A Randomized, Open-Label, Phase 2 Trial of CMB305 (Sequentially Administered LV305 and G305) and Atezolizumab in Patients With Locally Advanced, Relapsed, or Metastatic Sarcoma Expressing NY-ESO-1
Phase: PHASE2
Conditions: Sarcoma, Myxoid/Round Cell Liposarcoma, Synovial Sarcoma, Metastatic Sarcoma, Recurrent Adult Soft Tissue Sarcoma, Locally Advanced Sarcoma, Liposarcoma
Sponsor: Immune Design, a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)

Offici al Pr ot oc ol Title:  
N C T n u m ber:  
N C T 0 2 6 0 9 9 8 4
0 8- Marc h- 2 0 1 7
D oc u me nt D ate:  
A 
Ra n d o mize d, 
O pe n- La bel, 
P hase 
2 
Trial 
of 
C M B 3 0 5 
( Se q ue ntiall y A d mi nistere d L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u ma b 
i n Patie nts 
wit h L ocall y 
A d va nce d, 
Rela pse d, or 
Metastatic 
Sarc o ma E x pressi n g N Y- E S O- 1

C L O -5 1. 0 0 2 V 0 3  
P a ge 1  of 1 2 8  
 
 
 
C LI NI C A L P R O T O C O L  
 
A R a n d o mize d, O pe n -L a bel, P h ase 2 Tri al of C M B 3 0 5 ( Se q ue nti all y 
A d mi nistere d L V 3 0 5 a n d G 3 0 5) a n d A tez oliz u m a b i n P atie nts wit h L oc all y 
A d v a nce d, Rel a pse d, or Met ast atic S arc o m a E x pressi n g N Y -E S O - 1 
 
Pr ot oc ol N u m ber  
I M D Z- C 2 3 2 
I n vesti g ati o n al A ge nt 
C M B 3 0 5 ( L V 3 0 5 [le nti viral vect or e x pressi n g N Y- E S O - 1 
ge n e] a n d G 3 0 5 [ N Y- E S O - 1 rec o m bi na nt pr otei n pl us 
G L A -S E]) i n c o m bi nati o n wit h atez oliz u ma b 
S p o ns or  
I m m u ne Desi g n  
1 6 1 6 Eastla ke A ve. E, S uite 3 1 0 
Seattle, W A 9 8 1 0 2 
Tri al Re gistr ati o n  N u m bers  
Cli nical Trials. g o v #: N C T 0 2 6 0 9 9 8 4 
B B I N D : 1 6 5 8 9 
Versi o n a n d D ate 
Versi o n 0 3, 0 8 Marc h  2 0 1 7 
 
 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 2  of 1 2 8  
 
I N V E S TI G A T O R A G R E E M EN T P A G E  
I n vesti gat or: 
 
 
St u d y N u m ber : 
I M D Z-C 2 3 2  
Pr o d uct Na me:  
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d atez oliz u ma b 
St u d y Title:  
A Ra n d o mize d, O pe n- La bel, P hase 2 Trial of C M B 3 0 5 ( Se q ue ntiall y A d mi nistere d 
L V 3 0 5 a n d G 3 0 5) a n d A tez oliz u ma b i n Patie nts wit h L ocall y A d va nce d, Rela pse d, 
or Metastatic Sarc o ma E x pressi n g N Y -E S O -1  
D oc u me nt Date: 0 8  Marc h  2 0 1 7  
 
As Pri nci pal  I n vesti gat or, I a gree t o t he f oll o wi n g: 
•  
Kee p all d oc u m e ntati o n s u p plie d t o me or de vel o p e d b y m e c o ncer ni n g t his st u d y, a n d t hat 
has n ot bee n pr e vi o usl y p u blis he d, i n t he strictest c o nfi de nce. T his d oc u m e ntati o n i ncl u des, 
b ut is n ot li mite d t o, t he I n vesti gat or’s Br oc h u re (I B) a n d C ase Re p ort F or ms ( C R Fs). 
•  
T hat t he st u d y will n ot c o m me nce wit h o ut pri or writte n a p pr o val of a pr o perl y c o nstit ute d 
I nstit uti o nal Re vie w B oar d (I R B). N o c h a n ges will be ma de t o t he st u d y pr ot oc ol or c o nse nt 
f or ms wit h o ut pri or writte n a p pr o val of I m m u ne Desi g n a n d t he I nstit uti o nal Re vie w B o ar d, 
e x ce pt w here n ecess ar y t o eli mi nate a n i m me diate hazar d t o patie nts . 
•  
I m ple me nt a n d c o n d uct t he st u d y dili ge ntl y a n d i n strict c o m plia nce wit h t he pr ot oc ol, g o o d 
cli nical practices , a n d all a p plica ble la w s a n d re g ul ati o ns. 
•  
Acc ur atel y tra nsf er all r e q uire d data fr o m eac h patie nt’s s o urce d o c u me ntati o n  t o t he C R Fs. 
T he ori gi nal C R Fs will be s u b mitte d t o t he S p o ns or i n a ti mel y ma n n er at t he c o m pleti o n of 
t he trial, or as ot her wise s pecifie d b y t he S p o ns or. 
•  
Kee p a c o m plete a n d acc urate acc o u nti n g d uri n g a n d at t he c o m pleti o n of t he trial of all 
pr oce d ur es perf or me d wit h t he dr u g pr o vi de d b y t he S p o ns or. 
•  
All o w a ut h orize d re pres e ntati ves of I m m u n e Desi g n or re g ulat or y a ut h orit y re pres e ntati ves 
t o c o n d uct o n-site visits t o recei v e, re vi e w, a u dit, a n d c o p y trial d oc u me nts. I will pers o nall y 
meet wit h t hese re prese nt ati ves at m ut uall y c o n v e nie nt ti mes t o a ns wer a n y trial -relate d 
q uesti o ns. 
•  
Pr o vi de t he S p o ns or wit h a n I n vesti gat or’s s u m mar y wit hi n 9 0 da ys of c o m pleti o n of t he 
fi nal trial visit f or t he last patie nt e nr olle d, or as desi g nate d b y S p o ns or. 
•  
Mai ntai n all i nf or mati o n s u p plie d b y t he S p o ns or i n c o nfi de nce a n d, w h e n t his i nf or mati o n is 
s u b mitte d t o a n I R B, Et hical Re vie w C o m mittee, or a n ot her gr o u p, it will be s u b mitte d wit h 
a desi g n ati o n t hat t he material is c o nfi de ntial. 
T his pr ot oc ol was desi g n e d a n d will be c o n d u cte d, rec or d e d, a n d re p orte d i n c o m plia nce wit h t he 
pri nci ples of G o o d Cli nical Practice ( G C P) g ui d eli nes. T hese g ui deli nes are state d i n U. S. fe deral 
re g ulati o ns as well as “ G ui da nce f or G o o d Cli nical Practice,” I nter nati o nal C o nfere nce o n 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 3  of 1 2 8  
 
Har m o nisati o n (I C H) of Tec h nical Re q uire me nts f or Re gistrati o n of P har mace uticals f or H u ma n 
Use.  
I h a ve r ea d t his pr ot oc ol i n its e ntiret y, i ncl u di n g t he prece di n g state me nts, a n d I a gree t o c o m pl y 
wit h all as pects of t his trial.  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
I n v esti gat or Pri nte d Na m e 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
I n v esti gat or Si g nat ure   
  
  
  
 
Date  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
I nstit uti o n Na me 
 
 
 
 
 
 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 4  of 1 2 8  
 
S T U D Y S Y N O P SI S  
Title  
A Ra n d o mize d, O pe n- La bel, P hase 2 Trial of C M B 3 0 5 ( Se q ue ntiall y 
A d mi nister e d L V 3 0 5 a n d G 3 0 5) a n d A tez oliz u ma b i n Patie nts wit h L ocall y 
A d va nce d, Rela pse d, or Metastatic Sarc o ma E x pressi n g N Y -E S O - 1 
S p o ns or  
I m m u ne Desi g n 
Tri al Sites  
U p t o 2 0 sites i n t he Unite d S tates a n d Ca na da  
Tri al P h ase  
P hase 2  
I n vesti g ati o n al Dr u g 
P r o d uct s 
C M B 3 0 5 ( L V 3 0 5 [le nti viral vect or e x pressi n g N Y -E S O - 1] a n d G 3 0 5 [ N Y-E S O -
1 rec o m bi na nt pr otei n pl us gl uc o p yra n os yl li pi d A sta ble e m ulsi o n { G L A -S E } ]) 
T he d ose of L V 3 0 5 will c o n sist of 1 × 1 0 1 0 viral ge n o mes ( v g ) a d mi nistere d 
i ntra der mall y (I D). G 3 0 5 will c o nsist of G L A-S E ( 5  μ g) mi xe d wit h 2 5 0 μ g of 
N Y -E S O - 1 pr otei n a d mi nistere d i ntra m usc ularl y (I M) . 
A tez oliz u ma b (f or merl y M P D L 3 2 8 0 A, R oc he). A nti -pr o gra m me d deat h li ga n d - 1 
(a nti-P D -L 1 ) will be a d mi nistere d at a d ose of 1 2 0 0 m g/ da y i ntra ve n o us (I V) 
e ver y 3 wee ks i n c o m bi nati o n wit h C M B 3 0 5 or al o ne. 
P ur p ose a n d St u d y 
R ati o n ale 
T his st u d y will i n vesti gate a d di n g a pri me -b o ost i m m u n ot hera pe utic re gi me n 
( C M B 3 0 5) t hat ca n i n d uce N Y-E S O - 1-s pecific C D 8 T cells t o c o m ple me nt t he 
bl oc ka de of t he P D- L 1 c hec k p oi nt i n t he treat me nt of patie nts wit h l ocall y 
a d va nce d, rela pse d, or metastatic sarc o ma.  Precli nical st u dies ha ve de m o nstrate d 
t hat se q ue ntial d osi n g of L V 3 0 5 f oll o we d b y G 3 0 5 ca n i ncrease a nti -t u m or 
cell ular i m m u ne res p o nses o ver eac h a ge nt al o ne. Treat me nt c o m bi ne d wit h a n 
a nti-pr o gra m me d deat h rece pt or  li ga n d- 1 (a nti-P D - L 1) pr o d uct ma y 
s y ner gisticall y i ncrease t he effect.  
O bjecti ves  
Pri m ar y O bjecti ve  
•  
T o e val uate o verall s ur vi val ( O S) a n d pr o gressi o n -free s ur vi val ( P F S) wit h 
C M B 3 0 5 (se q ue ntiall y a d mi nistere d L V 3 0 5 a n d G 3 0 5) i n c o m bi nati o n wit h 
atez oliz u ma b or wit h  atez oliz u ma b al o ne, i n patie nts wit h l ocall y a d va nce d, 
rela pse d, or metastatic sarc o ma e x pressi n g N Y-E S O - 1 
Sec o n d ar y O b jecti ve 
•  
T o e val uate t he safet y of C M B 3 0 5 i n c o m bi nati o n wit h atez oliz u ma b a n d 
atez oliz u ma b al o ne i n patie nts wit h l ocall y a d va nce d, rela pse d, or metastatic 
sarc o ma e x pressi n g N Y-E S O - 1 
•  
T o e val uate  pr o gressi o n -free s ur vi val rates at 6 m o nt hs after start of st u d y 
treat me nt ( Da y 0) 
•  
T o e val uate t he i m m u ne res p o nse a n d hist ol o gic a n d m olec ular tiss ue 
c ha n ges i n t he t u m or tiss ue a n d peri p heral bl o o d 
•  
T o e val uate t he ti me t o ne xt treat me nt ( T T N T)  
•  
T o e val uate t he dista nt metastasis free s ur vi val ( D M F S)  
E x pl or at or y O bjecti ves  
•  
T o c o m pare efficac y assess me nts, s uc h as t u m or gr o wt h rate  ( T G R), a n d 
pr o gressi o n arrest rate  ( P A R) 
•  
T o c o m pare  P F S a n d O S  bet wee n treat me nt ar ms  
•  
T o e val uate t he i m m u n o ge nicit y of C M B 3 0 5 i n c o m bi nati o n wit h 
atez oliz u ma b c o m pare d t o atez oliz u ma b al o ne 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 5  of 1 2 8  
 
•  
T o e val uate a vaila ble pre -, o n-, a n d p ost-treat me nt t u m or tiss ue a n d bl o o d 
f or hist ol o gic, i m m u n o hist ol o gic, a n d ge n o mic mar kers 
•  
T o e val uate t he best o verall res p o nse rate ( O R R; b y Res p o nse E val uati o n 
Criteria i n S oli d T u m ors [ R E CI S T ] v 1 . 1 m o difie d t o use i m m u ne-relate d 
Res p o nse Criteria [ir R C]) a n d d urati o n of res p o nse ( D O R) 
•  
T o e val uate t he cli nical be nefit rate ( C B R)  
•  
T o e val uate t he q ualit y of life as a c o m p osite e n d p oi nt i ncl u di n g b ut n ot 
li mite d t o t he f oll o wi n g: w hile o n st u d y, t he inci de nce of h os pitalizati o n, 
tra nsf usi o ns, a n d la b orat or y mar kers (e g. a bs ol ute ne utr o p hil c o u nt, 
he m o gl o bi n, a n d plat elets) 
St u d y Desi g n  
T his is a ra n d o mize d, o pe n- la bel, P hase 2 trial of C M B 3 0 5, a re gi me n of L V 3 0 5 
a n d G 3 0 5, i n c o m bi nati o n wit h atez oliz u ma b or wit h  atez oliz u ma b al o ne i n 
patie nts wit h sarc o ma w h o ha ve ha d a n i na de q uate res p o nse, rela pse, a n d/ or 
u nacce pta ble t o xicit y wit h o ne or m ore pri or s yste mic, s ur gical , or ra diati o n 
ca ncer t hera pies.  T his st u d y will i n vesti gate w het her  a d di n g a pri me - b o ost 
i m m u n ot hera pe utic re gi me n ca n i n d uce N Y-E S O - 1-s p ecific C D 8 T cells t o 
a u g me nt t he cli nical efficac y of P D - 1 bl oc ka de.  F or t he c o m bi ne d treat me nt 
ar m, t he trial will be c o n d ucte d i n 4 p hases: Treat me nt P hase (st u d y Da ys 0 t o 
8 4), B o oster P ha se (p ost Da y  8 4 t o 1 year p ost Da y 0), Mai nte na nce P hase (fr o m 
1 year t o 2 years p ost Da y 0 ), a n d S ur vi val F oll o w- u p P hase ( q uarterl y 
t hereafter) (T a ble  1).  F or t he c o ntr ol ar m, t he trial will be c o n d ucte d i n 3 p hases: 
Treat me nt P hase (st u d y Da ys 0 t o 8 4), Mai nte na nce P hase ( p ost Da y 8 4 t o 2 
years p ost Da y 0 ), a n d S ur vi val F oll o w- u p P hase  ( q uarterl y t hereafter).  W hile 
t he st u d y will be o pe n-la bel, t u m or res p o nses will be a dj u dicate d b y bli n de d 
i n de pe n de nt ce ntralize d re vie w t o mi ni mize bias, if re q ueste d b y t he S p o ns or. 
U p t o 1 2 patie nts will be ra n d o mize d i n 1: 1 all ocati o n rati o t o recei ve C M B 3 0 5 
wit h atez oliz u ma b or atez oliz u ma b al o ne i n a Safet y R u n-i n, t he n patie nts will be 
ra n d o mize d i n a 1: 1 all ocati o n rati o. A p pr o xi matel y 8 0 patie nts ( 4 0 patie nts  per 
treat me nt ar m) will be e nr olle d.  Ra n d o mizati o n will be stratifie d b y disea se 
t y pe. Arc hi val t u m or s peci me ns will be o btai ne d fr o m all patie nts t o deter mi ne 
P D - L 1 m olec ular stat us. 
All patie nts will ha ve t u m or sa m ples scree ne d f or e x pressi o n of N Y -E S O - 1 f or 
eli gi bilit y. I ma gi n g will be perf or me d a p pr o xi matel y e ver y 6 wee ks  f or 1 2 
m o nt hs, t he n e ver y 1 2 wee ks f or t u m or sta gi n g u ntil pr o gressi o n. T u m or 
res p o nses will be assesse d b y R E CI S T v 1. 1 m o difie d t o use ir R C-s pecifie d 
c o nfir mati o n a n d u ni di me nsi o nal t u m or meas ure me nts. Patie nts will be f oll o we d 
o n st u d y u ntil c o nfir me d ra di o gra p hic pr o gressi o n t o deter mi ne O R R a n d P F S. I n 
a d diti o n, O S will be c ollecte d . F or patie nt deat hs , t he date of deat h will be 
d oc u me nte d b y t he l ocal p h ysicia n a n d/ or re gistries.  
I n t he c o m bi nati o n treat me nt ar m, C M B 3 0 5 treat me nt c o nsist s of 2 d oses  of 
L V 3 0 5 a d mi nistere d o n Da ys 0 a n d 1 4, f oll o we d e ver y 2 wee ks wit h alter nati n g 
d oses of G 3 0 5 a n d L V 3 0 5 (Fi g ure  1). I n t otal, 4 d oses of L V 3 0 5 a n d 3 d oses of 
G 3 0 5 will be a d mi nistere d o ver a peri o d of 3 m o nt hs. L V 3 0 5 will be 
a d mi nistere d I D at a d ose of 1  × 1 0 1 0 v g a n d G 3 0 5 will a d mi nistere d I M at a d ose 
of 5 μ g G L A -S E  mi xe d wit h 2 5 0 μ g of N Y-E S O - 1 pr otei n. Atez oliz u ma b 
( 1 2 0 0 m g/ d ose) will be a d mi nistere d I V e ver y 3 wee ks a n d ma y be c o nti n ue d u p 
t o 2 years u ntil t o xicit y de vel o ps or c o nfir me d pr o gressi o n. I n a d diti o n, a G 3 0 5 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 6  of 1 2 8  
 
b o oster d ose will be  gi ve n e ver y 6 wee ks i n t he first year u ntil c o nfir me d disease 
pr o gressi o n (t o c oi nci de wit h t he sta gi n g f oll o w- u p visit).  
Peri p heral bl o o d will be c ollecte d f or i m m u n o ge nicit y assa ys  at baseli ne, t he n o n 
Da y s 4 2 a n d 7 0, a n d o n Da y 9 8 ( ± 2 wee ks) .  Tiss ue bi o psies will be ta ke n 
bef ore treat me nt a n d o n Da y 4 2 , o n Da y 9 8 ( ± 2 wee ks) , at 6 m o nt hs or l o n ger 
(f or patie nts wit h treat me nt res p o nse), a n d at t he ti me of pr o gressi o n t o assess 
i m m u ne cell i n vasi o n, i ncl u di n g c ha n ges i n P D- L 1, C D 4, C D 8/ Ki- 6 7, a n d/ or 
C D 3/ perf ori n e x pressi o n. If a patie nt u n der g oes a t u m or bi o ps y at a n y ti me after 
disease pr o gr essi o n, i n vesti gat ors are str o n gl y e nc o ura ge d t o pr o vi de bi o ps y 
tiss ue t o t he s p o ns or f or i m m u ne res p o nse a n d t u m or c ha n ges a nal ysis. 
Bl o o d will be c ollecte d t o test f or L V 3 0 5 persiste nce at baseli ne, a n d 6, 1 2, a n d 
2 4 m o nt hs (if re q uire d) f oll o wi n g t he first st u d y treat me nt a d mi nistrati o n. 
De pe n di n g o n t he res ults fr o m t he 1 2- m o nt h sa m ple, a n n ual assess me nts ma y 
c o nti n ue u ntil 2 c o nsec uti ve sa m ples s h o w n o e vi de nce of L V 3 0 5 persiste nce. 
All seri o us a d verse e ve nts ( S A Es) a n d me dical e ve nts of i nterest ( M E OI s) 
dee me d p ote ntiall y relate d t o t he st u d y a ge nts will be re vie we d b y t he S p o ns or 
a n d a n i n de pe n de nt Data M o nit ori n g C o m mittee ( D M C). 
D osi n g i nterr u pti o ns are per mitte d i n t he case of me dical/ s ur gical e ve nts or 
l o gistical reas o ns n ot relate d t o st u d y t hera p y (e. g., electi ve s ur ger y, u nrelate d 
me dical e ve nts, patie nt vacati o n, a n d/ or h oli da ys). S u bjects s h o ul d res u me st u d y 
t hera p y wit hi n 3 wee ks of t he sc he d ule d i nterr u pti o n, u nless ot her wise disc usse d 
wit h t he S p o ns or. T he reas o n f or i nterr u pti o n s h o ul d be d oc u me nte d i n t he 
patie nt's st u d y rec or d.  Patie nts ma y c o nti n ue treat me nt i n t he a bse nce of 
s y m pt o matic pr o gressi o n base d o n t he criteria i n Secti o n 6. 3 . 
 
S afet y R u n -i n 
T he first 6 patie nts will be ra n d o mize d 1: 1 t o recei ve C M B 3 0 5 i n c o m bi nati o n 
wit h atez oliz u ma b or atez oliz u ma b al o ne ( usi n g a bl oc k size of 6) t o i n vesti gate 
t he safet y of t he se q ue ntial c o m bi nati o n. T he 3 patie nts  i n t he c o m bi nati o n ar m 
will be o bs er ve d f or treat me nt -e mer ge nt d ose-li miti n g t o xicities ( D L Ts) i n t he 
first 4 2 da ys of t hera p y. D uri n g t he safet y o bser vati o n peri o d, all S A E a n d D L T 
safet y e ve nts dee me d p ote ntiall y relate d t o t he st u d y a ge nts will be re vie we d b y 
t he S p o ns or a n d t he i n de pe nde nt D M C. If n o D L Ts are o bser ve d i n t he 
c o m bi nati o n ar m, e nr oll me nt of patie nts i nt o t he re mai n der of t he st u d y will 
c o m me nce. 
If 1 of t he 3 patie nts i n t he c o m bi nati o n treat me nt ar m e x perie nces a D L T d uri n g 
t he safet y “r u n-i n” e val uati o n, a n a d diti o nal 6 patie nts will be ra n d o mize d  ( 1: 1). 
If 2 or m ore of t he 6 patie nts i n t he c o m bi nati o n treat me nt ar m e x perie nce D L Ts, 
d osi n g i n t he C M B 3 0 5/ atez oliz u ma b treat me nt ar m will st o p, a n d t he safet y of 
t he c o m bi nati o n will be re vie we d b y t he S p o ns or a n d t he i n de pen de nt D M C. 
Base d o n t his re vie w, t he D M C ma y rec o m me n d, a n d t he S p o ns or ma y c h o ose, 
t o re d uce t he d ose of o ne or m ore c o m p o ne nts of C M B 3 0 5 ( d ose de-escalati o n) 
a n d treat a n a d diti o nal 3 t o 6 patie nts wit h t he c o m bi nati o n treat me nt re gi me n 
f oll o wi n g t he sa me 3 + 3 desi g n, or t he y ma y rec o m me n d st o p pi n g t he c o m bi ne d 
treat me nt. S h o ul d a l o wer d ose pr o ve t o be safe, patie nt e nr oll me nt i n t he 
ra n d o mize d treat me nt ar ms will c o m me nce usi n g t he l o wer d ose of t hat 
c o m p o ne nt. F oll o wi n g e val uati o n b y t he D M C a n d t he s p o ns or, a m o dificati o n t o 
t he d ose/treat me nt sc he d ule c o ul d be rec o m me n de d.  

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 7  of 1 2 8  
 
D ur ati o n of P atie nt 
P artici p ati o n  
T he e x pecte d d urati o n of a patie nt’s partici pati o n o n st u d y treat me nt is u p t o 2. 1 
years ; t his i ncl u des Scree ni n g, Treat me nt P hase , B o oster P hase (f or patie nts i n 
t he c o m bi ne d treat me nt ar m), a n d Mai nte na nce P hase .  O nce treat me nt is 
c o m plete d, or o nce patie nts ha ve pr o gresse d  or disc o nti n ue d treat me nt f or ot her 
reas o ns, patie nts  will e nter t he S ur vi val F oll o w - u p P hase d uri n g w hic h t he ir 
disease a n d s ur vi val stat us will be c ollecte d  e ver y 3 m o nt hs b y tele p h o ne u ntil 
t he st u d y is c o m plete d (last patie nt, last deat h i n t he st u d y).   
P atie nt P o p ul ati o n  
Patie nts wit h l ocall y a d va nce d, rela pse d, or metastatic sarc o ma p ost sta n dar d 
t hera p y wh o ha ve meas ura ble disease a n d w h ose t u m or e x presses N Y -E S O - 1, as 
detecte d b y i m m u n o hist oc he mistr y (I H C). 
I ncl usi o n Criteri a 
1.  L ocall y a d va nce d, rela pse d, or metastatic sarc o ma wit h meas ura ble t u m or 
b ur de n f oll o wi n g t hera p y, as defi ne d b y R E CI S T v 1. 1; t he t otal of all lesi o ns 
m ust be ≤ 1 2 c m (f or s y n o vial sarc o ma) or ≤1 5 c m (f or m y x oi d/r o u n d cell 
li p osarc o ma [M R C L ]). 
2.  T u m or hist ol o g y c o nsiste nt wit h s y n o vial sarc o ma or M R C L . 
3.  T u m or s peci me n p ositi ve f or N Y- E S O - 1 e x pressi o n b y I H C. 
4.  I na de q uate res p o nse, rela pse, a n d/ or u nacce pta ble t o xicit y wit h o ne or m ore 
pri or s yste mic, s ur gical, or ra diati o n ca ncer t hera pies . 
5.  Ha ve res ol uti o n of t o xic effect(s) of t he m ost rece nt pri or t hera p y t o Gra de  1 
or less (e xce pt Gra de  2 or less ne ur o pat h y or al o pecia). If s u bject recei ve d 
maj or s ur ger y or ra diati o n t hera p y, t he y m ust ha ve rec o vere d fr o m t he 
t o xicit y a n d/ or c o m plicati o ns fr o m t he i nter ve nti o n. 
6.  ≥1 8 years of a ge bef ore t he first sc he d ule d d ose . 
7.  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 of 0 or 1. 
8.  E C G wit h o ut e vi de nce of cli nicall y si g nifica nt a b n or malit y . 
9.  If fe male of c hil d beari n g p ote ntial ( F C B P), willi n g t o u n der g o pre g na nc y 
testi n g a n d a grees t o use at least 2 a de q uate barrier c o ntrace pti ve met h o ds 
d uri n g t he d osi n g peri o d a n d f or 9 0 da ys after  t he last i nj ecti o n of C M B 3 0 5 
or atez oliz u ma b. 
1 0.  If male a n d se x uall y acti ve wit h a F C B P, m ust a gree t o use hi g hl y effecti ve 
c o ntrace pti o n s uc h as late x c o n d o m d uri n g t he d osi n g peri o d a n d f or t hree 
m o nt hs after last C M B 3 0 5 i njecti o n . 
N ote : A bsti ne nce is acce pta ble f or eit her ge n der if t his is t he esta blis he d a n d 
preferre d c o ntrace pti o n f or t he s u bject.  
E xcl usi o n Criteri a  
1.  I n vesti gati o nal t hera p y wit hi n 4 wee ks pri or t o C M B 3 0 5 d osi n g. 
2.  Pri or a d mi nistrati o n of ot her N Y -E S O - 1-tar geti n g i m m u n ot hera pe utics. 
3.  Pri or treat me nt wit h C D 1 3 7 a g o nists or i m m u ne c hec k p oi nt bl oc ka de 
t hera pies, i ncl u di n g a nti-C T L A - 4, a nti P D- 1, a n d a nti P D-L 1 t hera pe utic 
a nti b o dies, or a n y ot her a nti b o d y or dr u g tar geti n g T- cell c osti m ulati o n. 
4.  Treat me nt wit h s yste mic i m m u n osti m ulat or y a ge nts ( i ncl u di n g b ut n ot 
li mite d t o i nterle u ki n- 2) wit hi n 4 wee ks or fi ve half -li ves of t he dr u g, 
w hic he ver is s h orter, pri or  t o first d ose. 
5.  Si g nifica nt i m m u n os u p pressi o n fr o m:  

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 8  of 1 2 8  
 
a. C o nc urre nt, rece nt ( ≤ 3  wee ks pri or t o t he first sc he d ule d osi n g ) or 
a ntici pate d nee d f or treat me nt wit h s yste mic c ortic oster oi ds (t he use of 
p h ysi ol o gic d oses of c ortic oster oi ds ma y be a p pr o ve d after c o ns ultati o n 
wit h t he S p o ns or). T he use of t o pical or i n hale d c ortic oster oi ds a n d 
mi neral oc ortic oi ds (e. g., fl u dr oc ortis o ne) is all o we d.  
b.  Ot he r i m m u n os u p pressi ve me dicati o ns ( ≤ 3 wee ks pri or t o t he first 
sc he d ule d d osi n g) i ncl u di n g b ut n ot li mite d t o c ycl o p h os p ha mi de, 
azat hi o pri ne, met h otre xate, t hali d o mi de, a n d a nti-t u m or necr osis fact or 
(a nti-T N F ) a ge nts or c o n diti o ns s u c h as c o m m o n varia ble 
h y p o ga m ma gl o b uli ne mia . 
6.  Ot her ca ncer t hera pies, i ncl u di n g c he m ot hera p y, ra diati o n, bi ol o gics or 
ki nase i n hi bit ors wit hi n 3 wee ks pri or t o t he first sc he d ule d d osi n g. 
7.  Has recei ve d c ol o n y sti m ulati n g fact ors ( C S Fs; i ncl u di n g gra n ul oc yte [ G]-
C S F, gra n ul oc yte- ma cr o p ha ge [ G M ]- C S F, or rec o m bi na nt er yt hr o p oieti n) 
wit hi n 4  wee ks pri or t o t he first sc he d ule d d osi n g . 
8.  Ps yc hiatric, ot her me dical ill ness, or ot her c o n diti o n t hat i n t he o pi ni o n of t he 
I n vesti gat or pre ve nts c o m plia nce wit h st u d y pr oce d ures or a bilit y t o pr ovi de 
vali d i nf or me d c o nse nt . 
9.  Hist or y of a ut oi m m u ne disease, i ncl u di n g b ut n ot li mite d t o m yast he nia 
gra vis, m y ositis, a ut oi m m u ne he patitis, s yste mic l u p us er yt he mat os us, 
r he u mat oi d art hritis, i nfla m mat or y b o wel disease, vasc ular t hr o m b osis 
ass ociate d wit h a nti p h os p h oli pi d s y n dr o me, We ge ner's gra n ul o mat osis, 
Sj ö gre n's s y n dr o me, G uillai n- Barré s y n dr o me, m ulti ple scler osis, vasc ulitis, 
or gl o mer ul o ne p hritis (see  A p pe n di x E f or a m ore c o m pre he nsi ve list of 
a ut oi m m u ne diseases) . 
•  
Pati e nts wit h a hist or y of a ut oi m m u ne-relate d h y p ot h yr oi dis m o n a sta ble 
d ose of t h yr oi d re place me nt h or m o ne ma y be eli gi ble f or t his st u d y.  
•  
Patie nts wit h c o ntr olle d T y pe 1 dia betes mellit us o n a sta ble i ns uli n 
re gi me n ma y be eli gi ble f or t his st u d y. 
1 0.  Hist or y o f i di o pat hic p ul m o nar y fi br osis (i ncl u di n g p ne u m o nitis), dr u g-
i n d uce d p ne u m o nitis, or ga nizi n g p ne u m o nia (i.e., br o nc hi olitis o blitera ns, 
cr y pt o ge nic or ga nizi n g p ne u m o nia), ris k of p ul m o nar y t o xicit y, or e vi de nce 
of acti ve p ne u m o nitis o n scree ni n g c hest C T sca n. Hist or y of ra diati o n 
p ne u m o nitis i n t he ra diati o n fiel d (fi br osis) is per mitte d. 
1 1.  Si g nifica nt car di o vasc ular disease, s uc h as Ne w Y or k Heart Ass ociati o n 
car diac disease (≥ Class  II), m y ocar dial i nfarcti o n wit hi n t he pre vi o us 
3 m o nt hs pri or t o st u d y treat me nt, u nsta ble arr h yt h mias, or u nsta ble a n gi na. 
1 2.  I na de q uate or ga n f u ncti o n, i ncl u di n g t he f oll o wi n g: 
a. Marr o w: a bs ol ute ne utr o p hil c o u nt ( A N C) ≤ 1 5 0 0/ m m 3, platelets 
< 7 5, 0 0 0/ m m 3, or he m o gl o bi n ( H b) < 1 0 g/ d L . 
b.  He patic: ala ni ne a mi n otra nsferase ( A L T), a n d as partate a mi n otra nsferase 
( A S T) > 2. 5  × t he u p per li mit of n or mal ( U L N) O R ≥ 5 × U L N f or 
s u bj ects wit h li ver metastases, t otal ser u m bilir u bi n > 1. 5  × U L N ( O R 
direct bilir u bi n ≥ U L N f or patie nts wit h t otal bilir u bi n le vels < 1. 5  ×  

