Conditions: Advanced Non-Small Cell Lung Carcinoma
Keywords: Advanced non-squamous NSCLC Advanced squamous NSCLC
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 28
Healthy volunteers: no

Brief summary:
The primary objective of the study is to compare the objective response rate (ORR) of high dose cemiplimab (HDREGN2810) and standard dose cemiplimab plus ipilimumab combination therapy (SDREGN2810/ipi) to the ORR of standard dose cemiplimab (SDREGN2810) in the second-line treatment of patients with advanced squamous or non-squamous non-small cell lung cancer (NSCLC), in patients whose tumors express programmed cell death ligand 1 (PD-L1) in \<50% of tumor cells.

Detailed description:

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

Interventions: intervention 1: SDREGN2810 intervention 2: SDREGN2810/ipi intervention 3: HDREGN2810
Intervention descriptions: intervention 1: Standard dose intravenous (IV) infusion intervention 2: Combination therapy dose IV intervention 3: High dose IV

Protocol document:
Prot_000.pdf: 


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  
                                        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  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  
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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 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  
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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 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  
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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 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 
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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 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 . 
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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 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 
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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 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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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 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 
                                        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 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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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 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 . 
                                        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 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.  
                                        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 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 . 
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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 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)  
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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 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.   
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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 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 
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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 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



SAP_001.pdf: 


Regeneron Pharmaceuticals, Inc. 
Protocol: R2810-ONC-1763 
Statistical Analysis Plan 
Dec 6, 2020 
 
CONFIDENTIAL 
Page 2 of 16 
The approval signatures below indicate that these individuals have reviewed the Statistical 
Analysis Plan (SAP) and agreed on the planned analysis defined in this document for 
reporting. 
 
 
See appended electronic signature page 
 
 
 
 
 
See appended electronic signature page 
  
 
 
  
See appended electronic signature page 
 
 
 
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Protocol: R2810-ONC-1763 
Statistical Analysis Plan 
Dec 6, 2020 
 
CONFIDENTIAL 
Page 3 of 16 
TABLE OF CONTENTS 
ABBREVIATIONS AND DEFINITION OF TERMS....................................................................5 
1. 
OVERVIEW .................................................................................................................7 
1.1. 
Background/Rationale ..................................................................................................7 
1.1.1. 
Background ...................................................................................................................7 
1.1.2. 
Rationale .......................................................................................................................7 
1.2. 
Study Objectives ...........................................................................................................8 
2. 
INVESTIGATION PLAN ............................................................................................8 
2.1. 
Study Design .................................................................................................................8 
3. 
ANALYSIS POPULATIONS ......................................................................................9 
3.1. 
Safety Analysis Set .......................................................................................................9 
3.2. 
Pharmacokinetic Analysis Set ......................................................................................9 
3.3. 
Immunogenicity Analysis Set .......................................................................................9 
4. 
ANALYSIS VARIABLES ...........................................................................................9 
4.1. 
Demographic and Baseline Disease ..............................................................................9 
4.2. 
Prior Treatment/Concomitant Medications and Procedures .......................................10 
4.3. 
Efficacy Variables ......................................................................................................10 
4.4. 
Safety Variables ..........................................................................................................11 
4.4.1. 
Adverse Events and Serious Adverse Events .............................................................11 
4.4.2. 
Adverse Events of Special Interest .............................................................................11 
4.4.3. 
Laboratory Safety Variables .......................................................................................12 
4.5. 
Pharmacokinetic Variables .........................................................................................12 
4.6. 
Immunogenicity Variables ..........................................................................................12 
5. 
STATISTICAL METHODS .......................................................................................12 
5.1. 
Patient Disposition ......................................................................................................12 
5.2. 
Demographics and Baseline Disease Characteristics .................................................12 
5.3. 
Prior/Concomitant Medications/Procedures ...............................................................13 
5.4. 
Exposure to Investigational Product ...........................................................................13 
5.5. 
Analyses of Efficacy Data ..........................................................................................13 
5.6. 
Analysis of Safety Data ..............................................................................................13 
5.6.1. 
Adverse Events ...........................................................................................................13 
5.7. 
Analysis of Pharmacokinetic and Immunogenicity Data ...........................................14 
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Regeneron Pharmaceuticals, Inc. 
Protocol: R2810-ONC-1763 
Statistical Analysis Plan 
Dec 6, 2020 
 
