -defi ne d pr o gressi ve disease o n 
t hera p y ma y c o nti n ue st u d y treat me nt if t he i n vesti gat or j u d ges t he patie nt t o 
be e x perie nci n g cli nical be nefit a n d if t he patie nt has n ot c o m plete d t he 
1 0 8 -wee k treat me nt peri o d.  If f urt her pr o gressi ve diseas e ( defi ne d as a n 
a d diti o nal 1 0 % i ncrease i n  t u m or b ur de n fr o m t he ti me of i nitial pr o gressi ve 
disease , or t he e mer ge nce of s y m pt o matic pr o gressi o n) is c o nfir me d, 
ce mi pli ma b  (a n d i pili m u ma b, if a p plica ble) m ust be disc o nti n ue d a n d ot her 
a nti -ca ncer t hera p y c o nsi dere d, if a p pr o priate.  
After disc o nti n ui n g st u d y treat me nt, patie nts will e nter t he f oll o w -u p peri o d.  
Eac h patie nt will ha ve t he first f oll o w -u p visit 1 4 t o 3 0  da ys  after t he last 
st u d y treat me nt, if treat me nt is disc o nti n ue d earl y d ue t o pr o gressi ve disease, 
t o xicit y, or f or a n ot her reas o n.  Ot her wise, eac h patie nt will ha ve t he first 
f oll o w-u p visit 1 4 t o 3 0  da ys after t he last c ycle visit.  F oll o w -u p visit  2 
t hr o u g h f oll o w-u p visit  7 will occ ur 2 8  da ys ( ± 7  da ys) fr o m t he pre vi o us 
visit.  S ur vi val data will t he n be c ollecte d b y p h o ne or at a n office visit e ver y 
3  m o nt hs u ntil deat h, l oss t o f oll o w -u p, or wit h dra wal of st u d y c o nse nt.   
St u d y D ur ati o n  
T he a p pr o xi mate d urati o n of t he acti ve st u d y assess me nts f or eac h patie nt, 
e xcl u di n g scree ni n g, will be 2 5 m o nt hs of st u d y treat me nt pl us 6  m o nt hs of 
f oll o w-u p.  After t he acti ve st u d y assess me nts are c o m plete, all patie nts will 
be f oll o we d f or s ur vi val.  
E n d of St u d y  Defi niti o n  
T he e n d of st u d y is defi ne d as t he last visit of t he last patie nt . 
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 1 3  of 1 2 9  
C O N FI D E N TI A L  
P o p ul ati o n  
 
 
S a m ple Size:   
A p pr o xi matel y 2 5 2 patie nts will be ra n d o mize d: a mi ni m u m of 2 0 1 patie nts 
( u p t o 2 1 5 t otal) wit h < 5 0 % of t u m or cells e x pressi n g P D-L 1 a n d a 
mi ni m u m of 5 1 patie nts ( u p t o 6 0 t otal) wit h ≥5 0 %  t u m or cells e x pressi n g 
P D -L 1 will be ra n d o mize d.  
 
T ar g et P o p ul ati o n:   
P atie nts i n t his st u d y will i ncl u de me n a n d w o me n ≥1 8 years of a ge, 
dia g n ose d wit h a d va nce d n o n -s q ua m o us or s q ua m o us N S C L C w h o recei ve d 
o nl y 1 pri or li ne of c he m ot her a p y as  treat me nt f or t heir a d va nce d disease  
Tre at me nts  
 
 
St u d y Dr u g  
 
D ose/ R o ute/ Sc he d ule:   
Ce mi pli ma b  a d mi nistere d at 3 5 0 m g as a n i ntra ve n o us (I V) i nf usi o n Q 3 W 
f or 1 0 8 wee ks ( “ S D R E G N 2 8 1 0”)  
 
St u d y Dr u g  
 
D ose/ R o ute/ Sc he d ule:   
Ce mi pli ma b  a d mi nistere d at 3 5 0 m g as a n I V i nf usi o n Q 3 W f or 1 0 8  wee ks 
i n c o m bi nati o n wit h i pili m u ma b a d mi nistere d I V at 5 0 m g Q 6 W f or u p t o 
4  d oses (“ S D R E G N 2 8 1 0/i pi”)  
 
St u d y Dr u g  
 
D ose/ R o ute/ Sc he d ule:   
Ce mi pli ma b  a d mi nistere d at 1 0 5 0 m g as a n I V i nf usi o n Q 3 W f or 1 0 8  wee ks 
(“ H D R E G N 2 8 1 0”) 
E n d p oi nts  
 
 
Pri m ar y:   
T he pri mar y e n d p oi nt is 
O R R, defi ne d as t he pr o p orti o n of patie nts 
ac hie vi n g C R or P R as assesse d b y a bli n de d I R C base d o n R E CI S T  1. 1 
assess me nts, i n patie nts w h ose t u m ors e x press P D -L 1 i n < 5 0 % of t u m or 
cells.  
 
Sec o n d ar y:   
T he sec o n dar y e n d p oi nts i n t he st u d y are : 
 
O bj ecti ve res p o nse rate i n all patie nts  
 
O verall s ur vi val i n patie nts w h ose t u m ors e x press P D-L 1 i n < 5 0 % 
of t u m or cells a n d i n all patie nts.  
O verall s ur vi val is  defi ne d as t he ti me fr o m ra n d o mizati o n t o t he 
date of deat h.  A patie nt w h o is l ost t o f oll o w-u p  will be ce ns ore d at 
t he last date t hat t he patie nt was k n o w n t o be  ali ve . 
 
P F S i n patie nts w h ose t u m ors e x press P D -L 1 i n < 5 0 % of t u m or 
cells a n d i n all patie nts. 
Pr o gressi o n -free s ur vi val is d efi ne d as t he ti me fr o m ra n d o mizati o n 
t o t he date of t he first d oc u me nte d t u m or pr o gressi o n, as 
deter mi ne d b y t he I R C ( bas e d o n R E CI S T  1. 1 assess me nts),  or 
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 1 4  of 1 2 9  
C O N FI D E N TI A L  
deat h .  P atie nts will be ce ns ore d acc or di n g t o t he r ules liste d bel o w: 
o  
P atie nts wit h o ut  a d oc u me nte d t u m or pr o gressi o n or deat h will 
be ce ns ore d o n t he date of t heir last e val ua ble t u m or 
assess me nt.   
o  
P atie nts 
wit h o ut  a n y e val ua ble t u m or assess me nts after 
ra n d o mizati o n a n d di d n ot die will be ce ns ore d o n t he date of 
ra n d o mizati o n. 
 
T he i nci de nces  of treat me nt -e mer ge nt a d verse e ve nts  ( T E A Es), 
seri o us 
a d verse 
e ve nts 
( S A Es), 
deat hs, 
a n d 
la b orat or y 
a b n or malities . 
P r o ce d ures a n d Assess me nts  
Pr oce d ures t o be perf or me d at scree ni n g will i ncl u de i nf or me d c o nse nt; 
assess me nt of i ncl usi o n/e xcl usi o n criteria; rec or di n g of me dical, o nc ol o g y, 
a n d 
c o nc o mita nt 
me dicati o ns 
hist ories; rec or di n g 
of 
de m o gra p hics; 
c ollecti o n a n d te sti n g of t u m or tiss ue sa m ples f or P D-L 1 assess me nt a n d f or 
e pi der mal gr o wt h fact or rece pt or ( E G F R) a n d a na plastic l y m p h o ma ki nas e 
( A L K) 
m utati o ns a n d c-r os o nc o ge ne rece pt or t yr osi ne ki nase ( R O S 1) 
f usi o ns; ra di o gra p hic t u m or assess me nt; t u m or b ur de n assessme nt; c hest 
X -ra y; ser u m pre g na nc y testi n g; 1 2-lea d electr ocar di o gra m; a d verse e ve nt 
( A E) rec or di n g; p h ysical e xa mi nati o n, i ncl u di n g vital si g ns, hei g ht, a n d 
wei g ht assess me nts; 
Easter n 
C o o perati ve 
O nc ol o g y 
Gr o u p ( E C O G) 
perf or ma nce stat us assess me nt; a n d l a b orat or y testi n g.  Sa m ples f or a n 
o pti o nal ge n o mic s u b -st u d y ma y als o be o btai ne d. 
D uri n g t he treat me nt peri o d, t he f oll o wi n g pr oce d ures will be perf or me d t o 
assess efficac y a n d safet y: 
Q O L 
meas ure me nt usi n g vali date d patie nt 
q uesti o n naires; p h ysical e xa m i nati o n; E C O G perf or ma nce st at us assess me nt; 
vital si g ns; la b orat or y testi n g, i ncl u di n g pre g na nc y testi n g f or w o me n of 
c hil d beari n g p ote ntial; a n d re c or di n g of A Es a n d c o nc o mit a nt me dicati o ns.  
C o m p ute d t o m o gra p h y f or ra di o gra p hic t u m or b ur de n assess me nt a n d t u m or 
b ur de n assess me nt base d o n R E CI S T  1. 1 criteria will b e perf or me d at 
pres pecifie d ti me p oi nts t hr o u g h o ut t he st u d y.  
Ot her 
assess me nts 
will i ncl u de 
i n vesti gat or 
assess me nts 
of 
hair 
re-pi g me ntati o n, ce mi pli ma b  c o nce ntrati o n meas ure me nt, ce mi pli ma b  A D A 
assess me nt, a n d bi o mar ker assess me nts.  Bi o mar ker pr oce d ures will i ncl u de 
t he use of t u m or tiss ue sa m ples f or vali dati o n of a d diti o nal P D-L 1 assa ys.  
After t he f oll o w -u p peri o d is c o m plete d, s ur vi val  data will be c ollecte d b y 
p h o ne or at a n office visit e ver y 3  m o nt hs u ntil deat h, l oss t o f oll o w -u p, or 
wit h dra wal of st u d y c o nse nt.  
St atistic al Pl a n  
T he 
pri mar y 
statistical 
h y p ot hesis 
is 
t hat 
S D R E G N 2 8 1 0/i pi 
or 
H D R E G N 2 8 1 0 will ha ve a hi g her res p o nse rate t ha n S D R E G N 2 8 1 0 i n 
patie nts w h ose t u m ors e x press P D -L 1 i n < 5 0 % of t u m or cells.  Base d o n t he 
o utc o me of a pe m br oliz u ma b st u d y i n a si milar setti n g ( K E Y N O T E -0 1 0), 
t he O R R is a p pr o xi matel y 1 0 % i n patie nts wit h P D-L 1 e x pressi o n of 1 % t o 
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 1 5  of 1 2 9  
C O N FI D E N TI A L  
< 5 0 % treate d 
wit h 
pe m br oliz u ma b.   T he 
s p o ns or 
ass u mes 
t hat 
S D R E G N 2 8 1 0 c o ul d ac hie ve a  si milar res p o nse rate of 1 0 % i n patie nts wit h 
P D -L 1 e x pressi o n < 5 0 % , a n d H D R E G N 2 8 1 0 or S D R E G N 2 8 1 0/i pi c o ul d 
ac hie ve a n O R R of 3 0 %; a n a bs ol ute i ncrease of 2 0 % c o m pare d wit h 
S D R E G N 2 8 1 0.  
B ase d o n t he ass u m pti o n a b o ve, e nr oll me nt  of 6 3  patie n ts per ar m wit h 
P D -L 1 e x pressi o n < 5 0 %  will ha ve 8 0 % p o wer at 
a 2 -si de d statistical 
si g nifica nce le vel of 0. 0 5 usi n g t he c hi -s q uare test f or S D R E G N 2 8 1 0/i pi or 
H D R E G N 2 8 1 0 v ers us S D R E G N 2 8 1 0 c o m paris o n .  C o nsi deri n g a dr o p o ut 
rate of 5 %, a p pr o xi matel y 2 0 1  pati e nts ( 6 7  per ar m) wit h P D -L 1 e x pressi o n 
< 5 0 %  will be nee de d .  It is esti mate d t hat a p pr o xi matel y 2 0 % of patie nts 
wit h N S C L C will ha ve P D -L 1 e x pressi o n i n ≥5 0 % of t u m or  cells.  T heref ore 
a t otal e nr oll me nt of ~ 2 5 2 patie nts ( 5 1 patie nts wit h P D -L 1 i n ≥5 0 % of  
t u m or cells) is e x pecte d t o yiel d 2 0 1 patie nts wit h P D-L 1 e x pressi o n i n 
< 5 0 % of t u m or cells.  
T he 
pri mar y 
e n d p oi nt 
of 
O R R 
will 
be 
a n al yz e d 
usi n g 
t he 
C oc hra n -Ma ntel -Hae nszel  t est  
stratif ie d  
b y  
stat us  
of  
hist ol o g y 
( n o n-s q ua m o us vers us s q ua m o us).  A n ass ociate d o d ds rati o a n d 9 5 % CI 
will be calc ulate d.  O bj ecti ve res p o nse rate a n d t he c orres p o n di n g e xact 9 5 % 
CI will be calc ulate d b y t he Cl o p per -P ears o n  met h o d f or eac h treat me nt ar m.   
T he sec o n dar y e n d p oi nts of O S  a n d P F S wil l be a nal yze d b y stratifie d 
l o g-ra n k test usi n g t he stat us of hist ol o g y ( n o n-s q ua m o us vers us s q ua m o us) 
as t he stratificati o n fact or.  
Fa mil y -wise  t y pe I 
err or of 
0. 0 5 
for t he 
a nal ysis 
of 
O R R 
of 
S D R E G N 2 8 1 0/i pi or  H D R E G N 2 8 1 0 vers us S D R E G N 2 8 1 0  c o m paris o ns is 
c o ntr olle d b y t he hierarc hic al gate -kee pi n g a p pr oac h .  T he pri mar y e n d p oi nt 
of O R R will be teste d first f or S D R E G N 2 8 1 0/i pi vers us S D R E G N 2 8 1 0.   If 
t he o utc o me of t he test is statisticall y si g nifica nt at 2 -si de d 0. 0 5 le vel, t he 
pri mar y e n d p oi nt of O R R will t he n be teste d f or H D R E G N 2 8 1 0  vers us 
S D R E G N 2 8 1 0  at 2 -si de d 0. 0 5 le vel. 
I n t his p hase 2 st u d y, t y pe I err or c o ntr ol will  n ot be a p plie d t o t he test of 
sec o n dar y e n d p oi nts. 
 
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 1 6  of 1 2 9  
C O N FI D E N TI A L  
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  
A C T H  
A dre n oc ortic otr o pic h or m o ne  
A D A(s)  
A nti -dr u g a nti b o d y(ies)  
A D L  
Acti vities of dail y li vi n g  
A E  
A d verse e ve nt  
A E SI  
A d verse e ve nt of s pecial i nterest  
A L K  
A na plastic l y m p h o ma ki nase  
A L T  
Ala ni ne a mi n otra nsferase  
A nti -C T L A -4  
A nti -c yt ot o xic T -l y m p h oc yte-ass ociate d a nti ge n  4  
A nti -P D -1  
A nti -pr o gra m me d deat h -1  
A nti -P D -L 1  
A nti -pr o gra m me d deat h li ga n d 1  
A S T  
As partate a mi n otra nsferase  
A T C  
A nat o mical t hera pe utic c he mical  
A U C  
Area u n der t he c ur ve  
B O R  
Best o verall res p o nse  
B P  
Bl o o d press ure  
C B C  
C o m plete bl o o d c o u nt  
CI  
C o nfi de nce i nter val  
C e oi 
C o nce ntrati o n at e n d of i nf usi o n 
C LI A  
Cli nical La b orat or y I m pr o ve me nt A me n d me nts  
C ma x  
T he pea k c o nce ntrati o n  
C N S  
Ce ntral ner v o us s yste m  
C R  
C o m plete res p o nse  
C R O  
C o ntract researc h or ga nizati o n  
C S C C  
C uta ne o us s q ua m o us cell carci n o ma  
C T  
C o m p ute d t o m o gra p h y  
C T L A -4  
C yt ot o xic T -l y m p h oc yte-ass ociate d pr otei n 4  
C tr o u g h 
L o west c o nce ntrati o n i n a d osi n g i nter val  
C V %  
Varia bilit y i n e x p os ure  
D N A  
De o x yri b o n ucleic aci d  
D O R  
D urati o n of res p o nse  
E C  
Et hics C o m mittee  
E C G  
Electr ocar di o gra m  
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 1 7  of 1 2 9  
C O N FI D E N TI A L  
E C O G  
Easter n C o o perati ve O nc ol o g y Gr o u p  
e C R F 
Electr o nic case re p ort f or m  
E D C  
Electr o nic data ca pt ure  
E G F R  
E pi der mal gr o wt h fact or rece pt or  
E O R T C Q L Q -C 3 0  
E ur o pea n Or ga nizati o n f or Researc h a n d Treat me nt of Ca ncer Q ualit y of Life 
Q uesti o n naire C ore 3 0  
E O R T C 
Q L Q -L C 1 3  
E ur o pea n Or ga nizati o n f or Researc h a n d Treat me nt of Ca ncer Q ualit y of Life 
Q uesti o n naire L u n g Ca ncer 1 3  
E -R  
E x p os ure -res p o nse 
E U  
E ur o pea n U ni o n  
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  
FI H  
First -i n-h u ma n  
G C P  
G o o d Cli nical Practice  
G F R  
Gl o mer ular filtrati o n rate  
H B V  
He patitis B vir us  
H C V  
He patitis C vir us  
H R  
Hazar d rati o  
I C F 
I nf or me d c o nse nt f or m 
I C H 
I nter nati o nal C o u ncil f or Har m o nisati o n 
I D M C 
I n de pe n de nt Data M o nit ori n g C o m mittee 
I g G 4 P 
I m m u n o gl o b uli n G 4 Pr otei n 
I H C 
I m m u n o hist oc he mistr y 
ir A E 
I m m u ne-relate d a d verse e ve nt 
I R B 
I nstit uti o nal Re vie w B oar d 
I R C 
I n de pe n de nt Re vie w C o m mittee 
ir T E A E 
I m m u ne-relate d treat me nt-e mer ge nt a d verse e ve nt  
I V 
I ntra ve n o us 
I V R S 
I nteracti ve v oice res p o nse s yste m 
I W R S 
I nteracti ve we b res p o nse s yste m 
Me d D R A  
Me dical Dicti o nar y f or Re g ulat or y Acti vities  
M RI  
Ma g netic res o na nce i ma gi n g  
N/ A  
N ot a p plica ble  
N CI -C T C A E  
Nati o nal Ca ncer I nstit ute C o m m o n T er mi n ol o g y Criteria f or A d verse E ve nts  
N E  
N ot e val ua ble  
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 1 8  of 1 2 9  
C O N FI D E N TI A L  
N S C L C  
N o n -s mall cell l u n g ca ncer 
O R R  
O bjecti ve res p o nse rate  
O S  
O verall s ur vi val  
P B M C  
Per i p heral bl o o d m o n o n uclear cell 
P C R  
P ol y merase c hai n reacti o n  
P D  
Pr o gressi ve disease  
P D -1  
Pr o gra m me d cell deat h -1  
P D -L 1  
Pr o gra m me d cell deat h li ga n d 1  
P D -L 2  
Pr o gra m me d cell deat h li ga n d 2  
P F S  
Pr o gressi o n -free s ur vi val 
P K  
P har mac o ki netic(s)  
P P D  
P urifie d pr otei n deri vati ve  
P R  
Partial res p o nse  
P T  
Preferre d ter m  
P T/ P T T  
Pr ot hr o m bi n ti me/ Partial t hr o m b o plasti n ti me  
Q O L  
Q ualit y of life  
Q 2 W  
E ver y 2 wee ks  
Q 3 W  
E ver y 3 wee ks  
Q 6 W  
E ver y 6 wee ks  
Q 9 W  
E ver y 9 wee ks  
Q 1 2 W  
E ver y 1 2 wee ks  
Q 1 8 W  
E ver y 1 8 wee ks  
Q 2 4 W  
E ver y 2 4 wee ks  
R E CI S T 1. 1  
Res p o nse E val uati o n Criteria i n S oli d T u m ors versi o n 1. 1  
Re ge ner o n  
Re ge ner o n P har mace uticals, I nc.  
R N A  
Ri b o n ucleic aci d  
R O S 1  
C -r os o nc o ge ne rece pt or t yr osi ne ki nase 
R R  
Res pirat or y rate  
S A E  
Seri o us a d verse e ve nt  
S A F  
Safet y a nal ysis set  
S A P  
Statistical a nal ysis pla n  
S D  
Sta ble disease  
S m P C  
S u m mar y of Pr o d uct C haracteristics  
S O C  
S yste m or ga n class  
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 1 9  of 1 2 9  
C O N FI D E N TI A L  
T 4  
T h yr o xi ne  
T E A E  
Treat me nt -e mer ge nt a d verse e ve nt 
te oi 
Ti me of e n d of i nf usi o n  
T M B  
T u m or m utati o n b ur de n  
T S H  
T h yr oi d -sti m ulati n g h or m o ne 
U L N  
U p per li mit of n or mal  
U S  
U nite d States  
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
 
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 2 0  of  1 2 9  
C O N FI D E N TI A L  
T A B L E O F C O N T E N T S  
A M E N D M E N T HI S T O R Y  .............................................................................................................2  
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 6  
1.  
I N T R O D U C TI O N ......................................................................................................2 7  
1. 1.  
I m m u n othera p y A ge nts f or N o n -S mall Cell L u n g Ca ncer  .........................................2 7  
1. 2.  
Ce mi pli ma b  .................................................................................................................3 0  
2.  
S T U D Y O BJ E C TI V E S  ..............................................................................................3 1  
2. 1.  
Pri mar y O bj ecti ve  .......................................................................................................3 1  
2. 2.  
Sec o n dar y O bj ecti ves  .................................................................................................3 1  
2. 2. 1.  
Sec o n dar y O bj ecti ves  .................................................................................................3 1  
2. 2. 2.  
E x pl orat or y O bjecti ves  ...............................................................................................3 1  
3.  
H Y P O T H E SI S A N D R A TI O N A L E  ..........................................................................3 2  
3. 1.  
H y p ot hesis  ..................................................................................................................3 2  
3. 2.  
Rati o na le .....................................................................................................................3 3  
3. 2. 1.  
Rati o nale f or St u d y D esi g n  .........................................................................................3 3  
3. 2. 2.  
Rati o nale f or E n d p oi nts a n d O bjecti ves  .....................................................................3 3  
3. 2. 3.  
Rati o nale f or C h oice of P atie nt P o p ulati o n  ................................................................3 4  
3. 2. 4.  
Rati o nale f or C o m bi nati o n of Ce mi pli ma b a n d I pili m u ma b  ......................................3 4  
3. 2. 5.  
Rati o nale f or Sta n dar d D ose Ce mi pli ma b D ose Selecti o n  .........................................3 5  
3. 2. 6.  
Rati o nale f or Hi g h D ose Ce mi pli ma b D ose Selecti o n  ...............................................3 6  
3. 2. 7.  
Rati o nale f or I pili m u ma b D ose S electi o n  ...................................................................3 7  
4.  
S T U D Y V A RI A B L E S ................................................................................................3 7  
4. 1.  
De m o gra p hic a n d Baseli ne C haracteristics  ................................................................3 7  
4. 2.  
Pri mar y a n d Sec o n dar y E n d p oi nts ..............................................................................3 7  
4. 2. 1.  
Pri mar y E n d p oi nt  ........................................................................................................3 7  
4. 2. 2.  
Sec o n dar y E n d p oi nts  ..................................................................................................3 8  
4. 2. 3.  
E x pl orat or y E n d p oi nts  ................................................................................................3 8  
4. 3.  
P har mac o ki netic Varia bl es  .........................................................................................3 9  
4. 4.  
A nti -Dr u g A nti b o d y Vari a bles  ...................................................................................3 9  
5.  
S T U D Y D E SI G N  .......................................................................................................3 9  
5. 1.  
St u d y Descri pti o n a n d D urati o n  .................................................................................3 9  
5. 1. 1.  
Scree ni n g  ....................................................................................................................4 0  
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
 
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 2 1  of  1 2 9  
C O N FI D E N TI A L  
5. 1. 2.  
Treat me nt Peri o d  ........................................................................................................4 1  
5. 1. 3.  
F oll o w -U p Peri o d  .......................................................................................................4 2  
5. 1. 4.  
E n d of St u d y Defi niti o n  ..............................................................................................4 3  
5. 2.  
Pla n ne d I nteri m A nal ysis  ............................................................................................4 3  
5. 3.  
St u d y C o m mittees  .......................................................................................................4 3  
5. 3. 1.  
I n d e pe n de nt Re vi e w C o m mittee .................................................................................4 3  
5. 3. 2.  
I n d e pe n de nt Data M o nit ori n g C o m mittee ..................................................................4 3  
6.  
S E L E C TI O N, WI T H D R A W A L, A N D R E P L A C E M E N T O F P A TI E N T S  ..............4 4  
6. 1.  
N u m ber of Patie nts Pla n ne d  .......................................................................................4 4  
6. 2.  
St u d y P o p ulati o n  .........................................................................................................4 4  
6. 2. 1.  
I n cl usi o n Criteria ........................................................................................................4 4  
6. 2. 2.  
E x cl usi o n Criteria  .......................................................................................................4 5  
6. 3.  
Pre mat ure Wit h dra wal fr o m t he St u d y  .......................................................................4 7  
6. 4.  
Re place me nt of Patie nts  .............................................................................................4 8  
7.  
S T U D Y T R E A T M E N T S ............................................................................................4 8  
7. 1.  
I n v esti gati o nal a n d Refere nce Treat me nts ..................................................................4 8  
7. 1. 1.  
Ce mi pli ma b ( R E G N 2 8 1 0)  ..........................................................................................4 8  
7. 1. 2.  
I pili m u ma b ..................................................................................................................4 9  
7. 2.  
Pre -Treat me nts  ............................................................................................................4 9  
7. 3.  
D ose M o dificati o n a n d St u d y Treat me nt Disc o nti n uati o n R ules  ...............................4 9  
7. 3. 1.  
“ Sta n dar d D ose” Ce mi pli ma b Pl us I pili m u ma b C o m bi nati o n a n d “ Hi g h 
D ose” Ce mi pli ma b T hera p y  .......................................................................................4 9  
7. 3. 1. 1.  
D osi n g D ela y R ules  ....................................................................................................4 9  
7. 3. 1. 2.  
Criteria f or Restarti n g “ Sta n dar d D ose” Ce mi pli ma b Pl us I pili m u ma b a n d 
“ Hi g h D ose” Ce mi pli ma b D osi n g  ..............................................................................5 0  
7. 3. 1. 3.  
D osi n g Disc o nti n uati o n R ules  ....................................................................................5 0  
7. 3. 2.  
Ce mi pli ma b Al o ne  ......................................................................................................5 2  
7. 3. 3.  
I m m u ne-Relate d A d v ers e E ve nts  ...............................................................................5 4  
7. 3. 4.  
I pili m u ma b ..................................................................................................................5 5  
7. 3. 5.  
Per ma ne nt St u d y Dr u g Disc o nti n uati o n  .....................................................................5 6  
7. 4.  
Ma na ge me nt of Ac ute R eacti o ns  ................................................................................5 6  
7. 4. 1.  
Ac ute I nf usi o n Reacti o ns  ............................................................................................5 6  
7. 4. 1. 1.  
I nterr u pti o n of t he I nf usi o n .........................................................................................5 7  
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
 
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 2 2  of  1 2 9  
C O N FI D E N TI A L  
7. 4. 1. 2.  
Ter mi nati o n of t he I nf usi o n  ........................................................................................5 8  
7. 5.  
Met h o d of Treat me nt Assi g n me nt  ..............................................................................5 8  
7. 5. 1.  
Bli n di n g  ......................................................................................................................5 9  
7. 6.  
Treat me nt L o gistics a n d Acc o u nta bilit y  .....................................................................5 9  
7. 6. 1.  
Pac ka gi n g, La beli n g, a n d St ora ge  ..............................................................................5 9  
7. 6. 2.  
S u p pl y a n d Dis p ositi o n of Treat me nts  .......................................................................5 9  
7. 6. 3.  
Treat me nt A cc o u nta bilit y  ...........................................................................................5 9  
7. 6. 4.  
Treat me nt C o m plia nce  ................................................................................................6 0  
7. 7.  
C o nc o mita nt Me dicati o ns  ...........................................................................................6 0  
7. 7. 1.  
Pr o hi bite d Me dicati o ns a n d Pr oce d ures  .....................................................................6 0  
7. 7. 2.  
Per mitte d Me dicati o ns a n d Pr oce d ures  ......................................................................6 0  
7. 8.  
Disease Pr o gressi o n W hile Recei vi n g Ce mi pli ma b  ...................................................6 1  
7. 9.  
P ost -St u d y Treat me nts a n d Pr oce d ures  ......................................................................6 1  
8.  
S T U D Y S C H E D U L E O F E V E N T S A N D P R O C E D U R E S  ......................................6 1  
8. 1.  
Sc he d ule of E ve nts  .....................................................................................................6 1  
8. 1. 1.  
Earl y Ter mi nati o n Visit  ..............................................................................................7 3  
8. 1. 2.  
U nsc he d ule d Visits  .....................................................................................................7 3  
8. 2.  
St u d y Pr oce d ures  ........................................................................................................7 3  
8. 2. 1.  
Pr oce d ures Perf or me d O nl y at t he Scree ni n g/ Baseli ne Visit  .....................................7 3  
8. 2. 2.  
Efficac y Pr oce d ures  ....................................................................................................7 4  
8. 2. 2. 1.  
Ra di o gra p hic T u m or Ass ess me nts  .............................................................................7 4  
8. 2. 2. 2.  
T u m or B ur de n Assess me nts  .......................................................................................7 5  
8. 2. 2. 3.  
Q ualit y of Lif e Q uesti o n naires  ...................................................................................7 5  
8. 2. 2. 4.  
S ur vi val Data C ollecti o n  .............................................................................................7 5  
8. 2. 2. 5.  
Hair Pi g me ntati o n Assess me nt  ...................................................................................7 6  
8. 2. 3.  
Safet y Pr oce d ures  .......................................................................................................7 6  
8. 2. 3. 1.  
P h ysical E x a mi nati o n  .................................................................................................7 6  
8. 2. 3. 2.  
E C O G Perf or ma n ce Stat us  .........................................................................................7 6  
8. 2. 3. 3.  
Wei g ht a n d Hei g ht  ......................................................................................................7 6  
8. 2. 3. 4.  
Vital Si g ns  ..................................................................................................................7 6  
8. 2. 3. 5.  
1 2 -Lea d Electr ocar di o gra m  ........................................................................................7 7  
8. 2. 3. 6.  
La b orat or y T esti n g  ......................................................................................................7 7  
8. 2. 3. 7.  
C o nc o mita nt Me dicati o n Rec or di n g  ...........................................................................7 8  
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
 
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 2 3  of  1 2 9  
C O N FI D E N TI A L  
8. 2. 3. 8.  
A d verse E v e nt Rec or di n g  ...........................................................................................7 8  
8. 2. 4.  
P har mac o ki netic a n d A nti -Dr u g A nti b o d y Pr oce d ures  ..............................................7 9  
8. 2. 4. 1.  
Dr u g C o nce ntr ati o n Meas ure me nts a n d Sa m ples  .......................................................7 9  
8. 2. 4. 2.  
A nti -Dr u g A nti b o d y M eas ure me nts a n d Sa m ples  ......................................................7 9  
8. 2. 5.  
Bi o mar ker Pr oce d ures  ................................................................................................7 9  
8. 2. 6.  
F ut ure Bi o me dical Res earc h  .......................................................................................8 0  
8. 2. 6. 1.  
Ge n o mics S u b -St u d y - O pti o nal  .................................................................................8 0  
9.  
S A F E T Y D E FI NI TI O N S, R E P O R TI N G, A N D M O NI T O RI N G  .............................8 1  
9. 1.  
O bli gati o ns of I n v esti gat or  .........................................................................................8 1  
9. 2.  
O bli gati o ns of S p o ns or  ...............................................................................................8 1  
9. 3.  
Defi niti o ns  ..................................................................................................................8 1  
9. 3. 1.  
A d ver se E v e nt .............................................................................................................8 1  
9. 3. 2.  
Seri o us A d verse E v e nt  ................................................................................................8 2  
9. 3. 3.  
A d verse E v e nts of S peci al I nt erest  .............................................................................8 3  
9. 3. 3. 1.  
I m m u ne-Relate d A d v ers e E ve nts  ...............................................................................8 3  
9. 3. 4.  
I nf usi o n Reacti o ns ......................................................................................................8 3  
9. 4.  
Rec or di n g a n d Re p orti n g A d verse E v e nts  ..................................................................8 4  
9. 4. 1.  
A d verse E v e nts  ...........................................................................................................8 4  
9. 4. 2.  
Seri o us A d verse E v e nts  ..............................................................................................8 4  
9. 4. 3.  
Ot her E ve nts t hat Re q uir e Accelerate d Re p orti n g t o S p o ns or  ...................................8 4  
9. 4. 4.  
Re p orti n g A d v erse E v e nts Lea di n g t o Wit h dra wal fr o m  t he St u d y ...........................8 5  
9. 4. 5.  
A b n or mal La b orat or y, Vital Si g ns, or Electr o car di o gra m Res ults  .............................8 5  
9. 4. 6.  
F oll o w -u p  ....................................................................................................................8 5  
9. 5.  
E val uati o n of Se verit y a n d Ca usalit y  .........................................................................8 6  
9. 5. 1.  
E val uati o n of Se verit y  ................................................................................................8 6  
9. 5. 2.  
E val uati o n of Ca usalit y  ...............................................................................................8 6  
9. 6.  
Safet y M o nit ori n g  .......................................................................................................8 7  
9. 7.  
I n v esti gat or Alert N otificati o n ....................................................................................8 7  
1 0.  
S T A TI S TI C A L P L A N ................................................................................................8 7  
1 0. 1.  
Statistical H y p ot hesis  ..................................................................................................8 7  
1 0. 2.  
J ustificati o n of Sa m ple Size........................................................................................8 8  
1 0. 3.  
A nal ysis Sets  ...............................................................................................................8 8  
1 0. 3. 1.  
Efficac y A nal ysis Sets  ................................................................................................8 8  
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
 
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 2 4  of  1 2 9  
C O N FI D E N TI A L  
1 0. 3. 2.  
Safet y A nal ysis Set  .....................................................................................................8 8  
1 0. 3. 3.  
A d diti o nal A nal ysis Sets .............................................................................................8 8  
1 0. 4.  
Statistical Met h o ds  ......................................................................................................8 9  
1 0 . 4. 1. 
Patie nt Dis p ositi o n  ......................................................................................................8 9  
1 0. 4. 2.  
De m o gra p h y a n d Baseli ne C haracteristics  .................................................................8 9  
1 0. 4. 3.  
Me dical Hist or y  ..........................................................................................................8 9  
1 0. 4. 4.  
Pri or Me dicati o ns/ C o nc o mita nt Me dicati o ns  .............................................................8 9  
1 0. 4. 5.  
Efficac y A nal yses  .......................................................................................................9 0  
1 0. 4. 5. 1.  
Pri mar y Efficac y A nal ysis  ..........................................................................................9 0  
1 0. 4. 5. 2.  
Sec o n dar y a n d E x pl orat or y Efficac y A nal ys es  ..........................................................9 0  
1 0. 4. 6.  
Safet y A nal yses  ..........................................................................................................9 0  
1 0. 4. 6. 1.  
A d verse E v e nts  ...........................................................................................................9 0  
1 0. 4 . 6. 2. 
Ot her Safet y A n al yses  ................................................................................................9 1  
1 0. 4. 6. 3.  
Treat me nt E x p os ure  ....................................................................................................9 1  
1 0. 4. 6. 4.  
Treat me nt C o m plia nce  ................................................................................................9 2  
1 0. 4. 7.  
A nal ysis of Dr u g C o nce ntrati o n Data  .........................................................................9 2  
1 0. 4. 8.  
E x p os ure -Res p o nse a n d P K/ P har mac o d y na mic a n al yses  ..........................................9 2  
1 0. 4. 9.  
A nal ysis of A nti -Dr u g A nti b o d y Data  ........................................................................9 2  
1 0. 4. 1 0.  
A nal ysis of Bi o mar ker Data  .......................................................................................9 2  
1 0. 5.  
M ulti plicit y C o nsi derati o ns  ........................................................................................9 2  
1 0. 6.  
I nteri m A nal ysis ..........................................................................................................9 3  
1 0. 7.  
A d diti o nal Statistical Data Ha n dli n g C o n ve nti o ns  .....................................................9 3  
1 0. 8.  
Statistical C o nsi derati o ns S urr o u n di n g t he Pr e mat ure Ter mi nati o n of a St u d y  .........9 3  
1 1.  
D A T A M A N A G E M E N T A N D E L E C T R O NI C S Y S T E M S  .....................................9 4  
1 1. 1.  
Data Ma na ge me nt  .......................................................................................................9 4  
1 1. 2.  
Electr o nic S yst e ms  ......................................................................................................9 4  
1 2.  
S T U D Y M O NI T O RI N G  ............................................................................................9 4  
1 2. 1.  
M o nit ori n g of St u d y Sites  ...........................................................................................9 4  
1 2. 2.  
S o urce D oc u m e nt Re q uire me nts  ................................................................................9 4  
1 2. 3.  
Case Re p ort F or m Re q uire me nts  ................................................................................9 5  
1 3.  
A U DI T S A N D I N S P E C TI O N S  .................................................................................9 5  
1 4.  
E T HI C A L A N D R E G U L A T O R Y C O N SI D E R A TI O N S  ..........................................9 5  
1 4. 1.  
G o o d Cli nical Practice State me nt  ...............................................................................9 5  
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
 
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 2 5  of  1 2 9  
C O N FI D E N TI A L  
1 4. 2.  
I nf or me d C o nse nt .......................................................................................................9 6  
1 4. 3.  
Patie nts’ C o nfi de ntialit y a n d Data Pr otecti o n  ............................................................9 6  
1 4. 4.  
I nstit uti o nal Re vie w B oar d/ Et hics C o m mittee ...........................................................9 6  
1 5.  
P R O T O C O L A M E N D M E N T S  ..................................................................................9 7  
1 6.  
P R E M A T U R E T E R MI N A TI O N O F T H E S T U D Y O R C L O S E -O U T O F A 
SI T E  ............................................................................................................................9 7  
1 6. 1.  
Pre mat ure Ter mi nati o n of t he St u d y  ...........................................................................9 7  
1 6. 2.  
Cl ose -o ut of a Site  ......................................................................................................9 7  
1 7.  
S T U D Y D O C U M E N T A TI O N  ...................................................................................9 8  
1 7. 1.  
Certificati o n of Acc urac y of Data  ...............................................................................9 8  
1 7. 2.  
Rete nti o n of Rec or ds  ..................................................................................................9 8  
1 8.  
D A T A Q U A LI T Y A S S U R A N C E  ..............................................................................9 8  
1 9.  
C O N FI D E N TI A LI T Y  ................................................................................................9 9  
2 0.  
FI N A N CI N G A N D I N S U R A N C E  .............................................................................9 9  
2 1.  
P U B LI C A TI O N P O LI C Y  ..........................................................................................9 9  
2 2.  
R E F E R E N C E S  .........................................................................................................1 0 0  
2 3.  
I N V E S TI G A T O R’ S A G R E EM E N T  ........................................................................1 0 5  
SI G N A T U R E O F S P O N S O R ’ S R E S P O N SI B L E O F FI CE R S  ...................................................1 2 9  
 
LI S T O F T A B L E S  
Ta ble  1:  
Ce mi pli ma b G ui deli nes f or T e m p orar y a n d Per ma ne nt Disc o nti n uati o ns f or 
T o xicit y  .......................................................................................................................5 3  
Ta ble  2:  
Ge neral Ce mi pli ma b Treat me nt H ol d G ui deli nes f or I m m u n e -Relate d 
A d verse  E v e nts  ...........................................................................................................5 5  
Ta ble  3:  
Sc he d ule of E ve nts:  Scree ni n g Visit Assess me nts a n d Pr oce d ures  ...........................6 2  
Ta ble  4:  
Sc he d ule of E ve nts:  Treat me nt Peri o d Assess me nts a n d Pr oce d ures  .......................6 4  
Ta ble  5:  
Sc he d ule of E ve nts:  F oll o w -U p Peri o d Assess me nts a n d Pr oce d ures  ......................7 1  
Ta ble  6:  
Res p o nse Acc or di n g t o Re vise d Res p o nse E val u ati o n Criteria i n S oli d 
T u m ors ( Versi o n  1. 1) i n Patie nts wit h Tar get (a n d N o n -Tar get) Lesi o ns  ................1 1 2  
 
LI S T O F FI G U R E S  
Fi g ure  1:  
St u d y Fl o w Dia gra m  ...................................................................................................4 0  
 
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
 
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 2 6  of  1 2 9  
C O N FI D E N TI A L  
LI S T O F A P P E N DI C E S  
A p pe n di x  1.  Fact ors t o C o nsi der i n Assessi n g t he Relati o ns hi p of A d verse E ve nts t o 
St u d y Dr u g  ................................................................................................................1 0 6  
A p pe n di x  2.  Res p o nse E val uati o n Criteria i n S oli d T u m ors:  R E CI S T G ui deli ne 
( Versi o n 1. 1) .............................................................................................................1 0 7  
A p pe n di x  3.  Rec o m me n de d D ose M o dific ati o n or Disc o nti n uati o n a n d S u p p orti ve 
Care G ui deli nes f or S pecific Ce mi pli ma b Dr u g -Relate d A d verse E ve nts  ...............1 1 4  
A p pe n di x  4.  Ce mi pl i ma b P har mac o ki netic, I m m u n o ge nicit y, a n d Bi o mar ker Sa m pli n g 
Sc he d ule  ....................................................................................................................1 2 8  
 
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
 
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 2 7  of  1 2 9  
C O N FI D E N TI A L  
1.  
I N T R O D U C TI O N 
L u n g ca ncer is o ne of t he m ost c o m m o nl y dia g n ose d ca n cers a n d is t he lea di n g ca use of 
ca ncer-relate d m ort alit y w orl d wi de (Sie gel 2 0 1 6 )(Bra y 2 0 1 3 ).  N o n-s mall cell l u n g ca n cer 
( N S C L C) acc o u nts f or 8 0 % t o 8 5 % of all l u n g ca n cers a n d is c o m p ose d of se veral 
hist o pat h ol o g ical s u bt y p es, t he m ost c o m m o n of w hic h i ncl u de a de n ocarci n o ma ( 4 0 % t o 6 0 %) 
a n d s q ua m o us cell carci n o ma ( 3 0 %).  T he m aj orit y of patie nts wit h N S C L C are f o u n d t o ha v e 
a d va nce d ca n cer at t he ti me of dia g n osis (Lei g hl 2 0 1 2 ).  With c he m ot hera p y, t hes e patie nts ha v e 
a me dia n o verall s ur vi val ( O S) of u p t o 1 2 t o 1 8 m o nt hs a n d a 5 -year s ur vi val rate of 
a p pr o xi matel y 1 8 % (Lei g hl 2 0 1 2 )(Sie gel 2 0 1 6 ). 
S yste mic t hera p y 
wit h plati n u m -base d d o u bl et c he m ot hera p y re gi me ns, 
wit h or 
wit h o ut 
mai nte na nce t h era p y, has bee n, u ntil rece ntl y, t h e sta n dar d first -li ne tr eat me nt f or all patie nts 
wit h a d va nce d N S C L C w h ose t u m ors d o n ot ha ve a n e pi der mal gr o wt h fact or rece pt or ( E G F R) 
m utati o n, a n a na plastic l y m p h o ma ki nase ( A L K) tra nsl ocati o n, or a C -r os o nc o ge n e rece pt or 
t yr osi ne ki n ase ( R O S 1) m utati o n (Besse 2 0 1 4 )(Etti n ger 2 0 1 6 )(Rec k 2 0 1 4 ).  Des pite i nitial 
t hera p y wit h plati n u m -b ase d d o u blet c he m ot hera p y re gi me ns, t he diseas e ofte n pr o gresses, a n d 
a d diti o nal treat me nt o pti o ns ha ve bee n li mite d.  T heref ore, n e wer t hera pe utic a p pr oac hes are 
nee de d t hat will i m pr o ve l o n g -ter m s ur vi val a n d q ualit y of life ( Q O L) i n patie nts wit h a d va nce d 
N S C L C.  
1. 1.  
I m m u n ot her a p y A ge nts f or N o n-S m all Cell L u n g C a ncer  
I n rece nt years, i m m u n ot hera pies ha v e bee n i n vesti gate d as p ote ntial t hera pe utic a p pr oac hes t hat 
will i m pr o ve l o n g -ter m s ur vi val a n d Q O L i n patie nts wit h a d va nce d N S C L C.  A c o m ple x 
cr oss-tal k b et wee n ca ncer cells a n d t he h ost i m m u ne s yste m t hat ca n b ot h i n hi bit a n d e n h a nce 
t u m or gr o wt h has rece ntl y b ee n cl arifie d (Vi n a y  2 0 1 5 ).  T u m ors m o d ulate a n d e va de t he h ost 
i m m u ne res p o nse t hr o u g h 
a 
n u m ber 
of mec ha nis ms, i ncl u di n g f or mati o n 
of 
a n 
i m m u ne-s u p pressi ve e n vir o n me nt wit hi n t he t u m or.  Pr o gra m me d cell deat h -1 ( P D -1) is a 
c o-rece pt or e x presse d o n t he s urface of acti vate d T-cells t hat me diat es i m m u n os u p pressi o n.  T he 
bi n di n g of P D -1 t o o ne of its li ga n ds, pr o gra m m e d cell deat h li ga n d  1  ( P D-L 1) or pr o gra m me d 
cell deat h li ga n d  2 ( P D -L 2), res ults i n t he i n hi biti o n of a c yt ot o xic T -cell res p o nse.  I ncreas e d 
e x pressi o n 
of 
P D -L 1 i n t he t u m or 
micr oe n vir o n me nt facilitates 
esca pe fr o m  t he 
i m m u ne-s ur veilla nce me cha nis m ( T -cell-i n d uce d a nti-t u m or acti vit y).  I n c o ntrast, bl oc ka de of 
t his i nteracti o n res ults i n a n e n ha n ce d T-cell res p o nse wit h a nti -t u m or acti vit y. 
A n u m ber of dia g n osti c P D -L 1 assa ys h a ve b ee n de v el o pe d t o i nf or m treat me nt decisi o ns 
(re vie we d i n Ratcliffe 2 0 1 7 ).  T he assa ys d e m o nstrate t hat t here is a br oa d ra n ge of P D-L 1  
e x pressi o n le vels i n t u m or cells fr o m N S C L C t u m or sa m ples (D’I n cecc o  2 0 1 5 )(Kerr 2 0 1 5 ).  A 
hi g h le vel of e x pressi o n has bee n c orrelate d wit h p o or patie nt pr o g n osis a n d resista nce t o 
sta n dar d-of -care (c he m ot hera p y) tr eat me nt (Creel a n 2 0 1 4 ).  Bl oc ka de of t he P D-1/ P D -L 1 T -cell 
c hec k p oi nt pat h w a y h as bee n s h o w n t o be a n effecti ve a n d well -t olerate d a p pr oac h t o sti m ulati n g 
t he i m m u ne res p o ns e a n d has ac hie ve d si g nifica nt o bjecti ve res p o nses i n patie nts wit h N S C L C 
(T o palia n  2 0 1 2 ).  A m o n g 
patie nts 
wit h a d va nce d, 
pre vi o usl y treate d s q ua m o us a n d 
n o n -s q ua m o us 
N S C L C, 
O S 
was si g nifica ntl y i m pr o ve d i n patie nts treate d wit h t he 
P D -1  i n hi bit or ni v ol u ma b c o m pare d t o t he O S i n t h ose treate d wit h d oceta xel, re gar dless of 
P D -L 1 e x pressi o n (B or g haei  2 0 1 5 )(Bra h mer  2 0 1 5 ).  Si milarl y, p atie nts wit h pre vi o usl y t reate d 
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
 