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 9  of 1 2 8  
 
U L N ; patie nts wit h Gil ber t’s Disease ma y be i ncl u de d if t heir t otal 
bilir u bi n is <  3. 0 m g/ d L) . 
c. Re nal: creati ni ne >  1. 5 × U L N . 
d.  Ot her: pr ot hr o m bi n ti me ( P T), i nter nati o nal n or malize d rati o (I N R), or 
partial t hr o m b o plasti n ti me ( P T T) > 1. 5 × U L N . 
1 3.  U nc o ntr olle d ple ural eff usi o n, perica r dial eff usi o n, or ascites re q uiri n g 
rec urre nt drai na ge pr oce d ures ( o nce m o nt hl y or m ore fre q ue ntl y). Patie nts 
wit h i n d welli n g cat heters (e. g., Ple ur X ® ) are all o we d. 
1 4.  U nc o ntr olle d t u m or -relate d pai n. Patie nts re q uiri n g pai n me dicati o n m ust be 
o n a sta ble re gi me n at st u d y e ntr y. S y m pt o matic lesi o ns a me na ble t o 
palliati ve ra di ot hera p y (e. g., b o ne metastases or metastases ca usi n g ner ve 
i m pi n ge me nt) s h o ul d be treate d pri or t o e nr oll me nt. As y m pt o matic 
metastatic lesi o ns w h ose f urt her gr o wt h w o ul d li kel y ca use f u n cti o nal 
deficits or i ntracta ble pai n (e. g., e pi d ural metastasis t hat is n ot prese ntl y 
ass ociate d wit h s pi nal c or d c o m pressi o n) s h o ul d be c o nsi dere d f or l oc o -
re gi o nal t hera p y if a p pr o priate pri or t o e nr oll me nt. 
1 5.  U nc o ntr olle d h y percalce mia ( >  1. 5  m m ol/ L i o niz e d calci u m ( Ca) or Ca 
> 1 2 m g/ d L or c orrecte d ser u m calci u m >  U L N) or s y m pt o matic 
h y percalce mia re q uiri n g c o nti n ue d use of bis p h os p h o nate t hera p y or 
de n os u ma b. Patie nts w h o are recei vi n g t hese a ge nts s pecificall y t o pre ve nt 
s keletal e ve nts a n d w h o d o n ot ha ve a hist or y of cli nicall y si g nifica nt 
h y percalce mia are eli gi ble. Patie nts w h o are recei vi n g de n os u ma b pri or t o 
e nr oll me nt m ust be willi n g a n d eli gi ble t o disc o nti n ue its use w hile o n st u d y 
a n d recei ve a bis p h os p h o nate i nstea d. 
1 6.  Hist or y of ot her ca ncer wi t hi n 3 years  (e xce pt f or a p pr o priatel y treate d 
carci n o ma i n sit u of t he cer vi x, n o n- mela n o ma s ki n carci n o ma, Sta ge  I 
uteri ne ca ncer, l ocalize d pr ostate ca ncer treate d wit h c urati ve i nte nt, d uctal 
carci n o ma i n sit u treate d s ur gicall y wit h c urati ve i nte nt, or ot her ca ncers wit h 
a si milar o utc o me) . 
1 7.  E vi de nce of acti ve t u berc ul osis or rece nt ( <  1 wee k pri or t o first sc he d ule d 
d osi n g ) cli nicall y si g nifica nt i nfecti o n re q uiri n g s yste mic t hera p y 
( pr o p h ylactic a nti bi otics [e. g., f or pre ve nti o n of a uri nar y tract i nfecti o n or 
c hr o nic o bstr ucti ve p ul m o nar y disease] are per mitte d ). 
1 8.  E vi de nce of acti ve he patitis B  ( He p B), he patitis C ( He p C), or H u ma n 
I m mu n o deficie nc y Vir us ( HI V ) i nfecti o n. Acti ve He p B  is defi ne d as ha vi n g 
a p ositi ve He p B  s urface a nti ge n ( H Bs A g) test at scree ni n g. Patie nts wit h 
past/res ol ve d He p B  i nfecti o n ( defi ne d as ha vi n g a ne gati ve H Bs A g test a n d a 
p ositi ve a nti b o d y t o He p B  c ore a nti ge n [a nti -H Bc ] a nti b o d y test) are eli gi ble. 
He p B  viral D N A m ust be ne gati ve i n t hese patie nts pri or t o t he first 
sc he d ule d d osi n g. Patie nts p ositi ve f or He p C  a nti b o d y are o nl y eli gi ble  if 
p ol y merase c hai n reacti o n ( P C R ) is ne gati ve f or He p C viral  R N A.  
1 9.  A d mi nistrati o n of a li ve, atte n uate d vacci ne wit hi n 4  wee ks pri or t o t he first 
sc he d ule d d osi n g or a ntici pati o n t hat s uc h a li ve atte n uate d vacci ne will be 
re q uire d d uri n g t he st u d y. I nfl ue nza vacci nati o n s h o ul d be gi ve n d uri n g 
i nfl ue nza seas o n o nl y (a p pr o xi matel y Oct o ber t o Marc h). Patie nts m ust n ot 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 1 0  of 1 2 8  
 
recei ve li ve, atte n uate d i nfl ue nza vacci ne (e. g., Fl u Mist® ) wit hi n 4 wee ks 
pri or t o t he first sc he d ule d d osi n g or at a n y ti me d uri n g t he st u d y. 
2 0.  K n o w n acti ve or u ntreate d ce ntral ne r v o us s yste m ( C N S) metastases. 
Patie nts wit h a hist or y of treate d as y m pt o matic C N S metastases are eli gi ble, 
pr o vi de d t he y meet all of t he f oll o wi n g criteria:  
a. N o metastases t o cere bell u m, brai n ste m, mi d brai n, p o ns, me d ulla, or 
wit hi n 1 0 m m of t he o ptic a p parat us ( o ptic ner ves a n d c hias m) . 
b.  N o e vi de nce of i nteri m pr o gressi o n ≥ 4 wee ks bet wee n t he c o m pleti o n of 
C N S -directe d t hera p y a n d t he scree ni n g ra di o gra p hic st u d y  a n d ≥ 2 
wee ks si nce disc o nti n uati o n of c ortic oster oi ds . 
c. N o o n g oi n g re q uire me nt f or de xa met has o ne as t hera p y f or C N S d isease; 
a ntic o n v ulsa nts at a sta ble d ose all o we d . 
2 1.  Pre g na nt, pla n ni n g t o bec o me pre g na nt wit hi n 6 m o nt hs of treat me nt, or 
n ursi n g. 
2 2.  K n o w n aller g y(ies) t o a n y c o m p o ne nt of C M B 3 0 5, atez oliz u ma b, or se vere 
aller gic reacti o ns t o m o n ocl o nal a nti b o dies, f usi o n pr otei ns, or C H O cell 
pr o d ucts. 
S af et y M o nit ori n g  
T he safet y pr ofiles f or C M B 3 0 5 a n d atez oliz u ma b are descri be d i n t heir 
res pecti ve I n vesti gat or’s Br oc h ures (I Bs). Safet y will be m o nit ore d b y e val uati n g 
s olicite d a n d s p o nta ne o usl y re p orte d a d verse e ve nts (A Es ), i ncl u di n g 
react o ge nicit y, s y m pt o ms, p h ysical e xa mi nati o n fi n di n gs, vital si g ns, la b orat or y 
fi n di n gs, a n d disc o nti n uati o ns f or A Es. A E se verit y assess me nts will be 
perf or me d usi n g Nati o nal Ca ncer I nstit ute ( N CI) C o m m o n T er mi n ol o g y Criteria 
f or A d verse E ve nts ( C T C A E) v 4. 0 3. A ll a d verse e ve nts, re gar dless of 
relati o ns hi p t o st u d y dr u g, s h o ul d be re p orte d u ntil 3 0 da ys after t he last d ose of 
st u d y dr u g or u ntil i nitiati o n of a n ot her a nti-ca ncer t hera p y, w hic he ver occ urs 
first.  
A Es ( b ot h n o n-seri o us a n d seri o us) ass ociate d wit h e x p os ure t o t he st u d y dr u gs 
ma y re prese nt a n i m m u n ol o gic eti ol o g y. T hese A Es ma y 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. T he st u d y dr u gs m ust 
be wit h hel d f or dr u g- relate d t o xicities as o utli ne d i n A p pe n di x F , as well as 
se vere or life-t hreate ni n g A Es.  
D at a M o nit ori n g C o m mittee 
A D M C will o perate i n acc or da nce wit h a si g ne d c harter a n d will c o nsist of 2 
e x perie nce d o nc ol o gists fa miliar wit h cli nical use of t he st u d y dr u gs a n d a n a d 
h oc bi ostatisticia n w h o is k n o wle d gea ble a b o ut statistical met h o ds f or cli nical 
trials a n d se q ue ntial a nal ysis of trial data. T he D M C will re vie w all c u m ulati ve 
safet y i nf or mati o n fr o m t he Safet y R u n-i n pri or t o rec o m me n dati o ns f or  f urt her 
patie nt e nr oll me nt. T hereafter, t he D M C will pr o vi de i n de pe n de nt re vie w of all 
safet y data e ver y 3 m o nt hs t o mi ni mize ris ks t o st u d y patie nts. All D L Ts a n d 
S A Es c o nsi dere d at least p ossi bl y relate d t o st u d y re gi me n will be re vie we d b y 
t he D M C a n d t he S p o ns or as t he y are re p orte d a n d o n a n o n g oi n g basis. T hese 
re vie ws ma y lea d t o m o dificati o n or st o p pi n g of t he treat me nt pr o gra m if relate d, 
treat me nt-e mer ge nt a d verse e ve nts i n dicate a safet y pr ofile t hat is i nc o nsiste nt or 
si g nifica ntl y w orse t ha n re p orte d wit h t he use of eit her C M B 3 0 5 or atez oliz u ma b 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 1 1  of 1 2 8  
 
al o ne. Relate d S A E re p orts will be e x pe dite d t o re g ulat or y a ut h orities, 
i n vesti gat ors, a n d D M C me m bers.  
T he preli mi nar y safet y of t he i n di vi d ual c o m p o ne nts of C M B 3 0 5 ( L V 3 0 5 a n d 
G 3 0 5) a n d of t he c o m bi nat orial re gi me n  ha ve bee n st u die d i n se parate P hase 1 
st u dies; t hat of t he C M B 3 0 5/atez oliz u ma b c o m bi nati o n will be i n vesti gate d 
d uri n g t he 3- 6 patie nt Safet y R u n -i n. D osi n g will be s us pe n de d i n t his st u d y if a 
D L T is o bser ve d i n o ne t hir d or m ore patie nts i n t he c o m bi nati o n treat me nt ar m 
(ass u mi n g a mi ni m u m of 1 2 c o m bi ne d re gi me n patie nts were e nr olle d at t hat 
p oi nt a n d w o ul d re prese nt t he i nitial de n o mi nat or), pe n di n g re vie w a n d 
rec o m me n dati o n fr o m t he D M C.  
T o xicities Ass oci ate d 
wit h At ez oliz u m a b 
A tez oliz u ma b ca n be ass ociate d wit h t he f oll o wi n g A Es a n d  will be wit h hel d 
u ntil res ol uti o n f or a n y of t he f oll o wi n g e ve nts: 
•  
Gra de ≥2 p ne u m o nitis  
•  
Gra de ≥3 s y m pt o matic he patic t o xicities t hat d o n ot res ol ve t o Gra de 2 
wit hi n 4 8 h o urs or Gra de ≥3 as y m pt o matic he patic t o xicities t hat d o n ot 
res ol ve t o Gra de ≤1 wit hi n 3 wee ks of o nset wit h t he f oll o wi n g e xce pti o ns: 
•  
F or patie nts wit h Gra de 2 A S T, A L T, or al kali ne p h os p hatase 
a b n or malit y at baseli ne, a n i ncrease t o > 8 x U L N t hat d oes n ot 
res ol ve t o Grade 2 wit hi n 4 8  h o urs (if s y m pt o matic) or Gra de ≥3 
as y m pt o matic he patic t o xicities t hat d o n ot res ol ve t o Gra de ≤1 
wit hi n 3  wee ks of o nset (if as y m pt o matic) will be c o nsi dere d a D L T.  
•  
Gra de ≥2  diarr hea or c olitis  
•  
S y m pt o matic h y p ot h yr oi dis m, h y pert h yr oi dis m, pa n h y p o pit uitaris m, or a n y 
Gra de ≥3 e n d ocri ne e ve nts 
•  
Gra de ≥3 oc ular e ve nts  
•  
Gra de ≥3 der mat ol o gic e ve nts  
•  
Gra de ≥2 ne ur o pat h y 
•  
Gra de ≥4 ne utr o pe nia ( A N C < 5 0 0/ µ L) lasti n g ≥7 da ys, t hr o m b oc yt o pe nia, 
a ne mia, or Gra de ≥3 fe brile ne utr o pe nia 
•  
Gra de ≥3 n o n - he mat ol o gic, n o n- he patic or ga n t o xicit y, e xcl u di n g t he 
f oll o wi n g: 
•  
Gra de  3 i m m u ne relate d A E t hat res ol ves t o Gra de ≤1 wit hi n 3 
wee ks of its o nset ( ma y i ncl u de e ve nts t hat res ol ve after me dical 
treat me nt, i ncl u di n g i m m u n os u p pressa nt t hera p y) 
•  
Gra de  3 na u sea or v o miti n g t hat res ol ves t o Gra de ≤1 wit hi n 
7 2 h o urs of a p pr o priate s u p p orti ve t hera p y 
•  
Gra de  ≥3 fati g ue t hat res ol ves t o Gra de ≤2 wit hi n 7 da ys  
•  
Gra de  3 art hral gia t hat ca n be a de q uatel y ma na ge d wit h s u p p orti ve 
care or t hat res ol ves t o Gra de ≤2 wit hi n 7 da ys  
•  
Gra de  3 fe ver (i n t he a bse nce of a n y cli nicall y si g nifica nt s o urce of 
fe ver) t hat res ol ves t o Gra de ≤2 wit hi n 7 da ys wit h s u p p orti ve care 
•  
Gra de ≥3 la b orat or y a b n or malit y t hat is as y m pt o matic a n d dee me d 
b y t he I n vesti gat or n ot t o be cli nicall y si g ni fica nt 
•  
Gra de 3 t u m or flare defi ne d as l ocal pai n, irritati o n, or ras h l ocalize d 
at sites of k n o w n or s us pecte d t u m or 
•  
Gra de 3 i nf usi o n reacti o n t hat res ol ves wit hi n 6 h o urs t o Gra de ≤1 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 1 2  of 1 2 8  
 
T hese reacti o ns , al o n g wit h a n y D L Ts , will be re vie we d b y t he data m o nit ori n g 
c o m mittee ( D M C ) o n a case -b y -case basis a n d ma y be c o nsi dere d D L Ts if t he y 
meet t he criteria o utli ne d a b o ve. A tez oliz u ma b treat me nt ca n be res u me d i n 
patie nts w h ose a d verse reacti o ns rec o ver t o Gra de 0 - 1. 
D ose  Li miti n g 
T o xicit y ( D L T)  
A E se verit y assess me nts will be perf or me d usi n g N CI C o m m o n T er mi n ol o g y 
Criteria f or A d verse E ve nts ( C T C A E) v 4. 0 3. U nacce pta ble t o xicit y is defi ne d 
w he n o ne t hir d or m ore of t he s u bjects treate d wit h t he c o m bi ne d re gi me n 
de vel o p a n A E c o nsi dere d Gra de 3 or hi g her a n d c o nsi dere d at least p ossi bl y 
relate d t o C M B 3 0 5 or atez oliz u ma b wit h t he e xce pti o ns bel o w. H os pitalizati o ns 
pri maril y i nte n de d t o e x pe dite dia g n ostic e val uati o ns or f or electi ve s ur ger y will 
n ot be c o nsi dere d as seri o us a d verse e ve nts ( S A Es) f or t he p ur p ose of 
ascertai ni n g D L T. 
A n y treat me nt e mer ge nt gra de 3 or hi g her A E t hat occ urs i n t he D L T assess me nt 
wi n d o w, w hic h is t he first 4 2 da ys after i nitiati o n of st u d y dr u g, t hat is dee me d 
p ossi bl y, pr o ba bl y or defi nitel y relate d t o t he c o m bi nati o n of C M B 3 0 5 a n d 
atez oliz u ma b will be c o nsi dere d D L Ts wit h t he f oll o wi n g e xce pti o ns:  
•  
Al o pecia or  v o miti n g ( u nless n ot c o ntr olle d b y o pti mal a nti-e metics)  
•  
He patic e nz y me ele vati o ns ass ociate d wit h t he baseli ne Gra de 2 
a b n or malities t hat are n ote d as e xce pti o ns a b o ve 
•  
Gra de 3 la b orat or y A Es t hat are as y m pt o matic a n d ret ur n t o baseli ne 
or t o Gra de 1 wit hi n 3 da ys, u nless i de ntifie d s pecificall y as D L T b y 
t he i n vesti gat or or t he Data M o nit ori n g C o m mittee ( D M C) 
•  
Gra de 3 fati g ue  
•  
Gra de 3 s yste mic reacti o ns (s uc h as fe ve r, hea dac he, i nfl ue nza li ke 
s y m pt o ms, m yal gia, malaise, or na usea) t hat ret ur n t o baseli ne or 
Gra de 1 wit hi n 3 da ys of st u d y i n oc ulati o n  
Atez oliz u ma b has a rec o g nize d safet y pr ofile.  A Es i n t he c o m bi ne d treat me nt 
ar m t hat are attri b ute d t o atez oliz u ma b wi ll be e val uate d b y t he D M C a n d 
s p o ns or, b ut will n ot be  i m me diatel y c o nsi dere d as D L T s e xce pt as n ote d a b o ve.  
All s uc h e ve nts s h o ul d be re p orte d t o t he S p o ns or i n a n e x pe dite d ma n ner ( wit hi n 
2 4 h o urs) a n d will be re vie we d b y t he D M C. Alt h o u g h t hese e ve nts will n ot 
c o ntri b ute a ut o maticall y t o t he D L T st o p pi n g criteria, t hese re vie ws ma y lea d t o 
m o dificati o n or st o p pi n g of t he treat me nt pr o gra m if relate d, treat me nt- e mer ge nt 
A Es i n dicate a safet y pr ofile t hat is i nc o nsiste nt or si g nifica ntl y w orse t ha n 
re p orte d wit h t he use of atez oliz u ma b al o ne. 
D uri n g t he safet y r u n-i n, t he f oll o wi n g patie nts will n ot be c o nsi dere d e val ua ble 
f or D L Ts a n d will be re place d: 
•  
Patie nts w h o wit h dra w or are wit h dra w n f or eit her st u d y treat me nt pri or t o 
c o m pleti n g t he D L T assess me nt  wi n d o w f or a n y reas o n ot her t ha n a D L T 
•  
Patie nts w h o d o n ot recei ve t he f ull assi g ne d d ose of eit her st u d y treat me nt 
d uri n g t he D L T assess me nt wi n d o w f or reacti o ns ot her t ha n a D L T.  
Re place d patie nts will re mai n o n st u d y treat me nt if t he y ot her wise meet criteria 
t o c o nti n ue d osi n g a n d c o nti n ue assess me nt. 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 1 3  of 1 2 8  
 
St atistic al  A n al ysis  
E n d p oi nts  
P ri m ar y  
T he p ri mar y e n d p oi nts are t he f oll o wi n g: 
•  
O S a n d P F S  
Sec o n d ar y  
T he sec o n dar y e n d p oi nts i ncl u de t he f oll o wi n g: 
•  
Safet y  
•  
Pr o gressi o n- free rate ( P F R) at 6 m o nt hs 
•  
T T N T  
•  
I m m u ne res p o nse a n d hist ol o gic a n d m olec ular tiss ue c ha n ges i n t u m or 
tiss ue or peri p heral bl o o d  
•  
D M F S  
E x pl or at or y 
T he e x pl or at or y e n d p oi nts are t he f oll o wi n g:  
•  
T G R  
•  
P A R  
•  
T o c o m pare O S a n d P F S bet wee n treat me nt ar ms  
•  
O R R as assesse d b y R E CI S T ( v 1. 1) m o difie d t o use ir R C  
•  
D O R  
•  
C B R  
•  
I m m u ne res p o nses as meas ure d b y c ha n ges fr o m baseli ne i n a nti-N Y -E S O - 1 
i m m u nit y 
•  
Bi o mar kers  
•  
Q ualit y of life  
S af et y  
T he safet y e n d p oi nts i ncl u de t he nat ure, fre q ue nc y, a n d se verit y of A Es a n d 
M E O Is, la b orat or y a b n or malities, a n d ot her safet y assess me nts (i ncl u di n g vital 
si g ns, L V 3 0 5 persiste nce, p h ysical e xa mi nati o n fi n di n gs, electr ocar di o gra ms 
[E C Gs ], etc.). 
St atistic al A n al yses  
Effic ac y  
T he pri mar y efficac y a nal ysis will be t he e val uati o n of O S a n d P F S usi n g 
Ka pla n - Meier met h o d ol o g y a n d will be perf or me d o n t he I T T P o p ulati o n f or 
eac h treat me nt ar m. Ka pla n-Meier pl ots a n d 9 5 % c o nfi de nce i nter vals ( CIs) f or 
7 5 %, 5 0 % a n d 2 5 % s ur vi val, if reac he d, will be pr o vi de d f or eac h treat me nt 
gr o u p. 
 
A sec o n dar y efficac y a nal ysis will be base d o n t he pr o p orti o n of patie nts t hat are 
pr o gressi o n-free at 6 m o nt hs after start of st u d y dr u g treat me nt ( Da y 0) .   
Ti me -t o- ne xt-treat me nt a n d dista nt metastasis free s ur vi val will be c o m pare d 
bet wee n treat me nt ar m s base d o n a stratifie d l o g-ra n k test.  
T he i m m u n ol o gic efficac y i n t u m or tiss ue a n d peri p heral bl o o d will be e val uate d 
b y c ha n ges i n c o nce ntrati o n of i m m u ne cells (e. g., C D 8 + T cells) a n d a nti b o dies. 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 1 4  of 1 2 8  
 
E x pl orat or y c o m paris o ns of t he  O S , P F S, a n d D O R bet wee n treat me nt ar ms will 
be base d o n stratifie d l o g- ra n k tests. O R R will be c o m pare d bet wee n treat me nt 
gr o u ps usi n g a stratifie d l o gistic re gressi o n m o del . Wei g hte d l o g-ra n k tests will 
be e x pl ore d if dela ye d treat me nt effect is o bser ve d ; T G R , P A R , C B R, a n d 
q ualit y of life  will be e val uate d f or eac h gr o u p.  
S af et y  
Descri pti ve statistics will be perf or me d f or all safet y i nf or mati o n i ncl u di n g A Es, 
S A Es, la b orat or y fi n di n gs a n d disc o nti n uati o ns of patie nts at all data c ollecti o n 
ti me p oi nts. N o f or mal statistical h y p ot hesis will be teste d. 
I m m u n o ge nicit y 
Descri pti ve statistics will be perf or me d c o m pari n g t he baseli ne a n d treat me nt 
a d mi nistrati o n peri p heral bl o o d N Y-E S O - 1-res p o nsi ve T cells bet wee n t he 2 
treat me nt ar ms. A nal yses will be perf or me d t o deter mi ne if t here are a n y 
statisticall y si g nifica nt c ha n ges fr o m baseli ne val ues. C ha n ges fr o m baseli ne i n 
serial a nti-N Y -E S O -1 a nti b o dies will be e x presse d as ge o metric mea n titers.  
Bi o m ar kers  
Descri pti ve statistics will be pr o vi de d f or bi o mar kers a n d treat me nts wil l be 
c o m pare d usi n g A N O V A, or n o n- para metric met h o d w he n a p pr o priate, of 
s pecific ge nes a n d/ or a nal ysis of ge ne- net w or ks (e. g., si g nali n g of i m m u ne cells) 
a n d ge ne m o d ules (e. g., sets of ge nes [t y picall y 1 0 0- 2 0 0]) t hat are u p- or d o w n-
re g ulate d i n c o ncert i n certai n c o n diti o ns or disease states (e. g., i nfecti o n, 
a ut oi m m u nit y, etc.) will be perf or me d. Data will be use d t o c o m pare t he baseli ne 
wit h res p o nses p ost -treat me nt.  A d diti o nall y, j oi nt m o dels of o verall s ur vi val a n d 
l o n git u di nal bi o mar ker data ma y be e x pl ore d. 
S a m ple Size  
T he me dia n P F S f or first-li ne c he m ot hera p y f or patie nts prese nti n g wit h or 
de vel o pi n g metastatic s y n o vial sarc o ma has bee n re p orte d t o be  2. 5 t o 8. 3 
m o nt hs; P F S wit h atez oliz u ma b i n t he p ost-c he m ot hera p y setti n g is u n k n o w n. 
T h us, n o p o wer calc ulati o ns base d o n c o m paris o ns of P F S were ma de . H o we ver, 
b ase d o n a n u nacce pta ble a n d desira ble me dia n P F S of 3 m o nt hs a n d 5. 2 m o nt hs, 
res pecti vel y, c orres p o n di n g P F Rs at 6 m o nt hs were deri ve d. Wit h a n 
u nacce pta ble P F R of 2 5 % a n d a n acce pta ble P F R of 4 5 %  at 6 m o nt hs, a Si m o n 
2- sta ge desi g n will be use d t o e xa mi ne t he P F R i n 4 0 patie nts i n eac h ar m 
(al p ha = 0. 1, beta = 0. 1 5).  F or t his st u d y, t w o gr o u ps of a p pr o xi matel y 4 0 patie nts 
eac h ( a p pr o xi mate l y 8 0 patie nts f or t he e ntire st u d y) will be d ose d wit h C M B 3 0 5 
wit h atez oliz u ma b or wit h atez oliz u ma b al o ne t o assess t he q uartiles ( 2 5 %, 5 0 %, 
a n d 7 5 %) of P F S wit h 9 5 % CIs a n d t he P F R at 6 m o nt hs. If fa v ora ble res ults are 
o bser ve d, t he st u d y ma y be e x pa n de d t o i m pr o ve t he esti mates of P F S. 
I nteri m A n al ysis 
A n e x pl orat or y a nal ysis of t he P F R at 6 m o nt hs after treat me nt i nitiati o n will be 
use d as a n o n - bi n di n g f utilit y a nal ysis f or eac h treat me nt ar m. U p o n o btai ni n g 
t he pr o gressi o n stat us after 6 m o nt hs o n st u d y fr o m t he first 3 6 ( 1 8 per ar m) a n d 
s u bse q ue ntl y fr o m all e nr olle d patie nts, i nteri m a nal yses will be perf or me d a n d 
prese nte d t o t he D M C, w hic h will i ncl u de esti mates of P F S a n d assess me nt of 
P F R. Base d o n t he ass u m pti o ns a b o ve, f utilit y g ui deli nes at Sta ge 1 will be base d 
o n 1 8 patie nts a n d will re q uire at least 6 patie nts t o be pr o gressi o n free t o 
c o nti n ue o n t o Sta ge 2. Wit h a n a d diti o nal 2 2 patie nts at t he e n d of Sta ge 2, at 
least 1 4 of t he t otal of 4 0 patie nts s h o ul d be pr o gressi o n free at 6 m o nt hs after 
i nitial d osi n g to rec o m me n d f urt her st u d y i n t his setti n g. F or t he p ur p oses of 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 1 5  of 1 2 8  
 
 
safet y m o nit ori n g, ke y safet y a nal ysis will als o be perf or me d q uarterl y. T he 
D M C will e val uate t he a vaila ble data a n d ma ke necessar y rec o m me n dati o ns t o 
t he st u d y. Details will be o utli ne d i n t he D M C c harter.  
A fi nal O S a nal ysis will be c o n d ucte d w he n at least 7 2 deat hs ha ve bee n 
o bser ve d , or s o o ner if t he S p o ns or s o deci des .   

I m m u ne Desi g n  
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 1 6  of 1 2 8  
 
T a ble 1 
Sc he d ule of E ve nts  – C o m bi n ati o n Tre at me nt Ar m  
 
Scree ni n g  
Tre at me nt P h ase  
B o oster P h ase  
M ai nte n a nce  
P h ase  
S ur vi v al 
F oll o w -u p q 
Visit  
1 
2 
3 
4 
5 
6 
7 
8 
9 
1 0  
1 1  
1 2  
1 3 +  
 
 
Ti meli ne – Wee ks
a 
-4 t o 0  
0 
2 
3 
4 
6 
8 
9 
1 0  
1 2  
1 4  
1 5  
E ver y 
3 w ks b 
E ver y 3 w ks b 
E ver y 3 m o s 
( 1 2 w ks) 
Pr oce d ures  
Ti meli ne –  D a ys  
-3 0 t o -1  
0  
1 4  
2 1  
2 8  
4 2  
5 6  
6 3  
7 0  
8 4  
9 8  
1 0 5  
 
 
 
I nf or me d c o nse nt/ HI P A Ac 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
I ncl usi o n/e xcl usi o n criteria 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
De m o gra p hics/ Me dical Hist or y  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
T u m or -s pecific t hera p y hist or y 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N Y -E S O -1 e x pressi o n o n pre -st u d y 
t u m or sa m pled 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
E nr oll me nt a n d ra n d o mizati o n  
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
Re p ort A Es a n d S A Es  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Rec or d a n y pre vi o us c o nc o mit a nt me ds  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Vital si g ns e 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
P h ysical e xa m f 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
E C G ( 1 2 -Lea d)  
X  
 
 
 
 
 
 
 
 
 
 
X  
 
 
 
T u m or sta gi n g, b y C T sca n g 
X  
 
 
 
 
X  
 
 
 
X  
 
 
X  
X  
 
E C O G  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
HI V, He p B, a n d He p C ( 5 m L) h 
X  
 
 
 
 
 
 
 
 
 
 
 
X h 
X h 
 
Bl o o d f or cell ular i m m u nit y ( 5 5  m L) i 
X  
X  
 
 
 
X  
 
 
X  
 
X i 
 
 
 
 
Bl o o d f or safet y la bs ( 1 0 m L) j 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
X  
X  
X  
 
T h yr oi d f u ncti o n tests k 
X  
 
 
 
 
 
 
 
 
X  
 
 
X k 
X k 
 
Uri nal ysis  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Uri ne sa m ple f or pre g na nc y test l 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
X  
X  
X  
 
St u d y dr u g: L V 3 0 5  
 
X  
X  
 
 
X  
 
 
X  
 
 
 
 
 
 
St u d y dr u g: G 3 0 5  
 
 
 
 
X  
 
X  
 
 
X  
 
 
X m  
 
 
St u d y dr u g: atez oliz u ma b  
 
X  
 
X  
 
X  
 
X  
 
X  
 
X n 
X n 
X n 
 
Bl o o d f or L V 3 0 5 persiste nce ( 8  m L) o 
X  
 
 
 
 
 
 
 
 
 
 
 
X o 
X o 
 
T u m or bi o ps y p  
X  
 
 
 
 
X  
 
 
 
 
X p  
 
 
X b 
 
S ur vi val Stat us  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X q 
Bl o o d v ol u me per visit ( m L)  
7 8  
6 5  
1 0  
1 0  
1 0  
6 5  
1 0  
1 0  
6 5  
1 0  
5 5  
1 0  
 
 
 
T otal bl o o d v ol u me  
7 8 
1 4
3  
1 5
3  
1 6
3  
1 7
3  
2 3
8  
2 4
8  
2 5
8  
3 2
3  
3 3 3  3 8
8  
3 9 8  
 
 
 

I m m u ne Desi g n  
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 1 7  of 1 2 8  
 
A b bre viati o ns: A E = a d verse e ve nt, C T  = c o m p ute d t o m o gra p h y; E C G = ele ctr o car di o gra m; E C O G = Easter n C o o p erati ve O nc ol o g y Gr o u p; He p B = he patitis B; He p C  = he patitis 
C; HI P A A = H u ma n i ns ura n ce P orta bilit y a n d Ac c o u nta bilit y Act; HI V = H u ma n i m m u n o d eficie n c y Vir us; me ds = me dicati o ns; m os = m o nt hs; P B M C = peri p heral bl o o d 
m o n o n uclear cells; S A E = seri o us a d verse e v e nt.  
a. A wi n d o w of ± 3 d a ys is p er mitte d f or Visits 3 t hr o u g h 1 2 . F oll o w-u p p h ase vi sits ( Visits 1 3+) will be p er mitte d a  wi n d o w of ± 4 da ys , T u m or ass ess me nts will be per mitte d a 
wi n d o w of ± 1 wee k . 
b.  P atie nt s will b e f oll o we d wit h visits e ver y 3 wee ks ( ± 4 d a ys)  f or 2 years (fr o m Da y 0) f or u ntil pr o gressi o n . T u m or size will be assess e d e ver y 6 wee ks f or  t he first ye ar, t he n 
e ver y 1 2 wee ks  u ntil  pr o gressi o n . P atie nts will t h e n h a ve n o f urt h er sta gi n g pr o ce d ures .  T u m or bi o psies will b e o btai n e d at 6 m o nt hs or l o n ger f or patie nts wit h treat me nt 
res p o nse. T u m or b i o psies will als o  b e o btai n e d at ti me of pr o gressi o n.   
c. I nf or me d c o nse nt a n d HI P A A a ut h orizati o n m ust b e si g n e d b ef ore a n y s cree ni n g st u d y-relate d pr o ce d ures are i nitiate d. Three  i nf or me d c o nse nts will be use d: o ne t o scree n 
t u m or sa m ple f or N Y-E S O - 1, o n e t o e n ga ge i n t h e st u d y pr ot o c ol, a n d a n a gree me nt t o c o nti n u e i n t he st u d y  a n d o btai n peri p heral bl o o d sa m ples a n d bi o psies  if t he patie nt 
meets t he criteria f or pr o gressi ve disease b ut wis h es t o re mai n o n st u d y .  
d.  D oc u me ntati o n of N Y -E S O -1 e x pressi o n i n  pri or  t u m or sa m ples ma y h a ve b ee n c ollecte d fr o m a n y pr o ce d ure p erf or me d bef ore basel i ne acti vities. T here is n o ti me li mit f or 
use of t he res ults fr o m t h e  I M D Z-a p pr o ve d  ce ntral la b. 
e. Vital si g n meas ure me nts  i n cl u d e te m p erat ure, p ulse, res pirat or y rate, a n d resti n g s yst olic a n d diast olic bl o o d press ure. O n t he da y of e ac h d osi n g, vital si g n s will be o btai ne d 
pre- d osi n g a n d 3 0 mi n utes after d osi n g.   F or t h e first atez oliz u ma b i nf usi o n, t h e p atie nt’s vital si g ns ( H R, res pirat or y rate, B P, a n d te m perat ure) s h o ul d be meas ure d  wit hi n 1 5 
mi n ute s of t h e i nf usi o n , d uri n g t he 6 0-mi n ute i nf usi o n (e ver y 1 5 [ ±  5] mi n utes), a n d 3 0 mi n utes after t h e i nf usi o n.  F or s u bse q ue nt i nf usi o ns, vital si g ns d o n ot nee d t o be 
o btai ne d d uri n g t h e i nf usi o n if t h e pri or i nf usi o n was t olerate d wit h o ut s y m pt o ms.  
f. O nce t he baseli n e p h ysical e x a m h as b ee n c o n d u cte d, a si m ple  s y m pt o m-directe d p h ysic al e xa m s h o ul d b e p erf or me d f or all s u bse q ue nt visits.  Hei g ht a n d wei g ht will be 
c ollecte d at Da y 0 o nl y.  
g.  I ma gi n g will b e p erf or me d b y C T sca n as d efi n e d b y R E CI S T/ir R C at scree ni n g a n d  e ver y 6 wee ks after first st u d y i njecti o n  f or t he first year, t he n e ver y 1 2 wee ks f or t u m or 
sta gi n g u ntil disease pr o gressi o n a n d i n cl u d es a c o nfir mat or y s ca n p erf or me d at least 4  wee ks later. Ma g n etic Res o n a n ce I ma gi n g ( M RI), b o ne sca ns, or P E T/ C T at baseli ne or 
s u bse q ue nt visits will b e p erf or me d o nl y if cli nicall y i n dicate d. 
h.  A n HI V  scree ni n g test will b e re peate d o n Da y 1 6 8 t o d eter mi n e if ser o c o n versi o n h as o cc urre d f oll o wi n g L V 3 0 5 i njecti o ns. If p ositi ve, f urt her testi n g ca n de m o nstrate t hat t he 
n or mal c o m ple me nt of HI V pr otei ns is n ot prese nt ( u nless t h e p atie nt h as d e vel o p e d a tr u e HI V i nfecti o n).  
i. Bl o o d f or i m m u n o ge nicit y  will b e c ollecte d at cli nical sites t h at are trai n e d i n p eri p h eral bl o o d m o n o n u clear cells ( P B M C) is olati o n. Baseli ne sa m ples  will be dra w n t wic e t o 
e ns ure a g o o d yiel d. At leas t 55 m L s h o ul d b e c ollecte d i n 8 Cell Pre p arati o n T u b es ( C P T )™ t u b es f or T -c ell res p o nse assa ys.  See t he La b Ma n ual f or pr ocessi n g details.  
j. I nitial safet y la bs are t o b e p erf or me d wit hi n 4 d a ys b ef ore  treat me nt i nitiati o n. O n treat me nt d a ys  duri n g t h e st u d y d osi n g peri o d, t he he mat ol o g y a n d cli nical c he mistr y 
la b orat ories m ust als o b e p erf or me d a n d re vie we d b ef ore d osi n g a n d  ma y b e p erf or me d u p t o 4 8 h o urs pri or t o t h e pla n ne d d osi n g.  
k.  T h yr oi d f u ncti o n tests (trii o d ot h yr o ni n e [ T 3 ], t h yr o xi n e [ T4 ], a n d t h yr oi d sti m ulati n g h or m o n e [ T S H]) s h o ul d b e ta ke n at i nitial scree ni n g a n d at least e ver y 3 m o nt hs w hile 
bei n g treate d wit h atez oliz u ma b . As t h yr oi d dis or d ers c o ul d o cc ur at a n y ti me as a res ult of atez oliz u ma b  treat me nt, p atie nts s h o ul d be m o nit ore d f or c ha n ges i n t h yr oi d f u ncti o n 
f or cli nical si g ns a n d s y m pt o ms of t h yr oi d dis or d ers (at t h e start of treat me nt, p eri o dicall y d uri n g treat me nt, a n d as i n dicate d base d o n cli nical e val uati o n). 
l. Uri ne pre g na n c y test m ust b e p erf or me d f or w o me n of c hil d b eari n g p ot e ntial wit hi n 7 2  h o urs b ef ore st u d y dr u g a d mi nistrati o n a n d ne gati ve bef ore st u d y dr u g a d mi nistrati o n , 
i ncl u di n g d uri n g t h e f oll o w-u p p eri o d if p atie nts are still recei vi n g b o oster d oses of G 3 0 5 a n d/ or atez oliz u ma b . Ser u m pre g na nc y test ma y be perf or me d if t he site’s sta n dar d 
o perati n g pr o ce d ure s all o w. 
m.  B o oster d oses of G 3 0 5 will b e gi ve n 6 wee ks f oll o wi n g t h e Da y 8 4  d ose a n d e ver y 6 wee ks t h ereaft er f or 1 ye ar (fr o m Da y 0) or u ntil disease pr o gressi o n  at t he sta gi n g visits . 
n.  A te z oliz u ma b s h o ul d b e c o nti n u e d e ver y 3 we e ks  f or 2 ye ars (fr o m Da y 0) or u ntil pr o gressi o n  u nless t o xicit y o cc urs.  
o.  P eri p heral bl o o d will b e c ollecte d at scree ni n g, Da y 16 8 , a n d 1 2 a n d 2 4 m o nt hs after i nitial i njecti o n t o test f or p ersiste n ce of L V 3 0 5. Sa m ples will be assa ye d f or prese nce of 
t he viral ge n o me b y p ol y merase c h ai n reacti o n ( P C R). De p e n di n g o n t h e res ults t hr o u g h 1 2 m o nt hs, a n n u al assess me nts ma y c o nti n ue u ntil 2 c o nsec uti ve sa m ples s h o w n o 
e vi de nce of L V 3 0 5 p ersiste n ce.  
p.  T he pre -treat me nt bi o ps y m ust b e c o m plete d ≤6 m ont hs pri or t o scree ni n g; if n ot a vaila ble, a fres h bi o ps y ma y b e i n cl u de d i n t he scree ni n g pr ocess.   T he tiss ue bi o ps y ta ke n o n 
Da y 9 8 ca n b e p erf or me d ± 2 wee ks fr o m t his st u d y visit; h o we ver, t h e p atie nt ma y o pt o ut of t h e Da y 9 8 bi o ps y after a disc us si on wit h a p h ysicia n  a n d d oc u me ntati o n  i n t he 
patie nt’s c hart . If a t u m or bi o ps y is n ot feasi ble, a bi o ps y ma y b e d o n e at a s u bse q u e nt visit wit h a p pr o val pr o vi d e d b y t he S p o ns or.  