CONFIDENTIAL 
Page 4 of 16 
5.7.1. 
Analysis of Pharmacokinetic Data ..............................................................................14 
5.7.2. 
Analysis of Immunogenicity Data ..............................................................................14 
5.8. 
Association of Immunogenicity with Exposure, Safety and Efficacy ........................15 
5.8.1. 
Immunogenicity and Exposure ...................................................................................15 
5.8.2. 
Immunogenicity and Safety and Efficacy ...................................................................15 
6. 
SOFTWARE ...............................................................................................................15 
7. 
REFERENCES ...........................................................................................................16 
 
 
 
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Protocol: R2810-ONC-1763 
Statistical Analysis Plan 
Dec 6, 2020 
 
CONFIDENTIAL 
Page 5 of 16 
ABBREVIATIONS AND DEFINITION OF TERMS 
 
ADA      
   Anti-drug antibody 
AE 
               Adverse event 
AESI                Adverse event of special interest 
BOR                Best overall response 
CI                       Confidence interval 
CSR 
               Clinical study report 
CR 
               Complete response 
CRF 
               Case report form 
ECG                   Electrocardiogram 
ECOG                Eastern Cooperative Oncology Group 
EOS 
               End of study 
FAS 
               Full analysis set 
ICH                    International Council for Harmonization   
irAE                   Immune-related adverse event 
IWRS                Interactive web response system 
MedDRA 
   Medical Dictionary for Regulatory Activities 
NCI-CTCAE    National Cancer Institute-Common Terminology Criteria for Adverse Event 
NE 
               Not evaluable  
NSCLC 
   Non-small cell lung cancer 
ORR                Objective response rate 
OS 
              Overall survival 
PD 
              Progressive disease 
PD-1        
  Programmed death-1 (receptor) 
PD-L1     
  Programmed death ligand 1 
PFS 
              Progression-free survival 
PK 
              Pharmacokinetic  
PR 
              Partial response 
PT                     Preferred term 
Q3W               Every 3 weeks 
Q6W               Every 6 weeks 
RECIST   
  Response Evaluation Criteria in Solid Tumor 
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Regeneron Pharmaceuticals, Inc. 
Protocol: R2810-ONC-1763 
Statistical Analysis Plan 
Dec 6, 2020 
 
CONFIDENTIAL 
Page 6 of 16 
SAE 
              Serious adverse event 
SAF 
              Safety analysis set 
SAP 
              Statistical analysis plan 
SAS 
              Statistical Analysis Systems (software) 
SD 
              Stable disease 
SOC               System organ class 
TEAE      
  Treatment-emergent adverse event 
WHODD 
  World Health Organization Drug Dictionary 
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Protocol: R2810-ONC-1763 
Statistical Analysis Plan 
Dec 6, 2020 
 