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 2 8  of  1 2 9  
C O N FI D E N TI A L  
P D -L 1 -p ositi ve N S C L C w h o were tr eate d wit h t h e P D-1 i n hi bit or pe m br oliz u ma b ha d i m pr o ve d 
O S c o m pare d t o t h ose treate d wit h d oceta xel ( P D -L 1 e x pressi o n i n at least 1 % o f t u m or cells) 
(Her bst  2 0 1 6 ).  T hese d ata esta blis he d t he us e of P D-1 i n hi bit ors i n t he sec o n d -li ne tr eat me nt 
para di g m  
of  
patie nts  
wit h  
N S C L C 
(K E Y T R U D A ®  [ pe m br oliz u ma b] 
Pac ka ge 
I ns ert)(K E Y T R U D A 
E ur o pea n 
U ni o n 
[ E U] 
S u m mar y 
of 
Pr o d uct 
C haract eristics 
[ S m P C])(O P DI V O ®  [ ni v ol u ma b] Pac ka ge I nsert)(O P DI V O E U S m P C )(Etti n ger 2 0 1 6 ).  
A t hir d P D -L 1 i n hi bit or, T E C E N T RI Q ®  (at ez oliz u ma b), has bee n  a p pr o ve d i n t he U S a n d t he 
E U f or t he tr eat me nt of metastatic N S C L C i n patie nts wit h disease pr o gressi o n d uri n g or after 
treat me nt 
wit h plati n u m-base d c he m ot hera p y.  
A p pr o val 
was base d o n 2 st u dies t hat 
de m o nstrate d i m pr o ve d efficac y o ver d oceta xel (Fe hre n bac her 2 0 1 6 )(Ritt me yer 2 0 1 7 ). 
K E Y N O T E -0 2 4 w as a n o pe n -la bel, p hase 3 st u d y t hat i ncl u de d 3 0 5 patie nts wit h pre vi o usl y 
u nt reate d, a d va nce d N S C L C w h ose t u m ors e x presse d P D-L 1 i n ≥5 0 % of t u m or cells.  T he 
patie nts were ra n d o mize d t o recei ve eit her p e m br oliz u ma b or t he i n vesti gat or’s c h oice of 
plati n u m -base d c h e m ot hera p y.  Cr oss o ver fr o m t he c he m ot hera p y gr o u p t o t he pe m br oliz u m a b 
gr o u p was per mitte d i n t he e v e nt of diseas e pr o gressi o n.  Me di a n pr o gressi o n -free s ur vi val ( P F S) 
was 
1 0. 3  m o nt hs  ( 9 5 % c o nfi de nce i nter val [ CI]:   6. 7  m o nt hs t o 
n ot reac h e d) i n t he 
pe m br oliz u ma b gr o u p vers us 6. 0  m o nt hs ( 9 5 %  CI:  4. 2 t o 6. 2  m o nt hs) i n t h e c h e m ot hera p y gr o u p 
( hazar d rati o [ H R] f or disease pr o gressi o n or deat h:  0. 5 0; 9 5 % CI:  0. 3 7 t o 0. 6 8; p < 0. 0 0 1).  T he 
res p o nse rat e was hi g h er i n t he pe m br oliz u ma b gr o u p t ha n i n t he c he m ot hera p y gr o u p ( 4 4. 8 % 
vers us 2 7. 8 %) (Rec k  2 0 1 6 ).  F urt her m ore, c o m pare d t o t he c he m ot hera p y gr o u p, f or t he 
pe m br oliz u ma b gr o u p t he 
me dia n d urati o n of res p o nse ( D O R) 
was l o n ger ( n ot reac he d 
[ra n ge:  1. 9 + t o 1 4. 5 +  m o nt hs] vers us 6. 3  m o nt hs [ra n ge:   2. 1 + t o 1 2. 6 + 
m o nt hs]) a n d 
treat me nt-e mer ge nt a d verse e v e nts  ( T E A Es) of a n y gra d e were less fre q ue nt ( occ urri n g i n 7 3. 4 % 
vers us 9 0. 0 % of p atie nts), as w ere T E A Es of gra d e 3, 4, or 5 ( 2 6. 6 % v ers us 5 3. 3 %) (Rec k 2 0 1 6 ).  
T he res ults of t his st u d y le d t o a p pr o val of pe m br oliz u ma b i n t he U nite d States ( U S), J a pa n, a n d 
s o me E ur o pea n c o u ntries f or first-li ne treat me nt of a d va nce d N S C L C i n patie nts w h ose t u m ors 
e x press  
P D -L 1 
i n 
≥5 0 %  of 
t u m or  
cells 
as 
d eter mi ne d 
b y  
t he 
P D -L 1 
i m m u n o hist oc he mistr y (I H C) 2 2 C 3 p har m D x assa y (P D -L 1 I H C  2 2 C 3 p har m D x  [ pac ka ge 
i nsert])(R oac h 2 0 1 6 ).  T his was t he first U S F o o d a n d Dr u g A d mi nistrati o n ( F D A) a p pr o val of a 
c hec k p oi nt  i n hi bit or f or first-li ne tr eat me nt of l u n g ca n cer.  T his a p pr o val als o e x pa n de d t h e 
pe m br oliz u ma b i n dicati o n i n sec o n d -li ne tr eat me nt of l u n g ca ncer t o i ncl u de all patie nts wit h 
N S C L C e x pressi n g P D -L 1 > 1 %.  
I n c o ntrast t o K E Y N O T E-0 2 4, t he p has e  3 C hec k Mate  0 2 6 st u d y i n v esti gati n g t he efficac y of 
first-li ne treat me nt wit h ni v ol u ma b c o m pare d t o plati n u m-base d d o u blet c he m ot hera p y i n 
patie nts wit h a d va nce d P D -L 1 -p ositi ve N S C L C ( defi ne d as prese nt i n 1 % or m ore t u m or cells) 
di d n ot meet its pri mar y e n d p oi nt (S oci ns ki  2 0 1 6 ).  E ve n i n a s u bset a nal ysis of t h ose patie nts 
wit h P D -L 1 e x pressi o n o n ≥5 0 % t u m or cells, ni v ol u ma b faile d t o de m o nstrate a n y i m pr o ve me nt 
o ver c h e m ot hera p y.  T h ere is c urre ntl y n o pr o ve n e x pla nati o n f or t his disc re pa n c y bet w ee n t h e 
2  st u dies.  A t otal of 5 4 1 patie nts were ra n d o mize d 1: 1 t o t he ni v ol u ma b or c he m ot hera p y 
treat me nt gr o u p.  Patie nts w h o pr o gresse d o n c h e m ot hera p y c o ul d cr oss o ver t o ni v ol u ma b as 
sec o n d-li ne treat me nt.  I n t he 4 2 3 patie nts w h ose t u m ors  e x presse d P D -L 1 i n 5 % or great er of 
t u m or cells, P F S was 4. 2 m o nt hs wit h ni v ol u ma b a n d 5. 9  m o nt hs wit h c he m ot hera p y ( H R:   1. 1 5; 
9 5 %  CI:   0. 9 1 t o 1. 4 5; p = 0. 2 5).  O verall s ur vi val was 1 4. 4  m o nt hs f or ni v ol u ma b vers us 
1 3. 2  m o nt hs f or c he m ot hera p y ( H R:   1. 0 2;  9 5 % CI:   0. 8 0 t o 1. 3 0).   
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
 
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 2 9  of  1 2 9  
C O N FI D E N TI A L  
A 
sec o n d t y p e 
of 
i m m u n o-o nc ol o g y 
a ge nt, 
a nti -c yt ot o xic 
T -l y m p h oc yt e-ass oci ate d 
a nti ge n 4  (a nti-C T L A -4), has als o bee n de m o nstrate d t o be cli nicall y acti ve i n a d va n ce d ca n cers.  
I pili m u ma b, a f ull y h u m a n m o n ocl o nal a nti-C T L A -4 a ge nt, has de m o nstr ate d cli nical acti vit y as 
a m o n ot hera p y i n mel a n o ma (W olc h o k 2 0 1 0 )(O’ Da y 2 0 1 0 ) a n d pr ostate ca ncer (Sl o vi n 2 0 1 3 ) 
a n d is n o w a p pr o ve d i n t he U S a n d E U f or treat m e nt of u nresect a ble or metastatic mela n o ma a n d 
f or t he a dj u va nt tr eat me nt of mela n o ma (Yer v o y Pac ka ge I nsert )(Yer v o y S m P C ).   
I n a d diti o n t o i m m u n o-o nc ol o g y a ge nts as m o n ot hera p y, t he p ote n tiall y a d diti ve or s y ner gistic 
effects of i m m u n o -o nc ol o g y t h era p e utics wit h differe nt mec h a nis ms of acti o n are n o w bei n g 
e val uate d i n 
N S C L C (re vie we d i n 
B uc h bi n der 
2 0 1 6 ).  
Ni v ol u ma b as c o m bi nati o n 
i m m u n ot hera p y 
wit h ipili m u ma b 
was e val uate d i n 
C hec k Mate  0 1 2, a p hase  1 st u d y i n 
treat me nt-naï ve patie nts wit h a d va nce d N S C L C (Hell ma n n 2 0 1 7 ).  Patie nts recei ve d ni v ol u ma b 
pl us i pili m u ma b at 1  of  3  d ose re gi me ns.  C o nfir m e d res p o nse rates w ere 4 7 % ( 9 5 %  CI:   3 1 % t o 
6 4 %) i n patie nts recei vi n g ni v ol u ma b e ver y 2 wee ks ( Q 2 W) pl us i pili m u ma b e ver y 1 2  wee ks 
( Q 1 2 W) a n d 3 8 % ( 9 5 % CI:   2 3 % t o 5 5 %) i n patie nts recei vi n g ni v ol u ma b Q 2 W pl us i pili m u ma b 
e ver y 6  w ee ks ( Q 6 W).  T he me dia n D O R was n ot reac h e d i n eit her tr eat me nt gr o u p ( m e dia n 
f oll o w-u p ti mes of 1 2. 8  m o nt hs i n t he patie nts recei vi n g ni v ol u ma b Q 2 W pl us i pili m u ma b 
Q 1 2 W a n d 1 1. 8 m o nt hs i n t he patie nts recei vi n g ni v ol u ma b Q 2 W pl us i pili m u ma b Q 6 W).  T he 
greatest p erce nta ge of res p o nses was n ot e d i n p a tie nts wit h t u m ors t hat e x presse d P D-L 1.  I n 
patie nts w h ose t u m ors e x presse d P D -L 1  i n ≥1 % of t u m or cells, c o nfir me d o bjecti ve res p o nses 
were ac hie ve d i n 1 2  of  2 1  ( 5 7 %) patie nts i n t he i pili m u ma b Q 1 2 W treat me nt gr o u p a n d 1 3 of 
2 3  ( 5 7 %) patie nts i n t he i pili m u ma b Q 6 W treat me nt gr o u p (Hell ma n n 2 0 1 7 ).  T he 1-year 
s ur vi val rate i n patie nts treate d wit h ni v ol u ma b 3 m g/ k g Q 2 W pl us i pili m u ma b 1  m g/ k g Q 6 W or 
Q 1 2 W was 1 0 0 % i n pati e nts wit h t u m ors t hat e x presse d P D -L 1  i n ≥5 0 % of t u m or cells ( n = 1 3) 
a n d was 7 6 % i n all -c o mers (all p atie nts re gar dless of P D -L 1 stat us [ n = 7 7]), c o m pare d t o 7 3 % f or 
patie nts recei vi n g ni v ol u ma b m o n ot hera p y ( n = 5 2).  O ne -year s ur vi val i n patie nts wit h t u m ors 
t hat e x presse d P D-L 1 i n > 1 % of t u m or cells was 9 1 % i n t he ni v ol u ma b 3  m g/ k g  pl us i pili m u ma b 
1  m g/ k g Q 1 2 W treat me nt gr o u p a n d 8 3 % i n t he ni v ol u ma b 3  m g/ k g pl us i pili m u ma b 1  m g/ k g 
Q 6 W treat me nt gr o u p ( n = 2 3 i n eac h treat me nt gr o u p) c o m pare d t o 7 3 % i n t he ni v ol u ma b 
m o n ot hera p y gr o u p ( n = 3 2) (Getti n ger 2 0 1 6 ).  T h e i m pr o ve d efficac y i n N S C L C patie nts w h ose 
t u m ors e x presse d P D-L 1 c o ntrasts t o t he p has e  3 st u d y i n patie nts wit h mel a n o ma (Lar ki n 2 0 1 5 ), 
w here t he a d diti o n of a nti -C T L A -4 t o a nti -pr o gra m me d deat h -1 (a nti -P D -1) pr o vi de d b e nefit 
pre d o mi na ntl y t o t h ose p atie nts w h ose t u m ors ha d l o w baseli ne P D -L 1 e x pressi o n.  
C o m bi nati o n i m m u n ot hera p y wit h d ur val u ma b (a nti -pr o gra m me d deat h li ga n d 1 [a nti -P D -L 1]) 
pl us tre meli m u ma b (a nti -C T L A -4) is c urre ntl y bei n g e val uate d i n 
m ulti ple ca ncer t y p es, 
i ncl u di n g ur ot helial carci n o ma ( N C T 0 2 5 1 6 2 4 1), s q ua m o us cell carci n o ma of t he hea d a n d n ec k 
( N C T 0 2 5 5 1 1 5 9), a n d re nal cell carci n o ma ( N C T 0 2 7 6 2 0 0 6). I n p atie nts wit h N S C L C, t he 
d ur val u ma b pl us tre meli m u ma b c o m bi nati o n de m o nstrate d cli nical acti vit y re gar dless of P D -L 1 
e x pressi o n le vels. I n vesti gat or -re p orte d c o nfir me d res p o nses occ urre d i n 2 3 % of patie nts 
( 9 5 % CI:   9 % t o 4 4 %) i n t he d ur val u ma b pl us tre meli m u ma b c o m bi nati o n t hera p y gr o u p, 
i ncl u di n g 2 2 % ( 9 5 % CI:   3 % t o  6 0 %) of patie nts wit h P D -L 1 -p ositi ve t u m ors (t u m ors t hat 
e x press P D -L 1 o n ≥2 5 % of t u m or cells) a n d 2 9 % ( 9 5 %  CI:   8 % t o 5 8 %) of patie nts wit h 
P D -L 1 -ne gati ve t u m ors (t u m ors t hat e x press P D -L 1 o n < 2 5 % of t u m or cells) (A nt o nia 2 0 1 6 ).  
Rece ntl y, h o w e ver, a p hase 3 trial d ur val u ma b i n c o m bi nati o n wit h tr e meli m u ma b faile d t o 
si g nifica ntl y i m pr o ve P F S o ver sta n dar d-of -care c he m ot hera p y i n P D -L 1 -p ositi ve patie nts wit h 
a d va nce d N S C L C (Astr a Ze n eca M Y S TI C Press Re lease, 2 7 J ul y 2 0 1 7). 
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
 
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 3 0  of  1 2 9  
C O N FI D E N TI A L  
I pili m u ma b pl us c he m ot hera p y als o d e m o nstrat e d i m pr o ve d me dia n O S o ver c he m ot hera p y 
al o ne ( 1 2. 2 vers us 8. 3  m o nt hs; p = 0. 2 3) i n pre vi o usl y u ntr eate d p atie nts wit h N S C L C w he n 
c he m ot hera p y 
was gi v e n first f oll o we d b y i pili m u ma b (“ p hase d i pili m u ma b”).  
Me dia n 
i m m u ne-relate d P F S, t he pri mar y e n d p oi nt, was si g nifica ntl y i m pr o ve d i n patie nts recei vi n g 
p hase d i pili m u ma b o ver c he m ot hera p y al o ne ( 5. 7  vers us 4. 6  m o nt hs; p = 0. 0 5) (L y n c h 2 0 1 2 ).  
1. 2.  
Ce mi pli m a b  
Ce mi pli ma b ( R E G N 2 8 1 0 ) is a hi g h-affi nit y, f ull y h u ma n, hi n ge -sta bilize d i m m u n o gl o b uli n G 4 
pr otei n  (I g G 4 P) a nti b o d y dir ecte d t o t he P D-1  rece pt or t h at p ote ntl y bl o c ks t he i nteracti o n of 
P D -1 wit h its li ga n ds, P D -L 1 a n d P D -L 2.  Re ge n er o n P har mace uticals, I nc. ( Re ge n er o n) i s 
de vel o pi n g ce mi pli ma b  as a f o u n dati o nal i m m u n o -o nc ol o g y a ge nt t o be c o m bi ne d wit h ma xi mal 
fle xi bilit y 
wit h ot her a nti-ca ncer i m m u n ot hera pies c urre ntl y i n pre -cli nical de vel o p me nt. 
Pre -cli nical d ata i n dicat e t hat ce mi pli ma b has a si milar efficac y t o ot her  a p pr o ve d a nti -P D -1 
a nti b o dies.  Data fr o m cli nical st u dies, t o date, i n dicate t hat ce mi pli ma b has p ote nt a nti -t u m or 
acti vit y a n d a n acce pta bl e safet y pr ofile.  
I n t h e pi v otal p hase 2 cli nical st u d y, R 2 8 1 0 -O N C -1 5 4 0 , of ce mi pli ma b i n 8 2 patie nts  wit h 
a d va nced c uta ne o us s q u a m o us cell carci n o ma ( C S C C), t he sec o n d dea dli est s ki n ca ncer after 
mela n o ma, ce mi pli ma b de m o nstrate d a n o verall res p o nse rate ( O R R) of 4 6. 3 %, as d eter mi ne d b y 
i n de pe n de nt re vie w. T he me dia n D O R ha d n ot yet bee n reac h e d at t he data c ut-off p oi nt ( 3 2 of 
3 8 res p o nses  are o n g oi n g).  At t he ti me of t his a nal ysis, all patie nts ha d a mi ni m u m f oll o w -u p of 
6 m o nt hs. T he safet y pr ofile  i n t he st u d y was ge n erall y c o nsiste nt wit h a p pr o ve d a nti-P D -1 
a ge nts.  
T he N S C L C e x pa nsi o n c o h ort of t he first-i n– h u ma n  ( FI H) st u d y R 2 8 1 0-O N C -1 4 2 3 (a d va nce d 
s oli d mali g na ncies) e nr olle d patie nts w h o ha ve rela pse d after, or were refract or y t o at least 
first-li ne t hera p y i n t h e rec urre nt or metastatic disease s etti n g.  Of t he 2 1 patie nts wit h N S C L C 
w h o  e nr olle d, 6 ha d parti al res p o nse ( P R) a n d 4 ha d sta ble disease ( S D).  T he O R R (calc ulate d 
as c o m plete res p o nse [ C R] + P R), per ce ntr al i n de pe n de nt re vie w was 2 8. 6 %  ( 6/ 2 1).  Disease 
c o ntr ol rate ( O R R + S D) was 5 7. 1 % ( 1 2/ 2 1; 1 patie nt was a n o n -C R/ n o n -pr o gressi ve dis ease 
[ P D]).  O verall, 9  patie nts (all fr o m E C 1) ha d P D d uri n g treat me nt wit h ce mi pli ma b.  I n t his 
p hase 1 st u d y, ce mi pli ma b was  ge n erall y well t olerate d a n d e x hi bite d a ntit u m or acti vit y i n 
N S C L C patie nts.   
C ollecti vel y,  t he esta blis he d 
s u peri or 
efficac y 
of 
a p pr o ve d 
a nti-P D -1 
a ge nts 
o ver 
sta n dar d-of -care i n t he sec o n d -li ne treat me nt of N S C L C , al o n g wit h data  s u g gesti n g ce mi pli ma b 
is c o m para ble i n effic ac y t o ot her a p pr o ve d a nti-P D -1 a nti b o dies, pr o vi de c o m pelli n g e vi de nce 
t o s u p p ort t he st u d y of ce mi pli ma b, eit her as m o n ot hera p y or i n c o m bi nati o n wit h ot her 
i m m u n ot hera p y, as sec o n d -li ne treat me nt f or N S C L C  patie nts . 
T he s t u d y descri be d h erei n ( R 2 8 1 0 -O N C -1 7 6 3 ) is a ra n d o mize d, o pe n-la bel, p hase 2 st u d y of t he 
c urre nt “sta n d ar d” d ose of ce mi pli ma b ( 3 5 0 m g d ose; “ S D R E G N 2 8 1 0 ”) vers us “ hi g h” d ose 
ce mi pli ma b 
( 1 0 5 0 
m g; 
“ H D R E G N 2 8 1 0") 
vers us 
ce mi pli ma b 
pl us 
i pili m u ma b 
( S D R E G N 2 8 1 0/i pi) c o m bi nati o n t hera p y f or t he treat me nt of patie nts wit h a d va nce d N S C L C 
w h o ha v e recei v e d o n e pri or c h e m ot hera p y treat me nt f or t heir a d va n ce d diseas e.  T he mai n g o al  
of t he st u d y is t o c o m pare t he efficac y of hi g h -d ose ce m pli ma b  or ce mi pli ma b  pl us i pili m u ma b 
c o m bi nati o n t hera p y wit h t hat of sta n dar d d ose ce mi pli ma b, as sec o n d -li ne treat me nt f or patie nts 
wit h a d va nce d N S C L C .  O t her a p pr o ve d a nti-P D -1 o r a nti-P D -L 1 a nti b o dies ha ve esta blis he d 
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
 
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 3 1  of  1 2 9  
C O N FI D E N TI A L  
effic ac y f or sec o n d-li ne treat me nt of N S C L C , a n d is partic ularl y effecti ve i n patie nts wit h P D-L 1 
e x pressi o n i n ≥5 0 % of t u m or cells . This st u d y see ks t o s pecificall y e v al uate t he efficac y of 
ce mi pli ma b i n patie nts w it h P D-L 1 e x pressi o n i n < 5 0 % of t u m or cells.  Acc or di n gl y,  t h e 
pri mar y e n d p oi nt  of t his st u d y is  t he O R R bas e d o n R E CI S T  1. 1 ass ess me nts, i n N S C L C patie nts 
w h ose t u m ors e x press  P D -L 1 e x pressi o n i n < 5 0 % of t u m or cells , w here t here is t he greater n ee d 
t o i m pr o ve o utc o me.  
A d diti o nal st u dies u n der wa y wit h ce mi pli ma b are detaile d i n t he I n vesti gat or’s Br oc h ure.  A n 
o ver vie w of  rel e va nt safet y (i ncl u di n g patie nt e x p os ure a n d i m m u ne -relate d a d v erse e ve nts 
[ir A Es]) a n d efficac y d ata f or ce mi pli ma b are a vaila ble i n t he latest e diti o n of t he I n v esti gat or’s 
Br oc h ure.  
2.  
S T U D Y O B J E C TI V E S  
2. 1.  
Pri m ar y O bjecti ve  
T he pri mar y o bjecti ve of t he st u d y is t o c o m pare t he 
O R R of hi g h d ose ce mi pli ma b 
(“ H D R E G N 2 8 1 0 ”) a n d sta n dar d d os e ce mi pli ma b  pl us i pili m u ma b c o m bi nati o n t hera p y 
(“ S D R E G N 2 8 1 0/i pi”) t o t he O R R of sta n d ar d d ose ce mi pli ma b  (“ S D R E G N 2 8 1 0”) i n t he 
sec o n d-li ne tr eat me nt of patie nts wit h a d va nce d s q ua m o us or n o n-s q ua m o us N S C L C, i n patie nts 
w h ose t u m ors e x press P D -L 1 i n < 5 0 %  of t u m or cel ls. 
2. 2.  
Sec o n d ar y O bjecti ves  
2. 2. 1.  
Sec o n d ar y O bjecti ves  
T he sec o n d ar y o bjecti ves of t he st u d y are t he f oll o wi n g:  
 T o c o m pare t he O R R  of H D R E G N 2 8 1 0 a n d S D R E G N 2 8 1 0/i pi t o t he O R R of 
S D R E G N 2 8 1 0  i n t he sec o n d-li ne treat me nt of p atie nts wit h a d va nce d s q ua m o us or 
n o n -s q ua m o us N S C L C i n all patie nts .  
 T o c o m pare t h e O S  of H D R E G N 2 8 1 0 , a n d S D R E G N 2 8 1 0/i pi c o m bi nati o n t hera p y 
c o m pare d t o t h e O S of S D R E G N 2 8 1 0 i n t he sec o n d-li ne treat me nt of p atie nts wit h 
a d va nce d s q ua m o us or n o n -s q ua m o us N S C L C i n patie nts wit h  P D -L 1 i n < 5 0 % of 
t u m or cells a n d i n all patie nts . 
 T o c o m pare t h e P F S  of H D R E G N 2 8 1 0 a n d S D R E G N 2 8 1 0/i pi c o m bi nati o n t hera p y t o 
t he P F S of S D R E G N 2 8 1 0 i n t he sec o n d-li ne treat me nt of patie nts wit h a d va nce d 
s q ua m o us or n o n -s q u a m o us N S C L C i n patie nts wit h  P D -L 1 i n < 5 0 % of t u m or cells 
a n d i n all patie nts.  
 T o e val uate t he safet y a n d t olera bilit y of H D R E G N 2 8 1 0 a n d S D R E G N 2 8 1 0/i pi 
c o m pare d t o t h ose of  S D R E G N 2 8 1 0 t hera p y  
2. 2. 2.  
E x pl or at or y  O bjecti ves  
 T o e val uate t he O S at 1 2 a n d 1 8 m o nt hs of H D R E G N 2 8 1 0 a n d S D R E G N 2 8 1 0/i pi 
vers us S D R E G N 2 8 1 0 t hera p y i n t he sec o n d -li ne treat me nt of patie nts wit h a d va nce d 
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
 
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 3 2  of  1 2 9  
C O N FI D E N TI A L  
s q ua m o us or n o n-s q ua m o us N S C L C i n patie nts w h ose t u m ors e x press P D-L 1 i n 
< 5 0 % of t u m or cells a n d i n all patie nts  
 T o e val uate Q O L i n patie nts wit h a d va nce d s q ua m o us or n o n -s q ua m o us N S C L C 
recei vi n g H D R E G N 2 8 1 0 a n d S D R E G N 2 8 1 0/i pi vers us S D R E G N 2 8 1 0 t hera p y 
 T o assess i m m u n o ge ni cit y as 
meas ure d b y a nti -dr u g a nti b o dies ( A D As) f or 
ce mi pli ma b  
 T o c haracterize t he P K of ce mi pli ma b w he n a d mi nistere d i n c o m bi n ati o n wit h 
i pili m u ma b or as H D R E G N 2 8 1 0 
 T o assess t he pre dicti v e utilit y of bas eli ne P D -L 1 t u m or e x pressi o n le vels o n 
i n dicat ors of cli nical r es p o nse  
 T o c o n d uct e x p os ure -res p o nse ( E-R) a nal yses f or rele va nt bi o mar kers (e x pl orat or y 
P K/ p har mac o d y na mic a n al yses) a n d E -R a nal yses f or safet y a n d efficac y e n d p oi nts, 
as a p pr o priat e  
 T o c o m pare t he rate of occ urre nce of hair re -pi g me ntati o n of patie nts i n eac h 
treat me nt ar m  
 T o e val u ate t u m or m utati o n b ur de n ( T M B) i n eac h tr eat me nt ar m a n d assess t he 
pre dicti ve utilit y of bas eli ne T M B o n cli nical res p o nses t o treat me nt  
 T o e val uate c ha n ge i n t u m or v ol u me i n eac h tr eat me nt ar m 
 T o e val uate c orrelati o n bet wee n e x p os ure, efficac y, a n d s afet y wit h peri p heral 
p har mac o d y n a mic bi o mar ker meas ures  i ncl u di n g t he i ncrease i n I C O S + C D 4 T-cell 
fre q ue n c y a n d ot her mar kers of T -cell acti vati o n  i n eac h tr eat me nt ar m. 
3.  
H Y P O T H E SI S A N D R A TI O N A L E  
3. 1.  
H y p ot hesis  
T he pri mar y h y p ot hesis of t his st u d y is t hat H D R E G N 2 8 1 0 or S D R E G N 2 8 1 0/i pi will ha ve a 
hi g her res p o nse ra te t ha n S D R E G N 2 8 1 0 i n patie nts w h ose t u m ors e x press P D-L 1 i n < 5 0 % of 
t u m or cells.  T he sec o n d ar y h y p ot heses are t hat: 
 H D R E G N 2 8 1 0 
or 
S D R E G N 2 8 1 0/i pi 
will 
ha ve 
a 
hi g h er res p o nse rate  t ha n 
S D R E G N 2 8 1 0 i n patie nts w h ose t u m ors e x press P D -L 1 < 5 0 % of t u m or cells  a n d i n all 
patie nts  
 H D R E G N 2 8 1 0 or S D R E G N 2 8 1 0/i pi 
will i m pr o ve 
O S a n d P F S c o m pare d 
wit h 
S D R E G N 2 8 1 0 i n patie nts w h ose t u m ors e x press P D -L 1 < 5 0 % of t u m or cells, i n patie nts 
w h ose t u m ors e x press P D -L 1 ≥5 0 % a n d i n all patie nts  
Hist oricall y , me di a n P F S i n patie nts wit h a d va nce d  s q ua m o us a n d n o n-s q u a m o us N S C L C treat e d 
wit h plati n u m -base d d o u blet c he m ot hera p y has ra n ge d fr o m a p pr o xi matel y 2. 7  t o 6. 4  m o nt hs 
(El -S he ns ha w y  2 0 1 2 )(Kell y  2 0 0 1 )(R osell  2 0 0 2 )(S ca gli otti  2 0 0 2 )(Sc hiller  2 0 0 2 )(S hi miz u  2 0 1 3 ) 
(Rec k  2 0 1 6 ).  Wit h t he e mer ge n ce of i m m u n ot hera p y a n d t he rec o g niti o n t hat N S C L C t u m ors 
e x press P D -L 1, t he effects of a variet y of P D -1/ P D -L 1 i n hi bit ors  as m o n ot hera p y a n d i n 
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
 
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 3 3  of  1 2 9  
C O N FI D E N TI A L  
c o m bi nati o n wit h c he m ot hera p y are bei n g i n vesti gat e d.  Acc u m ulati n g cli nical data s u g gest t hat 
a nti-P D -1 m o n ot hera p y ma y pr ol o n g O R R, P F S a n d O S i n N S C L C, wit h t he great est cli nical 
be nefit o bser v e d i n t u m ors e x pressi n g P D-L 1, es peciall y at hi g h le vels.   
A nti -P D -1 
m o n ot hera p y as a first -li ne treat me nt i n patie nts wit h a d va nce d 
N S C L C has 
de m o nstrate d efficac y (Getti n ger  2 0 1 6 )(Gar o n  2 0 1 5 ) a n d a si g nifica nt i m pr o ve me nt i n P F S 
c o m pare d t o c he m ot hera p y  (Rec k 2 0 1 6 ).  C o m bi nati o n i m m u n ot hera pies f or N S C L C ha ve als o 
de m o nstrate d cli nical a cti vit y (Hell ma n n 2 0 1 7 ).   
Ce mi pli ma b  cli nical st u d y data ( Secti o n  1 ) i n a d diti o n t o t he de m o nstrate d cli nical acti vit y of 
i pili m u ma b s u p p ort t he h y p ot hesis t hat H D R E G N 2 8 1 0 a n d S D R E G N 2 8 1 0/i pi c o m bi nati o n 
t hera p y m a y i m pr o ve O R R i n patie nts wit h a d va nce d s q uam o us or n o n -s q ua m o us N S C L C wit h 
t u m ors e x pressi n g P D-L 1 < 5 0 % . 
3. 2.  
R ati o n ale  
3. 2. 1.  
R ati o n ale f or St u d y Desi g n  
T his st u d y is a ra n d o mi ze d, gl o bal,  o pe n -la bel, p hase 2 st u d y c o m pari n g H D R E G N 2 8 1 0 a n d 
S D R E G N 2 8 1 0 /i pi t o S D R E G N 2 8 1 0 i n t he sec o n d-li ne treat me nt of p atie nts wit h a d va nce d 
s q ua m o us or n o n-s q ua m o us N S C L C. 
T his st u d y will be o pe n -la bel beca use i pili m u ma b is a d mi nistere d at a Q 6 W d osi n g re gi me n 
c o m pare d wit h ce mi pli ma b , w hic h is a d mi nistere d e ver y 3 wee ks ( Q 3 W).  I n a d diti o n, t he 
differe n ces i n a d mi nistrati o n a n d  k n o w n disti nct t o xicities of t he t hera pies d o n ot le n d 
t he msel ves t o mas ki n g. 
T he st u d y p o p ul ati o n is li mite d t o pre vi o us a n d c urre nt s m o kers as t he be nefit of P D -1 bl oc ka de 
has n ot bee n s h o w n t o t he sa me e xte nt i n n o n -s m o kers, li kel y d u e t o t he l o wer m utati o nal b ur de n 
i n t his p o p ulati o n (Rec k 2 0 1 6 ). 
3. 2. 2.  
R ati o n ale f or E n d p oi nts a n d O bjecti ves  
T he pri mar y o bje cti ve of t his st u d y is t o c o m pare t he 
O R R of 
H D R E G N 2 8 1 0 a n d 
S D R E G N 2 8 1 0/i pi t o S D R E G N 2 8 1 0 i n t he sec o n d-li ne treat me nt of p atients wit h a d va nce d 
s q ua m o us or n o n-s q ua m o us N S C L C i n patie nts w h ose t u m ors e x press P D-L 1 i n < 5 0 % of t u m or 
cells.  O verall s ur vi val is t he ulti mate e n d p oi nt of ce mi pli ma b  c o m bi nati o n t hera p y b e nefit .  T his 
is a p hase 2 st u d y d esi g ne d t o descri be  a n i m pr o ve me nt i n O R R as a n i n dicat or of e n ha n ce d 
effic ac y of eit her hi g her e x p os ure of a nti -P D -1 or c o m bi nati o n of a nti -P D -1 a n d a nti -C T L A -4 . 
O bjecti ve res p o nse rate, defi ne d as t he pr o p orti o n of patie nts w h o ac hie ve C R or P R base d o n 
R E CI S T  1. 1 criteria (Eise n ha uer  2 0 0 9 ) as assesse d b y t he i n v esti gat or  a n d c o nfir me d b y a n 
i n de pe n de nt re vi e w c o m mittee, was c h ose n as t h e pri mar y e n d p oi nt beca use O R R is rec o g nize d 
as a mar k er of cli nical b e nefit.  O bjecti ve res p o nse rate is a n a p pr o va bl e e n d p oi nt i n t he U S a n d 
is als o acce pta ble i n t h e E U f or st u dies w here t he e x peri me ntal t hera p y is li kel y t o b e well 
t olerate d.  Pr o gressi ve disease 
will be deter mi ne d base d o n t he 
R E CI S T 1. 1 criteria 
(Eise n ha uer  2 0 0 9 ).  T he first ra di o gra p hic t u m or assess me nt will occ ur after 9  wee ks of st u d y 
treat me nt, a n d s u bse q u e nt assess me nts will occ ur e ver y 9 wee ks ( Q 9 W) d uri n g year  1, Q 1 2 W  
d uri n g 
year  2, a n d  Q 1 2 W d uri n g f oll o w -u p or u ntil i n de pe n de nt re vie w c o m mittee 
(I R C)-assesse d  R E CI S T  1. 1 -defi ne d P D  or earl y treat me nt disc o nti n uati o n f or a n ot her reas o n.  
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
 
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 3 4  of  1 2 9  
C O N FI D E N TI A L  
F urt her, t o di mi nis h bias i n t he assess me nt of disease pr o gressi o n i n t his o pe n -la bel st u d y, a n 
I R C, w hic h will be bli n de d t o treat me nt assi g n me nt, will be utilize d t o a dj u dicat e t u m or 
res p o nses.  O v erall s ur vi val at 1 2 m o nt hs, 1 8 m o nt hs, a n d e n d of tr eat me nt a n d P F S will be 
assesse d as sec o n d ar y e n d p oi nts, des pite t he ac k n o wle d ge d li mitati o ns.  Fr o m a patie nt 
pers pecti ve, pres er vati o n of Q O L is i m p orta nt; t heref ore, Q O L will be ass esse d t hr o u g h t he use 
of 2  vali date d q uesti o n naires.  
Rece nt fi n di n gs i n dicate t hat hair re -pi g m e ntati o n ma y b e a mar ker f or t u m or res p o nse , a n d this 
will als o be e x a mi ne d (Ri vera 2 0 1 7 ).  A d diti o nall y, t u m or v ol u me m a y be c o rrelate d wit h 
s ur vi val a n d bi o mar kers a n d will be assesse d (Nis hi n o  2 0 1 6 ). 
3. 2. 3.  
R ati o n ale f or C h oice of P ati e nt P o p ul ati o n  
Data s u g gest t hat t u m or cell P D -L 1 e x pressi o n ma y c orrel ate wit h a nti -P D -1 cli nical acti vit y i n 
b ot h s q ua m o us a n d n o n -s q ua m o us N S C L C (Ga d geel  2 0 1 6 )(Getti n ger  2 0 1 5 )(Hell ma n n 2 0 1 7 ) 
a n d t hat hi g h le vels of P D -L 1 e x pressi o n were pre vi o usl y c orrelate d wit h p o or patie nt pr o g n osis 
a n d resista nce t o  c yt ot o xic  treat me nt i n N S C L C (Creela n 2 0 1 4 ). 
A nti -P D -L 1 m o n ot hera p y st u dies h a ve b ee n c o n d ucte d i n patie nts wit h N S C L C.  F or e x a m ple, i n 
a n e x pl orat or y a nal ysis of a n o n g oi n g st u d y, ni v ol u ma b m o n ot hera p y i n c he m ot hera p y -n aï ve 
patie nts wit h a d va nce d N S C L C res ulte d i n hi g h er res p o ns e rates a n d m ore pr ol o n ge d P F S a n d 
1 -year O S rates as t he l e vel of P D -L 1 e x pressi o n i ncrease d ( 1 %, 5 %, 1 0 %, 2 5 %, a n d 5 0 %) 
(Getti n ger  2 0 1 5 ).  A st u d y of p e m br oliz u ma b m o n ot hera p y ( K E Y N O T E-0 2 1) i n patie nts wit h 
N S C L C s h o w e d a hi g h er res p o nse rate a n d l o n ger P F S a n d O S rates i n pati e nts e x pressi n g ≥5 0 % 
P D -L 1 t ha n i n u ntreate d a n d pre vi o usl y tr eate d p atie nts e x pressi n g < 5 0 % P D -L 1 (Gar o n  2 0 1 5 ).  
A p hase 1 st u d y o f ni v ol u ma b m o n ot hera p y or ni v ol u ma b c o m bi ne d wit h i pili m u ma b i n patie nts 
wit h a d va nce d N S C L C ( C hec k Mate  0 1 2) de m o nstrate d t he greatest be n efit i n patie nts e x pressi n g 
P D -L 1 ≥5 0 % wit h a n O R R of 9 2 % (Hell ma n n 2 0 1 7 )(Getti n ger 2 0 1 6 ).  A p hase  3 st u d y 
( C hec k Mate 0 2 6) i n vesti gati n g t he effi cac y of first -li ne treat me nt wit h ni v ol u ma b m o n ot hera p y 
c o m pare d t o plati n u m -b ase d d o u blet c he m ot hera p y i n patie nts wit h a d va nce d N S C L C a n d 
P D -L 1 -p ositi ve t u m ors faile d t o meet its pri mar y e n d p oi nt of P F S.  E ve n i n a s u bset a nal ysis of 
t h ose patie nts wit h P D-L 1 e x pressi o n i n ≥5 0 % of t u m or cells, ni v ol u ma b faile d t o de m o nstrat e 
a n y i m pr o ve me nt o ver c he m ot hera p y (S oci ns ki  2 0 1 6 ). 
Ge nerall y, a nti -P D -1 m o n ot hera p y h as bee n s h o w n t o be m ore efficaci o us i n N S C L C patie nts  
w h ose t u m ors e x press P D -L 1 i n ≥5 0 % of t u m or cells b ut less efficaci o us i n patie nts w h ose 
t u m ors e x press P D-L 1 i n  < 5 0 % of t u m or cells.  I n or der t o treat patie nts w h ose  t u m ors e x press 
l o wer le v els of P D-L 1, a c o m bi nati o n i m m u n ot hera p y re gi me n 
will li kel y b e re q uire d.   
Acc or di n gl y, t he pri mar y o bjecti ve of t his st u d y is t o e val uate t he efficac y of ce mi pli ma b, b ot h 
as m o n ot hera p y a n d as c o m bi nati o n t hera p y, i n N S C L C patie n ts wit h P D-L 1 e x pressi o n i n < 5 0 % 
of t u m or cells.  F or c o m paris o n, t his st u d y will t heref ore als o e val uate efficac y of ce mi pli ma b i n 
patie nts wit h N S C L C w h ose t u m ors ha ve P D -L 1 i n ≥5 0 % of t u m or cells, w here efficac y of  
a nti-P D -L 1 bl oc ka de h as bee n esta blis h e d, a n d i n all N S C L C patie nts.  
3. 2. 4.  
R ati o n ale f or C o m bi n ati o n of Ce mi pli m a b  a n d I pili m u m a b  
C o m bi nati o n i m m u n ot hera pies t hat i ncl u de a n a nti -C T L A -4 a ge nt a n d a n a nti -P D -1/ P D -L 1 a ge nt 
ha ve t he p ote ntial f or a d diti ve or s y ner gistic effects (re vie we d i n  B u c h bi n der 2 0 1 6 ).   
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
 
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 3 5  of  1 2 9  
C O N FI D E N TI A L  
Cli nical acti vit y of t he c o m bi nati o n of a nti -P D -L 1 a n d a nti -C T L A -4 has bee n de m o nstrate d i n 
st u dies of d ur val u ma b pl us tre meli m u ma b (A nt o nia 2 0 1 6 ) (Secti o n 1 ) a n d ni v ol u ma b pl us 
i pili m u ma b ( descri be d i n detail bel o w). 
I pili m u ma b has s h o w n pr o mise i n m ulti ple t u m or t y p es a n d is a p pr o ve d as m o n ot hera p y a n d i n 
c o m bi nati o n wit h  ni v ol u ma b f or a d va n ce d mela n o ma.  I pili m u ma b pl us ni v ol u ma b c o m bi nati o n 
t hera p y w as a p pr o ve d f or t he treat me nt of a d va nce d 
mela n o ma b as e d o n t he res ults of 
C hec k Mate  0 6 7 t hat d e m o nstrate d si g nifica ntl y i m pr o ve d P F S i n patie nts treate d 
wit h 
c o m bi nati o n t he ra p y ( 1 1. 5 m o nt hs; 9 5 % CI:   8. 9 t o 1 6. 7  m o nt hs) c o m pare d wit h i pili m u ma b 
m o n ot hera p y ( 2. 9  m o nt hs; 9 5 %  CI:   2. 8 t o 3. 4 m o nt hs; H R f or deat h or disease pr o gressi o n, 
0. 4 2; 
9 9. 5 % 
CI:   0. 3 1 t o 
0. 5 7; 
p < 0. 0 0 1) 
a n d 
ni v ol u ma b 
m o n ot hera p y ( 6. 9  m o nt hs; 
9 5 %  CI:   4. 3  to 9. 5 m o nt hs; H R f or t he c o m p aris o n wit h i pili m u ma b, 0. 5 7; 9 9. 5 %  CI:   0. 4 3 
t o 0. 7 6; p < 0. 0 0 1) (Lar ki n  2 0 1 5 ). 
I pili m u ma b pl us ni v ol u ma b c o m bi nati o n t hera p y h as als o de m o nstrat e d cli nical acti vit y i n 
N S C L C ( Secti o n  1 ) as a first-li ne treat me nt i n a d va nce d N S C L C.  I n t he C hec k Mate 0 1 2 st u d y, 
c o nfir me d res p o nse rates were 4 7 % ( 9 5 %  CI:   3 1 % t o 6 4 %) i n patie nts recei vi n g ni v ol u ma b 
Q 2 W pl us i pili m u ma b Q 1 2 W a n d 3 8 % ( 9 5 %  CI:   2 3 % t o 5 5 %) i n patie nts recei vi n g ni v ol u ma b 
Q 2 W pl us i pili m u ma b Q 6 W.  T he greatest perce nta ge of res p o nses was n ote d i n patie nts wit h 
t u m ors t hat e x presse d P D-L 1 (Hell ma n n 2 0 1 7 ), w hic h is i n c o ntrast wit h t he p hase 3 st u d y i n 
mela n o ma (Lar ki n 2 0 1 5 ), i n w hic h t he a d diti o n of a n a nti-C T L A -4 a ge nt t o a n a nti -P D -1 a ge nt 
pr o vi de d a b e nefit pre d o mi na ntl y i n patie nts wit h l o w baseli ne P D -L 1 p ositi vit y.  T h e 1 -year 
s ur vi val rat e i n p atie nts wit h t u m ors t hat e x press e d P D-L 1 i n ≥5 0 % of t u m or cells ( n = 1 3) was 
1 0 0 % a n d i n all -c o mers ( n = 7 7) was 7 6 %, c o m p are d t o 7 3 % f or patie nts recei vi n g ni v ol u ma b 
m o n ot hera p y ( n = 5 2) (G etti n ger 2 0 1 6 )(see Secti o n 1  f or a d diti o nal details).   
Ce mi pli ma b  a n d i pili m u ma b are i m m u n o -o nc ol o g y a ge nts wit h differe nt mec ha nis ms of acti o n.  
Ce mi pli ma b  is a m o n ocl o nal a nti b o d y t o t he P D-1 rece pt or t hat bl oc ks P D -1/ P D -L 1 -m e diate d 
T -cell i n hi biti o n, w hereas i pili m u ma b is a n i n hi bit or of c yt ot o xic T -l y m p h oc yte-ass ociat e d 
pr otei n 4 ( C T L A -4 ).  Base d o n t he u ni q ue mec ha nis ms of acti o n, t he a nti-P D -1/a nti -P D -L 1 
acti o n of ce mi pli ma b  a n d t he a nti -C T L A -4 acti o n of i pili m u ma b ha ve t h e p ote ntial f or a d diti ve 
or s y n er gistic effects (B u c h bi n der 2 0 1 6 ). 
3. 2. 5.  
R ati o n ale f or St a n d ar d D ose Ce mi pli m a b  D ose Selecti o n  
T he ce mi pli ma b d ose of 3 5 0  m g Q 3 W has b ee n selecte d f or t he d e vel o p me nt of ce mi pli ma b i n 
all f ut ure st u dies.  
T he prefere n ce f or a flat d ose o ver a b o d y -wei g ht -a dj uste d d ose f or a nti -P D -1 m o n ocl o nal 
a nti b o dies is s u p p orte d b y a wi de safet y mar gi n ( n o ma xi m u m t olerate d d ose  o bser ve d), a flat 
E -R relati o ns hi p f or safet y a n d efficac y o ver t he t hera pe utic d osi n g ra n ge, a n d si milar vari a bilit y 
i n e x p os ure ( C V %) after flat a n d b o d y-wei g ht -a dj uste d d oses (Fres h w at er 2 0 1 7 )(Z h a o  2 0 1 7a ).  
I n fact, pe m br oliz u ma b a n d ni v ol u ma b were i nitiall y a p pr o ve d at b o d y-wei g ht -a dj uste d d oses of 
2  m g/ k g Q 3 W a n d 3  m g/ k g Q 2 W, res pecti vel y, a n d were rece ntl y a p pr o ve d b y t he U S F D A at 
flat d oses of 2 0 0 m g Q 3 W a n d 2 4 0  m g Q 2 W, res pecti vel y, f or  t he treat me nt of mela n o ma a n d 
N S C L C (K E Y T R U D A Pac ka ge I nsert )(O P DI V O Pac ka ge I ns ert ).   
A flat I V ce mi pli ma b  d ose of 3 5 0  m g Q 3 W was selecte d bas e d o n p o p ulati o n P K m o deli n g a n d  
si m ulati o n, i ncl u di n g p o p ulati o ns (e g, J a pa n or ot her c o u ntries i n t he Asia/ Pacific Ri m) w here, 
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
 