I m m u ne Desi g n  
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 1 8  of 1 2 8  
 
q.  O nce patie nts h a ve pr o gresse d  a n d st u d y dr u gs are disc o nti n u e d f or m ore t h a n 3 0 d a ys , t h eir p h ysicia ns will b e c o ntacte d b y t he sites e ver y 3 m o nt hs b y tele p h o ne u ntil t he 
st u d y is c o m plete d (last p atie nt, last d eat h i n t h e st u d y) t o assess O S.  T h e atte n di n g p h ysicia n will be c o ntacte d q u arterl y or data base searc he d  u ntil st u d y c o m pleti o n f or 
i de ntificati o n of s u bse q u e nt treat me nts a n d s ur vi val stat us. 

I m m u ne Desi g n  
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 1 9  of 1 2 8  
 
T a ble 2 
Sc he d ule  of E ve nts – C o ntr ol Ar m   
 
Scree ni n g  
Tre at me nt P h ase  
M ai nte n a nce  P h ase  
S ur vi v al 
F oll o w -u p n 
Visit  
1 
2 
3 
4 
5 
6 
7 
8 
9 
1 0 +  
 
Ti meli ne – Wee ks
a 
-4 t o 0  
0 
3 
6 
9 
1 0  
1 2  
1 4  
1 5  
E ver y 
3 w ks b 
E ver y 3 
m o nt hs ( 1 2 
w ks)  
Pr oce d ures  
Ti meli ne –  D a ys  
-3 0 t o -1  
0  
2 1  
4 2  
6 3  
7 0  
8 4  
9 8  
1 0 5  
 
 
I nf or me d c o nse nt/ HI P A Ac 
X  
 
 
 
 
 
 
 
 
 
 
I ncl usi o n/e xcl usi o n criteria 
X  
 
 
 
 
 
 
 
 
 
 
De m o gra p hics/ me dical hist or y  
X  
 
 
 
 
 
 
 
 
 
 
T u m or -s pecific t hera p y hist or y 
X  
 
 
 
 
 
 
 
 
 
 
N Y -E S O -1 e x pressi o n o n pre -st u d y t u m or sa m ple scree nd 
X  
 
 
 
 
 
 
 
 
 
 
E nr oll me nt a n d ra n d o mizati o n  
 
X  
 
 
 
 
 
 
 
 
 
Re p ort A Es a n d S A Es  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Rec or d a n y pre vi o us/c o nc o mit a nt me dicati o ns  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Vital si g ns e 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
P h ysical e xa m f 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
E C G ( 1 2 -Lea d)  
X  
 
 
 
 
 
 
 
X  
 
 
T u m or sta gi n g, b y C T sca n g 
X  
 
 
X  
 
 
X  
 
 
X  
 
E C O G  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
HI V, He p B, a n d He p C ( 5 m L)  
X  
 
 
 
 
 
 
 
 
 
 
Bl o o d f or cell ular i m m u nit y ( 5 5  m L) h 
X  
X  
 
X  
 
X  
 
X  
 
 
 
Bl o o d f or safet y la bs ( 1 0 m L) i 
X  
X  
X  
X  
X  
 
X  
 
X  
X  
 
T h yr oi d f u ncti o n tests j 
X  
 
 
 
 
 
X  
 
 
X j 
 
Uri nal ysis  
X  
 
 
 
 
 
 
 
 
 
 
Uri ne sa m ple f or pre g na nc y test k 
X  
X  
X  
X  
X  
 
X  
 
X  
X  
 
St u d y dr u g: atez oliz u ma b  
 
X  
X  
X  
X  
 
X  
 
X  
X l 
 
T u m or bi o ps y m  & b  
X  
 
 
X  
 
 
 
X m  
 
X b  
 
S ur vi val Stat us  
 
 
 
 
 
 
 
 
 
 
X n 
Bl o o d v ol u me per visit ( m L)  
7 0  
6 5  
1 0  
6 5  
1 0  
5 5  
1 0  
5 5  
1 0  
 
 
T otal bl o o d v ol u me  
7 0  
1 3 5  
1 4 5  
2 1 0  
2 2 0  
2 7 5  
2 8 5  
3 4 0  
3 5 0  
 
 
A b bre viati o ns: A E = a d verse e ve nt, C T  = c o m p ute d t o m o gra p h y; E C G = 1 2 -lea d electr o car 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; He p B = he patitis B; 
He p C  = he patitis C; HI P A A = H u ma n i ns ura n ce P orta bilit y a n d Ac c o u nta bilit y Act; HI V = H u ma n i m m u n o d eficie n c y Vir us; S A E = seri o us a d verse e ve nt.  
a. A wi n d o w of ± 3 d a ys is p er mitte d f or Visits 3 t hr o u g h 9 . F oll o w-u p p h ase visits ( Visits 1 0 +) will b e p er mitte d a wi n d o w of ± 4 da ys , T u m or assess me nts will be per mitte d a 
wi n d o w of ± 1 wee k . 

I m m u ne Desi g n  
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 2 0  of 1 2 8  
 
b.  P atie nts will b e f oll o we d wit h visits e ver y 3 wee ks ( ± 4 d a ys) f or 2 years (fr o m Da y 0) f or atez oliz u ma b treat me nt u ntil pr o gressi o n. T u m or size will be assesse d e ver y 6 wee ks 
f or t he first year, t h e n e ver y 1 2 wee ks u ntil pr o gressi o n. P atie nts will t h e n h a ve n o f urt h er sta gi n g pr o ce d ures .  T u m or bi o psies will be o btai ne d at 6 m o nt hs or l o n ger f or 
patie nts wit h treat me nt res p o nse.  T u m or b i o psies will als o b e o btai n e d at ti me of pr o gressi o n.    
c. I nf or me d c o nse nt a n d HI P A A a ut h orizati o n m ust b e si g n e d b ef ore a n y s cree ni n g st u d y-relate d pr o ce d ures are i nitiate d. Three  i nf or me d c o nse nts will be use d: o ne t o scree n 
t u m or sa m ple f or N Y-E S O - 1, o n e t o e n ga ge i n t h e st u d y pr ot o c ol , a n d a n a gree me nt t o c o nti n u e i n t he st u d y if t h e p atie nt meets t he criteria f or pr o gressi ve disease b ut wis hes t o 
re mai n o n st u d y.  
d.  D oc u me ntati o n  of N Y -E S O -1 e x pressi o n i n  pri or  t u m or sa m ples ma y h a ve b ee n c ollecte d fr o m a n y pr o ce d ure p erf or me d bef ore baseli ne acti vities. T here is n o ti me li mit f or 
use of t he res ults fr o m t h e I M D Z-a p pr o ve d ce ntral la b. 
e. Vital si g n meas ure me nts i n cl u d e te m p erat ure, p ulse,  res pirat or y rate, a n d resti n g s yst olic a n d diast olic bl o o d press ure. O n t he da y of e ac h d osi n g, vital si g ns will be o btai ne d 
pre- d osi n g a n d 3 0 mi n utes after d osi n g.   F or t h e first atez oliz u ma b i nf usi o n, t h e p atie nt’s vital si g ns ( H R, res pirat or y rate , B P, a n d te m perat ure) s h o ul d be meas ure d wit hi n 1 5 
mi n ute s of t h e i nf usi o n , d uri n g t he 6 0-mi n ute i nf usi o n (e ver y 1 5 [ ±  5] mi n utes), a n d 3 0 mi n utes after t h e i nf usi o n.  F or s u bse q ue nt i nf usi o ns, vital si g ns d o n ot nee d t o be 
o btai ne d d uri n g t h e i nf usi o n if  t h e pri or i nf usi o n was t olerate d wit h o ut s y m pt o ms. 
f. O nce t he baseli n e p h ysical e x a m h as b ee n c o n d u cte d, a si m ple s y m pt o m -directe d p h ysic al e xa m s h o ul d b e p erf or me d f or all s u bse q ue nt visits.  Hei g ht a n d wei g ht will be 
c ollecte d at Da y 0 o nl y.  
g.  I ma gi n g will be p erf or me d  b y C T sca n as d efi n e d b y R E CI S T/ir R C at scree ni n g a n d  e ver y 6 wee ks after first st u d y i njecti o n  f or t he first year, t he n e ver y 1 2 wee ks f or t u m or 
sta gi n g u ntil disease pr o gressi o n  a n d i n cl u d es a c o nfir mat or y s ca n p erf or me d at least 4 wee ks late r. M RI, bo n e sca ns  or P E T/ C T  at baseli ne or s u bse q ue nt visits will be 
perf or me d o nl y if cli nicall y i n dicate d.  
h.  Bl o o d f or i m m u n o ge nicit y will b e c ollecte d at  cli nical sites t h at are trai n e d i n p eri p h eral bl o o d m o n o n u clear cells ( P B M C) is olati o n. Baseli ne sa m ples will be dra w n t wic e t o 
e ns ure a g o o d yiel d. At least 5 5 m L s h o ul d b e c ollecte d i n 8 Cell Pre p arati o n T u b es ( C P T )™  t u b es f or T -cell res p o nse assa ys.   See t he La b Ma n ual f or pr ocessi n g details.  
i. I nitial safet y la bs are t o b e p erf or me d wit hi n 4 da ys b ef ore treat me nt i nitiati o n. O n treat me nt d a ys  duri n g t h e st u d y d osi n g peri o d, t he he mat ol o g y a n d cli nical c he mistr y 
la b orat ories m ust als o b e p erf or me d a n d re vie we d b ef ore d osi n g a n d ma y b e p erf or me d u p t o 4 8 h o urs pri or t o t h e pla n ne d d osi n g.  
j. T h yr oi d f u ncti o n tests (trii o d ot h yr o ni n e [ T 3 ], t h yr o xi n e [ T4 ], a n d t h yr oi d sti m ulati n g h or m o n e [ T S H]) s h o ul d b e ta ke n at i nitial scree ni n g a n d at least e ver y 3 m o nt hs w hi le 
bei n g treate d wit h atez oliz u ma b . As t h yr oi d dis or d ers c o ul d o cc ur at a n y ti me as a res ult of atez oliz u ma b  treat me nt, p atie nts s h o ul d be m o nit ore d f or c ha n ges i n t h yr oi d f u ncti o n 
f or cli nical si g ns a n d s y m pt o ms of t h yr oi d dis or d ers (at t h e start of treatme nt, p eri o dicall y d uri n g treat me nt, a n d as i n dicate d base d o n cli nical e val uati o n).  
k.  Uri ne pre g na n c y test m ust b e p erf or me d f or w o me n of c hil d b eari n g p ote ntial wit hi n 7 2 h o urs b ef ore st u d y dr u g a d mi nistrati o n a n d ne gati ve bef ore st u d y dr u g a d mi nistrati o n , 
i ncl u di n g d uri n g t h e f oll o w-u p p eri o d if atez oliz u ma b  a d mi nistrati o n is c o nti n u e d . Ser u m pre g n a n c y test ma y b e p erf or me d if t he site’s sta n dar d o perati n g pr oce d ures all o w.  
l. Ate z oliz u ma b  s h o ul d b e c o nti n u e d e ver y 3 we e ks f or 2 ye ars (fr o m Da y 0) or u ntil disease pr o gressi o n  u nless t o xicit y occ urs.  
m.  T he pre -treat me nt bi o ps y m ust b e c o m plete d ≤6 m o nt hs pri or t o scree ni n g; if n ot a vaila ble, a fres h bi o ps y ma y b e i n cl u de d i n t he scree ni n g pr ocess.   T he tiss ue bi o ps y ta ke n o n 
Da y 9 8 ca n b e p erf or me d ± 2 wee ks fr o m t his st u d y visit; h o we ver, t h e p atie nt ma y o pt o ut of t h e Da y 9 8 bi o ps y after a disc ussi o n wit h a p h ysicia n a n d d oc u me ntati o n  i n t he 
patie nt’s c hart .  If a t u m or bi o ps y is n ot feasi ble, a bi o ps y ma y b e d o n e at a s u bse q u e nt visit wit h a p pr o val pr o vi d e d b y t he S p o ns or.  
n.  O nce patie nts h a ve pr o gresse d  a n d st u d y dr u gs are disc o nti n u e d f or m ore t h a n 3 0 d a ys , t h eir p h ysicia ns will b e c o ntacte d b y t he sites e ver y 3 m o nt hs b y tele p h o ne u ntil t he 
st u d y is c o m plete d (last p atie nt, last d eat h i n t h e st u d y) t o assess O S.  T h e atte n di n g p h ysicia n will be c o ntacte d  q u arterl y u ntil st u d y c o m pleti o n f or i de ntificati o n of s u bse q ue nt 
treat me nts a n d s ur vi val stat us. 
 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 2 1  of 1 2 8  
 
 
Fi g ure  1 D osi n g Sc he d ule f or E ac h Tre at me nt Ar m  
A.  C o m bi n ati o n Tre at me nt Ar m  
 
 
B.   C o ntr ol Ar m  
 
A b bre viati o ns: P B M C = p e ri p h eral bl o o d m o n o n u clear cell; C PI  = c h ec k p oi nt i n hi bit or . 
Re d s yri n ge = L V 3 0 5 i njecti o ns; Gre e n arr o ws = G 3 0 5 i njecti o ns; bl u e a nti b o dies i n dicate atez oliz u ma b  treat me nt d a ys. 
T he c o m bi nati o n treat me nt ar m will c o nsist of a d mi nistrati o n of C M B 3 0 5 a n d atez oliz u ma b  ( A). D osi n g of C M B 3 0 5 ( L V 3 0 5 
a n d G 3 0 5) will o cc ur e ver y 2  we e ks b e gi n ni n g wit h t h e a d mi nistrati o n of 2 c o nsec uti ve d oses of L V 3 0 5  f oll o we d b y alter nati n g 
a d mi nistrati o n of G 3 0 5 a n d L V 3 0 5 f or 1 2 wee ks  (i.e. d uri n g t h e Treat me nt P h ase). A tez oliz u ma b will b e a d mi nistere d e ver y 3 
we e ks. T he c o ntr ol ar m ( B) wi ll recei v e d atez oliz u ma b  al o n e e ver y 3  wee ks.  
N ote :  F or t he c o m bi n e d treat me nt ar m ( A), t h e trial will b e c o n d u cte d i n 4 p h ases: Treat me nt P h ase (st u d y Da ys 0 t o 8 4), 
B o oster P hase ( p ost Da y 8 4 t o 1 year p ost Da y 0), Mai nte n a n ce P h ase (fr o m 1 year t o 2 years p ost Da y 0), a n d S ur vi val F oll o w -
u p P hase ( q uarterl y t h ereafter).  F or t h e c o ntr ol ar m ( B), t h e trial will b e c o n d u cte d i n 3 p h ases: Treat me nt P h ase (st u d y Da ys 0 t o 
8 4), Mai nte na nce P h ase ( p ost Da y 8 4 t o 2 years p ost Da y 0), a n d S ur vi val F oll o w -u p P h a se ( q u arterl y t h ereaft er).  D osi n g wit h 
atez oliz u ma b  ma y c o nti n u e u p t o 2 years u ntil c o nfir me d pr o gressi o n  i n b ot h treat me nt ar ms. G 3 0 5 ma y b e gi v e n e ver y 6 wee ks 
f oll o wi n g t he Da y 8 4 d ose  f or u p t o 1 year (fr o m Da y 0) as a b o oster i njecti o n d uri n g t h e re sta gi n g f oll o w-u p visits.  

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 2 2  of 1 2 8  
 
 
T A B L E O F C O N T E N T S  
I N V E S TI G A T O R A G R E E M EN T P A G E  ................................................................................... 2 
S T U D Y S Y N O P SI S  ....................................................................................................................... 4 
T A B L E O F C O N T E N T S  ............................................................................................................ 2 2 
LI S T O F T A B L E S  ....................................................................................................................... 2 7 
LI S T O F FI G U R E S  ..................................................................................................................... 2 7 
LI S T O F A P P E N DI C E S  ............................................................................................................. 2 7 
1. 0  
G E N E R A L I N F O R M A TI O N  ......................................................................................... 2 8 
1. 1  
S p o ns or a n d I n vesti gat or I nf or mati o n  ................................................................... 2 8 
1. 2  
Pr ot oc ol Re visi o n Hist or y  ...................................................................................... 2 8 
2. 0  
LI S T O F A B B R E VI A TI O N S  ......................................................................................... 3 0 
3. 0  
I N T R O D U C TI O N A N D R A TI O N A L E ......................................................................... 3 4 
3. 1  
S u m mar y of K n o w n a n d P ote ntial Ris ks t o H u ma n S u bjects ................................ 3 8 
3. 2  
St u d y R ati o nale  ...................................................................................................... 4 1 
4. 0  
O B J E C TI V E S  .................................................................................................................. 4 2 
4. 1  
O bjecti ves  .............................................................................................................. 4 2 
4. 1. 1  
Pri mar y O bj ecti ve  ................................................................................. 4 2 
4. 1. 2  
Sec o n dar y O bj ecti ves  ............................................................................ 4 2 
4. 1. 3  
E x pl orat or y O bjecti ves .......................................................................... 4 2 
4. 2  
E n d p oi nts  ............................................................................................................... 4 3 
4. 2. 1  
Pri mar y E n d p oi nts  ................................................................................. 4 3 
4. 2. 2  
Sec o n dar y E n d p oi nts  ............................................................................. 4 3 
4. 2. 3  
E x pl orat or y E n d p oi nt  ............................................................................ 4 3 
4. 2. 4  
Safet y E n d p oi nts  ................................................................................... 4 3 
5. 0  
I N V E S TI G A TI O N A L P L A N ......................................................................................... 4 5 
5. 1  
O verall Trial D esi g n a n d Pla n ................................................................................ 4 5 
5. 2  
D osi n g Re gi me n a n d Rati o nale  ............................................................................. 4 7 
5. 3  
Rati o nale f or D ose Sel ecti o n  ................................................................................. 4 7 
5. 4  
Safet y M o nit ori n g  .................................................................................................. 4 8 
5. 4. 1  
Safet y R u n -i n ........................................................................................ 4 8 
5. 4. 2  
D o se-Li miti n g T o xicities  ...................................................................... 4 9 
5. 4. 3  
T o xicities Ass ociate d wit h Atez oliz u ma b  ............................................. 5 0 
5. 5  
St u d y St o p pi n g R ule  .............................................................................................. 5 1 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 2 3  of 1 2 8  
 
 
5. 6  
D osi n g D ela ys/ D ose M o dificati o ns  ....................................................................... 5 1 
5. 7  
O verall St u d y D urati o n a n d F oll o w- U p  ................................................................. 5 2 
5. 8  
I n d e pe n de nt Data M o nit ori n g C o m mittee ( D M C) ................................................ 5 2 
5. 9  
Arc hi val Tiss ue  ...................................................................................................... 5 3 
6. 0  
S E L E C TI O N A N D WI T H D R A W A L  O F P A TI E N T S  ................................................ 5 5 
6. 1  
I n cl usi o n Criteria ................................................................................................... 5 5 
6. 2  
E x cl usi o n Criteria  .................................................................................................. 5 5 
6. 3  
St u d y Disc o nti n uati o n a n d Patie nt Wit h dra wal Criteria  ........................................ 5 8 
7. 0  
S T U D Y T R E A T M E N T S  ................................................................................................. 6 2 
7. 1  
I n v esti gati o nal Dr u gs ............................................................................................. 6 2 
7. 1. 1  
L V 3 0 5  ................................................................................................... 6 2 
7. 1. 1. 1  
I n v esti gati o nal Dr u g Pac ka gi n g a n d La beli n g ................. 6 3 
7. 1. 1. 2  
St ora ge a n d Dis p ositi o n of t he I n vesti gati o nal Dr u g 
Pr o d ucts  ............................................................................ 6 3 
7. 1. 1. 3  
D ose Pre parati o n f or A d mi nistrati o n t o t he Patie nt  ......... 6 3 
7. 1. 2  
G 3 0 5  ...................................................................................................... 6 3 
7. 1. 2. 1  
I n v esti gati o nal Dr u g Pac ka gi n g a n d La beli n g ................. 6 3 
7. 1. 2. 2  
St ora ge a n d Dis p ositi o n of t he I n vesti gati o nal Dr u g 
Pr o d ucts  ............................................................................ 6 4 
7. 1. 2. 3  
D ose Pre parati o n f or A d mi nistrati o n t o t he Patie nt  ......... 6 4 
7. 1. 3  
Atez oliz u ma b  ........................................................................................ 6 4 
7. 1. 3. 1  
I n v esti gati o nal Dr u g Pac ka gi n g a n d La beli n g ................. 6 4 
7. 1. 3. 2  
St ora ge a n d Dis p ositi o n of t he Dr u g Pr o d uct    ................ 6 5 
7. 1. 3. 3  
D ose Pre parati o n f or A d mi nistrati o n t o t he Patie nt  ......... 6 5 
7. 2  
Treat me nt A d mi nistrati o n  ...................................................................................... 6 5 
7. 2. 1  
Ra n d o mizati o n  ...................................................................................... 6 6 
7. 2. 2  
D ose M o dificati o n G ui deli nes  .............................................................. 6 6 
7. 3  
Dr u g Acc o u nta bilit y ...............................................................................................6 7  
7. 4  
Pri or a n d C o nc o mita nt T hera p y  ............................................................................. 6 7 
7. 4. 1  
Pri or T hera p y  ........................................................................................ 6 7 
7. 4. 2  
Pr o hi bite d C o nc o mita nt T hera p y  .......................................................... 6 8 
7. 4. 3  
Per mitte d C o nc o mita nt T hera p y  ........................................................... 6 9 
7. 4. 4  
S u p p orti ve Care G ui deli nes f or Atez oliz u ma b Treat me nt  .................... 6 9 
7. 4. 4. 1  
I nf usi o n-relat e d Reacti o ns ............................................... 7 0 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 2 4  of 1 2 8  
 
 
7. 5  
Diet/ Acti vit y/ Ot her C o nsi derati o ns  ....................................................................... 7 0 
7. 5. 1  
Diet  ........................................................................................................ 7 0 
7. 5. 2  
C o ntrace pti o n  ........................................................................................ 7 1 
8. 0  
S T U D Y P R O C E D U R E S  ................................................................................................. 7 2 
8. 1  
Visit Wi n d o ws  ....................................................................................................... 7 2 
8. 2  
St u d y Visits  ............................................................................................................ 7 2 
8. 2. 1  
Scree ni n g Visit(s): Wee ks  - 4 t o 0 ( Da ys - 3 0 t o -1)  ............................... 7 2 
8. 2. 2  
Wee ks  0-1 2 Treat me nt Visits ( Treat me nt P hase, St u d y D a ys  0 t o 
8 4)  ......................................................................................................... 7 4 
8. 2. 3  
P ost- C M B 3 0 5 L o n g -t er m Treat me nt St u d y Visits ............................... 7 5 
8. 2. 3. 1  
B o oster P hase ( C o m bi ne d Treat me nt Ar m O nl y: p ost 
Da y 8 4 t o 1 year p ost Da y 0)  ........................................... 7 5 
8. 2. 3. 2  
Mai nte na nce P has e ( C o m bi ne d Treat me nt Ar m: Fr o m 
1 Year t o 2 Y ears P ost D a y  0; C o ntr ol Ar m: P ost Da y 
8 4 t o 2 Years P ost Da y 0)  ................................................ 7 6 
8. 2. 4  
L o n g T er m F oll o w- u p ( S ur vi val F oll o w- u p P hase)  .............................. 7 7 
9. 0  
A S S E S S M E N T S O F E F FI C A C Y A N D S A F E T Y  ........................................................ 7 8 
9. 1  
Ti mi n g of Assess me nts  .......................................................................................... 7 8 
9. 2  
De m o gra p hics, M e dical Hist or y, a n d Baseli ne C haract eristics  ............................. 7 8 
9. 3  
Efficac y Assess me nts ............................................................................................. 7 8 
9. 3. 1  
T u m or Res p o nse Base d u p o n R E CI S T a n d ir R C  ................................. 7 8 
9. 3. 2  
I m m u ne Res p o ns e ................................................................................. 7 8 
9. 3. 3  
E x pl orat or y Bi o mar kers  ........................................................................ 7 9 
9. 4  
Safet y Assess me nts  ................................................................................................ 7 9 
9. 4. 1  
Defi niti o ns  ............................................................................................. 7 9 
9. 4. 2  
A d ve rse E v e nt Se verit y ......................................................................... 8 1 
9. 4. 3  
Relati o ns hi p t o I n vesti gati o nal Dr u g  .................................................... 8 2 
9. 4. 4  
A d verse E v e nt C ollecti o n Peri o d  .......................................................... 8 2 
9. 4. 5  
A d verse E v e nt Re p orti n g  ...................................................................... 8 2 
9. 4. 6  
Seri o us A d verse E v e nt Re p orti n g  ......................................................... 8 3 
9. 4. 7  
A d verse E v e nt F oll o w- u p  ..................................................................... 8 4 
9. 4. 8  
Me dical E ve nts of I nt erest  .................................................................... 8 5 
9. 4. 9  
Pre g n a nc y  .............................................................................................. 8 6 
9. 4. 1 0  
La b or at or y Safet y Assess me nts  ............................................................ 8 7 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 2 5  of 1 2 8  
 
 
9. 4. 1 0. 1  
T h yr oi d F u ncti o n Tests  .................................................... 8 8 
9. 4. 1 1  
Ot her La b or at or y Tests  ......................................................................... 8 8 
9. 4. 1 2  
Vital Si g ns  ............................................................................................. 8 9 
9. 4. 1 3  
P h ysical E x a mi nati o n  ............................................................................ 8 9 
9. 4. 1 4  
1 2- Lea d Electr ocar di o gra m ( E C G)  ....................................................... 8 9 
9. 4. 1 5  
L V 3 0 5 Persiste nce  ................................................................................ 8 9 
1 0. 0  
S T A TI S TI C A L C O N SI D E R A TI O N S  ........................................................................... 9 0 
1 0. 1  
St u d y E n d p oi nts  ..................................................................................................... 9 0 
1 0. 2  
Data A nal ysis  ......................................................................................................... 9 0 
1 0. 2. 1  
A na l ysis P o p ulati o ns ............................................................................. 9 0 
1 0. 2. 2  
A nal ys es  ................................................................................................ 9 0 
1 0. 2. 2. 1  
Patie nt Dis p ositi o n  ........................................................... 9 0 
1 0. 2. 2. 2  
Baseli ne C haracteristics  ................................................... 9 0 
1 0. 2. 2. 3  
Treat me nt A d mi nistrati o n/ C o m plia nce ............................ 9 1 
1 0. 2. 2. 4  
Efficac y A nal yses  ............................................................ 9 1 
1 0. 2. 2. 5  
Safet y  ............................................................................... 9 2 
1 0. 2. 2. 6  
E x p l orat or y ...................................................................... 9 2 
1 0. 3  
I nteri m A nal ysis ..................................................................................................... 9 3 
1 0. 3. 1  
Sa m ple Size  ........................................................................................... 9 4 
1 0. 4  
M ulti plicit y  ............................................................................................................ 9 4 
1 1. 0  
DI R E C T A C C E S S T O S O U R C E D A T A/ D O C U M E N T A TI O N  ................................ 9 5 
1 2. 0  
D A T A Q U A LI T Y C O N T R O L  A N D Q U A LI T Y A S S U R A N C E ................................. 9 5 
1 3. 0  
E T HI C A L C O N SI D E R A TI O N S  .................................................................................... 9 6 
1 3. 1  
I n d e pe n de nt Et hics C o m mittee (I E C) or I nstit uti o nal Re vie w B o ar d (I R B) ......... 9 6 
1 3. 2  
Et hical C o n d uct of t he St u d y  ................................................................................. 9 6 
1 3. 3  
Patie nt I nf or mati o n a n d C o nse nt  ........................................................................... 9 6 
1 3. 4  
Patie nt C o nfi de ntialit y  ........................................................................................... 9 7 
1 4. 0  
D A T A H A N D LI N G A N D R E C O R D K E E PI N G  .......................................................... 9 7 
1 4. 1  
Case Re p ort F or ms  ................................................................................................. 9 7 
1 4. 2  
R ec or d Rete nti o n  ................................................................................................... 9 7 
1 5. 0  
FI N A N CI N G A N D C O M P E N S A TI O N  ......................................................................... 9 8 
1 6. 0  
C H A N G E S I N S T U D Y C O N D U C T  .............................................................................. 9 8 
1 6. 1  
Pr ot oc ol A me n d me nts  ............................................................................................ 9 8 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 2 6  of 1 2 8  
 
 
1 6. 2  
Pr ot oc ol De viati o n Re p orti n g  ................................................................................ 9 8 
1 7. 0  
P U B LI C A TI O N P O LI C Y  ............................................................................................... 9 9 
1 8. 0  
R E F E R E N C E S  ............................................................................................................... 1 0 0 
A P P E N DI C E S  ............................................................................................................................ 1 0 4 
 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 2 7  of 1 2 8  
 
 
LI S T O F T A B L E S  
Ta ble  1 
Sc he d ule of E ve nts – C o m bi nati o n Treat me nt Ar m  .............................................. 1 6 
Ta ble  2 
Sc he d ule of E ve nts – C o ntr ol Ar m  ........................................................................ 1 9 
Ta ble  3 
L V 3 0 5 Dr u g Pr o d uct C o m p o ne nts  ........................................................................ 6 2 
Ta ble  4 
A d verse E v e nt Se verit y Assess me nt  ...................................................................... 8 1 
Ta ble  5 
Assess me nt of Relati o ns hi p  ................................................................................... 8 2 
 
LI S T  O F F I G U R E S 
Fi g ure  1 
D osi n g Sc he d ul e f or E ac h Treat me nt Ar m  ............................................................ 2 1 
Fi g ure  2 
L V 3 0 5 Bi n di n g a n d E ntr y via D C- SI G N i nt o D Cs, I n d u cti o n of C D 8 T- Cell 
Res p o nses a n d S u bse q ue nt T u m or Cell Killi n g ..................................................... 3 5 
Fi g ure  3 
I nteracti o n of Pr o d ucts a n d Cells i n a Z Ve x ™ Pri me, G L A A S B o ost t hat 
Ge ner ates a S y ner gistic I m m u ne Res p o nse t o L ys e T u m or Cells  ......................... 3 6 
Fi g ure  4 
T hera p e utic Efficac y A gai nst S u bc uta ne o us T u m or Gr o wt h of a 7- d ose 
Se q ue ntial C o m bi nat orial Re gi me n of Z V e x 2. 0/ m T R P 1 a n d rec o m bi na nt 
m T R P 1/ G L A- S E i n C 5 7 B L/ 6 Mice Wit h or Wit h o ut a nti- P D - 1/ P D-L 1 
bl oc ka de  ................................................................................................................. 3 8 
Fi g ure  5 
C o n diti o ns f or C o nti n ui n g Atez oliz u ma b Al o ne or i n C o m bi nati o n i n t he 
Prese nce of  I ncreas e d Ra di o gra p hi c T u m or Size .................................................. 6 0 
 
LI S T O F A P P E N DI C E S  
A p pe n di x A  
E C O G Perf or ma n ce Stat us  .................................................................................. 1 0 4 
A p pe n di x B  
Me dical E ve nts of I nt erest  ................................................................................... 1 0 5 
A p pe n di x C  
R E CI S T a n d I m m u ne- R elate d Res p o nse Criteria ................................................ 1 0 7 
A p pe n di x D  
C o m paris o n of R E CI S T v 1. 1 vs. R E CI S T- base d ir R C  ....................................... 1 0 9 
A p pe n di x E  
Pree xisti n g A ut oi m m u ne Dise ases  ...................................................................... 1 1 1 
A p pe n di x F  
D ose M o dificati o n a n d S u p p orti ve Care G ui deli nes f or Atez oliz u ma b  .............. 1 1 2 
 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 2 8  of 1 2 8  
 
 
1. 0  
G E N E R A L  I N F O R M A TI O N 
1. 1  
S p o ns or a n d I n vesti g at or I nf or m ati o n 
Tri al S p o ns or 
I m m u ne Desi g n C or p orati o n 
1 6 1 6 Eastla ke A ve. E, S uite 3 1 0 
Seattle, W A 9 8 1 0 2 
 
S p o ns or’s Me dic al M o nit or  
 
I m m u ne Desi g n C or p orati o n 
6 0 1 Gate wa y Bl v d., S uite 2 5 0 
S o ut h Sa n Fra ncisc o, C A 9 4 0 8 0 
 
 
 
Le a d Pri nci p al I n vesti g at or 
R o bert Ma ki, M. D, P h D, M o u nt Si nai Me dical Ce nter, Ne w Y or k, N Y 
 
1. 2  
Pr ot oc ol  R e visi o n Hist or y  
Versi o n  Date  
C o m me nt 
0 1 
2 9 J ul y 2 0 1 5 
I nitial versi o n 
0 2 
2 7 Se pte m ber 
2 0 1 5 
Re vise d t he atez oliz u ma b ris k pr ofile a n d A E ma na ge me nt 
g ui deli nes a n d c orrecte d i nter nal i nc o nsiste ncies , ad de d t o xicities 
attri bute d t o atez oliz u ma b i n t he D L T e val uati o n, u p date d ti mi n g of 
i m m u n o ge nicit y bl o o d dra ws, a d de d assess me nts f or a nti-
t hera pe utic a nti b o dies a n d t h yr oi d f u n cti o n, u p date d a n d si m plifie d 
j ustificati o n of sa m ple size a n d i nteri m a nal ysis, a d de d M E OI 
P P D
P P D