CONFIDENTIAL 
Page 7 of 16 
1. 
OVERVIEW 
The purpose of the statistical analysis plan (SAP) is to ensure the credibility of the study results 
by pre-specifying the statistical approaches for the analysis of study data prior to database lock. 
The SAP is intended to be a comprehensive and detailed description of the strategy to be used in 
the analysis of data for R2810-ONC-1763 study (Study 1763). It is the first and final plan prior to 
database lock based on Study 1763 Protocol Amendment 2. 
Study 1763 is a phase 2, randomized, open-label study of high dose cemiplimab and standard dose 
cemiplimab plus ipilimumab combination therapy versus standard dose cemiplimab therapy in the 
second-line treatment of patients with advanced squamous or non-squamous non-small cell lung 
cancer (NSCLC).  
Due to program de-prioritization, the Sponsor decided to cease enrollment for this study, effective 
on 14 January 2019.  As a result, only 28 patients were randomized into the study. As enrollment 
to this study was terminated prematurely, the efficacy objectives stated in the study protocol will 
not be analyzed as planned. All statistical analyses will be exploratory in nature.  
1.1. 
Background/Rationale  
1.1.1. 
Background 
Lung cancer is one of the most commonly diagnosed cancers and is the leading cause of cancer-
related mortality worldwide (Siegel 2016, Bray 2013). NSCLC accounts for 80% to 85% of all 
lung cancers and is composed of several histopathological subtypes, the most common of which 
include adenocarcinoma (40% to 60%) and squamous cell carcinoma (30%). Most patients with 
NSCLC are found to have advanced cancer at the time of diagnosis (Leighl 2012). In recent years, 
immunotherapies have been investigated as potential therapeutic approaches that will improve 
long-term survival and quality of life (QOL) in patients with advanced NSCLC. 
Cemiplimab (REGN2810) is a human IgG4 monoclonal antibody (mAb) to the programmed cell 
death-1 (PD-1) receptor that blocks PD-1/ programmed death ligand 1(PD-L1) mediated T cell 
inhibition. Cemiplimab is being evaluated in more than 20 phase 1-3 clinical studies. Regeneron 
has initiated phase 2 and phase 3 trials of cemiplimab in several indications:  advanced or 
metastatic PD-L1 positive NSCLC, advanced cutaneous squamous cell carcinoma (CSCC), 
advanced basal cell carcinoma (BCC), and metastatic or recurrent cervical cancer after platinum-
based therapy. Cemiplimab has received approval in the United States (US) on 28 Sep 2018 and 
in the European Union (EU) on 28 Jun 2019 for the treatment of patients with metastatic CSCC or 
patients with locally advanced CSCC who are not candidates for curative surgery or curative 
radiation. In 2021, cemiplimab has received approval in US for the first-line treatment of patients 
with non-small cell lung cancer (NSCLC) expressing PD-L1 in ≥50% tumor cells and for the 
treatment of advanced BCC.   
1.1.2. 
Rationale  
The established superior efficacy of approved anti-PD-1 agents over standard-of-care in the 
second-line treatment of NSCLC, along with data suggesting cemiplimab is comparable in efficacy 
to other approved anti-PD-1 antibodies, provide compelling evidence to support the study of 
cemiplimab, either as monotherapy or in combination with other immunotherapy, as second-line 
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Protocol: R2810-ONC-1763 
Statistical Analysis Plan 
Dec 6, 2020 
 
CONFIDENTIAL 
Page 8 of 16 
treatment for NSCLC patients. Other approved anti-PD-1 or anti-PD-L1 antibodies which have 
established efficacy for second-line treatment of NSCLC suggest that they are particularly 
effective in patients with PD-L1 expression ≥ 50% of tumor cells. Thus, the original main goal of 
Study 1763 was to seek to specifically evaluate the efficacy of cemiplimab in patients with PD-L1 
expression in < 50% of tumor cells, where there is the greater need to improve outcome.  
1.2. 
Study Objectives  
The original primary, secondary and exploratory objectives of this study are described in  
Section 2 of the Study 1763 Protocol Amendment 2. Due to the early termination of enrollment 
into Study 1763 and a small sample size, the original objectives will not be analyzed as planned. 
The efficacy endpoints of objective response rate (ORR), duration of response (DOR), 
progression-free survival (PFS) and overall survival (OS) and will be summarized descriptively. 
No statistical comparisons will be performed. In addition, important demographics, baseline tumor 
characteristics, exposure, and TEAEs will be summarized. 
2. 
INVESTIGATION PLAN 
2.1. 
Study Design 
This is a phase 2, randomized, open-label study of high dose cemiplimab and standard dose 
cemiplimab plus ipilimumab combination therapy versus standard dose cemiplimab therapy in the 
second-line patients with NSCLC. Patients in this study include men and women ≥18 years of age, 
diagnosed with advanced non-squamous or squamous NSCLC who have received only 1 prior line 
of chemotherapy as treatment for their advanced disease. 
This study was originally designed to enroll 201 randomized patients with PD-L1 expression in 
<50% of tumor cells (67 patients per treatment arm) based on the assumptions specified in section 
10.2 of study protocol.  Due to program de-prioritization, the Sponsor decided to stop the 
enrollment into Study 1763 as of 14 January 2019 and to administratively close the study while 
allowing the enrolled subjects to continue with the study treatments.  A total of 28 patients were 
randomized to the three treatment arms as below: 
• 8 patients in Arm A (SDREGN2810) with treatment planned as cemiplimab 350 mg 
intravenous (IV) infusion every three weeks (Q3W)  
• 11 patients in Arm B (SDREGN2810 /ipi) with treatment planned as cemiplimab 
350 mg IV Q3W + ipilimumab 50 mg IV every six weeks (Q6W, on day 1 of every 
other treatment cycle of cemiplimab) for up to 4 doses   
• 9 patients in Arm C (HDREGN2810) with treatment planned as cemiplimab 1050 mg 
IV Q3W  
The treatment period for all the randomized patients is 108 weeks unless treatment is discontinued 
early due to RECIST 1.1-defined disease progression (PD), unacceptable toxicity, withdrawal of 
consent, initiation of another anti-cancer treatment. The approximate duration of the active study 
assessments for each patient, excluding screening, will be 25 to 31 months. This encompasses 25 
months of study treatment plus 6 months of follow-up. After the active study assessments are 
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Protocol: R2810-ONC-1763 
Statistical Analysis Plan 
Dec 6, 2020 
 