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 3 6  of  1 2 9  
C O N FI D E N TI A L  
o n a vera ge, t he b o d y wei g ht i n t he p o p ulati o n is sli g htl y l o wer as c o m pare d t o Wester n patie nts 
( wit h b o d y wei g ht distri b uti o n ar o u n d a mea n of 6 0 k g vers us 8 0 k g) (S hi miz u  2 0 1 6 ). A s mall 
(a p pr o xi matel y 1 6 %) a n d cli nicall y u ni m p orta nt i ncreas e i n e x p os ure of ce mi pli ma b  i n ser u m is 
pre dicte d o n a vera ge i n Asia n a n d/ or J a pa nes e patie nts vers us t he e xisti n g data i n 
Wester n 
patie nts  (see t he latest e diti o n of t he ce mi pli ma b I n vesti gat or’s Br oc h ure).  Wit h t he lac k of a n y 
a d de d safet y si g nal i n t he e xisti n g cli nical dat a at d oses u p t o 1 0 m g/ k g, t h e e xisti n g data s u p p ort 
t he use of t he 3 5 0 m g Q 3 W treat me nt re gi me n f or t he gl o bal d e vel o p me nt of ce mi pli ma b . 
3. 2. 6.  
R ati o n ale f or Hi g h D ose Ce mi pli m a b  D ose Sel ecti o n  
T he hi g h d os e of ce mi pli ma b , na mel y 1 0 5 0 m g Q 3 W, was selecte d t o be 3-f ol d hi g h er t ha n t he 
3 5 0 -m g Q 3 W d ose t o be use d i n t his st u d y a n d is e x pecte d t o res ult i n ce mi pli ma b  e x p os ure 
cl ose t o t hat o bser ve d after t he 1 0  m g/ k g Q 2 W d ose i n t he FI H st u d y, w hic h di d n ot re veal 
d ose -li miti n g t o xicities. 
Si m ulati o ns of ce mi pli ma b  e x p os ure ( l o west c o nce ntrati o n i n a d osi n g i nter val [C tr o u g h], area 
u n der t he c ur ve at 1 2 w ee ks [ A U C 1 2 W], a n d pea k c o nce ntrati o n  [C ma x ]) after d oses of 1 0 5 0 m g 
Q 3 W i n a p o p ulati o n of 1 0 0 0 patie nts wit h a b o d y wei g ht distri b uti o n ar o u n d 8 0 k g i n dicate d 
t hat e x p os ure wit h t he 1 0 5 0 m g Q 2 W flat d ose was si milar ( < 2 0 % differe nce) t o t hat o bser ve d 
after t he d os e of 1 0  m g/ k g Q 2 W i n t he FI H st u d y.  
C hatterjee s o u g ht t o c haracterize t he relati o ns hi p bet wee n pe m br oliz u ma b d ose, e x p os ure, a n d 
res p o nse i n K E Y N O T E -0 0 1 (C hatterjee 2 0 1 6 ).  Patie nts recei ve d pe m br oli z u ma b 2  m g/ k g Q 3 W 
( n = 5 5), 1 0 m g/ k g Q 3 W ( n = 2 3 8), or 1 0 m g/ k g Q 2 W ( n = 1 5 6).  T he relati o ns hi p bet wee n t he 
esti mate d pe m br oliz u ma b area u n der t he c o nce ntrati o n – ti me c ur ve at stea d y state o ver 6 wee ks 
( A U Css– 6 wee ks) a n d t he l o n git u di nal c h a n ge i n t u m or siz e was a nal yz e d b y re gressi o n a n d 
n o n -li near mi x e d effects m o deli n g.  O verall res p o nse rates were 1 5 % at 2 m g/ k g Q 3 W, 2 5 % at 
1 0  m g/ k g Q 3 W, a n d 2 1 % at 1 0 m g/ k g Q 2 W.  Re gressi o n a nal yses of perce nt a ge c h a n ge fr o m 
baseli ne i n t u m or siz e vers us A U C ss– 6 wee ks i n dicat e d a flat relati o ns hi p (re gressi o n sl o pe p > 0. 0 5).  
Si m ulati o ns s h o we d t he E -R rel ati o ns hi p t o be si milarl y fl at, t h us i n dicati n g t hat t he l o w est 
e val uate d d ose of 2 m g/ k g Q 3 W t o li kel y b e at or near t h e efficac y plat ea u.  E x p os ure – safet y 
a nal ysis s h o w e d t he a d verse e v e nt ( A E ) i nci de nce t o be si milar a m o n g t he cli nicall y teste d 
d oses.  T he a ut h ors c o ncl u de d t hat, base d o n t he o bser ve d cli nical data a n d c o m pre he nsi v e 
cli nical p har mac ol o g y 
m o deli n g a n d si m ulati o n, t he a p pr o ve d 2  m g/ k g 
Q 3 W d ose of 
pe m br oliz u ma b pr o vi des cli nicall y si g nifi ca nt a ntit u m or acti vit y  i n N S C L C, wit h a n efficac y a n d 
safet y pr ofile c o m para ble t o t h ose o bser ve d wit h d oses of 1 0 m g/ k g Q 3 W or 1 0 m g/ k g Q 2 W.  
A meta -a n al ysis (Jia 2 0 1 5) of 1 6 trials i ncl u d e d pe m br oliz u ma b, ni v ol u ma b, atez oliz u ma b, a n d 
d ur val u ma b . O ve rall, O R R i n t he w h ole p o p ulati o n wit h P D-1 bl oc ka ge tr eat me nt is 2 2. 5 %.  
A d diti o nall y, t he rat e of Gra de s 3  t o 4 A Es is 1 6. 7 % a n d dr u g -relate d d eat h rate is 2. 5 %.  
I n e x pl orat or y a n al ys es of ni v ol u ma b, a greater O R R was prese nt i n t he me dia n-d ose c o h ort 
(3  m g/ k g) t ha n i n b ot h t he l o w -d ose ( 1 m g/ k g) a n d hi g h -d ose ( 1 0 m g/ k g) c o h orts (l o w -d os e 
vers us me dia n -d ose: O R = 0. 1 2, p = 0. 0 0 0 2; m e dia n -d ose vs. hi g h -d os e: O R = 1. 4 7, p = 0. 1 8).  T he 
a ut h ors c o ncl u de d t hat a me dia n -d ose ( 3 m g/ k g) mi g ht be a prefere ntial d osa ge o f a nti-P D -1 
a ge nts (Jia 2 0 1 5). 
K E Y N O T E -0 1 0 was a ra n d o mize d, o pe n -la bel, p h ase 2/ 3 st u d y i n 1 0 3 4 patie nts wit h pre vi o usl y 
treate d N S C L C wit h P D-L 1 e x pressi o n o n at least 1 % of t u m or cells w h o were ra n d o ml y 
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
 
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 3 7  of  1 2 9  
C O N FI D E N TI A L  
assi g ne d t o recei ve p e m br oliz u ma b 2 m g/ k g, pe m br oliz u ma b 1 0 m g/ k g, or d oceta xel 7 5 m g/ m² 
Q 3 W (Her bst 2 0 1 6 ).  Pr o gressi o n -free s ur vi val was si milar f or eac h pe m br oliz u ma b d ose i n 
patie nts wit h a t u m or pr o p orti o n sc ore of 5 0 % or greater ( H R 1. 0 1) a n d i n t he t otal p o p ulati o n 
( H R 1. 0 9).  T he res p o nse rates f or t he t otal p o p ulati o n were 1 8 % f or b ot h pe m br oliz u ma b gr o u ps 
c o m pare d t o 9 % f or t he patie nts recei vi n g d ocet a x el w hic h s u p p orte d t h e si milar efficac y a n d  
safet y of pe m br oliz u ma b 2 a n d 1 0 m g/ k g Q 3W.  H o we ver, w he n cl osel y l o o ki n g at t he O S 
be nefit i n t he 2  differe nt pe m br oliz u ma b gr o u ps, t he patie nts recei vi n g d os es of 1 0  m g/ k g Q 3 W 
a p pear t o ha ve i ncrease d be nefit c o m pare d t o t he patie nts d ose d wit h 2  m g/ k g Q 3 W.  I n patie nts 
wit h a P D -L 1 t u m or pr o p orti o n sc ore of 5 0 % or great er, t he H R f or O S f or pe m br oliz u ma b 
2  m g/ k g vers us d ocet a x el was 0. 5 4 ( p = 0. 0 0 0 2), a n d f or p e m br oliz u ma b 1 0  m g/ k g v ers us 
d oceta x el, it was 0. 5 0 ( p < 0. 0 0 0 1).  Me dia n O S was 1 4. 9 m o nt hs f or t he pe m br oliz u ma b 2 m g/ k g 
gr o u p, 1 7. 3 m o nt hs f or t he pe m br oliz u ma b 1 0 m g/ k g gr o u p, a n d 8. 2  m o nt hs f or t he d ocet a x el 
gr o u p.  I n t he t otal p o p ulati o n, t he H R f or pe m br oliz u ma b 2  m g/ k g vers us d oceta xel was 
0. 7 1  ( p = 0. 0 0 0 8), 
a n d t he 
H R f or 
pe m br oliz u ma b 
1 0 
m g/ k g 
vers us 
d oceta xel 
was 
0. 6 1  ( p < 0· 0 0 0 1).  
Me di a n 
O S 
was 1 0. 4  m o nt hs f or t he pe m br oliz u ma b 2 
m g/ k g gr o u p, 
1 2. 7  m o nt hs f or t he pe m br oliz u ma b 1 0 m g/ k g gr o u p, a n d 8. 5 m o nt hs f or t he d oceta xel gr o u p.  
O ne year O S was 4 3. 2 % vers us 5 2. 3 % vers us 3 4. 6 %.  T hese data de m o nstrate a tre n d t o a n 
i ncreas e i n be nefit wit h hi g her d os es of P D-1 i n hi bit ors i n N S C L C.  
3. 2. 7.  
R ati o n ale f or I pili m u m a b D ose Selecti o n  
Rece nt data prese nte d b y Brist ol -Me yers S q ui b b, I n c. de m o nstrate d hi g h er t u m or s hri n ka ge i n 
patie nts treate d wit h ni v ol u ma b at 3 m g/ k g Q 2 W pl us i pili m u ma b at 1 m g/ k g  Q 6 W or Q 1 2 W 
c o m pare d t o ni v ol u ma b m o n ot hera p y (Z ha o 2 0 1 7 b ).  T he i nci de nce of A Es was si milar f or 
ni v ol u ma b m o n ot hera p y a n d ni v ol u ma b pl us i pili m u ma b at 1 m g/ k g Q 6 W or Q 1 2 W, b ut was 
hi g her i n treat me nt gr o u ps wit h m ore fre q ue n t a n d/ or hi g her i pili m u ma b d osi n g.  Base d o n t he 
prese nte d ris k -be n efit assess me nt (Z ha o 2 0 1 7 b ) a n d E-R a n al yses, t he rec o m me n de d d os e of 
i pili m u ma b i n N S C L C is 1 m g/ k g Q 6 W, w hi c h is e q ui vale nt t o a p pr o xi matel y 5 0  m g, t he d os e 
pr o p ose d i n t he pres e nt st u d y.   
4.  
S T U D Y V A RI A B L E S  
4. 1.  
De m o gr a p hic a n d B aseli ne C h ar acteristics  
Baseli ne c h aracteristics will i ncl u de sta n dar d de m o gra p h y (e g, a ge, race, et h nicit y, wei g ht, 
ge n d er, a n d hei g ht) a n d disease c haracteristics, i ncl u di n g P D -L 1 stat us a n d 
me dical a n d 
o nc ol o g y hist or y.  
4. 2.  
Pri m ar y a n d Sec o n d ar y E n d p oi nts  
4. 2. 1.  
Pri m ar y E n d p oi nt  
T he pri mar y e n d p oi nt is O R R, defi ne d as t he pr o p orti o n of patie nts ac hie vi n g C R or P R as 
assesse d b y a bli n de d I R C base d o n R E CI S T  1. 1 assess me nts , i n patie nts w h ose t u m ors e x press 
P D -L 1 i n < 5 0 % of t u m or cells.   
O bjecti ve res p o nse rate is defi ne d as t h e n u m ber of patie nts wit h a b est o verall res p o nse ( B O R) 
of c o nfir me d C R or P R di vi de d b y t he n u m ber of patie nts i n t he efficac y a nal ysis set.  
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
 
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 3 8  of  1 2 9  
C O N FI D E N TI A L  
Best o verall res p o nse will be defi n e d as t h e best r es p o nse rec or de d , as det er mi ne d b y t h e I R C per 
R E CI S T  1. 1, bet wee n t h e date of ra n d o mizati o n a n d t he date of t he first o bjecti vel y d o c u me nte d 
pr o gressi o n or t he d ate of s u bse q ue nt a nti -ca n cer t hera p y, w hic h e ver c o mes first.  
Rati o nale f or O R R as t he pri mar y e n d p oi nt is pr o vi de d i n Secti o n  3. 2. 2 .  
4. 2. 2.  
Sec o n d ar y E n d p oi nts  
T he sec o n d ar y e n d p oi nts i n t he st u d y are:  
 O bjecti ve res p o ns e rat e i n all patie nts  
 O verall s ur vi val i n p atie nts w h ose t u m ors e x press P D-L 1 i n < 5 0 % of t u m or cells a n d i n all 
patie nts.  
O verall s ur vi val is d efi ne d as t he ti me fr o m ra n d o mizati o n t o t he date of d eat h.  A p atie nt 
w h o is l ost t o f oll o w-u p  will be ce ns ore d at t he last date  t hat t he p atie nt was k n o w n t o be 
ali ve. 
 P F S i n patie nts w h ose t u m ors e x press P D -L 1 i n < 5 0 % of t u m or cells a n d i n all patie nts.  
Pr o gressi o n -free s ur vi val is defi ne d as t he ti me fr o m ra n d o mizati o n t o t he date of t he first 
d oc u me nte d t u m or pr o gressi o n, as d eter mi ne d b y t h e I R C ( base d o n R E CI S T  1. 1 
assess me nts [Eise n ha uer  2 0 0 9 ][see A p pe n di x  2 ]), or deat h.  Patie nts will be ce ns ore d 
acc or di n g t o t he r ules liste d bel o w:  
o  Patie nts wit h o ut  a d oc u me nte d t u m or pr o gressi o n or deat h will be ce ns ore d o n t he 
date of t heir last e v al ua bl e t u m or assess me nt .   
o  Patie nts wit h o ut  a n y e val ua ble t u m or assess me nts after ra n d o mizati o n a n d di d n ot 
die will be ce ns or e d o n t he date of ra n d o mizati o n.  
 T he i nci de nces of T E A Es, seri o us a d verse e ve nts ( S A Es), deat hs, a n d l a b orat or y 
a b n or malities.  
4. 2. 3.  
E x pl or at or y  E n d p oi nts  
E x pl orat or y  e n d p oi nts will i ncl u de t he f oll o wi n g:  
 Q ualit y of lif e as meas ure d b y t h e E ur o pea n Or ga nizati o n f or Researc h a n d Treat me nt 
of Ca ncer Q ualit y of Life Q uesti o n naire C ore  3 0  ( E O R T C Q L Q -C 3 0) a n d Q ualit y of 
Lif e Q uesti o n nair e L u n g Ca nce r 1 3  ( E O R T C Q L Q -L C 1 3)  
 Rate  of occ urre n ce  of h air re-pi g me ntati o n as d eter mi ne d  b y i n vesti gat or assess me nt 
 T u m or m utati o n b ur de n as assesse d b y t he F o u n dati o n Me dici ne “ F o u n d ati o n O ne ® ” 
pa nel  
 C ha n ges i n  tu m or v ol u m e  
 I C O S + C D 4 T-cell fre q u e nc y a n d ot her mar k ers of T -cell acti vati o n  
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
 
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 3 9  of  1 2 9  
C O N FI D E N TI A L  
4. 3.  
P h ar m ac o ki netic V ari a bles  
Ce mi pli ma b  c o nce ntrati o n i n t he sera of ra n d o mize d patie nts will be assess e d at m ulti ple ti me 
p oi nts t hr o u g h o ut t he treat me nt a n d f oll o w -u p peri o ds.  
P har mac o ki netic varia bles ma y i ncl u de, b ut are n ot l i mite d t o, t he f oll o wi n g: 
 C e oi –  c o nce ntr ati o n at e n d of i nf usi o n  
 C tr o u g h –  prei nf usi o n c o nce ntrati o n  
 te oi –  ti me of e n d of i nf usi o n 
Sa m ples will als o be o btai ne d  f or ce mi pli ma b  c o nce ntrati o n assess me nts at t he i nitial d ose visit  
(c ycle 1, d a y 1). 
4. 4.  
A nti -Dr u g A nti b o d y V ari a bles  
T he A D A v aria bles will be meas ur e d i n sa m ples fr o m ra n d o mize d patie nts a n d i ncl u de t he stat us 
of A D A res p o nse a n d titer as f oll o ws:  
 Treat me nt -b o oste d A D A res p o nse - d efi ne d as a p ositi ve res p o nse i n t he A D A assa y 
after t he first d ose t hat is greater t ha n or e q u al t o 9-f ol d o ver bas eli ne titer l e vels, 
w he n baseli ne res ults are p ositi ve  
 Treat me nt -e mer ge nt A D A res p o nse - d efi ne d as a p ositi ve res p o nse i n t he A D A assa y 
after t he first d ose w he n baseli ne res ults are ne gati ve or m issi n g 
Titer cate g or y is defi ne d base d o n val ues as t he f oll o wi n g (titer val u e cate g or y):  
 L o w (titer < 1 0 0 0)  
 M o derate ( 1 0 0 0 ≤ titer ≤1 0, 0 0 0)  
 Hi g h (titer > 1 0, 0 0 0)  
Sa m ples will als o be o btai ne d  f or A D A m eas ure me nts  at t he i nitial d ose visit  (c ycl e 1, da y 1). 
5.  
S T U D Y D E SI G N  
5. 1.  
St u d y Descri pti o n a n d D ur ati o n  
T his is a p hase 2, ra n d o mize d, o pe n -la bel st u d y of H D R E G N 2 8 1 0 a n d S D R E G N 2 8 1 0/i pi vers us 
S D R E G N 2 8 1 0 i n t he 
sec o n d-li ne treat me nt of patie nts 
wit h a d va nce d s q ua m o us or 
n o n -s q ua m o us N S C L C wit h t u m ors e x pressi n g P D -L 1  i n < 5 0 % of t u m or cells.   A st u d y fl o w 
dia gra m is prese nte d i n  Fi g ure  1 .  Patie nts wit h ≥5 0 % P D -L 1 e x pressi o n i n t u m or cells will als o 
be i ncl u de d f or c o m paris o n.  
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
 
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 4 0  of  1 2 9  
C O N FI D E N TI A L  
Fi g ure  1 : 
St u d y Fl o w Di a gr a m   
 
A b bre viati o ns:  N S C L C = n o n -s mall cell l u n g ca ncer; O R R =o bjecti ve res p o nse rate;  O S = o verall s ur vi val; 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 -fre e s ur vi val; Q 3 W =e ver y 3  we e ks ; Q 6 W =e ver y 6  wee ks ; R =ra n d o miz e d; W = we e ks 
 
T he st u d y will c o nsist of t he f oll o wi n g 3  peri o ds: scree ni n g, treat me nt, a n d f oll o w -u p.  After 
scree ni n g, eli gi ble patie nts will be  ra n d o mize d t o Treat me nt Ar m A ( S D R E G N 2 8 1 0), Treat me nt 
Ar m B ( S D R E G N 2 8 1 0/i pi), or Treat me nt 
Ar m  C ( H D R E G N 2 8 1 0).  Treat me nt m ust  be 
disc o nti n ue d earl y d ue t o R E CI S T  1. 1 -defi n e d P D , wit h dra wal of c o nse nt, deat h, u nacce pta ble 
t o xicit y, i nitiati o n of a n ot her a nti-ca ncer treat me nt, a n d ma y be dis c o nti n ue d  i n s pecific i nsta nces 
of c o nfir me d C R , P R , or S D (see bel o w).  After disc o nti n ui n g st u d y treat m e nt, patie nts will e nter 
t he f oll o w-u p peri o d.  
T he a p pr o xi mate d urati o n of t he acti ve st u d y assess me nts f or eac h patie nt, e x cl u di n g scree ni n g, 
will be 2 5 t o 3 1  m o nt hs.  T his e n c o m pass es 2 5 m o nt hs of st u d y tr eat m e nt pl us 6  m o nt hs of 
f oll o w-u p.  After t he acti ve p orti o n of t he st u d y is c o m plete, all patie nts will be f oll o we d f or 
s ur vi val. 
5. 1. 1.  
Scree ni n g  
Patie nts will u n der g o a s cree ni n g e v al uati o n t o deter mi ne t heir eli gi bilit y wit hi n 2 8  da ys  pri or t o 
ra n d o mizati o n (Ta ble  3 ).  Pr o gra m me d cell deat h li ga n d 1 e x pressi o n i n a t u m or tiss ue sa m ple 
(arc hi v al tiss ue, if ≤5 m o nt hs ol d, or rece ntl y o btai ne d o n -st u d y bi o ps y c ollecte d d uri n g 
scree ni n g; f or c ollecti o n i nstructi o ns, refer t o t he la b orat or y ma n ual) will be assesse d usi n g t he 
P D -L 1 I H C 2 2 C 3 p har m D x assa y b y a ce ntral la b orat or y ( Secti o n  8. 2. 5 ).  T u m or m uta ti o n 
b ur de n will als o be assesse d. Gi ve n t hat n o n -s q u a m o us (s pecificall y a d e n o carci n o ma) hist ol o g y 
is m ore pre vale nt t ha n s q ua m o us hist ol o g y, it is pre dict e d t hat a p pr o xi matel y 7 0 % of p atie nts 
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
 
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 4 1  of  1 2 9  
C O N FI D E N TI A L  
e nr olli n g i n t he st u d y will ha ve n o n -s q u a m o us N S C L C, a n d 3 0 % of p atie nts will ha ve s q ua m o us 
N S C L C.  T u m or tiss ue sa m ples will als o be teste d f or E G F R m utati o ns a n d A L K  tra nsl oc ati o ns 
as 
well as f or 
R O S 1 f usi o ns .  Patie nts 
w h ose t u m ors are p ositi ve f or a n y of t hes e 
m utati o ns/f usi o ns ( b y testi n g at scree ni n g) will n ot b e eli gi ble f or t he st u d y.  
Baseli ne ra di o gra p hic t u m or assess me nts s h o ul d als o be p erf or me d wit hi n 2 8  da ys pri or t o  
ra n d o mizati o n (Ta ble  3 ).  T hese assess me nts will n ot be re vie we d b y t he I R C f or eli gi bilit y 
assess me nt.  
I nf or me d c o nse nt 
m ust be o btai n e d pri or t o a n y st u d y-relate d pr oce d ures.  Assess me nts 
perf or me d as part of sta n dar d -of -care t hat fall wit hi n t he scree ni n g wi n d o w ( 2 8  da ys pri or t o  
ra n d o mizati o n) b ut bef ore i nf or me d c o ns e nt is o btai ne d ma y b e us e d f or s cree ni n g a n d nee d n ot 
be re peate d f or e nr oll me nt eli gi bilit y.  
5. 1. 2.  
Tre at me nt Peri o d  
E li gi ble patie nts wit h a d va nce d N S C L C will be ra n d o mize d 1: 1: 1 t o o ne of t he f oll o wi n g 
treat me nt ar ms: 
Tre at me nt Ar m A  
 Treat me nt Ar m A:  Ce mi pli ma b  3 5 0 m g Q 3 W f or 1 0 8 wee ks ( S D R E G N 2 8 1 0)  
Tre at me nt Ar m B  
 Treat me nt Ar m B:  Ce mi pli ma b  3 5 0 m g Q 3 W f or 1 0 8 wee ks pl us  i pili m u ma b 5 0 m g 
Q 6 W f or u p t o 4 d oses ( S D R E G N 2 8 1 0/i pi)  
 I pili m u ma b 5 0 m g fl at d ose a d mi nistere d I V o n da y 1 of e ver y ot her treat me nt c ycle 
(ie, e ver y 4 2 da ys or Q 6 W) f or u p t o 4 d oses  
Tre at me nt Ar m C  
 Treat me nt Ar m C:  Ce mi pli ma b  1 0 5 0 m g Q 3 W f or 1 0 8 wee ks ( H D R E G N 2 8 1 0)  
All Tre at me nt Ar ms  
Patie nts will recei ve t h eir assi g ne d treat me nt f or t he tr eat me nt p eri o d (as n ote d a b o ve), or 
treat me nt m ust  be disc o nti n ue d earl y d u e t o R E CI S T  1. 1 -d efi ne d P D , u nacce pta ble t o xicit y, 
wit h dra wal of c o ns e nt, deat h, i nitiati o n of a n ot her a nti -ca ncer treat me nt .  Treat me nt ma y b e 
disc o nti n ue d i n s pecific i nsta nces of c o nfir me d C R, P R , or S D. 
Ra n d o mizati o n will be stratifie d b y hist ol o g y ( n o n -s q ua m o us vers us s q ua m o us) a n d P D -L 1 le vel 
( < 1 % vers us 1 % t o 4 9 % vers us ≥5 0 %) .   
Treat me nt s h o ul d be gi n wit hi n 3 da ys of  ra n d o mizati o n.  Details of t he treat me nt re gi me ns are 
pr o vi de d i n Secti o n  7. 1 .   
F or t he p ur p os es of t his st u d y, a tr eat me nt c ycl e will be defi ne d as 2 1  da ys or 3  wee ks.  
La b orat or y res ults f or safet y assess me nts m ust be a vaila ble pri or t o d osi n g o n da y  1 of eac h 
d osi n g  c ycl e (Ta bl e  4 ). 
Details of d os e m o dificati o ns a n d st u d y dr u g per ma ne nt a n d te m p orar y disc o nti n uati o n criteria 
are disc usse d i n Secti o n  7. 3 . 
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R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
 
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 4 2  of  1 2 9  
C O N FI D E N TI A L  
Ra di o gra p hic t u m or assess me nts will be o btai ne d Q 9 W be gi n ni n g at wee k  9  ( da y 6 3  ± 5  da ys) 
d uri n g year  1 a n d Q 1 2 W be gi n ni n g at wee k  5 5 (first ra di o gra p hic t u m o r assess me nt i n year 2 
perf or me d at e n d of w ee k 5 4) d uri n g year  2, u ntil I R C -assesse d R E CI S T  1. 1 -defi ne d P D , 
wit h dra wal of c o ns e nt, d eat h, or i nitiati o n of a n ot her a nti -ca ncer treat me nt.  See Secti o n  8. 2. 2. 1  
f or detaile d ti mi n g of ra di o gra p hi c t u m or assess me nts.  Patie nts w h o disc o nti n ue f or reas o ns 
ot her t ha n pr o gressi o n w h o are n ot atte n di n g treat me nt visits ma y h a v e ra di o gra p hic t u m or 
assess ments bet wee n Q 9 W a n d Q 1 2 W u ntil R E CI S T  1. 1 -d efi ne d P D , wit h dra wal of c o ns e nt, 
deat h, or i nitiati o n of a n ot her a nti -ca ncer treat me nt.  
I n v esti gat ors a n d t he bli n de d I R C ( Secti o n 5. 3. 1 ) 
will assess res p o nse t o t hera p y usi n g 
R E CI S T  1. 1 criteria  (A p pe n di x  2 ).  R E CI S T  1. 1 -defi ne d P D  deter mi ne d b y t h e i n vesti gat or will 
be use d f or cli nical ma n a ge m e nt of t h e patie nt.  R E CI S T  1. 1 -b ase d t u m or b ur de n ass ess me nts b y 
t he bli n de d I R C will be use d f or e v al uati o n of effi cac y e n d p oi nts. 
After at least 6 m o nt hs ( 2 4 wee ks) of tr eat me nt, a patie nt wit h c o nfir me d C R ma y c h o os e t o 
disc o nti n ue treat me nt earl y a n d b e f oll o we d f or t he d urati o n of t he st u d y.  A patie nt wit h a P R 
t hat has sta bilize d after 6 m o nt hs a n d is n o l o n ger c ha n gi n g after 3 s uccessi ve t u m or ass ess me nts 
ma y als o c h o ose t o disc o nti n ue treat me nt earl y a n d  be f oll o we d f or t he d urati o n of t he st u d y.   
Patie nts w h o e x perie nce R E CI S T  1. 1 -defi ne d P D  o n t hera p y m a y c o nti n ue st u d y treat me nt if t he 
i n vesti gat or j u d ges t he patie nt t o be e x perie nci n g cli nical be nefit a n d if t he patie nt has n ot 
c o m plete d t he 1 0 8 -wee k  treat me nt peri o d ( Secti o n 7. 8 ).  Alter nati vel y, t hese patie nts ma y o pt t o 
i nitiate a ne w a nti-ca ncer treat me nt.  If a p atie nt c o nti n ues treat me nt wit h ce mi pli ma b  be y o n d t he 
i nitial deter mi nati o n of P D , st u d y assess me nts sh o ul d c o nti n ue as per  Ta ble  4 .  If o n t he ne xt 
sc he d ule d ra di o gra p hic t u m or assess me nt, 
R E CI S T 1. 1 -d efi ne d f urt her P D  is c o nfir me d 
( Secti o n 7. 8 ), ce mi pli ma b  t hera p y will be disc o nti n ue d.  F urt her pr o gressi o n will be defi ne d as 
a n a d diti o nal 1 0 % i ncrease i n t u m or b ur de n fr o m t he ti me of i nitial P D  o r t he e mer ge nce of 
s y m pt o matic pr o gressi o n.   
Safet y will be ass esse d t hr o u g h t he occ urre nce of A Es, rec or di n g of c o n c o mita nt me dicati o ns, 
vital si g n e val uati o n, p h ysical e x a mi nati o n, Easter n C o o perati ve O nc ol o g y Gr o u p  (E C O G ) 
perf or ma n ce stat us, a n d l a b orat or y a nal yses  (T a bl e  4 ).   
T o assess disease -relat e d s y m pt o ms, p atie nts will be as ke d t o c o m plete Q O L  q uesti o n nair es at 
ti me p oi nts s pecifie d i n Ta ble  4 . 
Bl o o d sa m ples will be c ollecte d t o me as ure c o nce ntrati o ns of ce mi pli ma b a n d ce mi pli ma b  A D A 
titers i n ser u m.  Bl o o d sa mples will be c ollecte d t o meas ure bi o mar kers  ass ociate d wit h cli nical 
res p o nse t o ce mi pli ma b  i ncl u di n g, b ut n ot li mite d t o, peri p heral bl o o d m o n o n uclear cells 
( P B M Cs), c yt o ki n es, cir c ulati n g t u m or n ucleic aci ds, a n d ot her p ote ntial bi o mar kers of i nterest 
(Ta ble  4 ). 
5. 1. 3.  
F oll o w -U p Peri o d  
Patie nts w h o disc o nti n ue st u d y treat me nt d ue t o P D  s h o ul d ret ur n t o t he cli nic 1 4 t o 3 0 da ys after 
t he last st u d y treat me nt t o c o m plete t he e n d of st u d y ass ess me nts (foll o w -u p visit 1) .  
Patie nts w h o disc o nti n ue st u d y treat me nt f or a reas o n ot her t ha n P D  s h o ul d ret ur n t o t he cli nic 
1 4  t o 3 0 da ys  aft er t h e last c ycle visit f or f oll o w -u p visit 1 a n d t he n c o nti n ue wit h f oll o w -u p 
visit  2 t hr o u g h f oll o w -u p visit  7.  
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Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
 
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 4 3  of  1 2 9  
C O N FI D E N TI A L  
S ur vi val data will t he n be c ollecte d b y p h o n e or at a n office visit e ver y 3  m o nt hs, u ntil deat h, 
l oss t o f oll o w-u p, or wit h dra wal of st u d y c o nse nt.  
 Patie nts will e nter t he f oll o w -u p peri o d after disc o nti n uati o n of treat me nt, eit her b y 
c o m pleti n g t he 1 0 8-w ee k treat me nt peri o d, at t he ti me of R E CI S T  1. 1 -defi ne d P D , or 
w he n t he decisi o n is ma de t o disc o nti n ue ce mi pli ma b treat me nt earl y.  
 Patie nts w h o c o m plete d t he treat me nt peri o d wit h o ut R E CI S T  1. 1 -defi ne d P D  or w h o 
disc o nti n ue d st u d y treat me nt earl y f or reas o ns ot her t ha n R E CI S T  1. 1 -defi ne d  P D  
s h o ul d c o nti n ue t o ha ve ra di o gra p hic t u m or ass ess me nts Q 1 2 W.  
 Patie nts w h o disc o nti n ue d ce mi pli ma b treat me nt after at least 6 m o nt hs [ 2 4  wee ks] 
d ue t o 
C R, P R, or S D a n d e ntere d f oll o w -u p at t hat ti me , w h o 
de vel o p  
R E CI S T  1. 1 -defi ne d P D  d uri n g  f oll o w-u p , m a y b e offere d t he o pti o n f or retreat me nt 
wit h ce mi pli ma b at t he sa me d os e as recei ve d d uri n g i nitial  treat me nt.  St u d y 
assess me nts f or t hese p atie nts will be perf or me d as s pecifie d i n  Ta ble  4 .   
 F oll o w -u p st u d y ass ess me nts will be perf or me d as s pecifie d i n  Ta ble  5 .  Patie nts will 
ha ve bl o o d sa m ples ta ke n f or P K a n d A D A testi n g as s p ecifie d i n  T a ble  5 . 
5. 1. 4.  
E n d of St u d y Defi niti o n  
T he e n d of st u d y is defi n e d as t he last visit of t he  last patie nt.   
5. 2.  
Pl a n ne d I nteri m A n al ysis  
N o i nteri m a nal ysis is pla n ne d.  T here will be a n earl y s afet y re vie w b y t h e I n d e pe n de nt Data 
M o nit ori n g C o m mittee ( I D M C) as detaile d i n Secti o n  5. 3. 2 . 
5. 3.  
St u d y C o m mittees  
T w o i n de pe n de nt st u d y c o m mittees will be utilize d: a n I R C ( Secti o n  5. 3. 1 ) an d a n I D M C 
( Secti o n 5. 3. 2 ). 
5. 3. 1.  
I n de pe n de nt Re vie w C o m mittee 
A bli n de d I R C c o m p ose d o f me m bers w h o are i n de pe n de nt fr o m t he s p o ns or a n d t he st u d y 
i n vesti gat ors 
will re vie w all a vaila ble ( de-i de ntifie d) ra di o gra p hic t u m or assess me nts t o 
deter mi ne t u m or res p o ns e base d o n R E CI S T 1. 1 criteria.  T he I R C -deter mi ne d t u m or res p o nse 
will be use d i n  t he a nal ysis of t he P F S a n d O R R e n d p oi nts.  Details of t h e I R C res p o nsi bilities 
a n d pr oce d ures will be s p ecifie d i n t he I R C c h arter.  
5. 3. 2.  
I n de pe n de nt D at a M o nit ori n g C o m mittee 
A n I D M C, c o m p ose d of me m bers w h o are i n de pe n de nt fr o m t he s p o ns or a n d t he st u d y 
i n vesti gat ors, will m o nit or patie nt safet y b y c o n d ucti n g f or mal re vie ws of acc u m ulate d safet y 
data t hat will be bli n de d b y treat me nt ar m; if re q ueste d, t he I D M C ma y h a ve access t o t he 
treat me nt all ocati o n c o de or a n y ot her re q u este d data f or t he p ur p oses of a ris k-be nefit 
assess me nt.  
T he I D M C will pr o vi de t he s p o ns or wit h a p pr o priate rec o m me n d ati o ns o n t he c o n d uct of t he 
cli nical st u d y t o e ns ure t he pr otecti o n a n d safet y of t he patie nts e nr olle d i n t he st u d y.  T he I D M C 
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Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
 
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 4 4  of  1 2 9  
C O N FI D E N TI A L  
will als o i nstit ute a n y meas ures t h at ma y b e re q uire d f or e ns uri n g t he i nte grit y of t h e st u d y 
res ults d uri n g t he st u d y e x ec uti o n.   
All acti vities a n d res p o nsi bilities of t he I D M C are descri be d i n t he I D M C c harter.  
6.  
S E L E C TI O N, WI T H D R A W A L, A N D R E P L A C E M E N T O F 
P A TI E N T S  
6. 1.  
N u m ber of P atie nts Pl a n ne d  
A p pr o xi matel y 2 5 2  p atie nts will  be ra n d o mize d at a p pr o xi matel y 8 0  sites gl o ball y .   
6. 2.  
St u d y P o p ul ati o n  
Patie nts i n t his st u d y will i ncl u de me n a n d w o m e n ≥1 8 years of a ge, w h o are dia g n os e d wit h 
a d va nce d s q ua m o us or n o n -s q ua m o us N S C L C.  A mi ni m u m of 2 0 1 patie nts ( u p t o 2 1 5 t otal) 
wit h  < 5 0 % of t u m or cells e x pressi n g P D -L 1 a n d a mi ni m u m of 5 1 patie nts ( u p t o 6 0  t otal) wit h 
≥5 0 % t u m or cells e x pressi n g P D -L 1 ( meas ure d usi n g t he P D-L 1 I H C 2 2 C 3 p har m D x assa y) will 
be ra n d o mize d.  Patie nts are re q uir e d t o  ha ve recei ve d o nl y 1  pri or li ne of c he m ot hera p y as 
treat me nt f or t heir a d va n ce d diseas e. 
T o be eli gi ble f or t he st u d y, patie nts m ust meet all of t he i ncl usi o n criteria ( Secti o n  6. 2. 1 ) a n d 
n o ne of t he e x cl usi o n criteria ( Secti o n  6. 2. 2 ). 
6. 2. 1.  
I ncl usi o n Criteri a 
A patie nt m ust meet t he f oll o wi n g criteria t o be eli gi ble f or i ncl usi o n i n t he st u d y: 
1.  Me n a n d w o me n ≥1 8 years of a ge  
2.  Patie nts wit h hist ol o gicall y or c yt ol o gi call y d o c u me nte d s q ua m o us or n o n -s q ua m o us 
N S C L C wit h sta ge III b or sta ge IIIc disease  w h o are n ot ca n di dat es f or treat me nt wit h 
defi niti ve c o nc urre nt c h e m o -ra diati o n or patie nts wit h sta ge I V disease.  Patie nts m ust  
ha ve P D  after recei vi n g o ne  pri or li ne of c h e m ot hera p y treat me nt f or a d v a n ce d  N S C L C .  
3.  A vaila bilit y of a n arc hi val or o n -st u d y o btai ne d f or mali n-fi x e d, paraffi n-e m be d de d t u m or 
tiss ue bi o ps y sa m ple. G ui da nce o n bi o ps y sites: 
a. Arc hi val or fres h bi o psies are acce pta ble;  
b.  If a n arc hi val bi o ps y is use d, it has t o be less t ha n 5 m o nt hs ol d; 
c. T he bi o ps y s h o ul d be fr o m a metastatic or rec urre nt site w hic h has n ot pre vi o usl y 
bee n irra diate d.  
E x ce pti o n: t h e pri mar y t u m or is still i n place a n d t he ot her metastatic sites are eit her n ot 
accessi ble ( brai n) or ca n n ot be use d ( b o ne) or t he bi o ps y w o ul d p ut t he pati e nt at ris k  
4.  Bi o ps y e val ua bl e f or e x pressi o n  of P D -L 1 as d eter mi ne d b y t he P D-L 1 I H C 2 2 C 3 
p har m D x ass a y p erf or me d b y t he ce ntral la b orat or y  
5.  At least 1 ra di o gra p hi call y meas urea ble l esi o n b y c o m p ute d t o m o gra p h y ( C T) per 
R E CI S T  1. 1 criteria (see  A p pe n di x  2 ).  Tar get l esi o ns ma y be l o cate d i n a pre vi o usl y 
irra diate d fi el d if t here is d oc u me nte d (ra di o gra p hi c) disease pr o gressi o n i n t hat site 
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R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
 
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 4 5  of  1 2 9  
C O N FI D E N TI A L  
6.  E C O G perf or ma nce stat us of  ≤1  
7.  A de q uate or ga n a n d b o n e marr o w f u ncti o n as defi ne d bel o w:  
a. He m o gl o bi n ≥9. 0  g/ d L  
b.  A bs ol ute ne utr o p hil c o u nt ≥1. 5 × 1 0 9/ L 
c. Platelet c o u nt  ≥7 5, 0 0 0/ m m 3 
d.  Gl o mer ular filtrati o n rate ( G F R)  > 3 0 m L/ mi n/ 1. 7 3 m 2 
e. T otal bilir u bi n ≤1. 5  × u p per li mit of n or mal ( U L N) (if li ver metastases ≤3  ×  U L N), 
wit h t he e x ce pti o n of patie nts dia g n os e d wit h cli nicall y c o nfir me d Gil bert’s s y n dr o me  
f. As partate a mi n otra nsferase ( A S T) a n d ala ni ne a mi n otra nsferase ( A L T) ≤3 ×  U L N or 
≤5  ×  U L N, if li ver met astases  
g.  Al kali ne p h os p hatase  ≤2. 5 ×  U L N ( or ≤5. 0  ×  U L N, if li ver or b o ne metast ases)  
h.  A L T < 3 U L N a n d bilir u bi n  < 2  x U L N    
8.  Wi lli n g a n d a ble t o c o m pl y wit h cli nic visits a n d st u d y-relate d pr oce d ures 
9.  Pr o vi de si g ne d i nf or me d c o nse nt  
1 0.  A ble t o u n dersta n d a n d c o m plete st u d y -relate d q u esti o n naires 
6. 2. 2.  
E xcl usi o n Criteri a  
A patie nt w h o meets a n y of t he f oll o wi n g criteri a will be e x cl u de d fr o m  t he st u d y: 
1.  Patie nts w h o ha ve ne ver s m o ke d, defi ne d as s m o ki n g ≤1 0 0 ci garettes i n a lifeti me  
2.  Acti ve or u ntreate d brai n metastases or s pi nal c or d c o m pressi o n.  Patie nts are eli gi ble if 
ce ntral n er v o us s yste m ( C N S) metastas es are a de q u atel y treate d a n d pati e nts ha v e 
ne ur ol o gi call y ret ur n e d t o baseli ne (e x ce pt f or resi d ual si g ns or s y m pt o ms relate d t o t he 
C N S treat me nt) f or at least 2 wee ks pri or t o ra n d o mizati o n.  Patie nts m ust be off 
(i m m u n os u p pressi ve d oses of) c ortic oster oi d t hera p y (see e x cl usi o n criteria 7 ) f or d etails 
o n ti mi n g of disc o nti n uati o n of ster oi ds)  
3.  Patie nts wit h t u m ors teste d p ositi ve f or E G F R ge ne m utati o ns, A L K ge ne tra nsl ocati o ns, 
or R O S 1 f usi o ns .  All patie nts will ha ve t heir t u m or e val uate d f or E G F R m utati o ns, A L K 
rearra n ge m e nt, a n d R O S 1 f usi o ns b y a ce ntr al la b orat or y.  
4.  E nce p halitis, me ni n gitis, or u nc o ntr olle d seiz ures i n t he year pri or t o ra n d o mizati o n. 
5.  Hist or y of i nterstitial l u n g  diseas e (e g, i di o pat hic p ul m o nar y fi br osis or or ga nizi n g 
p ne u m o nia), or acti ve, n o ni nfecti o us p ne u m o nitis t hat re q uire d i m m u ne -s u p pressi ve 
d oses of gl uc oc ortic oi ds t o assist wit h ma na ge me nt, or of p ne u m o nitis wit hi n t he last 
5  years.  A hist or y of ra diati o n p ne u m o nitis i n t he ra diati o n fiel d is per mitte d  as l o n g as 
p ne u m o nitis res ol ve d ≥6 m o nt hs pri or t o ra n d o mizati o n. 
6.  O n g oi n g or rece nt e vi de nce of si g nifi ca nt a ut oi m m u ne disease t hat re q uire d treat me nt 
wit h s yste mic i m m u n os u p pressi ve treat me nts, 
w hi c h 
ma y 
s u g gest 
a ris k 
of 
i m m u ne-relate d treat me nt-e mer ge nt a d verse e ve nts (ir T E A Es).  T h e f oll o wi n g are n ot 
e x cl usi o nar y: vitili g o, c hil d h o o d ast h ma t hat has res ol ve d, resi d ual h y p ot h yr oi dis m t hat 
re q uire d o nl y h or m o ne re place me nt, or ps ori asis t hat d oes n ot re q uire s yste mic treat me nt 
7.  Patie nts wit h a c o n diti o n re q uiri n g c ortic oster oi d t hera p y ( > 1 0 m g pre d nis o ne/ da y or 
e q ui vale nt) wit hi n 1 4 da ys of ra n d o mizati o n.  P h ysi ol o gic re place me nt d oses are all o we d 
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
 
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 4 6  of  1 2 9  
C O N FI D E N TI A L  
e ve n if t h e y are > 1 0 m g of pre d nis o ne/ da y or e q ui vale nt, as l o n g as t he y are n ot bei n g 
a d mi nistere d f or i m m u n os u p pressi ve i nte nt.  I n hale d or t o pical ster oi ds are per mitte d, 
pr o vi de d t hat t he y are n ot f or treat me nt of a n a ut oi m m u ne dis or der  
8.  Pre vi o us treat me nt wit h i delalisi b (Z Y D E LI G ® ) at a n y ti me  
9.  Pri or treat me nt wit h a n a nti -C T L A -4 a nti b o d y or a nti -P D -1/ P D -L 1 f or l u n g ca ncer  
1 0.  A n ot her mali g na n c y t hat is pr o gressi n g or re q uires treat me nt, wit h t he e x ce pti o n of 
n o n mela n o mat o us s ki n ca ncer t hat has u n der g o ne p ote ntiall y c urati ve t hera p y, i n sit u 
cer vical carci n o ma, or a n y ot her l ocalize d t u m or t hat has bee n tr eate d, a n d t he patie nt is 
dee me d t o be i n c o m plete re missi o n f or at least 2 years pri or t o ra n d o mizati o n, a n d n o 
a d diti o nal t hera p y is re q uire d d uri n g t he st u d y p eri o d   
1 1.  U nc o ntr olle d i nfecti o n wit h h u ma n i m m u n o defic ie nc y vir us ( HI V), he patitis B vir us 
( H B V) or he p atitis C vir us ( H C V) i nfecti o n; or dia g n osis of i m m u n o defi cie nc y . 
T he f oll o wi n g are all o we d:  
a. Patie nts wit h HI V w h o h a ve c o ntr olle d i nf ecti o n ( u n detecta ble vir al l oa d a n d C D 4 
c o u nt a b o ve 3 5 0 eit her s p o nta ne o usl y or o n a sta ble a nti viral re gi me n). 
b.  Pati e nts wit h he patitis B ( He p B s urface a nti ge n p ositi ve ) w h o ha ve c o ntr olle d 
i nfecti o n (ser u m He patitis B vir us D N A p ol y merase c hai n r eacti o n ( P C R ) t hat is 
bel o w t he li mit of detecti o n A N D recei vi n g a nti -vi ral t hera p y f or he p atitis B). 
c. Patie nts w h o are H e patitis C vir us a nti b o d y p ositi ve ( H C V A b +) w h o ha v e c o ntr olle d 
i nfecti o n ( u n dete cta ble H C V R N A b y P C R eit her s p o nta ne o usl y or i n res p o nse t o a 
s uccessf ul pri or c o urse of a nti-H C V t hera p y ). 
1 2.  Acti ve i nfecti o n re q uiri n g s yste mic t hera p y wit hi n 1 4 da ys pri or t o ra n d o mizati o n 
1 3.  T reat me nt-relate d i m m u ne-me diate d A Es fr o m i m m u ne -m o d ulat or y a ge nts (i ncl u di n g 
b ut n ot li mite d t o a nti -P D 1/ P D -L 1  m o n ocl o n al a nti b o dies, a nti -C T L A 4 m o n ocl o nal 
a nti b o dies, a n d p h os p hati d yli n osi ti de 3-ki nase  i n hi bit ors) t hat ha ve n ot res ol ve d t o 
baseli ne at le ast 3  m o nt hs pri or t o i nitiati o n of treat me nt wit h st u d y t h era p y.  Patie nts are 
e x cl u de d fr o m treat me nt wit h ce mi pli ma b if t he y e x perie nce d i m m u ne-me diate d A Es 
relate d t o pri or treat me nt with a bl oc ker of t he P D -1/ P D -L 1 pat h w a y t hat were gra de 3 or 
4 i n se verit y a n d/ or re q uire d disc o nti n uati o n of t he a ge nt, re gar dless of ti me of 
occ urre nce  
1 4.  Recei pt of a n i n vesti gati o nal dr u g or de vice wit hi n 3 0 da ys of ra n d o mizati o n or wit hi n 
5  half -li ves of th e i n vesti gati o nal dr u g or t hera p y pri or t o ra n d o mizati o n  ( w hic he v er is 
l o n ger) 
1 5.  Recei pt of a li ve v acci ne wit hi n 3 0 da ys pri or t o r a n d o mizati o n.  
1 6.  Maj or s ur ger y or si g nifi ca nt tra u matic i nj ur y wit hi n 4 wee ks pri or t o ra n d o mizati o n  
1 7.  D oc u me nte d aller gic or ac u te h y perse nsiti vit y reacti o n attri b ute d t o a nti b o d y treat me nts 
i n ge n eral or t o a ge nts s p ecificall y use d i n t he st u d y 
1 8.  K n o w n ps yc hiatric or s u bsta nce a b use dis or d er t hat w o ul d i nterfere wit h partici pati o n 
wit h t he re q uire me nts of t he st u d y, i ncl u di n g c urre nt use of a n y illicit dr u gs  
1 9.  Pre g n a nt or breastfee di n g w o me n  
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Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
 
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 4 7  of  1 2 9  
C O N FI D E N TI A L  
2 0.  W o me n of c hil d beari n g p ot e ntial * w h o are u n willi n g t o practice hi g hl y effecti ve 
c o ntrace pti o n pri or t o t he i nitial d ose/start of t he first treat me nt, d uri n g t he st u d y, a n d f or 
at least 6 m o nt hs after t he last d ose.  Hi g hl y effecti ve c o ntr ace pti ve meas ures i ncl u de 
sta ble use of c o m bi ne d (estr o ge n a n d pr o gest o ge n c o ntai ni n g) h or m o nal c o ntrace pti o n 
( oral, i ntra va gi nal, tr a ns der mal) or pr o gest o ge n-o nl y h or m o nal c o ntrace pti o n ( oral, 
i njecta ble, i m pla nta ble) ass ociate d wit h i n hi biti o n of o v ulati o n i nitiate d 2 or 
m ore 
me nstr ual c ycles pri or t o scree ni n g; i ntra ut eri ne de vice; i ntra uteri ne h or m o ne -releasi n g 
s yste m; bilateral t u bal li gati o n; vasect o mize d part ner; a n d or se x ual a bsti ne nce †, ‡ . 
* P ost me n o pa u sal w o me n m ust be a me n orr hei c f or at least 1 2 m o nt hs i n or der n ot t o 
be c o nsi dere d of c hil d beari n g p ot e ntial.  Pre g na n c y t esti n g a n d c o ntrace pti o n are 
n ot re q uire d f or w o me n wit h a d oc u me nte d h ysterect o m y or t u bal li gati o n.  
† Se x ual a bsti ne nce is c o nsi dere d  a hi g hl y effecti ve met h o d o nl y if d efi ne d as 
refrai ni n g fr o m heter ose x ual i nterc o urse d uri n g t he e ntire peri o d of ris k ass ociate d 
wit h t he st u d y treat me nts.  
‡ Peri o dic a bsti ne nce (e g, cale n dar, s y m pt ot her mal, a n d p ost o v ulati o n met h o ds), 
wit h dra wal ( c oit us i nterr u pt us), s per mici des o nl y, a n d lactati o nal a me n orr h ea 
met h o d ( L A M) are n ot a cce pta bl e met h o ds of c o ntrace pti o n.  A fe male c o n d o m a n d 
a male c o n d o m s h o ul d n ot be use d t o get her.  
Se x uall y acti ve me n a n d t heir part ners m ust use hi g hl y effecti ve c o ntrace pt i o n as 
descri be d a b o ve.  C o ntrace pti o n is n ot re q uire d f or me n wit h d oc u me nte d 
vasect o m y.  
2 1.  Patie nts w h o are c o m mitte d t o a n i nstit uti o n b y virt ue of a n or der iss ue d eit her b y t he 
j u dicial or t he a d mi nistrati ve a ut h orities will be e xcl u de d fr o m t his st u d y. 
2 2.  M e m ber of t he cli nical site st u d y tea m a n d/ or his/ her i m me diate fa mil y, u nless pri or 
a p pr o val is gra nte d b y t h e s p o ns or.  
2 3.  Acti ve or lat e nt t u berc ul osis.  Lat e nc y s h o ul d b e c o nfir me d b y p urifie d pr otei n deri vati ve 
( P P D)/ Q ua ntiF E R O N  testi n g acc or di n g t o l ocal g ui deli nes. 
6. 3.  
Pre m at ure Wit h dr a w al fr o m t he St u d y  
A patie nt has 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, a n d wit h o ut 
re perc ussi o ns. 
T he i n vesti gat or a n d/ or s p o ns or ha ve t he ri g ht t o wit h dra w a patie nt fr o m  t he st u d y if it is n o 
l o n ger i n t he i nterest of t he patie nt t o c o nti n ue i n t he st u d y or if t he patie nt’s c o nti n uati o n i n t he 
st u d y places t he scie ntifi c o utc o me of t he st u d y at ris k (e g, if a p atie nt d oes n ot or ca n n ot f oll o w 
st u d y pr oce d ures).  A n e x cessi ve rate of wit h dr a wals w o ul d re n der t he st u d y u ni nter preta ble; 
t heref ore, u n necessar y wit h dra wal of patie nts s h o ul d be a v oi de d. 
Patie nts w h o are wit h dra w n pre mat urel y fr o m t he st u d y will be as k e d t o c o m plete st u d y 
assess me nts, as descri be d i n Secti o n  8. 1. 1 . 
R ules f or disc o nti n uati o n of st u d y tr eat me nt are disc usse d i n Secti o n  7. 3. 5 . 
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Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
 