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 2 9  of 1 2 8  
 
 
defi niti o ns t o a ne w A p p e n di x B, a n d clarifie d t u m or i nter pretati o n 
g ui deli nes. 
0 3 
0 8 Marc h  
2 0 1 7 
O verall S ur vi val was a d d e d t o t he pri mar y o bjecti ve a n d st u d y 
e n d p oi nt.  T he e val uati o n of t he i m m u ne res p o nse a n d hist ol o gic 
a n d m olec ular tiss ue c h a n ges  i n t u m or tiss ue c h a n ges or  peri p heral 
bl o o d, ti me t o ne xt treat me nt, a n d dista nt metastasis free s ur vi val 
were a d de d as s ec o n dar y o bjecti ves a n d st u d y e n d p oi nts.  T he 
e val uati o n of best o verall res p o nse rate a n d d urati o n of res p o nse 
was u p date d t o be e x pl orat or y o bj ecti ves/e n d p oi nts, a n d t he 
e valuati o n of cli nical b e n efit rate  a n d t he q ualit y of life were a d d e d 
as e x pl orat or y o bjecti ves a n d st u d y e n d p oi nts.  C o m paris o n of 
o verall s ur vi val a n d pr o gressi o n- free s ur vi val w as als o a d de d as 
e x pl orat or y e n d p oi nts. Pr o gressi o n-free s ur vi val st u d y e n d p oi nt w as 
u p date d.  T reat me nt p has es ( Treat me nt P hase, B o oster P hase, 
Mai nte na nce  P has e, a n d S ur vi val F oll o w- u p P has e ) were 
i nc or p orate d i nt o t he st u d y desi g n.  Peri p h eral bl o o d a n d tiss ue 
bi o ps y c ollecti o n w as u p date d t o occ ur i n all e nr olle d p atie nts.  F or 
tiss ue bi o psies, Da y 9 8, at 6 m o nt hs or l o n ger (f or patie nts wit h 
treat me nt res p o ns e), a n d t he ti me of pr o gressi o n w ere a d d e d as 
c ollecti o n visits.  I n a d diti o n, f or St u d y Da y 9 8, p eri p heral bl o o d 
a n d tiss ue bi o ps y c ol lecti o n was u p date d t o occ ur ± 2 wee ks a n d 
t hat patie nts ma y o pt o ut of t his bi o ps y o n t his visit.  T u m or bi o ps y 
c ollecti o n pr oce d ures f or patie nts wit h pr o gressi ve disease w as 
clarifie d a n d u p date d.  T he met h o d ol o g y f or t he statistical efficac y 
a nal ysis was u p date d.  T he c ollecti o n of bl o o d f or a nti- t hera p e utic 
a nti b o dies was re m o ve d .  St u d y pr oce d ures w ere clarifie d t o 
ill ustrate t hat 3 i nf or me d c o nse nt f or ms (i ncl u di n g a n a gree me nt t o 
o btai n bl o o d sa m ples a n d bi o psies if t he patie nt pr o gresses  b ut 
wis hes  t o re mai n o n st u d y) are t o b e c ollecte d.  Vital si g ns 
meas ure me nt t i mes were clarifie d.  S ur vi val f oll o w- u p c o ntact 
met h o ds were u p d ate d.  T he st u d y rati o nale w as u p date d.  Details 
re gar di n g t he c ollecti o n of arc hi v al tiss ue were a d de d.  A d diti o nal 
a d mi nistrati ve c ha n ges w ere ma d e t hr o u g h o ut t he d oc u me nt t o 
e ns ure cl arit y a n d c o nsist e nc y t hr o u g h o ut t he pr ot oc ol. 
 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 3 0  of 1 2 8  
 
 
2. 0  
LI S T O F A B B R E VI A TI O N S  
A b bre vi ati o n  
Descri pti o n  
A D L  
acti vities of dail y li vi n g 
A E  
a d verse e ve nt 
A F  
a q ue o us f or m ulati o n 
A g  
a nti ge n 
A L T  
ala ni ne a mi n otra nsferase 
A N C  
a bs ol ute ne utr o p hil c o u nt  
A N O V A  
a nal ysis of varia nce 
A P C  
a nti ge n-prese nti n g cell  
A S T  
as partate a mi n otra nsferase  
A T A  
a nti-t hera pe utic a nti b o dies 
B C T  
bl o o d c ollecti o n t u be  
BI C R  
bli n de d i n de pe n de nt ce ntralize d re vie w  
B P  
bl o o d press ure  
C F R  
C o de of Fe deral Re g ulati o ns  
C H O  
C hi nese ha mster o var y  
CI  
c o nfi de nce i nter val 
C L  
mea n a p pare nt cleara nce  
C PI  
c hec k p oi nt i n hi bit or 
C P T  
Cell Pre parati o n T u bes  
C R F  
Case Re p ort F or m  
C R  
c o m plete res p o nse 
C R P  
C -reacti ve pr otei n 
C S F  
c ol o n y sti m ulati n g fact or 
C T  
ca ncer/testis a nti ge n  or C o m p ute d T o m o gra p h y  
C T L  
c yt ot o xic T -l y m p h oc yte 
D C  
de n dritic cell  
D C -SI G N  
D C -s pecific i ntercell ular a d hesi o n m olec ule- 3- gra b bi n g n o n-i nte gri n 
rece pt or ( C D 2 0 9) 
D L T  
d ose li miti n g t o xicit y  
D M C  
Data M o nit ori n g C o m mittee  
D M F S  
dista nt metastasis free s ur vi val  
D M P C  
1, 2 -di m yrist o yl -s n-gl ycer o -3 -p h os p h oc h oli ne  

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 3 1  of 1 2 8  
 
 
A b bre vi ati o n  
Descri pti o n  
D O R  
d urati o n of res p o nse  
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  
e C R F 
electr o nic C R F 
E D C  
electr o nic data ca pt ure 
E O S  
e n d-of -st u d y visit 
F C B P  
fe male of c hil d beari n g p ote ntial 
F D A  
F o o d a n d Dr u g A d mi nistrati o n  
F F P E  
f or mali n-fi xe d paraffi n-e m be d de d 
G C P  
G o o d Cli nical Practice  
G -C S F  
gra n ul oc yte c ol o n y sti m ulati n g fact or  
G L A  
gl uc o p yra n os yl li pi d A  
G L A A S  
gl uc o p yra n os yl li pi d A a dj u va nt s yste m 
G L A -S E  
gl uc o p yra n os yl li pi d A sta ble e m ulsi o n  
G M -C S F  
gra n ul oc yte -macr o p ha ge c ol o n y sti m ulati n g fact or  
H b  
he m o gl o bi n  
H Bc  
He patitis B c ore a nti ge n  
H Bs A g  
He patitis B s urface a nti ge n  
He p B  
He patitis B  
He p C  
He patitis C  
HI P A A  
Healt h I ns ura nce P orta bilit y a n d Acc o u nta bilit y Act  
HI V  
H u ma n Im m u n o deficie nc y V ir us 
H R  
heart rate  
I B 
I n vesti gat or’s Br oc h ure 
I C F 
inf or me d co nse nt for m  
I C H  
I nter nati o nal C o nfere nce o n Har m o nisati o n  
I M D Z 
I m m u ne Desi g n C or p orati o n 
I D 
i ntra der mal 
I E C 
I n de pe n de nt Et hics C o m mittee 
I F N 
i nterfer o n 
I g 
i m m u n o gl o b uli n 
I H C 
i m m u n o hist oc he mistr y 
I L 
i nterle u ki n 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 3 2  of 1 2 8  
 
 
A b bre vi ati o n  
Descri pti o n  
I M 
i ntra m usc ular 
I N R 
i nter nati o nal n or malize d rati o 
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 
ir C R 
i m m u ne-relate d c o m plete res p o nse 
ir P D 
i m m u ne-relate d pr o gressi ve disease 
ir P R 
im m u ne -relate d partial res p o nse 
ir R C 
im m u ne -relate d res p o nse criteria 
ir S D 
im m u ne -relate d sta ble disease 
I V 
i ntra ve n o us 
I W R S 
i nteracti ve we b res p o nse s yste m 
L V  
le nti viral vect or  
m A b  
m o n ocl o nal  a nti b o d y 
M E OI  
me dical e ve nt of i nterest  
M H C  
maj or hist oc o m pati bilit y c o m ple x  
MI T T  
m o difie d i nte nt -t o-treat 
M RI  
ma g netic res o na nce i ma gi n g  
M R C L  
m y x oi d/r o u n d cell li p osarc o ma  
M T D  
ma xi m u m t olerate d d ose  
N CI C T C A E  
Nati o nal Ca ncer I nstit ute C o m m o n T o xicit y Criteria f or A d verse E ve nts  
N K  
nat ural killer  
N S AI D  
n o nster oi dal a nti -i nfla m mat or y dr u g 
N S C L C  
n o n -s mall-cell l u n g carci n o ma  
O R R  
o verall res p o nse rate  
O S  
o verall s ur vi val  
P A R  
pr o gressi o n arrest rate  
P B M C  
peri p heral bl o o d m o n o n uclear cells  
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 deat h -1 rece pt or 
P D -L 1  
P D -1 li ga n d  
P E T  
p ositr o n e missi o n t o m o gra p h y  
P F R  
pr o gressi o n -free rate 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 3 3  of 1 2 8  
 
 
A b bre vi ati o n  
Descri pti o n  
P F S  
pr o gressi o n -free s ur vi val 
P R  
partial res p o nse  
P T  
pr ot hr o m bi n ti me  
P T T  
partial t hr o m b o plasti n ti me  
R B C  
re d bl o o d cell 
R E CI S T  
Res p o nse E val uati o n Criteria i n S oli d T u m ors  
S A E  
seri o us a d verse e ve nt 
S A P  
Statistical A nal ysis Pla n  
S C  
s u bc uta ne o us 
S D  
sta ble disease 
S E  
sta ble oil i n water e m ulsi o n/sta ble e m ulsi o n 
SI N V  
S i n d bis vir us 
SI N Var 1  
D C -SI G N tar geti n g S i n d bis vir us e n vel o pe gl yc o pr otei n 
SI R S  
s yste mic i nfla m mat or y res p o nse s y n dr o me 
S O P  
sta n dar d o perati n g pr oce d ures 
S V G m u  
S i n d bis v ir us gl yc o pr otei n m uta nt 
T 3 
trii o d ot h yr o xi ne 
T 4 
t h yr o xi ne 
T A A  
t u m or-ass ociate d a nti ge n 
T G R  
t u m or gr o wt h rate 
T L R 4  
t oll-li ke rece pt or 4 
T N F  
t u m or necr osis fact or 
T R P 1  
t yr osi ne-relate d pr otei n-1  
T S H  
t h yr oi d sti m ulati n g h or m o ne 
T T N T  
ti me t o ne xt treat me nt 
U L N  
u p per li mit of n or mal  
U S  
U nite d States  
v g  
vect or ge n o mes  
V ss 
v ol u me of distri b uti o n at stea d y state  
W B C  
w hite bl o o d cell  
 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 3 4  of 1 2 8  
 
 
3. 0  
I N T R O D U C TI O N A N D R A TI O N A L E  
T he de vel o p me nt of i m m u n ot hera pe utic pr o d ucts t hat tar get s pecific t u m ors a n d a p pr o pri atel y 
har ness t he i m m u ne s yste m t o kill t u m or cells is a pr o misi n g a p pr o ac h f or t he treat me nt of 
h u ma n mali g na n cies. E ff ecti ve t her a pe utic i m m u nizati o n strate gies f or ca n cer re q uire t he 
i n d ucti o n of p ote nt, sta ble, a n d self-re n e wi n g C D 8 T cell p o p ulati o ns directe d a gai nst defi ne d 
t u m or-ass ociate d tar gets  ( T A As). Hu ma n t u m or cells e x press a variet y of T A As t hat are n ot 
e x presse d , or ar e mi ni mall y e x presse d , i n n or mal tiss ues, a n d ca n ser ve as tar gets f or t h e h ost 
cell ular i m m u ne s yst e m  t o i n d uce t u m or destr ucti o n. T he de vel o p me nt of effecti ve ca ncer 
t hera pe utic pr o d ucts ma y re q uire b ot h t he i n d ucti o n of a p pr o priat e cell ular i m m u ne res p o nses 
a n d a mec h a nis m t o o ver c o me  e vasi o n mec ha nis ms. 
N Y -E S O -1 is a T A A a n d was o ne of t he first ca n cer-testis ( CT) a nti ge ns ( A g) descri be d.1  It is 
c o nsi dere d o n e of t he t o p te n ca ncer A gs  o n t he list f or all ca n cers. 2 N or mall y, its e x pressi o n is 
restricte d t o ger m cells a n d is n ot see n i n n or mal s o matic tiss ues. H o we ver, N Y -E S O - 1 
e x pressi o n is see n i n a p pr o xi matel y 1/ 4 t o 1/ 3 of mela n o ma, l u n g, es o p ha gea l, li ver, gastric, 
pr ostate, o varia n, a n d bla d der ca n cers. U p t o 4 5 % of mela n o mas a n d ≥8 0 % of sarc o mas re p ort e d 
N Y -E S O -1 e x pressi o n. 3 ,4 ,5 ,6 T h us, i m m u n ot hera pe utics tar geti n g N Y-E S O - 1 ha ve t he p ote ntial t o 
be br oa dl y a p pl ica ble t o a variet y of ca n cer i n dicati o ns.  
I m m u ne Desi g n (I M D Z) has de vel o pe d a le nti viral vect or ( L V)- bas e d i m m u n ot hera pe utic 
platf or m calle d Z V e x ™ e n gi n eer e d t o deli ver A g -e nc o di n g n uclei c aci ds t o de n dritic cells ( D Cs) 
i n viv o7 e na bli n g dir ect A g  pr ese ntati o n t o ge nerat e effecti ve a nti -t u m or C D 8 T cell res p o ns es. 
L V 3 0 5 is a l e ntiviral vect or  t hat e nc o des N Y-E S O -1 a n d is desi g ne d t o ge n erate N Y -E S O - 1-
s pecific C D 8 T- cell p o p ulati o ns i n patie nts w here n o s uc h p o p ulati o ns ca n be detect e d; t here b y 
pri mi n g a T- cell me diate d res p o nse . L V 3 0 5 ca n als o e x pa n d pre-e xistin g N Y -E S O - 1-s pecific 
C D 8 T-cell p o p ulati o ns. 6 
L V 3 0 5 s electi vel y e nt ers D Cs via t he d e n dritic cell-specific intercell ular a d hesi o n m olec ule - 3-
gr a b bi n g n o n- i nte gri n r ece pt or ( D C-SI G N, als o k n o w n as C D 2 0 9; s ee Fi g ure  2). F oll o wi n g cell 
e ntr y a n d tra ns d u cti o n, t he e nc o d e d A g (i.e., N Y- E S O - 1) is e x presse d b y t h e cell ular mac hi ner y 
a n d s u bse q ue ntl y pres e nte d as pe pti des via t he m aj or hist oc o m pati bilit y c o m ple x ( M H C ) class I 
pat h wa y, w hic h, i n a ni m al m o dels, has res ulte d i n t he ge nerati o n of r o b ust C D 8 T- cell res p o ns es 
a n d pr otecti ve a nti- t u m or i m m u nit y. T he pr ot ot y p e vect or utilizes a n e n gi n eere d Si n d bis vir us 
( SI N V) gl yc o pr ot ei n as t he pse u d ot y pi n g e n vel o p e. T his e n vel o pe, Si n d bis vir us gl yc o pr otei n 
m uta nt ( S V G m u), was de m o nstrate d t o utilize t he D C - SI G N rece pt or o n D Cs t o e na ble D C 
tra ns d ucti o n b y v ect or p articles a n d, as a res ult, i n d uce hi g h ma g nit u de C D 8 T-cell i m m u ne 
res p o nses after a si n gle i m m u nizati o n i n mice.8 ,9  

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 3 5  of 1 2 8  
 
 
Fi g ure  2  L V 3 0 5 Bi n di n g a n d E ntr y vi a D C-SI G N i nt o D Cs, I n d ucti o n of C D 8 T -Cell 
Res p o nses a n d S u bse q ue nt T u m or Cell Killi n g  
 
A g  = a nti ge n; D C  = d e n dritic cell; D C -SI G N  = d e n dritic cell -s p ecific i ntercell ular a d h esi o n m olec ule - 3-gra b bi n g n o n -i nte gri n 
rece pt or ( C D 2 0 9); M H C- 1 = maj o r hist o c o m p ati bilit y c o m ple x-1.  
G 3 0 5 is c o m p ose d of a f ull-le n gt h N Y-E S O - 1 rec o m bi na nt pr otei n a n d a n a dj u va nt, 
gl uc o p yr a n os yl li pi d A- sta ble e m ulsi o n (G L A -S E ).6 Gl uc o p yra n os yl li pi d A ( G L A) is a s y nt h etic 
T oll -li ke rece pt or 4 ( T L R 4) a g o nist. T L R 4 is a cell s urface rece pt or f o u n d o n t he s urface of 
ma n y i m m u ne cells s uc h as D Cs, w hic h acti vates t he i n nate i m m u ne res p o nse w he n e x p ose d t o 
e n d ot o xi n li pi d A. G L A i m pr o ves t he i m m u n o ge ni cit y of a wi de variet y of A gs  b y i ncreasi n g t he 
ma g nit u de of t h e T h 1 i m m u ne res p o nse mar ke d b y a hi g h A g- s pecific i m m u n o gl o b uli n (I g) rati o 
of I g G 2:I g G 1 a n d i ncrease d pr o d ucti o n of i nfla m mat or y c yt o ki n es (e. g., i nterfer o n [I F N]γ, t u m or 
necr osis fac t or [ T N F] α, a n d i nterle u ki n [I L]- 1 2). He nce, G L A ca n acti vat e A g -s pecific C D 4 
T cells t hat are k n o w n t o s u p p ort a n d pr o m ote C D 8 T- cell res p o ns es s pecifi c t o t he sa me A g  b y 
pr ol o n gi n g t he s ur vi val a n d e n ha nci n g t he f u n cti o n of t he C D 8 T cells. As a T L R 4 a g o nist, 
G L A -S E is ai me d at acti vati n g A g -pres e nti n g cells ( A P Cs) li ke D Cs t o b o ost t he i m m u ne 
res p o nse t o t he c o-a d mi nistere d A g, i.e., N Y-E S O - 1.6 
C M B 3 0 5 is a n acti ve i m m u n ot hera p y a p pr o ac h t h at c o m bi nes t he 2 differe nt st u d y a ge nts, 
L V 3 0 5 a n d G 3 0 5 . It is desi g ne d t o i n d uce a ntit u m or res p o nses t o t he T A A  N Y -E S O - 1. As 
ill ustrate d i n Fi g ur e  3, eac h a ge nt ca n prefere ntiall y sti m ulate differe nt p orti o ns of t he i m m u ne 
s yste m a n d, w h e n gi ve n se q ue ntiall y, c o m ple me nt eac h ot her , l ea di n g t o a d diti ve, if n ot 
s y ner gistic, eff ects. F urt her  details  ca n be f o u n d i n t he C M B 3 0 5 I B.6 
Tr a ns d ucti o n of D Cs    → → →
M H C -I A g pr es e nt ati o n
D C -SI G N
C D 8 T C ell
R es p o ns e
D C
T u m or C ell
T u m or C ell
D e at h
V ect or P articl es

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 3 6  of 1 2 8  
 
 
Fi g ure  3  I nter acti o n of Pr o d ucts a n d Cells i n a Z Ve x ™ Pri me, G L A A S B o ost t h at 
Ge ner ates a S y ner gistic I m m u ne R es p o nse t o L yse T u m or Cells  
 
C T Ls = c yt ot o xic T -l y m p h o cyte; D C  = d e n dritic cells ; G L A A S = Gl u c o p yr a n os yl li pi d A A dj u va nt S yste m.  
S o urce: Fi g ure  1 of t h e C M B 3 0 5 I B6 
 
P recli nical m o dels, usi n g eit her of t he C M B 3 0 5 c o m p o ne nts ( L V 3 0 5 or G 3 0 5) al o ne ha v e s h o w n 
e n ha nce d i m m u ne res p o nses i n C D 4 a n d C D 8 T-cell res p o nses t o a s pecific A g. T h e se q ue ntial 
a d mi nistrati o n of t he C M B 3 0 5 c o m p o ne nts als o f urt her e n h a nce d t h e res p o nse a n d de m o nstrate d 
t hat t he de vel o p me nt or pri mi n g of C D 8 T cells usi n g a n L V  f oll o we d b y t h e b o osti n g of t he 
i m m u ne res p o nse usi n g a pr otei n-a dj u va nt a p pr oac h ca n lea d t o p ote nt sti m ulati o n of a nti-t u m or 
i m m u nit y.6 T his s o -calle d heter ol o g o us pri me- b o ost a p pr oac h ca pitalizes o n t he a bilit y of eac h 
a ge nt t o sti m ulate differe nt c o m p o ne nts of t he i m m u ne s yste m ( e. g., C D 4 hel per T cells, C D 8 
c yt ol ytic T cells, nat ural killer [ N K ] cells, a nti b o dies, a n d A P Cs ) t hat are re q uire d t o acti vate a n d 
ge n erat e p ote nt a n d l o n g -lasti n g i m m u nit y. Mice treate d wit h t his a p pr oac h ha ve de m o nstrat e d 
t hat L V 3 0 5 pri maril y elicits C D 8 T-cell res p o nses a n d pea k C D 4 T-cell res p o nses are o bs er ve d 
f oll o wi n g b o ost t hera p y wit h G 3 0 5 a d mi nistrati o n. Usi n g a  B 1 6 F 1 0 mela n o ma m o use m o del, the 
c o m bi nati o n of a n L V  wit h se q ue ntial G L A - pr ot ei n d osi n g res ulte d i n great er  C D 4 a n d C D 8 
T- cell res p o ns es a n d r e d uce d t u m or gr o wt h t ha n were s ee n wit h t he use of eit her a ge nt al o ne. 6 
I nteri m res ults fr o m P has e  1 cli nical st u dies wit h eac h c o m p o ne nt of C M B 3 0 5 ha ve als o 
de m o nstrate d fa v ora ble r es p o nses. T he L V 3 0 5 tri al has de m o nstrate d a n i ncreas e d T -cell 
res p o nse a n d d ecr ease d disease pr o gr essi o n i n patie nts treate d wit h t he v ect or. A p pr o xi matel y 
6 7 % of patie nts ha ve ac hie ve d a r es p o nse of sta bl e disease ( S D) wit h a n a v era ge of ~ 2 8 8 da ys 
a n d pr o gressi o n -free rat e (P F R) of 4 2 %. 1 0 Res ults fr o m t he G 3 0 5 st u d y ha v e s h o w n a si g nifica nt 
h u m oral a n d C D 4 T-cell res p o nses a gai nst N Y- E S O - 1 a n d 6 7 % of patie nts ac hie ve d S D wit h a 
mea n d urati o n of 2 4 5 d a ys. 1 1 T he first i n - h u ma n trial wit h t he C M B 3 0 5 c o m bi nati o n pr o d uct is 
c urre ntl y o n g oi n g ( Pr ot o c ol I M D Z- C 1 3 1). W hile  n o i nteri m efficac y res ults are a v aila ble, t he 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 3 7  of 1 2 8  
 
 
p r o d uct is bei n g well t olerate d wit h n o d ose-li miti n g t o xicities (D L Ts ) see n i n t he d ose-
escalati o n p has e of t he tri al . 
T he pr o gra m me d d eat h ( P D )- 1 rece pt or-li ga n d i nt eracti o n is a maj or p at h w a y hijac ke d b y t u m ors 
t o s u p press i m m u ne c o ntr ol.1 2 T he n or mal f u ncti o n of P D-1, e x presse d o n t he cell s urface of 
acti vate d T cells u n der h ealt h y c o n diti o ns, is t o d o w n- m o d ulate u n wa nte d or e x cessi ve i m m u ne 
res p o nses, i ncl u di n g a ut oi m m u ne reacti o ns. P D - 1 bi n ds t w o li ga n ds, pr o gra m me d-deat h rece pt or 
li ga n d-1 ( P D - L 1) a n d P D- L 2. Alt h o u g h h ealt h y or ga ns e x press little (if a n y) pr o gra m me d -deat h 
recep t or- 1 li ga n d (P D -L 1 ), a vari et y of ca n cers were de m o nstrate d t o e x press a b u n da nt le vels of 
t his T-cell i n hi bit or 1 3 ,1 4 w hic h pla ys a critical r ol e i n i m m u ne e vasi o n b y t u m ors 1 5. P D - L 1 als o 
bi n ds t o rece pt or B 7. 1 f o u n d o n acti vate T cells, B cells a n d m o n oc ytes a n d d o w nre g ulates 
i m m u ne res p o nses i n peri p heral tiss ues.1 6 ,1 7 As a c o nse q ue nce, t h e P D - 1/ P D- L 1 pat h wa y is a n 
attracti ve tar get f or t hera pe uti c i nter ve nti o n i n ca n cer. 1 3 
C o nse q ue ntl y, t he a nti -t u m or f u ncti o n of the ne wl y e x pa n de d C D 8 T cell p o p ulati o n  create d b y 
C M B 3 0 5 is at ris k of i n hi biti o n b y i m m u ne c h ec k p oi nts li ke P D - 1/ P D-L 1  f o u n d o n t u m or cells. 
W he n acti vate d, t he P D - 1/P D -L 1 a xis ne gati vel y affects t he a bilit y of T  cells t o pr oliferate, 
ge n erat e c yt o ki nes, a n d kill ca ncer cells. 2 0 ,2 1 Bl oc ki n g t he i nteracti o n of P D-1 wit h its li ga n ds, 
usi n g a m o n ocl o nal a nti b o d y ( m A b) a gai nst P D- L 1 ca n rest ore i m m u ne f u n cti o n a n d e n ha n ce 
a nti-t u m or i m m u ne res p o nses. T he i n hi biti o n of P D- L 1 a n d P D- 1 i nteracti o n i n m o use t u m or 
m o dels has res ulte d i n a nti- t u m or effects.2 2 ,2 3 T o re m o ve t his t u m or-i n d uce d i m m u ne bl oc ka de 
wit h treat me nts s uc h as C M B 3 0 5 f or e n h a nced a nti-t u m or acti vit y, c hec k p oi nt i n hi bit ors ( C PI) 
s uc h as atez oliz u ma b  (f or merl y M P D L 3 2 8 0 A, R oc he) c o ul d b e use d. 
A tez oliz u ma b is a n a nti-P D -L 1 m A b  b ei n g i n v esti gate d as a treat me nt of s oli d t u m ors a n d 
he mat ol o gical mali g n a nces.  Hi g h l e vels of P D-L 1 are e x presse d o n a wi de variet y of ca ncer 
cells, histi oc ytes, a n d ot h er cells wit hi n t he t u m or micr oe n vir o n me nt. T he bi n di n g of P D- 1 o n 
t u m or-i nfiltrati n g T cells t o its li ga n d P D- L 1 l ea ds t o i n hi biti o n of a nti-t u m or i m m u ne acti vit y. It 
has bee n i n vesti gate d i n a rece nt P hase  1a d os e-es calati o n st u d y of 1 4 0 pati e nts i ncl u di n g 
a p pr o xi matel y 2 9 % of p atie nts wit h mela n o ma a n d 2 2 % of patie nts wit h n o n- s mall cell l u n g 
carci n o ma ( N S C L C). 2 4 T he eff ect of t hes e i n hi bit ors i n treati n g s arc o m as is c urre ntl y u n k n o w n. 
Cli nicall y, a nti -P D - 1/P D -L 1 bl o c ki n g a nti b o dies are acti ve as a si n gle a ge nt, b ut are li mite d i n 
t heir a bilit y t o i n d uce o bj ecti ve res p o ns es (c o mplete res p o nse [ C R ] a n d partial res p o nse [ P R ]). It 
is h y p ot hesize d t hat t u m or-reacti ve T cells are prese nt, b ut are b ei n g s u p presse d b y t his pat h wa y 
a n d bl oc ki n g t his a xis w o ul d rest ore a nti-t u m or i m m u nit y. T h us, i n ca ncer p atie nts t he 
P D - 1/P D - L 1 p at h wa y is h y p ot hesize d t o bl oc k t he i m m u ne res p o nse s uc h t hat C D 8 T cells 
ge n erat e d b y t he i m m u ne res p o nse t o C M B 3 0 5 w o ul d be affecte d b y t his pat h wa y. T heref ore, 
C M B 3 0 5 acti vit y ma y b e e n ha nce d if use d wit h a P D - L 1 bl oc ki n g a nti b o d y, es peciall y i n t he 
prese nce o f t u m or e x pressi ng P D -L 1.  

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 3 8  of 1 2 8  
 
 
A p recli nical I M D Z st u d y wit h  mela n o ma ( B 1 6 F 1 0) t u m or-bea ri n g mice acti vel y treate d wit h a n 
L V  e x pressi n g a m o us e h o m ol o g of a T A A ass oci ate d wit h mela n o ma cells ( t yr osi ne-rel ate d 
pr otei n- 1 [ T R P 1 ]) a n d i n c o m bi nati o n wit h a nti -P D - 1 a n d a nti-P D -L 1  t h era p y res ulte d i n 
c o ntr olle d t u m or gr o wt h ( u n p u blis he d I M D Z st u d y dat a, 2 0 1 5). As s h o w n i n Fi g ure  4, res ults 
were si g nifica ntl y b etter wit h t he c o m bi nati o n treat me nt t ha n wit h t he L V pr o d uct al o ne or 
e m pt y-v ect or c o ntr ol.  
Fi g ure  4 T her a pe utic Effic ac y A g ai nst S u bc ut a ne o us T u m o r Gr o wt h of a 7- d ose 
Se q ue nti al C o m bi n at ori al Re gi me n of Z Ve x 2. 0 / m T R P 1 an d rec o m bi n a nt 
m T R P 1/ G L A -S E i n C 5 7 B L/ 6 Mice  Wit h or Wit h o ut a nti-P D -1/ P D -L 1 bl oc k a de  
 
G F P = Gree n fl u oresce nt pr otei n  (vect or c o ntr ol) ; P D 1 = a nti -pr o gra m me d d eat h rece pt or -1 a nti b o d y ( cl o n e R M P 1 -1 4 was 
use d); P D -L 1  = pr o gra m me d d eat h rece pt or li ga n d -1; S C  = s u b c uta n e o us; T R P 1 = a T A A e x press e d i n mela n o ma cells 
(e x presse d via Z V e x 2. 0 le nti viral vect or); w kl y  = we e kl y.  
B 1 6 F 1 0 t u m ors were i m pla nte d i n t h e f o ot p a ds of C 5 7 B L/ 6 mice. At 1 2 d a ys p ost -i m pla ntati o n, t u m ors were p al p a ble a n d o n 
a vera ge a p pr o xi matel y 4 x 4 x 3  m m i n size. Starti n g at d a y 1 2, t h e t h era p y c o nsiste d of eit h er wee kl y S C a d mi nistrati o n of 
Z V e x 2. 0/ m T R P 1 ( 3  × 1 0 1 0 v g;  bl u e  li n e) at t h e b ase of t h e tail or wee kl y a d mi nistrati o n of Z V e x 2. 0/ m T R P 1 ( L) a n d 3  μ g 
rec o m bi na nt m T R P 1/ G L A-S E ( 5 μ g ; P) usi n g t h e re gi me n L- L- P- L- P- L-P. T h e latter gr o u p was f urt h er di vi d e d i nt o mice 
recei vi n g I P i njecti o ns of a nti-P D 1/ P D -L 1 (re d li n e) or is ot y p e c o ntr ol ( ora n ge) a nti b o dies. A n e gati ve c o ntr ol gr o u p was m oc k -
treate d wit h t he irrele va nt vect or Z V e x 2. 0/ G F P ( blac k h as h e d) or a nti-P D 1/ P D -L 1 ( bl u e h as h e d). T u m or sizes were ass esse d 
e ver y 3 or 4 da ys ( A ). S ur vi val was m o nit ore d a n d rec or d e d usi n g a Ka pla n-Meier pl ot f or t h e t hree  treat me nt gr o u ps ( B). 
S o urce: U n p u blis h e d I M D Z st u d y d ata, 2 0 1 5  
 
3. 1  
S u m m ar y of K n o w n a n d P ote nti al Ris ks t o H u m a n S u bjects  
St u d y p atie nts e x p ose d t o ge n e tra nsf er tec h n ol o g y s uc h as C M B 3 0 5 are at ris k of l o n g late n c y 
a d verse e ve nts ( A Es) s uc h as pr ol o n ge d persiste nce, i nte grati o n of ge n etic material i nt o h ost 
ge n o m es, pr ol o n ge d e x pr essi o n of tra ns ge n e, a n d altere d e x pressi o n of h ost ge n o me, etc. Viral 
vect or persiste nce c o ul d res ult i n c o nti n ue d e x pressi o n of t he tra ns ge ne or dela ye d effects of 
viral i nfecti o n. L V 3 0 5 has bee n hi g hl y e n gi neere d fr o m t he nati ve le nti viral vect or7 t o mi ni mize 
s uc h safet y ris ks t o patie nts. O nl y esse ntial viral ge n o me c o m p o ne nts ha v e bee n i ncl u de d s uc h as 
t h ose w hic h: per mit o nl y a si n gle r o u n d of i nfecti o n, pr o hi bit re plicati o n i nsi de t he cell, a n d t he 
ge n o m e has  bee n  m o difie d t o be self-i nacti vati n g, s o t hat n o viral tra nscri pts ca n be ma de after 
i nfecti o n.6 F urt her m or e, t he L V 3 0 5 c o nstr u ct has a s plit ge n o me a n d t he h o m ol o g y bet wee n t he 
se parat e d c o m p o ne nts has bee n re d u ce d t o mi ni mize t he li keli h o o d of rec o m bi nati o n a n d 
A  
B  

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 3 9  of 1 2 8  
 
 
re plicati o n a n d has b ee n re n der e d i nte grati o n defi cie nt. Aside fr o m t he m o dificati o ns t o t he wil d -
t y pe v ect or, t he tar get cells (D Cs e x pressi n g t he D C -SI G N rece pt or ) t y picall y o nl y s ur vi ve f or u p 
t o t hree wee ks.6 All fact ors c o nsi dere d, t h e persist e nce of L V 3 0 5 i n h u ma ns is e x pecte d t o be 
s h ort-li ve d. 
D ue t o t he nat ure of t he L V 3 0 5 v ect or, t here ma y be a  c o n cer n t hat p atie nts recei vi n g L V 3 0 5 
ma y h a ve a p ot e ntial ris k of c o ntracti n g a SI N V-li ke i nfecti o n. SI N V is wi del y a n d c o nti n u o usl y 
f o u n d i n i nsects (t he mai n vect ors ar e C ulex  a n d C uliset a  m os q uit oes) a n d verte brates i n E urasia, 
Africa, a n d Ocea nia; h o we ver, cli nical i nfecti o ns are rare a n d m ost e x cl usi vel y re p orte d i n 
N ort her n E ur o p e a n d n o fatalities ha ve bee n re p orte d. SI N V i nfecti o n i n h u ma ns is us uall y sile nt 
t h o u g h it ca n ma nif est as a mil d fl u -li ke ill ness mar ke d b y fe ver, ras h, art hritis, hea dac h e, 
m yal gia , a n d j oi nt ma nifestati o ns w hic h ca n p ersist f or m o nt hs or years. 6 Base d o n t he a bs e nce 
of SI N V i nfecti o ns i n t he U S, it is c o nsi dere d hi g hl y u nli kel y t hat a n y patie nts e nr olle d i n t he 
st u d y will ha ve pr e-e xisti n g a nti b o dies t o SI N V t h at w o ul d ne utralize L V 3 0 5. L V 3 0 5 als o lac ks 
t he necess ar y ge n es t o re plicate a n d pr o d u ce SI N V; 6 t heref ore, it is hi g hl y u nli kel y t hat 
i n oc ulati o n of L V 3 0 5 will res ult i n a SI N V-li ke h u ma n i nfecti o n. 
T here is s u bsta ntial e x perie nce usi n g viral v ect ors or rec o m bi na nt p e pti des, wit h or wit h o ut 
vacci ne a dj u va nts, t o i m m u nize ca ncer p atie nts wit h N Y -E S O - 1. Pre vi o usl y e m pl o ye d v ect ors 
ha ve i ncl u de d v acci nia, f o wl p o x, a n d ca nar y p o x, n o ne of w hic h h a ve bee n ass ociate d wit h 
seri o us a d vers e e v e nts ( S A Es) t hat were c o nsi dere d p ossi bl y, pr o ba bl y or d efi nitel y relate d t o t he 
st u d y tar get A g .1 N Y -E S O - 1 A g or pe pti de fra g m e nts ha ve bee n a d mi nistere d t o m ore t ha n 7 5 0 
patie nts i n least 4 1 cli nical trials as vacci nes or h y perse nsiti vit y i njecti o ns a n d were ge nerall y 
well t olerate d. 6 
Des pite t he ris ks, precli nical a n d t he c urre nt cli nical safet y pr ofile of eac h of t he C M B 3 0 5 
c o m p o ne nts, L V 3 0 5 a n d G 3 0 5, i n dicate t hat t he se q ue ntial c o m bi nati o n of t hese a ge nts s h o ul d 
be well t olerate d wit h mi ni mal ris k (see t he C M B 3 0 5 I B). Precli nical st u dies i n mice , ra b bits, 
a n d n o n- h u ma n pri mates, ha ve s h o w n L V 3 0 5, G L A- S E, N Y -E S O - 1, a n d C M B 3 0 5 are well -
t olerate d. Saf et y a n d t o xic ol o g y e val uati o ns i n a re peat- d os e st u d y wit h B A L B/c mice s h o we d 
o nl y mil d i nfla m mati o n at t he i njecti o n sites w hic h was res o l vi n g i n t he rec o ver y p hase 
sa m ples.6 
G L A has bee n e xte nsi vel y e v al uate d i n h u ma n s u bjects. 6 ,2 5 O ver 1 0 0 0 h u ma n s u bjects ha ve bee n 
i njecte d wit h G L A a dj u v a nt i n eit her of its f or m ul ati ons ( S E or t he a q ue o us f or m ulati o n [ A F]) 
wit h or wit h o ut A g. D osi n g has ra n ge d fr o m 0. 5 t o 1 0 μ g wit h re p eat d osi n g a n d > 2 7 0 h u ma n 
s u bjects ha ve ha d 1 year of s yste m atic p ost - vacci nati o n f oll o w- u p wit h  n o n ote w ort h y l o n g 
late nc y A Es  or a ut oi m m u ne or i nfla m mat or y A Es re p orte d.6 T he m ost c o m m o nl y o bser v e d A Es, 
t o date ha ve b ee n i njecti o n site reacti o ns of mil d t o m o derate se v erit y ( usi n g t he c o nser v ati ve 
“ 2 0 0 7 F D A T o xicit y Gra di n g Scale f or H ealt h y A d ult a n d A d olesce nt V ol u nteers E nr olle d i n 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 4 0  of 1 2 8  
 