CONFIDENTIAL 
Page 9 of 16 
complete, all patients are followed for survival which will be collected every 3 months after follow-
up visit 1, until death, loss to follow-up, or withdrawal of study consent.  
3. 
ANALYSIS POPULATIONS 
In accordance with guidance from the International Conference of Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) guideline ICH E9 
Statistical Principles for Clinical Trials (ICH, 1998), all analyses except for pharmacokinetic and 
immunogenicity analyses, will be based on safety analysis set.    
3.1. 
Safety Analysis Set 
The safety analysis set (SAF) includes as all randomized patients who received any study 
treatment.   
3.2. 
Pharmacokinetic Analysis Set  
The PK population includes all randomized patients (safety population) who receive cemiplimab 
and who have at least 1 non-missing cemiplimab concentration assay result following the first dose 
of cemiplimab up to the end of the study. 
3.3. 
Immunogenicity Analysis Set  
The ADA analysis set (AAS) includes all treated patients who received any amount of study drug 
and had at least one non-missing ADA result following the first dose of study drug. The ADA 
analysis set is based on the actual treatment received (as treated) rather than as randomized. 
4. 
ANALYSIS VARIABLES 
4.1. 
Demographic and Baseline Disease  
Demographic variables include the following:  
• Age at screening (year) (quantitative and qualitative variable: <65, >=65 years) 
• Sex (Male, Female) 
• Race (American Indian/Alaskan Native, Asian, Black/African American, Native 
Hawaiian/Other Pacific Islander, White, and Other) 
• Ethnicity (Hispanic or Latino, Not Hispanic or Latino) 
• Height (cm) 
• Body weight (kg) 
• BMI (kg/𝑚2) 
• Smoking Status (Past smoker, Current smoker) 
• ECOG performance status (0, 1)  
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Regeneron Pharmaceuticals, Inc. 
Protocol: R2810-ONC-1763 
Statistical Analysis Plan 
Dec 6, 2020 
 