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 4 8  of  1 2 9  
C O N FI D E N TI A L  
6. 4.  
Re pl ace me nt of P atie nts  
Patie nts pre mat urel y disc o nti n ue d fr o m t he st u d y or st u d y tr eat me nt will n ot be re place d.  
7.  
S T U D Y T R E A T M E N T S  
7. 1.  
I n vesti g ati o n al a n d Refere nce Tre at me nts 
Patie nts will be ra n d o mize d t o recei ve o ne of t he f oll o wi n g treat me nt re gi me ns:   
 Treat me nt Ar m A:  Ce mi pli ma b  3 5 0 m g Q 3 W f or 1 0 8 wee ks as a n I V i nf usi o n 
( S D R E G N 2 8 1 0) 
 Treat me nt Ar m B:  Ce mi pli ma b  3 5 0 m g Q 3 W f or 1 0 8 wee ks as a n I V i nf usi o n pl us  
i pili m u ma b 5 0 m g Q 6 W f or u p t o 4 d oses as a n I V i nf usi o n (S D R E G N 2 8 1 0/i pi)  
 Treat me nt Ar m C:  Ce mi pli ma b  1 0 5 0 m g Q 3 W f or 1 0 8 wee ks as a n I V i nf usi o n 
( H D R E G N 2 8 1 0) 
Patie nts will recei ve t heir assi g ne d treat me nt f or t he treat me nt peri o d (as n ot e d a b o ve) or u ntil 
R E CI S T  1. 1 -defi ne d P D  or earl y tr eat me nt disc o nti n uati o n f or a n ot her reas o n.  
St u d y treat me nt will be a d mi nistere d b y t he i n v esti gat or or ot her desi g n ate d st u d y pers o n nel.  
7. 1. 1.  
Ce mi pli m a b  ( R E G N 2 8 10 ) 
Ce mi pli ma b  is a c o vale nt heter otetra m er c o nsisti n g of t w o dis ulfi de-li n ke d h u ma n hea v y c hai ns, 
eac h of w hic h is c o val e ntl y b o n de d t hr o u g h dis ulfi de li n ka ges t o a h u ma n ka p pa li g ht c hai n.  T he 
a nti b o d y p ossesses a n a p pr o xi mate m olec ular wei g ht of 1 4 3. 6 k Da b ase d o n t he pri mar y 
se q ue nce.  T h ere is a si n gle N-li n ke d gl yc os yl ati o n site o n eac h hea v y c h ai n, l ocate d wit hi n t he 
c o nsta nt re gi o n i n t he Fc p orti o n of t he m olec ule.  T he ce mi pli ma b hea v y c hai n p ossesses a n 
I g G 4 is ot y pe c o nsta nt re gi o n.  T he v aria bl e d o mai ns of the hea v y a n d li g ht c h ai ns c o m bi ne t o 
f or m P D-1 bi n di n g site wit hi n t he a nti b o d y.  
Ce mi pli ma b  is ma n ufact ure d b y Re ge ner o n P har mace uticals, I nc a n d will be s u p plie d as a li q ui d 
i n sterile, si n gle-use vials.  Eac h vial will c o ntai n ce mi pli ma b  at a c o nce ntrati o n of 5 0  m g/ m L.   
See Secti o n  7. 6  f or det ails o n pac ka gi n g, la beli n g, a n d st ora ge. 
Ce mi pli ma b  will be a d mi nistere d i n a n o ut patie nt setti n g as a 3 0 -m i n ute ( ± 1 0 mi n utes) 
I V i nf usi o n.   
I nstr u cti o ns o n d ose pre parati o n are pr o vi de d i n t he p har mac y 
ma n ual.  I nstr ucti o ns o n 
ma na ge me nt of ac ute i nf usi o n reacti o ns are pr o vi de d i n Secti o n  7. 4. 1 . 
Ce mi pli ma b  will be a d mi nistere d al o ne Q 3 W ( S D R E G N 2 8 1 0 a n d H D R E G N 2 8 1 0) or i n 
c o m bi nati o n wit h i pili m u ma b (a d mi nistere d Q 6 W f or u p t o 4  d oses; S D R E G N 2 8 1 0/i pi) a n d t he n 
al o ne f or t he re mai n der of t he treat me nt peri o d.   
W he n a d mi nistere d i n c o m bi nati o n wit h i pili m u ma b,  i nf use ce mi pli ma b first f oll o we d b y 
i pili m u ma b o n t he sa me da y.  Use s e parate i nf usi o n ba gs a n d filters f or eac h i nf usi o n.  T he 
i n vesti gat or s h o ul d refer t o t he latest versi o n of t he I n v esti gat or’s Br oc h ure f or f urt her details 
a n d g ui d a nce.  
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Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
 
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 4 9  of  1 2 9  
C O N FI D E N TI A L  
7. 1. 2.  
I pili m u m a b 
I pili m u ma b s h o ul d be pr oc ure d b y t he st u d y sites as l ocal c o m mercial pr o d ucts i n s o me c o u ntries 
a n d w here all o we d b y l ocal re g ulati o ns; f or ot her c o u ntries, Re ge n er o n ma y pr o vi d e t he 
i pili m u ma b t o t he st u d y sites.  See Secti o n 7. 6  f or details o n pac ka gi n g, ha n dli n g, a n d st ora ge. 
I pili m u ma b 5 0 m g flat d ose will be a d mi nistere d I V o ver a p pr o xi matel y 9 0 mi n utes o n da y 1 
e ver y 4 2  da ys f or u p t o 4 d oses i n c o m bi nati o n wit h ce mi pli ma b.  A d mi nistrati o n s h o ul d a d here 
t o t he l ocal prescri bi n g i nf or mati o n a n d practice g ui deli nes. 
I nstr u cti o ns o n d ose pre parati o n are pr o vi de d i n t he p har mac y 
ma n ual.  I nstr ucti o ns o n 
ma na ge me nt of ac ute i nf usi o n reacti o ns are pr o vi de d  i n Secti o n 7. 4. 1 .   
I pili m u ma b s h o ul d be i nf use d after ce mi pli ma b  o n t he sa me da y.  Us e se parate i nf usi o n ba gs a n d 
filters f or eac h i nf usi o n.  
7. 2.  
Pre -T re at me nts  
Pre -me dicati o ns are n ot r e q uire d  pri or t o t he first a d mi nistrati o n of ce mi pli ma b.  Pre-m e dicati o ns 
will be all o we d at s u bs e q ue nt d oses d e pe n di n g o n t he nee d t o m a na ge a n y o bs er ve d l o w -gra de 
i nf usi o n reacti o ns ( Secti o n 7. 4. 1. 1 ).  
Pre -me dicati o ns s h o ul d be pr oc ure d b y t h e st u d y sites as l ocal c o m mercial pr o d ucts w here 
all o we d b y l oc al re g ulati o ns . W here n ot all o we d by l o cal re g ulati o ns,  Re ge n er o n ma y pr o vi de 
t he pre-m e dicati o ns  u p o n disc ussi o n wit h t he me dical  m o nit or.   Prefere nce s h o ul d be gi v e n t o 
re gi me ns t hat are all o we d b y l oc al re g ulati o ns. 
7. 3.  
D ose M o dific ati o n a n d St u d y Tre at me nt Disc o nti n u ati o n R ules  
7. 3. 1.  
“ St a n d ar d D o se ” Ce mi pli m a b  Pl us I pili m u m a b C o m bi n ati o n a n d “ Hi g h D ose ”  
Ce mi pli m a b  T her a p y  
7. 3. 1. 1.  
D osi n g Del a y R ules  
D uri n g t he S D R E G N 2 8 1 0/i pi or H D R E G N 2 8 1 0 t hera p y p eri o d, a d mi nistrati o n of ce mi pli ma b 
(a n d of i pili m u ma b, if a n A E occ urs o n t he d a y of a pla n ne d i pili m u ma b d osi n g), m ust be 
dela ye d d ue t o t he f oll o wi n g A Es:  
 Eit her fe brile ne utr o p e nia or ne utr o pe nia < 5 0 0 cells/ m m³ f or > 1  wee k des pite t he 
use of gr o wt h f act ors  
 A n y gra d e ≥2 n o n -s ki n, st u d y dr u g -rel ate d A E, e x ce pt f or fati g u e a n d la b orat or y 
a b n or malities a n d e x ce pt f or A Es t hat re q uire st u d y treat me nt disc o nti n uati o n (as 
liste d bel o w) 
 A n y gra de 3 st u d y dr u g -relate d l a b orat or y a b n or malit y (e x ce pt f or l y m p h o pe nia; 
A S T; A L T; or t otal bilir u bi n, as y m pt o matic li pase, or a m yl ase)  
 Gra de 3 l y m p h o pe nia will n ot re q uire a d ose  d ela y  
 If t he p atie nt ha d a bas eli ne A S T, A L T, or t otal bilir u bi n le vel t hat was 
wit hi n n or mal li mits, d osi n g s h o ul d be dela ye d f or a st u d y dr u g -relate d 
gra de  ≥2  t o xicit y 
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Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
 
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 5 0  of  1 2 9  
C O N FI D E N TI A L  
 If t he p atie nt ha d a bas eli ne A S T, A L T, or t otal bilir u bi n le vel t hat was 
wit hi n t he gra d e  1 t o xicit y ra n ge, d osi n g s h o ul d be d ela ye d f or a st u d y 
dr u g -relat e d gra d e ≥3 t o xicit y 
 A n y gra d e st u d y 3 dr u g -relate d a m yl ase or li pas e a b n or malit y t hat is n ot 
ass oci ate d wit h s y m pt o ms or cli nical ma nifestati o ns of pa ncreatitis will 
n ot re q uire a d os e dela y  
 A n y gra de 3 s ki n st u d y dr u g -relat e d A E 
 A n y A E, la b orat or y a b n or malit y, or i nterc urre nt ill ness t hat, i n t he j u d g me nt of t he 
i n vesti gat or, warra nts del a yi n g t he d os e of st u d y tr eat me nt  
Res u m pti o n of treat me nt ma y be at t he i nitial d ose re gi me n or t he d osi n g i nter val f or i pili m u ma b 
c o ul d be i ncreas e d fr o m Q 6 W t o Q 1 2 W, base d u p o n t he discreti o n of t he i n vesti gat or a n d t he 
s p o ns or.  D ose m o dificati o n of H D R E G N 2 8 1 0 or S D R E G N 2 8 1 0 are n ot  per mitte d.  
A re peat occ urre nce of t he sa me A E  after res u m pti o n of treat me nt will re q uire per ma ne nt 
disc o nti n uati o n of S D R E G N 2 8 1 0/i pi or H D R E G N 2 8 1 0.  
7. 3. 1. 2.  
Criteri a f or R est arti n g  “ St a n d ar d D ose ”  Ce mi pli m a b  Pl us I pili m u m a b a n d 
“ Hi g h D ose ”  Ce mi pli m a b  D osi n g  
Patie nts 
ma y res u me tr eat me nt wit h S D R E G N 2 8 1 0/i pi or H D R E G N 2 8 1 0 w he n t he st u d y 
dr u g -relat e d A E(s) res ol v e t o gra de ≤1 or baseli ne val ue, wit h t he f oll o wi n g e x ce pti o ns: 
 Patie nts ma y res u me st u d y treat me nt i n t he pres e n ce of gra de 2 fati g u e.  
 Patie n ts w h o ha ve n ot e x perie nce d a gra de 3 st u d y dr u g -relat e d s ki n A E ma y 
res u me st u d y treat me nt i n t he prese n ce of gra de 2 s ki n t o xicit y. 
 Patie nts wit h baseli ne gra de 1 A S T, A L T, or t otal bilir u bi n le vel w h o re q uire d ose 
dela ys f or reas o ns ot her t ha n a 2 -gra de  s hift i n A S T, A L T, or t otal bilir u bi n ma y 
res u me st u d y treat me nt i n t he prese n ce of gra de 2 A S T, A L T, O R t otal bilir u bi n. 
 Patie nts wit h A S T, A L T, a n d/ or t otal bilir u bi n val ues meeti n g disc o nti n uati o n 
criteria s h o ul d ha v e st u d y treat me nt per ma ne ntl y disc o n ti n ue d. 
 St u d y d r u g-relate d p ul m o nar y t o xicit y, diarr hea, or c olitis m ust res ol ve t o baseli ne 
bef ore st u d y tr eat me nt is res u me d.  
 St u d y d r u g-relate d e n d o cri n o pat hies a de q u atel y c o ntr olle d wit h o nl y p h ysi ol o gic 
h or m o ne re pla ce me nt ma y res u me st u d y treat me nt.  
 A n y A E t hat meets t h e disc o nti n uati o n r ules bel o w re q uir es t hat t he patie nt 
disc o nti n ue st u d y treat me nt.  
7. 3. 1. 3.  
D osi n g Disc o nti n u ati o n R ules  
T he f oll o wi n g cate g ories re q uir e p er ma ne nt disc o nti n uati o n of 
S D R E G N 2 8 1 0/i pi a n d 
H D R E G N 2 8 1 0:  
 A n y gra de 2 st u d y dr u g -relate d u v eitis, e ye p ai n, or bl urre d visi o n t hat d oes n ot 
res p o n d t o t o pical t hera p y a n d d o es n ot i m pr o ve t o gra de 1 se v erit y wit hi n t he 
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
 
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 5 1  of  1 2 9  
C O N FI D E N TI A L  
retreat me nt peri o d or t hat re q uires s yste mic tr eat me nt re q uir e st u d y treat me nt 
disc o nti n uati o n.  
 A n y gra de 3 n o n -ski n, st u d y dr u g -relate d A E lasti n g > 7 da ys re q uir es st u d y 
treat me nt 
disc o nti n uati o n, 
wit h t he f oll o wi n g 
e x ce pti o ns f or la b orat or y 
a b n or malities:  
 Gra de 3 st u d y dr u g -relat e d u veitis, p ne u m o nitis, br o nc h os pas m, c olitis, diarr hea, 
h y perse nsiti vit y reacti o n, o r i nf usi o n reacti o n of a n y d urati o n re q uir e st u d y 
treat me nt disc o nti n uati o n. 
 Gra de 3 st u d y dr u g -rel ate d e n d ocri n o pat hies a de q uatel y c o ntr olle d wit h o nl y 
p h ysi ol o gic 
h or m o ne 
re place me nt 
d o 
n ot 
re q uire 
st u d y 
treat me nt 
disc o nti n uati o n.  
 Gra de 3 
st u d y dr u g -relate d la b orat or y a b n or malities d o n ot re q uire st u d y 
treat me nt disc o nti n uati o n e x ce pt f or t he f oll o wi n g: 
 Gra de 3 st u d y dr u g -relat e d t hr o m b oc yt o p e nia > 7 da ys or ass ociate d wit h 
blee di n g re q uir es st u d y tr eat me nt disc o nti n uati o n.  
 A n y st u d y dr u g -relate d li ver f u ncti o n test a b n or malit y t hat meets t he 
f oll o wi n g criteria re q uires st u d y treat me nt disc o nti n uati o n: 
 
A S T or A L T > 5 t o 1 0  ×  U L N f or > 2  wee ks  
 
A S T or A L T > 1 0  ×  U L N  
 
T otal bilir u bi n > 3  × U L N  
 
C o nc urre nt A S T or A L T > 3  ×  U L N a n d t otal bilir u bi n > 2  ×  U L N  
 Gra de 4 a ne mia  
 A n y 
ot her  gra de 4 A E or la b orat or y a b n or malit y re q uires st u d y tr eat me nt 
disc o nti n uati o n, e x ce pt f or t he f oll o wi n g e ve nts, w hic h d o n ot re q uire st u d y tr eat me nt 
disc o nti n uati o n:  
 Gra de 4 n e utr o pe nia ≤7  d a ys  
 Gra de 4 l y m p h o pe nia or le u k o pe nia  
 Is olate d gra de 4 a m yl as e or li pase a b n or malities t hat are n ot ass ociate d wit h 
s y m pt o ms or cli nical ma nifestati o ns of pa ncreatitis 
 Is olat e d gra d e 4 ele ctr ol yt e i m bala nces/a b n or malities t hat are n ot ass ociat e d wit h 
cli nical se q uela e a n d are c orrecte d wit h s u p ple me ntati o n/a p pr o priate ma na ge m e nt 
wit hi n 7 2  h o urs of o nset  
 Gra de 4 st u d y dr u g -relate d e n d ocri n o pat h y A Es, s uc h as a dre n al i ns uffi cie nc y, 
a dre n oc ortic otr o pic  
h or m o ne  
( A C T H)  
deficie nc y,  
h y p ert h yr oi dis m, 
h y p ot h yr oi dis m, or gl uc ose i nt olera n ce, t h at res ol ve or ar e a d e q uatel y c o ntr olle d 
wit h p h ysi ol o gi c h or m o ne re place me nt (c ortic oster oi ds, t h yr oi d h or m o nes) or 
gl uc ose c o ntr olli n g a ge nts, as a p plica bl e, 
ma y n ot re q uir e st u d y tr eat me nt 
disc o nti n uati o n per a p pr o val fr o m t he Me dical M o nit or  
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
 
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 5 2  of  1 2 9  
C O N FI D E N TI A L  
 A n y st u d y tr eat me nt d ela y r es ulti n g i n n o d osi n g f or > 6  wee ks ( ce mi pli ma b ), 
> 1 2  wee ks (i pili m u ma b Q 6 W), or > 1 8  wee ks (i pili m u ma b Q 1 2 W, if d ose was re vise d 
t o 
Q 1 2 W d ue t o a t o xicit y or a n ot her reas o n) re q uires st u d y treat me nt 
disc o nti n uati o n, wit h t he e x ce pti o n of d osi n g d ela ys t o ma na ge st u d y dr u g -relat e d 
A Es, s uc h as pr ol o n ge d ster oi d ta pers a n d wit h t he e x ce pti o n of dela ys n ote d i n t he 
ne xt b ullete d ite m.  
 St u d y tr eat me nt dela ys res ulti n g i n n o d osi n g f or > 6  wee ks ( ce mi pli ma b ), > 1 2 wee ks 
(i pili m u ma b Q 6 W), or > 1 8 wee ks (i pili m u ma b Q 1 2 W, if d ose was re vise d t o Q 1 2 W 
d ue t o a t o xicit y or a n ot her reas o n) t hat occ ur f or n o n -st u d y dr u g -rel ate d reas o ns are 
per mitte d a n d ma y n ot re q uire st u d y tr eat me nt disc o nti n uati o n, if a p pr o ve d b y t he 
Me dical M o nit or.  
 A n y A E, l a b orat or y a b n or malit y, or i nt erc urre nt ill ness, w hic h, i n t he j u d g me nt of t he 
i n vesti gat or, pres e nts a s u bsta ntial cli nical ris k t o t he p atie nt 
wit h c o nti n ue d 
ce mi pli ma b  or i pili m u ma b d osi n g, re q uires st u d y treat me nt disc o nti n uati o n.  
If t h e i n vesti gat or deter mi nes t hat a ny  A E  detaile d a b o ve  is defi nitel y relate d t o i pili m u ma b 
base d o n l o cal prescri bi n g i nf or mati o n a n d practice g ui deli nes, t h e patie nt ma y disc o nti n ue 
treat me nt wit h i pili m u ma b a n d c o nti n ue treat me nt wit h o nl y ce mi pli ma b. 
A d diti o nal g ui deli nes f or disc o nti n uati o n  of i pili m u ma b are pr o vi de d i n Secti o n  7. 3. 4 . 
7. 3. 2.  
Ce mi pli m a b  Al o ne  
T he f oll o wi n g ce mi pli ma b  treat me nt h ol d g ui deli nes s h o ul d be f oll o we d f or patie nts i n 
Treat me nt Ar ms  A a n d C t hr o u g h o ut t h e c o urse of t he st u d y a n d f or p atie nts i n Treat me nt Ar m  B 
f oll o wi n g c o m pleti o n of i pili m u ma b d osi n g ( w he n ce mi pli ma b  will be a d mi nistere d al o ne).  
Ce mi pli ma b  treat me nt ma y b e hel d u p o n occ urre n ce of a treat me nt-relat e d A E at a n y ti me o n t he 
st u d y.  Res u m pti o n of ce mi pli ma b  t hera p y aft er res ol uti o n or sta bilizati o n of t he c o n diti o n is 
all o we d at t he discreti o n of t he i n vesti gat or a n d s p o ns or if res u mi n g treat me nt  is t h o u g ht t o be i n 
t he best i nterest of t he p atie nt, wit h t he e x ce pti o n of t he f oll o wi n g cate g ories: 
 Patie nts wit h e ve nts t hat re q uire ce mi pli ma b  t o be disc o nti n ue d per ma ne ntl y or 
hel d f or m ore t ha n 8 4 d a ys fr o m t he last sc he d ule d d ose  
 Patie nts wit h gra d e ≥2 u veitis.  Patie nts wit h gra de  2 u v eitis will ge nerall y be 
disc o nti n ue d fr o m ce mi pli ma b  treat me nt u nless t here is res ol uti o n t o gra de ≤1 as 
o utli ne d i n A p pe n di x  3  A N D disc ussi o n wit h a n d a p pr o val b y t he 
Me dical 
M o nit or.  All patie nts wit h gra d e  ≥3 u veitis will be per ma ne ntl y disc o nti n ue d fr o m 
ce mi pli ma b  
D ose m o dificati o n of H D R E G N 2 8 1 0 fr o m 1 0 5 0 m g t o 7 5 0 m g ma y b e  per mitte d  f oll o wi n g 
disc ussi o n wi t h t he s p o ns or.   
G ui deli nes f or ce mi pli ma b  te m p orar y dis c o nti n uati o ns, i ncl u di n g del a ys a n d i nterr u pti o ns, 
criteria f or restarti n g, a n d per ma ne nt disc o nti n uati o ns f or t o xicit y are o utli ne d i n Ta ble  1  a n d 
A p pe n di x  3 . 
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
 
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 5 3  of  1 2 9  
C O N FI D E N TI A L  
T a ble  1 : 
Ce mi pli m a b  G ui deli nes f or T e m p or a r y  a n d Per m a ne nt Disc o nti n u ati o ns f or 
T o xicit y  
T o xicit y  
Gr a de  H ol d 
Tre at me nt ?  
Rest arti n g 
Criteri a  
Rest arti n g 
D ose/ Sc he d ule  
Disc o nti n u ati o n 
Criteri a  
He m at ol o gic al t o xicit y ( ot her 
t h a n gra de 3 t hr o m b oc yt o pe nia > 7 
da ys or ass ociate d wit h blee di n g)  
1, 2, 3  
N o  
N/ A  
N/ A  
N/ A  
4  
Yes  
T o xicit y 
res ol ves t o 
gra de 0 t o 1 
or baseli ne  
Sa me d ose a n d 
sc he d ulea 
 
T o xicit y d oes n ot 
res ol ve wit hi n 8 4 da ys 
of last i nf usi o n.  
Per m a ne nt 
disc o nti n u ati o n s h o ul d 
be c o nsi dere d f or a ny 
sever e or 
life-t hre ate ni n g eve nt. 
Gra de 3 t hr o m b oc yt o pe nia > 7 
da ys or ass ociate d wit h blee di n g  
3  
Yes  
T o xicit y 
res ol ves t o 
gra des 0 t o 
1 or 
baseli ne  
Sa me d ose a n d 
sc he d ulea 
 
T o xicit y d oes n ot 
res ol ve wit hi n 8 4 da ys 
of last i nf usi o n.  
Per m a ne nt 
disc o nti n u ati o n s h o ul d 
be c o nsi dere d f or a ny 
sever e or 
life-t hre ate ni n g eve nt. 
N o n he m at ol o gic al t o xicit y  
N ote:   E xce pti o ns t o be treate d as 
f or gra de 1 t o xicit y: 
 
Gra de 2 al o pecia  
 
Gra de 2 fati g ue  
 
Cli nicall y 
i nsi g nifica nt la b 
a b n or malit y n ot 
meeti n g A E criteria  
A d diti o nal e xce pti o ns are detaile d 
i n A p pe n di x  3   
1  
N o  
N/ A  
N/ A  
N/ A  
 
2  
C o nsi der 
wit h h ol di n g 
f or persiste nt 
s y m pt o ms 
T o xicit y 
res ol ves t o 
gra des 0 t o 
1 or 
baseli ne  
Cli nic al A E res olves 
wit hi n 4 weeks :  Sa me 
d ose a n d sc he d ule  
Cli nic al A E d oes n ot 
res olve  
wit hi n  
4 
weeks:   Disc o nti n ue  
T o xicit y d oes n ot 
res ol ve wit hi n 8 4 da ys 
of last i nf usi o n.  
 
 
3  
Yes  
T o xicit y 
res ol ves t o 
gra des 0 t o 
1 or 
baseli ne  
Sa me d ose a n d 
sc he d ulea 
 
T o xicit y d oes n ot  
res ol ve wit hi n 8 4 da ys 
of last i nf usi o n.  
 
4  
Yes  
N/ A  
N/ A  
P atie nt m ust b e 
disc o nti n ue d.  
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
 
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 5 4  of  1 2 9  
C O N FI D E N TI A L  
A b bre viati o ns:  A E =a d verse e ve nt; ir A E =i m m u ne -relate d a d verse e ve nt; N/ A = n ot a p plica ble 
F or a d diti o nal i nf or mati o n re g ar di n g A Es wit h a p ote ntial f or bei n g ir A Es, see  T a ble  2  a n d A p pe n di x  3 . 
aD ose m o dific ati o n of ce mi pli ma b  ma y be c o nsi dere d after disc ussi o n wit h t he s p o ns or.  
 
A p pe n di x  3  i ncl u des rec o m me n dati o ns f or t he ma na ge me nt of s p ecific treat me nt-relate d A Es 
a n d w he n t o dela y a n d/ or disc o nti n ue ce mi pli ma b .  T hese g ui deli nes are i nte n de d t o be a p plie d 
w he n t he i n vesti gat or det er mi nes t he e v e nts t o be treat me nt -relate d. 
A d diti o nal reas o ns f or ce mi pli ma b  per ma ne nt disc o nti n uati o n i ncl u de t he f oll o wi n g:  
 Ce mi pli ma b a n d i pili m u ma b  d osi n g will be p er m a ne ntl y disc o nti n ue d i n t he e v e nt of 
pre g na nc y.  
 I n t he e ve nt of a n i nf usi o n reacti o n of gra de 3 or greater se v erit y d uri n g or directl y 
f oll o wi n g ce mi pli ma b  i nfusi o ns, d osi n g s h o ul d be st o p pe d, a n d t he patie nt m ust be 
per ma ne ntl y disc o nti n ue d fr o m ce mi pli ma b  treat me nt.  I nf usi o n reacti o ns are defi ne d 
i n Secti o n 9. 3. 4 . 
 I n a d diti o n, ce mi pli ma b  f or a n y patie nt ma y be disc o nti n ue d f or ot her safet y reas o ns 
or c o m plia nce iss ues at t he discreti o n of t he i n vesti gat or or s p o ns or.  A p atie nt ma y 
c h o ose t o disc o nti n ue ce mi pli ma b  or st u d y p artici pati o n at a n y ti me f or a n y reas o n.  
After at le ast 6 m o nt hs ( 2 4 wee ks) of treat me nt, patie nts i n Treat me nt Ar ms A a n d C wit h 
c o nfir me d C R ma y c h o ose t o st o p ce mi pli ma b treat me nt earl y a n d b e f oll o we d f or t he d urati o n 
of t he st u d y.  A patie n t wit h a P R t hat has sta bilize d after 6 m o nt hs a n d is n o l o n ger c ha n gi n g 
after 3 s u ccessi v e t u m or assess me nts ma y als o c h o ose t o st o p ce mi pli ma b treat me nt earl y a n d be 
f oll o we d f or t he d urati o n of t he st u d y. 
A patie nt w h o per ma n e ntl y dis c o nti n ues ce mi pli mab  treat me nt s h o ul d c o nti n ue f oll o w-u p i n t he 
st u d y wit h o ut a d diti o nal ce mi pli ma b  treat me nt u ntil R E CI S T 1. 1 -d efi ne d  P D , c o m pleti o n of all 
st u d y assess me nts, or cl os ure of t he st u d y (Secti o n  6. 3  a n d Secti o n  8. 1. 1 ). 
7. 3. 3.  
I m m u ne-Rel at e d A d verse E ve nts  
I n v esti gat ors m ust be e xtre mel y vi gila nt a n d be rea d y t o i nter ve n e earl y i n t he ma na ge m e nt of 
ir A Es beca use t he o ns et of s y m pt o ms of ir A Es (e g, p n e u m o nitis) ma y b e s u btle.  I m m u ne-relat e d 
T E A Es ha v e bee n re p orte d wit h ce mi pli ma b  a n d wit h ot her a nti -P D -1 a nti b o dies; t hese are 
c o nsi dere d c o nsiste nt wit h t he me c ha nis m of acti o n of a nti -P D -1 a nti b o dies.  
A n ir T E A E ca n occ ur s h ortl y after t he first d ose or se veral m o nt hs after t he last d ose of 
treat me nt.  All A Es of u n k n o w n eti ol o g y ass ociate d wit h dr u g e x p os ure s h o ul d be e val uate d f or a 
p ossi ble i m m u ne eti ol o g y.  Eff orts s h o ul d be ma de t o r ule o ut n e o plastic, i nfecti o us, meta b olic, 
t o xic, or ot her eti ol o gic ca uses pri or t o la beli n g a n A E as a n ir T E A E.  S u g geste d ma na ge me nt 
g ui deli nes are pr o vi d e d i n  A p pe n di x  3  a n d Ta ble  2  f or certai n a nti-P D -1 ir T E A Es . 
Base d o n t he e mer gi n g safet y pr ofile of ce mi pli ma b  a n d ot her a nti b o dies tar geti n g t he 
P D -1/ P D -L 1 a xis (We ber 2 0 1 5 )(Nai d o o 2 0 1 5 ), t he f oll o wi n g w or ki n g case defi niti o ns are 
pr o vi de d t o h el p i n vesti gat ors disti n g uis h ir T E A Es fr o m n o n -i m m u ne A Es.  T hes e case 
defi niti o ns pertai n t o t he m ore c o m m o nl y re p orte d ir T E A Es ass ociat e d wit h P D -1 i n hi biti o n 
(We ber 2 0 1 5 )(N ai d o o 2 0 1 5 ), a n d is n ot e x ha usti ve of all p ossi ble ir A Es.  Cli nical prese ntati o ns 
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
 
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 5 5  of  1 2 9  
C O N FI D E N TI A L  
of les s c o m m o n ir A Es, i ncl u di n g ne ur ol o gic, m usc ul os keletal, car diac, re nal, a n d oc ular e ve nts 
(Zi m mer 2 0 1 6 )(H of ma n n 2 0 1 6 ), s h o ul d be re vie we d i n patie nts wit h c o ncer ni n g prese nt ati o ns. 
T he i n vesti gat o r s h o ul d refer t o t he latest versi o n of t he I n v esti gat or’s Br oc h ure f or f urt her 
details a n d g ui d a nce.  T he case d efi niti o ns ha ve n ot bee n vali date d, a n d are i nte n de d o nl y as 
g ui da n ce f or i n vesti gat ors t o hel p disti n g uis h ir T E A Es fr o m n o n -i m m u ne A Es.  I n vesti gat ors’ 
cli nical j u d g me nt ma y i ncl u de ot her fact ors w he n deter mi ni n g i m m u ne -relate d ness.  T he case 
defi niti o ns f or ir A Es m a y e v ol ve as cli nical e x perie nce i ncreases wit h ce mi pli ma b  a n d ot her 
a nti b o dies tar geti n g t he P D -1/ P D -L 1 a xis.  
T a ble  2 : 
Ge ner al Ce mi pli m a b  Tre at me nt H ol d G ui deli nes f or I m m u ne -Rel at e d 
A d verse  E ve nts  
Se verit y  Wit h h ol d/ Disc o nti n ue Ce mi pli m a b  
Tre at me nt ?  
S u p p orti ve C are  
Gra d e 1  
N o acti o n  
Pr o vi de s y m pt o matic treat me nt  
Gra d e 2  
Ma y wit h h ol d treat me nt  
C o nsi der s yste mic c ortic oster oi ds i n a d diti o n t o 
a p pr o priate s y m pt o matic treat me nt  
Gra d es 
3 a n d 4  
Wit h h ol d treat me nt  
Disc o nti n ue if u na ble t o re d uce 
c ortic oster oi d d ose t o < 1 0  m g per da y 
pre d nis o ne e q ui vale nt wit hi n 1 2 wee ks of 
t o xicit y 
F or a n y se vere ( gra de 3 -4) ir A E, if s y m pt o ms w orse n or 
d o n ot i m pr o ve o n a de q uate c ortic oster oi ds wit hi n 4 8 t o 
7 2  h o urs, c o nsi der a d di n g a d diti o nal i m m u n os u p pressi ve 
a ge nts (t o be selecte d fr o m a ge nts s uc h as i nfli xi ma b, 
C T X, c ycl os p ori ne, a n d m yc o p he n olate m ofetil).  Referral 
of t h e patie nt t o a s pecialize d u nit f or assess me nt a n d 
treat me nt s h o ul d be c o nsi dere d. 
A b bre viati o ns:  C T X =c ycl o p h os p ha mi de; ir A E =i m m u ne -rel ate d a d verse e ve nt 
7. 3. 4.  
I pili m u m a b 
I pili m u ma b-relate d t o xicities s h o ul d be ma na ge d i n acc or da nce wit h l ocal prescri bi n g 
i nf or mati o n a n d practice g ui deli nes.   
I pili m u ma b s h o ul d als o be disc o nti n ue d f or t he f oll o wi n g reas o ns: 
 I pili m u ma b d osi n g will be per ma n e ntl y disc o nti n u e d i n t he e ve nt of pre g na nc y.  
 I n t he e ve nt of a n i nf usi o n reacti o n of gra de 3 or greater se v erit y d uri n g or directl y 
f oll o wi n g i nf usi o ns, d osi n g s h o ul d be st o p pe d, a n d t he patie nt m ust b e p er ma ne ntl y 
disc o nti n ue d fr o m i pili m u ma b treat me nt.  I nf usi o n reacti o ns are d efi ne d i n 
Secti o n  9. 3. 4 . 
 I pili m u ma b ma y be disc o nti n ue d f or ot her safet y reas o ns or c o m plia nce iss ues at t he 
discreti o n of t he i n vesti gat or or s p o ns or.  A p atie nt ma y c h o ose t o disc o nti n ue 
ce mi pli ma b  pl us i pili m u ma b c o m bi nati o n t hera p y or st u d y p artici pati o n at a n y ti me 
f or a n y reas o n.  
 I pili m u ma b ma y b e disc o nti n ue d f or a n y reas o n liste d i n t he l ocal prescri bi n g 
i nf or mati o n a n d practice g ui deli nes. 
If a patie nt e x perie nces a t o xicit y t hat is k n o w n t o be ass ociate d o nl y wit h i pili m u ma b t hera p y, 
i pili m u ma b will be disc o nti n ue d, b ut ce mi pli ma b ma y b e c o nti n ue d.   
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
 
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 5 6  of  1 2 9  
C O N FI D E N TI A L  
7. 3. 5.  
Per m a ne nt St u d y Dr u g Disc o nti n u ati o n  
Patie nts w h o per ma ne ntl y disc o nti n ue fr o m st u d y dr u g a n d w h o d o n ot wit h dra w fr o m t he st u d y  
will be as ke d t o ret ur n t o t he cli nic f or all re mai ni n g st u d y visits per t he visit sc he d ule.  
Patie nts w h o per ma n e ntl y disc o nti n ue fr o m st u d y dr u g a n d w h o o pt t o wit h dra w fr o m t he st u d y 
will be as ke d t o c o m plete st u d y assess me nts, per Secti o n  8. 1. 1 . 
7. 4.  
M a n a ge me nt of Ac ute Re acti o ns  
7. 4. 1.  
Ac ute I nf usi o n Re acti o ns  
E mer ge nc y e q ui p me nt a n d me dicati o n f or t he tr eat me nt of i nf u si o n reacti o ns m ust be a vaila ble 
f or i m me diate use.  Vital si g ns s h o ul d be cl osel y m o nit ore d acc or di n g t o  Ta ble  3 , Ta ble  4 , a n d 
Ta ble  5 .  All i nf usi o n reacti o ns m ust be re p orte d as A Es (as defi n e d i n Secti o n 9. 4. 1 ) a n d gra de d 
usi n g t he gra di n g s cales as i nstr ucte d i n Secti o n  9. 5. 1 . 
Ac ute i nf usi o n reacti o ns are defi ne d as a n y A Es t hat occ ur d uri n g t h e i nf usi o n or wit hi n 1 d a y  
after t he i nf usi o n is c o m plete d.  E mer ge nc y e q ui p me nt a n d me dicati o n f or t he treat me nt of t hese  
p ote ntial a d verse effects (e g, a nti hista mi nes, br o nc h o dilat ors, I V sali ne, c ortic oster oi ds, 
aceta mi n o p he n, a n d/ or e pi ne p hri ne) m ust be a vaila ble f or i m me diate use.  I nf usi o n reacti o ns 
m ust be gra d e d acc or di n g t o t he c urre nt versi o n of t he Nati o nal Ca ncer I nstit ute C o m m o n 
Ter mi n ol o g y Criteri a f or A d verse E v e nts ( N CI -C T C A E) gra di n g scale ( Secti o n  9. 5. 1 ). 
I n t he e v e nt of a n i nf usi o n reacti o n of gra de 3 or greater s e verit y d uri n g or directl y f oll o wi n g 
ce mi pli ma b or i pili m u ma b i nf usi o n, d osi n g s h o ul d be st o p pe d, a n d t he patie nt 
m ust be 
per ma ne ntl y disc o nti n ue d fr o m treat me nt.  I nf usi o n reacti o ns are defi ne d i n Secti o n  9. 3. 4 . 
Ac ute i nf usi o n reacti o ns ca n i ncl u de c yt o ki ne release s y n dr o me, a n gi oe de ma, or a na p h yla xis a n d 
differ fr o m aller gi c/ h y p erse nsiti ve reacti o ns, alt h o u g h s o me of t he ma nifestati o ns are c o m m o n t o 
b ot h A Es.  Si g ns a n d s y m pt o ms us uall y d e vel o p d uri n g or s h ortl y aft er dr u g i nf usi o n a n d 
ge n erall y res ol ve c o m pletel y wit hi n 2 4  h o urs of t h e c o m pleti o n of i nf usi o n.   
Si g ns/s y m pt o ms ma y i ncl u de t he f oll o wi n g:  
 Aller gi c reacti o n/ h y pers e nsiti vit y  (i ncl u di n g dr u g fe ver) 
 Art hral gia (j oi nt pai n)  
 Br o nc h os p as m  
 C o u g h  
 Dizzi ness  
 D ys p n ea (s h ort n ess of breat h)  
 Fati g ue (ast he nia, let har g y, malaise)  
 Hea dac he  
 H y p erte nsi o n  
 H y p ote nsi o n  
 M yal gia ( m uscle pai n)  
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
 
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 5 7  of  1 2 9  
C O N FI D E N TI A L  
 Na usea  
 Pr urit us/itc hi n g  
 Ras h/ des q ua mati o n  
 Ri g ors/c hills  
 Dia p h oresis (s weati n g)  
 Tac h ycar dia  
 T u m or pai n ( o nset or e x acer bati o n of t u m or pai n d ue t o treat me nt)  
 Urticaria ( hi ves, welts, w heals)  
 V o miti n g  
7. 4. 1. 1.  
I nterr u pti o n of t he I nf usi o n 
T he i nf usi o n s h o ul d be i nterr u pte d if a n y of t he f oll o wi n g A Es are o bser ve d:  
 C o u g h  
 Ri g ors/c hills  
 Ras h, pr urit us (itc hi n g)  
 Urticaria ( hi ves, welts, w heals)  
 Dia p h oresis (s weati n g)  
 H y p ote nsi o n  
 D ys p n ea (s h ort n ess of breat h)  
 V o miti n g  
 Fl us hi n g  
T he reacti o n(s) s h o ul d be treate d s y m pt o maticall y, a n d t he i nf usi o n ma y be restarte d at 5 0 % of 
t he ori gi nal rate. 
If i n vesti gat ors feel t here is a me dical nee d f or treat me nt or disc o nti n uati o n of t he i nf usi o n ot her 
t ha n descri be d a b o v e, t he y s h o ul d use cli nical j u d g me nt t o pr o vi de t he a p pr o priate res p o nse 
acc or di n g t o t y pical cli nical practice.  
F or patie nts w h o e x perie nce i nf usi o n -rel ate d h y p erse nsiti vit y reacti o ns t hat are less t ha n gra d e 3 
a n d w h o pla n t o c o nti n ue treat me nt, pre -me dicati o n will be re q uire d f or retreat me nt.  
F or gr a de 1 s y m pt o ms  ( mil d reacti o n; i nf usi o n i nterr u pti o n n ot i n dicate d; i nter venti o n n ot 
i n dicate d), t he f oll o wi n g pr o p h yl actic 
m e dicati o ns are rec o m me n de d f or f ut ure i nf usi o ns:  
di p he n h y dra mi ne 5 0  m g ( or e q ui vale nt) a n d/ or aceta mi n o p he n/ paraceta m ol 3 2 5  t o 1 0 0 0 m g at 
least 3 0 mi n utes pri or t o s u bse q ue nt ce mi pli ma b i nf usi o ns. 
F or g r a d e 2 s y m pt o ms  ( m o derate reacti o n t hat re q uires t hera p y or i nf usi o n i nterr u pti o n b ut f or 
w hic h s y m pt o ms res ol ve pr o m ptl y 
wit h a p pr o priate treat me nt s uc h as a nti hista mi nes, 
n o nster oi dal a nti -i nfla m mat or y dr u gs, n arc otics, c ortic oster oi ds, a n d/ or I V fl ui ds; pro p h ylactic 
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Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
 
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 5 8  of  1 2 9  
C O N FI D E N TI A L  
me dicati o ns i n dicate d ≤2 4  h o urs), t he f oll o wi n g pr o p h ylactic me di cati o ns are rec o m me n d e d f or 
f ut ure i nf usi o ns:  di p he n h y dra mi ne 5 0 m g ( or e q ui vale nt) a n d/ or acet a mi n o p he n/ paraceta m ol 
3 2 5  t o 1 0 0 0 m g at l east 3 0 mi n utes pri or t o s u bse q ue nt ce mi pli ma b  i nf usi o ns.  If n ecess ar y, 
c ortic oster oi ds ( u p t o  2 5 m g of h y dr oc ortis o ne or e q ui vale nt) ma y be us e d.  
See t he l ocal prescri bi n g i nf or mati o n a n d practice g ui deli nes f or ma na ge me nt of i nf usi o n 
i nterr u pti o ns f or i pili m u ma b. 
7. 4. 1. 2.  
Ter mi n ati o n of t he I nf usi o n  
T he i nf usi o n s h o ul d be ter mi nate d a n d N O T restarte d if a n y of t he f oll o wi n g A Es o cc ur: 
 A na p h yl a xis  
 Lar y n geal/ p har y n geal e d e ma  
 Se vere br o nc h os pas m  
 C hest pai n  
 Seiz ure  
 Se vere h y p ote nsi o n  
 Ot her ne ur ol o gic al s y m pt o ms (c o nf usi o n, l oss of c o nsci o us ness, parest hesia, 
paral ysis, etc)  
 A n y ot h er s y m pt o m or si g n t hat, i n t h e o pi ni o n of t he i n vesti gat or, warra nts 
disc o nti n uati o n of t he i nf usi o n  
I n t he e v e nt of a n i nf usi o n reacti o n of gra de 3 or greater s e verit y d uri n g or directl y f oll o wi n g 
ce mi pli ma b or i pili m u ma b, d osi n g s h o ul d be st o p pe d, a n d t h e patie nt m ust be per ma n e ntl y 
disc o nti n ue d fr o m treat m e nt.  
See t he l ocal prescri bi n g i nf or mati o n a n d practice g ui deli nes f or ma na ge me nt of i nf usi o n 
ter mi nati o n f or i pili m u ma b. 
7. 5.  
Met h o d of Tre at me nt Assi g n me nt  
Eac h patie nt w h o si g ns t h e i nf or me d c o ns e nt f or m (I C F) will be assi g ne d a patie nt n u m ber a n d 
trac ke d ce ntrall y as des cri be d i n t he i nteracti ve v oice res p o nse s yst e m (I V R S)/i nteracti ve we b 
res p o nse s yste m (I W R S) ma n ual.  Patie nts  will be ra n d o mize d i n a 1: 1: 1  rati o acc or di n g t o a 
ce ntral ra n d o mizati o n sc he me pr o vi d e d b y a n I V R S/I W R S t o t he d esi g nate d st u d y p har macist 
( or a ut h orize d desi g nee).  Patie nts will be ra n d o mize d after pr o vi di n g i nf or me d c o nse nt, after 
c o m pleti n g scree ni n g assess me nts, a n d after t he i n vesti gat or has verifie d  patie nt eli gi bilit y.   
Ra n d o mizati o n will be stratifie d b y hist ol o g y ( n o n -s q ua m o us vers us s q u a m o us) a n d le vels of 
P D -L 1 e x pressi o n ( < 1 % vers us 1 % t o 4 9 % vers us ≥5 0 %) .  T he stratificati o n fact or of P D -L 1 
e x pressi o n le vel will be use d f or t he p ur p os e of b ala nci n g t he treat me nt assi g n me nt o nl y a n d will 
n ot be i ncl u de d i n t he a n al ysis m o dels f or  pri mar y a n d s ec o n dar y e n d p oi nts.    
Patie nts 
will 
be ra n d o mize d 
1: 1: 1 t o recei ve 
S D R E G N 2 8 1 0, 
S D R E G N 2 8 1 0/i pi, 
or 
H D R E G N 2 8 1 0.   
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
 
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 5 9  of  1 2 9  
C O N FI D E N TI A L  
7. 5. 1.  
Bli n di n g  
T his is a n o pe n -la bel st u d y.  T o re d uce bias, ra di o gra p hic t u m or assess me nts will be perf or me d 
b y a n I R C bli n de d t o treat me nt assi g n me nt.  
7. 6.  
Tre at me nt L o gistics a n d Acc o u nt a bilit y  
7. 6. 1.  
P ac k a gi n g, L a beli n g, a n d St or a ge  
Ce mi pli ma b  
O pe n -la bel ce mi pli ma b  will be s u p plie d as a li q ui d i n sterile, si n g le-us e vials t hat will dis pla y t h e 
pr o d uct l ot n u m ber o n t he la bel.  Eac h vial will c o ntai n ce mi pli ma b at a c o nce ntrati o n of 
5 0  m g/ m L.  C e mi pli ma b  will be refri gerate d at t he site at a te m perat ure of 2° C t o 8° C.  T he 
te m perat ur e of t he st ora ge refri gerat or s h o ul d be c hec k e d a n d rec or de d at least dail y as 
prescri be d i n t he st u d y ma n ual.   F urt her st ora ge i nstr ucti o ns will be pr o vi de d i n t he p har mac y 
ma n ual.  
A p har macist or ot her q ualifie d i n di vi d ual will be i de ntifie d at eac h site t o pre pare ce mi pli ma b 
f or a d mi nistrati o n.  Details o n st ora ge a n d pre p arati o n f or dr u g pr o d uct f or I V a d mi nistrati o n 
will be pr o vi de d i n t he p har mac y refere n ce ma n ual.  
I pili m u ma b 
I nstr u cti o ns o n st or a ge will be pr o vi de d i n t he p har mac y ma n ual.  A p har macist or ot h er 
q ualifie d i n di vi d ual will be i de ntifie d at eac h site t o pre pare i pili m u ma b f or a d mi nistrati o n.  
Detaile d pre parati o n a n d a d mi nistrati o n i nstr ucti o ns will be pr o vi de d t o t h e sites i n t he p har m ac y 
ma n ual.  
I pili m u ma b will be refri gerate d at t he site at a te m perat ur e of 2° C t o 8° C, a n d t he refri gerat or 
te m perat ur e will be l o g ge d dail y. 
7. 6. 2.  
S u p pl y a n d Dis p ositi o n of Tre at me nts  
Ce mi pli ma b  
St u d y dr u g will be s hi p pe d at a te m perat ure of 2º C t o 8º C t o t he i n vesti gat or or desi g nee at 
re g ular i nter vals or as n ee de d d uri n g t he st u d y.  At s pecifie d ti me p oi nts d uri n g t he st u d y (e g, 
i nteri m site m o nit ori n g visits), at t he site cl ose-o ut visit, a n d f oll o wi n g dr u g rec o nciliati o n a n d 
d oc u me ntati o n b y t he site m o nit or, all o pe ne d a n d u n o pe ne d st u d y dr u g will be destr o ye d or 
ret ur ne d t o t he s p o ns or or desi g n ee. 
I pili m u ma b 
O pe n -la bel i pili m u ma b will be s u p plie d l ocall y or ma y b e pr o vi de d b y Re ge n er o n.  
7. 6. 3.  
Tre at me nt Acc o u nt a bilit y  
All dr u g acc o u nta bilit y rec or ds m ust be ke pt c urre nt.  
T he i n vesti gat or m ust be a ble t o acc o u nt f or all o p e ne d a n d u n o p e ne d st u d y dr u g.  T h ese rec or ds 
s h o ul d c o ntai n t he dates, q ua ntit y, a n d st u d y me di cati o n 
 Dis pe nse d t o eac h patie nt,  
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
 