 
Pre ve nti ve Vacci ne Cli nical Trials” 2 6). T he o nl y n ote d la b orat or y a b n or malities were tra nsi e nt 
i ncreas es i n ac ute p h ase r eacta nts ( e. g., C-reacti ve pr otei n [ C R P] a n d fi bri n o ge n) a n d peri p heral 
bl o o d ne utr o p hils. O verall, fe wer t ha n 4 % of A Es re p orte d i n ass o ciati o n wit h G L A-c o ntai ni n g 
v acci nes h a ve bee n Gr a d e  3 i n se verit y.6 E x pecte d A Es are liste d i n t he I B  f or C M B 3 0 5 a n d 
i ncl u de i njecti o n site reacti o ns, fe ver, fati g ue, c hills, m yal gia, a n d art hral gi a.   
L V 3 0 5 a n d G 3 0 5 ha v e b ee n a d mi nistere d i n a li mite d n u m ber of s u bjects; h o we ver, t he vacci ne 
f or m ulati o ns c o ntai ni n g r ec o m bi na nt N Y-E S O -1 pr otei n or s y nt hetic pe pti d es are ge nerall y s afe 
a n d well-t oler ate d. M ost re p orte d A Es h a ve b ee n Gra de  1-2 i njecti o n site reacti o ns or fl u -li ke 
s y m pt o ms6, (see t he N Y-E S O -1 I B , C M B 3 0 5 I B, a n d ref t o press rel ease). N o si g nifica nt A Es or 
S A Es were n ote d. S A Es t hat were n ote d were u nrelate d t o st u d y treat me nt .  
A n u m ber of ris ks a n d/ or t o xicities ha ve bee n i de ntifie d wit h t he use of atez oliz u ma b  i n 
i ncl u di n g der m at ol o gic r eacti o ns (e. g., ras h, pr urit us, dr y s ki n, et c.), he p atitis (as e vi de nce d b y 
ele vati o ns i n as partat e a mi n o tra nsferas e [ A S T ], ala ni ne a mi n otra nsferas e [ A L T ], a n d al kali ne 
p h os p hatase), h y p ot h yr oi dis m, i nfl ue nza- li ke ill ness (e. g., fe v er, fati g u e, ast he nia, c hills, etc.), 
i nf usi o n-relate d r eacti o ns (e. g., fe v er, c hills, d ys p n ea, fl us hi n g), a n d p n e u m o nitis (fre q ue ntl y i n 
patie nts wit h l u n g ca n cer). I n a d diti o n, ot her p ote ntial ris ks i de ntifie d wit h atez oliz u ma b  use 
i ncl u de t he f oll o wi n g: c olitis, e n d ocri ne dis or ders, h y perse nsiti vit y, ne ur ol o gic dis or d ers, a n d 
pericar dial eff usi o n. F urt her m ore, t he d e vel o p me nt of a nti- t hera p e utic a nti b o dies ( A T As) a gai nst  
atez oliz u ma b  ha ve bee n o bser ve d i n patie nts i n all d ose c o h orts a n d w as ass ociate d wit h c ha n ges 
i n P K f or s o me patie nts i n t he l o wer d ose c o h orts of atez oliz u ma b  ( 0. 3, 1, a n d 3 m g/ k g)  b ut has 
n ot ha d a si g nifi ca nt i m pact o n P K f or d oses fr o m 1 0 t o 2 0 m g/ k g. T o date, n o clear relati o ns hi p 
bet wee n t he d etecti o n of A T As a n d A Es or i nf usi o n reacti o ns has b ee n o bser ve d. S pecific d etails 
re gar di n g t hes e t o xicities are pr o vi d e d i n A p pe n di x F . 
T he rece nt u p date t o t he Atez oliz u ma b I n v esti gat or’s Br oc h ure (I B) o utli n es m ore stri n ge nt 
a p pr oac h es f or t h e ma na ge m e nt of i m m u ne- me di ate d t o xicit y. Gi v e n t his, t he ma na ge me nt of 
gastr oi ntesti nal, der mat ol o gic, e n d ocri ne, p ul m o nar y t o xicit y, he p at ot o xicit y, p ote ntial 
pa ncreatic or e ye t o xicit y a n d ot her i m m u ne me diate d a d vers e e ve nts has b ee n u p date d i n t his 
pr ot oc ol a n d ar e referre d t o t he I B. S yste mic i m m u ne acti vati o n ( SI A) h as bee n i de ntifie d as a 
p ote ntial ris k of atez oliz u ma b w he n gi ve n i n c o m bi nati o n wit h ot her i m m u n o m o d ulati n g a ge nts. 
T he ma na ge m e nt rec o m me n dati o ns re gar di n g earl y i de ntificati o n a n d m a n a ge me nt of SI A h a ve 
bee n a d d e d.  
O verall, it is n ot e x pecte d t hat t he a d mi nistrati o n of atez oliz u ma b will a d d safet y c o n cer ns t o 
C M B 3 0 5, gi v e n t heir diff ere nt r o utes of a d mi nistrati o n a n d n o n- o verl a p pi n g mec ha nis ms of 
acti o n. Ca ncer i m m u n ot hera pies h a ve pre vi o usl y b ee n c o m bi ne d wit h c h ec k p oi nt i n hi bit ors. A 
G V A X vacci ne c o m bi ne d wit h t he c hec k p oi nt i n hi bit or i pili m u ma b was teste d i n a P hase 1 
st u d y.1 7 I n t hat st u d y, i m m u ne-relat e d a d verse e v e nts (ir A Es) were si milar i n i nci de nce a n d 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 4 1  of 1 2 8  
 
 
c haracter as ha d bee n pr e vi o usl y o bser v e d wit h si n gle a ge nt i pili m u ma b . I pili m u ma b was als o 
e val uate d i n  c o m bi nati o n wit h t he ca ncer vacci ne P R O S T V A C i n patie nts wit h metastatic 
castrati o n -r esista nt pr ostate ca n cer. N o d ose-li miti n g t o xicities were see n a n d o nl y si de effects 
t y pical of i pili m u ma b were o bser v e d.1 8 T he re p orts fr o m t hese cli nical trials s u g gest t hat  w h e n 
use d i n c o m bi nati o n, ca n cer i m m u n ot hera p e utic a p pr oac hes are n ot li kel y t o  e n ha nce t he t o xicit y 
of C PIs . 
3. 2  
St u d y R ati o n ale 
T he de vel o p me nt of i m m u n ot hera pies t hat har ness t he i m m u ne s yste m t o kill s pecific, tar get e d 
t u m or cells is a pr o misi n g a p pr oac h f or t he treat m e nt of h u ma n mali g n a nci es wit h a n u m ber of 
a p pr o ve d tr eat me nt o pti o n f or vari o us mali g na n cies. T he c o n ce pt of e n h a n ci n g t he i m m u ne 
s yste m t o self a n d n o n-self A gs h as s h o w n t hat a c o m bi ne d pri me- b o ost a p pr oac h yiel ds 
c o nsi dera bl y hi g her res p o nses t ha n eit her a p pr oac h al o ne. 2 0 Precli nical w or k has de m o nstrate d 
t hat c o m bi ni n g L V 3 0 5 a n d G 3 0 5 i n a se q ue ntial ma n ner (i.e., C M B 3 0 5) res ults i n a n a d diti ve or 
s y ner gistic eff ect i n t he d e vel o p me nt of a nti ge n-s pecific C D 8 a n d C D 4 T cells, as well as 
a nti b o d y- pr o d uci n g B cells. T he use of s uc h a p pr o ac hes, al o n g wit h i m m u ne C PIs, ha v e bee n 
s h o w n t o e n ha nce t he a nti-t u m or res p o nse precli nicall y i n a mela n o ma m o d el (Fi g ure  4). 
I m m u ne t hera p y i n onc ol o g y has d e m o nstrate d efficac y t hat d oes n ot occ ur wit hi n t he first wee ks 
of a d mi nistrati o n a n d ma y ha v e a d ela ye d res p o ns e w hic h warra nts c ollecti o n of efficac y 
assess me nts at later ti mes d uri n g a n d after acti ve t hera p y.  T his  st u d y will e val uate t he safet y, 
efficac y, a n d i m m u n o ge nicit y b y cli nical a n d bi o m ar ker assess me nts of C M B 3 0 5 i n c o m bi nati o n 
wit h atez oliz u ma b  i n patie nts wit h l ocall y a d v a nce d, rela pse d, or metastatic sarc o ma. 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 4 2  of 1 2 8  
 
 
4. 0  
O B J E C TI V E S  
4. 1  
O bjecti ves  
4. 1. 1  
Pri m ar y  O bjecti ve  
T he pri mar y o bjecti ve is  t o e val uate o verall s ur vi v al ( O S) a n d pr o gressi o n-free s ur vi val (P F S ) 
wit h C M B 3 0 5 (se q ue ntiall y a d mi nistere d L V 3 0 5 a n d G 3 0 5) i n c o m bi nati o n wit h atez oliz u ma b  
or wit h  atez oliz u ma b  al o ne, i n patie nts wit h l ocall y a d v a nce d, rela ps e d, or metastatic sarc o m a 
e x pressi n g N Y -E S O - 1. 
4. 1. 2  
Sec o n d ar y  O bjecti ves  
T he sec o n d ar y o bjecti ves are t he f oll o wi n g: 
•  
T o e val uate t he s afet y of C M B 3 0 5 i n c o m bi nati o n wit h atez oliz u ma b  a n d atez oliz u ma b  
al o ne i n patie nts wit h l ocall y a d v a nce d, rela ps e d, or metastatic sarc o ma e x pressi n g N Y -
E S O - 1. 
•  
T o e val uate  pr o gressi o n -free s ur vi val rates at 6 m o nt hs after start of st u d y treat me nt 
( Da y 0) 
•  
T o e val uate t he i m m u ne res p o nse a n d hist ol o gic a n d m olec ular tiss ue c ha n ges i n t he 
t u m or tiss ue a n d peri p her al bl o o d 
•  
T o e val uate t he ti me t o ne xt treat me nt ( T T N T) 
•  
T o e val uate t he dista nt m etastasis free s ur vi val ( D M F S)  
 
4. 1. 3  
E x pl or at or y O bjecti ves 
T he e x pl orat or y o bj ecti v es are t h e f oll o wi n g:  
•  
T o c o m pare effi cac y assess me nts, s uc h as t u m or gr o wt h rate ( T G R) , a n d pr o gressi o n 
arrest r ate ( P A R)  
•  
T o c o m pare P F S a n d O S 2 8  bet wee n treat me nt ar ms  
•  
T o e val uate t he i m m u n o ge ni cit y of C M B 3 0 5 i n c o m bi nati o n wit h atez oliz u ma b  
c o m pare d t o at ez oliz u ma b  al o ne 
•  
T o e val uate a vaila ble pr e -, o n-, a n d p ost-treat me nt t u m or tiss ue a n d bl o o d f or hist ol o gic, 
i m m u n o hist ol o gic, a n d ge n o mic mar kers 
•  
T o e val uate t he b est o ver all res p o nse rate ( O R R; b y Res p o nse E v al uati o n Criteria i n 
S oli d T u m ors [ R E CI S T ] v 1. 1 m o difie d t o use i m m u ne-relat e d Res p o nse Criteria 
[ir R C]2 7) a n d d urati o n of res p o nse ( D O R) 
•  
T o e val uate t he cli nical b e nefit rat e  ( C B R) 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 4 3  of 1 2 8  
 
 
•  
T o e val uate t he q u alit y of life as a c o m p osite e n d p oi nt i ncl u di n g b ut n ot li mite d t o t he 
f oll o wi n g: w hile o n st u d y, t he i nci d e nce of h os pitalizati o n, tra nsf usi o ns, a n d la b orat or y 
ma r kers (e g. a bs ol ute ne utr o p hil c o u nt, he m o gl o bi n a n d platelets) 
4. 2  
E n d p oi nts  
4. 2. 1  
Pri m ar y E n d p oi nts  
T he pri mar y e n d p oi nts ar e t he f oll o wi n g: 
•  
O S  
•  
P F S  
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 ncl u de t he f oll o wi n g: 
•  
Safet y  
•  
P F R at 6 m o nt hs 
•  
T T N T  
•  
I m m u ne res p o nse a n d hist ol o gic a n d m olec ular tiss ue c ha n ges i n t u m or tiss ue or 
peri p her al bl o o d 
•  
D M F S  
4. 2. 3  
E x pl or at or y E n d p oi nt  
T he e x pl orat or y e n d p oi nts are t he f oll o wi n g: 
•  
T G R  
•  
P A R  
•  
T o c o m pare O S a n d P F S bet wee n treat me nt ar ms  
•  
O R R as assesse d  b y R E CI S T ( v 1. 1) m o difie d t o use irR C  
•  
D O R  
•  
C B R  
•  
I m m u ne res p o nses as meas ure d b y c h a n ges fr o m baseli ne i n a nti-N Y -E S O -1 i m m u nit y  
•  
Bi o mar kers  
•  
Q ualit y of lif e  
4. 2. 4  
S af et y E n d p oi nts  
T he safet y e n d p oi nts i ncl u de t he nat ure, fre q u e nc y, a n d se verit y of A Es, me dical e ve nts of 
i nterest (M E OI ; see A p p e n di x B ), la b orat or y a b n or malities, a n d ot her safet y assess me nts 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 4 4  of 1 2 8  
 
 
(i ncl u di n g vital si g ns, L V 3 0 5 persiste nce, p h ysi cal e x a mi nati o n fi n di n gs, electr ocar di o gra ms 
[E C Gs ], etc.). 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 4 5  of 1 2 8  
 
 
5. 0  
I N V E S TI G A TI O N A L P L A N  
5. 1  
O ver all Tri al Desi g n  a n d Pl a n 
T his is a ra n d o mize d, o pe n-la bel, P hase 2 tri al of C M B 3 0 5, a treat me nt re gi me n of L V 3 0 5 a n d 
G 3 0 5, i n c o m bi nati o n wit h atez oliz u ma b  or wit h  atez oliz u ma b  al o ne i n patie nts wit h sarc o ma 
w h o ha ve ha d a n i na de q u ate res p o nse, rela ps e, a n d/ or u nacce pta ble t o xicit y wit h o ne or m ore 
pri or s yste mic, s ur gical , or ra diati o n ca ncer t hera pies. A p pr o xi matel y 8 0 p atie nts at u p t o 2 0 sites 
i n t he U nite d States ( U S) a n d Ca na da  will be e nr olle d.  
All patie nts will ha ve t u m or sa m ples scree ne d f or e x pressi o n of N Y- E S O - 1 t o determi ne 
eli gi bilit y. Ar c hi val t u m or s peci me ns will be o btai ne d fr o m patie nts t o deter mi ne P D-L 1 
m olec ular stat us. Patie nts will be ra n d o mize d  i n a 1: 1 all ocati o n rati o t o recei ve C M B 3 0 5 i n 
c o m bi nati o n wit h atez oliz u ma b  or atez oliz u ma b  al o ne. Ra n d o mizati o n will be 1: 1 a n d stratifie d 
b y  diseas e t y pe .  F or t he c o m bi ne d treat me nt ar m, t he trial will be c o n d ucte d i n 4 p hases: 
Treat me nt P hase (st u d y Da ys 0 t o 8 4), B o oster P hase ( p ost Da y 8 4 t o 1 ye ar p ost Da y 0), 
Mai nte na nce P has e (fr o m 1 year t o 2 years p ost Da y 0), a n d S ur vi val F oll o w- u p P hase (q u arterl y 
t hereafter).  F or t he c o ntr ol ar m, t he trial will be c o n d ucte d i n 3 p hases: Treat me nt P hase (st u d y 
Da ys 0 t o 8 4), Mai nte na n ce P hase ( p ost D a y 8 4 t o 2 years p ost Da y 0), a n d S ur vi val F oll o w- u p 
P hase (q uarterl y t hereaft er ). 
C M B 3 0 5 treat me nt will c o nsist of 2  d oses of L V 3 0 5 a d mi nistere d o n Da ys 0 a n d 1 4, f oll o we d 
e ver y 2 w ee ks wit h alter nati n g d oses of G 3 0 5 a n d  L V 3 0 5. I n t otal, 4 d oses of L V 3 0 5 a n d 3 d oses 
of G 3 0 5 will be a d mi nistere d o ver a p eri o d of 3 m o nt hs. Patie nts will recei ve C M B 3 0 5 
acc or di n g t o d oses a n d tr eat me nt sc he d ules d eter mi ne d i n pre vi o us st u dies. L V 3 0 5 will be 
a d mi nistere d i ntra der mall y (I D) at a d os e of 1  × 1 0 1 0 vect or ge n o mes ( v g) a n d G 3 0 5 will 
a d mi nistere d i ntra m usc ul arl y (I M) at a d ose of G L A -S E ( 5  μ g) mi x e d wit h 2 5 0 μ g of N Y-E S O - 1 
pr otei n. A tez oliz u ma b will be g i ve n i ntra v e n o usl y (I V) e ver y 3 w ee ks a n d ma y b e c o nti n ue d u p 
t o 2 years u ntil t o xicit y d e vel o ps or c o nfir me d pr o gressi o n. A G 3 0 5 b o oster d ose will be gi ve n 
e ver y 6 w ee ks  i n t he first year u ntil disease pr o gressi o n (t o c oi nci de wit h t he sta gi n g f oll o w- u p 
visit s). T he c o ntr ol ar m (atez oliz u ma b  treat me nt al o ne) will ret ur n t o t he cli nic f or d osi n g e ver y 
3 wee ks  u ntil pr o gressi o n or t o xicit y de v el o ps. 
Peri p heral bl o o d will be c ollecte d f or i m m u n o ge nicit y assa ys at baseli ne, t he n o n Da y s 4 2, 7 0, 
a n d 9 8 ( ± 2 wee ks). Tiss u e bi o psies will be ta ke n i n eac h treat me nt gr o u p fr o m c o nse nti n g 
s u bjects bef or e treat me nt a n d o n Da y 4 2, o n D a y 9 8 ( ± 2 wee ks),  at 6 m o nt hs or l o n ger (f or 
patie nts wit h treat me nt res p o nse), a n d at t he ti me of pr o gressi o n  to assess i m m u ne cell i n vasi o n , 
i ncl u di n g c h a n ges i n P D- L 1, C D 4, C D 8/ Ki- 6 7 a n d/ or C D 3/ perf ori n e x pressi o n.  If a patie nt 
u n der g oes a t u m or bi o ps y at a n y ti me after diseas e pr o gressi o n, i n vesti gat ors are str o n gl y 
e nc o ura ge d t o pr o vi de bi o ps y tiss ue t o t he s p o ns or f or i m m u ne res p o ns e a n d t u m or c ha n ges 
a nal ysis.  

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 4 6  of 1 2 8  
 
 
I ma gi n g will be perf or me d a p pr o xi matel y e v er y 6  wee ks  f or 1 2 m o nt hs, t he n e ver y 1 2 wee ks f or 
t u m or sta gi n g u ntil pr o gr essi o n. T u m or res p o nses will be assesse d at t he sit es b y e val uati n g 
t u m or i ma ges/sca ns usi n g R E CI S T m o difie d t o use ir R C-s pecifie d c o nfir m ati o n a n d 
u ni di me nsi o nal t u m or meas ure m e nts. A dj u dicati o n will be perf or me d  b y bli n de d i n de pe n de nt 
ce ntral r e vie w ( BI C R) f oll o wi n g t he sa me r ules. T he ir R C m o dificati o n re q uires a c o nfir mati o n 
of C R/ P R/ pr o gressi ve disease ( P D ) at least 4 w ee ks later wit h i ma gi n g; o nce c o nfir me d, t h e date 
of pr o gressi o n is defi n e d as t he first date t hat t he t otal t u m or b ur de n was s h o w n t o ha ve 
i ncreas e d b y at least 2 0 % c o m pare d wit h t he n a dir. 
Patie nts will be f oll o we d u ntil c o nfir me d ra di o gra p hic disease  pr o gressi o n t o deter mi ne O R R  
a n d P F S. I n a d diti o n, O S  stat us will be f oll o we d u p u ntil t he e n d of t he trial. If t he patie nt dies, 
t he date of deat h will be d oc u me nte d b y t he l ocal p h ysicia n a n d/ or re gistries.  
A ll S A Es, D L Ts, a n d M E OIs dee me d p ote ntiall y relate d t o t he st u d y a ge nts will be re vie we d b y 
t he S p o ns or a n d a n i n de p e n de nt Data M o nit ori n g C o m mittee ( D M C). 
F oll o wi n g c o m pleti o n of C M B 3 0 5 d osi n g, patie nts will c o nti n ue wit h cli nical assess me nt a n d 
i ma gi n g a p pr o xi matel y e ver y 6 wee ks u ntil disease pr o gressi o n, as d efi ne d b y R E CI S T ( v 1. 1) 
m o difie d t o use ir R C. T he e x pecte d d urati o n of a patie nt’s partici pati o n i n t he trial is u p t o 
2. 1 years, i ncl u di n g Scree ni n g, Treat me nt P hase, B o oster P hase (f or p atie nts i n  t he c o m bi ne d 
treat me nt ar m), a n d Mai nte na nce P has e  ( wit h f oll o w- u p visits u ntil disease pr o gressi o n). Patie nts 
will t he n e nter  t he S ur vi v al F oll o w- u p P hase a n d t heir p h ysi cia ns will be c o ntacte d e v er y 
3 m o nt hs b y tele p h o ne t o assess O S. 
F or patie nts r eceivi n g C M B 3 0 5, peri p h eral b l o o d will be c ollecte d f or a n assa y t o test f or L V 3 0 5 
persiste nce at baseli ne, at 2 4 wee ks, a n d at 1 2 a n d 2 4 m o nt hs f oll o wi n g t he first L V 3 0 5 
i njecti o n. De pe n di n g o n t he res ults t hr o u g h 1 2 m o nt hs, a n n ual assess me nts ma y c o nti n ue u ntil 
2 c o nsec uti ve sa m ples s h o w n o e vi de nce of L V 3 0 5 persiste nce.  
Patie nts w h o disc o nti n ue st u d y treat me nt f or reas o ns ot her t ha n disease pr o gressi o n 
(e. g., t o xicit y) s h o ul d c o nti n ue t o u n der g o s c he d ule d t u m or assess me nts at t he sa me fre q ue nc y as 
w o ul d ha ve bee n f oll o we d if t he patie nt ha d re mai ne d o n st u d y dr u g u ntil t he patie nt dies, 
e x perie nces diseas e pr o gressi o n, wit h dra ws c o ns e nt, starts a ne w a nti-ca ncer t hera p y, or u ntil t he 
st u d y cl oses, w hi c he ver occ urs first. 
F or patie nts w h o are o n st u d y a n d di d n ot ha v e t u m or pr o gressi o n, a bi o ps y is re q uire d at D a y 9 8 
(a p pr o xi matel y 3 m o nt hs after start of treat me nt ).  T he patie nt ma y o pt o ut of t he Da y 9 8 bi o ps y 
after a disc ussi o n wit h a p h ysicia n  a n d d oc u me ntati o n i n t he patie nt’s c hart.  If a t u m or bi o ps y is 
n ot feasi ble, a bi o ps y s h o ul d be d o ne at a s u bse q u e nt visit wit h a p pr o val pr o vi de d b y t he 
S p o ns or. 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 4 7  of 1 2 8  
 
 
F or patie nts w h o h a ve pr o gr essi ve diseas e or a t u m or res p o nse f or 6 m o nt hs or l o n ger, a bi o ps y 
will be o btai ne d t o d oc u me nt c ha n ges i n i ntrat u m oral hist ol o g y a n d i ntrat u m oral i m m u ne 
c ha n ges at t he ti me of pr o gr essi o n.  
F or patie nts w h o h a ve ha d pr o gressi ve disease w hile o n st u d y a n d are i n a l o n g- ter m f oll o w- u p, 
if a bi o ps y is o btai ne d f or a n y reas o n (i.e. f or a n o nst u d y reas o n), a s a m ple t o assess l o n g ter m 
t u m or a n d i m m u ne s yste m c ha n ges s h o ul d be pr o vi de d t o t he S p o ns or. 
O n -st u d y ra di ot her a p y a n d s ur geries s h o ul d c o nti n ue t o be rec or de d u ntil d oc u me nte d 
ra di o gra p hic pr o gressi o n, e ve n if pr o gressi o n occ urs after st u d y treat me nt disc o nti n uati o n. N o n-
pr ot oc ol s yste mic a nti -ca ncer t hera pies a d mi nistere d bef ore d oc u me nt e d ra di o gra p hi c 
pr o gressi o n s h o ul d be rec or de d as c o nc o mita nt m e dicati o ns. 
5. 2  
D osi n g Re gi me n  a n d R ati o n ale 
L V 3 0 5 will be a d mi nistere d as 2 c o ns ec uti ve d oses f oll o we d b y alter nat e d osi n g of G 3 0 5 a n d 
L V 3 0 5 e ver y 2 wee ks. A tez oliz u ma b will be gi ve n I V i n c o m bi nati o n wit h C M B 3 0 5 e ver y 
3 wee ks starti n g o n D a y 0 ( Fi g ure  1). T he c o ntr ol ar m (i.e., at ez oliz u ma b  o nl y) will be d ose d 
wit h t he atez oliz u ma b  e ver y 3 wee ks starti n g at D a y 0. N ote t hat d osi n g of atez oliz u ma b  will 
c o nti n ue e ver y 3 wee ks u p t o 2 years u nt il t o xicit y de vel o ps f or p atie nts i n b ot h st u d y ar ms. 
F urt her d etails re gar di n g treat me nt a d mi nistrati o n are pr o vi d e d i n Secti o n  7. 2 . 
T he d osi n g re g i me n was c h ose n base d o n precli nical data, P hase 1 cli nical data, p u blis he d 
literat ure, a n d disc ussi o ns wit h I n vesti gat ors. T h e d osi n g of C M B 3 0 5 f oll o ws t he sa me re gi me n 
t hat is bei n g use d i n a P h ase 1 b st u d y c o n d ucte d b y I M D Z ( Pr ot oc ol I M D Z- C 1 3 1) a n d is 
d esi g ne d t o ma xi mize t he pri me - b o ost de vel o p me nt of N Y-E S O - 1-s p ecific C D 8 T cells. Ti mi n g 
of t he first 2 d oses was a dj uste d (fr o m 3 t o 2 wee ks a part) t o si m plif y t he s c he d ule, w hic h is n ot 
e x pecte d t o aff ect t he i m m u n o ge nicit y. Gi ve n t h e fi n di n gs fr o m precli nical st u dies a n d t he 
pre dicte d mec ha nis ms of acti o n w he n gi ve n as a pri me- b o ost, L V 3 0 5 a n d G 3 0 5 are e x pecte d t o 
ha ve s y ner gistic effects a n d i n d uce a str o n g a nti- t u m or T cell ( C T L) res p o nse i n ca ncer patie nts. 6 
I n precli nical st u dies, this heter ol o g o us pri me- b o ost a p pr oac h ca n res ult i n t he i n d ucti o n of 
a p pr o xi matel y 5 x m ore C D 8 T cells t ha n i m m u nizati o n wit h t he L V al o ne a n d ca n als o facilitate 
t he i n d ucti o n of A g-s pecific C D 4 T cells a n d a nti b o d y-ge nerati n g B  cells. I n a d diti o n t o 
i ncreasi n g t he ma g nit u de of t he C T L res p o nse, a me m or y C T L res p o nse is als o e n ha nce d, w hic h 
s u p p orts l o n g-ter m i m m u ne s ur veilla nce.6   
5. 3  
R ati o n ale f or D ose Selecti o n 
T he d oses of t he C M B 3 0 5 c o m p o ne nts c h ose n f or t his st u d y are t he f oll o wi n g: 1 × 1 0 1 0 v g of 
L V 3 0 5, 2 5 0 µ g N Y -E S O - 1, a n d 5 µ g G L A -S E. T hese d oses w ere c h ose n  b ase d o n se parate 
P hase  1 st u dies of eac h a ge nt ( Pr ot o c ols I D-L V 3 0 5 - 2 0 1 3- 0 0 1 a n d I D C-G 3 0 5 - 2 0 1 3- 0 0 1) a n d 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 4 8  of 1 2 8  
 
 
a vaila ble safet y a n d i m m u n o ge ni cit y d ata w hic h d e m o nstrate d t hat t he C M B 3 0 5 c o m p o ne nts 
were s afe a n d effecti ve i n b o osti n g t he i m m u ne res p o nse a gai nst N Y -E S O - 1 a n d ac hie vi n g S D  
a n d/ or P F S. 1 0 ,1 1 F urt her m ore, t he first i n- h u ma n tri al of C M B 3 0 5 is c urre ntl y bei n g c o n d ucte d 
( Pr ot oc ol I M D Z- C 1 3 1) usi n g t he sa me d os es c h os e n f or t his st u d y. T h e use of L V 3 0 5 a n d 
C M B 3 0 5 is als o bei n g i n vesti gate d i n c o m bi nati o n wit h at ni- P D - 1 a ge nts i n t hese P hase 1 
st u dies. At t he ti me of t his pr ot oc ol, n o D L Ts or treat me nt-relate d S A Es ha ve bee n re p orte d i n 
o ver 4 d oze n patie nts treate d i n t hese cli nical st u dies . 
A tez oliz u ma b will be d ose d acc or di n g t o a vaila bl e P K data fr o m pre vi o us cli nical st u dies. 
Preli mi nar y P K dat a of 0. 0 3- 2 0 m g/ k g atez oliz u ma b  a p peare d t o s h o w li near P K at d oses 
≥1  m g/ k g. F o r t h e 1 m g/ k g a n d 2 0 m g/ k g d ose gr o u ps, t he mea n a p pare nt cleara nce ( CL ) a n d 
mea n v ol u me of distri b uti o n at stea d y st ate ( V
ss) h a d a ra n ge of 3. 1 1 t o 4. 1 4 m L/ k g a n d 4 8. 1 t o 
6 7. 0 m L/ k g, res p ecti vel y, w hic h was c o nsiste nt wit h t he e x pecte d pr ofile of a n I g G 1 a nti b o d y i n 
h u ma ns. T he fi x e d d ose of 1 2 0 0 m g ( e q ui vale nt t o a n a vera ge b o d y wei g ht- base d d ose of 
1 5 m g/ k g) w as selecte d o n t he bases of b ot h n o n- cli nical st u dies a n d a vaila ble cli nical acti vit y, 
safet y, P K, a n d i m m u n o ge nicit y d ata de vel o p e d b y R oc he. A nti-t u m or acti vit y has bee n 
o bser ve d acr oss d oses fr o m 1 m g/ k g t o 2 0 m g/ k g a d mi nistere d e ver y 3 wee ks . T he ma xi m u m 
t olerate d d ose ( M T D) of atez oliz u ma b  was n ot reac he d a n d n o D L Ts ha ve bee n o bser v e d at a n y 
d ose i n t he P K st u d y.  
5. 4  
S af et y  M o nit ori n g  
5. 4. 1  
S af et y R u n -i n 
T he  first 6 patie nts will be ra n d o mize d 1: 1 t o recei ve t he C M B 3 0 5 i n c o m bi nati o n wit h 
atez oliz u ma b  or atez oliz u ma b  al o ne ( usi n g a bl oc k size of 6) t o i n vesti gate t he safet y of t he 
se q ue ntial c o m bi nati o n. T he 3 patie nts i n t he c o m bi nati o n ar m will be o bser ve d f or treat me nt 
e mer ge nt D L Ts i n t he first 4 2 da ys of t h era p y. D uri n g t he s afet y o bser vati o n peri o d, all S A E a n d 
D L T s afet y e ve nts dee m e d p ote ntiall y relate d t o t he st u d y a ge nts will be re vie we d b y t he 
S p o ns or a n d t he i n de pe n de nt D M C. If n o D L Ts are o bser v e d, e nr oll me nt of patie nts i nt o t he 
re mai n der of t he st u d y will c o m me nce. 
If 1 of t he 3 p atie nts in t he c o m bi nati o n treat me nt ar m e x perie nces a D L T d uri n g t he s afet y “r u n -
i n” e val uati o n, a n a d diti o nal 6 patie nts will be ra n d o mize d ( 1: 1). If 2 or m ore of t he 6 p atie nts i n 
t he c o m bi nati o n treat me nt ar m e x perie nce D L Ts, d osi n g i n t he C M B 3 0 5 pl us atez oliz u ma b  
c o m bi nati o n treat me nt ar m will st o p, a n d t he safet y of t he c o m bi nati o n will be re vie w e d b y t he 
S p o ns or a n d t he i n de pe n de nt D M C. Base d o n t his re vie w, t he D M C ma y rec o m me n d, a n d t he 
S p o ns or ma y c h o os e, t o r e d uce t he d os e of o ne or m ore c o m p o ne nts of C M B 3 0 5 ( d ose d e-
escalati o n) a n d treat a n a d diti o nal 3 t o 6 patie nts wit h t he c o m bi nati o n treat me nt re gi me n 
f oll o wi n g t he sa m e 3 + 3 d esi g n, or t h e y ma y rec o m men d st o p pi n g t he c o m bi ne d treat me nt. 
S h o ul d a l o wer d ose pr o v e t o be saf e, patie nt’s e nr oll me nt i n t he ra n d o mize d treat me nt ar ms will 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 4 9  of 1 2 8  
 
 
c o m me nce usi n g t he l o w er d ose of t hat c o m p o ne nt. F oll o wi n g e v al uati o n b y t he D M C a n d t h e 
s p o ns or, a m o dificati o n t o t he d ose/treat me nt sc h e d ule c o ul d be rec o m me n de d.  
5. 4. 2  
D ose -Li miti n g  T o xicities  
A E se verit y ass ess me nts will be perf or me d usi n g N CI C o m m o n Ter mi n ol o g y Criteria f or 
A d verse E v e nts ( C T C A E) v 4. 0 3. U nacce pta ble t o xicit y is defi ne d w he n o n e t hir d or m ore of t h e 
s u bjects treate d wit h t he c o m bi ne d re gi me n de v el o p a n A E c o nsi dere d Gra de 3 or hi g her a n d 
c o nsi dere d at least p ossi bl y rel ate d t o C M B 3 0 5 or atez oliz u ma b  wit h t he e xce pti o ns bel o w. 
H os pitalizati o ns pri maril y i nte n de d t o e x pe dite dia g n ostic e val uati o ns or f or electi ve s ur ger y will 
n ot be c o nsi dere d as seri o us a d verse e ve nts ( S A Es) f or t he p ur p os e of as certai ni n g D L T. 
A n y tr eat me nt e mer ge nt gr a de 3 or hi g h er A E t hat occ urs i n t he D L T assess me nt wi n d o w, w hic h 
is t he first 4 2 da ys after i nitiati o n of st u d y dr u g, t hat is dee me d p ossi bl y, pr o ba bl y or defi nitel y 
relate d t o t he c o m bi nati o n of C M B 3 0 5 a n d at ez oliz u ma b will be c o nsi dere d D L Ts wit h t he 
f oll o wi n g e x ce pti o ns:  
•  
Al o pecia  or v o miti n g ( u nless n ot c o ntr olle d b y o pti mal a nti-e metics)  
•  
He patic e nz y me ele v ati o ns ass ociate d wit h t he baseli ne Gra d e 2 a b n or malities t hat are 
n ote d as e x ce pti o ns a b o v e 
•  
Gra de 3 la b orat or y A Es t hat  are as y m pt o matic a n d ret ur n t o baseli ne or t o Gra de 1 wit hi n 
3 da ys, u nl ess i de ntifie d s pecificall y as D L T b y t he i n vesti gat or or t he D ata M o nit ori n g 
C o m mittee ( D M C)  
•  
Gra de 3 fati g ue  
•  
Gra de 3 s yste mic reacti o ns (s uc h as fe ver, h ea dac he, i nfl ue nza li ke s y m pt o ms, m yal gia, 
malaise, or na usea) t hat r et ur n t o baseli ne or Gra d e 1 wit hi n 3 da ys of st u d y i n oc ulati o n  
Atez oliz u ma b has a rec o g nize d saf et y pr ofile. A Es i n t he c o m bi ne d treat m e nt ar m t hat are 
attri b ute d t o atez oliz u ma b will be e val uate d b y t h e D M C a n d s p o ns or, b ut will n ot be 
i m me diatel y c o nsi dere d as D L T s e x ce pt as n ote d (Secti o n 5. 4. 3 ). All D L Ts s h o ul d be re p orte d t o 
t he S p o ns or i n a n e x pe dite d ma n ner ( wit hi n 2 4 h o urs) a n d will be re vie we d b y t he D M C. 
Alt h o u g h t hese e ve nts will n ot c o ntri b ute a ut o maticall y t o t he D L T st o p pi n g criteria, t hes e 
re vie ws ma y lea d t o m o dificati o n or st o p pi n g of t h e treat me nt pr o gra m if relate d, treat me nt-
e mer ge nt A Es i n d icate a safet y pr ofile t h at is i nc o nsiste nt or si g nifica ntl y w orse t ha n re p orte d 
wit h t he use of atez oliz u ma b al o ne. 
D uri n g t h e saf et y r u n -i n, t he f oll o wi n g patie nts will n ot be c o nsi dere d e v al ua ble f or D L Ts a n d 
will be re place d:   