CONFIDENTIAL 
Page 10 of 16 
Baseline tumor characteristics include the following:  
• Histology (Non-squamous, Squamous) 
• Brain metastases status (Yes, No) 
• EGFR mutant (Mutant, Wildtype) 
• ALK translocation (Present, Not present) 
• ROS1 (Rearranged, not rearranged) 
• PD-L1 expression level (<1%, 1-49%, >=50%) 
• Cancer stage at screening 
4.2. 
Prior Treatment/Concomitant Medications and Procedures 
Medications will be coded to the ATC level 2 (therapeutic main group) and ATC level 4 
(chemical/therapeutic subgroup), according to WHO Drug Dictionary (WHODD).  
Prior medications/procedures: medications taken or procedures performed prior to administration 
of the study drug, including prior cancer-related systemic therapy, prior cancer-related surgery and 
prior cancer-related radiotherapy.  
Concomitant medications/procedures: medications taken or procedures performed from the time 
of informed consent until 90 days after the last study treatment will be considered concomitant 
treatment. This includes medications and other therapies for which administration started before 
the study and are ongoing during the study, as well as any therapies started in the follow-up period 
to treat a study drug-related AE.  
4.3. 
Efficacy Variables  
Objective response rate (ORR) will be based on both blinded independent review committee (IRC) 
and investigator assessment using the RECIST Version 1.1 (Eisenhauer 2009, see Appendix 2 in 
study protocol). ORR is defined as the number of patients with a best over response (BOR) of 
confirmed complete response (CR) or partial response (PR). BOR is defined as the best response, 
as determined per RECIST 1.1, between the date of randomization and the date of first documented 
tumor progression or the date of subsequent anti-cancer therapy, whichever comes first.  
Duration of response (DOR) will be determined for patients with best overall response of CR or 
PR. DOR is measured from the time measurement criteria are first met for CR/PR (whichever is 
first recorded) until the first date of recurrent of progressive disease (radiographic), or death due 
to any cause. Patients who never progress while being followed will be censored at the last valid 
tumor measurement (on or prior to the date of new anti-tumor therapy if applicable). 
Progression-free survival (PFS) is defined as the time from randomization to the date of the first 
documented tumor progression, or death due to any cause, whichever occurred earlier. PFS will 
be assessed by IRC and investigator assessment using RECIST 1.1. Patients will be censored 
according to the rules listed below: 
• Patients who do not have a documented tumor progression or death will be censored 
on the date of their last evaluable tumor assessment.   
                                        VV-RIM-00179240-1.0 Approved - 10 Dec 2021 GMT-5:00


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Protocol: R2810-ONC-1763 
Statistical Analysis Plan 
Dec 6, 2020 
 