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 6 0  of  1 2 9  
C O N FI D E N TI A L  
 Ret ur ne d fr o m e ac h p atie nt (if a p plica ble), a n d  
 Dis p ose d of at t he site or ret ur ne d t o t he s p o ns or or desi g n ee.  
All acc o u nta bilit y rec or ds m ust be ma de a vaila bl e f or i ns pecti o n b y t he s p o ns or a n d re g ulat or y 
a ge nc y i ns pect ors; a n o n y mize d p h ot oc o pies m ust be pr o vi de d t o t he s p o ns or at t he c o ncl usi o n of 
t he st u d y. 
7. 6. 4.  
Tre at me nt C o m pli a nce  
All treat me nts will be a d mi nistere d at t he st u d y site, a n d  a d mi nistrati o n will be rec or de d o n t he 
electr o nic case re p ort f or m ( e C R F).  All d osi n g rec or ds f or eac h p atie nt will be ke pt b y t h e site. 
All dr u g c o m plia nce rec or ds m ust be ke pt c urre nt a n d ma de a vaila ble f or i ns pecti o n b y t he 
s p o ns or a n d re g ulat or y a ge nc y i ns pect ors.  
7. 7.  
C o nc o mit a nt Me dic ati o ns  
A n y treat me nt a d mi nistere d fr o m t he ti me of i nf or me d c o ns e nt u ntil 9 0  da ys after t he last st u d y 
treat me nt will be c o nsi d ere d a c o nc o mita nt me dicati o n.  T his i ncl u des me dicati o ns t hat were 
starte d bef ore t he st u d y a n d are o n g oi n g d uri n g t he st u d y, as well as a n y t hera pies start e d i n t he 
f oll o w-u p peri o d t o treat a st u d y dr u g -relate d A E.  All c o nc o mita nt tr eat m e nts m ust be rec or de d 
i n t he st u d y e C R F wit h t he ge neric n a me, d ose, d ose u nit, fre q ue nc y, i n dicati o n, a n d start/st o p 
date, as a p pr o priate.  
7. 7. 1.  
Pr o hi bite d Me dic ati o ns a n d Pr oce d ures  
W hile partici pati n g i n t his st u d y, a patie nt ma y n ot recei ve a n y i n v esti gati o nal dr u g or treat me nt 
f or treat me nt of a t u m or ot her t ha n ce mi pli ma b or i pili m u ma b.   
Treat me nt wit h i delalisi b, be vaciz u ma b, or necit u m u ma b is n ot o ne of t he pr ot oc ol – defi ne d 
treat me nt o pti o ns.  If t he treati n g p h ysicia n belie ves t hat treat me nt 
wit h o ne of t hese 
3  me dicati o ns is re q uire d f or a p atie nt c o nsi deri n g e nr oll me nt t o t he st u d y a n d st u d y -s p ecifie d 
treat me nt o pti o ns are n ot s ufficie nt, t hat patie nt s h o ul d n ot e nr oll i n t he st u d y.  
A n y ot her me dicati o n t hat is c o nsi dere d necessar y f or t he patie nt’s welfare a n d is n ot e x pecte d t o 
i nterfere wit h t he e val u ati o n of ce mi pli ma b ma y b e gi v e n at t he discreti o n of t he i n vesti gat or.  
7. 7. 2.  
Per mitte d Me dic ati o ns a n d Pr oce d ures  
It is rec o m me n de d t h at patie nts d o n ot recei ve c o nc o mita nt s yste mic c ortic oster oi ds s uc h as 
h y dr oc ortis o ne,  
pre d nis o ne,  
pre d nis ol o ne  
( S O L U  M E D R O L
® ),  
or  
de x a met has o ne 
( D E C A D R O N® ) at a n y ti me t hr o u g h o ut t h e st u d y, e x ce pt i n t he case of a life-t hreate ni n g 
e mer ge n c y a n d/ or t o treat a n ir A E.  
P h ysi ol o gic re pl ace me nt d oses of s yst e mic c ortic oster oi ds are p er mitte d, e ve n if > 1 0  m g/ da y 
pre d nis o ne e q ui vale nts.  A brief c o urse of c ortic oster oi ds f or pr o p h yl a xis (e g, c o ntr ast d ye 
aller g y) or f or treat me nt of n o n -a ut oi m m u ne c o n diti o ns (e g, del a ye d -t y pe h y p erse nsiti vit y 
reacti o n ca use d b y c o nta ct aller ge n) is per mitte d. 
Treat me nts f or b o n e met astases (e g, bis p h os p h o n ates, de n os u ma b) are p er mitte d.  
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
 
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 6 1  of  1 2 9  
C O N FI D E N TI A L  
7. 8.  
Dise ase Pr o gressi o n W hile  Recei vi n g Ce mi pli m a b  
It is rec o g niz e d t hat a mi n orit y of p atie nts treate d wit h i m m u n ot hera p y ma y deri v e cli nical 
be nefit des pite i nitial e vi de nce of P D .  Patie nts tr eate d wit h ce mi pli ma b 3 5 0  m g or 1 0 5 0  m g will 
be per mitte d t o c o nti n ue treat me nt be y o n d i ni ti al R E CI S T 1. 1 -defi ne d P D  if t he i n vesti gat or 
percei v es t he patie nt t o be e x perie nci n g cli nical be nefit, t he patie nt h as n ot c o m plete d t he 
1 0 8 -wee k tr eat me nt peri o d, a n d t he patie nt meets t he f oll o wi n g criteria: 
 T he i n vesti gat or assesse d disease pr o gressi o n  was n ot ra pi d . 
 T he patie nt c o nti n ues t o meet all ot her st u d y eli gi bilit y criteria.  
 T he patie nt is t olera nt of ce mi pli ma b a n d has a sta ble perf or m a nce st at us.  
 Treat me nt be y o n d pr o gressi o n will n ot dela y a n i m mi ne nt i nter ve nti o n t o pre ve nt 
seri o us c o m plicati o ns of disease pr o gressi o n.  
I ma gi n g s h o ul d be p erf or me d wit hi n 9 wee ks of t he i nitial assess me nt of P D  t o deter mi ne 
w het her t here has bee n a decrease i n t he ori gi nal t u m or siz e or c o nti n ue d P D .  I n t hese patie nts, 
f urt her pr o gressi o n will be defi ne d as a n a d diti o n al 1 0 % i ncrease i n t u m or b ur de n fr o m t he ti me 
of i nitial P D ; t his i ncl u des a n i ncreas e i n t he s u m of all tar get lesi o ns a n d/ or t he de v el o p me nt of 
ne w lesi o ns.  If f urt her P D  is c o nfir me d, ce mi pli ma b  m ust be disc o nti n ue d a n d ot her a nti -ca ncer 
t hera p y c o nsi dere d, if a p pr o priate. 
If a patie nt c o nti n ues tr eat me nt wit h ce mi pli ma b  be y o n d t h e i nitial deter mi nati o n of P D , st u d y 
assess me nts s h o ul d c o nti n ue as per T a ble  4 .  Patie nts w o ul d be re q uire d t o re -c o nse nt usi n g a 
se parat e I C F. 
7. 9.  
P ost -St u d y Tre at me nts a n d Pr oce d ures  
P atie nts will be c o ntacte d e ver y 3 m o nt hs  b y tel e p h o ne f or s ur vi val stat us, if a vaila ble, u ntil 
deat h, l oss t o f oll o w -u p, or st u d y ter mi nati o n b y t he s p o ns or.  
8.  
S T U D Y S C H E D U L E O F E V E N T S A N D P R O C E D U R E S  
8. 1.  
Sc he d ule of E ve nts  
St u d y assess me nts a n d pr oce d ures are pres e nte d i n Ta ble  3  f or scree ni n g, i n Ta ble  4  f or t he 
treat me nt peri o d, a n d i n Ta ble  5  f or t he f oll o w-u p peri o d.  
 
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
 
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 6 5  of  1 2 9  
C O N FI D E N TI A L  
St u d y Pr oc e d ur e  
Ye ar 1  
Ye ar 2 ( St arti n g at C ycle 1 9)  
N otes  
D a y  1,  
C ycle  1  
D a y 1,  
E ac h C ycle  
( E ver y 2 1 D a ys 
± 3  D a ys)  
D a y 1, E ver y 
Ot he r C ycle 
( E ver y 4 2 D a ys 
± 3  D a ys)  
E ver y 3 
C ycles  
( 9 Wee ks 
[ 6 3 D a ys] 
± 5  D a ys)  
D a y 1,  
E ac h C ycle  
( E ver y 
2 1  D a ys 
± 3  D a ys)  
E ver y 3 
C y cles 
( 9 Wee ks 
[ 6 3 D a ys] 
± 5  D a ys)  
E ver y 
4  C ycles  
( 1 2 Wee ks 
± 5  D a ys)  
t h e c hest/a b d o me n/ p el vis 
a n d ot h er areas bei n g 
m o nit ore d.  
 Re gar dless of w he n 
patie nts e nter t he f oll o w -
u p peri o d, t he 
ra di o gra p hic t u m or 
assess me nt sc he d ule 
o utli ne d i n 
Secti o n  8. 2. 2. 1  s h o ul d be 
f oll o we d, u ntil 
R E CI S T  1. 1 -defi n e d P D , 
wit h dra wal of c o nse nt, 
deat h, or i nitiati o n of  
a n ot h er a nti -ca ncer 
treat me nt. 
 Brai n sca ns d uri n g t h e 
treat me nt a n d f oll o w-u p 
peri o ds s h o ul d be 
perf or me d as cli nicall y 
i n dicate d e xce pt f or 
patie nts wit h a hist or y of 
brai n metastases, w h o 
s h o ul d ha ve s ur veilla nce 
i ma gi n g as descri b e d i n 
Se cti o n  8. 2. 2. 1 . . 
 F or patie nts w h o ha ve  
R E CI S T  1. 1 -defi n e d  P D  
w hile recei vi n g 
ce mi pli ma b  or after 
c o m pleti o n of 
ce mi pli ma b  treat me nt, 
i ma gi n g s h o ul d be 
perf or me d wit hi n 
9  wee ks of t h e ori gi n al 
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
 
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 6 7  of  1 2 9  
C O N FI D E N TI A L  
St u d y Pr oc e d ur e  
Ye ar 1  
Ye ar 2 ( St arti n g at C ycle 1 9)  
N otes  
D a y  1,  
C ycle  1  
D a y 1,  
E ac h C ycle  
( E ver y 2 1 D a ys 
± 3  D a ys)  
D a y 1, E ver y 
Ot he r C ycle 
( E ver y 4 2 D a ys 
± 3  D a ys)  
E ver y 3 
C ycles  
( 9 Wee ks 
[ 6 3 D a ys] 
± 5  D a ys)  
D a y 1,  
E ac h C ycle  
( E ver y 
2 1  D a ys 
± 3  D a ys)  
E ver y 3 
C y cles 
( 9 Wee ks 
[ 6 3 D a ys] 
± 5  D a ys)  
E ver y 
4  C ycles  
( 1 2 Wee ks 
± 5  D a ys)  
1 2 -Lea d E C G  
 
 
 
 
 
 
 
A 1 2 -lea d E C G s h o ul d be 
ac q uire d as cli nicall y 
i n dicate d, per t he discreti o n 
of t h e i n vesti gat or.  
He mat ol o g y ( C B C 
Wit h Differe ntial)  
X  
X  
 
 
X  
 
 
 Bl o o d sa m ples ma y be 
c ollecte d ≤7 2  h o urs pri or 
t o d osi n g o n t h e da y 1 
visit of eac h c ycl e.  
 Res ults m ust b e 
o btai ne d/re vie we d pri or 
t o d osi n g. 
 Scree ni n g la b orat or y 
e xa mi n ati o ns perf or me d 
wit hi n 7 da ys of c ycle 1 
da y 1 d o n ot nee d t o be 
re peate d f or t his visit, 
u nless cli nicall y 
i n dicate d. 
Ser u m C he mistr y  
X  
X  
X ( A C T H m ust 
be teste d i n 
Treat me nt Ar m 
B, o nl y pri or t o 
i pili m u ma b 
d osi n g)  
 
X  
 
 
 Bl o o d sa m ple ma y be 
c ollecte d ≤7 2  h o urs pri or 
t o d osi n g o n t h e da y 1 
visit of eac h c ycl e.  
 Res ults m ust b e 
o btai ne d/re vie we d pri or 
t o d osi n g. 
 Scree ni n g la b orat or y 
e xa mi n ati o ns perf or me d 
wit hi n 7 da ys of i nitial 
d ose visit a n d wit hi n 7 
da ys of c ycle 1 da y 1 d o 
n ot nee d t o be re peate d 
f or t his visit, u nless 
cli nicall y i n dicate d. 
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
 
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 6 8  of  1 2 9  
C O N FI D E N TI A L  
St u d y Pr oc e d ur e  
Ye ar 1  
Ye ar 2 ( St arti n g at C ycle 1 9)  
N otes  
D a y  1,  
C ycle  1  
D a y 1,  
E ac h C ycle  
( E ver y 2 1 D a ys 
± 3  D a ys)  
D a y 1, E ver y 
Ot he r C ycle 
( E ver y 4 2 D a ys 
± 3  D a ys)  
E ver y 3 
C ycles  
( 9 Wee ks 
[ 6 3 D a ys] 
± 5  D a ys)  
D a y 1,  
E ac h C ycle  
( E ver y 
2 1  D a ys 
± 3  D a ys)  
E ver y 3 
C y cles 
( 9 Wee ks 
[ 6 3 D a ys] 
± 5  D a ys)  
E ver y 
4  C ycles  
( 1 2 Wee ks 
± 5  D a ys)  
A m ylas e a n d Li p ase 
testi n g 
X  
 
 
X  
 
X  
 
 
C oa g ulati o n Test s 
 
 
 
 
 
 
 
As cli nicall y i n dicate d  
Pre g na nc y Testi n g  
X  
X  
 
 
X  
 
 
W o me n  
of  
c hil d beari n g 
p ote ntial  
m ust  
ha ve  
a 
ne gati ve ser u m pre g na nc y 
test wit hi n 7 2 h o urs pri or t o 
st u d y 
treat me nt 
a d mi nistrati o n 
o n 
c ycle  1 
da y  1 a n d a ne gati ve uri ne 
pre g na nc y t est pri or t o st u d y 
treat me nt a d mi nistrati o n o n 
da y 1 of ea c h s u bse q ue nt 
treatme nt 
c ycle 
or 
m ore 
fre q ue ntl y  
per  
l o cal 
sta n dar d.  
T h yr oi d F u ncti o n 
Tests  
X  
 
X ( Treat me nt 
Ar m B; o nl y 
pri or t o 
i pili m u ma b 
d osi n g)  
X  ( Treat me nt 
Ar m B after 
c o m pleti o n of 
i pili m u ma b 
d osi n g)  
 
X  
 
 F or Treat me nt Ar m A 
a n d C, T S H (a n d free T 4 
if T S H is a b n or mal) will 
be teste d at scree ni n g a n d 
Q 9 W . 
 F or Tre at me nt Ar m B , 
T S H (a n d free T 4 if T S H 
is a b n or mal) will be 
teste d at scree ni n g a n d 
Q 9 W.  T S H (a n d free T 4 
if T S H is a b n or mal) 
m ust  be teste d ≤7 2 h o urs 
pri or t o d osi n g 
i pili m u ma b a n d t h e 
res ults m ust b e re vie we d 
pri or t o d osi n g 
i pili m u ma b. 
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
 
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 7 0  of  1 2 9  
C O N FI D E N TI A L  
St u d y Pr oc e d ur e  
Ye ar 1  
Ye ar 2 ( St arti n g at C ycle 1 9)  
N otes  
D a y  1,  
C ycle  1  
D a y 1,  
E ac h C ycle  
( E ver y 2 1 D a ys 
± 3  D a ys)  
D a y 1, E ver y 
Ot he r C ycle 
( E ver y 4 2 D a ys 
± 3  D a ys)  
E ver y 3 
C ycles  
( 9 Wee ks 
[ 6 3 D a ys] 
± 5  D a ys)  
D a y 1,  
E ac h C ycle  
( E ver y 
2 1  D a ys 
± 3  D a ys)  
E ver y 3 
C y cles 
( 9 Wee ks 
[ 6 3 D a ys] 
± 5  D a ys)  
E ver y 
4  C ycles  
( 1 2 Wee ks 
± 5  D a ys)  
pri or t o c ollecti o n of t he 
sa m ple. 
A b bre viati o ns:  A C T H =a dre n oc ortic otr o pic h or m o ne; A D A =a nti -dr u g a nti b o d y; A U C =ar ea u n der t he c ur ve; B P = bl o o d press ure; C B C =c o m plete bl o o d c o u nt; 
D N A = d e o x yri b o n ucleic aci d; 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; G F R = gl o mer ular filtr ati o n rate; H D R E G N 2 8 1 0 =“ Hi g h 
d ose” ce mi pli ma b ; I V =i ntra ve n o us; N CI-C T C A E = Nati o nal Ca ncer I nstit ute C o m m o n T er mi n ol o g y Criteria f or A d verse E ve nts; P B M C = peri p heral bl o o d 
m o n o n uclear cell; P E = p h ysical e xa mi nati o n; P K = p har mac o ki netic; Q 3 W =e ver y 3  wee ks; Q 6 W =e ver y 6 wee ks; Q 1 8 W =e ver y 1 8 wee ks; Q 2 4 W =e ver y 
2 4  wee ks; R E CI S T 1. 1 = Res p o nse E val uati o n Criteria i n S oli d T u m ors versi o n 1. 1; S D R E G N 2 8 1 0 =“ Sta n dar d d ose” ce mi pli ma b ; S D R E G N 2 8 1 0/i pi =” Sta n dar d 
D ose” ce mi pli ma b  i n c o m bi nati o n wit h u p t o 4 c ycles of i pili m u ma b; T 4 =t h yr o xi ne; T S H =t h yr oi d -sti m ulati n g h or m o ne
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 7 3  of  1 2 9  
C O N FI D E N TI A L  
8. 1. 1.  
E arl y Ter mi n ati o n Visit  
Patie nts w h o wit h dra w fr o m t he st u d y d uri n g t he treat me nt peri o d will be as ke d t o ret ur n t o t he 
cli nic t o c o m plete f oll o w -u p visit 1 st u d y ass ess me nts (Ta ble  5 ) as a n earl y ter mi nati o n visit.  
Patie nts w h o wit h dra w fr o m t he st u d y  d uri n g t he f oll o w -u p peri o d will be as ke d t o ret ur n t o t he 
cli nic t o c o m plete visits of t he f oll o w -u p peri o d as i n dicate d i n  Ta ble  5 . 
Patie nts w h o dis c o nti n ue st u d y treat me nt d ue t o P D  s h o ul d ret ur n t o t he cli nic 1 4 t o 3 0 da ys after 
t he last st u d y treat me nt t o c o m plete t he e n d of st u d y ass ess me nts (foll o w -u p visit  1) .  
Patie nts w h o disc o nti n ue st u d y treat me nt f or a reas o n ot her t ha n P D  s h o ul d ret ur n t o t he cli nic 1 4 
t o 3 0 da ys after t he last c ycl e visit f or f oll o w -u p visit 1 a n d t he n c o nti n ue wit h f oll o w -u p visit  2 
t hr o u g h f oll o w-u p visit  7.  
8. 1. 2.  
U nsc he d ule d Visits  
All atte m pts s h o ul d be ma de t o kee p p atie nts o n t he st u d y s c he d ule.  U ns c he d ule d visits ma y be 
necessar y t o re p eat testi n g f oll o wi n g a b n or mal la b orat or y res ults, f or f oll o w -u p of A Es, or f or 
a n y ot her reas o n, as warra nte d.  I n res p o ns e t o a d verse e ve nts of s pecial i nterest  ( A E SIs), s uc h as 
a na p h yla xis or h y pers e nsiti vit y, A D A s a m ples ma y be c ollecte d cl oser t o t he e ve nt base d o n t he 
j u d g me nt of t he i n vesti gat or a n d/ or Me dical M o nit or. 
8. 2.  
St u d y Pr oce d ures  
8. 2. 1.  
Pr o ce d ures Perf or me d O nl y at t he Scree ni n g/ B aseli ne Visit  
I nf or me d c o nse nt 
m ust be o btai n e d pri or t o a n y st u d y-relate d pr oce d ures.  Assess me nts 
perf or m e d as part of sta n dar d -of -care t h at fall wit hi n t he scree ni n g wi n d o w ( 2 8 d a ys pri or t o 
ra n d o mizati o n) b ut bef ore i nf or me d c o ns e nt is o btai ne d ma y b e us e d f or s cree ni n g a n d nee d n ot 
be re peate d f or e nr oll me nt eli gi bilit y.  
T he f oll o wi n g pr oce d ures will be pe rf or me d f or t he s ole p ur p ose of deter mi ni n g st u d y eli gi bilit y 
or c haracterizi n g t he bas eli ne p o p ulati o n:  
 Me dical/ O nc ol o g y hist or y  
 De m o gra p hics  
 Re vie w of i ncl usi o n/e x cl usi o n criteria  
 C ollecti o n of t u m or tiss ue sa m ple f or P D -L 1 a n d t u m or m utati o n b ur de n assess me nt 
b y t he ce ntral la b orat or y  
 A f or mali n -fi x e d, paraffi n-e m be d de d tiss ue bl oc k or u nstai ne d sli de of t u m or 
tiss ue sa m ple (arc hi val tiss ue, if ≤5 m o nt hs ol d, or rece ntl y o btai ne d, o n -st u d y 
t u m or bi o ps y c ollecte d at scree ni n g) m ust be pr o vi de d.  T u m or bi opsies s h o ul d be 
of s ufficie nt siz e t o e ns ure a n a de q u ate a m o u nt of tiss ue f or a nal ysis (e x cisi o nal, 
i ncisi o nal, or c ore nee dle; fi ne nee dle as pirates are n ot acce pta ble).  C o m plete 
i nstr ucti o ns o n t he c ollecti o n, pr ocessi n g, h a n dli n g, a n d s hi p me nt of all sa m ples 
will be pr o vi de d i n t he la b orat or y ma n ual.  
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 7 4  of  1 2 9  
C O N FI D E N TI A L  
 T u m or tiss ue sa m ples 
will als o be teste d f or E G F R 
m utati o ns a n d 
A L K 
tra nsl ocati o ns as well as f or R O S 1 f usi o ns. 
 Baseli ne ra di o gra p hic t u m or assess me nt of t h e c hest, a b d o me n, pel vis, a n d all ot her 
k n o w n or s us p ecte d sites of dis ease b y Hi g h -res ol uti o n C T.  T he sa me i ma gi n g 
m o dalit y s h o ul d be use d t hr o u g h o ut t he st u d y.   
 Baseli ne t u m or b ur de n assess me nt  
 Baseli ne wei g ht a n d hei g ht  
 T u berc ul osis testi n g  
 Ser u m pre g na n c y test i n w o me n of c hil d beari n g p ote ntial wit hi n 7 2  h o urs pri or t o 
a d mi nistrati o n of t he first st u d y treat me nt a d mi nistrati o n  
 Baseli ne 1 2 -lea d E C G a n d c hest X-ra y  
 Sa m ple f or a ge n o mics s u b -st u d y ( o pti o nal) 
F or t he c o m plete list of pr oce d ures perf or me d at scree ni n g t o det er mi ne eli gi bilit y, i ncl u di n g 
t h ose t hat are use d t hr o u g h o ut t he st u d y (ie, n ot o nl y f or d eter mi ni n g eli gi bilit y), see T a ble  3 . 
8. 2. 2.  
Effic ac y Pr o ce d ures  
8. 2. 2. 1.  
R a di o gr a p hic T u m or Assess me nts  
Hi g h -res ol uti o n C T wit h c o ntrast is t he preferre d i ma gi n g m o dality  f or assessi n g ra di o gra p hic 
t u m or res p o nse, i ncl u di n g t u m or v ol u me .  I n pati e nts w h o m c o ntrast is strictl y c o ntrai n dicat e d, 
n o n -c o ntrast sca ns will s uffice.  T he c hest, a b d o me n, a n d pel vis m ust be i ma ge d al o n g wit h a n y 
ot her k n o w n or s us pecte d sites of disease.  C o m p ute d t o m o gra p h y  s ca ns will be assesse d b y t he 
S p o ns or f or t he e val u ati o n of gr oss t u mor v ol u me.  
At scree ni n g, C T or m a g n etic res o na n ce i ma gi n g ( M RI ) of t he brai n wit h c o ntrast ( u nless 
c o ntrai n dicate d) s h o ul d be perf or me d i n patie nts 
wit h a k n o w n hist or y of treat e d brai n 
metastasis, if n ot perf or me d i n t he pri or 6 0  da ys.  A d diti o nal sites o f k n o w n disease (i ncl u di n g 
C N S) s h o ul d be i ma ge d at scree ni n g.  
After t he baseli ne t u m or assess me nt, ra di o gra p hic t u m or assess me nts will be o btai ne d i n all 
patie nts Q 9 W be gi n ni n g at wee k  9  ( da y 6 3  ± 5  da ys) d uri n g year  1 a n d Q 1 2 W be gi n ni n g at 
wee k  5 5 (first  ra di o gra p hic t u m or assess me nt i n year 2 perf or me d at e n d of wee k 5 4) d uri n g 
year  2, u ntil I R C -assesse d R E CI S T  1. 1 -d efi ne d P D , wit h dra wal of c o nse nt, deat h, or i nitiati o n of 
a n ot her a nti -ca ncer treat me nt.  Patie nts w h o disc o nti n ue f or reas o ns ot her t ha n pr o gressi o n w h o 
are n ot atte n di n g treat me nt visits ma y h a ve ra di o gra p hic t u m or assess me nts bet wee n Q 9 W a n d 
Q 1 2 W u ntil R E CI S T  1. 1 -defi ne d P D , wit h dra wal of c o nse nt, deat h, or i nitiati o n of a n ot her 
a nti-ca ncer treat me nt.  
Ra di o gra p hic t u m or assess me nts will occ ur at t he f oll o wi n g ti me p oi nts:  
E n d of wee k 9  ± 5 d a ys (e n d of c ycl e 3 ) 
E n d of wee k 1 8  ± 5 d a ys (e n d of c ycle 6 ) 
E n d of wee k 2 7  ± 5 d a ys (e n d of c ycle 9 ) 
E n d of wee k 3 6  ± 5 d a ys (e n d of c ycle 1 2 ) 
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 7 5  of  1 2 9  
C O N FI D E N TI A L  
E n d of wee k 4 5  ± 5 d a ys (e n d of c ycle 1 5 ) 
E n d of wee k 5 4  ± 5 d a ys (e n d of c ycle 1 8 ) 
E n d of wee k 6 6  ± 5 d a ys (e n d of c ycle 2 2 ) 
E n d of wee k 7 8  ± 5 d a ys (e n d of c ycle 2 6 ) 
E n d of wee k 9 0  ± 5 d a ys (e n d of c ycle 3 0 ) 
E n d of wee k 1 0 2  ± 5 d a ys (e n d of c ycl e 3 4 ) 
I n t h e f oll o w-u p p eri o d, ra di o gra p hic ass ess me nts f or all patie nts w h o h a v e n ot e x perie nce d P D  
s h o ul d be perf or m e d Q 1 2 W or u ntil R E CI S T 1. 1 -defi ne d P D , wit h dr a wal of c o nse nt, deat h, or 
i nitiati o n of a n ot her a nti-ca ncer treat me nt.  
T u m or assess me nts s h o ul d be perf or me d e ve n if d osi n g is i nterr u pte d.  Wee ks are i n refere nce t o 
t he cale n d ar wee k a n d s h o ul d n ot be a dj uste d d ue t o d osi n g dela ys/i nterr u pti o ns.   
Brai n sca ns d uri n g t he treat me nt a n d f oll o w -u p peri o ds s h o ul d be perf or me d as  cli nicall y 
i n dicate d e x ce pt f or patie nts wit h a hist or y of metastases, w h o s h o ul d ha v e s ur veilla nce i ma gi n g 
a p pr o xi matel y e ver y 1 8 wee ks f or year 1 a n d e v er y 2 4  wee ks f or year  2 or s o o ner, if i n dicate d.  
F or patie nts i d e ntifie d as ha vi n g R E CI S T  1. 1 -d efi ne d  P D  w hile recei vi n g or after c o m pleti o n of 
st u d y tr eat me nt, s u bse q u e nt i ma gi n g s h o ul d be p erf or me d wit hi n 9 wee ks of t he i nitial t u m or 
assess me nt of pr o gressi o n.  
8. 2. 2. 2.  
T u m or B ur de n Assess me nts  
T u m or 
meas ure me nts 
will 
be 
perf or me d i n 
acc or da n ce 
wit h 
R E CI S T  1. 1 
cr iteria 
(Eise n ha uer  2 0 0 9 )(A p p e n di x  2 ) a n d s h o ul d be d o ne b y t he sa me i n vesti gat or or ra di ol o gist f or 
eac h assess me nt , t o t he e xte nt feasi ble. 
I n v esti gat ors a n d t he bli n de d I R C ( Secti o n 5. 3. 1 ) 
will assess res p o nse t o t hera p y usi n g 
R E CI S T  1. 1 criteria.  R E CI S T  1. 1 -d efi ne d P D  d eter mi ne d b y t h e i n vesti gat or will be us e d f or 
cli nical ma na ge me nt of t he patie nt.  R E CI S T  1. 1 -base d t u m or b ur de n ass ess me nts b y t he bli n de d 
I R C will be use d f or e val uati o n of efficac y e n d p oi nts. 
8. 2. 2. 3.  
Q u alit y of Life Q uesti o n n aires  
Patie nt -re p orte d o utc o m es will be meas ure d at t he fre q ue n c y i n dicate d i n Ta ble  4  a n d Ta ble  5  
usi n g t he f oll o wi n g v ali date d patie nt self -a d mi nistere d q uesti o n naires:  E O R T C  Q L Q -C 3 0 a n d 
E O R T C  Q L Q -L C 1 3 (Ber g ma n  1 9 9 4 )(Bj or dal  2 0 0 0 ).  Patie nts will be as k e d t o c o m plete t h ese 
q uesti o n naires pri or t o a n y st u d y pr oce d ures bei n g p erf or me d at a gi ve n st u d y visit ( d uri n g  t he 
treat me nt a n d f oll o w-u p peri o ds).   
8. 2. 2. 4.  
S ur vi v al D at a C ollecti o n  
E ver y eff ort will be ma de t o c ollect s ur vi val data o n all p atie nts  u n til t heir deat h, l oss t o 
f oll o w-u p or wit h dra wal of st u d y c o ns e nt. T his  i ncl u des patie nts w h o wit h dra w fr o m t he st u d y 
f or a n y reas o n b ut h a ve n ot wit h dra w n c o nse nt t o c ollect s ur vi val i nf or m ati o n, as i n dicat e d i n 
Ta ble  5 .  If t he deat h of a patie nt is n ot re p ort e d, t he date of t he last patie nt c o ntact i n t his st u d y 
will be use d i n t he deter mi nati o n of t he patie nt’s last k n o w n date ali ve.  T his will be c o m plete d 
b y tele p h o n e c o nta ct or a n office visit.  
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 7 6  of  1 2 9  
C O N FI D E N TI A L  
8. 2. 2. 5.  
H air Pi g me nt ati o n Assess me nt  
D uri n g scree ni n g, i n vesti gat ors will be as k e d t o descri be t h e patie nt’s hair pi g me nt ati o n. After 
scree ni n g, i n v esti gat ors will be as ke d t o assess w het her t here has b ee n a n y c h a n ge i n hair 
pi g me ntati o n fr o m  S cree ni n g t o  F oll o w -u p Visit 1/ E n d of St u d y V isit t o d oc u me nt hair 
re-pi g me ntati o n (T a ble  3  a n d Ta ble  5 ). 
8. 2. 3.  
S afet y Pr oce d ures  
8. 2. 3. 1.  
P h ysic al E x a mi n ati o n  
A c o m plete or li mite d p h ysical e x a mi nati o n  will be perf or me d at t he visits s pecifie d i n  Ta ble  3 , 
Ta ble  4 , a n d  Ta ble  5 . C are s h o ul d be t a ke n to e x a mi ne a n d assess a n y a b n or malities t hat ma y be 
prese nt, as i n dicat e d b y t he patie nt’s me dical hist or y.  
C o m plete p h ysi cal e x a mi nati o ns  will be perf or me d pri or t o t he i nitial d ose of st u d y tr eat me nt 
a n d pri or t o d osi n g o n c ycle 1 da y 1, a n d at ot her visi ts if i n dicate d, a n d will i ncl u de e x a mi nati o n 
of t he s ki n, h ea d, e yes, n ose, t hr oat, n ec k, j oi nts, l u n gs, h eart, p ulse, a b d o me n (i ncl u di n g li ver 
a n d s plee n), l y m p h n o des, a n d e xtre mities, as well as a brief ne ur ol o gic e x a mi nati o n.    
Li mite d p h ysi cal e x a mi n ati o n will i ncl u de, at least, e x a mi nati o n of t he l u n gs, heart, a b d o me n, 
a n d s ki n. 
8. 2. 3. 2.  
E C O G Perf or m a nce St at us  
Easter n C o o perati ve O n c ol o g y Gr o u p perf or m a nce stat us will be meas ure d at a fre q u e nc y 
i n dicate d i n Ta ble  3 , Ta ble  4   a n d Ta ble  5  . 
8. 2. 3. 3.  
Wei g ht a n d Hei g ht  
B o d y wei g ht me as ure me nts will be o btai ne d at scree ni n g a n d at f oll o w -u p acc or di n g t o  T a ble  3  
a n d Ta ble  5 .  Wei g ht s h o ul d be o btai ne d wit h t h e patie nt weari n g u n der gar me nts or ver y li g ht 
cl ot hi n g, wit h n o s h oes, a n d w it h a n e m pt y bla d der.  T he s a me s cale s h o ul d be use d t hr o u g h o ut 
t he st u d y.  T he use of cali brate d bal a nce scales is rec o m me n de d, if p ossi ble.  Self-re p orte d 
wei g hts are n ot a cce pta bl e.  
Hei g ht s h o ul d be meas ur e d at scree ni n g; self -re p orte d hei g hts are n ot acce pta ble.  
8. 2. 3. 4.  
Vit al Si g ns  
Vital si g ns, i ncl u di n g te m perat ure, s eate d bl o o d press ure, h eart rate, a n d res pirat or y rate, will be 
c ollecte d at ti me p oi nts acc or di n g t o Ta ble  3 , Ta ble  4 , a n d T a ble  5 .  Vital si g ns s h o ul d be 
perf or me d b ef ore bl o o d is dra w n d uri n g visits re q uiri n g bl o o d dra ws.  
Bl o o d press ur e s h o ul d be meas ur e d i n t he sa me ar m at all st u d y visits ( w he n feasi ble) a n d after 
t he patie nt has bee n resti n g q uietl y i n t he seat e d p ositi o n f or at least 5 mi n utes.  
At i nitial d osi n g,  c ycle 1 da y 1 , a n d o n all s u bse q ue nt treat me nt da ys, vital si g ns will be c ollect e d 
pri or t o i nf usi o n of treat me nt.  Vital si g ns s h o ul d als o be o btai ne d a p pr o xi matel y 1 5 mi n utes 
( ± 1 0 mi n utes) after c o m pleti o n of t he i nf usi o n.  
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 7 7  of  1 2 9  
C O N FI D E N TI A L  
8. 2. 3. 5.  
1 2 -Le a d Electr oc a r di o gr a m  
A sta n dar d 1 2 -lea d E C G will be perf or me d at scree ni n g a n d w he n cli nicall y i n dicate d, per t he 
discreti o n of t he i n vesti gat or, d uri n g t he acti ve treat me nt peri o d (T a ble  3  a n d Ta ble  4 ).  
Electr ocar di o gra ms ( E C Gs) s h o ul d be perf or me d bef ore bl o o d is dra w n d uri n g visits re q uiri n g 
bl o o d dra ws.   
T he patie nt s h o ul d be rela x e d a n d i n a rec u m be nt p ositi o n f or at least 5 mi n utes bef ore rec or di n g 
a n E C G.  T he E C G will be re vie we d b y t he i n v esti gat or or a n a ut h orize d d esi g nee at t he site a n d 
will be a vaila ble f or c o m paris o n wit h s u bse q ue nt E C Gs.  T he E C G traci n g will be retai ne d wit h 
t he s o urce.  
A n y E C G fi n di n g t hat is j u d ge d b y t he i n vesti gat or as a cli nicall y si g nifica nt c ha n ge ( w orse ni n g) 
c o m pare d wit h t he b aseli ne val ue will be c o nsi dere d a n A E, rec or de d, a n d m o nit ore d.  
8. 2. 3. 6.  
L a b or at or y Testi n g  
He mat ol o g y, c he mistr y, a n d pre g na nc y t esti n g sa m ples will b e a n al yze d b y t h e site’s l ocal 
la b orat or y. 
Sa m ples f or la b orat or y testi n g will be c ollecte d at ti me p oi nts acc or di n g t o  Ta ble  3 , Ta ble  4 , a n d 
Ta ble  5 .  Tests will i ncl u de t he f oll o wi n g: 
He m at ol o gy ( C B C wit h Differe nti al) 
He m o gl o bi n  
Differe ntial:  
He mat ocrit  
 
Ne utr o p hils  
Re d bl o o d cells  
 
L y m p h oc ytes  
W hite bl o o d cells  
 
M o n oc ytes  
Re d cell i n dices  
 
Bas o p hils  
Platelet c o u nt  
 
E osi n o p hils  
F or he mat ol o g y, bl o o d sa m ples ma y be c ollecte d ≤7 2 h o urs pri or t o d osi n g o n t he da y 1 visit of 
eac h c ycle.  Res ults m ust be o btai ne d/re vie we d pri or t o d osi n g.   
Ser u m C he mistry  
S o di u m  
T otal pr otei n, ser u m  
T otal bilir u bi n  
P otassi u m  
Creati ni ne  
Ma g nesi u m  
C h l ori de 
Bl o o d urea nitr o ge n a 
P h os p h or us  
Bicar b o nate  b 
As partate a mi n otra nsferase  
Uric aci d  
Calci u m  
Ala ni ne a mi n otra nsferase  
A dre n oc ortic otr o pic h or m o ne c 
Gl uc ose  
Al kali ne p h os p hatase  
 