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 5 0  of 1 2 8  
 
 
•  
Patie nts w h o wit h dra w or are wit h dra w n f or eit her st u d y treat me nt pri or t o c o m pleti n g 
t he D L T assess me nt wi n d o w f or a n y reas o n ot her t ha n a D L T 
•  
Patie nts w h o d o n ot recei ve t he f ull assi g n e d d ose of eit her st u d y treat me nt  d uri n g t he 
D L T assess me nt wi n d o w f or reacti o n ot her t ha n a D L T.  
Re place d patie nts will re mai n o n st u d y treat me nt if t he y ot h er wise meet crit eria t o c o nti n ue 
d osi n g a n d c o nti n ue assess me nts. 
5. 4. 3  
T o xicities Ass oci ate d wit h Atez oliz u m a b  
A tez oliz u ma b will be wit h hel d u ntil res ol uti o n  (i.e., ret ur n t o Gra de 0-1)  f or t he f oll o wi n g 
e ve nt(s):  
•  
Gra de ≥2 p n e u m o nitis 
•  
Gra de ≥3 s y m pt o matic h e patic t o xicities t hat d o n ot res ol ve t o Gra d e 2 wit hi n 4 8 h o urs or 
Gra de ≥3 as y m pt o matic he patic t o xicities  t hat d o n ot res ol ve t o Gra d e ≤1 wit hi n 3 wee ks 
of o nset wit h t he f oll o wi n g e x ce pti o ns:  
•  F or patie nts wit h Gr a de 2 A S T, A L T, al kali ne p h os p hatase a b n or malit y at b aseli ne, 
a n i ncrease t o  > 8 × t he u p per li mit of n or mal ( U L N) t hat d oes n ot res ol ve t o Gra de 2 
wit hi n 4 8 h o urs (if s y m pt o matic) or Gra de ≥3 as y m pt o matic he patic t o xicities t hat d o 
n ot res ol ve t o Gra d e ≤1 wit hi n 3 wee ks of o nset (if as y m pt o matic) will be c o nsi dere d 
a D L T.  
•  
Gra de ≥2  diarr hea or c olitis 
•  
S y m pt o matic h y p ot h yr oi dis m, h y pert h yr oi dis m, p a n h y p o pit uitaris m, or a n y Gra de ≥3 
e n d ocri ne e ve nts  
•  
Gra de ≥3 o c ular e v e nts 
•  
Gra d e ≥3 d er mat ol o gic e ve nts 
•  
Gra de ≥2 n e ur o pat h y 
•  
Gra de ≥4 n e utr o pe nia (a bs ol ute ne utr o p hil c o u nt [ A N C ] < 5 0 0/ µ L) l asti n g ≥7 da ys, 
t hr o m b oc yt o pe ni a, a ne mi a, or Gra de ≥3 fe brile ne utr o pe nia 
•  
Gra de ≥3 n o n- he mat ol o gic, n o n- he patic or ga n t o xicit y, e x cl u di n g t he f oll o wi n g: 
•  Gra de 3 i m m u ne r elate d A E  (ir A E) t hat res ol ves t o Gra de ≤1 wit hi n 3 wee ks of its 
o nset ( ma y i ncl u de e v e nts t hat res ol ve aft er me dical treat me nt, i ncl u di n g 
i m m u n os u p pressa nt t hera p y) 
•  Gra de 3 n a usea or v o miti n g t hat res ol ves t o Gra d e ≤1 wit hi n 7 2 h o urs of a p pr o priate 
s u p p orti ve t hera p y 
•  Gra de  ≥3 fati g u e t hat r es ol ves t o Gra de  ≤2 wit hi n 7 da ys  
•  Gra de 3 art hral gia t h at ca n be a de q u atel y ma na ge d wit h s u p p orti ve care or t hat 
res ol ves t o Gra d e ≤2 wit hi n 7 da ys 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 5 1  of 1 2 8  
 
 
•  Gra de 3 fe ver (i n t he a bs e nce of a n y cli nicall y si g nifica nt s o urce of fe v er) t hat 
res ol ves t o Gra d e ≤2 wit hi n 7 da ys wit h s u p p orti v e care 
•  Gra de  ≥3 la b orat or y a b n or malit y t hat is as y m pt o matic a n d dee me d b y t he 
I n v esti gat or n ot t o be cli nicall y si g nifica nt 
•  Gra de 3 t u m or flare d efi n e d as l ocal pai n, ir ritati o n, or ras h l ocalize d at sites of 
k n o w n or s us pecte d t u m or 
•  Gra de 3 i nf usi o n r eacti o n t hat res ol ves wit hi n 6 h o urs t o Gra de ≤1 
T hese reacti o ns , al o n g wit h a n y D L Ts , will be re vi e we d b y t he D M C o n a case -b y -case b asis a n d 
ma y b e c o nsi der e d D L Ts if t he y meet t he criteria o utli ne d a b o ve.  Atez oliz u ma b treat me nt ca n be 
res u me d i n patie nts w h os e a d vers e reacti o ns rec o v er t o Gra d e 0- 1. 
5. 5  
St u d y St o p pi n g  R ule  
T he preli mi nar y safet y of t he i n di vi d ual c o m p o ne nts of C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) ha ve b ee n 
st u die d i n se parate P has e  1 st u dies; h o we ver, t he s afet y of t he C M B 3 0 5/ atez oliz u ma b  
c o m bi nati o n will be i n vesti gate d d uri n g t he 6- 1 2 patie nt Safet y R u n -i n. T h e safet y pr ofile of 
C M B 3 0 5 is disc usse d i n t he I B.6 D osi n g will be s us pe n de d i n t his st u d y if D L T is o bser ve d i n 
o ne t hir d or m ore patie nts o n t he c o m bi ne d re gi m e n (ass u mi n g a mi ni m u m of 1 2 c o m bi ne d 
re gi me n patie nts were e nr olle d at t hat p oi nt a n d w o ul d re prese nt t he i nitial de n o mi nat or), 
pe n di n g r e vie w a n d rec o m me n dati o n fr o m t he D M C. 
T he S p o ns or ma y als o c h o ose t o ter mi nate t his st u d y at a n y ti me. I n vesti gat ors will be n otifie d if 
t he st u d y is place d o n h ol d, c o m plete d, or cl ose d. 
5. 6  
D osi n g Del a ys/ D ose M o dific ati o ns  
T here are n o a dj ust me nts f or d ose dela ys f or a gi v e n patie nt. Treat me nt del a ys of > 1 4 da ys fr o m 
t he treat me nt pla n f or C M B 3 0 5 c o m p o ne nts pri or t o Visit 1 2 are n ot per mitte d. If a patie nt 
e x perie nces  a D L T d uri n g t he st u d y, t heir treat me nt will be s us pe n de d. F urt her treat me nt of t his 
patie nt  wit h L V 3 0 5, G 3 0 5, or atez oliz u ma b  will be ma de o n a case -b y -case basis f oll o wi n g 
e val uati o n of t he ris ks/ be nefits b y t he I n vesti gat or a n d Me dical M o nit or i n c o ns ultati o n wit h t he 
D M C.  
D osi n g i nterr u pti o ns are per mitte d i n t he case of me dical/s ur gical e v e nts or l o gistical reas o ns n ot 
relate d t o st u d y t hera p y ( e. g., electi ve s ur ger y, u nrelate d me dical e ve nts, patie nt vacati o n, a n d/ or 
h oli da ys). Patie nts s h o ul d res u me st u d y t hera p y wit hi n 3 wee ks of t he sc h e d ule d i nterr u pti o n, 
u nless ot her wise disc usse d wit h t he S p o ns or. T he reas o n f or t he i nterr u pti o n s h o ul d be 
d oc u me nte d i n t he patie nt's st u d y rec or d. F urt her details re gar di n g d osi n g dela ys a n d 
m o dificati o ns are pr o vi d e d i n Secti o n  7. 2. 2 . 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 5 2  of 1 2 8  
 
 
5. 7  
O ver all St u d y D ur ati o n a n d F oll o w- U p  
T he e x pecte d d ur ati o n of patie nt partici pati o n o n st u d y treat me nt is 2. 1 years. T he st u d y p eri o d 
will c o nsist of S cree ni n g (st u d y D a y - 3 0 t o - 1), T reat me nt P hase  (st u d y Da ys 0 t o 8 4), B o oster 
P hase ( i n t he c o m bi ne d tr eat me nt ar m)  wit h c o nti n uati o n of G 3 0 5 b o osters ( p ost Da y 8 4 t o 
1 year  [ p ost Da y 0] or u ntil disease pr o gressi o n), Mai nte na nce P has e wit h c o nti n uati o n of 
atez oliz u ma b  treat me nt (f or t he c o m bi ne d treat me nt ar m, 1 year t o 2 years [ p ost Da y 0] a n d, f or 
t he c o ntr ol ar m, p ost Da y 8 4 t o 2 years  [ p ost Da y 0], or u ntil disease pr o gressi o n), a n d S ur vi val 
F oll o w- u p P hase (q u arterl y t her eaft er ).  T h e o verall st u d y d urati o n will de p e n d o n s pee d of 
e nr oll me nt a n d ti me t o t he n u m ber of e ve nts.   
F oll o wi n g c o m pleti o n of C M B 3 0 5 d osi n g, patie nts will c o nti n ue wit h i ma gi n g a n d cli nical 
assess me nt e ver y 6 - 9 wee ks u ntil disease pr o gressi o n, as defi ne d b y t he R E CI S T v 1. 1 criteria 
m o difie d t o use ir R C (Secti o n 6. 3 ). Patie nts or t heir p h ysicia ns will t he n be c o ntacte d b y t he sites 
e ver y 3 m o nt hs b y tele p h o ne t o assess O S. 
F or patie nts r ecei vi n g C M B 3 0 5, b l o o d will be c ollecte d t o test f or L V 3 0 5 persiste nce at baseli ne 
a n d t he n at 6, 1 2, a n d 2 4 m o nt hs f oll o wi n g t he first st u d y treat me nt a d mi nistrati o n. De pe n di n g 
o n t he res ults fr o m t he 1 2- m o nt h sa m ple, a n n ual assess me nts ma y c o nti n ue u ntil 2 c o nsec uti ve 
yearl y sa m ples s h o w n o e vi de nce of L V 3 0 5 persiste nce. 
Patie nts wit h c o nfir me d r a di o gr a p hic disease pr o gressi o n b y ir R C will be f oll o we d t hereafter b y 
t he site e ver y 3 m o nt hs b y c o nt acti n g t heir pri mar y p h ysicia n b y tel e p h o ne as l o n g as t h e y are 
a ble t o e n ga ge i n f oll o w- u p u ntil date of deat h rec or de d. F oll o w- u p t ele p h o ne c o ntact will 
ascert ai n vital stat us, as well as p ossi ble occ urre n ce of sec o n d mali g na nci es a n d a n y S A E t hat 
mi g ht be p ossi bl y r elate d t o C M B 3 0 5 treat me nt. 
5. 8  
I n de pe n de nt D at a M o nit ori n g C o m mittee  ( D M C) 
A D M C will be esta blis he d t o pr o vi de i n de pe n d e nt re vie w of safet y dat a a n d t o ass ure t hat t he 
ris k t o patie nts is mi ni mize d. T he D M C will o perate i n acc or da n ce wit h a si g ne d c h arter a n d will 
be c o m p ose d of 2 o n c ol o gis ts fa miliar wit h cli nical use of t he st u d y dr u gs a n d a n a d h oc 
i n de pe n de nt, k n o wle d gea ble bi ostatisticia n.  
Safet y d ata will be c ollecte d a n d m o nit ore d o n a n o n g oi n g basis t hr o u g h o ut t he st u d y. I M D Z will 
s u m marize all a vaila ble s afet y a n d la b orat or y d ata on all patie nts at re g ular i nter vals (at least 
e ver y 3 m o nt hs) d uri n g t he st u d y, as s pecifie d i n t he D M C c hart er. I M D Z a n d t he D M C will 
c o n d uct se parate r e vie ws of t hese data f or a n y s afet y tre n ds t hat mi g ht i m pact t he treat me nt of 
patie nts. Safet y iss ues t hat arise o ut of s uc h o n g oi n g re vie ws c o ul d lea d t o m o dificati o ns of t he 
treat me nt pr o gr a m. 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 5 3  of 1 2 8  
 
 
T he u n bli n de d D M C will re vie w all c u m ulati ve s afet y i nf or mati o n fr o m t he Safet y R u n -I n pri or 
t o rec o m me n dati o ns f or f urt her patie nt e nr oll me nt (Secti o n  5. 4. 1 ). All relate d a n d u ne x pecte d 
(i.e., e x pe dite d) S A Es a n d D L Ts will be re vie w e d as i n di vi d ual cases arise; relate d a n d 
u ne x pecte d  S A E re p orts will be e x pe dite d t o re g ul at or y a ut h orities, i n vesti gat ors, a n d D M C 
me m bers. D L Ts a n d S A Es c o nsi dere d at least p ossi bl y relate d t o st u d y re gi me n will be re vie we d 
b y t he D M C a n d t h e S p o ns or as t he y are re p orte d a n d o n a n o n g oi n g basis. T hese re vi e ws ma y 
lea d t o m o dificati o n or st o p pi n g of t he treat me nt pr o gra m if relate d, treat me nt-e mer ge nt a d vers e 
e ve nts i n dicate a s afet y pr ofile t hat is i nc o nsiste nt or si g nifica ntl y w orse t ha n re p orte d wit h t he 
use of eit her C M B 3 0 5 or atez oliz u ma b al o ne. T he D M C will als o perf or m peri o dic re vi e ws of all 
A Es, la b orat or y res ults, a n d patie nt disc o nti n uati o ns. 
T he D M C ma y c o n ve n e o n a n a d- h oc basis t o e val uate a n y ur ge nt s afet y iss ues. U p o n re q u est, 
t he D M C will be gr a nte d access t o a n y a vaila bl e d ata perti ne nt t o t he iss ues u n der e val u ati o n. 
I M D Z will pr o vi de c u m ulati ve data, as s pecifie d i n t he D M C c harter, t o t he D M C f or re vie w. 
5. 9  
Arc hi v al Tiss ue  
A re pr ese ntati ve f or mali n -fi x e d paraffi n e m be d de d ( F F P E) arc hi val t u m or s peci me n c ollect e d at 
first dia g n osis a n d/ or s u bse q ue nt t u m or rec urre n ce(s) c o nsiste nt wit h t he patie nt’s dia g n osis is 
re q uire d f or N Y -E S O - 1 dia g n osis a n d p artici pati o n i n t his st u d y. A mi ni m u m of 8 u nstai ne d 
serial secti o ns ar e nee de d.  D oc u me ntati o n of N Y- E S O - 1 e x pressi o n i n pri or t u m or sa m ples ma y 
h a ve bee n c ollecte d fr o m a n y pr oce d ure p erf or m e d bef ore b aseli ne acti vities. T here is n o ti me 
li mit f or use of t he res ults fr o m t he I M D Z-a p pr o v e d ce ntral la b.  
I n a d diti o n, a pre -treat me nt t u m or sa m ple ( F F P E bl oc k [ preferre d] or a mi ni m u m of 1 7 u nstai ne d 
serial secti o ns, i ncl u di n g 5 sli des at 4 µ m a n d 1 2 sli des at 7 µ m) s h o ul d be deri ve d fr o m a fres h 
bi o ps y or a pri or r esecti o n/ bi o ps y perf or me d ≤6 m o nt hs pri or t o scree ni n g f or i m m u ne a nal ysis. 
T his s peci me n m ust be acc o m pa nie d b y t he ass ociate d pat h ol o g y re p o rt. Fi ne- nee dl e as pirati o n, 
br us hi n g, cell pellet fr o m ple ural eff usi o n, a n d la v a ge sa m ples are n ot acce pta ble. T u m or tiss ue 
fr o m b o ne metastas es is n ot e val ua ble f or t u m or P D- L 1 e x pressi o n a n d is t heref ore n ot 
acce pta ble. F or c ore nee dle bi o ps y s peci me ns,  at least t hree c ores s h o ul d b e s u b mitte d f or 
e val uati o n. 
 
 
 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 5 4  of 1 2 8  
 
 
F or sa m ples n ot meeti n g mi ni m u m re q uire me nts f or size/sli de n u m ber, c o ntact t he Me dical 
M o nit or via y o ur site c o ntact wit h i nf or mati o n o n tiss ue size a n d t u m or c o nte nt/ n u m ber of sli des 
t o deter mi ne eli gi bilit y. 
Alter nati vel y, or if t he ar c hi val t u m or sa m ple d oes n ot meet mi ni m u m re q uire me nts, t he patie nt 
ma y b e off ere d t he o pti o n of u n der g oi n g a pretreat me nt pr oce d ure (e x cisi o nal or c ore t u m or 
bi o ps y) t o o btai n a n a de q uate t u m or sa m ple. Acce pta ble sa m ples i ncl u de c ore nee dl e bi o psies f or 
dee p t u m or tiss ue ( mi ni m u m 3 c ores) or e x cisi o nal, i ncisi o nal, p u nc h, or f orce ps bi o psies f or 
c uta ne o us, s u bc uta n e o us (S C ), or m uc osal lesi o ns. A si milar bi o ps y will be ta ke n f or s peci me ns 
o n Da y  4 2, o n Da y 9 8 ( ± 2 wee ks),  at 6 m o nt hs or l o n ger (f or p atie nts wit h treat me nt res p o nse), 
a n d at t he ti me of pr o gr essi o n.  
 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 5 5  of 1 2 8  
 
 
6. 0  
S E L E C TI O N A N D WI T H D R A W A L O F P A TI E N T S  
T his st u d y pla ns t o e nr oll patie nts wit h l ocall y a d v a nce d, rela pse d, or metastatic sarc o ma w h ose 
t u m or e x presses t he N Y-E S O - 1. 
Patie nt eli gi bilit y criteria i n t he pr o p ose d trial ha v e bee n d esi g n e d t o e ns ure t hat t he e nr olle d 
patie nts are a de q uatel y h ealt h y t o t oler ate i n vesti gati o nal t hera p y, ill e n o u g h t o be a p pr o priat e f or 
i n vesti gati o nal t her a p y, a n d ha ve s uffici e ntl y l o w t u m or b ur de n or i n d ole nt disease t o be 
a p pr o priate f or a v acci ne t hera p y. P ote ntial  ris ks i ncl u de i njecti o n site reacti o ns a n d s yste mic 
A Es, w hic h c o ul d i ncl u d e i m m u n ol o gicall y-relate d A Es. Safet y m o nit ori n g will be i nte nsi ve a n d 
c o m pre he nsi ve wi t h car ef ul m o nit ori n g f or ac ute a d verse reacti o ns a n d i ncl u des re g ular re vie ws 
b y a n i n d e pe n de nt D M C. 
6. 1  
I ncl usi o n Criteri a 
P atie nts m ust meet A L L  of t he f oll o wi n g criteri a  t o be e nr olle d i n t he st u d y:  
1.  L ocall y a d va n ce d, r ela ps e d, or metastatic sarc o ma wit h m eas ura ble t u m or b ur de n 
f oll o wi n g t her a p y, as defi ne d b y R E CI S T v 1. 1; t he t otal of all lesi o ns m ust be ≤1 2 c m 
(f or s y n o vial sar c o ma) or ≤1 5 c m (f or m y x oi d/r o u n d cell li p osarc o ma [ M R C L]) 
2.  T u m or hist ol o g y c o nsiste nt wit h s y n o vial sarc o m a or M R C L  
3.  T u m or s peci me n  p ositi ve f or N Y-E S O - 1 e x pressi o n b y I H C  
4.  I n a de q uat e res p o ns e, rela pse, a n d/ or u nacce pt a ble t o xicit y wit h o ne or m ore pri or 
s yste mic, s ur gical, or r a diati o n ca ncer t hera pi es  
5.  Ha ve r es ol uti o n of t o xic effect(s) of t h e m ost rece nt pri or t hera p y t o Gra de 1 or less 
(e x ce pt Gra d e 2 or less n e ur o pat h y or al o pecia). If s u bject recei ve d maj or s ur ger y or 
ra diati o n t hera p y, t h e y m ust ha ve rec o vere d fr o m t he t o xicit y a n d/ or c o m plicati o ns fr o m 
t he i nter ve nti o n. 
6.  ≥1 8 years of a ge bef ore t he first sc he d ule d d os e 
7.  Easter n C o o per ati ve O nc ol o g y Gr o u p ( E C O G) p erf or ma nce stat us of 0 or 1 
8.  Electr ocar di o gra m ( E C G ) wit h o ut e vi de nce of cli nicall y si g nifica nt a b n or malit y  
9.  If fe mal e of c hil d beari n g p ote ntial ( F C B P), willi n g t o u n der g o pre g n a nc y testi n g a n d 
a grees t o use at least 2 a d e q uate barrier c o ntrace pti ve met h o ds d uri n g t h e d osi n g peri o d 
a n d f or 9 0 da ys after t he last i njecti o n of C M B 3 0 5 or atez oliz u ma b 
1 0.  If male a n d s e xuall y acti ve wit h a F C B P, m ust a gree t o use hi g hl y effecti ve c o ntrace pti o n 
s uc h as late x c o n d o m d uri n g t he d osi n g peri o d a n d f or t hree m o nt hs after last C M B 3 0 5 
i njecti o n 
N ote : A bsti ne nce is acce pta ble f or eit her ge n der if t his is t he esta blis he d a n d preferre d 
c o ntrace pti o n f or t he s u bject. 
6. 2  
E xcl usi o n Criteri a  
P atie nts meeti n g a n y of t he f oll o wi n g criteria will n ot  be eli gi ble f or partici pati o n i n t he st u d y: 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 5 6  of 1 2 8  
 
 
1.  I n v esti gati o nal t hera p y wit hi n 4 wee ks pri or t o C M B 3 0 5 d osi n g 
2.  Pri or a d mi nistrati o n of ot her N Y- E S O - 1-tar geti n g i m m u n ot hera pe utics  
3.  Pri or treat me nt wit h i m m u ne c hec k p oi nt t hera pies, i ncl u di n g a nti -C T L A - 4, a nti P D- 1, 
a n d a nti P D- L 1 t hera p e utic a nti b o dies, or a n y ot her a nti b o d y or dr u g tar geti n g T cell 
c osti m ulati o n  
4.  Treat me nt wit h s yste mic i m m u n osti m ulat or y a ge nts (i ncl u di n g b ut n ot li mite d t o I L-2) 
wit hi n 4 wee ks or fi ve h alf-li ves of t he dr u g, w hic he ver is s h orter, pri or t o first d ose 
5.  Si g nifica nt i m m u n os u p pressi o n fr o m: 
 C o nc urre nt, r ece nt ( ≤3 w ee ks pri or t o t he first sc h e d ule d osi n g) or a ntici pat e d nee d 
f or treat me nt wit h s yste mic c ortic oster oi ds (t he use of p h ysi ol o gic d os es of 
c ortic oster oi ds ma y be a p pr o ve d aft er c o ns ultati o n wit h t he S p o ns or). T he use of 
t o pical or i n hale d c ortic oster oi ds a n d mi neral oc ortic oi ds (e. g., fl u dr oc ortis o ne) is 
all o we d.  
 Ot her i m m u n os u p pressi ve me dicati o ns ( ≤3 wee ks pri or t o t he first sc he d ule d d osi n g) 
i ncl u di n g b ut n ot li mite d t o c ycl o p h os p h a mi de, azat hi o pri ne, met h otre x ate, 
t hali d o mi de, a n d a nti-t u m or necr osis fact or (a nti-T N F ) a ge nts or c o n diti o ns s uc h as 
c o m m o n varia ble h y p o ga m ma gl o b uli ne mia . 
6.  Ot her ca n cer t hera pi es, i ncl u di n g c h e m ot hera p y, ra diati o n, bi ol o gics or ki nase i n hi bit ors 
wit hi n 3  wee ks pri or t o t he first sc he d ule d d osi n g 
7.  Has recei ve d c ol o n y sti m ulati n g fact ors ( C S Fs; i n cl u di n g gra n ul oc yte [ G] -C S F, 
gr a n ul oc yte- m acr o p h a ge [ G M] - C S F, or rec o m bi na nt er yt hr o p oieti n) wit hi n 4 wee ks pri or 
t o t he first sc he d ule d d osi n g 
8.  Ps yc hiatric, ot h er me dical ill ness, or ot her c o n diti o n t hat i n t he o pi ni o n of t he 
I n v esti gat or pre v e nts c o m plia nce wit h st u d y pr o ce d ures or a bilit y t o pr o vi de vali d 
i nf or me d c o nse nt 
9.  Hist or y of a ut oi m m u ne disease, i ncl u di n g b ut n ot li mite d t o m yast he ni a gra vis, m y ositis, 
a ut oi m m u ne he patitis, s yste mic l u p us er yt h e mat os us, r he u mat oi d art hritis, i nfla m mat or y 
b o wel disease, v asc ular t hr o m b osis ass ociate d wit h a nti p h os p h oli pi d s y n dr o me, 
We ge n er's gr a n ul o mat osis, Sj ö gre n's s y n dr o me, G uillai n- Barré s y n dr o me, m ulti ple 
scler osis, vasc ulitis, or gl o mer ul o ne p hritis (see A p pe n di x E  f or a m ore c o m pre he nsi ve 
list of a ut oi m m u ne diseases) 
•  Patie nts wit h  a hist or y of a ut oi m m u ne-relate d h y p ot h yr oi dis m o n a sta ble d ose of 
t h yr oi d r e place me nt h or m o ne ma y b e eli gi ble f or t his st u d y. 
•  Patie nts wit h c o ntr olle d T y pe 1 di a betes mellit us o n a sta ble i ns uli n re gi me n ma y be 
eli gi ble f or t his st u d y.  
1 0.  Hist or y of i di o pat hic p ul m o nar y fi br osis (i ncl u di n g p ne u m o nitis), dr u g-i n d uce d 
p ne u m o nitis, or ga nizi n g p ne u m o nia (i.e., br o n c hi olitis o blitera ns, cr y pt o ge nic or ga nizi n g 
p ne u m o nia), ris k of p ul m o nar y t o xicit y, or e vi de n ce of acti ve p ne u m o nitis o n scree ni n g 
c hest C T sca n. His t or y of ra diati o n p ne u m o nitis i n t he ra diati o n fiel d (fi br osis) is 
per mitte d.  

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 5 7  of 1 2 8  
 
 
1 1.  Si g nifica nt car di o vasc ul ar disease, s uc h as Ne w Y or k Heart Ass ociati o n car diac diseas e 
( ≥Class II), m y ocar dial i nfarcti o n wit hi n t he pre vi o us 3 m o nt hs pri or t o st u d y treat me nt, 
u nsta ble arr h yt h mias, or u nsta ble a n gi na 
1 2.  I n a de q uat e or ga n f u ncti o n, i ncl u di n g t he f oll o wi n g: 
 Marr o w: A N C ≤1 5 0 0/ m m
3, platelets < 7 5, 0 0 0/ m m3, or he m o gl o bi n ( H b) < 1 0  g/ d L  
 He patic: A L T, a n d A S T > 2. 5 × U L N  (O R ≥ 5 × U L N f or s u bjects wit h li ver 
metastases), t otal ser u m bilir u bi n > 1. 5  × U L N ( O R direct bilir u bi n ≥U L N f or patie nts 
wit h t otal bilir u bi n le vels < 1. 5  × U L N; p atie nts wit h Gil bert’s Disease ma y be 
i ncl u de d if t heir t otal bilir u bi n is < 3. 0 m g/ d L) 
 Re nal: creati n i ne > 1. 5 × U L N  
 Ot her: pr ot hr o m bi n ti me ( P T), i nter nati o nal n or malize d rati o (I N R), or parti al 
t hr o m b o plasti n ti me ( P T T) > 1. 5 × U L N  
1 3.  U nc o ntr olle d ple ur al eff usi o n, pericar dial eff usi o n, or ascites re q uiri n g rec urre nt drai na ge 
pr oce d ur es ( o nce m o nt hl y or m ore fre q ue ntl y). Patie nts wit h i n d welli n g cat heters (e. g., 
Ple ur X ® ) are all o we d. 
1 4.  U nc o ntr olle d t u m or-r elat e d pai n. Patie nts re q uiri n g pai n me di cati o n m ust be o n a sta ble 
re gi me n at st u d y e ntr y. S y m pt o matic lesi o ns a me n a ble t o palliati ve ra di ot hera p y (e. g., 
b o n e metastases or m etastases ca usi n g ner ve i m pi n ge m e nt) s h o ul d be treate d pri or t o 
e nr oll me nt. As y m pt o matic metastatic lesi o ns w h ose f urt her gr o wt h w o ul d li kel y ca use 
f u ncti o nal deficits or i ntr acta ble p ai n (e. g., e pi d ural metastasis t hat is n ot prese ntl y 
ass ociate d wit h s pi nal c or d c o m pressi o n) s h o ul d b e c o nsi dere d f or l oc o-re gi o nal t hera p y 
if a p pr o priate pri or t o e nr oll me nt. 
1 5.  U nc o ntr olle d h y per calce mia ( >  1. 5 m m ol/ L i o nize d calci u m ( Ca) or Ca >  1 2 m g/ d L or 
c orrecte d ser u m calci u m > U L N) or s y m pt o matic h y p erca l ce mia re q uiri n g c o nti n ue d use 
of bis p h os p h o nate t hera p y or d e n os u ma b. Patie nts w h o are recei vi n g t h ese a ge nts 
s pecificall y t o pre v e nt s k eletal e ve nts a n d w h o d o n ot ha ve a hist or y of cli nicall y 
si g nifica nt h y p ercalce mi a are eli gi ble. Patie nts w h o are recei vi n g d e n os u ma b pri or t o 
e nr oll me nt m ust be willi n g a n d eli gi ble t o disc o nti n ue its use w hile o n st u d y a n d recei ve 
a bis p h os p h o nate i nstea d. 
1 6.  Hist or y of ot h er ca ncer wit hi n 3 years (e x ce pt f or a p pr o priatel y treate d carci n o ma i n sit u 
of t he cer vi x, n o n- mela n o ma s ki n carci n o ma, Sta ge I uteri ne ca n cer, l ocalize d pr ostate 
ca ncer treate d wit h c ur ati ve i nte nt, d uctal carci n o ma i n sit u treate d s ur gicall y wit h 
c urati ve i nte nt, or ot her ca ncers wit h a si milar o utc o me)  
1 7.  E vi de nce of acti ve t u berc ul osis or rece nt ( < 1 we e k pri or t o first sc he d ule d d osi n g) 
cli nicall y si g nifica nt i nf ecti o n re q uiri n g s yst e mic t hera p y ( pr o p h ylactic a nti bi otics [e. g., 
f or pre v e nti o n of a uri nar y tract i nfecti o n or c hr o ni c o bstr ucti ve p ul m o nar y disease] are 
per mitte d)  
1 8.  E vi de nce of acti ve he p atit is B ( He p B), h e patitis C ( He p C), or H u m a n I m m u n o deficie nc y 
Vir us ( HI V) i nfecti o n. A cti ve He p B is defi ne d as ha vi n g a p ositi ve He p B s urface a nti ge n 
( H Bs A g) test at scr ee ni n g. Patie nts wit h past/res ol ve d He p B viral i nfecti o n ( defi ne d as 
ha vi n g a ne gati ve H Bs A g test a n d a p ositi ve a nti b o d y t o He p B c ore a nti ge n [a nti- H Bc] 
a nti b o d y test) are eli gi ble. He p B viral D N A m ust be ne gati ve i n t hese p atie nts pri or t o t he 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 5 8  of 1 2 8  
 
 
first sc he d ule d d osi n g. Patie nts p ositi ve f or He p C a nti b o d y are o nl y eli gi ble if 
p ol y mer ase c h ai n reacti o n ( P C R) is ne gati ve f or He p C viral R N A.  
1 9.  A d mi nistrati o n of a li ve, atte n uate d vacci ne wit hi n 4 wee ks pri or t o t he first sc he d ule d 
d osi n g or a ntici p ati o n t hat s uc h a li ve atte n uate d v acci ne will be re q uire d d uri n g t he 
st u d y. I nfl u e nza vacci n ati o n s h o ul d be gi ve n d uri n g i nfl ue nza seas o n o nl y 
(a p pr o xi matel y O ct o ber t o Marc h). Patie nts m ust n ot recei ve li ve, atte n uat e d i nfl ue nza 
vacci ne (e. g., Fl u Mist ® ) wit hi n 4 wee ks pri or t o t he first sc he d ule d d osi n g or at a n y ti me 
d uri n g t he st u d y. 
2 0.  K n o w n acti ve or u ntre at e d ce ntral ner v o us s yste m ( C N S) metastases. Patie nts wit h a 
hist or y of tr eate d as y m pt o matic C N S metastases are eli gi ble, pr o vi de d t he y meet all of 
t he f oll o wi n g criteria: 
a. N o metastases t o cere b ell u m, brai n ste m, mi d brai n, p o ns, me d ulla, or wit hi n 1 0 m m 
of t he o ptic a p parat us ( o ptic ner ves a n d c hias m) 
b.  N o e vi de nce of i nteri m pr o gressi o n ≥4 wee ks bet wee n t he c o m pleti o n of C N S-
directe d t hera p y a n d t h e scree ni n g ra di o gra p hi c st u d y  a n d ≥2 wee ks si nce 
disc o nti n uati o n of c ortic oster oi ds 
c. N o o n g oi n g r e q uire me nt f or de x a met has o ne as t h era p y f or C N S diseas e; 
a ntic o n v ulsa nts at a sta bl e d ose all o we d  
2 1.  Pre g n a nt, pla n ni n g t o b ec o me pre g na nt wit hi n 6 m o nt hs of treat me nt, or n ursi n g 
2 2.  K n o w n aller g y(i es) t o a n y c o m p o n e nt of C M B 3 0 5, atez oliz u ma b , or se vere aller gic 
reacti o ns t o m o n ocl o nal a nti b o dies, f usi o n pr otei ns, or C H O cell pr o d ucts 
6. 3  
St u d y Disc o nti n u ati o n a n d P atie nt Wit h dr a w al Criteri a  
W hile patie nts will be e nc o ura ge d t o c o nti n ue o n st u d y f or s afet y f oll o w- u p, patie nts M U S T  be 
disc o nti n ue d fr o m recei vi n g f urt h er st u d y a ge nt f or t he f oll o wi n g reas o ns: 
•  
S y m pt o matic d eteri or ati o n attri b ute d t o disease pr o gressi o n as deter mi ne d b y t he 
i n vesti gat or after i nte grat e d assess me nt of ra di o gra p hic data, bi o ps y res ults, a n d cli nical 
stat us (see Fi g ure  5) 
•  
I nt olera ble t o xicit y rel ate d t o st u d y treat me nt, i ncl u di n g de v el o p me nt of a n ir A E 
deter mi ne d b y t he i n vesti gat or a n d Me dical M o nit or t o be u nacce pta ble gi v e n t he 
i n di vi d ual patie nt’s p ote ntial res p o nse t o t hera p y a n d se verit y of t he e v e nt  
•  
A n y me di cal c o n diti o n t hat ma y j e o par dize t he patie nt’s safet y if he or s he c o nti n ues o n 
st u d y treat me nt 
•  
Use of a n ot her n o n- pr ot o c ol a nti- ca n cer t hera p y 
•  
Wit h dra wal of i nf or me d c o nse nt ( patie nt’s d ecisi o n t o wit h dra w f or a n y reas o n). 
•  
Pre g n a nc y (N O T E : All F C B Ps s h o ul d be i nstr uct e d t o c o ntact t he I n v esti gat or 
i m me diatel y if t he y s us p ect t he y mi g ht b e pre g n a nt at a n y ti me d uri n g st u d y 
partici pati o n .) 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 5 9  of 1 2 8  
 