CONFIDENTIAL 
Page 11 of 16 
• Patients who do not have a documented tumor progression or death before initiation 
of new anti-tumor therapy will be censored on the date of their last evaluable tumor 
assessment prior to or on the date of new anti-tumor therapy.  
• Patients who do not have any evaluable tumor assessments after randomization and 
do not die will be censored on the date of randomization. 
Overall survival (OS) is defined as the time from the date of randomization to the date of death 
due to any cause.  A patient who has not died will be censored at last known date of contact.   
4.4. 
Safety Variables  
Patient safety will be assessed through the collection of reported adverse events (AEs) and clinical 
laboratory data.  
4.4.1. 
Adverse Events and Serious Adverse Events  
An Adverse Event (AE) is any untoward medical occurrence in a patient or clinical investigation 
patient administered a study drug and which does not necessarily have to have a causal relationship 
with the study drug.  
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose according 
to the criteria specified in the study protocol Section 9.3.2. 
All AEs after initiation of study treatment and until 90 days after the last study treatment, 
regardless of relationship to study treatment, will be reported on the AE eCRF.  After signing the 
informed consent but prior to initiation of study drug, only the SAE and Non-SAEs associated 
with a protocol-mandated intervention (e.g., AEs related to an invasive procedure such as a biopsy) 
will be reported on the AE eCRF. Additionally, any SAE or other AE of concern that the 
investigator believes may be related to study drug and that occurs later than 90 days after last study 
treatment will be reported.  
The relationship of AEs to study drug will be assessed by the investigator and be determined based 
on protocol specified criteria. All adverse events are to be coded to a “Preferred Term (PT)” and 
associated primary “System Organ Class (SOC)” according to the Medical Dictionary for 
Regulatory Activities (MedDRA). 
4.4.2. 
Adverse Events of Special Interest   
An AE of special interest (AESI) are AEs (serious or non-serious) required to be monitored, 
documented, and managed in a pre-specified manner as described in the protocol. All AESIs will 
be reported within 24 hours of identification using the same reporting process as for SAE reporting. 
In this study, AESI are listed below (as provided in the protocol), along with each AESI detailed 
definition: 
• Grade 2 or greater infusion related reaction (IRR) 
• Grade 2 or greater allergic/hypersensitivity reactions 
• Grade 3 or greater immune-related adverse event (irAE) 
• irAEs of any grade in patients previously treated with PI3-K inhibitor 
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An IRR is any AE that occurs during or within 1 day after the infusion is completed.   
An irAE is any AE with unknown etiology associated with drug exposure and consistent with an 
immune phenomenon described in Section 7.3.3 of the study protocol.  
4.4.3. 
Laboratory Safety Variables  
The clinical laboratory data consists of serum chemistry, hematology, pregnancy test and other.  
4.5. 
Pharmacokinetic Variables 
Pharmacokinetic (PK) variables include cemiplimab concentrations in serum at each time point. 
4.6. 
Immunogenicity Variables  
The immunogenicity variables are ADA status, titer, and time-point/visit.  
5. 
STATISTICAL METHODS 
At the time of the administrative close-out of the study, a total of 28 patients were randomized. 
With limited data, there will be no statistical comparison in efficacy analysis. The scope of efficacy 
analyses at the time of administrative close-out of the study includes descriptive statistics of ORR, 
DOR, PFS, and OS. No comparison will be performed. In addition, important demographics, 
baseline tumor characteristics, exposure, and TEAEs will be summarized.  
For continuous variables, descriptive statistics will include the following: the number of patients 
reflected in the calculation (n), mean, median, standard deviation, minimum, and maximum. 
For categorical or ordinal data, frequencies and percentages will be displayed for each category. 
The denominator will be determined by the analysis population used for the summary. 
5.1. 
Patient Disposition 
For patient disposition, the following summaries will be provided based on SAF population by 
treatment arm: 
• The total number of screened patients 
• The total number of patients in the SAF by treatment arm  
• The total number of patients who discontinued treatment and the primary reasons for 
treatment discontinuation 
• The total number of patients who discontinued study and the primary reasons for 
study discontinuation 
5.2. 
Demographics and Baseline Disease Characteristics  
Patients demographics and baseline tumor characteristics variables given in Section 4.1 will be 
summarized by treatment arm based on the SAF population.  
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5.3. 
Prior/Concomitant Medications/Procedures 
Prior cancer related therapy will be summarized based on SAF population by treatment arm.   
5.4. 
Exposure to Investigational Product 
Exposure will be summarized based on SAF by treatment arm and include the following: 
• Duration of exposure (in weeks)  
• Number of doses administered  
The number of patients exposed will be presented by specific time point periods (e.g., weeks 3, 6 
, 12, 18, 24, 36, 48, 72 and 108) for each treatment arm.  
5.5. 
Analyses of Efficacy Data 
The analysis of all efficacy variables will be based on the SAF population by treatment arm.  
ORR and the corresponding 95% exact confidence interval (CI) will be calculated by Clopper-
Pearson method (Clopper 1934).  
Best overall response: CR/PR/SD/PD/NE will be summarized by treatment arm: 
• Not evaluated response includes the missing and unknown response 
• CR/PR must be confirmed by repeated assessments no less than 4 weeks apart 