Al b u mi n  
Lactate de h y dr o ge nase  
 
a T he urea test is acce pta ble i nstea d of bl o o d urea nitr o ge n at ce nters w here t his is c o m m o nl y use d i nstea d of t he 
bl o o d urea nitr o ge n.  
b T he partial press ure of car b o n di o xi de  test is a n acce pta ble test at ce nters w here t his is c o m m o nl y use d i nstea d of 
t he bicar b o nate test. 
c A dre n oc o rtic otr o pic h or m o ne ( A C T H) will be i ncl u de d o nl y f or t he 4 c ycles w he n i pili m u ma b is a d mi nistere d a n d 
o nl y i n Treat me nt Ar m B.  
F or c h e mistr y, bl o o d sa m ples ma y b e c ollect e d ≤7 2  h o urs pri or t o d osi n g o n t he da y 1 visit of 
eac h c ycle.  Res ults m ust be o btai n e d/re vie we d pri or t o d osi n g.  F or Treat me nt Ar m B, A C T H 
s h o ul d be teste d d uri n g t he 4 c ycles i pili m u ma b is a d mi nistere d. 
Ot her L a b or at ory Tests  
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 7 8  of  1 2 9  
C O N FI D E N TI A L  
C o a g ul ati o n Tests:  Pr ot hr o m bi n ti me/ partial t hr o m b o plasti n ti me ( P T/ P T T) will be a nal yz e d b y 
t he site’s l ocal la b orat or y.  Testi n g will be perf or me d at scree ni n g a n d t he n as cli nicall y 
i n dicate d. 
T h yr oi d F u ncti o n Tests:    
T h yr oi d -sti m ulati n g h or m o ne ( T S H) will be a nal yz e d b y t he site’s l ocal la b orat or y.   
F or Treat me nt Ar m B, T S H will be teste d at scree ni n g, bef or e i pili m u ma b d oses  ( Q 6 W) t he n 
Q 9 W, as cli nicall y i n dicate d.  If T S H is o utsi de of n or mal ra n ge, a free t h yr o xi ne ( T 4) s h o ul d be 
meas ure d at t he i n vesti gati ve site’s l ocal la b orat or y.   T h yr oi d f u ncti o n test  (a n d free T 4 if T S H is 
a b n or mal) m ust be test e d ≤7 2 h o urs pri or t o d osi n g i pili m u ma b  a n d t he res ults m ust be re vi e we d 
pri or t o d osi n g i pili m u ma b,  a n d o n c ycl es w he n i pili m u ma b is n ot d ose d . 
F or T reat me nt Ar ms A a n d C, T S H (a n d free T 4 if T S H is a b n or mal) is teste d at scree ni n g, Q 9 W, 
a n d as cli nicall y i n di c ate d.  If T S H is a b n or mal, free T 4 s h o ul d be meas ure d at t he i n v esti gati ve 
site’s l ocal la b orat or y.   
T u berc ul osis 
Testi n g:   P P D/ Q ua nti F E R O N testi n g acc or di n g t o l ocal 
g ui deli nes i n 
t u berc ul osis-e n de mic areas.  
A m yl ase a n d Li p ase Testi n g:   Testi n g will be p erf or me d at s cree ni n g a n d Q 9 W . 
Pre g n a ncy Testi n g  
W o me n of c hil d beari n g p ote ntial m ust ha ve a ne gati ve ser u m pre g n a nc y test wit hi n t he 7 2  h o urs 
pri or t o  st u d y treat me nt a d mi nistrati o n o n c ycle 1 da y 1 a n d a n e gati ve uri n e pre g na n c y test pri or 
t o st u d y treat me nt a d mi nistrati o n o n da y 1 of eac h s u bse q ue nt treat me nt c ycle, or m ore 
fre q ue ntl y, per l ocal sta n dar d. 
A b n or m al L a b or at ory V al ues a n d L a b or at ory A dverse Eve nts  
 All la b orat or y val ues m ust be re vie we d b y t he i n v esti gat or or a n a ut h orize d desi g nee.  
 Si g nifica ntl y a b n or mal test res ults t hat occ ur after start of treat me nt m ust b e re p eate d 
t o c o nfir m t he nat ure a n d de gree of t he a b n or malit y.  W he n necessar y, a p pr o priate 
a ncillar y i n vesti gati o ns s h o ul d be i nitiate d.  If t he a b n or malit y fails t o res ol ve or 
can n ot be e x plai ne d b y e ve nts or c o n diti o ns u nrelate d t o t h e st u d y me di cati o n or its 
a d mi nistrati o n, t he Me dical M o nit or m ust be c o ns ulte d.  
 T he cli nical si g nifi ca nce of a n a b n or mal test val ue, wit hi n t he c o nte xt of t he disease 
u n der st u d y, m ust be d eter mi ne d  b y t he i n vesti gat or.  
Criteria f or re p orti n g la b orat or y val ues as a n A E are pr o vi d e d i n Secti o n  9. 4. 5 . 
8. 2. 3. 7.  
C o nc o mit a nt Me dic ati o n Rec or di n g  
C o nc o mita nt m e dicati o n will be c ollecte d at ti me p oi nts acc or di n g t o  Ta ble  3 , Ta ble  4 , a n d 
Ta ble  5 .  See Secti o n  7. 7  f or details o n rec or di n g c o nc o mita nt me dicati o ns. 
8. 2. 3. 8.  
A d verse E ve nt R ec or di n g  
A d verse e ve nts will be c ollecte d at ti me p oi nts acc or di n g t o  T a ble  3 , Ta bl e  4 , a n d Ta ble  5 .  See 
Secti o n  9. 4  f or details o n rec or di n g a n d re p orti n g A Es. 
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 7 9  of  1 2 9  
C O N FI D E N TI A L  
8. 2. 4.  
P h ar m a c o ki netic a n d A nti -Dr u g A nti b o d y Pr oce d ures  
I n a d diti o n t o t he pr oce d ures detaile d bel o w, P K/a nti b o d y sa m ples will als o be ta ke n t o meas ure 
dr u g c o nce ntrati o ns/ A D A, as a p pr o priate, i n cas e of A E SIs.  
8. 2. 4. 1.  
Dr u g C o nce ntr ati o n Me as ure me nts a n d S a m pl es  
Ce mi pli ma b  c o nce ntrati o ns i n t he sera of p atie nts 
will be 
me as ure d usi n g a vali date d 
e nz y me-li n ke d i m m u n os or be nt assa y met h o d at visits a n d ti me p oi nts i n dicate d i n Ta ble  4 , 
Ta ble  5 , a n d A p pe n di x  4 .  T he act ual ti me of eac h bl o o d dra w m ust be rec or de d.  Pre d ose is 
defi ne d as b ef ore t he start of t he first ce mi pli ma b  i nf usi o n.  Pre d ose sa m ples ma y b e c ollecte d 
≤7 2  h o urs pri or t o da y  1 d osi n g.  Prei nf usi o n is defi ne d as bef ore t h e start of s u bse q ue nt 
ce mi pli ma b i nf usi o ns. 
Meas ure me nt of i pili m u ma b c o nce ntrati o ns i n ser u m i n t he P K sa m ples of patie nts ra n d o mize d 
t o Treat me nt Ar m B ma y be c o nsi dere d i n t he f ut ure. 
A n y u n use d sa m ples c ollecte d f or dr u g c o nce ntrati o n meas ure m e nts ma y b e use d f or e x pl orat or y 
bi o mar ker researc h.  
8. 2. 4. 2.  
A nti -Dr u g A nti b o d y Me as ure me nts a n d S a m pl es  
Sa m ples f or ce mi pli ma b  i m m u n o ge nicit y ( A D A) assess me nts will be c ollecte d fr o m patie nts 
pri or t o d osi n g at ti me p oi nts liste d i n  Ta ble  4 , d uri n g t he f oll ow -u p p eri o d as s h o w n i n  Ta ble  5 , 
a n d as i n dicate d i n  A p p e n di x  4 .  A n y u n use d sa m ples c ollecte d f or i m m u n o ge ni cit y assess me nts 
ma y be use d f or e x pl orat or y researc h or t o i n vesti gat e A Es  of i nterest .  T hese sa m ples ma y als o 
be use d f or A D A ass ess me nts of i pili m u ma b.  
8. 2. 5.  
Bi o m ar ker Pr oce d ures  
F or bi o mar ker assess me nts, a f or mali n -fi x e d, paraffi n-e m be d de d tiss ue bl o c k or u nstai ne d sli des 
of t u m or tiss ue bi o ps y s a m ples (arc hi val tiss ue, if ≤5  m o nt hs ol d, or rece ntl y o btai n e d bi o ps y 
c ollecte d d uri n g o n -st u d y) m ust be pr o vi de d.  T u m or tiss ue bi o ps y s a m ples s h o ul d be of 
s ufficie nt siz e t o e ns ur e a n a de q u ate a m o u nt of tiss ue f or a nal ysis (e x cisi o nal, i ncisi o nal, or c ore 
nee dle; fi ne nee dle as pirates are n ot acce pta ble).  C o m plete i nstr ucti o ns o n t he c ollecti o n, 
pr ocessi n g, ha n dli n g, a n d s hi p me nt of al l sa m ples will be pr o vi de d i n t he la b orat or y ma n ual. 
Wit h t he use of t he c ollecte d t u m or tiss ue s a m ples, t he f oll o wi n g bi o mar ker -bas e d stratificati o n 
strate gies will be i m ple me nte d i n t his st u d y: 
 A P D -L 1 I H C 2 2 C 3 p h ar m D x assa y will be utilize d as t he cli ni cal st u d y ass a y t o 
assess P D -L 1 e x pressi o n le vels i n rece ntl y o btai ne d t u m or tiss ue sa m ples ( o n -st u d y 
bi o ps y c ollect e d at scree ni n g visit or arc hi v al tiss ue, if ≤5  m o nt hs ol d).   
 T he P D -L 1 I H C 2 2 C 3 p har m D x assa y is a vali d ate d, a ut o mate d, i n -vitr o dia g n ost ic 
assa y t h at 
was 
de vel o pe d as a c o m pa ni o n 
dia g n ostic f or 
pe m br oliz u ma b 
(R oac h  2 0 1 6 ).  D uri n g de vel o p me nt, t he P D-L 1 I H C 2 2 C 3 p har m D x assa y was 
a nal yti call y vali date d  f or re p eata bilit y a n d re pr o d uci bilit y at 3 i n de pe n d e nt Cli nical 
La b orat or y I m pr o v e me nt A me n d me nts ( C LI A) -certifie d la b orat ories a n d cli nicall y 
vali date d i n K E Y N O T E -0 0 1, a cli nical st u d y of pe m br oliz u ma b i n patie nts wit h 
N S C L C.  Base d o n t h ese st u dies, t he P D -L 1 I H C 2 2 C 3 p har m D x assa y was 
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 8 0  of  1 2 9  
C O N FI D E N TI A L  
de m o nstrate d t o b e a r o b ust  P D -L 1 I H C assa y a n d was a p pr o ve d b y t h e F D A as a 
c o m pa ni o n dia g n ostic f or pe m br oliz u ma b.  F urt h er details o n t he assa y are pr o vi de d 
i n t he pac ka ge i nsert (P D -L 1 I H C 2 2 C 3 p har m D x Pac ka ge I ns ert ). 
 T he F o u n dati o n 
Me di ci ne “F o u n dati o n O ne ® ” p a nel will b e utilize d f or p ost-h oc 
a nal ys es acc or di n g t o t u m or m utati o n b ur de n . 
T u m or tiss ue bi o ps y s a m ples will als o be teste d f or E G F R m utati o ns, A L K tra nsl oc ati o ns, a n d 
R O S 1 f usi o ns at a ce ntral la b f or d eter mi nati o n of st u d y eli gi bilit y.  T he res ults m ust i n dicate 
t hat t he p atie nt is ne gati ve f or E G F R m utati o ns, A L K tra nsl ocati o ns, a n d R O S 1 f usi o ns f or 
e nr oll me nt i n t his st u d y.  
A d diti o nal testi n g ma y b e e m pl o ye d t o deter mi ne P D -L 1 e x pressi o n le vels b y utilizi n g a n ot her 
P D -L 1 I H C assa y i n t he sa me tiss ue s p eci me ns.  T his a p pr oac h 
ma y pr o vi de a better 
u n dersta n di n g of t he perf or ma nce of P D -L 1 e x pressi o n le vel as a pre dicti ve bi o mar ker of 
res p o nse t o ce mi pli ma b .  Of s pecial i nterest is P D-L 1 e x pressi o n acr oss differ e nt cell t y pes 
i ncl u di n g t u m or cells, str o ma cells, a n d i nfiltrati n g i m m u ne cells.  T u m or tiss ue sa m ples ma y  
als o be us e d f or vali dati o n of f ut ure c o m pa ni o n dia g n ostic assa ys i n cl u di n g, b ut n ot li mite d t o, 
P D -L 1 assa ys.  
T he use of t he P D -L 1 I H C 2 2 C 3 p har m D x assa y f or decisi o ns re gar di n g tr eat me n t wit h 
ce mi pli ma b is c o nsi dere d i nvesti gati o nal.   
After c o m pleti o n of P D -L 1 e x pressi o n a nal ysis, t he re m ai ni n g t u m or tiss ue sa m ples ma y be use d 
t o st u d y t he bi o mar kers ass ociate d wit h cli nical res p o nse t o ce mi pli ma b i ncl u di n g, b ut n ot 
li mite d t o, w h ole-e x o me se q ue nci n g of t u m or ge n o me a n d t u m or m utati o nal l oa d  (as detaile d i n 
Secti o n  8. 2. 6. 1 ).  Tiss ue per mitti n g, a d diti o nal a n al yses , i ncl u di n g b ut n ot li mite d t o t u m or D N A 
a n d R N A se q ue n ci n g, hist ol o gic a n al ys es , a n d i n sit u R N A h y bri dizati o n , ma y b e perf or me d . 
Bi o mar ker ser u m a n d plas ma sa m ples will be c ollecte d fr o m all patie nts e nr olle d i n t h is st u d y at 
m ulti ple visits a n d ti me p oi nts i n dicate d i n Ta ble  4 , Ta ble  5 , a n d A p pe n di x  4  t o st u d y t he 
p ote ntial p har mac o d y na mics or pre dicti ve bi o mar kers of res p o ns e t o ce mi pli ma b  (al o ne or i n 
c o m bi nati o n wit h i pili m u ma b) i ncl u di n g, b ut n ot li mite d t o, P B M C, c yt o ki nes a n d circ ula ti n g 
t u m or n ucleic aci ds (refer t o t he la b orat or y ma n ual). 
A t u m or tiss ue bi o ps y sa m ple s h o ul d be o btai ne d at t he ti me of R E CI S T  1. 1 -defi ne d P D . 
8. 2. 6.  
F ut ure Bi o me dic al Rese arc h  
T he u n use d bi o mar ker sa m ples f or st u d y-relate d researc h, as well as u n use d P K a n d A D A 
sa m ples, will be st ore d f or u p t o 1 5 years after t he fi nal date of t he dat a base l oc k .  T hese u n use d 
sa m ples ma y be utilize d f or f ut ure bi o me dical res earc h of l u n g carci n o ma a n d ot her diseases .  N o 
a d diti o nal sa m ples will be c ollecte d f or f ut ure bi o me dical researc h .  After 1 5 years, a n y resi d ual 
sa m ples will be destr o ye d. 
8. 2. 6. 1.  
Ge n o mics S u b -St u d y - O pti o n al  
Patie nts w h o a gree t o partici pate i n t he ge n o mics s u b -st u d y will be re q uir e d t o si g n a se p arate 
ge n o mics s u b -st u d y I C F bef ore c ollecti o n of t h e s a m ples.  Patie nts are n ot re q uire d t o partici pate 
i n t he ge n o mics s u b-st u d y i n or der t o e nr oll i n t he pri mar y st u d y.  Sa m pl es f or D N A e xtracti o n 
s h o ul d be c ollecte d o n da y 1/ baseli ne ( pre d os e) b ut ma y be c ollecte d at a n y st u d y visit.   
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 8 1  of  1 2 9  
C O N FI D E N TI A L  
D N A sa m ples f or t he  ge n o mics s u b -st u d y will be d o u ble-c o d e d as defi ne d b y t he I nter n ati o nal 
C o u ncil f or Har m o nisati o n (I C H) g ui deli ne E 1 5.  S u b -st u d y s a m ples will be st ore d f or u p t o 
1 5  years aft er t he fi nal date of t he data base l oc k a n d ma y be use d f or res earc h p ur p oses.  T he 
p ur p ose of t h e ge n o mic a nal ys es is t o i de ntif y ge n o mic ass ociati o ns wit h cli nical or bi o mar ker 
res p o nses, ot her cli nical o utc o me meas ures, a n d p ossi ble A Es.  I n a d diti o n, ass ociati o ns bet wee n 
ge n o mic varia nts a n d pr o g n osis or pr o gressi o n of ot her diseas es ma y als o b e st u die d.  T hes e data 
ma y be us e d or c o m bi ne d wit h data c ollecte d fr o m ot her st u dies t o i d e ntif y a n d v ali date ge n o mi c 
mar kers rel ate d t o t he st u d y dr u g or ot her diseases.  
A nal ys es 
ma y i ncl u de se q u e nce 
deter mi nati o n or si n gle n ucle oti de p ol y m or p his m st u dies of ca n di date ge n es a n d s urr o u n di n g 
ge n o mic re gi o ns.  
Ot her 
met h o ds, i ncl u di n g 
w h ole -e x o me se q ue nci n g, 
w h ole -ge n o me 
se q ue nci n g, a n d D N A c o p y n u m ber variati o n ma y als o be p erf or me d.  T he list of met h o ds ma y 
be e x pa n de d t o i ncl u de n o vel met h o d ol o g y t hat m a y be de v el o pe d d uri n g t he c o urse of t his st u d y 
or sa m ple st ora ge p eri o d.  
9.  
S A F E T Y D E FI NI TI O N S, R E P O R TI N G, A N D M O NI T O RI N G  
F or t he p ur p os es of t his secti o n, st u d y tr eat me nt refers t o ce mi pli ma b a n d i pili m u ma b. 
9. 1.  
O bli g ati o ns of I n vesti g at or  
T he i n vesti gat or m ust pr o m ptl y re p ort t o t he I nstit uti o nal Re vie w B oar d (I R B)/ Et hics C o m mittee 
( E C) all u na ntici p ate d pr o ble ms i n v ol vi n g ris ks t o patie nts acc or di n g t o l ocal re g ulati o ns.  T his 
i ncl u des deat h fr o m a n y ca use a n d all S A Es relate d t o t he use of t he st u d y dr u g.  It is 
rec o m me n de d t hat all S A Es be re p orte d t o t he I R B/ E C, acc or di n g t o l ocal re g ulati o ns, re gar dless 
of assesse d  ca usalit y.  
9. 2.  
O bli g ati o ns of S p o ns or  
D uri n g t he c o urse of t he st u d y, t he s p o ns or will re p ort i n a n e x pe dite d ma n ner all S A Es t h at are 
b ot h u ne x pecte d a n d at l east reas o na bl y rel ate d t o t he st u d y dr u g (s us pecte d, u ne x pecte d, seri o us 
a d verse reacti o ns), t o t he healt h a ut h orities, I R B/ E Cs as a p p r o priate, a n d t o t he i n vesti gat ors.  
A n y A E n ot liste d as a n e x pecte d e ve nt i n t he Refere n ce Safet y I nf or mati o n secti o n of t he 
ce mi pli ma b I n v esti gat or’s Br oc h ure or i n t he Refere nce Safet y I nf or mati o n/ U S Pac ka ge I nsert  of 
I pili m u ma b will be c o nsi dere d as u n e x pecte d.   
I n a d diti o n, t he s p o ns or will re p ort all ot h er S A Es t o t he healt h a ut h orities, acc or di n g t o l ocal 
re g ulati o ns, if t his is a p plica ble t o t he c o u ntr y re q uire me nts.  
At t he c o m pleti o n of t he st u d y, t he s p o ns or will re p ort all safet y o bs er vati o ns ma de d uri n g t h e 
c o n d uct of t he st u d y i n t he cli nical st u d y re p ort t o healt h a ut h orities a n d I R B/ E Cs, as 
a p pr o priate.  
9. 3.  
Defi niti o ns  
9. 3. 1.  
A d verse E ve nt  
A n A E is a n y u nt o war d me dical occ urre nce i n a patie nt -a d mi nistere d a st u d y dr u g t hat ma y or 
ma y n ot ha v e a ca usal  rel ati o ns hi p wit h t he st u d y dr u g.  T h eref ore, a n A E is a n y u nfa v ora ble a n d 
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 8 2  of  1 2 9  
C O N FI D E N TI A L  
u ni nte n de d si g n (i ncl u di n g a b n or mal l a b orat or y fi n di n g), s y m pt o m, or disease t h at is te m p orall y 
ass ociate d wit h t he use of a st u d y dr u g, w het h er or n ot c o nsi dere d relate d t o t he st u d y dr u g.  
A n A E als o i ncl u des a n y w ors e ni n g (i e, a n y cli nicall y si g nifica nt c h a n ge i n fre q ue nc y a n d/ or 
i nte nsit y) of a pre-e xisti n g c o n diti o n t hat is te m p orall y ass ociate d wit h t he use of t he st u d y dr u g.  
Pr o gressi o n of u n d erl yi n g m ali g na nc y will n ot b e c o n si dere d a n A E if it is clearl y c o nsiste nt 
wit h t he t y pic al pr o gressi o n patter n of t he u n derl yi n g ca n cer (i ncl u di n g ti me c o urse, affect e d 
or ga ns, etc).  Cli nical s y m pt o ms of pr o gressi o n ma y be re p ort e d as A Es if t he s y m pt o m ca n n ot 
be deter mi ne d as e x cl usi ve l y d ue t o t he pr o gressi o n of t he u n derl yi n g mali g na n c y or d oes n ot fit 
t he e x pecte d patter n of pr o gressi o n f or t he dise ase u n der st u d y. 
If t here is a n y u ncertai nt y a b o ut a n A E bei n g d ue o nl y t o pr o gressi o n of t he u n derl yi n g 
mali g na n c y, it s h o ul d be re p orte d as a n A E or S A E as o utli ne d i n Secti o n  9. 3. 2 . 
9. 3. 2.  
Seri o us A d verse E ve nt  
A n S A E is a n y u nt o w ar d me dical occ urre n ce t hat at a n y d ose:  
 Res ults i n de at h  –  i ncl u des all d eat hs, e v e n t h ose t hat a p pear t o b e c o m pletel y 
u nrelate d t o st u d y dr u g (e g, a car acci de nt i n w hic h a patie nt  is a passe n ger) 
 Is life-t hre ate ni n g –  i n t he vie w of t h e i n vesti gat or, t he p atie nt  is at i m me diate ris k of 
deat h at t he ti me of t he e ve nt.  T his d oes n ot i ncl u de a n A E t hat ha d it occ urre d i n a 
m ore se vere f or m, mi g ht ha ve ca use d deat h  
 Re q uires i n -patie nt h os pit aliz ati o n  or pr ol o n g ati o n of e xisti n g h os pit aliz ati o n .  
I n-patie nt h os pitaliz ati o n is defi ne d as a d missi o n t o a h os pital or  a n e mer ge nc y r o o m 
f or l o n ger t ha n 2 4 h o urs.  Pr ol o n gati o n of e xisti n g h os pitalizati o n is defi ne d as a 
h os pital sta y t hat is l o n ger t ha n was ori gi nall y a ntici pat e d f or t he e ve nt or is 
pr ol o n ge d d ue t o t he de v el o p me nt of a ne w A E as deter mi ne d b y t he i n vest i gat or or 
treati n g p h ysi cia n 
 Res ults i n persiste nt or si g nifica nt dis a bilit y/i nc a p acit y  (s u bsta ntial disr u pti o n of 
o ne’s a bilit y t o c o n d u ct n or mal life f u ncti o ns)  
 Is a c o n ge nit al a n o m al y/ birt h defect  
 Is a n i m p ort a nt me dic al e ve nt - I m p orta nt me di cal e ve nts ma y n ot be i m me diatel y 
life-t hreat e ni n g or res ult i n deat h or h os pitalizati o n b ut ma y je o par dize t he patie nt  or 
ma y re q uire i nter ve nti o n t o pre ve nt o ne of t he ot her seri o us o utc o mes liste d a b o ve 
(e g, i nte nsi ve treat me nt i n a n e mer ge nc y r o o m or at h o me f or aller gic br o nc h os pas m; 
bl o o d d yscrasias or c o n v ulsi o ns t hat d o n ot res ult i n h os pitalizati o n; or de vel o p me nt 
of dr u g de pe n d e nc y or dr u g a b us e).  
H os pitalizati o n or deat h d ue s olel y t o ma nifest ati o ns c o nsiste nt wit h t y pical pr o gressi o n of 
u n derl yi n g mali g na n c y will n ot be c o nsi dere d a n S A E.  
Seri o us a d verse e ve nts m ust be re p orte d as direct e d i n Secti o n  9. 4. 2 . 
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 8 3  of  1 2 9  
C O N FI D E N TI A L  
9. 3. 3.  
A d verse E ve nts of S peci al I nterest  
A n A E SI ( seri o us or n o n-seri o us) is o ne of s cie ntific a n d me dical c o ncer n s pecifi c t o t h e 
s p o ns or’s pr o d uct or pr o gra m, f or w hic h o n g oi n g m o nit ori n g a n d ra pi d c o m m u nicati o n b y t he 
i n vesti gat or t o t he s p o ns or ca n b e a p pr o priate.  S uc h a n e v e nt mi g ht warra nt f urt her i n vesti gati o n 
i n or der t o c haracterize a n d u n dersta n d it.  De pe n di n g o n t he nat ure of t he e ve nt, ra pi d 
c o m m u nicati o n b y t he st u d y s p o ns or t o ot her parties (e g, re g ulat ors) mi g ht als o be warra nt e d.  
All A E SIs, seri o us a n d n o n -seri o us, m ust be re p orte d wit hin 2 4 h o urs of i de ntificati o n usi n g t h e 
sa me re p orti n g pr ocess as f or S A E re p orti n g, per Secti o n 9. 4. 2 .  A d verse e ve nts of s pecial 
i nterest f or t his st u d y i ncl u de t he f oll o wi n g:  
 Gra de 2 or greater i nf usi o n -relate d reacti o ns 
 Gra de 2 or greater aller gi c/ h y p erse nsiti vit y reacti o ns  
 Gra de 3 or greater ir A Es  
 ir A Es of a n y gra de i n patie nts pre vi o usl y tr eate d wit h PI 3 -K i n hi bit or  
N ote:  A n ir A E ca n occ ur s h ortl y after t he first d ose or se veral m o nt hs after t he l ast d ose of st u d y 
treat me nt.  All A Es of u n k n o w n eti ol o g y ass ociate d wit h ce mi pli ma b e x p os ure s h o ul d be 
e val uate d t o deter mi ne p ossi ble i m m u ne eti ol o g y.   If a n ir A E is s us pecte d, 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 xic, or ot her eti ol o gic ca us es pri or t o 
la beli n g a n A E as a n ir A E.  Det aile d g ui da nce of m a na ge m e nt of ir A Es is pr o vi de d i n 
Secti o n  7. 3. 3  a n d A p pe n di x  3 .  T he rec o m me n dati o ns i n Secti o n 7. 3. 3  a n d A p pe n di x  3  s h o ul d be 
see n as g ui deli nes, a n d t he treati n g p h ysi cia n s h o ul d e x ercise cli nical j u d g me nt bas e d o n t he 
s y m pt o ms a n d c o n diti o ns of t he i n di vi d ual patie nt.  F or a n y A E t hat is of a t y pe k n o w n t o be 
p ote ntiall y i m m u ne -relat e d (e g, ras h, c olitis, ele vate d tra nsa mi nases, e n d o cri ne, or p ne u m o nitis) 
b ut is dee me d n ot t o be a n ir A E b y t he i n vesti gat or, t he s p o ns or ma y re q uest a d diti o nal 
i nf or mati o n.  
Refer t o t he st u d y ma n ual f or t he pr oce d ures t o be f oll o we d.  
9. 3. 3. 1.  
I m m u ne-Rel at e d A d verse E ve nts  
Detaile d g ui da nce of ma na ge me nt of ir A Es is pr o vi de d i n Secti o n  7. 3. 3  a n d A p pe n di x  3 .   
N ote re g ar di n g ir A Es:   F or a n y A E t hat is of a t y pe k n o w n t o be p ote ntiall y i m m u ne -relate d 
(e g, ras h, c olitis, ele vate d tra nsa mi nases, e n d o cri n e, or p ne u m o nitis) b ut is dee me d n ot t o be a n 
ir A E b y t h e i n vesti gat or, t he s p o ns or ma y re q u est a d diti o nal i nf or mati o n. 
9. 3. 4.  
I nfusi o n Re acti o ns  
I nf usi o n-relat e d reacti o ns are k n o w n t o occ ur wit h pr otei n t hera p e utic i nf usi o ns a n d ha ve bee n 
o bser ve d i n ce mi pli ma b  st u dies.  Ac ute i nf usi o n reacti o ns are defi n e d as a n y A Es t hat o cc ur 
d uri n g t he i nf usi o n or wit hi n 1 da y  after t h e i nf usi o n is c o m plete d.  Si g ns a n d s y m pt o ms us uall y 
de vel o p d uri n g or s h ortl y after dr u g i nf usi o n a n d ge nerall y res ol ve c o m plet el y wit hi n 2 4 h o urs of 
t he c o m pleti o n of i nf usi o n. 
All i nf usi o n reacti o ns m ust be re p orte d as A Es ( d efi ne d i n Secti o n  9. 4. 1 ) a n d gra de d usi n g t he 
gra di n g s cales as i nstr uct e d i n Secti o n  9. 5. 1 . 
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 8 4  of  1 2 9  
C O N FI D E N TI A L  
9. 4.  
Rec or di n g a n d Re p orti n g A d verse E ve nts  
9. 4. 1.  
A d verse E ve nts  
T he i n vesti gat or ( or desi g nee) will see k i nf or mati o n o n A Es at eac h patie nt c o ntact, a n d rec or d 
all A Es t hat occ ur fr o m t he ti me t he i nf or me d c o nse nt is si g ne d u ntil 9 0  da ys after t he e n d of 
st u d y treat me nt.  After i nf or me d c o nse nt has b ee n o btai ne d b ut pri or t o i nitiati o n of st u d y 
treat me nt, o nl y t h e f oll o wi n g cate g ories of A Es s h o ul d be re p orte d o n t h e A E e C R F: 
 S A Es  
 N o n -S A Es ass ociate d w it h a pr ot oc ol-ma n date d i nter ve nti o n (e g, A Es rel ate d t o a n 
i n vasi ve pr oce d ure s uc h as a bi o ps y) 
Ot her A Es t hat o cc ur aft er i nf or me d c o nse nt b ut pri or t o first treat me nt s h o ul d be re p ort e d o n t he 
me dical hist or y e C R F.  
All A Es after i nitiati o n of st u d y trea t me nt a n d u ntil 9 0  da ys after t he last st u d y tr eat me nt, 
re gar dl ess of relati o ns hi p t o st u d y treat me nt, will be re p orte d o n t he A E e C R F.  A d diti o nall y, 
a n y S A E or ot h er A E of c o ncer n t h at t he i n vesti gat or belie ves ma y be relate d t o st u d y tr eat me nt 
a n d t hat occ urs l ater t ha n 9 0  da ys after l ast st u d y treat me nt s h o ul d be re p orte d.  
I nf or mati o n o n f oll o w-u p f or A Es is pr o vi de d i n Secti o n  9. 4. 6 .  La b orat or y, vital si g ns, or E C G 
a b n or malities are t o b e rec or de d as A Es as o utli ne d i n  Secti o n  9. 4. 5 . 
9. 4. 2.  
Seri o us A d verse E ve nts  
All S A Es, re gar dless of assess me nt of ca us al relati o ns hi p t o st u d y dr u g, m ust be re p orte d t o t he 
s p o ns or ( or d esi g nee) wit hi n 2 4 h o urs of b ec o mi n g a ware of t he e v e nt.  Refer t o t he st u d y 
refere nce ma n ual f or t he pr oce d ure t o be f oll o we d. 
I nf or mati o n n ot a vaila bl e at t he ti me of t h e i nitial re p ort m ust be d o c u me nte d i n a f oll o w -u p 
re p ort.  S u bsta ntiati n g data s uc h as rele va nt h os pital or me dical rec or ds a n d dia g n ostic test 
re p orts ma y als o be re q u este d. 
I n t he e ve nt t hat t he i n vesti gat or is i nf or me d of a n S AE t hat occ urs m ore t ha n 9 0  da ys after t h e 
last d ose of st u d y treat me nt, o nl y t h ose S A Es or ot her A Es of c o ncer n dee me d b y t he 
i n vesti gat or t o be relate d t o st u d y treat me nt will be re p orte d t o t he s p o ns or.  T he i n vesti gat or 
s h o ul d 
ma ke e ver y eff ort t o o btain f oll o w -u p i nf or mati o n o n t he o utc o me of a n y 
treat me nt-relate d S A E a n d/ or u ntil t he e ve nt is c o nsi dere d c hr o ni c a n d/ or st a ble. 
9. 4. 3.  
Ot her E ve nts t h at Re q uire Acceler ate d Re p orti n g t o S p o ns or  
T he f oll o wi n g e ve nts als o re q uire re p orti n g t o t he s p o ns or ( or d esi g n ee) wit hi n 2 4 h o urs of 
lear ni n g of t he e ve nt: 
S y m pt o m ati c O ver d ose of St u d y Dr u g:   Acci de ntal or i nte nti o nal o ver d ose of at least 2  ti mes 
t he i nte n de d d ose of st u d y dr u g wit hi n t he i nte n de d t hera p e utic wi n d o w, if 
ass ociate d wit h a n A E.  
Pre g n a nc y:   Alt h o u g h  pre g na n c y is n ot c o nsi dere d a n A E, it is t he res p o nsi bilit y of t he 
i n vesti gat or t o re p ort t o t he s p o ns or ( or desi g nee), 
wit hi n 2 4 h o urs of 
i de ntificati o n, a n y pre g n a nc y occ urri n g i n a fe m ale or fe mal e part ner of a male , 
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 8 5  of  1 2 9  
C O N FI D E N TI A L  
d uri n g t h e st u d y or wit hi n 1 8 0  da ys of t he last d ose of st u d y dr u g.  A n y 
c o m plicati o n of pre g na n c y affecti n g a fe male st u d y p atie nt, fe m ale part ner of a 
male st u d y p atie nt, a n d/ or fet us or n e w b or n t hat meets t he S A E criteria m ust be 
re p orte d as a n S A E.  O utc o me f or all pre g na ncies s h o ul d be re p orte d t o t he 
s p o ns or. 
Refer t o t he st u d y ma n ual f or t he pr oce d ures t o be f oll o we d.  
9. 4. 4.  
Re p orti n g A d verse E ve nts Le a di n g t o Wit h dr a w al fr o m t he St u d y  
All A Es t hat lea d t o a patie nt’s wit h dra wal fr o m t he st u d y m ust be r e p orte d t o t he s p o ns or’s 
Me dical M o nit or wit hi n 3 0 da ys.   
Refer t o t he st u d y ma n ual f or t he pr oce d ures t o be f oll o we d.  
9. 4. 5.  
A b n or m al L a b or at or y, Vit al Si g ns, or Electr oc ar di o gr a m Res ults  
T he criteri a f or d eter mi ni n g w h et her a n a b n or mal o bjecti ve test fi n di n g s h o ul d be re p orte d as a n 
A E i ncl u de:  
 T he test res ult is ass ociat e d wit h acc o m p a n yi n g s y m pt o ms, a n d/ or  
 T he test res ult re q uir es a d diti o nal dia g n ostic testi n g or me dical/s ur gi cal i nter ve nti o n, 
a n d/ or 
 T he test res ult lea ds t o a c ha n ge i n d osi n g ( o utsi de of pr o t oc ol-sti p ulate d d ose 
a dj ust me nts), disc o nti n uati o n fr o m t he st u d y, si g nifica nt a d diti o nal c o nc o mita nt dr u g 
treat me nt, or ot her t h era p y 
C o ntact t he Me dical M o nit or i n t he e ve nt t he i n vesti gat or feels t hat a n a b n or mal test fi n di n g 
s h o ul d be re p orte d as a n AE, alt h o u g h it d oes n ot meet a n y of t he a b o ve criteria.  
Re peati n g a n a b n or mal t est, i n t he a bse n ce of a n y of t he a b o v e c o n diti o ns, d oes n ot c o nstit ute a n 
A E.  A n y a b n or m al test res ult t hat is det er mi ne d t o be a n err or d o es n ot re q uire re p orti n g as a n 
A E.  
E val uati o n of se verit y of la b orat or y a b n or malities will be assesse d acc or di n g t o t he scale 
o utli ne d i n Secti o n  9. 5. 1 . 
9. 4. 6.  
F oll o w -u p  
I nf or mati o n f or a n y n o n-S A E t hat starts d uri n g t h e treat me nt p eri o d or wit hi n 9 0  da ys aft er last 
d ose of st u d y treat me nt will be c ollect e d fr o m t he ti me of t he e v e nt u ntil t he res o l uti o n of t h e 
e ve nt or u ntil t he patie nt’s last st u d y visit, w hic he ver c o mes first.  
Seri o us a d vers e e ve nt i nf or mati o n will be c ollecte d u ntil t he e ve nt is c o nsi dere d c hr o nic a n d/ or 
sta ble. 
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 8 6  of  1 2 9  
C O N FI D E N TI A L  
9. 5.  
E v al u ati o n of Se verit y a n d C a us alit y  
9. 5. 1.  
E v al u ati o n of Se verit y  
T he se v erit y of A Es (i ncl u di n g test fi n di n gs classifie d as A Es) will be gra d e d usi n g t he c urre nt 
versi o n of t he N CI -C T C A E gra di n g s yste m.  A d v erse e v e nts n ot liste d i n t he N CI -C T C A E will 
be gra de d acc or di n g t o t he f oll o wi n g s cale:  
Gra de 1 ( Mil d): 
Mil d; as y m pt o mat ic 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 v e nti o n n ot i n dicate d  
Gra de 2 ( M o derate): 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 ( A D L) *  
Gra de 3 ( Se v ere): 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 pitaliz ati 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 A D L * *  
Gra de 4 ( Life – t hr eate ni n g): Lif e-t hreate ni n g c o ns e q ue nces; ur ge nt i nter ve nti o n i n dicate d 
Gra de 5 ( Deat h): Deat h relate d t o A E  
*I nstr u m e ntal A D L refers t o pre pari n g meals, s h o p pi n g f or gr oceries or cl ot hes, usi n g t he 
tele p h o ne, ma na gi n g m o ne y, etc. 
* * Self -care A D L refers t o bat hi n g, dressi n g a n d u n dressi n g, fee di n g self, usi n g t he t o ilet, 
ta ki n g me dicati o ns, a n d n ot be dri d de n. 
If a la b orat or y val u e is c o nsi dere d a n A E, its se verit y s h o ul d b e bas e d o n t he de gree of 
p h ysi ol o gical i m pair me nt t he val ue i n dicates.  
9. 5. 2.  
E v al u ati o n of C a us alit y  
Rel ati o ns hi p of A dverse Eve nts t o St u dy Dr u g:  
T he re lati o ns hi p of A Es t o st u d y dr u g will be ass esse d b y t he i n vesti gat or a n d will be a cli nical 
decisi o n base d o n all a v aila ble i nf or mati o n.  T he f oll o wi n g q uesti o n will be a d dresse d:  
Is t here a reas o na ble p ossi bilit y t hat t he A E m a y h a ve bee n ca us e d b y t he stu d y dr u g?  
T he p ossi ble a ns wers are:  
N ot Rel at e d:   T here is n o reas o na bl e p ossi bilit y t hat t he e ve nt ma y h a ve b ee n ca use d b y t he 
st u d y dr u g 
Rel ate d:    
T here is a reas o n a ble p ossi bilit y t hat t he e v e nt ma y ha v e bee n ca us e d b y t he st u d y 
dr u g  
A list of fact ors t o c o nsi d er w he n assessi n g t he rel ati o ns hi p of A Es t o st u d y dr u g is pr o vi d e d i n 
A p pe n di x  1 . 
T he i n vesti gat or s h o ul d j ustif y t he ca usalit y assess me nt of eac h S A E.  
Rel ati o ns hi p of A dverse Eve nts t o St u dy C o n d uct:  
T he relati o ns hi p of A Es t o st u d y c o n d u ct will be assesse d b y t h e i n vest i gat or a n d will be a 
cli nical decisi o n base d o n all a vaila ble i nf or mati o n.  T he f oll o wi n g q u esti o n will be a d dresse d:  
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 8 7  of  1 2 9  
C O N FI D E N TI A L  
Is t here a reas o na ble p ossi bilit y t hat t he A E m a y h a ve bee n ca us e d b y st u d y c o n d uct? 
T he p ossi ble a ns wers are:  
N ot Rel at e d:   T here is n o r eas o na bl e p ossi bilit y t hat t he e ve nt ma y h a ve b ee n ca use d b y st u d y 
c o n d uct  
Rel ate d:    
T here is a reas o n a ble p ossi bilit y t hat t he e v e nt ma y ha v e bee n ca us e d b y st u d y 
c o n d uct  
A list of fact ors t o c o nsi d er w he n assessi n g t he rel ati o ns hi p of A Es t o st u d y c o n d u ct is pr o vi de d 
i n A p pe n di x  1 . 
T he i n vesti gat or s h o ul d j ustif y t he ca usalit y assess me nt of eac h S A E.  
9. 6.  
S afet y M o nit ori n g  
T he i n vesti gat or will m o nit or t he safet y of t he st u d y patie nt at his/ her site(s) as per t he 
re q uire me nts of t his pr ot oc ol a n d c o nsiste nt wit h c urre nt G o o d Cli nical Practice ( G C P).  A n y 
q uesti o ns or c o ncer ns s h o ul d be disc usse d wit h t he s p o ns or i n a ti mel y fas hi o n.  T he s p o ns or will 
m o nit or t he safet y data fr o m acr oss all st u d y sit es.  T h e Me dical M o nit or will ha ve pri mar y 
res p o nsi bilit y f or t he e m er gi n g s afet y pr ofile of t he c o m p o u n d b ut will be s u p p orte d b y ot her 
de part me nts (e g, P har mac o vi gila n ce a n d 
Ris k  Ma na ge me nt a n d 
Bi ostatistics a n d 
Data 
Ma na ge me nt).  Safet y m o nit ori n g will be perf or me d o n a n o n g oi n g basis (e g, i n di vi d ual re vie w 
of S A Es) a n d o n a p eri o dic c u m ulati ve a g gre gate basis.  
9. 7.  
I n vesti g at or Alert N otific ati o n 
Re ge n er o n ( or desi g nee) will i nf or m a ll i n vesti gat ors partici pati n g i n t his cli nical st u d y, as well 
as i n a n y ot her cli nical st u d y usi n g t he sa me i n vesti gati o nal dr u g, of a n y S A E t hat meets t he 
rele va nt re q uire me nts f or e x pe dite d re p orti n g (a n A E t hat is seri o us, u ne x pecte d base d o n t he 
I n v esti gat or’s Br oc h ure or t his pr ot oc ol, a n d has a reas o na bl e s us pecte d ca usal relati o ns hi p t o t he 
me dici nal/st u d y dr u g).  
1 0.  
S T A TI S TI C A L P L A N  
T his secti o n pr o vi des t he basis f or t he statistical a nal ysis pla n ( S A P) f or t he st u d y.  T he S A P 
ma y be re vise d d uri n g t h e  st u d y t o acc o m m o date a me n d me nts t o t he cli nical st u d y pr ot oc ol a n d 
t o ma ke c ha n ges t o a d a pt t o u ne x pecte d iss ues i n st u d y e x ec uti o n a n d dat a t hat ma y affect t he 
pla n ne d a nal yses.  T h e fi nal S A P will be iss ue d bef ore t h e data base is l oc k e d.  
A nal ysis varia b les are liste d i n Secti o n  4 . 
Alt h o u g h t he st u d y is o pe n -la bel, a n y a n al ys es or s u m maries ge nerate d b y ra n d o mize d treat me nt 
assi g n me nt or act u al treat me nt recei ve d, a n d access t o t h ose a nal yses or s u m maries, will be 
li mite d a n d d oc u me nte d. 
1 0. 1.  
St atistic al H y p ot hesis  
T he pri mar y statistical h y p ot hesis is t hat H D R E G N 2 8 1 0 or S D R E G N 2 8 1 0/i pi will ha ve a hi g h er 
res p o nse rate t ha n S D R E G N 2 8 1 0 i n patie nts w h ose t u m ors e x press P D-L 1 i n < 5 0 % of t u m or 
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 8 8  of  1 2 9  
C O N FI D E N TI A L  
cells.  T he sec o n dar y st atistical h y p ot heses are t hat H D R E G N 2 8 1 0 or S D R E G N 2 8 1 0/i pi will 
i ncreas e O S a n d/ or P F S as c o m pare d t o S D R E G N 2 8 1 0 i n patie nts w h ose t u m ors e x press P D-L 1 
i n < 5 0 % of t u m or cells.    
1 0. 2.  
J ustific ati o n of S a m ple Size  
I n t he K E Y N O T E -0 1 0 st u d y (Her bs t 2 0 1 6), t he res p o nse rates f or t h e t otal p o p ulati o n were 1 8 % 
f or b ot h t he pe m br oliz u ma b 2 m g/ k g Q 3 W ar m a n d t he 1 0 m g/ k g Q 3 W ar m c o m pare d t o 9 % f or 
t he patie nts recei vi n g d o ceta x el.  I n t he s u b gr o u p of patie nts wit h P D-L 1 e x pressi o n o n at least 
5 0 % of t u m o r cells, t he res p o nse rate was 3 0 % i n t he pe m br oliz u ma b 2 m g/ k g gr o u p, 2 9 % i n t he 
pe m br oliz u ma b 1 0  m g/ k g gr o u p, a n d 8 % i n t he d oceta xel gr o u p.  T his i m plies t he res p o nse rate 
f or t he pe m br oliz u ma b 2 m g/ k g gr o u p or t he 1 0  m g/ k g Q 3 W gr o u p is ~ 1 0 % i n t he s u b g r o u p of 
patie nts wit h P D -L 1 e x pressi o n i n less t ha n 5 0 % of t u m or cells .  
Ass u mi n g t hat t he res p o nse rate f or S D R E G N 2 8 1 0 is 1 0 % a n d t hat t he res p o nse rate f or eac h of 
t he H D R E G N 2 8 1 0 a n d S D R E G N 2 8 1 0/i pi treat me nt ar ms is 3 0 %, e nr oll me nt of 6 3  patie nts per 
ar m will yiel d 8 0 % p o wer t o dete ct statistical si g nifi ca nce at t he 
2 -si de d 0. 0 5  le v el f or 
H D R E G N 2 8 1 0 or S D R E G N 2 8 1 0/i pi , vers us S D R E G N 2 8 1 0 .  C o nsi deri n g a 5 % dr o p o ut rate, 
e nr oll me nt of a p pr o xi matel y 2 0 1  ra n d o mize d patie nts (6 7  patie nts per ar m)  wit h P D -L 1 
e x pressi o n i n < 5 0 %  of t u m or cells  is nee de d f or t h e st u d y. 
It is esti mate d t hat ~ 2 0 % of patie nts wit h N S C L C will ha ve P D-L 1 e x pressi o n i n ≥5 0 % of t u m or  
cells.  T heref ore a t otal e nr oll me nt of ~ 2 5 2 patie nts ( 5 1 patie nts wit h P D-L 1 i n ≥5 0 % of t u m or 
cells) is e x pecte d t o yiel d 2 0 1 patie nts wit h P D -L 1 e x pressi o n i n < 5 0 %  of t u m or cells .  T he 
ra n d o mizati o n will be stratifie d base d o n P D-L 1 e x pressi o n , as descri be d i n Secti o n  7. 5 , a n d will 
be m o nit ore d t o e ns ur e t hat t he st u d y e nr olls ~ 2 0 1 patie nts wit h P D-L 1  e x pressi o n  i n < 5 0 % of 
t u m or cells a n d ~ 5 1 patie nts wit h P D-L 1 e x pressi o n i n ≥5 0 % of t u m or cells. 
T he sa m ple siz e calc ulati o n is base d o n a c hi -s q u are test wit h n o c o nti n uit y c orrecti o ns.   
1 0. 3.  
A n al ysis Sets  
1 0. 3. 1.  
Effic ac y A n al ysis Sets  
T he f ull a nal ysis set ( F A S) i ncl u des all ra n d o mize d patie nts a n d will b e t he i nte nti o n -t o-tr eat 
p o p ulati o n.  T he F A S is base d o n t he treat me nt all ocati o n (as ra n d o mize d).   All efficac y 
e n d p oi nts will be a nal yz e d usi n g t he F A S.   T he pri mar y effi cac y e n d p oi nt will be a nal yz e d wit h 
t he strat u m of patie nts i n t he F A S w h o ha v e P D-L 1 e x pressi o n i n < 5 0 % of t u m or cells.  
1 0. 3. 2.  
S afet y A n al ysis Set  
T he safet y a n al ysis set ( S A F) i ncl u des al l ra n d o mi ze d patie nts w h o recei ve d a n y st u d y dr u g; it is 
base d o n t he tr eat me nt recei ve d (as treat e d).  Treat me nt c o m plia nce/a d mi nistrati o n a n d all 
cli nical safet y varia bles will be a nal yze d usi n g t h e S A F.  
1 0. 3. 3.  
A d diti o n al  A n al ysis Sets  
T he P K p o p ulati o n i ncl u de s all ra n d o mize d patie nts (safet y p o p ulati o n) w h o recei v e ce mi pli ma b 
a n d w h o ha ve at least 1 n o n -missi n g ce mi pli ma b  c o nce ntr ati o n assa y res ult f oll o wi n g t he first 
d ose of ce mi pli ma b  u p t o t he e n d of t he st u d y.  
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 8 9  of  1 2 9  
C O N FI D E N TI A L  
T he A D A a n al ysis set i ncl u des all treate d p ati e nts w h o recei v e d a n y st u d y dr u g a n d ha d at least 
1  n o n -missi n g p ost -baseli ne A D A assa y res ult f oll o wi n g t he first d ose of st u d y dr u g.  
1 0. 4.  
St atistic al Met h o ds  
F or c o nti n u o us varia bl es, descri pti ve statistics will i ncl u de t he f oll o wi n g i nf or mati o n:  t he 
n u m ber of patie nts reflecte d i n t he calc ulati o n ( n), mea n, me dia n, sta n dar d de viati o n, mi ni m u m, 
a n d ma xi m u m.   
F or cate g orical or or di nal data, fre q ue nci es a n d perce nta ges will be dis pla ye d f or eac h cate g or y.  
T he descri pti ve s u m mar y of ti me -t o-e ve nt data will i nc l u de me dia n ti me t o e ve nt a n d t he 
c orres p o n di n g 9 5 %  CI usi n g t he Ka pla n -Mei er met h o d.  
1 0. 4. 1.  
P ati e nt Dis p ositi o n  
T he f oll o wi n g will be pr o vi de d:  
 T he t otal n u m ber of scree ne d patie nts:  met t he i n cl usi o n criteria re gar di n g t he tar get 
i n dicati o n a n d si g ne d t h e I C F 
 T he t otal n u m ber of patie nts i n t he F A S  
 T he t otal n u m ber of patie nts i n t he S A F  
 T he t otal n u m ber of p atie nts w h o disc o nti n ue d treat me nt a n d t he reas o ns f or 
treat me nt disc o nti n uati o n 
 T he t otal n u m ber of p atie nts w h o disc o nti n ue d t he st u d y a n d t he reas o ns f o r 
disc o nti n uati o n  
 A listi n g of patie nts tr eat e d b ut n ot ra n d o mize d, patie nts ra n d o mize d b ut n ot treate d, 
a n d patie nts ra n d o mize d b ut n ot treate d as ra n d o mize d  
 A listi n g of patie nts pre mat urel y disc o nti n ue d fr o m treat me nt a n d st u d y, al o n g wit h 
reas o ns f or disc o nti n uati o n 
1 0. 4. 2.  
De m o gr a p h y a n d B aseli ne C h ar acteristics  
De m o gra p hic a n d baseli n e c haracteristics will be s u m marize d descri pti vel y b y treat me nt ar m a n d 
b y all patie nts c o m bi ne d.   
1 0. 4. 3.  
Me dic al Hist or y  
Me dical hist or y will be s u m marize d b y pri mar y s yste m or ga n cl a ss ( S O C) a n d preferre d ter m 
( P T) f or eac h tr eat me nt ar m, wit h t he ta ble s orte d b y decreasi n g fre q ue nc y of S O C, f oll o we d b y 
P T, base d o n t he o verall i nci de nce b et wee n treat m e nt ar ms.  
1 0. 4. 4.  
Pri o r Me dic ati o ns/ C o nc o mit a nt Me dic ati o ns  
N u m ber a n d pr o p orti o n of patie nt s ta ki n g pri or/ c o nc o mita nt me dicati o n will be s u m marize d b y 
decreasi n g fre q ue n c y of a n at o mical t hera pe uti c c h e mical ( A T C) le vel 2 a n d A T C le vel  4 
acc or di n g t o t he c urre nt versi o n of t he W orl d Healt h Or ga nizati o n Dr u g Di cti o nar y, b ase d o n t he 
o verall i nci de nce bet w ee n treat me nt ar ms.  
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 9 0  of  1 2 9  
C O N FI D E N TI A L  
Listi n gs of pre -tr eat me nt me dicati o n a n d c o n c o mita nt me dicati o ns will i ncl u de ge n eric n a me, 
A T C le vels  2 a n d 4, i n dicati o n, t he st u d y da y o ns et, t he st u d y e n d date ( defi ne d si milarl y as f or 
st u d y o nset da y), o n g oi n g stat us, d ose, fre q u e nc y, a n d r o ute.  
F or me di cati o ns t hat are starte d b ef ore treat me nt, t he st u d y da y o nset is defi ne d as t he d ate of 
me dicati o n start t o date of t he first d ose of tr eat me nt; f or me dicati o ns t h at are starte d o n or after 
treat me nt, t he st u d y da y o nset is defi ne d as t he date of me dicati o n start t o date of t he first 
d ose  +  1.  
1 0. 4. 5.  
Effic ac y A n al yses  
T he pri mar y e n d p oi nt of O R R will be a nal yze d w he n all e nr olle d patie nts ha ve a n o p p ort u nit y t o 
c o m plete 7 m o nt hs of st u d y treat me nt  a n d h a ve ha d at least t w o o n -treat me nt t u m or assess me nts .  
T he sec o n dar y e n d p oi nt of O S will be a nal yze d 1 2 m o nt hs after t he a nal ysis  of O R R.  T he 
sec o n dar y e n d p oi nt of P F S will be a nal yz e d at t h e sa me ti me as a n al ysis of O R R.  
1 0. 4. 5. 1.  Pri m ar y Effic ac y A n al ysis  
T he pri mar y e n d p oi nt of O R R will be  a nal yze d usi n g t he C oc hra n -Ma ntel -Hae nszel test 
stratifie d b y stat us of hist ol o g y ( n o n-s q ua m o us v ers us s q ua m o us).  A n ass ociate d o d ds rati o a n d 
9 5 % CI will be cal c ulate d.  O bjecti ve res p o nse rate a n d t he c orres p o n di n g e x act 9 5 % CI will be 
calc ulate d b y t h e Cl o p per -Pears o n met h o d f or eac h treat me nt ar m.  
T he pri mar y e n d p oi nt of O R R will be teste d first f or S D R E G N 2 8 1 0/i pi vers us S D R E G N 2 8 1 0 .  
If t he o utc o me of t he test is statisticall y si g nifica nt at t he 2 -si de d 0. 0 5 le vel, t he pri mar y e n d p oi nt 
of O R R will t he n  be teste d f or H D R E G N 2 8 1 0 vers us S D R E G N 2 8 1 0 at t he 2 -si de d 0. 0 5 le vel. 
S u b gr o u p a nal ys es will be perf or m e d f or eac h stratificati o n fact or s pecifie d a n d deter mi ne d at 
ra n d o mizati o n.  Ot her s u b gr o u p a nal yses b ase d o n baseli ne c haracteristics ma y als o be e x p l ore d. 
1 0. 4. 5. 2.  Sec o n d ar y a n d E x pl or at or y Effic ac y A n al yses  
O bjecti ve res p o nse rate i n all patie nts will be a nal yz e d usi n g t he sa me met h o d as t hat use d f or 
a nal ysis of t he pri mar y e n d p oi nt.   
T he e n d p oi nt s of O S  a n d P F S  will be a nal yz e d b y a stratifi e d l o g -ra n k t est usi n g t h e stat us of 
hist ol o g y ( n o n -s q ua m o us vers us s q ua m o us) as t he stratificati o n fact or.  T he H R a n d its 2 -si de d 
9 5 % CI will be esti mate d b y a str atifie d C o x re gressi o n m o del, usi n g t he treat me nt as c o v ariate.  
T he c ha n ge i n E O R T C Q L Q -C 3 0 a n d E O R T C Q L Q -L C 1 3 sc ores fr o m first assess me nt t o t he 
e n d of t he st u d y will be s u m marize d descri pti vel y at eac h p ost -baseli ne ti me p oi nt a n d c o m pare d 
usi n g a mi x e d effects m o del, if a p pr o priat e.  
1 0. 4. 6.  
S afet y A n al yses  
Safet y o bser vati o ns a n d meas ur e me nts, i ncl u di n g dr u g e x p os ure, A Es, la b orat or y d ata, vital 
si g ns, a n d E C O G p erf or ma nce stat us, will be s u m marize d a n d prese nte d i n ta bles a n d listi n gs.  
1 0. 4. 6. 1.  A d verse E ve nts  
Defi niti o ns  
F or safet y vari a bles, 3 o bser vati o n peri o ds are defi ne d:  
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 9 1  of  1 2 9  
C O N FI D E N TI A L  
 T he pre -tr eat me nt peri o d is defi ne d as t he ti me fr o m si g ni n g t he I C F t o bef ore t he 
first d ose of st u d y dr u g. 
 T he o n -treat me nt peri o d is defi ne d as t he da y fr o m t he first d ose of st u d y dr u g t o t he 
da y of t he last d ose of st u d y dr u g pl us 9 0  da ys.  
 T he p ost -treat me nt p eri o d is defi ne d as t he ti me after f oll o w-u p visit 1.  
Treat me nt -e mer ge nt a d v erse e v e nts are d efi ne d as t h ose t hat are n ot prese nt at baseli ne or 
re pres e nt t he e x acer bati o n of a pre-e xisti n g c o n diti o n d uri n g t he o n -tr eat me nt peri o d. 
A n alysis  
All A Es re p ort e d i n t his st u d y will be c o de d usi n g t he c urre ntl y a vaila bl e versi o n of t he M e dical 
Dicti o nar y f or Re g ulat or y A cti vities ( Me d D R A ).  C o di n g will be t o l o w est-le vel ter ms.  T he 
ver bati m te xt, t he P T, a n d t he pri mar y S O C will be liste d.  
S u m marie s of all T E A Es b y treat me nt ar m will i ncl u de t he f oll o wi n g: 
 T he n u m ber ( n) a n d perce nta ge ( %) of p atie nts wit h at least 1 T E A E b y S O C a n d P T  
 T E A Es b y se v erit y ( gra de d acc or di n g t o t he c urre nt versi o n of t he N CI -C T C A E), 
prese nte d b y S O C a n d P T  
 T E A Es b y o ut c o me  
 T E A Es b y relati o ns hi p t o st u d y dr u g (relate d, n ot r elate d), prese nte d b y S O C a n d P T  
 A E SI  
Deat hs a n d ot her S A Es will be liste d a n d s u m marize d b y treat me nt ar m.  
E ve nts of N CI -C T C A E gra de  3 a n d gra d e  4 se verit y will be s u m marize d b y treat me nt ar m.  
Treat me nt -e mer ge nt a d v erse e v e nts lea di n g t o per ma ne nt treat me nt disc o nti n uati o n will be liste d 
a n d s u m mariz e d b y tr eat me nt ar m.  
1 0. 4. 6. 2.  Ot her S afet y A n al yses  
Vit al Si g ns  
Vital si g ns (te m perat ur e, heart rate, seate d bl o o d press ure, a n d res pirati o n rate) will be 
s u m marize d b y b aseli ne a n d c ha n ge fr o m baseli ne t o eac h sc he d ule d assess me nt ti me wit h 
descri pti ve statistics.  
L a b or at ory Tests  
La b orat or y test res ults 
will be liste d, a n d t he n u m ber a n d perce nta ge of patie nts 
wit h 
N CI -C T C A E gra de 3 or gra de 4 la b orat or y val u es w ill be s u m marize d b y la b orat or y test.  S hift 
ta bles ma y b e ge n erate d if a p plica ble. 
1 0. 4. 6. 3.  Tre at me nt E x p os ure  
Treat me nt d ur ati o n, d ose i nte nsit y, a n d n u m ber of c ycles a d mi nistere d will be s u m marize d b y 
treat me nt ar m.   
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 9 2  of  1 2 9  
C O N FI D E N TI A L  
1 0. 4. 6. 4.  Tre at me nt C o m pli a nce  
Treat me nt c o m plia nce, 
i ncl u di n g d ose, n u m ber of d oses, ti mi n g a n d a p plica ble st u d y 
c o nc o mita nt pr oce d ures, will be s u m marize d b y treat me nt ar m.  T he a n al ysis met h o ds will be 
detaile d i n t he S A P.  
1 0. 4. 7.  
A n al ysis of Dr u g C o nce ntr ati o n D at a  
Ce mi pli ma b  c o nce ntrati o ns i n ser u m will be re p o rte d o v er ti me as i n di vi d ual val ues wit h 
descri pti ve statistics.  
Ipili m u ma b c o nce ntrati o ns i n ser u m sa m ples ma y b e a nal yz e d, t he res ults of w hic h ma y b e 
re p orte d i n t he sa m e wa y as f or ce mi pli ma b  c o nce ntrati o ns.  
1 0. 4. 8.  
E x p os ure -Res p o nse a n d P K/ P h ar m ac o d y n a mic  a n a l yses 
E x p os ure -Res p o nse relati o ns hi ps will be perf or me d as a p pr o priat e f or rele va nt e n d p oi nts of 
effic ac y, s uc h as O R R, O S, a n d/ or P F S, a n d e n d p oi nts of safet y, s uc h as ir A Es.  
E x pl orat or y P K/ P har mac o d y n a mic  a n al yses will be c o n d uct e d o n rel e va nt bi o mar kers , as 
a p pr o priate.  
1 0. 4. 9.  
A n al ysis of A nti -Dr u g A nti b o d y D at a  
T he A D A varia bles des cri be d i n Secti o n  4. 4  will be s u m marize d usi n g descri pti ve statistics i n 
t he A D A a nal ysis set.  Fre q u e nc y ta bles of t he pr o p orti o n of patie nts wit h treat me nt-e mer ge nt  
a n d treat me nt-b o oste d 
A D A res p o nse 
will be pre se nte d as a bs ol ute occ urre nce ( n) a n d 
perce nt a ge of patie nts ( %), prese nte d b y treat me nt ar ms.  
Pl ots of ce mi pli ma b  c o nce ntrati o ns will be e x a mi ne d, a n d t he i nfl ue nce of A D As o n i n di vi d ual 
c o nce ntr ati o n -ti me pr ofiles ma y be e v al uate d.  A n assess me nt of t he i m pact of A D As o n safet y 
a n d effi cac y m a y be pr o vi de d.  
Si milar a nal yses will be c o n d ucte d f or i pili m u ma b as necess ar y.  
1 0. 4. 1 0.  
A n al ysis of Bi o m ar ker D at a  
Bi o mar ker a n al ys es i n t his st u d y will be e x pl orat or y i n nat ur e, a n d res ults will be s u m marize d i n 
a se parate r e p ort.  Detail e d descri pti o n of statistical met h o ds t hat will be use d f or bi o mar ker data 
a nal ys es will be pr o vi de d i n a se parate Bi o mar ker A nal ytical Pla n.  
1 0. 5.  
M ulti plicit y C o nsi der ati o ns  
Fa mil y -wise t y pe I err or of 0. 0 5 f or t he a nal ysis of O R R of S D R E G N 2 8 1 0/i pi or H D R E G N 2 8 1 0 
vers us S D R E G N 2 8 1 0 c o m paris o ns is c o ntr olle d b y t he hi erarc hical gate -k ee pi n g a p pr oac h.  T h e 
pri mar y e n d p oi nt of O R R will be teste d first f or S D R E G N 2 8 1 0/i pi vers us S D R E G N 2 8 1 0 
c o m paris o n, if t he o utc o me of t he test is statisticall y si g nifica nt at t he 2-si de d 0. 0 5 le vel, t h e 
pri mar y e n d p oi nt of O R R will t hen  be teste d f or H D R E G N 2 8 1 0 vers us S D R E G N 2 8 1 0 at 2 -si de d 
0. 0 5 le vel.  
I n t his p has e 2  st u d y t y pe I err or c o ntr ol will  n ot be a p plie d t o t he test of sec o n dar y e n d p oi nts.  
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 9 3  of  1 2 9  
C O N FI D E N TI A L  
1 0. 6.  
I nteri m A n al ysis 
N o i nteri m a nal ysis is pla n ne d f or t his st u d y.  T h ere will be a n earl y safet y re vie w c o n d u cte d b y 
t he I D M C as detaile d i n Secti o n  5. 3. 2 . 
1 0. 7.  
A d diti o n al St a tistic al D at a H a n dli n g C o n ve nti o ns 
T he f oll o wi n g a nal ysis a n d data c o n ve nti o ns will be f oll o we d:  
Defi niti o n of baseli ne:  
 U nless ot her wise s pecifi e d, t he last assess me nt bef ore t he i nitial a d mi nistrati o n of 
ce mi pli ma b  will be c o nsi dere d t he baseli ne e v al ua ti o n. 
Ge neral r ules f or ha n dli n g missi n g d ata:  
 U nless ot her wise s pecifie d, t here will be n o i m p utati o ns f or missi n g data.  
 T he patter n of missi n g d ata a n d p ote ntial pr o g n ostic fact ors f or missi n g data ( Q O L, 
cli nical ne ur ol o gic assess me nt, a n d me ntal stat us)  will be e x a mi ne d t o g ui de t he use 
of pr o per statistical m o dels.  
 If t h e start date of a n A E or c o nc o mita nt me dicati o n is i nc o m plete or missi n g, it will 
be ass u me d t o ha ve occ urre d o n or after t he i nta ke of st u d y dr u g e x ce pt if a n 
i nc o m plete date (e g, m o nt h a n d year) cl earl y i n dicates t hat t he e ve nt start e d pri or t o 
treat me nt.  If t he partial date i n dicates t he sa me m o nt h or year of t he i nta ke of st u d y 
dr u g d ate, t he n t he start date b y t he st u d y dr u g i nta ke date will be i m p ute d; ot her wise, 
t he missi n g da y or m o nt h b y t he first da y or t he first m o nt h will be i m p ute d.  
Visit wi n d o ws:  
 Assess me nts ta ke n o utsi de of pr ot oc ol all o wa ble 
wi n d o ws 
will be dis pla ye d 
acc or di n g t o t he e C R F assess me nt rec or de d b y t he i n vesti gat or.  
U nsc he d ule d assess me nts:  
 E xtra assess me nts (la b orat or y data or vital si g ns ass ociate d wit h n o n-pr ot o c ol -defi ne d 
cli nical visits or o btai ne d i n t he c o urse of i n v esti gati n g or ma na gi n g A Es) will be 
i ncl u de d i n t he listi n gs b ut n ot i n t he s u m maries.  If m or e t ha n 1 la b orat or y v al ue is 
a vaila ble f or a gi ve n visit, t he first o bser vati o n will be use d i n s u m maries, a n d all 
o bser vati o ns will be pres e nte d i n listi n gs.  
1 0. 8.  
St atistic al C o nsi der ati o ns S urr o u n di n g t he Pre m at ure Ter mi n ati o n 
of a St u d y  
T he st u d y is e x pecte d t o e n d after t he last visit of t he last pati e nt (ie, w he n t he last patie nt 
c o m pletes t he f oll o w-u p visit 7 or disc o nti n ues earl y) .   
If t he st u d y is ter mi nat e d pre mat urel y, o nl y t h ose para m eters re q uire d f or t he de v el o p me nt 
pr o gra m a n d/ or re p orti n g t o re g ulat or y a ut h orities will be s u m marize d.  I n v e sti gat or a n d s p o ns or 
res p o nsi bilities s urr o u n di n g t he pre mat ure ter mi nati o n of a st u d y are prese nte d i n Secti o n  1 6. 1 . 
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 9 4  of  1 2 9  
C O N FI D E N TI A L  
1 1.  
D A T A M A N A G E M E N T A N D E L E C T R O NI C S Y S T E M S  
1 1. 1.  
D at a M a n a ge me nt  
A data ma n a ge me nt pl a n s pecif yi n g all rele va nt as pects of data pr ocessi n g f or t he st u d y 
(i ncl u di n g d ata vali dati o n, clea ni n g, c orrecti ng, a n d releasi n g) will be mai ntai ne d a n d st ore d at 
Re ge n er o n.  
A me dical c o di n g pla n will s pecif y t he pr ocess es a n d t he dicti o nar y us e d f or c o di n g.  All data 
c o di n g (e g, A Es, b aseli ne fi n di n gs, me di cati o n, a n d me dical hist or y/s ur gical hist or y) will be 
d o ne usi n g i nter nati o nall y rec o g niz e d a n d acce pte d dicti o naries.  
T he e C R F data f or t his st u d y will be c ollecte d usi n g a n electr o nic data ca pt ure ( E D C) t o ol.  User 
trai ni n g m ust be d oc u m e nte d bef ore t he user is gra nte d access t o t he E D C s yste m. 
1 1. 2.  
Electr o nic S yste m s 
Electr o nic s yste ms t hat ma y b e use d t o pr ocess a n d/ or c ollect data i n t his st u d y will i ncl u de t he 
f oll o wi n g: 
 I V R S/I W R S s yst e m –  ra n d o mizati o n, st u d y dr u g s u p pl y 
 E D C s yste m –  data ca pt ure  
 Statistical A nal ysis S yste m ( S A S ® ) –  statistical re vie w a n d a n al ysis 
 P har mac o vi gila nce s afet y dat a base  
 A R G U S safet y data b ase  
1 2.  
S T U D Y M O NI T O RI N G  
1 2. 1.  
M o nit ori n g of St u d y Sites  
T he st u d y m o nit or a n d/ or desi g n ee (e g, c o ntr act researc h or ga nizati o n [ C R O] m o nit or) will visit 
eac h site pri or t o e nr oll me nt of t he first patie nt a n d peri o dicall y d uri n g t he st u d y.  T h e 
i n vesti gat or m ust all o w st u d y-relate d m o nit ori n g. 
T he st u d y m o nit ors will perf or m o n g oi n g s o urce data re vie w t o v erif y t h at data rec or de d i n t he 
e C R F b y a ut h orize d site pers o n nel are acc urat e, c o m plete, a n d v erifia ble fr o m s o urce d oc u me nts, 
t hat t he safet y a n d ri g hts of patie nts are bei n g pr otecte d, a n d t hat t he st u d y is bei n g c o n d ucte d i n 
acc or da nce wit h t he c urre nt a p pr o ve d pr ot oc ol versi o n a n d a n y ot her st u d y a gree m e nts, I C H 
G C P, a n d all a p plica ble re g ul at or y re q uir e me nts.  
1 2. 2.  
S o urce D oc u me nt Re q uire me nts  
I n v esti gat ors are re q uir e d t o pre pare a n d mai ntai n a de q uate a n d acc urate patie nt rec or ds (s o urce 
d oc u me nts).  
T he i n vesti gat or m ust kee p all s o urce d o c u me nts o n file wit h t he eC R F.  Case re p ort f or ms a n d 
s o urce d oc u m e nts m ust be a vaila ble at all ti mes f or i ns pecti o n b y a ut h orize d re pres e ntati ves of 
t he s p o ns or a n d re g ul at or y aut h orities.  
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 9 5  of  1 2 9  
C O N FI D E N TI A L  
1 2. 3.  
C ase Re p ort F or m Re q uire me nts  
St u d y data o bt ai ne d i n t h e c o urs e of t h e cli nical st u d y will be rec or de d o n e C R Fs wit hi n t he E D C 
s yste m b y tr ai ne d site p ers o n nel.  All re q uire d e C R Fs m ust be c o m plet e d f or eac h a n d e ver y 
patie nt e nr olle d i n t he s t u d y.  After re vie w of t h e cli nical d ata f or eac h p atie nt, t he i n vesti gat or 
m ust pr o vi de a n electr o nic si g n at ure.  A c o p y of eac h p atie nt  eC R F cas e b o o k is t o be retai ne d b y 
t he i n vesti gat or as part of t he st u d y rec or d a n d m ust be a vaila ble at all ti mes f or i ns pecti o n b y 
a ut h orize d re pres e ntati ves of t he s p o ns or a n d re g ulat or y a ut h orities.  
C orrecti o ns t o t he e C R F  will be e ntere d i n t he e C R F b y t he i n vesti gat or or a n a ut h orize d 
desi g nee.  All c h a n ges, i ncl u di n g d etails re gar di n g t he d ate a n d pers o n p erf or mi n g  c orrecti o ns, 
will be a vaila ble via t he a u dit trail, w hic h is part of t he E D C s yste m.  F or c orrecti o ns ma de via 
data q ueries, a reas o n f or a n y alterati o n m ust be pr o vi de d.  
1 3.  
A U DI T S A N D I N S P E C TI O N S  
T his st u d y ma y be s u bject t o a q ualit y ass ur a nce a u dit or i ns pecti o n b y t he s p o ns or or re g ulat or y 
a ut h orities.  S h o ul d t his occ ur, t he i n vesti gat or is res p o nsi ble f or t he f oll o wi n g:  
 I nf or mi n g t he s p o ns or of a pla n ne d i ns pe cti o n b y t he a ut h orities as s o o n as 
n otificati o n is recei ve d a n d a ut h orizi n g t he s p o ns or’s part ici pati o n i n t he i ns pecti o n 
 Pr o vi di n g access t o all necess ar y facilities, st u d y d ata, a n d d o c u me nts f or t he 
i ns pecti o n or a u dit 
 C o m m u nicati n g a n y i nf or mati o n arisi n g fr o m i ns pecti o n b y t h e re g ulat or y a ut h orities 
t o t he s p o ns or i m me diatel y 
 Ta ki n g all a p pr o p riat e meas ures re q ueste d b y t he s p o ns or t o res ol ve t h e pr o ble ms 
f o u n d d uri n g t h e a u dit or i ns pecti o n 
D oc u me nts s u bject t o a u dit or i ns pecti o n i ncl u de, b ut are n ot li mite d t o, all s o urce d oc u me nts, 
e C R Fs, me dical rec or ds, c orres p o n d e nce, I C Fs, I R B/ E C files,  d oc u me ntati o n of certificati o n a n d 
q ualit y c o ntr ol of s u p p orti n g l a b orat ories, a n d rec or ds rele va nt t o t he st u d y m ai ntai ne d i n a n y 
s u p p orti n g p har mac y facilities.  C o n diti o ns of st u d y 
material st ora ge are als o s u bject t o 
i ns pecti o n.  I n a d diti o n, re prese nt ati ves of t he s p o ns or ma y o bser ve t he c o n d uct of a n y as pect of 
t he cli nical st u d y or its s u p p orti n g acti vities b ot h wit hi n a n d o utsi de of t he i n vesti gat or's 
i nstit uti o n. 
I n all i nsta nces, t he c o nfi de ntialit y of t he d ata m ust be res pecte d. 
1 4.  
E T HI C A L A N D R E G U L A T O R Y C O N SI D E R A TI O N S  
1 4. 1.  
G o o d Cli nic al Pr actice St ate me nt  
It is t he res p o nsi bilit y of b ot h t he s p o ns or a n d t he i n vesti gat or(s) t o e ns ure t hat t his cli nical st u d y 
will be c o n d u cte d i n acc or da n ce wit h t he et hical pri nci ples t hat ha v e t heir ori gi n i n t he 
Declar ati o n of Helsi n ki a n d t hat are c o nsiste nt wit h t he I C H g ui d eli nes f or G C P a n d a p plica ble 
re g ulat or y re q uire me nts. 
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 9 6  of  1 2 9  
C O N FI D E N TI A L  
1 4. 2.  
I nf or me d C o nse nt 
T he pri nci ples of i nf or me d c o nse nt are des cri be d i n I C H g ui deli nes f or G C P.  
T he I C F use d b y t he i n vesti gat or m ust be re vie we d  a n d a p pr o ve d b y t he s p o ns or pri or t o 
s u b missi o n t o t he a p pr o priate I R B/ E C.  A c o p y of t he I R B/ E C -a p pr o ve d I C F a n d d oc u m e ntati o n 
of a p pr o val m ust be pr o vi de d t o t he s p o ns or bef ore st u d y dr u g will be s hi p pe d t o t he st u d y site.  
It is t he res p o nsi bilit y of t he i n vesti gat or or d esi g n ee (if acce pta bl e b y l ocal re g ulati o ns) t o o btai n 
writte n i nf or me d c o nse nt fr o m e ac h p atie nt pri or t o his/ her partici p ati o n i n t he st u d y a n d after t he 
ai ms, met h o ds, o bjecti ves, a n d p ote ntial hazar ds of t he st u d y ha ve b ee n e x plai ne d  t o t he patie nt 
i n a la n g u a ge t h at he/s he ca n u n d ersta n d.  T he I C F s h o ul d be si g n e d a n d dat e d b y t he patie nt a n d 
b y t he i n vesti gat or or a ut h orize d desi g nee w h o re vie we d t he I C F wit h t he patie nt.   
 Patie nts w h o ca n write b ut ca n n ot rea d will ha ve t he I C F re a d t o t he m bef ore si g ni n g 
a n d dati n g t h e I C F.  
 Patie nts w h o ca n u n d ersta n d b ut w h o ca n neit her write n or rea d will ha ve t he I C F 
rea d t o t he m i n t he prese nce of a n i m partial wit ness, w h o will si g n a n d dat e t he I C F t o 
c o nfir m t hat i nf or me d c o nse nt was gi ve n.  
T he ori gi nal I C F m ust b e ret ai ne d b y t h e i n vesti gat or as p art of t he p atie nt’s st u d y rec or d, a n d a 
c o p y of t he si g ne d I C F m ust be gi ve n t o t he patie nt.  
If n e w safet y i nf or mati o n res ults i n si g nifica nt c ha n ges i n t he ris k-be nefit assess me nt, t he I C F 
m ust be  re vie we d a n d u p date d a p pr o priatel y.  All st u d y patie nts m ust be i nf or me d of t h e ne w 
i nf or mati o n a n d pr o vi de t heir writte n c o nse nt if t he y wis h t o c o nti n ue i n t he st u d y.  T h e ori gi nal 
si g ne d, re vise d I C F m ust be mai ntai ne d i n t he p atie nt’s st u d y rec or d, a n d a c o p y m ust b e gi ve n 
t o t he patie nt. 
A writte n i nf or m e d c o nse nt s h o ul d be o btai n e d f or treat me nt b e y o n d ra di ol o gi c diseas e 
pr o gressi o n, ac k n o wle d gi n g t hat t his practice is n ot c o nsi dere d sta n dar d i n t he treat me nt of 
ca ncer.  
1 4. 3.  
P atie nts’ C o nfi de nti alit y a n d D at a Pr otecti o n  
T he i n vesti gat or m ust ta ke all a p pr o pri ate meas ures t o e ns ure t h at t he a n o n y mit y of eac h st u d y 
patie nt will be mai ntai ne d.  Patie nts s h o ul d be i de ntifie d b y a patie nt i de ntificati o n n u m ber, o nl y, 
o n e C R Fs or ot h er d oc u me nts s u b mitte d t o t he  s p o ns or.  D oc u m e nts t hat will n ot be s u b mitte d t o 
t he s p o ns or (e g, si g ne d I C F) m ust be ke pt i n strict c o nfi de nce. 
T he patie nt’s a n d i n vesti gat or’s pers o nal dat a, w hic h ma y be i ncl u de d i n t he s p o ns or d ata base, 
will be treate d i n c o m pli a nce wit h all a p plica ble l a ws a n d re g ulati o ns.  T he s p o ns or s hall ta ke all 
a p pr o priate meas ur es t o safe g u ar d a n d pre ve nt access t o t his data b y a n y u n a ut h orize d t hir d 
part y.  
1 4. 4.  
I nstit uti o n al Re vie w B o ar d/ Et hics C o m mittee 
A n a p pr o priat el y c o nstit ute d I R B/ E C, as descri be d i n I C H g u i deli nes f or G C P, m ust re vie w a n d 
a p pr o ve t he f oll o wi n g:  
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 9 7  of  1 2 9  
C O N FI D E N TI A L  
 T he pr ot oc ol, I C F, a n d a n y ot her 
materials t o be pr o vi de d t o t he patie nts 
(e g, a d vertisi n g) bef ore a n y patie nt ma y b e e nr olle d i n t he st u d y  
 A n y a me n d me nt or m o dificati o n t o t he st u d y pr ot oc ol or I C F b ef ore i m ple me ntati o n, 
u nless t he c ha n ge is necessar y t o eli mi nate a n i m me diate hazar d t o t he patie nt, i n 
w hic h case t h e I R B/ E C s h o ul d be i nf or me d as s o o n as p ossi ble  
 O n g oi n g st u dies o n a n a n n ual basis or at i nter vals a p pr o priate t o t he de gree of ris k  
I n a d diti o n, t he I R B/ E C s h o ul d be i nf or me d of a n y e v e nt li kel y t o affect t he safet y of p atie nts or 
t he c o nti n ue d c o n d uct of t he cli nical st u d y. 
A c o p y of t he I R B/ E C a p pr o val letter wit h a c urre nt list of t he I R B/ E C me m bers a n d t heir 
f u ncti o ns m ust be recei v ed b y t he s p o ns or pri or t o s hi p me nt of dr u g s u p plies t o t he i n vesti gat or.  
T he a p pr o val letter s h o ul d i ncl u de t he st u d y n u m ber a n d title, t he d oc u me nts re vie we d, a n d t he 
date of t he re vie w.  
Rec or ds of t h e I R B/ E C re vie w a n d a p pr o val of all st u d y d oc u me nts (i ncl u di n g a p pr o val of 
o n g oi n g st u dies) m ust be ke pt o n file b y t h e i n vesti gat or.  
1 5.  
P R O T O C O L A M E N D M E N T S  
T he s p o ns or ma y n ot i m ple me nt a c h a n ge i n t he desi g n of t h e pr ot oc ol or I C F wit h o ut a n 
I R B/ E C-a p pr o ve d a me n d me nt.  Re g ulat or y a p pr o vals will als o b e s o u g ht as re q uire d b y 
re g ulat or y g ui da n ce. 
1 6.  
P R E M A T U R E T E R MI N A TI O N O F T H E S T U D Y O R 
C L O S E -O U T O F A SI T E  
1 6. 1.  
Pre m at ure Ter mi n ati o n of t he St u d y  
T he s p o ns or has t he ri g ht t o ter mi nate t he st u d y pre mat urel y.  Reas o ns ma y i n cl u de efficac y, 
safet y, or f utilit y, a m o n g ot hers.  S h o ul d t he s p o ns or deci de t o ter mi nate t he st u d y, t he 
i n vesti gat or(s) will be n otifie d i n writi n g. 
1 6. 2.  
Cl ose -o ut of a Site  
T he s p o ns or a n d t he i n vesti gat or ha v e t he ri g ht t o cl ose -o ut a site pre mat urel y.  
I nvesti g at or’s Decisi o n 
T he i n vesti gat or m ust n otif y t he s p o ns or of a desire t o cl ose -o ut a site i n writi n g, pr o vi di n g at 
least 3 0 da ys’ n otice .  T he fi nal d ecisi o n s h o ul d be ma de t hr o u g h m ut ual a gree me nt wit h t he 
s p o ns or.  B ot h parties will arra n ge t h e cl ose-o ut pr oce d ures aft er  re vie w a n d c o ns ultati o n. 
S p o ns or’s Decisi o n  
T he s p o ns or will n otif y t he i n vesti gat or(s) of a decisi o n t o cl ose -o ut a st u d y site i n writi n g.  
Reas o ns ma y i ncl u de t he f oll o wi n g, a m o n g ot hers:  
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 9 8  of  1 2 9  
C O N FI D E N TI A L  
 T he i n vesti gat or has recei ve d all ite ms a n d i nf or mati o n necess ar y t o perf or m t he 
st u d y b ut has n ot e nr olle d a n y p atie nts wit hi n a reas o na ble peri o d of ti me.  
 T he i n vesti gat or has vi olate d a n y f u n da me nt al o bli gati o n i n t he st u d y a gree m e nt, 
i ncl u di n g, b ut n ot li mite d t o, breac h of t his pr ot oc ol (a n d a n y a p plica ble 
a me n d ments), breac h of t he a p plica ble la ws a n d re g ulati o ns, or breac h of a n y 
a p plica ble I C H g ui deli nes.  
 T he t otal n u m ber of patie nts re q uire d f or t he st u d y has  e nr olle d earlier t h a n e x pecte d.  
I n all cas es, t he a p pr o priate I R B/ E C a n d Healt h A ut h orities m ust be i nf or me d acc or di n g t o 
a p plica ble re g ulat or y re q uire me nts, a n d a de q uat e c o nsi derati o n m ust be gi ve n t o t he pr otecti o n 
of t he patie nts’ i nterests.  
1 7.  
S T U D Y D O C U M E N T A TI O N  
1 7. 1.  
Certific ati o n of Acc ur ac y of D at a  
A decl arati o n ass uri n g t h e acc urac y a n d c o nte nt of t he da t a rec or de d o n t he e C R F m ust be si g n e d 
electr o nicall y b y t h e i n vesti gat or.  T his si g n e d d eclarati o n acc o m p a nies eac h set of p atie nt  fi nal 
eC R Fs t hat will be pr o vi de d t o t he s p o ns or.  
1 7. 2.  
Rete nti o n of Rec or ds  
T he i n vesti gat or m ust retai n all esse ntial st u d y d oc u me nts, i ncl u di n g I C Fs, s o urce d oc u me nts, 
i n vesti gat or c o pies of e C R Fs, a n d dr u g acc o u nta bilit y rec or ds f or at least 1 5 years f oll o wi n g t he 
c o m pleti o n or disc o nti n u ati o n of t he st u d y, or l o n ger, if a l o n ger p eri o d is re q uire d b y rele va nt 
re g ulat or y a ut h orities.  T he i n vesti gat or m ust o btai n writte n a p pr o val fr o m  t he s p o ns or bef ore 
discar di n g or destr o yi n g a n y esse ntial st u d y d oc u me nts f oll o wi n g st u d y c o m pleti o n or 
disc o nti n uati o n.  Rec or ds m ust be destr o ye d i n a ma n ner t hat e ns ures c o nfi de ntialit y.  
If t he i nvesti gat or’s p ers o nal sit uati o n is s uc h t hat arc hi vi n g ca n n o l o n ger be e ns ure d, t h e 
i n vesti gat or m ust i nf or m t he s p o ns or ( writte n n otificati o n), a n d t he rele va nt rec or ds will be 
tra nsferre d t o a m ut uall y a gree d-u p o n desti nati o n.  
1 8.  
D A T A Q U A LI T Y A S S U R A N C E  
I n acc or da nce wit h I C H E 6, t he s p o ns or is res p o nsi ble f or q u alit y ass ur a nce t o e ns ure t hat t he 
st u d y is c o n d ucte d a n d t he dat a ge n erat e d, rec or de d, a n d re p orte d i n c o m plia nce wit h t he 
pr ot oc ol, G C P, a n d a n y a p plica ble re g ul at or y re q uire me nt(s).  T he pla n ne d q ualit y ass ura nce a n d 
q ualit y c o ntr ol pr o ce d ures f or t he st u d y are s u m marize d bel o w.  
D at a M a n a ge m e nt  
T he s p o ns or is res p o nsi ble f or t he data m a na ge m e nt of t his st u d y i n cl u di n g q u alit y c hec ki n g of 
t he data ( Secti o n 1 1. 1 ). 
St u dy M o nit ori n g  
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 9 9  of  1 2 9  
C O N FI D E N TI A L  
T he i n vesti gat or m ust all o w st u d y -rel ate d m o nit ori n g, I R B/ E C re vi e w, a u dits, a n d i ns pecti o ns 
fr o m rele v a nt healt h re g ulat or y a ut h orities, a n d pr o vi de direct access t o s o urce d ata d oc u me nts 
( Secti o n 1 2. 1 , Secti o n  1 2. 2 , a n d Secti o n  1 2. 3 )   
T he st u d y m o nit ors will perf or m o n g oi n g s o urce data re vie w t o v erif y t h at data rec or de d i n t he 
C R F b y a ut h orize d sit e pers o n nel are acc urate, c o m plete, a n d verifi a ble fr o m s o urce d oc u me nts, 
t hat t he safet y a n d ri g hts of patie nts are bei n g pr otecte d, a n d t hat t he st u d y is bei n g c o n d ucte d i n 
acc or da nce wit h t he c urre nt a p pr o ve d pr ot oc ol versi o n a n d a n y ot her st u d y a gree m e nts, I C H 
G C P, a n d all a p plica ble r e g ul at or y re q uir e me nts ( Secti o n  1 2. 1 ).   
All s u bject/ patie nt data c ollecte d d uri n g t he st u d y will be rec or de d o n p a p er or electr o nic C R F 
u nless t he dat a are tra ns mitte d t o t he s p o ns or or desi g nee electr o nicall y (e g, la b orat or y data) .  
T he i n vesti gat or is res p o nsi ble f or affir mi n g t hat data e ntries i n t h e C R F are acc urate a n d c orrect 
b y electr o nicall y si g ni n g a d eclara ti o n t hat acc o m pa nies eac h s et of pati e nt/s u bject fi nal C R F 
( Secti o n 1 2. 3  a n d Secti o n  1 7. 1 ).  
St u dy D oc u m e nt ati o n  
T he i n vesti gat or 
m ust 
mai ntai n acc urate d o c u me ntati o n (s o urce data) t hat s u p p orts t he 
i nf or mati o n e ntere d i n t h e C R F ( Secti o n 1 2. 2 ).  
T he i n vesti gat or will ret ai n all rec or ds a n d d oc u me nts, i n cl u di n g si g n e d I C Fs, pertai ni n g t o t he 
c o n d uct of t his st u d y f or at least 1 5 years after st u d y c o m pleti o n, u nless l ocal re g ulati o ns or 
i nstit uti o nal p olicies re q uire a l o n ger rete nti o n p eri o d.  N o rec or ds ma y be destr o ye d d uri n g t he 
rete nti o n peri o d wit h o ut t he writte n a p pr o val of t he s p o ns or.  N o rec or ds ma y be tr a nsferre d t o 
a n ot her l ocati o n or p art y wit h o ut writte n n otif icati o n t o t he s p o ns or ( Secti o n 1 7. 2 ). 
1 9.  
C O N FI D E N TI A LI T Y  
C o nfi de ntialit y of i nf or m ati o n is pr o vi de d as a se p arate a gree me nt.  
2 0.  
FI N A N CI N G A N D I N S U R A N C E  
Fi na nci n g a n d i ns ura nce i nf or mati o n is pr o vi de d as a se parate a gree m e nt.  
2 1.  
P U B LI C A TI O N P O LI C Y  
T he p u blicati o n p olic y is pr o vi de d as a s e parate a gree me nt. 
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
 