 
•  
Ter mi nati o n of t he st u d y b y S p o ns or f or s afet y or ot her reas o ns. 
•  
I m pris o n me nt or t h e c o m p uls or y det e nti o n f or treat me nt of eit her a ps yc hi atric or 
p h ysical ill ness (e. g., i nfecti o us disease). 
•  
A n y cli nical A E, la b or at or y a b n or malit y or i nterc urre nt ill ness t hat, i n t he o pi ni o n of t he 
I n v esti gat or, i n dicates t h at c o nti n ue d d osi n g o n t h e st u d y is n ot i n t he best i nterest of t he 
patie nt . 
•  
Patie nts w h o ca n n ot t oler ate C M B 3 0 5, atez oliz u ma b , or o ut patie nt st u d y pr oce d ures. 
•  
P D  b y ir R C criteria.2 7  
As l o n g as t he y ar e recei vi n g atez oliz u ma b  a n d/ or c o m bi nati o n treat me nt, patie nts will be 
per mitte d t o c o nti n ue st u d y treat me nt if t he R E CI S T v 1. 1 criteria f or P D are met pr o vi de d t he y 
meet all of t he f oll o wi n g criteria  (Fi g ure  5): 
•  
E vi de nce of cli nical be nefit as assesse d b y t he I n v esti gat or  
•  
A bse nce of s y m pt o ms a n d si g ns (i ncl u di n g w ors e ni n g of la b orat or y val u es; e. g., n e w or 
w orse ni n g h y per calce mia) i n dicati n g u ne q ui v ocal pr o gressi o n of diseas e 
•  
N o decli ne i n E C O G perf or ma nce stat us t hat ca n b e attri b ute d t o disease pr o gressi o n 
•  
A bse nce of t u m or gr o wt h at critical a n at o mical sites (e. g., le pt o me ni n geal disease) t hat 
ca n n ot be ma n a ge d b y pr ot oc ol- all o we d me dical i nter ve n ti o ns 
•  
Patie nts f or w h o m a p pr o ve d t hera pies e xist m ust pr o vi de writte n c o nse nt t o ac k n o wle d ge 
deferri n g t h ese treat me nt o pti o ns i n fa v or of c o nti n ui n g st u d y treat me nt at t he ti me of 
i nitial a p pare nt pr o gr essi o n. 
 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 6 0  of 1 2 8  
 
 
Fi g ure  5 C o n diti o ns  f or C o nti n ui n g Atez oliz u m a b Al o ne or i n C o m bi n ati o n i n t he 
Prese nce of  I ncre ase d R a di o gr a p hic T u m or Size 
 
E C O G P S  =  Easter n C o o p erati ve O n c ol o g y Gr o u p p erf or ma n ce stat us; I C F
 =  I nf or me d C o nse nt F or m; R E CI S T =  Res p o nse 
E val uati o n Criteria i n S oli d T u m ors  v 1. 1 . 
U nless c o nse nt is wit h dr a w n a n d t he p atie nt is u n willi n g t o c o nti n ue wit h safet y f oll o w- u p, t he 
patie nt is l ost t o f oll o w - u p, or t he st u d y is ter mi nat e d, all eff orts s h o ul d be ma de t o c o nti n ue 
safet y m o nit ori n g of all p atie nts w h o recei ve d C M B 3 0 5 a n d/ or atez oliz u ma b . A safet y 
e val uati o n s h o ul d al wa ys be d o ne at t he last site visit if feasi ble.  
Patie nts w h o wit h dra w fr o m t he st u d y pri or t o t he E O S  s h o ul d be f oll o we d f or ne w A Es f or at 
least 3 0 da ys after t heir l ast d ose of C M B 3 0 5 a n d/ or atez oliz u ma b . If t he p atie nt wit h dra ws 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 6 1  of 1 2 8  
 
 
pre mat urel y a n d is u n willi n g t o c o nti n ue safet y f oll o w- u p, a n y s u bse q ue nt S A E t hat ma y be 
ca usall y rel ate d t o C M B 3 0 5 or atez oliz u ma b  t hat c o mes t o t he atte nti o n of t he site staff s h o ul d 
be re p ort e d t o I M D Z. 
Patie nts i n w h o m ra di o gr a p hic disease pr o gressi o n is c o nfir me d at a s u bse q ue nt t u m or 
assess me nt ma y be c o nsi dere d f or c o nti n ue d st u d y treat me nt at t he discreti o n of t he I n vesti gat or 
pr o vi de d t he y meet t he criteria a b o ve. 
Patie nts w h o ha ve per m a ne ntl y disc o nti n ue d at ez oliz u ma b  m ust disc o nti n ue st u d y treat me nt if 
t he y meet criteri a f or dis ease pr o gressi o n per R E CI S T/ir R C. T he pri mar y reas o n f or st u d y 
treat me nt disc o nti n uati o n s h o ul d be d oc u me nte d o n t he a p pr o priat e electr o nic Case Re p ort F or m 
(e C R F). Patie nts w h o pr e mat urel y dis c o nti n ue st u d y treat me nt will n ot be re place d. 
Patie nts w h o disc o nti n ue st u d y treat me nt f or reas o ns ot her t ha n disease pr o gressi o n 
(e. g., t o xicit y) s h o ul d c o nti n ue t o u n der g o s c he d ule d t u m or assess me nts at t he sa me fre q ue nc y as 
w o ul d ha ve bee n f oll o we d if t he patie nt ha d re mai ne d o n st u d y dr u g u ntil t he patie nt dies, 
e x perie nces diseas e pr o gressi o n, wit h dra ws c o ns e nt, starts a ne w a nti-ca ncer t hera p y, or u ntil t he 
st u d y cl oses, w hi c he ver occ urs first. 
O n -st u d y ra di ot her a p y a n d s ur geries s h o ul d c o nti n ue t o be rec or de d u ntil d oc u me nte d 
ra di o gra p hic pr o gressi o n, e ve n if pr o gressi o n occ urs after st u d y treat me nt disc o nti n uati o n. N o n-
pr ot oc ol s yste mic a nti -ca ncer t hera pies a d mi nistere d bef ore d oc u me nt e d ra di o gra p hi c 
pr o gressi o n s h o ul d be rec or de d as c o nc o mita nt m e dicati o ns. 
T he pri mar y r eas o n f or st u d y treat me nt disc o nti n uati o n s h o ul d be d oc u me nte d o n t he a p pr o pri ate 
e C R F. Patie nts w h o disc o nti n ue st u d y treat me nt pre mat urel y will n ot be re place d.  
T he S p o ns or has t he ri g ht t o ter mi nate t his st u d y at a n y ti me. Reas o ns f or ter mi nati n g t he st u d y 
ma y i ncl u d e, b ut are n ot li mite d t o, t he f oll o wi n g: 
•  
T he i nci de nce or se v erit y of a d vers e e ve nts i n t his or ot her st u dies i n dicates a p ote ntial healt h 
hazar d t o patie nts. 
•  
Patie nt e nr oll me nt is u nsatisfact or y.  
 
T he S p o ns or will n otif y t he i n vesti gat or if t he S p o ns or deci des t o disc o nti n ue t he st u d y.  
T he S p o ns or has t he ri g ht t o cl ose a site at a n y ti me.  Reas o ns f or cl osi n g a site ma y i ncl u d e, b ut 
are n ot li mite d t o, t he f oll o wi n g:  
•  
E x cessi vel y sl o w recr uit me nt  
•  
P o or pr ot oc ol a d her e nce 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 6 2  of 1 2 8  
 
 
•  
I n acc urate or i nc o m plete data rec or di n g  
•  
N o n -c o m plia nce wit h t he I nter nati o nal C o nfere nce o n Har m o nisati o n (I C H) g ui deli ne f or 
G o o d Cli nical Practice  ( G C P)N o st u d y acti vit y (i.e., all patie nts ha ve c o m plete d a n d all 
o bli gati o ns ha ve b ee n f ulfille d) 
 
7. 0  
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 Dr u g s 
T he i n vesti gati o nal dr u g is C M B 3 0 5, a pri me- b o ost c o m bi nat orial re gi me n  c o m prise d of 2 
differe nt acti ve i m m u n ot hera p y a ge nts, L V 3 0 5 a n d G 3 0 5 a d mi nistere d se q ue ntiall y t o pri me a n d 
b o ost t he i m m u ne s yste m i n or der t o i n d uce a str o n g C D 8 T cell res p o nse a gai nst t u m or cells 
res ulti n g i n t u m or re gressi o n. T he pri me- b o ost t hera p y is bei n g teste d i n c o m bi nati o n wit h 
i n vesti gati o nal a nti-P D -L 1 C PI atez oliz u ma b . 
7. 1. 1  
L V 3 0 5 
L V 3 0 5 is t he pr o d uct na me f or Z Ve x 2. 0 e nc o di n g t he N Y- E S O -1 C T a n ti ge n. It is a m o difie d 
L V - base d o n I M D Z’s Z Ve x ™ platf or m desi g ne d t o tar get pr o d ucti o n of N Y-E S O - 1 i n D Cs via a 
m o difie d  Si n d bis vir us gl yc o pr otei n ( SI N V ar 1). It has bee n e n gi n eere d t o e n ha nce safet y s uc h 
t hat it is de n dritic cell-tr o pic, re plicati o n-i nc om pet e nt, a n d i nte grati o n- d eficie nt .7 L V 3 0 5 
c o ntai ns 1 × 1 0 1 0 v g/ m L i n Tris b uffer (p H 7. 5) c o ntai ni n g 5 % s ucr ose a n d L- ar gi ni ne as 
o utli ne d i n Ta ble  3. 
T a ble 3  
L V 3 0 5 Dr u g Pr o d uct C o m p o ne nts 
C o m p o ne nt  
A m o u nt per m L  
A m o u nt per vi al  
F u ncti o n  
L V 3 0 5  
1 × 1 0 1 0 v g/ m L  
1. 4  × 1 0 1 0 v g/ m L  
Acti ve c o m p o ne nt  
L- ar gi ni ne  
8. 7 1  m g/ m L  
1 2. 2  m g/ vial  
E xci pie nt  
Tris b uffer  
6. 0 6  m g/ m L  
8. 4 8  m g/ vial  
E xci pie nt  
S ucr ose  
5 0  m g/ m L  
7 0  m g/ vial  
E xci pie nt  
v g = viral ge n o mes.  
S o urce: C M B 3 0 5 I n vesti gat or Br o c h ure 6 
 
F or f urt her det ails re gar di n g L V 3 0 5, its pr o perties, a n d f or m ulati o n, please c o ns ult t he C M B 3 0 5 
I B.6   

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 6 3  of 1 2 8  
 
 
7. 1. 1. 1  
I n vesti g ati o n al Dr u g P a c k a gi n g a n d L a beli n g  
T he L V 3 0 5 i n vesti gati o nal Dr u g Pr o d uct will be s u p plie d i n a o ne- vial c o nfi g urati o n  w here a 
1 m L i njecti o n v ol u me will c orres p o n d t o t he t otal d ose. Eac h vial c o ntai ns 1. 4 m L of f or m ulate d 
L V 3 0 5 ( 1 × 1 01 0 v g/ m L) pac ka ge d i n a 2 m L vial.  
7. 1. 1. 2  
St or a ge a n d Dis p ositi o n of t he I n vesti g ati o n al Dr u g Pr o d ucts 
L V 3 0 5 m ust be st or e d at – 6 0° C ( or c ol der) . U p o n c o m pleti o n of t he st u d y, all re mai ni n g 
materials m ust  be ret ur n e d t o I M D Z u nl ess ot her wise i nstr ucte d.  
7. 1. 1. 3  
D ose Pre p ar ati o n f or A d mi nistr ati o n t o t he P atie nt  
T he Dr u g Pr o d uct will be use d as pr o vi de d i n t he vial. I nstr u cti o ns detaili n g t ha wi n g of t he vial 
a n d pre parati o n of d osi n g s yri n ges will be pr o vi de d i n t he P har mac y M a n ual.  
O ne  ( 1) m L of t h e t ha we d pr o d uct will be a d mi nistere d as 8 × 1 2 5 μ L I D i njecti o ns ( 2 i njecti o ns 
o ver eac h delt oi d a n d 2 o ver eac h of t he q u a drice ps) o n Da ys 0, 1 4, 4 2, a n d 7 0 as o utli ne d i n t he  
Sc he d ule of E ve nts  (T a bl e  1) a n d t he P har mac y M a n ual. Eac h I D i njecti o n s h o ul d be at least 
3 c m fr o m t he nei g h b ori n g i njecti o n. 
7. 1. 2  
G 3 0 5 
G 3 0 5 is c o m prise d of r ec o m bi na nt N Y- E S O- 1 f ull-le n gt h pr otei n wit h  a His-ta g t h at is clea ve d 
pri or t o fi nal p urificati o n  ( 18 2 a mi n o aci ds a n d ~ 1 8 K Da) , w hi c h is mi x e d wit h G L A -S E t o f or m  
a 2 % oil/ water e m ulsi o n. G L A is a s y nt hetic Li pi d  A a nal o g t hat  ca n bi n d t o t he T L R 4 rece pt or 
acti vati n g t he i n n ate i m m u ne res p o nse i n a n u m ber of differe nt i m m u ne cells i ncl u di n g D Cs.6 
G 3 0 5 ca n i n d uce t he acti vati o n of a p ote nt a da pti v e i m m u ne res p o nse a gai nst N Y-E S O - 1 
i n v ol vi n g a nti b o dies, C D 4 + T cells, a n d ot her effect or i m m u ne cells. F or f urt her i nf or mati o n 
re gar di n g G 3 0 5, its c o m p o ne nts, pr o perties, a n d f or m ulati o n, please c o ns ult t he C M B 3 0 5 I B.6   
7. 1. 2. 1  
I n vesti g ati o n al Dr u g P a c k a gi n g a n d L a beli n g  
T he I n vesti gati o nal Dr u g Pr o d uct G 3 0 5 will be s u p plie d i n a 2- vial c o nfi g urati o n. O ne vial will 
c o ntai n t he f or m ulate d pr otei n a nti ge n N Y-E S O - 1 a n d t he sec o n d vial will c o ntai n  t he a dj u va nt 
G L A -S E.  
Al o n g wit h G L A, t h e G L A- S E f or m ulati o n c o ntai ns s q uale ne ( oil), gl ycer ol, t oc o p her ol 
( vita mi n E), 1, 2- di m yrist o yl -s n-gl ycer o - 3- p h os p h oc h oli ne ( D M P C), s urfacta nt (p ola x a mer ), a n d 
a m m o ni u m p h os p hate b uffer. 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 6 4  of 1 2 8  
 
 
N Y -E S O - 1 pr otei n will b e  pac k a ge d as 5 0 0 µ g of pr otei n / m L i n 2 m L vials, eac h c o ntai ni n g 
0. 6 5 m L of f or m ulate d pr otei n. G L A- S E will be  pac ka ge d i n 3 m L clear gl ass vials eac h 
c o ntai ni n g 0. 8 m L of f or m ulate d a dj u va nt. 
Detaile d i nstr ucti o ns f or a d mi xi n g t he pr otei n wit h a dj u va nt will be pr o vi de d i n t h e P har mac y 
Ma n ual.  
7. 1. 2. 2  
St or a ge a n d Dis p ositi o n of t he I n vesti g ati o n al Dr u g Pr o d ucts 
T he N Y -E S O - 1 pr otei n m ust be st ore d at - 6 0°C (or c ol der) . G L A-S E is a n e m ulsi o n t hat m ust 
be st ore d at 2  t o 8°C . G L A -S E M U S T N O T B E F R O Z E N . U p o n c o m pleti o n of t he st u d y, all 
re mai ni n g m aterials m ust be ret ur n e d t o I M D Z u nl ess ot her wise i nstr ucte d. 
7. 1. 2. 3  
D ose Pre p ar ati o n f or A d mi nistr ati o n t o t he P atie nt 
D ose pre p arat i o n i nstr ucti o ns will be pr o vi de d i n t he P har mac y M a n ual. O n e ( 1 ) m L of t he 
mi x e d pr o d uct will be a d mi nistere d via I M i njecti o n i n t he delt oi d  or fe m oral re gi o n (a nteri or 
u p per t hi g h) usi n g alte r n ati n g li m b i nject sites o n Da ys 2 8, 5 6, a n d 8 4 as o utli ne d i n t he Sc he d ule 
of E ve nts ( Ta ble  1 a n d T a ble  2) a n d t he P har mac y Ma n ual. 
7. 1. 3  
Atez oliz u m a b  
A tez oliz u ma b (f or merl y M P D L 3 2 8 0 A) is a n a nti-P D - L 1 h u ma n I g G 1 m A b c o nsisti n g of 2 
hea vi n g c hai ns ( 4 4 8 a mi n o aci ds) a n d 2 li g ht c hai ns ( 2 1 4 a mi n o aci ds) pr o d uce d i n C hi nese 
ha mster o var y ( C H O) cell. It was e n gi neere d  wit h a si n gle a mi n o aci d s u bstit uti o n (as para gi ne t o 
ala ni ne) at p ositi o n 2 9 8 of t he hea v y c hai n res ulti n g i n n o n- gl yc os ylat e d a nti b o d y mi ni mizi n g its 
a bilit y t o bi n d t o Fc-rece pt ors. T his l os s of bi n di n g eli mi nates Fc-effect or f u ncti o n a n d de pleti o n 
of P D -L 1 e x pressi n g cells. A tez oliz u ma b is bei n g i n vesti gate d as a p ote ntial t hera p y i n h u ma ns 
a gai nst s oli d t u m ors a n d he mat ol o gic m ali g na n cies.  Atez oliz u ma b is c o ntrai n dicate d f or p atie nts 
wit h a  hist or y of s e ver e aller gic a na p h ylactic reacti o ns t o c hi meric, h u ma n or h u ma nize d 
a nti b o dies, or f usi o n pr otei ns, as well as f or patie nts wit h k n o w n h y pers e nsiti vit y t o C H O cell 
pr o d ucts or a n y c o m p o ne nt of t he atez oliz u ma b f or m ulati o n. 
7. 1. 3. 1  
I n vesti g ati o n al Dr u g P a c k a gi n g a n d L a beli n g  
T he atez oliz u ma b  dr u g pr o d uct is pr o vi de d i n a si n gle- us e, 2 0-m L glass vi al as a c ol orl ess -t o-
sli g htl y-yell o w, sterile, preser v ati ve -free clear li q ui d s ol uti o n i nte n de d f or I V a d mi nistrati o n. 
T he vial is desi g n e d t o deli ver 2 0 m L ( 1 2 0 0 m g) of atez oliz u ma b  s ol uti o n b ut ma y c o nt ai n m ore 
t ha n t he state d v ol u me t o e na ble deli ver y of t he e ntire 2 0 m L v ol u me. T h e atez oliz u ma b  dr u g 
pr o d uct is f or m ulate d as 6 0 m g/ m L atez oliz u ma b  i n 2 0 m M histi di ne acetate, 1 2 0 m M s ucr ose, 
0. 0 4 % p ol ys or b ate 2 0, p H 5. 8. 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 6 5  of 1 2 8  
 
 
F or f urt her det ails , see t h e atez oliz u ma b  P har mac y Ma n u al a n d I B. 
7. 1. 3. 2  
St or a ge a n d Dis p ositi o n of t he Dr u g Pr o d uct    
A tez oliz u ma b m ust be refri gerat e d at 2° C t o 8° C ( 3 6° F t o 4 6° F) u p o n recei pt u ntil use. 
A tez oliz u ma b vials s h o ul d n ot be use d be y o n d t he e x pirati o n date pr o vi de d b y t he ma n ufact urer. 
N o preser vati ve is use d i n atez oliz u ma b  dr u g pr o d uct; t heref ore, t he vial is i nte n de d f or si n gle 
use o nl y. Discar d a n y u n use d p orti o n of dr u g left i n a vial. Vial c o nte nts s h o ul d n ot be fr oze n or 
s ha ke n a n d s h o ul d be pr otecte d fr o m direct s u nli g ht. U p o n c o m pleti o n of t he st u d y, all re mai ni n g 
materials m ust be ret ur n e d t o I M D Z.  
7. 1. 3. 3  
D ose Pre p ar ati o n f or A d mi nistr ati o n t o t he P atie nt  
A d mi nistrati o n of atez oliz u ma b  will be perf or me d i n a setti n g wit h e mer ge nc y m e dical facilities 
a n d staff w h o are trai ne d t o m o nit or f or a n d res p o n d t o me dical e mer ge ncies. A d ose of 1 2 0 0 m g 
atez oliz u ma b  will be a d mi nistere d b y I V i nf usi o n e ver y 3 w ee ks. T h e i n vesti gati o nal pr o d u cts 
will be deli vere d i n i nf usi o n ba gs wit h I V i nf usi o n li nes wit h pr o d uct c o ntacti n g s urfaces of 
p ol y vi n yl c hl ori de ( P V C) a n d p ol y olefi n a n d 0. 2 µ m i n -li ne filters (filter me m bra ne of 
p ol yet hers ulf o ne). N o i nc o m pati bilities ha ve bee n o bser ve d bet w ee n atez oliz u ma b  a n d P V C or 
p ol y olefi n i nf usi o n materials ( ba gs a n d i nf usi o n li nes). 
S pecific i nstr ucti o ns f or t he pre parati o n a n d a d mi nistrati o n of t he atez oliz u ma b  i nf usi o n s ol uti o n 
are c o nt ai ne d wit hi n t he P har mac y Ma n u al.  
7. 2  
Tre at me nt  A d mi nistr ati o n  
F or patie nts r a n d o mize d t o t he c o m bi nati o n treat me nt ar m , t he d osi n g re gi me ns f or L V 3 0 5 a n d 
G 3 0 5 will mi mic t h ose use d i n pre vi o us P hase 1 st u dies. T he d ose of eac h a ge nt will be gi ve n 
acc or di n g t o t he s c he d ules o utli ne d i n Ta ble  1 (c o m bi nati o n d osi n g ar m wit h atez oliz u ma b ) or 
Ta ble  2 (c o ntr ol ar m). 
T w o d oses of L V 3 0 5 will be a d m i nistere d 2 wee ks a part o n Wee ks  0 a n d 2, w hic h will be 
f oll o we d e ver y 2 wee ks wit h G 3 0 5 alter nati n g wit h L V 3 0 5 (Fi g ure  1A ). T he alter nati n g re gi me n 
t hat will be use d was desi g ne d pri maril y t o ma xi mize t he i n d ucti o n of C D 8 T-effect or/ me m or y 
cells b y L V 3 0 5 a n d t he n e x pa n d or b o ost t he m wit h t he G 3 0 5. N o ncli nical st u dies s u g gest t hat 
i njecti o ns e ver y 2– 4 w ee ks ge n erat e t he m ost d ura ble a n d hi g h est ma g nit u de i m m u ne 
res p o nses6 ,2 0 a n d t hat t he res p o nses c o nti n ue t o be b o oste d wit h a d diti o nal treat me nts.  
Patie nts will be gi ve n a n I V i nf usi o n of 1 2 0 0 m g atez oliz u ma b  o ver 3 0 t o 6 0 mi n utes e ver y 
3 wee ks starti n g o n D a y  0 u ntil disease pr o gressi o n or u nacce pta ble t o xicit y (Fi g ure  1A & B ). T he 
i nitial d ose of atez oliz u ma b will be deli vere d o v er 6 0 (±  1 5) mi n utes. If t he first i nf usi o n is 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 6 6  of 1 2 8  
 
 
t olerate d wit h o ut i nf usi o n-ass ociate d A Es , t he sec o n d i nf usi o n ma y be d eli vere d o ver 3 0 (±  1 0) 
mi n utes. If t he 3 0- mi n ute i nf usi o n is well t olerate d, all  s u bse q ue nt i nf usi o ns ma y b e deli vere d 
o ver 3 0 ( ±  1 0) mi n utes. F or t he first i nf usi o n, t he p atie nt’s vital si g ns (H R , res pirat or y rate, B P , 
a n d te m perat ure) s h o ul d be meas ur e d wit hi n 1 5 mi n utes of t he i nf usi o n, d uri n g t he 6 0- mi n ute  
i nf usi o ns (e ver y 1 5 [±  5] mi n utes), a n d 3 0 mi n utes after t he i nf usi o n. F or s u bse q ue nt i nf usi o ns, 
vital si g ns d o n ot nee d t o be o btai ne d d uri n g t he i nf usi o n if t he pri or i nf usi o n was t olerate d 
wit h o ut s y m pt o ms.  T he ma na ge me nt of a n y i nf usi o n-relate d reacti o ns are o utli ne d i n 
Secti o n  7. 4. 4. 1 . 
Patie nts  i n b ot h st u d y ar ms will be treate d wit h at ez oliz u ma b  t hera p y al o n e e ver y 3 wee ks 
starti n g at fr o m Da y 0 u ntil disease pr o gressi o n or u nacce pta ble t o xicit y.  D ue t o a d mi nistrati ve 
reas o ns, atez oliz u ma b  treat me nt ma y b e a d mi nistere d u p t o 3 da ys bef ore or after t h e sc he d ul e d 
d osi n g da y. 
A n y o v er d ose or i nc orr ect a d mi nistrati o n of st u d y dr u g s h o ul d be n ot e d o n t he St u d y Dr u g 
A d mi nistrat i o n electr o nic Case Re p ort F or m (e C R F) . A Es  ass oci ate d wit h  a n o ver d ose or 
i nc orrect a d mi nistrati o n of st u d y dr u g s h o ul d be rec or de d o n t h e A d verse E ve nt e C R F.  F urt her 
details are pr o vi d e d i n Secti o n  9. 4. 1 . 
7. 2. 1  
R a n d o miz ati o n 
Patie nts will be ra n d o mize d 1: 1 t o t he c o m bi nati o n d osi n g ar m or c o ntr ol ar m of t he st u d y n o 
m ore t ha n 4 da ys pri or t o d osi n g ( D a y 0). Ra n d o mizati o n will be stratifie d b y t y pe of disease .3 0 
A n a ut o mate d i nteracti ve we b res p o ns e s yst e m (I W R S) will be use d t o ma na ge t he 
ra n d o mizati o n a n d treat me nt assi g n me nt.  Patie nts w h o wit h dra w fr o m t h e st u d y will n ot be 
re place d. Refer t o t he St u d y Ref ere n ce M a n ual f or details o n ra n d o mizati o n a n d re gistrati o n. 
7. 2. 2  
D ose M o dific ati o n G ui deli nes  
D osi n g i nterr u pti o ns are per mitte d i n case of m e dical/s ur gical e v e nts or l o gistical reas o ns n ot 
related t o st u d y t hera p y ( e. g., electi ve s ur ger y, u nrelate d me dical e ve nts, patie nt vacati o n, a n d/ or 
h oli da ys). Patie nts s h o ul d be place d b ac k o n st u d y t hera p y wit hi n 3 wee ks of sc he d ule d 
i nterr u pti o n, u nless ot her wise disc usse d wit h S p o ns or. T he reas o n f or i nterr u pti o n s h o ul d be 
d oc u me nte d i n t he patie nt’s st u d y rec or ds. 
T here are n o a dj ust me nts f or d ose dela y f or a gi ve n patie nt, a n d treat me nt d ela ys f or t he 
C M B 3 0 5 c o m p o ne nts t hat are > 1 4 da ys fr o m t he treat me nt pla n bef ore Visit 1 2 will n ot be 
all o we d. D uri n g t he st u d y, if a p atie nt e x perie nces a D L T, treat me nt of t hat patie nt will be 
s us pe n de d. A patie nt ma y be c o nsi der e d f or recei vi n g f urt h er i njecti o ns of t he L V 3 0 5, G 3 0 5, or 
atez oliz u ma b  i n vesti gati o nal dr u g pr o d uct o n a case-b y -case basis f oll o wi n g e v al uati o n of t he 
be nefit/ris k rati o t o t he p atie nt b y t he I n vesti gat or a n d Me dical M o nit or, i n c o ns ultati o n wit h t he 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 6 7  of 1 2 8  
 
 
i n de pe n de nt D M C (e. g., f or patie nts w h o ha v e e x perie nce d a t u m or res p o nse a n d ha d a n o n-life- 
a n d n o n-or ga n -t hreate ni n g D L T, c o nti n uati o n of treat me nt as per pr ot oc ol ma y b e c o nsi dere d).  
N o re d ucti o n or m o dificati o n of t he atez oliz u ma b  d ose will be all o we d. A n y t o xicities ass ociate d 
or p ossi bl y ass oci ate d wit h atez oliz u ma b  treat me nt s h o ul d be ma na ge d acc or di n g t o sta n dar d 
me dical practice.  A d diti o nal tests, s uc h as a ut oi m m u ne ser ol o g y or bi o psies, ma y be use d t o 
deter mi ne a p ossi ble i m m u n o ge nic eti ol o g y. As a res ult, st u d y treat me nt m ust be wit h hel d f or 
A Es or i nf usi o ns reacti o ns ass ociate d wit h atez oliz u ma b  treat me nt as o utli ne d i n A p pe n di x F . 
W hile m ost ir A Es o bser ve d wit h i m m u n o m o d ulat or y a ge nts ha v e bee n mil d a n d self-li miti n g, 
s uc h e ve nts s h o ul d be r ec o g nize d earl y a n d treate d pr o m ptl y t o a v oi d p ote ntial maj or 
c o m plicati o ns.  T he pri mar y a p pr o ac h t o Gra de 1- 2 ir A Es is s u p p orti ve a n d s y m pt o matic care; f or 
hi g her gra d e ir A Es, ster oi ds b y m o ut h or pare nterall y are gi ve n, a n d eit her s ki p pi n g a d ose or 
st o p pi n g t hera p y is a p pr o priate. Rec urre nt Gra de 2 ir A Es ma y als o ma n date s ki p pi n g a d ose of 
atez oliz u ma b  or t he use of ster oi ds as o utli ne d i n A p pe n di x F . 
Disc o nti n uati o n of atez oliz u ma b  ma y n ot ha ve i m me diate t hera p e utic effect, a n d t here is n o 
a vaila ble a nti d ote f or atez oliz u ma b . I n se v ere cas es, i m m u ne-relate d t o xicities ma y be ac utel y 
ma na ge d wit h t o pical c ortic oster oi ds, s yste mic c ortic oster oi ds, or T N F α  i n hi bit ors as o utli ne d i n 
A p pe n di x F . 
7. 3  
Dr u g Acc o u nt a bilit y  
U n der n o cir c u msta nces is it per mitte d t o use st u d y s u p plies f or a n y p ur p os es ot her t ha n t h ose 
s pecifie d i n t his Pr ot oc ol.  
T he I n vesti gat or or m e dicall y q u alifie d, a ut h orize d dele gate will be pr o vi d e d wit h f or ms t o 
e na ble acc ur ate r ec or di n g of all st u d y d oses at t he st u d y facilit y at all ti mes. T he I n vesti gat or, or 
desi g nee, m ust si g n a st ate me nt t hat  he/s he has recei ve d st u d y i njecti o ns i nte n de d f or t h e st u d y. 
At a n y gi v e n ti me, t he fi g ur es of s u p plie d, use d, a n d re mai ni n g d os es of st u d y dr u g m ust matc h. 
At t he e n d of t he st u d y, it m ust be p ossi ble t o rec o ncile deli ver y rec or ds wit h t h ose of use d a n d 
u n use d st oc ks. Acc o u nt m ust be gi ve n of a n y discre pa n cies.  
7. 4  
Pri o r a n d C o nc o mit a nt T her a p y  
7. 4. 1  
Pri o r  T her a p y  
A n y i n vesti gati o nal a ge nt or ca ncer t hera p y is pr o hi bite d d uri n g t he 2 1 da ys pri or t o Da y 0, 
i ncl u di n g c h e m ot hera p y, ra diati o n, ki nase i n hi bit ors, i m m u n ot hera p y, G-C S F, G M - C S F, or ot her 
bi ol o gics. S yste mic c orti c oster oi d use is n ot per mitte d wit hi n f o ur wee ks pri or t o d osi n g. Patie nts 
w h o ha ve pr e vi o usl y recei ve d N Y- E S O - 1 direct e d i m m u n ot hera pies or a n y a nti b o d y or dr u g 
tar geti n g T-cell c osti m ulati o n  will n ot be eli gi ble.  