• SD criteria must be met at least once for a minimum duration of 39 days (7 days/week 
* 6 weeks – 3 days) after first dose date 
DOR will be summarized for confirmed responders (CR or PR) using Kaplan-Meier method by 
treatment arm. Median DOR along with its 95% CI will be presented using Kaplan-Meier method 
for each treatment arm. The Kaplan-Meier curves will be displayed by treatment arm. 
Observed DOR will be summarized for confirmed responders (CR or PR) by treatment arm. 
The distribution of PFS and OS will be estimated using the Kaplan-Meier method based on SAF, 
respectively. The median OS and PFS along with their 95% CI will be presented by treatment arm, 
respectively. The Kaplan-Meier curves will be displayed by treatment arm.  
No statistical tests will be performed to compare the treatment difference in ORR, DOR, PFS, or 
OS.   
5.6. 
Analysis of Safety Data 
The analysis of safety will be performed by treatment arm based on the SAF.  
5.6.1. 
Adverse Events 
For safety variables, 3 observation periods are defined as follows: 
• The pre-treatment period is defined as the time from signing the informed consent 
form (ICF) to before the first dose of study drug. 
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• The on-treatment period is defined as the time from the day of first dose of study drug 
to the day of the last dose of study drug plus 90 days, or to 1 day before patients 
receive another new anti-cancer systemic therapy, whichever earlier.  
• The post-treatment period is defined as the time starting 1 day after the end of on-
treatment period. 
The focus of adverse event reporting will be on treatment-emergent adverse events (TEAEs). 
TEAEs are the AEs that developed or worsened during the on-treatment period and any treatment-
related AEs that occur during the post-treatment period. Summaries of TEAEs will include TEAEs, 
treatment related TEAEs, serious TEAEs, TEAEs leading to permanent treatment discontinuation, 
and TEAEs leading to death. The number and proportions of patients reporting at least 1 AE will 
be presented by SOC, PT and NCI grade. Counts will be provided for each PT within each SOC.  
Percentages will be calculated using the number of patients from the SAF. 
5.7. 
Analysis of Pharmacokinetic and Immunogenicity Data  
5.7.1. 
Analysis of Pharmacokinetic Data 
Cemiplimab concentrations in the serum of patients randomized to all the three treatment Arms 
will be reported at multiple time points throughout the treatment and follow-up periods. 
Cemiplimab concentrations over time and pharmacokinetic parameters will be summarized with 
descriptive statistics.  
5.7.2. 
Analysis of Immunogenicity Data 
The immunogenicity variables ADA status and titer by time-point/visit will be summarized using 
descriptive statistics. Immunogenicity will be characterized by ADA status, ADA category and 
maximum titer observed in patients in the ADA analysis sets.  
The ADA status of each patient may be classified as one of the following:   
• Positive  
• Pre-existing - If the baseline sample is positive and all post baseline ADA titers are 
reported as less than 9-fold the baseline titer value  
• Negative - If all samples are found to be negative in the ADA assay.  
 The ADA category of each positive patient is classified as:  
• Treatment-boosted - A positive result at baseline in the ADA assay with at least one 
post baseline titer result ≥9-fold the baseline titer value   
• Treatment-emergent - A negative result or missing result at baseline with at least one 
positive post baseline result in the ADA assay. 
The maximum titer category of each patient is classified as:  
• Low (titer <1,000)  
• Moderate (1,000 ≤ titer ≤ 10,000)  
• High (titer >10,000)  
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 The following will be summarized by treatment group and ADA titer level:  
• Number (n) and percent (%) of ADA-negative patients 
• Number (n) and percent (%) of pre-existing patients 
• Number (n) and percent (%) of treatment-emergent ADA positive patients 
• Number (n) and percent (%) of treatment-boosted ADA positive patients 
 Listing of all ADA titer levels will be provided for patients with pre-existing, treatment-emergent 
and treatment-boosted ADA response.  
5.8. 
Association of Immunogenicity with Exposure, Safety and Efficacy 
5.8.1. 
Immunogenicity and Exposure 
Potential association between immunogenicity variables and systemic exposure to REGN2810 will 
be explored by treatment groups. Plots of individual REGN2810 concentration time profiles may 
be provided to examine the potential impact of ADA category and maximum titer category on 
these profiles.  
5.8.2. 
Immunogenicity and Safety and Efficacy 
Potential association between immunogenicity variables and safety or efficacy may be explored, 
as appropriate. 
6. 
SOFTWARE  
All analyses will be done using SAS Version 9.4 or above.
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7. 
REFERENCES  
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Clopper, C. & Pearson, E.S. (1934). ‘The use of confidence or fiducial limits illustrated in the case 
of the binomial’, Biometrika, 404 – 413.  
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response 
evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009; 
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Ettinger DS, Wood DE, Akerley W, Bazhenova LA, Borghaei H, Camidge DR, et al. NCCN 
Guidelines insights: non-small cell lung cancer, version 4.2016. J Natl Compr Canc Netw 2016; 
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Leighl NB. Treatment paradigms for patients with metastatic non-small-cell lung cancer: first-, 
second-, and third-line. Curr Oncol 2012;19: S52-8.ICH. 
ICH Harmonized tripartite guideline: Statistical principles for clinical trials (E9). International 
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Human Use 1998. 
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin 2016; 66:7-30. 
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