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 1 0 0  of  1 2 9  
C O N FI D E N TI A L  
2 2.  
R E F E R E N C E S  
A nt o nia S, G ol d ber g S B, Bal ma n o u kia n A, C h aft J E, Sa n b or n R E, G u pta A, et al. Safet y a n d 
a ntit u m o ur acti vit y of d ur val u ma b pl us tre meli m u ma b i n n o n -s mall cell l u n g ca ncer: a 
m ultice ntre, p hase 1 b st u d y. La n cet O n c ol 2 0 1 6; 1 7( 3): 2 9 9 -3 0 8.  
Ber g m a n B, Aar o ns o n N K, A h me dzai S, Kaasa S, S ulli va n M. T he E O R T C Q L Q -L C 1 3: a  
m o d ular s u p ple me nt t o t he E O R T C C ore Q ualit y of Lif e Q uesti o n nair e ( Q L Q -C 3 0) f or use i n 
l u n g ca ncer cli nical trials. E O R T C St u d y Gr o u p o n Q ualit y of Lif e. E ur J Ca ncer 
1 9 9 4; 3 0 A( 5): 6 3 5 -4 2.  
Besse B, A djei A, Baas P, Mel d gaar d P, Nic ols o n M, Paz -Ares L, et a l. 2 n d E S M O c o nse ns us 
c o nfere nce o n l u n g ca n cer: n o n -s mall-cell l u n g ca ncer first -li ne/s ec o n d a n d f urt her li nes of 
treat me nt i n a d va n ce d disease. A n n O n c ol 2 0 1 4; 2 5: 1 4 7 5-8 4.  
Bj or dal K, d e Graeff A, Fa yers P M, Ha m merli d E, va n P ottels ber g h e C, C urra n D, et a l. A 
1 2  c o u ntr y fiel d st u d y of t he E O R T C Q L Q -C 3 0 ( versi o n 3. 0) a n d t he hea d a n d nec k ca ncer 
s pecific m o d ule ( E O R T C Q L Q-H; N 3 5) i n h ea d a n d nec k patie nts. E O R T C Q ualit y of Lif e 
Gr o u p. E ur J Ca ncer 2 0 0 0; 3 6( 1 4): 1 7 9 6 -8 0 7.  
B or g haei H, Paz -Ares L, H or n L, S pi gel D R, Stei ns M, Rea d y N E, et al. Ni v ol u ma b vers us 
d oceta x el i n a d va nce d n o n -s q ua m o us n o n-s mall-cell l u n g ca n cer. N E n gl J Me d 
2 0 1 5; 3 7 3: 1 6 2 7 -3 9.  
Bra h m er J, Rec ka m p K L, Baas P, Cri n ò L, E ber har dt W E, P o d d u bs ka ya E, et al. Ni v ol u ma b 
vers us d oceta x el i n a d va nce d  s q ua m o us-cell n o n-s mall-cell l u n g ca ncer. N E n gl J Me d 
2 0 1 5; 3 7 3: 1 2 3 -3 5.  
Bra y F, Re n J S, Mas u yer E, Ferl a y J. Esti mates of gl o bal ca ncer pre vale nce f or 2 7 sites i n t he 
a d ult p o p ulati o n i n 2 0 0 8. I nt J Ca ncer 2 0 1 3; 1 3 2: 1 1 3 3 -4 5.  
B uc h bi n der EI, D esai A. C T L A -4  a n d P D-1 pat h w a ys: si milarities, differe n ces, a n d i m plicati o ns 
of t heir i n hi biti o n. A m J Cli n O nc ol 2 0 1 6; 3 9: 9 8 -1 0 6.  
C hatterjee M, T ur n er D C, Feli p E, Le n a H, Ca p p uzz o F, H or n L, et al. S yst e matic e val uati o n of 
pe m br oliz u ma b d osi n g i n patie nts wit h a d va nce d n o n -s mall-cell l u n g ca n cer. A n n O nc ol 
2 0 1 6; 2 7: 1 2 9 1 -8.  
Creela n B C. U p date o n i m m u ne c hec k p oi nt i n hi bit ors i n l u n g ca n cer. C a ncer C o ntr ol 
2 0 1 4; 2 1: 8 0 -9.  
D’I ncecc o A, A n dre ozzi M, L u d o vi ni V, R ossi E, Ca p o da n n o A, La n di L, et al. P D -1 a n d P D -L 1 
e x pressi o n i n m olec ularl y sele cte d n o n -s mall-cell l u n g ca ncer patie nts. Br J Ca ncer 
2 0 1 5; 1 1 2: 9 5 -1 0 2.  
Eise n ha uer E A, T herasse P, B o gaerts J, Sc h wartz L H, Sar ge nt D, F or d R, et al. Ne w res p o ns e 
e val uati o n criteri a i n s oli d t u m o urs: re vise d R E CI S T g ui deli n e ( versi o n 1. 1). E ur J Ca ncer 
2 0 0 9; 4 5: 2 2 8 -4 7.  
El -S he ns ha w y H M, Tae ma S, El -Za h af E, El -Bes h bes hi W, El dee n D S, Fat h y A. A d v a nce d 
n o n -s mall cell l u n g ca ncer i n el derl y p atie nts: t he sta n dar d e v er y 3-wee ks v ers us wee kl y 
paclita x el wit h car b o plati n. C hest 2 0 1 2; 6 1: 4 8 5 -9 3.  
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
 
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 1 0 1  of  1 2 9  
C O N FI D E N TI A L  
Etti n ger D S, W o o d D E, A kerle y W, Baz he n o va L A, B or g h aei H, Ca mi d ge D R, et al. N C C N 
G ui deli nes i nsi g hts: n o n -s mall cell l u n g ca ncer, versi o n 4. 2 0 1 6. J Natl C o m pr Ca nc Net w 
2 0 1 6; 1 4: 2 5 5 -6 4.  
E ur o pea n Me dical A ge n c y ( E M A) G ui deli ne  o n t h e E val uati o n of A ntica ncer Me dici nal 
Pr o d ucts i n Ma n. Dece m ber  2 0 1 5.  
htt p:// w w w.e ma.e ur o pa. e u/ d ocs/e n _ G B/ d oc u m e nt _li brar y/ Sci e ntific _ g ui deli ne/ 2 0 1 6/ 0 3/ W C 5 0 0
2 0 3 3 2 0. p df  
Fe hre n bac h er L, S pira A, Balli n ger M, K o wa netz M, Va nstee n kiste J, Mazieres J, et al. 
Atez oliz u ma b vers us d oceta x el f or patie nts wit h pre vi o usl y tr eate d n o n -s mall-cell l u n g ca n cer 
( P O P L A R): a m ultice ntr e, o pe n-la b el, p hase 2 ra n d o mise d c o ntr olle d trial. La n cet 
2 0 1 6; 3 8 7( 1 0 0 3 0): 1 8 3 7 -4 6.  
F o o d a n d Dr u g A d mi nistrati o n ( F D A) G ui da n ce f or I n d u str y o n Cli nical Trial E n d p oi nts f or t he 
A p pr o val of N o n -S mall Cell L u n g Ca ncer Dr u gs a n d Bi ol o gics. A pril 2 0 1 5. 
htt ps:// w w w.f da. g o v/ d o w nl oa ds/ Dr u gs/ G ui d a nce C o m plia nce Re g ulat or yI nf or mati o n/ G ui da nces/
U C M 2 5 9 4 2 1. p df  
Fres h w ater T, K o n dic A, A ha ma di M, Li C H, d e Greef R, de Al wis D, St o ne J A, et al. 
E val uati o n of d osi n g str ate g y f or pe m br oliz u ma b f or o nc ol o g y i n dicati o ns. J I m m u n ot her Ca n cer 
2 0 1 7; 1 6( 5): 4 3.  
Ga d geel S M, Ste ve ns o n J, La n ger C, Ga n d hi L, B or g h aei H, Pat nai k A, et al. Pe m br oliz u ma b 
( pe m br o) pl us c h e mot hera p y as fr o nt -li ne t h era p y f or a d va n ce d N S C L C: K E Y N O T E-0 2 1 
c o h orts A-C. J Cli n O nc ol 2 0 1 6; 3 4( S u p pl); a bstract 9 0 1 6.  
Gar o n E B, Riz vi N A, H ui R, Lei g hl N, Bal ma n o u kia n A S, E der J P, et al. Pe m br oliz u ma b f or t he 
treat me nt of n o n-s mall-cell l u n g ca ncer. N E n gl J Me d 2 0 1 5; 3 7 2: 2 0 1 8 -2 8.  
Getti n ger S N, Hell ma n n M D, S he p her d F A, A nt o nia SJ, Bra h mer J R, Ma n C h o w L Q, et al. 
First -li ne m o n ot hera p y wit h ni v ol u ma b ( NI V O; a nti-pr o gra m me d deat h -1 [ P D -1]) i n a d va nce d 
n o n -s mall cell l u n g ca ncer ( N S C L C): safet y, efficac y a nd c orrelati o n of o utc o mes wit h P D -1 
li ga n d ( P D-L 1) e x pressi o n. J Cli n O nc ol 2 0 1 5; 3 3( S u p pl); a bstract 8 0 2 5.  
Getti n ger S, Riz vi N A, C h o w L Q, B or g haei H, Bra h mer J, Rea d y N, et al. First -li ne ni v ol u ma b 
m o n ot hera p y a n d ni v ol u ma b pl us i pili m u ma b i n patie nts wi t h a d va nce d N S C L C: L o n g-ter m 
o utc o mes fr o m C hec k Mate 0 1 2. I A S L C 1 7t h W orl d C o n gress 2 0 1 6;a bstr act O A 0 3. 0 1.  
Hell ma n n M D, Riz vi N A, G ol d ma n J W, Getti n ger S N, B or g haei H, Bra h m er J R, et al. 
Ni v ol u ma b pl us i pili m u ma b as first -li ne treat me nt f or a d va n ce d n o n-small -cell l u n g ca ncer 
( C hec k Mate 0 1 2): res ults of a n o pe n-l a bel, p hase 1, m ultic o h ort st u d y. La n cet O nc ol 
2 0 1 7; 1 8: 3 1 -4 1.  
Her bst R S, Baas P, Ki m D W, Feli p E, Pérez -Gracia J L, Ha n J Y, et al. Pe m br oliz u ma b vers us 
d oceta x el f or pre vi o usl y treate d, P D -L 1 -p ositi ve, a d va nce d n o n -s mall-cell l u n g ca ncer 
( K E Y N O T E-0 1 0): a ra n d o mise d c o ntr olle d trial. La ncet 2 0 1 6; 3 8 7: 1 5 4 0 -5 0.  
H of ma n n L, F orsc h ner A, L o q uai C, G ol di n ger S M, Zi m mer L, U q urel S, et al. C uta ne o us, 
gastr oi ntesti nal, he p atic, e n d ocri ne, a n d re n al si de -effect s of a nti-P D -1 t hera p y. E ur J Ca ncer 
2 0 1 6; 6 0: 1 9 0 -2 0 9.  
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
 
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 1 0 2  of  1 2 9  
C O N FI D E N TI A L  
Jia M, Fe n g W, Ka n g S, Z ha n g Y, S he n J, He J, et al.  E val uati o n of t he efficac y a n d s afet y of 
a nti-P D -1 a n d a nti -P D -L 1 a nti b o d y i n t he treat me nt of n o n -s mall cell l u n g ca ncer ( N S C L C): a 
meta -a nal ysis. J T h oracic Dis 2 0 1 5; 7( 3): 4 5 5-6 1.  
Kell y W K, C urle y T, Sl o vi n S, Heller G, Mc Caffre y J, Baj ori n D, et al. Paclita xel, estra m usti ne 
p h os p hate, a n d car b o plati n i n patie nts wit h a d va nce d pr ostate ca n cer. J Cli n O nc ol 
2 0 0 1; 1 9: 4 4 -5 3.  
Kerr K M,  Ts a o M S, Nic h ols o n A G, Yata be Y, Wist u ba II, Hirsc h F R; I A S L C Pat h ol o g y 
C o m mittee. Pr o gra m me d deat h -li ga n d 1 i m m u n o hist oc he mistr y i n l u n g ca n cer: i n w hat state is 
t his art? J T h orac O nc ol 2 0 1 5; 1 0: 9 8 5-9.  
K E Y T R U D A [ pac ka ge i nsert]. W hite h o use Stati o n, N Y: M erc k & C o; 2 0 1 5.  
Lar ki n J, C hiari o n -Sile ni V, G o nzalez R, Gr o b JJ, C o we y C L, La o C D, et al. C o m bi ne d 
ni v ol u ma b a n d i pili m u ma b or m o n ot hera p y i n u ntreate d mel a n o ma. N E n gl J Me d 
2 0 1 5; 3 7 3: 2 3 -3 4.   
Lei g hl N B. Treat me nt para di g ms f or patie nts wit h metastatic n o n -s mall-cel l l u n g ca n cer: 
first-, sec o n d-, a n d t hir d-li ne. C urr O nc ol 2 0 1 2; 1 9: S 5 2-8.  
L y n c h TJ, B o n dare n k o I, L uft A, Ser wat o ws ki P, Barl esi F, C hac k o R, et al. I pili m u ma b i n 
c o m bi nati o n wit h paclita x el a n d car b o plati n as first -li ne treat me nt i n sta ge III B/I V n o n– s mall 
cell l u n g ca ncer: res ults fr o m a ra n d o mize d, d o u ble -bli n d, m ultice nter p has e II st u d y. J Cli n 
O nc ol 2 0 1 2; 3 0: 2 0 4 6 -5 4.  
M Y S TI C Press Rele ase, 2 7 J ul y 2 0 1 7. 
htt ps:// w w w.ast raze neca. c o m/ me dia-ce ntr e/ press -releases/ 2 0 1 7/astraze neca-rep orts -i nitial-res ults
-fr o m-t he-o n g oi n g -m ysti c -trial-i n-sta ge-i v-l u n g-ca ncer -2 7 0 7 2 0 1 7. ht ml.  
Nai d o o J, Pa ge D B, Li B T, C o n nell L C, Sc hi n dler K, Lac o ut ur e M E, et al. T o xicities of t he 
a nti-P D -1 a n d a nti -P D -L 1 i m m u ne c hec k p oi nt a nti b o dies. A n n O nc ol ( 2 0 1 5) 2 6: 2 3 7 5 -2 3 9 1.  
Ni s hi n o M, Da hl ber g S E, F ult o n L E, Di g u m art h y S R, Hata b u H, J o h ns o n B E, et al. V ol u metri c 
t u m or res p o nse a n d pro gressi o n i n E G F R -m uta nt N S C L C patie nts treate d wit h erl oti ni b or 
g efiti ni b. Aca d Ra di ol 2 0 1 6; 2 3( 3): 3 2 9 -3 6.  
O’ Da y SJ, Mai o M, C hiari o n -Sile ni V, Ga je ws ki T F, Pe ha m ber ger H, B o n dare n k o I N, et al. 
Efficac y a n d safet y of i pili m u ma b m o n ot hera p y i n patie nts wit h pretreat e d a d va nce d mela n o ma: 
a m ultice nter si n gle -ar m p hase II st u d y. A n n O n c ol 2 0 1 0; 2 1: 1 7 1 2 -7.  
O P DI V O [ pac ka ge i nsert]. Pri ncet o n, NJ: Brist ol -M yers S q ui b b C o m pa n y; 2 0 1 5.  
O P DI V O [ S u m mar y of Pr o d uct C haracteristics]. Pri ncet o n, NJ: Brist ol -M yers S q ui b b C o m pa n y; 
2 0 1 5.  
P D -L 1 I H C  2 2 C 3 p har m D x  [ pac ka ge i nsert]. Car pi nteria, C A: Da k o; 2 0 1 6.  
Ratcliffe MJ, S har pe A, Mi d ha A, Bar ker C, Sc ott M, Sc orer P, et al. A gree me nt bet wee n 
pr o gra m me d cell deat h li ga n d -1 dia g n ostic assa ys acr oss m ulti ple pr otei n e x pressi o n c ut -offs i n 
n o n -s mall cell l u n g ca ncer. Cli n Ca ncer Res 2 0 1 7 J a n 1 0. [ E p u b a hea d of pri nt]. 
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
 
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 1 0 3  of  1 2 9  
C O N FI D E N TI A L  
Rec k M, P o pat S, Rei n m ut h N, De R u yss c her D, Kerr K M, P et ers S; E S M O G ui deli nes W or ki n g 
Gr o u p. Metastatic n o n -s mall-cell l u n g ca ncer ( N S C L C): E S M O cli nical practice g ui d eli nes f or 
dia g n osis, treat me nt a n d f oll o w -u p. A n n O nc ol 2 0 1 4; 2 5 S u p pl 3:iii 2 7 -3 9.  
Rec k M, R o drí g u ez -A bre u D, R o bi ns o n A G, H ui R, Cs őszi T, F ü l ö p A, et al. Pe m br oliz u ma b 
vers us c he m ot hera p y f or P D -L 1 -p ositi ve n o n -s mall-cell l u n g ca ncer. N E n gl J Me d 
2 0 1 6; 3 7 5( 1 9): 1 8 2 3 -3 3.  
Ritt me yer A, Barlesi F, Water ka m p D, Par k K, Ciar diell o F, v o n Pa wel J, et al. Atez oliz u ma b 
vers us d oceta x el i n patie nts wit h pre vi o usl y treate d n o n -s mall-cell l u n g ca n cer ( O A K): a p hase 3, 
o pe n -la bel, m ultice ntre ra n d o mise d c o ntr olle d trial. La n cet 2 0 1 7; 3 8 9( 1 0 0 6 6): 2 5 5 -2 6 5.  
Ri vera N, B oa da A, Biels a MI, Fer na n d ez -Fi g ueras M T, Carcere n y E, M ora n M T, et al. Hair 
re pi g m e ntati o n d uri n g i m m u n ot hera p y treat me nt wit h a n a nti -p r o gra m me d cell deat h 1 a n d 
a nti-pr o gra m me d cell deat h li ga n d 1 a ge nt f or l u n g ca ncer. J A M A Der mat ol 
2 0 1 7 ;1 5 3 ( 1 1): 1 1 6 2-1 1 6 5 . 
R oac h C, Z h a n g N, C ori glia n o E, J a nss o n M, T ola d G, P o nt o G, et al. De v el o p me nt of a 
c om pa ni o n dia g n ostic P D -L 1 i m m u n o hist oc he mistr y ass a y f or p e m br oliz u ma b t hera p y i n 
n o n -s mall-cell l u n g ca n cer. A p pl I m m u n o hist oc he m M ol M or p h ol 2 0 1 6; 2 4: 3 9 2 -7.  
R osell R, Gatz e meier U, Bettic her D C, Ke p pler U, Mac ha H N, Pir ker R, et al. P hase III 
ra n d o mise d trial c o m pari n g paclita x el/car b o plati n wit h paclita xel/cis plati n i n patie nts wit h 
a d va nce d n o n -s mall-cell l u n g ca ncer: a c o o p erati v e m ulti nati o nal trial. A n n O nc ol 
2 0 0 2; 1 3: 1 5 3 9 -4 9.  
Sca gli otti G V, De M ari nis F, Ri nal di M, Cri n ò L, Gri delli C, Ricci S, et al. P hase III ra n d o mize d 
trial c o m pari n g t hree plati n u m-base d d o u blets i n a d va nce d n o n -s m all-cell l u n g ca ncer. J Cli n 
O nc ol 2 0 0 2; 2 0: 4 2 8 5 -9 1.  
Sc hiller J H, Harri n gt o n D, Bela ni C P, La n ger C, Sa n dler A, Kr o o k J, et al. C o m paris o n of f o ur 
c he m ot hera p y re gi me ns f or  a d va nce d n o n -s mall-cell l u n g ca ncer. N E n gl J Me d 2 0 0 2; 3 4 6: 9 2 -8.  
S hi miz u T, Set o T, Hirai F, Ta ke n o ya ma M, N os a ki K, Ts ur uta ni J, et.al. P hase 1 st u d y of 
pe m br oliz u ma b ( M K -3 4 7 5; a nti -P D -1 m o n ocl o nal a nti b o d y) i n J a pa nese p atie nts wit h a d va nce d 
s oli d t u m ors. I n vest Ne w Dr u gs 2 0 1 6; 3 4: 3 4 7-5 4.  
S hi miz u T, Y o k oi T, Ta ma ki T, Ki bata K, I n a ga ki N, N o m ura S. C o m parati ve a nal ysis of 
car b o plati n a n d p aclita x el c o m bi nati o n c he m ot hera p y s c he d ules i n pre vi o usl y u ntreate d patie nts 
wit h a d va nce d n o n -s mall cell l u n g ca ncer. O nc ol Lett 2 0 1 3; 5: 7 6 1-7.  
Sie gel R L, Miller K D, J e mal A.  Ca ncer statistics, 2 0 1 6. C A Ca ncer J Cli n 2 0 1 6; 6 6: 7 -3 0.  
Sl o vi n S F, Hi ga n o C S, Ha mi d O, Tej wa ni S, Harzstar k A, Al u m kal JJ, et al. I pili m u ma b al o ne or 
i n c o m bi nati o n wit h ra di ot hera p y i n metastatic castrati o n -resista nt pr ostate ca ncer: res ults fr o m 
a n o pe n-la b el, m ultice nter p hase I/II st u d y. A n n O nc ol 2 0 1 3; 2 4: 1 8 1 3-2 1.  
S oci ns ki M, Creela n B, H or n L, Rec k M, Paz -Are L, Stei ns M, et al. C hec k Mate 0 2 6: A p hase 3 
trial of ni v ol u ma b vs i n vesti gat or’s c h oice (I C) of plati n u m -base d d o u blet c he m ot hera p y 
( P T-D C) as first -li ne t hera p y f or sta ge I V/rec urre nt pr o gra m me d deat h li ga n d 1 ( P D-L 1) -p ositi ve 
N S C L C. A n nals of O n c ol 2 0 1 6; 2 7 S u p pl 6: L B A 7 _ P R.  
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
 
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 1 0 4  of  1 2 9  
C O N FI D E N TI A L  
T o palia n S L, H o di F S, Bra h mer J R, Getti n ger S N, S mit h D C, Mc Der m o tt D F, et al. Safet y, 
acti vit y, a n d i m m u ne c orrelates of a nti – P D -1 a nti b o d y i n ca ncer. N E n gl J Me d 
2 0 1 2; 3 6 6: 2 4 4 3 -5 4.  
Vi na y D S, R ya n E P, Pa w elec G, Tali b W H, Sta g g J, El k or d E, et al. I m m u ne e vasi o n i n ca n cer: 
mec ha nistic basis a n d t hera pe utic strat e gies.  Se mi n Ca ncer Bi ol 2 0 1 5; 3 5: S 1 8 5 -9 8.  
We ber J S, Ya n g J C, At ki ns M B, Disis M L. T o xicities of i m m u n ot hera p y f or t he practiti o ner. J 
Cli n O nc ol 2 0 1 5; 3 3: 2 0 9 2 -9.  
W olc h o k J D, Ne y ns B, Li nette G, Ne grier S, L utz k y J, T h o mas L, et al. I pili m u ma b 
m o n ot hera p y i n patie nts wit h pretreat e d a d va n ce d mela n o ma: a ra n d o mise d, d o u ble -bli n d, 
m ultice ntre, p hase 2, d os e -ra n gi n g st u d y. La n cet O nc ol 2 0 1 0; 1 1: 1 5 5-6 4.  
Y E R V O Y [ pac ka ge i nsert]. Pri ncet o n, NJ: Brist ol -M yers S q ui b b C o m pa n y; 2 0 1 7.  
Y E R V O Y  [ S u m mar y of Pr o d uct C haracteristics]. Pri ncet o n, NJ: Brist ol-M yers S q ui b b 
C o m pa n y; 2 0 1 6.  
Z ha o X, S ur ya w a ns hi S, Hr us ka M, Fe n g Y, Wa n g X, S he n J, et al. Assess me nt of ni v ol u ma b 
be nefit -ris k pr ofile of a 2 4 0-m g fl at d ose rel ati ve t o a 3 -m g/ k g d osi n g re gi me n i n patie nts wit h 
a d va nce d t u m ors. A n n O nc ol 2 0 1 7a; d oi: 1 0. 1 0 9 3/a n n o nc/ m d x 2 3 5.  
Z ha o X, Fe n g Y, Wa n g X, Y o u n g T C, Maier S, Bell o S, et al. T u m or gr o wt h d y na mic ( T G D) 
m o deli n g a n d safet y a n al ysis of ni v ol u ma b ( ni v o) pl us i pili m u ma b (i pi) i n first -li ne ( 1 L) patie nts 
( P T S) wit h n o n-s mall cell l u n g ca n cer ( N S C L C). A S P C T 2 0 1 7 b A n n ual Meeti n g.  
Zi m mer L, G ol di n ger S M, H of ma n n L, et al. Ne ur ol o gical, res pir at or y, m usc ul os keletal, car diac 
a n d oc ular si de -effects of a nti -P D -1 t hera p y. E ur J Ca ncer 2 0 1 6; 6 0 2 1 0e 2 2 5.  
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
 
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 1 0 5  of  1 2 9  
C O N FI D E N TI A L  
2 3.  
IN V E S TI G A T O R’ S A G R E E M E N T  
I h a ve rea d t he attac he d pr ot oc ol:  A Ra n d o mize d, O pe n-La b el St u d y of C o m bi nati o ns of 
Sta n dar d a n d Hi g h D ose R E G N 2 8 1 0 ( Ce mi pli ma b; A nti -P D -1 A nti b o d y) a n d I pili m u ma b 
( A nti-C T L A -4 A nti b o d y) i n t he Sec o n d -li ne Treat me nt of Patie nts wit h A d va nce d  N o n -S mall 
Cell L u n g Ca ncer . 
I a gree t o c o m pl y wit h t he c urre nt I nter n ati o nal C o u ncil f or Har m o nisati o n G ui deli nes f or G o o d 
Cli nical Practice a n d t he la ws, r ules, re g ul ati o ns, a n d g ui deli nes of t h e c o m m u nit y, c o u ntr y, 
state, or l ocalit y relati n g t o t he c o n d uct of t he cli nical st u d y. 
I als o a gree t hat pers o ns de barre d fr o m c o n d ucti n g or w or ki n g o n cli nical st u dies b y a n y c o urt or 
re g ulat or y a ge nc y will n ot be all o we d t o c o n d uct or w or k o n st u dies f or t h e s p o ns or or a 
part ners hi p i n w hic h t he s p o ns or is i n v ol ve d.  I will i m me diatel y dis cl ose it i n writi n g t o t he 
s p o ns or if a n y pers o n w h o is i n v ol ve d i n t he st u d y is de barre d or if a n y pr ocee di n g f or 
de bar me nt is pe n di n g or, t o t he best of m y k n o wl e d ge, t hr eate ne d.  
T his d oc u me nt c o ntai ns c o nfi de ntial i nf or mati o n of t he s p o ns or, w hic h m ust n ot be discl ose d t o 
a n y o n e ot her t ha n t h e reci pie nt st u d y st aff a n d me m bers of t he I R B/ E C.  I a gree t o e ns ure t hat 
t his i nf or mati o n will n ot be use d f or a n y p ur p ose ot her t ha n t he e v al uati o n or c o n d uct of t he 
cli nical i n vesti gati o n wit h o ut t he pri or writte n c o nse nt of t he s p o ns or. 
 
 
 
 
( Si g nat ur e of I n v esti gat or) 
 
( Date) 
 
 
 
( Pri nte d Na me) 
 
 
 
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
 
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 1 0 6  of  1 2 9  
C O N FI D E N TI A L  
A P P E N DI X  1.  F A C T O R S T O C O N SI D E R I N A S S E S SI N G T H E 
R E L A TI O N S HI P O F A D V E R S E E V E N T S T O S T U D Y 
D R U G  
Is t here a reas o na ble p ossi bilit y t hat t he e v e nt ma y ha ve bee n ca us e d b y t he st u d y dr u g or st u d y 
c o n d uct?  
N o:  
 D ue t o e xter nal ca uses s uc h as e n vir o n me ntal fact ors or ot her treat me nt(s) bei n g 
a d mi nistere d  
 D ue t o t he patie nt’s disease state or cli nical c o n diti o n  
 D oes n ot f oll o w a reas o n a ble te m p oral se q ue n ce f oll o wi n g t he ti me of a d mi nistrati o n 
of t he d ose of st u d y dr u g  
 D oes n ot rea p p ear or w orse n w he n d osi n g wit h st u d y dr u g is r es u me d  
Yes:  
 C o ul d n ot be e x plai ne d b y e n vir o n me ntal fact ors or ot her treat me nt(s) bei n g 
a d mi nistere d  
 C o ul d n ot be e x plai ne d  b y t he patie nt’s disease state or cli nical c o n diti o n  
 F oll o ws a reas o na ble te m p oral se q ue n ce f oll o wi n g t h e ti me of a d mi nistrati o n of t he 
d ose of st u d y dr u g  
 Res ol ves or i m pr o ves aft er disc o nti n uati o n of st u d y dr u g  
 Rea p pears or w ors e ns w he n d osi n g wit h st u d y dr u g is res u m e d  
N O T E:  T his list is n ot e x ha usti ve.  
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
 
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 1 0 7  of  1 2 9  
C O N FI D E N TI A L  
A P P E N DI X  2.  R E S P O N S E E V A L U A TI O N C RI T E RI A I N  S O LI D 
T U M O R S:  R E CI S T G UI D E LI N E ( V E R SI O N 1. 1)  
T his a p pe n di x has bee n e x cer pte d, wit h s o me e dits f or gra m mar a n d st yl e, fr o m t he re vise d 
Res p o nse E val uati o n Criteria i n S oli d T u m ors ( R E CI S T) g ui deli ne ( v ersi o n  1. 1 ; 
Eise n ha uer  2 0 0 9 ).  F or f ull details pertai ni n g t o t he R E CI S T 1. 1 criteria, please refer t o t he 
p u blicati o n.  
1.  Assess me nt of T u m o r B ur de n Me as ur a ble Dise ase at B aseli ne  
O verall t u m or b ur de n m ust be assesse d at b aseli ne a n d will be use d as a c o m parat or f or 
s u bse que nt meas ur e me nts.  T u m or lesi o ns will be c ha racterize d as me as ura ble or 
n o n -meas ura bl e as f oll o ws:  
Res p o nse a n d pr o gressi o n will be e val uate d i n t his st u d y usi n g t h e i nter nati o nal criteria pr o p os e d 
b y t he re vise d R E CI S T g ui deli ne ( versi o n 1. 1;  Eise n ha uer  2 0 0 9 ).  C ha n ges i n t he lar gest 
dia meter ( u ni di me nsi o nal meas ure me nt) of t he t u m or lesi o ns a n d t he s h ortest dia meter i n t he 
case of m ali g n a nt l y m p h n o des are us e d i n t he R E CI S T criteria.  
1. 1.  Me as ur a ble dise ase  
T u m or lesi o ns m ust be acc urat el y m eas ure d i n at least 1 di me nsi o n (l o n gest dia meter i n t he pla ne 
of meas ure m e nt is t o be rec or de d) wit h a mi ni m u m size of  
 1 0 m m b y c o m p ute d t o m o gra p h y ( C T) sca n ( C T sca n slice t hic k ness n o greater t ha n 
5  m m)  
 1 0 m m cali per m eas ure me nt b y cli nical e x a m (lesi o ns w hic h ca n n ot be acc uratel y 
meas ure d wit h c ali pers s h o ul d be rec or de d as n o n meas ura ble)  
 2 0 m m b y c hest X -ra y 
 M ali g n a nt l y m p h n o des:   T o be c o nsi dere d pat h ol o gicall y e nlar ge d a n d meas ura ble, 
a l y m p h n o de m ust be ≥1 5 m m ( ≥1. 5  c m) i n s h ort a xis w he n assesse d b y C T sca n 
( C T sca n slice t hic k ness rec o m me n de d t o be n o greater t ha n 5 m m [ 0. 5 c m]).  At 
baseli ne a n d i n f oll o w -u p, o nl y t he s h ort a xis will be meas ure d a n d f oll o we d.  
1. 2.  N o n me as ur a ble dise ase   
All ot her lesi o ns, i nc l u di n g s mall lesi o ns (l o n gest dia meter < 1 0 m m or pat h ol o gical l y m p h n o des 
wit h ≥1 0  t o < 1 5  m m s h ort a xis), are c o nsi dere d n o n meas ura ble disease.  B o ne lesi o ns, 
le pt o me ni n geal disease, ascites, ple ural/ pericar dial eff usi o ns, l y m p ha n gitis c utis/ p ul m o nitis, 
i nfla m mat or y breast disease, a n d a b d o mi nal mass es ( n ot f oll o we d b y C T, ma g n etic res o n a nce 
i ma gi n g [ M RI], or p ositr o n e missi o n t o m o gra p h y [ P E T]) are c o nsi dere d n o n meas ura ble. 
1. 2. 1.  S peci al C o nsi der ati o ns  
B o ne lesi o ns:  
 B o ne s ca n, P E T sca n, or plai n fil ms are  n ot c o nsi dere d a de q uat e i ma gi n g tec h ni q ues 
t o meas ure b o ne lesi o ns.  H o we ver, t h ese tec h ni q ues ca n be use d t o c o nfir m t he 
prese nce or disa p p eara nce of b o ne lesi o ns.  
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
 
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 1 0 8  of  1 2 9  
C O N FI D E N TI A L  
 L ytic b o ne lesi o ns or 
mi x e d l ytic -blastic lesi o ns, 
wit h i de ntifia ble s oft tiss ue 
c o m p o ne nt s, t hat ca n b e e val uate d b y cr oss secti o nal i ma gi n g tec h ni q u es s uc h as C T 
or M RI ca n b e c o nsi dere d meas ura ble lesi o ns if t he s oft tiss ue c o m p o ne nt meets t he 
defi niti o n of meas ura bilit y des cri be d a b o ve.  
 Blastic b o ne lesi o ns are n o n -meas ura bl e.  
C ystic lesi o n s: 
C ystic lesi o ns t hat meet t he criteri a f or ra di o gra p hicall y d efi ne d si m ple c ysts s h o ul d n ot be 
c o nsi dere d mali g na nt lesi o ns ( neit her meas ura ble n or n o n meas ura ble) si nc e t he y are, b y 
defi niti o n, si m ple c ysts.  “ C ystic lesi o ns” t h o u g ht t o re prese nt c ystic metast ases ca n b e 
c o nsi dere d me as ura bl e lesi o ns if t he y meet t he d efi niti o n of meas ura bilit y d escri be d a b o ve.  
H o we ver, if n o nc ystic lesi o ns are pres e nt i n t he sa me patie nt, t hese are preferre d f or selecti o n as 
tar get lesi o ns. 
Lesi o ns wit h pri or l ocal trea t me nt: 
 T u m or lesi o ns sit uate d i n a pre vi o usl y irra di ate d area, or i n a n area s u bject e d t o ot her 
l oc ore gi o nal t hera p y, are us uall y n ot c o nsi dere d meas ura ble u nless t here has bee n 
de m o nstrate d  pr o gressi o n i n t he lesi o n.  
1. 3.  Met h o ds of Assess me nt  
All meas ur e me nts m ust be rec or de d i n metric n ot ati o n, usi n g cali pers if cli nicall y assesse d.  All 
baseli ne e val u ati o ns s h o ul d be perf or m e d as cl osel y as p ossi ble t o t he be gi n ni n g of treat me nt a n d 
ne ver m ore t ha n 4 wee ks bef ore t h e be gi n ni n g of t he treat me nt.  
T he sa m e met h o d of assess me nt a n d t he sa me tec h ni q ue s h o ul d be use d t o c haract erize eac h 
i de ntifie d a n d re p orte d lesi o n at baseli ne a n d d uri n g f oll o w-u p.  I ma gi n g -base d e val uati o n is 
preferre d t o e val uati o n b y cli nic al e x a mi nati o n u nless t he lesi o n(s) bei n g f oll o we d ca n n ot be 
i ma ge d b ut are assessa bl e b y cli nical e xa m. 
 Cli nic al lesi o ns .  Cli nical lesi o ns will o nl y b e c o nsi dere d meas ura ble w he n t he y are 
s u perficial a n d ≥1 0 m m ( ≥1 c m) i n dia meter , as assesse d usi n g cali pers (e g, s ki n 
n o d ules).  
 C hest X -r a y.  C hest C T is preferre d o ver c hest X-ra y, partic ularl y w he n pr o gressi o n 
is a n i m p orta nt e n d p oi nt, si nce C T is m ore se nsiti ve t ha n X -ra y, p artic ularl y i n 
i de ntif yi n g ne w lesi o ns.  Lesi o ns o n c hest X -ra y ma y be c o nsi dere d meas ura ble if 
t he y are clearl y d efi ne d a n d s urr o u n de d b y aerat e d l u n g.  
 C T a n d M RI .  C T is t he best c urre ntl y a v aila ble a n d re pr o d uci ble met h o d t o meas ure 
lesi o ns selecte d f or res p o nse assess me nt.  T his g ui deli ne has defi ne d meas ura bilit y of 
lesi o ns o n C T sca n bas e d o n t he ass u m pti o n t hat C T slice t hic k ness is 5 m m or less.  
W he n C T sca ns ha ve slice t hic k ness greater t ha n 5 m m, t he mi ni m u m siz e f or a 
meas ura ble l esi o n s h o ul d be t wice t he slice t hic k ness.  M RI is als o acce pta ble i n 
certai n sit uati o ns (e g, f or b o d y sca ns).  
 P E T -C T .  At prese nt, t he l o w d ose or atte n uati o n c orrecti o n C T p orti o n of a 
c o m bi ne d P E T -C T is n ot al wa ys of o pti mal dia g n ostic C T q ualit y f or use wit h 
R E CI S T meas ur e me nts.  H o we ver, if t he site ca n d o c u me nt t hat t he C T perf or me d as 
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
 
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 1 0 9  of  1 2 9  
C O N FI D E N TI A L  
part of a P E T -C T is of i de ntical dia g n ostic q ualit y t o a dia g n ostic C T ( wit h 
i ntra ve n o us a n d oral c o ntrast), t he n t he C T p orti o n of t he P E T-C T ca n b e use d f or 
R E CI S T me as ure me nts a n d ca n be use d i nterc h a n gea bl y wit h a c o n ve n ti o nal C T i n 
acc uratel y me as uri n g ca ncer l esi o ns o ver ti me.  N ote, h o we v er, t h at t he P E T p orti o n 
of t he C T i ntr o d uces a d diti o nal data t hat m a y bias a n i n vesti gat or if it is n ot r o uti nel y 
or seriall y perf or me d.  
 Ultr as o u n d .  Ultras o u n d is n ot usef ul i n assess m e nt of lesi o n siz e a n d s h o ul d n ot be 
use d as a met h o d of me as ure me nt.   
 E n d osc o p y, l a p ar osc o p y .  T he utilizati o n of t hese tec h ni q ues f or o bjecti ve t u m or 
e val uati o n is n ot a d vise d.   
 T u m or m a r kers .  T u m or mar kers al o ne ca n n ot b e use d t o assess r es p o nse. 
 C yt ol o g y, hist ol o g y .  T hese tec h ni q ues ca n be us e d t o differe ntiate b et wee n P Rs a n d 
C Rs i n rare cases (e g, resi d ual lesi o ns i n t u m or t y pes, s uc h as ger m cell t u m ors, 
w here k n o w n resi d ual b e ni g n t u m ors ca n re mai n).  
1. 4.  B aseli ne D oc u me nt ati o n of T ar get a n d  N o n -T ar get Lesi o ns  
T ar get lesi o ns:  W he n m ore t ha n o ne meas ura bl e lesi o n is prese nt at baseli ne, all lesi o ns u p t o a 
ma xi m u m of 5 lesi o ns t otal (a n d a ma xi m u m of 2 lesi o ns per or ga n) re prese ntati ve of all 
i n v ol ve d or ga ns s h o ul d be i de ntifie d as tar get lesi o ns a n d will be rec or de d a n d meas ure d at 
baseli ne .  Tar get lesi o ns s h o ul d be selecte d b ase d o n  t heir siz e (lesi o ns wit h t he l o n gest 
dia meter), be re prese ntati ve of all i n v ol ve d or ga ns, a n d s h o ul d le n d t he msel ves t o re pr o d uci ble 
re peat e d meas ur e me nts. 
L y m p h n o des merit s peci al me nti o n si nce t he y are n or mal a nat o mical str uct ures , w hic h ma y b e 
visi ble b y i ma gi n g e ve n if n ot i n v ol ve d b y t u m or.  Pat h ol o gical n o des t hat are defi ne d as 
meas ura ble a n d ma y be i de ntifie d as tar get lesi o ns m ust meet t he criteri o n of a s h ort a xis of 
≥1 5  m m b y C T s ca n.  O nl y t he s h ort a xis of t hese n o des will c o ntri b ute t o t he baseli ne s u m.  All 
ot her pat h ol o gi cal n o des (t h ose wit h s h ort a xis  ≥1 0 m m b ut < 1 5 m m) s h o ul d be c o nsi dere d 
n o n -tar get lesi o ns.  N o des t hat ha ve a s h ort a xis < 1 0 mm are c o nsi dere d n o n -pat h ol o gical a n d 
s h o ul d n ot be rec or de d or f oll o we d. 
A s u m of t he dia meters (l o n gest f or n o n -n o dal lesi o ns, s h ort a xis f or n o dal lesi o ns) f or all tar get 
lesi o ns will be calc ulate d a n d re p ort e d as t he bas eli ne s u m dia meters.  T he baseline s u m 
dia meters will be use d as a refere n ce t o f urt her c h aract erize a n y o bjecti ve t u m or re gressi o n i n t he 
meas ura ble di me nsi o n of t he disease.  
N o n -t ar get lesi o ns:  All ot her lesi o ns ( or sites of disease) i ncl u di n g pat h ol o gical l y m p h n o des 
s h o ul d be i de ntifie d as n o n-tar get lesi o ns a n d s h o ul d als o be rec or de d at b aseli ne.  Meas ure me nts 
of t hese lesi o ns are n ot re q uire d, b ut t he prese n ce, a bse nce, or, i n rare cases, u ne q ui v ocal 
pr o gressi o n of eac h s h o ul d be n ote d t hr o u g h o ut f oll o w -u p.   I n a d diti o n, it is p ossi ble t o rec or d 
m ulti ple n o n -tar get lesi o ns i n v ol vi n g t he sa me or ga n as a si n gle ite m o n t h e case rec or d f or m 
(e g, ‘ m ulti ple e nlar ge d p el vic l y m p h n o des’ or ‘ m ulti ple li ver metastases’). 
1. 5.  Res p o nse Criteri a  
T his secti o n pr o vi des t he defi niti o ns of t he criteria use d t o deter mi ne o bjecti ve t u m or res p o nse 
f or tar get a n d n o n-tar get lesi o ns. 
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
 
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 1 1 0  of  1 2 9  
C O N FI D E N TI A L  
1. 5. 1.  E v al u ati o n of T ar get Lesi o ns  
 C o m plete Res p o nse ( C R):   Disa p peara nce of all tar get lesi o ns .  A n y p at h ol o gical 
l y m p h n o des ( w het h er tar get or n o n-tar get) m ust ha ve re d ucti o n i n s h ort a xis t o 
< 1 0  m m ( < 1  c m).  
 P arti al Res p o nse ( P R):  At least a 3 0 % decrease i n t he s u m of t he dia meters of 
tar get lesi o ns, ta ki n g as r efere nce t he baseli ne s u m dia meters. 
 Pr o g ressi ve Dise as e ( P D):  At least a 2 0 % i ncrease i n t he s u m of t he dia meters of 
tar get lesi o ns, ta ki n g as refere nce t he s mallest s u m o n st u d y (t his i ncl u des t he 
baseli ne s u m if t hat is t h e s mallest o n st u d y).  I n a d diti o n t o t he relati ve i ncreas e of 
2 0 %, t he s u m m ust als o de m o nstrate a n a bs ol ute i ncreas e of at least 5 m m ( 0. 5 c m).  
(N ote: t he a p peara nce of o ne or m ore n e w lesi o ns is als o c o nsi dere d pr o gressi o ns). 
 St a ble Dise ase ( S D):  Neit her s ufficie nt s hri n k a ge t o q ualif y f or P R n or s uffici e nt 
i ncreas e t o q ualif y f or P D , ta ki n g as refere nce t h e s mallest s u m dia meters w hile o n 
st u d y. 
S pecial n otes o n t he assess me nt of tar get lesi o ns:  
 L y m p h n o des:  L y m p h n o des i de ntifie d as tar get lesi o ns s h o ul d al wa ys ha ve t he 
act ual s h ort a xis 
meas ure me nt rec or de d a n d s h o ul d be 
meas ure d i n t he sa me 
a nat o mical pla n e as t he baseli ne e x a mi na ti o n, e ve n if t h e n o des re gress t o bel o w 
1 0  m m o n st u d y.  T his mea ns t hat w he n l y m p h n o des are i ncl u de d as tar get lesi o ns, 
t he ‘s u m’ of lesi o ns ma y n ot be zer o e v e n if C R criteria are met, si nce a n or mal 
l y m p h n o de is defi n e d as ha vi n g a s h ort a xis of < 1 0 m m.  
 Tar get l esi o ns t hat bec o me ‘t o o s mall t o m eas ure’:  All lesi o ns ( n o dal a n d n o n -n o dal) 
rec or de d at baseli ne s h o ul d ha ve t heir act ual 
meas ure me nts rec or de d at eac h 
s u bse q ue nt e val uati o n, e ve n w he n ver y s mall (e g, 2 m m).  If t he ra di ol o gist is a ble t o 
pr o vi de a n act ual me as ure, t hat s h o ul d be rec or de d, e ve n if it is b el o w 5 m m.  
H o we ver, w he n s uc h a lesi o n bec o mes diffic ult t o assi g n a n e x act meas ure t o, t he n 
t he f oll o wi n g criteria s h o ul d be f oll o we d:  (i) If it is t he o pi ni o n of t he ra di ol o gist t hat 
t he lesi o n has li kel y disa p peare d, t he meas ure me nt s h o ul d be rec or de d as 0 m m.  (ii) 
If t he lesi o n is belie ve d t o be prese nt a n d is fai ntl y s ee n b ut t o o s mall t o meas ure, a 
defa ult val ue of 5  m m s h o ul d be assi g ne d ( n ote:  i n case of a l y m p h n o de b elie ve d t o 
be prese nt a n d fai ntl y see n b ut t o o s mall t o meas ure, a d efa ult val u e of 5 m m s h o ul d 
be assi g ne d i n t his cir c u msta nce as well).  T his defa ult val ue is deri ve d fr o m t he 5 
m m C T slice t hic k ness ( b ut s h o ul d n ot be c ha n ge d wit h var yi n g C T slice t hic k ness).  
 Lesi o n s t hat s plit or c oalesce o n treat me nt:  W he n n o n-n o dal lesi o ns ‘fra g me nt,’ t he 
l o n gest dia met ers of t he fra g me nte d p orti o ns s h o ul d be a d de d t o get her t o calc ulate t he 
tar get lesi o n s u m.  Si milarl y, as lesi o ns c o ales ce, a pla ne b et wee n t he m ma y be 
mai ntai ne d  t hat w o ul d ai d i n o btai ni n g ma xi mal dia meter meas ure me nts of eac h 
i n di vi d ual lesi o n.  If t h e lesi o ns ha ve c o alesce d s u c h t hat t he y are n o l o n ger se para bl e, 
t he vect or of t he l o n gest dia meter i n t his i nsta n ce s h o ul d be t he ma xi mal l o n gest 
dia meter f or t h e ‘c o alesce d lesi o n’. 
 
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
 
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 1 1 1  of  1 2 9  
C O N FI D E N TI A L  
1. 5. 2.  E v al u ati o n of N o n -t ar get Lesi o ns 
W hile s o me n o n -tar get lesi o ns ma y act uall y b e meas ura ble, t he y n ee d n ot b e meas ure d a n d 
i nstea d s h o ul d be assesse d o nl y q ualitati vel y at t he ti me p oi nts s pecifie d i n t he pr ot oc ol. 
 C o m plete Res p o nse:  Disa p peara nce of all n o ntar get lesi o ns a n d n or malizati o n of 
t u m or mar ker le vel.  All l y m p h n o des m ust be n o n pat h ol o gical i n siz e ( < 1 0  m m s h ort 
a xis). 
 N o n -C R/ N o n -P D:   Persiste nce of o n e or 
m ore n o ntar get lesi o n(s) a n d/ or 
mai nte na nce of t u m or mar ker l e vel a b o ve t he n or mal li mits.  
 Pr o g ressi ve Dise ase:  A p peara nce of o ne or m ore n e w lesi o ns a n d/ or u ne q ui v ocal 
pr o gressi o n of e xisti n g n o ntar get lesi o ns .  U ne q ui v ocal pr o gressi o n s h o ul d n ot 
n or mall y tr u m p tar get lesi o n stat us .  It m ust be re prese ntati ve of o verall dis ease st at us 
c ha n ge, n ot a si n gle lesi o n i ncreas e.  
Alt h o u g h a clear pr o gressi o n of “ n o ntar get” lesi o ns o nl y is e x ce pti o nal, t he o pi ni o n of t he 
treati n g p h ysi cia n s h o ul d pre vail i n s uc h cir c u msta nces, a n d t he pr o gressi o n stat us s h o ul d be 
c o nfir me d at a later ti me b y t he re vie w p a nel ( or i n vesti gat or). 
1. 6.  Ne w Lesi o ns  
T he a p peara nce of ne w 
mali g n a nt lesi o ns d e n otes disease pr o gressi o n; t heref ore, s o me 
c o m me nts o n detecti o n of ne w lesi o ns are i m p orta nt.  T here are n o s pecific criteria f or t he 
i de ntificati o n of ne w ra di o gra p hi c lesi o ns; h o we ver, t he fi n di n g of a ne w lesi o n s h o ul d be 
u ne q ui v ocal:  ie, n ot attri b uta ble t o differe nces i n sca n ni n g tec h ni q ue, c ha n ge i n i ma gi n g 
m o dalit y or fi n di n gs t h o u g ht t o re pres e nt s o met hi n g ot her t ha n t u m or (f or e x a m ple, s o me ‘ ne w’ 
b o ne lesi o ns ma y be si m pl y h eali n g or flare of pre -e xisti n g lesi o ns).  T his is partic ularl y 
i m p orta nt w he n t he patie nt’s baseli ne lesi o ns s h o w P R or C R.  F or e x a m ple, necr osis of a li ver 
lesi o n ma y be re p ort e d o n a C T sca n re p ort as a ‘ne w’ c ystic lesi o n, w hic h it is n ot.  
A lesi o n i de ntifie d o n a f oll o w -u p st u d y i n a n a nat o mical l ocati o n t hat was n ot sca n ne d at 
baseli ne is c o nsi dere d a ne w lesi o n a n d will i n dicate diseas e pr o gressi o n.  A n e x a m ple of t his is 
t he patie nt w h o h as visceral dis ease at bas eli ne a n d w hile o n st u d y h as a C T or M RI brai n 
or dere d, w hi c h re veals metastases.  T he patie nt’s brai n metastases are c o nsi dere d t o be e vi de nce 
of P D  e ve n if he/s he di d n ot ha ve brai n i ma gi n g at baseli ne.  If a ne w lesi o n is e q ui v ocal (f or 
e x am ple, beca us e of its s mall siz e) c o nti n ue d t hera p y a n d f oll o w -u p e v al uati o n will clarif y if it 
tr ul y re prese nts ne w dis ease.  If re p eat sca ns c o nfir m t here is defi nitel y a ne w lesi o n, t he n 
pr o gressi o n s h o ul d be declare d usi n g t he date of t he i nitial sca n.  
W hile F D G -P E T res p o nse assess me nts nee d a d diti o nal st u d y, it is s o meti mes reas o na ble t o 
i nc or p orate t he use of F D G-P E T sca n ni n g t o c o m ple me nt C T sca n ni n g i n assess me nt of 
pr o gressi o n ( partic ularl y p ossi ble ‘ ne w’ dise ase).  Ne w lesi o ns o n t he basis of F D G -P E T 
i ma gi n g ca n be i de ntifie d acc or di n g t o t he f oll o wi n g al g orit h m: 
a. Ne gati ve F D G -P E T at baseli ne wit h a p ositi ve F D G -P E T at f oll o w -u p is a si g n of P D  
base d o n a ne w lesi o n.  
b.  N o F D G -P E T at b aseli ne a n d a p ositi ve F D G -P E T at f oll o w -u p:  If t he p ositi ve 
F D G -P E T at f oll o w -u p c orres p o n ds t o a ne w site of disease c o nfir me d b y C T, t his is 
P D .  If t he p ositi ve F D G-P E T at f oll o w -u p is n ot c o nfir me d as a ne w site of dise ase 
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
 
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 1 1 2  of  1 2 9  
C O N FI D E N TI A L  
o n C T, a d diti o nal f oll o w -u p C T sca ns are nee de d t o deter mi ne if t here is tr ul y 
pr o gressi o n oc c urri n g at t hat site (if s o, t he date of P D  will be t he date of t he i nitial 
a b n or mal F D G -P E T sca n).  If t he p ositi ve F D G -P E T at f oll o w -u p c orres p o n ds t o a 
pree xisti n g site of disease o n C T t hat is n ot pr o gressi n g o n t he basis of t he a nat o mic 
i ma ges, t his is n ot P D . 
c. F D G -P E T ma y b e use d t o u p gra d e a res p o nse t o a C R i n a ma n ner si milar t o a bi o ps y 
i n cases w here a resi d ual ra di o gra p hic a b n or m alit y is t h o u g ht t o re prese nt fi br osis or 
scarri n g.  T he us e of F D G-P E T i n t his cir c u msta nce s h o ul d be pr os pecti vel y 
de scri be d i n t he pr ot oc ol a n d s u p p ort e d b y diseas e-s pecifi c me dical literat ure f or t he 
i n dicati o n.  H o we ver, it m ust be ac k n o wle d ge d t hat b ot h a p pr oac hes ma y lea d t o 
false-p ositi ve C R d ue t o li mitati o ns of F D G -P E T a n d bi o ps y res ol uti o n/se nsiti vit y.  
N ote:  A “ p ositi ve” F D G -P E T sca n lesi o n mea ns o ne t hat is F D G a vi d wit h a n u pta ke greater 
t ha n t wice t hat of t he s urr o u n di n g tiss ue o n t he att e n uati o n c orrecte d i ma ge. 
1. 7.  E v al u ati o n of Best O ver all Res p o nse  
T he best o verall res p o ns e ( B O R) is t he b est res p o nse r ec or de d fr o m t he start of t h e tr eat me nt 
u ntil t he e n d of treat me nt ta ki n g i nt o acc o u nt a n y re q uire me nt f or c o nfir mati o n.  T he patie nt's 
best res p o nse assi g n me nt will de pe n d o n t he fi n di n gs of b ot h tar get a n d n o n -tar get dise ase a n d 
will als o ta ke i nt o c o nsi derati o n t he a p p eara nce of ne w lesi o ns.  
Re vise d R E CI S T 1. 1 (Eise n ha uer  2 0 0 9 ) is s u m marize d i n Ta ble  6 . 
T a ble  6 : 
Res p o nse Acc or di n g t o Re vise d Res p o nse E v al u ati o n Criteri a i n S oli d 
T u m ors ( Versi o n  1. 1) i n P ati e nts wit h T ar get ( a n d N o n -T ar get) Lesi o ns  
T ar get 
Lesi o ns  
N o n -T ar get Lesi o ns  
Ne w 
Lesi o ns  
O ver all 
Res p o nse *  
C R  
C R  
N o  
C R  
C R  
N o n -C R/ n o n -P D  
N o  
P R  
C R  
N ot e val uate d  
N o  
P R  
P R  
N o n -C R/ n o n -P D/ n ot e val uate d  
N o  
P R  
S D  
N o n -C R/ n o n -P D/ n ot e val uate d  
N o  
S D  
P D  
A n y  
Yes or n o  
P D  
A n y  
P D *  
Yes or n o  
P D  
A n y  
A n y  
Yes  
P D  
A b bre viati o ns:  C R =c o m plete res p o nse; P D = pr o gressi ve disease; P R = partial res p o nse; S D =sta ble disease  
*I n e xce pti o nal circ u msta nces, u ne q ui v ocal pr o gressi o n i n n o n -tar get lesi o ns ma y be acce pte d as P D. 
N ote:   P atie nts wit h a gl o bal deteri orati o n of healt h stat us re q uiri n g disc o nti n uati o n of treat me nt wit h o ut o bj ecti ve 
e vi de nce of disease pr o gressi o n at t hat ti me s h o ul d be re p orte d as “ sy m pt o m atic deteri or ati o n. ”  E ver y eff ort 
s h o ul d be ma d e t o d oc u me nt t he o bj ecti ve pr o gressi o n e ve n after disc o nti n uati o n of treat me nt.  
1. 8.  Missi n g Assess me nts a n d U ne v al u a ble Desi g n ati o n  
W he n n o i ma gi n g/ meas ure me nt is d o ne at all at a partic ular ti me p oi nt, t he patie nt is n ot 
e val ua ble ( N E) at t hat ti me p oi nt.  If o nl y a s u bset of lesi o n meas ure me nts are ma de at a n 
assess me nt, us uall y t he case is als o c o nsi dere d N E at t hat ti me p oi nt, u nle ss a c o n vi nci n g 
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
 
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 1 1 3  of  1 2 9  
C O N FI D E N TI A L  
ar g u me nt ca n b e ma d e t h at t he c o ntri b uti o n of t he i n di vi d ual missi n g lesi o n(s) w o ul d n ot c ha n ge 
t he assi g ne d ti me p oi nt res p o nse.  T his w o ul d be m ost li kel y t o ha p pe n i n t he cas e of pr o gressi ve 
disease.  F or e x a m ple, if a p atie nt ha d a base li ne s u m of 5 0 m m wit h 3 m eas ure d lesi o ns a n d at 
f oll o w-u p o nl y 2 lesi o ns were ass esse d, b ut t h os e ga v e a s u m of 8 0 m m, t he patie nt will ha ve 
ac hie ve d pr o gressi ve dis ease stat us, r e gar dless of t he c o ntri b uti o n of t he missi n g lesi o n.  
1. 9.  Best O ver all Res p o nse:  All Ti me P oi nts  
T he B O R is d eter mi ne d o nce all t he d ata f or t h e patie nt is k n o w n.  Best res p o nse det er mi nati o n 
i n st u dies w here c o nfir m ati o n of C R or P R I S N O T re q uir e d:  Best res p o nse i n t hese st u dies is 
defi ne d as t he best res p o nse acr oss all ti me  p oi nts (f or e x a m ple, a p atie nt w h o has S D at first 
assess me nt, P R at sec o n d assess me nt, a n d pr o gressi ve disease o n last assess me nt has a B O R of 
P R).  
W he n S D is belie ve d t o be best res p o nse, it m ust als o meet t he pr ot oc ol -s p ecifie d 
mi ni m u m ti me fr o m bas el i ne.  If t h e mi ni m u m ti me is n ot met w he n S D is ot her wise t he best 
ti me p oi nt res p o nse, t he patie nt’s best res p o nse de pe n ds o n t he s u bse q ue nt assess me nts.  F or 
e x a m ple, a patie nt w h o has S D at first assess me nt, pr o gressi ve dise ase at sec o n d a n d d oes n ot 
me et mi ni m u m d urati o n f or S D, will ha ve a best res p o nse of pr o gressi ve disease.  T he sa me 
patie nt l ost t o f oll o w -u p after t he first S D assess m e nt w o ul d be c o nsi dere d u ne val ua ble.  
2. 0.  D ur ati o n of o ver all res p o nse  
T he d urati o n of o v erall res p o nse is meas ure d  fr o m t he ti me meas ure me nt criteria are first met f or 
C R/ P R ( w hic he ver is first rec or de d) u ntil t he first date t hat rec urre nt or pr o gressi ve disease is 
o bjecti vel y d o c u me nte d (ta ki n g as refere nce f or pr o gressi ve dise ase t he s mallest meas ure me nts 
rec or de d on st u d y).  T he d urati o n of o verall C R is meas ure d fr o m t he ti me meas ure m e nt criteri a 
are first met f or C R u ntil t he first date t hat rec urre nt disease is o bjecti vel y d oc u me nte d.  
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 1 1 4  of  1 2 9  
C O N FI D E N TI A L  
A P P E N DI X  3.  R E C O M M E N D E D D O S E M O D I FI C A TI O N O R DI S C O N TI N U A TI O N A N D 
S U P P O R TI V E C A R E G UI D E LI N E S F O R S P E CI FI C C E MI P LI M A B  D R U G -R E L A T E D 
A D V E R S E E V E N T S   
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 1 1 5  of  1 2 9  
C O N FI D E N TI A L  
 
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 1 1 6  of  1 2 9  
C O N FI D E N TI A L  
 
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 1 1 7  of  1 2 9  
C O N FI D E N TI A L  
 
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 1 1 8  of  1 2 9  
C O N FI D E N TI A L  
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 1 1 9  of  1 2 9  
C O N FI D E N TI A L  
 
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 1 2 0  of  1 2 9  
C O N FI D E N TI A L  
 
 
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 1 2 1  of  1 2 9  
C O N FI D E N TI A L  
 
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 1 2 2  of  1 2 9  
C O N FI D E N TI A L  
 
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 1 2 3  of  1 2 9  
C O N FI D E N TI A L  
 
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 1 2 4  of  1 2 9  
C O N FI D E N TI A L  
 
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 1 2 5  of  1 2 9  
C O N FI D E N TI A L  
 
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 1 2 6  of  1 2 9  
C O N FI D E N TI A L  
 
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 1 2 7  of  1 2 9  
C O N FI D E N TI A L  
 
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 1 2 8  of  1 2 9  
C O N FI D E N TI A L  
A P P E N DI X  4.  C E MI P LI M A B  P H A R M A C O KI N E TI C, 
I M M U N O G E NI CI T Y, A N D BI O M A R K E R S A M P LI N G 
S C H E D U L E  
St u d y Visit  
P K S a m pli n g Ti me a 
A nti -Dr u g 
A nti b o d y 
S a m pli n g Ti me a 
Ser u m a n d Pl as m a 
Bi o m ar ker S a m ples 
S a m pli n g Ti me a 
Scree ni n g  
 
C ollect o n -st u d y or arc hi val ( ≤5 m o nt hs ol d) t u m or tiss ue sa m ple 
C ycle 1, da y 1  
 
Pre d ose  
 
E n d of i nf usi o n  
 
Pre d ose  
 
Pre d ose  
 
C ollect bl o o d 
sa m ple f or D N A 
C ycle 2, da y 1  
 
Prei nf usi o n  
 
E n d of i nf usi o n  
 
 
Prei nf usi o n  
C ycle 3, da y 1  
 
Prei nf usi o n  
 
E n d of i nf usi o n  
 
 
C ycle 4, da y 1  
 
Prei nf usi o n  
 
E n d of i nf usi o n  
 
 
Prei nf usi o n  
C ycle 9, da y 1  
 
Prei nf usi o n  
 
Prei nf usi o n  
 
C ycle 1 8, da y 1  
 
Prei nf usi o n  
 
Prei nf usi o n  
 
C ycle 2 6, da y 1  
 
Prei nf usi o n  
 
 
C ycle 3 0, da y 1  
 
Prei nf usi o n  
 
E n d of i nf usi o n  
 
 
C ycle 3 4, da y 1  
 
Prei nf usi o n  
 
E n d of i nf usi o n  
 
 
F oll o w -u p visit 1  
 
C ollect at visit  
 
C ollect at visit  
 
C ollect at visit  
F oll o w -u p visit 2  
 
C ollect at visit  
 
 
F oll o w -u p visit 3  
 
C ollect at visit  
 
 
F oll o w -u p visit 7  
 
C ollect at visit  
 
C ollect at visit  
 
At t he ti me of 
R E CI S T  1. 1 -defi ne d 
pr o gressi ve disease  
 
C ollect at visit b 
 
C ollect at visit b 
 
C ollect at visit b c 
A b bre viati o ns:  D N A = de o x yri b o n ucleic aci d; 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 ors  
a Pre d ose is defi ne d as bef ore t he start of t he first ce mi pli ma b i nf usi o n.  Pre d ose sa m ples ma y be c ollecte d ≤7 2  pri or 
t o da y 1 d osi n g.  Prei nf usi o n is defi ne d as a n y ti me bef ore t he start of s u bse q ue nt ce mi pli ma b i nf usi o n o n t he da y 
of i nf usi o n.  E n d of i nf usi o n is defi ne d as wit hi n 1 0 mi n utes after t he i nf usi o n has c o m plet e d.  
b Sa m ples ma y be c ollecte d f or u p t o 1 0 da ys after t his st u d y visit.  
c A t u m or bi o ps y s h o ul d als o be c ollecte d at t his ti me p oi nt ( o pti o nal)  
 
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0

Cli nic al St u d y Pr ot oc ol  
 
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o b al  
 
Re ge ner o n P h ar m a ce utic als, I nc . 
 
P a ge 1 2 9  of  1 2 9  
C O N FI D E N TI A L  
SI G N A T U R E O F S P O N S O R ’ S R E S P O N SI B L E O F FI CE R S  
( Scie ntific/ Me dic al M o nit or, Re g ul at or y Re prese nt ati ve, Cli nic al St u d y Te a m Le a d, a n d 
Bi ost atistici a n)  
T o t he best of my k n o wle d ge, t his re p ort acc ur atel y descri bes t he c o n d uct of t he st u dy a n d t he 
d at a ge ner ate d.  
St u d y Title:  
A Ra n d o mize d, O pe n -La bel St u d y of C o m bi nati o ns of Sta n dar d a n d Hi g h D ose 
R E G N 2 8 1 0 ( Ce mi pli ma b; A nti -P D -1 A nti b o d y) a n d I pili m u ma b ( A nti -C T L A -4 
A nti b o d y) i n t he Sec o n d -Li ne Treat me nt of  Patie nts wit h A d va nce d  N o n -S mall 
Cell L u n g Ca ncer  
Pr ot oc ol N u m ber:  
R 2 8 1 0 -O N C -1 7 6 3  
Pr ot oc ol Versi o n  
R 2 8 1 0 -O N C -1 7 6 3 A me n d me nt 2 Gl o bal  
 
See a p pe n d e d ele ctr o nic si g n at ure p a ge  
S p o ns or’s Res p o nsi ble Scie ntific/ Me dical M o nit or  
 
 
See a p pe n d e d ele ctr o nic si g n at u re p a ge 
S p o ns or’s Res p o nsi ble Re g ul at or y Re pres e ntati ve  
 
 
See a p pe n d e d ele ctr o nic si g n at ure p a ge  
S p o ns or’s Res p o nsi ble Cli nical St u d y T ea m Lea d  
 
 
See a p pe n d e d ele ctr o nic si g n at ure p a ge  
S p o ns or’s Res p o nsi ble Bi ostatisticia n  
 
 
 
                                        V V- RI M- 0 0 0 4 1 5 1 5- 1. 0 A p pr o ve d - 0 1 Ma y 2 0 1 8 G M T- 5: 0 0