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 6 8  of 1 2 8  
 
 
7. 4. 2  
Pr o hi bite d C o nc o mit a nt T her a p y  
A n y c o nc o mita nt t hera p y i nte n de d f or t he treat me nt of ca ncer, w h et her healt h 
a ut h orit y−a p pr o ve d or e x peri me ntal, is pr o hi bite d. T he f oll o wi n g treat me nts are pr o hi bite d  
d uri n g st u d y u ntil t he e n d of t he st u d y or t u m or pr o gressi o n: 
•  
A n y c he m ot her a p y, h or m o nal t hera p y, i m m u n ot hera p y, ra di ot hera p y, h er bal t hera p y , or 
i n vesti gati o nal dr u g ot her t ha n L V 3 0 5, G 3 0 5, or atez oliz u ma b . 
•  
A n y c ortic oster oi d ( > 1 0 m g/ da y pre d nis o ne or e q ui vale nt d ose ) wit hi n 3 w ee ks of f irst 
st u d y treat me nt a n d d uri n g t he st u d y peri o d. H o w e ver, s yste mic gl uc o c orti c oi ds are 
per mitte d t o m o d ulate s y m pt o ms f or a n M E OI of s us pecte d i m m u n ol o gic eti ol o g y. 
•  
Ot her c o nc urre nt i m m u n os u p pressi ve me dicati o ns s uc h as met h otre x ate, c ycl os p ori n e, 
a n d azat hi o pri ne. 
•  
Li ve v acci n es wit hi n 3 0 da ys pri or t o t he first d os e of trial treat me nt a n d w hile 
partici pati n g i n t he tri al. E x a m ples of li ve vacci nes i ncl u de, b ut are n ot li mite d t o, t he 
f oll o wi n g: measles, m u m ps, r u bella, c hic k e n p o x, yell o w fe ver, ra bies, B C G, a n d t y p h oi d 
( oral) vacci ne. Seas o nal i nfl ue nza vacci n es f or i nj ecti o n are ge nerall y kille d vir us 
vacci nes a n d ar e all o we d. H o we ver, i ntra nas al i nfl ue nza vacci n es (e. g., Fl u Mist ®) are 
li ve atte n uate d vacci nes, are n ot all o we d. 
N o pre me dicati o n will be a ll o we d f or t he first d ose of atez oliz u ma b . Pre me dicati o n ma y b e 
a d mi nistere d f or s u bse q u e nt i nf usi o ns at t he discreti o n of t he treati n g p h ysi cia n after c o ns ultati o n 
wit h t he Me dical M o nit or.  
After D a y 8 4 , certai n f or ms of ra di ot hera p y m a y be c o nsi dere d f or p ai n palliati o n if patie nts are 
deri vi n g b e nefit ( e. g., treat me nt of k n o w n b o n y metastases).  
Patie nts e x perie nci n g a mi x e d res p o nse re q uiri n g l ocal t hera p y (e. g.,  s ur ger y, stere otactic 
ra di os ur ger y, radi ot her a p y, a n d ra di ofr e q ue n c y a bl ati o n) f or c o ntr ol of t hree or fe w er lesi o ns 
ma y still be eli gi ble t o c o nti n ue st u d y treat me nt. Patie nts w h o recei ve l ocal t hera p y directe d at a 
tar get lesi o n will n o l o n ger be e v al ua ble f or ra di o gra p hic res p o nse b ut will re mai n e val u a ble f or 
pr o gressi o n. S uc h  cas es m ust be disc usse d wit h a n d a p pr o ve d b y t he M e dical M o nit or.  
T here are n o k n o w n pr oce d ure- relate d ris ks wit h use of atez oliz u ma b . T he f oll o wi n g t hera pi es 
are e x cl u de d w hile p atie nts are recei vi n g st u d y dr u g: 
•  
Patie nts w h o are r ecei vi n g a rece pt or acti vat or of n uclear fact or k a p pa B li ga n d ( R A N K L ) 
i n hi bit or ( de n os u ma b) pri or t o e nr oll me nt m ust be willi n g a n d eli gi ble t o recei ve a 
bis p h os p h o nate i nstea d; de n os u ma b c o ul d p ote ntiall y alter t he acti vit y a n d t he safet y of 
atez oliz u ma b . 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 6 9  of 1 2 8  
 
 
•  
I m m u n osti m ulat or y a ge nts n ot part of st u d y treat me nt, i ncl u di n g b ut n ot li mite d t o I F N-γ or 
I L- 2; t hese a ge nts, i n c o m bi nati o n wit h atez oliz u ma b , c o ul d p ote ntiall y i n creas e t he ris k f or 
a ut oi m m u ne c o n diti o ns.  
•  
I m m u n os u p pr essi ve me dicati o ns, i ncl u di n g b ut n ot li mite d t o c ycl o p h os p ha mi de, 
azat hi o pri ne, met h otre x ate, a n d t hali d o mi de; t hese a ge nts c o ul d p ote ntiall y alter t he acti vit y 
a n d t he saf et y of atez oliz u ma b. S yste mic c ortic oster oi ds, T N F -α  i n hi bit ors, m yc o p h e n olate 
a n d ot her i m m u ne s u p pre ssa nts ma y b e a d mi nistere d f or t he treat me nt of i m m u ne-relate d 
t o xicities at t he discreti o n of t he treati n g p h ysicia n after c o ns ultati o n wit h t he Me dical 
M o nit or. 
 
I n a d diti o n, all patie nts s h o ul d n ot recei ve ot her i m m u n osti m ulat or y a ge nts f or 1 0 wee ks after 
t he last d ose of atez oliz u ma b . Atez oliz u ma b is n ot meta b olize d via c yt oc hr o me P 4 5 0 e nz y m es or 
c o nj u gati o n/ gl uc ur o ni d ati o n reacti o ns. N o dr u g i nteracti o n st u dies f or atez oliz u ma b ha ve bee n 
c o n d ucte d or are pl a n ne d. T here are n o k n o w n i nteracti o ns wit h ot her me di ci nal pr o d ucts or 
ot her f or m of i nter acti o ns. 
7. 4. 3  
Per mitte d C o nc o mit a nt T her a p y  
T he f oll o wi n g m e dicati o ns will be per mitte d  d uri n g t he st u d y: 
•  
A nti hista mi nes  
•  
A ntie metics  
•  
A nti diarr heals  
•  
As piri n  
•  
N o nster oi dal a nti- i nfla m mat or y dr u gs ( N S AI Ds) 
7. 4. 4  
S u p p orti ve C are G ui deli nes f or A tez oliz u m a b Tre at me nt  
S u bjects s h o ul d recei ve a p pr o priate s u p p orti ve care meas ures as dee me d necessar y b y t he 
treati n g i n v esti gat or relat e d t o atez oliz u ma b treat me nt. G ui da nce re gar di n g t he i de ntificati o n, 
e val uati o n, a n d s u p p orti v e car e meas ure f or t he m a na ge me nt of t h ese e v e nts wit h p ote ntial 
i m m u n ol o gic eti ol o g y, i n cl u di n g i nf usi o n-relate d reacti o ns, are o utli ne d i n A p pe n di x F . W here 
a p pr o priate, t h ese g ui deli nes i ncl u de t he use of c ortic oster oi ds, a d diti o nal a nti- i nfla m mat or y 
a ge nts, or ot her c o nc o mita nt me dicati o ns if s y m pt o ms d o n ot i m pr o ve wit h a d mi nistrati o n of 
c ortic oster oi ds. F or eac h dis or der, atte m pts s h o ul d be ma de t o r ule o ut ot her ca uses s u c h as 
metastatic disease or bact erial or vir al i nfecti o n, w hic h mi g ht re q uire a d diti o nal s u p p orti ve care. 
T hese treat me nt g ui d eli nes are i nte n d e d t o be a p plie d w he n t he I n v esti gat or deter mi nes t he 
e ve nts t o be rel ate d t o atez oliz u ma b . N ote , if after t he e val uati o n t he e v e nt is deter mi ne d t o be 
n ot relate d, t he I n v esti gat or is i nstr ucte d t o f oll o w t he re p orti n g g ui da nce b ut d oes n ot nee d t o 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 7 0  of 1 2 8  
 
 
f oll o w t he treat me nt g ui d a nce (s u m marize d i n A p pe n di x F  al o n g wit h d ose m o dificati o n 
g ui deli nes). 
7. 4. 4. 1  
I nf usi o n-rel ate d Re acti o ns  
S y m pt o ms t hat occ ur d uri n g or wit hi n 2 4 h o urs after a n i nf usi o n of atez oliz u ma b  ma y b e part of 
a n ac ute i nf usi o n r eacti o n. T he  n o n-seri o us s y m pt o ms s h o ul d be rec or d e d as se parate A Es  o n t he 
A E  e C R F. Seri o us s y m pt o ms s h o ul d be re p orte d as o ne S A E  wit h t he m ost me dicall y  si g nifica nt 
si g n or s y m pt o m as t he pri mar y e ve nt ter m. A d diti o nal si g ns a n d s y m pt o ms s h o ul d be re p orte d 
i n t he ‘ Ad diti o nal Case Details ’ secti o n of t he A E  e C R F pa ge . 
I nf usi o n-relat e d reacti o ns will be ma na ge d  acc or di n g t o se verit y acc or di n g t o t he f oll o wi n g 
pr oce d ur es: 
•  
I n t he e ve nt t hat a p atie nt e x perie nces a mil d i nf usi o n-relate d e ve nt (N ati o nal Ca ncer 
I nstit ute C o m m o n T o xicit y Criteria f or A d verse E ve nts [N CI C T C A E ] Gra de  1), t he 
i nf usi o n rate s h o ul d be re d uce d t o half t he rate b ei n g gi ve n at t he ti me of e v e nt o nset. 
O nce t he e ve nt has r es ol ve d, t he I n vesti gat or s h o ul d wait 3 0 mi n utes w hile deli veri n g t he 
i nf usi o n at t he re d uce d rate. If t olerat e d, t he i nf usi o n rate ma y t he n b e i ncrease d t o t he 
ori gi nal r ate.  
•  
I n t he e ve nt t hat a p atie nt e x perie nces a m o d erate i nf usi o n-relate d e ve nt ( N CI C T C A E 
Gra de  2) or fl us hi n g, fe v er, or t hr oat p ai n, t he pati e nt s h o ul d ha ve his or her i nf usi o n 
i m me diatel y i nterr u pt e d a n d s h o ul d recei ve a g gressi ve s y m pt o matic treat me nt. T he 
i nf usi o n s h o ul d be restart e d o nl y after t h e s y m pt o ms ha ve a de q u atel y res ol ve d t o baseli ne 
gr a de. T h e i nf usi o n ra te at restart s h o ul d be h alf t he i nf usi o n rate t hat w as i n pr o gress at 
t he ti me of t he o nset of t he i nf usi o n-relat e d e ve nt. 
•  
F or se v ere or life -t hr eate ni n g i nf usi o n-relate d e v e nts ( N C I C T C A E Gra de  3 or 4), t he 
i nf usi o n s h o ul d be st o p pe d i m me diatel y, a n d a g gressi ve res uscitati o n a n d s u p p orti ve 
meas ures s h o ul d be i nitiate d. Patie nts e x perie nci n g se v ere or life -t hreate ni n g i nf usi o n-
relate d e v e nts will n ot recei ve f urt her i nf usi o n a n d will be f urt her ma n a ge d as cli nicall y 
i n dicate d u ntil t he e ve nt r es ol ves. 
F urt her d etails re gar di n g t he ma na ge me nt of I nf usi o n- relate d reacti o ns are pr o vi de d i n 
A p pe n di x F . 
7. 5  
Diet/ Acti vit y/ Ot her  C o nsi der ati o ns  
7. 5. 1  
Diet  
S u bjects s h o ul d mai ntai n a n or mal diet u nless m o dificati o ns are re q uire d t o ma na ge a n A E s uc h 
as diarr hea, na us ea, or v o miti n g. 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 7 1  of 1 2 8  
 
 
7. 5. 2  
C o ntr ace pti o n  
A ni mal re pr o d ucti o n st u dies ha ve n ot bee n c o n d u cte d wit h C M B 3 0 5 t o e v al uate t he effect of t he 
c o m p o ne nts o n re pr o d u cti o n or fetal de v el o p me nt. A tez oliz u ma b ma y h a ve a d verse effects o n a 
fet us i n uter o a n d it is n ot k n o w n if atez oliz u ma b  t hera p y has a n y a d v erse effects o n t he 
c o m p ositi o n of s per m. F urt her m ore, h u ma n I g Gs are k n o w n t o cr oss t he pl ace ntal b arrier a n d t he 
P D - 1/ P D- L 1 p at h wa y has bee n li n ke d wit h pre g n a nc y mai nte na n ce.3 1 
C urre ntl y, t here is n o h u ma n data de m o nstrati n g t he effects of t his li ne of C PI t hera p y i n 
pre g na nc y, l actati o n, or r e pr o d ucti ve p ote ntial. T h eref ore, n o n- pre g na nt, n o n- breast -fee di n g 
w o me n ma y o nl y b e e nr olle d i nt o t he trial if t he y are willi n g t o use 2 met h o ds of birt h c o ntr ol or 
are c o nsi d ere d hi g hl y u nli kel y t o c o n cei ve. Hi g hl y u nli kel y t o c o ncei ve is d efi ne d as:  
1.  S ur gicall y sterilize d,  
2.  P ost me n o pa usal (a w o ma n w h o is ≥ 4 5 years of a ge a n d has n ot ha d me ns es f or greater 
t ha n 1 year will be c o nsi dere d p ost me n o pa us al), or  
3.  N ot heter ose x uall y acti ve f or t he d urati o n of t h e st u d y.  
T he 2 birt h c o ntr ol met h o ds ca n be eit her 2 barrier met h o ds, or a barrier m et h o d pl us a h or m o nal 
met h o d t o pre ve nt pre g n a nc y. S u bjects s h o ul d start usi n g birt h c o ntr ol fr o m St u d y Visit  1 
t hr o u g h o ut t he st u d y peri o d u p t o 9 0 da ys after t he last d ose of st u d y t hera p y.  
T he f oll o wi n g are c o nsi d ere d a d e q uate b arri er met h o ds of c o ntrace pti o n: dia p hra g m, c o n d o m ( b y 
t he part ner), c o p per i ntra uteri ne de vice, s p o n ge, or s per mici de as p er l ocal re g ulati o ns or 
g ui deli nes. A p pr o priate h or m o nal c o ntrace pti ves will i ncl u de a n y re gistere d a n d mar kete d 
c o ntrace pti ve a ge nt t hat c o ntai ns a n estr o ge n a n d/ or a pr o gestati o nal a ge nt (i ncl u di n g oral, S C , 
i ntra uteri ne, or I M a ge nts). 
S u bjects s h o ul d be i nf or me d t hat ta ki n g t he st u d y me dicati o n ma y i n v ol ve u n k n o w n ris ks t o t he 
fet us ( u n b or n ba b y) if pr e g n a nc y w ere t o o cc ur d uri n g t he st u d y. I n or der t o partici pate i n t he 
st u d y, t he y m ust a d her e t o t he c o ntrace pti o n re q uire me nt ( des cri be d a b o ve) f or t he d urati o n of 
t he st u d y a nd d uri n g t h e f oll o w- u p peri o d. If t here is a n y q u esti o n t hat a patie nt will n ot relia bl y 
c o m pl y wit h t he r e q uire me nts f or c o ntrace pti o n, t hat patie nt s h o ul d n ot be e ntere d i nt o t he st u d y. 
It is u n k n o w n w h et her atez oliz u ma b  or a n y c o m p o ne nts of C M B 3 0 5 are e x crete d i n h u ma n mil k. 
Si nce ma n y dr u gs ar e e x crete d i n h u ma n mil k, a n d beca use of t he p ote ntial f or seri o us a d v erse 
reacti o ns i n t he n ursi n g i nfa nt, s u bjects w h o are breast-fee di n g are n ot eli gi ble f or e nr oll me nt. 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 7 2  of 1 2 8  
 
 
8. 0  
S T U D Y  P R O C E D U R E S  
T his st u d y will be c o n d u cte d i n c o m plia nce wit h t he pr ot oc ol a p pr o v e d b y t he I nstit uti o nal 
Re vie w B o ar d  (I R B), a n d acc or di n g t o G C P sta n dar ds. N o de viati o n fr o m t he pr ot oc ol will be 
i m ple me nte d wit h o ut t he pri or re vie w a n d a p pr o v al of t he I R B, e x ce pt w here it ma y b e necessar y 
t o eli mi nate a n i m me diate hazar d t o a researc h p atie nt . I n s u c h cas e, t he de viati o n will be 
re p orte d t o t he I R B as s o o n as p ossi ble (als o see S ecti o n  1 6. 2 ). 
8. 1  
Visit  Wi n d o ws  
V isits fr o m Da y 0 t o 1 0 5 will ha ve a wi n d o w of ± 3 da ys fr o m t he s pecifie d st u d y da y. F oll o w- u p 
p hase visits (after Da y 1 0 5) will ha ve a w i n d o w of ± 4 da ys. Refer t o t he Sc he d ule of E ve nts 
(Ta ble  1 a n d T a ble  2) f or t he ti mi n g of visits a n d t he s pecific pr oce d ures t h at will be perf orm e d 
at eac h visit.  
8. 2  
St u d y Visits  
8. 2. 1  
Scree ni n g  Visit(s): Wee ks  - 4 t o 0 ( D a ys - 3 0 t o - 1) 
Patie nts will u n der g o scr ee ni n g a n d e nr oll me nt pr oce d ures u p t o 3 0 d a ys pri or t o St u d y Da y 0. 
Assess me nts ma y o cc ur at m ulti ple visits. Scree ni n g pr o ce d ures/assess me nts i ncl u de t he 
f oll o wi n g: 
1.  C o nse nt f or a ssess me nt of t u m or bi o ps y s ur gical s peci me n  
N o trial -s pecifi c sta gi n g or bi o ps y pr o ce d ures will be u n derta k e n pri or t o c o m pleti o n of t he 
c o nse nti n g pr ocess. H o w e ver, if a patie nt has ha d tests perf or me d pri or t o pr o vi di n g 
i nf or me d c o nse nt as p art of sta n dar d of care (c o nsi dere d sta n d ar d f or t he patie nt a n d r o uti ne 
me dical practice, bas e d u p o n t heir prese ntati o n at t he ti me), a n d A L L of t he f oll o wi n g 
c o n diti o ns are met, t he n t hese data ma y b e all o we d as part of t he st u d y dat a: 
•  T he tests f ulfill all re q uir e me nts of t he st u d y, i. e., are c o m plet e a n d f oll o w t he 
pr oce d ur es o utli ne d i n t he st u d y;  
•  T he tests ha ve bee n c o m plete d wit hi n t he s pecifie d n u m ber of da ys t o perf or m pre-
treat me nt assess me nts; a n d  
•  It is me dicall y u n wise t o re peat a test/ pr oce d ure or it p oses u n d ue a d diti o nal ris k t o 
t he patie nt.  
N Y -E S O - 1 e x pressi o n will be deter mi ne d f or pre-st u d y t u m or sa m ples b y I H C. T u m or tiss ue 
s peci me ns fr o m a n y pri or s ur gical resecti o n or bi o ps y ma y b e e x a mi ne d f or N Y-E S O - 1 
e x pressi o n, a n d t he a nal ysis will be perf or me d b y a ce ntral la b. A se p arate scree ni n g c o nse nt 
f or m will be a vaila ble a n d ma y b e use d t o scree n patie nt t u m or sa m ples f or N Y-E S O - 1 
e x pressi o n pri or t o si g ni n g t he pri mar y  c o nse nt f or m f or partici pati o n o n t his cli nical st u d y. 
H o we ver, pre- a n d o n-st u d y bi o psies ma y als o be re q uire d f or i m m u ne testi n g if lesi o ns are 
accessi ble.  

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 7 3  of 1 2 8  
 
 
N Y -E S O - 1 testi n g res ults of t u m or tiss ue o btai ne d i n c o nj u ncti o n wit h a differe nt I M D Z 
st u d y ma y als o be us e d t o q ualif y f or t his trial if t he testi n g w as perf or me d b y a n I M D Z-
a p pr o ve d ce ntral la b. F or t his st u d y, t here is n o ti me li mit o n w he n t he test was perf or me d 
a n d t he use of its res ults t o q ualif y f or t his st u d y. C o nfir mati o n of N Y- E S O - 1 e x pressi o n 
s h o ul d be ma de bef ore b e gi n ni n g ot her s cree ni n g pr oce d ures. T u m or hist ol o g y i ncl u di n g a n 
e val uati o n of i m m u ne cell i n vasi o n a n d c o m p ositi o n will als o be e x a mi ne d. 
2.  I nf or me d c o ns e nt/ H u ma n I ns ura nce P orta bilit y a n d Acc o u nta bilit y Act (HI P A A ) 
a ut h orizati o n 
Pri or t o st u d y e nr oll me nt , eac h p atie nt will recei v e c o m plete i nf or m ati o n, b ot h ver ball y 
a n d i n writi n g, a b o ut t he nat ure of t he st u d y, t he a ntici pate d ris ks, disc o mf ort ass ociate d 
wit h t he st u d y, a n d a b o ut t he ri g ht t o i nterr u pt p artici pati o n i n t he st u d y at a n y ti me. Pri or 
t o partici pati o n i n t he st ud y, eac h p atie nt ( or re prese ntati ve) will ha ve si g ne d t he writte n, 
I R B-a p pr o ve d I nf or me d C o nse nt F or m (I C F) a n d HI P A A f or m. T his s h o ul d be d o ne 
wit hi n 3 0 da ys pri or t o t h eir a ntici pate d d osi n g start date ( D a y  0).   A n a gree me nt t o 
c o nti n ue i n t he st u d y a n d o btai n t u m or bi o ps y if t he patie nt meets t he criteri a f or 
pr o gressi ve disease b ut wis hes t o re mai n o n st u d y s h o ul d als o be o btai n e d. 
3.  Re vie w of i ncl usi o n/e x cl usi o n criteria a n d d eter mi nati o n of patie nt eli gi bilit y 
(Secti o n  6. 0 ). 
4.  De m o gra p hics 
5.  Me dical hist or y – i n cl u des a re vi e w of s yste ms, ge neral me di cal a n d s ur gi cal hist or y, 
c o nc o mita nt ill nesses, c urre nt me dicati o ns , a n d t u m or-s pecific t h era p y hist or y. O nc ol o gic 
baseli ne disease c haracteristics/ hist or y will be rec or de d ( dia g n osis , diseas e sta ge, E C O G 
stat us [A p pe n di x A ], a n d R E CI S T lesi o ns [A p pe n di x C ]). ( A n y c ha n ges t o Me dical 
Hist or y fr o m i nitial c ollecti o n of data t o Da y  - 1 s h o ul d be u p date d t o t he rec or ds.) 
6.  F ull P h ysical e x a mi nati o n, i ncl u di n g hei g ht, wei g ht, vital si g ns (i ncl u di n g te m perat ure, 
res pirat or y r ate, H R, a n d resti n g B P ), a n d 1 2-lead E C G.  
7.  Assess me nt of dia g n osis a n d sta ge of disease  (t u m or sta gi n g), i ncl u di n g C o m p ute d 
T o m o gr a p h y ( C T) of c hest, a b d o me n, pel vis. Ot her assess me nts s uc h as ma g netic 
res o na nce i ma gi n g (M RI ), b o ne sca n or p ositr o n e missi o n t o m o gra p h y (P E T )/ C T s h o ul d 
be perf or me d  o nl y if i n dicate d f or t he ca ncer i n dicati o n. 
8.  Bl o o d sa m ple c ollecti o n . U p t o 7 8 m L of bl o o d will be c ollecte d f or t h e f oll o wi n g 
e val uati o ns: 
•  
HI V/ He p B/ He p C testi n g ( 5  m L)  – As part of st u d y eli gi bilit y, patie nts m ust ha ve a 
ne gati ve HI V t est at scr ee ni n g.  L V 3 0 5 is a n e n gi n eere d L V t hat c o ntai ns ge nes ori gi nall y 
deri ve d fr o m HI V a n d it is n ot k n o w n if treat me nt wit h L V 3 0 5 will res ult i n 
ser oc o n versi o n of patie nts t o p ositi ve u p o n HI V scree ni n g . Sec o n d ar y c o nfir mat or y 
assa ys s uc h as Wester n Bl ot ca n be use d t o de m o nstrate t hat t he n or mal c o m ple me n t of 
HI V pr otei ns is n ot prese nt ( u nless t he patie nt has de vel o pe d a tr u e HI V i nfecti o n). 
Patie nts i n t he c o m bi ne d treat me nt ar m  will be pr o vi de d wit h a car d fr o m t h e st u d y 
S p o ns or descri bi n g t h e p ossi bilit y of a s cree ni n g test bec o mi n g p ositi ve a n d t he 
i mp orta nce of c o nfir mat or y testi n g. I n t he e ve nt a st u d y patie nt s h o ul d ha ve a p ositi ve 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 7 4  of 1 2 8  
 
 
scree ni n g HI V test, t he site s h o ul d i nf or m a n d c o ns ult I M D Z f or rec o m me n dati o ns o n t he 
m ost a p pr o priate c o nfir mat or y t est t o use. 
•  
C ell ular i m m u nit y ( a p pr o xi matel y 5 5 m L)  – c ollecte d i n 8 C P T ™ He pari n t u bes f or T-
Cell res p o nse assa y s a n d perf or me d at sites w here staff are trai ne d i n p eri p h eral bl o o d 
m o n o n uclear cell ( P B M C) is olati o n . 
•  
S afet y l a b orat or y e val uati o ns ( 1 0 m L) – i ncl u d es he mat ol o g y a n d  cli nical c he mistr y. 
•  
L V 3 0 5 p ersiste nce testi n g ( 8  mL)  – O nl y f or t h os e s u bjects ra n d o mize d t o t he 
c o m bi nati o n treat me nt ar m.  
9.  Uri nal ysis  
1 0.  Uri ne pre g n a nc y test f or F C B Ps  
1 1.  T h yr oi d f u ncti o n tests (trii o d ot h yr o ni ne [ T 3 ], t h yr o xi ne [ T4 ], a n d t h yr oi d sti m ulati n g 
h or m o ne [ T S H]) 
1 2.  T u m or bi o ps y ( f or patie nts w h o pr o vi de c o nse nt f or t he bi o ps y pr oce d ure). T he pre-
treat me nt bi o ps y m ust be c o m plete d ≤ 6 m o nt hs pri or t o scree ni n g. If u na v aila ble, a ne w 
bi o ps y ma y be p erf or me d. 
1 3.  Ra n d o mizati o n a n d e nr oll me nt i nt o t he st u d y 
O nce patie nts ha v e bee n pr o perl y c o ns e nte d, a n d all i ncl usi o n/e x cl usi o n a n d scree ni n g 
criteria h a ve bee n d oc u m e nte d as bei n g met, patie nts wil l be e nr olle d i nt o t he st u d y. 
Ra n d o mizati o n m ust occ ur n o m ore t ha n 4 da ys b ef ore Da y  0. 
8. 2. 2  
Tre at me nt P h ase ( Wee ks  0- 1 2 Tre at me nt Visits , St u d y D a y s 0 t o 8 4) 
T he f oll o wi n g pr oce d ures  will be perf or me d  at all st u d y visits  f or s u bjects i n b ot h treat me nt 
ar ms: 
1.  A Es a n d S A Es  (i ncl u di n g M E OIs) 
2.  C o nc o mita nt Me dicati o ns 
3.  Vital Si g ns  (te m per at ure, H R, resti n g B P) o btai ne d pre- d ose a n d 3 0 mi n utes, p ost- d ose.  F or 
t he first atez oliz u ma b i nf usi o n, t he patie nt’s vital si g ns ( H R, res pirat or y rat e, B P, a n d 
te m perat ur e) s h o ul d be meas ure d wit hi n 1 5 mi n ute of t he i nf usi o n, d uri n g t he 6 0-mi n ute 
i nf usi o n (e ver y 1 5 [ ± 5] mi n utes), a n d 3 0 mi n utes after t he i nf usi o n.  F or s u bse q ue nt 
i nf usi o ns, vital si g ns d o n ot nee d t o be o btai ne d d uri n g t he i nf usi o n if t he pri or i nf usi o n was 
t olerate d wit h o ut s y m pt o ms. 
4.  P h ysical e x a mi nati o n: si m ple tar gete d p h ysical e x a mi nati o n  
5.  E C O G stat us  
6.  Uri ne pre g n a nc y test f or F C B P  o n treat me nt da ys. Note: pre g na n c y test m ust be perf or m e d 
wit hi n 7 2 h o urs bef ore st u d y dr u g a d mi nistrati o n a n d ne gati ve b ef ore st u d y dr u g 
a d mi nistrati o n.  
7.  Bl o o d sa m ples ( 1 0 m L) f or safet y la b orat or y e v al uati o ns wit hi n 4 da ys bef ore treat me nt 
i nitiati o n a n d u p t o 4 8 h o urs bef or e eac h s u bse q ue nt d ose. 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 7 5  of 1 2 8  
 
 
T he f oll o wi n g pr oce d ures will occ ur at select st u d y visits acc or di n g t o t he st u d y visit sc he d ule 
pr o vi de d i n Ta ble  1 a n d Ta ble  2: 
•  
Bl o o d sa m ples will be c ollecte d  at selecte d sites o n St u d y Da y s 0, 4 2, a n d 7 0 f or 
i m m u n ol o gical assess me nts i ncl u di n g cell ular i m m u nit y ( 55 m L ). 
•  
A bl o o d sa m ple will be c ollecte d at St u d y D a y  8 4 f or t h yr oi d f u ncti o n tests. 
•  
T u m or Sta gi n g: i ncl u des C T sca ns t o e val uate pr o gressi o n per R E CI S T/ ir R C will be 
perf or me d e ver y 6 wee ks. M RI, b o ne s ca ns  or P E T/ C T  will o nl y be p erf or me d if 
cli nicall y necessar y.  
•  
T u m or bi o ps y o n D a ys 0 a n d 4 2   
•  
Patie nts  i n t he c o m bi nati o n treat me nt ar m will recei ve  st u d y dr u g L V 3 0 5 at St u d y Da y 0, 
Wee k 2, 6, a n d 1 0; G 3 0 5 will be a d mi nistere d at Wee ks 4, 8, a n d 1 2. 
•  
A tez oliz u ma b will b e a d mi nistere d e ver y 3 w ee ks ( Wee ks  0, 3, 6, 9, a n d 1 2). 
 
8. 2. 3  
P ost - C M B 3 0 5 L o n g-ter m Tre at me nt St u d y Visit s  
F oll o wi n g t he Treat me nt P hase, patie nts i n t he c o m bi ne d treat me nt ar m will e nter t he B o oster 
P hase ( p ost Da y 8 4 t o 1 year p ost Da y 0); patie nts w h o c o m plete t he B o oster P hase will t he n 
e nter t he Mai nte n a nce p h ase ( 1 year t o 2 years p ost Da y 0). P atie nts i n t he c o ntr ol ar m will e nter 
t he Mai nte na nce P hase ( p ost Da y 8 4 t o 2 years p ost Da y 0).   
8. 2. 3. 1  
B o oster P h ase ( C o m bi n e d Tre at me nt Ar m O nl y: p ost D a y 8 4 t o 1 ye ar p ost D a y 
0) 
T he f oll o wi n g pr oce d ures will be perf or me d i n t h e c o m bi ne d treat me nt ar m d uri n g t hese visits : 
1.  A Es a n d S A Es  (i ncl u di n g M E OIs) 
2.  C o nc o mita nt Me dicati o ns  
3.  Vital Si g ns  
4.  P h ysical e x a mi nati o n: si m ple tar gete d e x a mi nati o n  
5.  E C O G stat us  
6.  A G 3 0 5 b o oster will be gi ve n i n t he c o m bi ne d treat me nt ar m 6 wee ks f oll o wi n g t he D a y 8 4 
d ose a n d e ver y 6 wee ks  t hereafter f or 1 year  (fr o m Da y 0) or u ntil disease pr o gressi o n. 
7.  A tez oliz u ma b a d mi nistrati o n will be a d mi nistere d o n Da y 1 0 5 a n d e v er y 3 wee ks  t hereaft er 
f or 1 year (fr o m Da y 0) or u ntil t o xicit y d e vel o ps  or pr o gressi o n.  Aft er D a y 1 0 5 , o ne of t hree 
atez oliz u ma b d oses ma y be dela ye d b y  1 wee k ( 2 8 da ys i nstea d of 2 1 da ys f or o ne c ycle) 
t o all o w f or vacati o ns. 
8.  Uri ne pre g n a nc y test m ust be perf or m e d f or F C B P wit hi n 7 2 h o urs bef ore st u d y dr u g 
a d mi nistrati o n a n d ne gati ve bef or e st u d y dr u g a d mi nistrati o n, if patie nts are still recei vi n g 
b o oster d oses of G 3 0 5 a n d/ or atez oliz u ma b. 
 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 7 6  of 1 2 8  
 
 
Bl o o d sa m ples f or cell ular i m m u nit y  ( 5 5 m L) a n d a t u m or bi o ps y will occ ur o n Da y 9 8  
( ± 2 wee ks) a n d t he f oll o wi n g pr o ce d ures will occ ur o n Da y 1 0 5: 
•  1 2- lea d E C G 
•  Bl o o d f or safet y la b or at or y e val uati o ns ( 1 0 m L)  
•  Uri ne pre g n a nc y test f or F C B Ps  
•  A d mi nistrati o n of atez oliz u ma b  
All s u bjects will ret ur n t o t he cli nic e ver y 3 wee ks f or 1 year (fr o m Da y 0) or u ntil disease 
pr o gressi o n ( w hic h e ver is later) f or th e f oll o wi n g assess me nts:  
1.  A Es a n d S A Es (i ncl u di n g M E OIs; o nl y t h ose p ossi bl y relat e d t o st u d y dr u g will be re p orte d) 
2.  C o nc o mita nt Me dicati o ns ( o nl y t h ose relate d will be re p ort e d) 
3.  Vital Si g ns  
4.  P h ysical E x a mi nati o n (s y m pt o m -s pecific) 
5.  E C O G stat us  
6.  Bl o o d f or safet y la b or at or y e val uati o ns ( 1 0 m L ) 
7.  T h yr oi d f u ncti o n tests s h o ul d be m o nit ore d at least e ver y 3 m o nt hs  
8.  T u m or sta gi n g  b y  C T  e v er y 6 wee ks  f or t he first year, t he n e ver y 1 2 wee ks 
T he f oll o wi n g pr oce d ures will occ ur at select st u d y visits acc or di n g t o t he st u d y visit sc he d ule 
pr o vi de d i n Ta ble  1: 
•  
A t u m or bi o ps y s h o ul d b e perf or m e d at 6 m o nt hs or l o n ger (f or patie nts wit h treat me nt 
res p o nse) a n d at t he ti me of pr o gressi o n  
•  
A bl o o d sa m ple will be c ollecte d at Da y  1 6 8 f or HI V testi n g ( 5 m L).  
•  
Bl o o d sa m ples will be c ollecte d at Da y 1 6 8 
 
8. 2. 3. 2  
M ai nte n a nce P h ase ( C o m bi ne d Tre at me nt Ar m: F r o m 1 Ye ar t o 2 Ye ars P ost 
D a y  0; C o ntr ol Ar m: P o st D a y 8 4 t o 2 Ye a rs P ost D a y 0) 
T he f oll o wi n g pr oce d ures will be perf or me d t h ese visits: 
1.  A Es a n d S A Es  (i ncl u di n g M E OIs) 
2.  C o nc o mita nt Me dicati o ns  
3.  Vital Si g ns  
4.  P h ysical e x a mi nati o n: si m ple tar gete d e x a mi nati o n  
5.  E C O G stat us  
6.  F or patie nts i n t he c o ntr ol ar m, a tez oliz u ma b a d mi nistrati o n will be a d mi nistere d o n Da y 1 0 5 
a n d e ver y 3 wee ks  t h ereafter f or 1 year (fr o m D a y 0) or u ntil t o xicit y de vel o ps  or 
pr o gressi o n. After Da y 1 0 5 , o ne of t hree atez oliz u ma b d oses ma y be del a ye d b y 1 w ee k ( 2 8 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 7 7  of 1 2 8  
 
 
da ys i nstea d of 2 1 da ys f or o ne c ycl e) t o all o w f or vacati o ns.   F or patie nts i n t he c o m bi ne d 
treat me nt ar m, at ez oliz u ma b a d mi nistrati o n will c o nti n ue t o be  a d mi nistere d e ver y 3  wee ks  
f or 1 year (fr o m 1 year t o 2 year p ost Da y 0) or u ntil t o xicit y de v el o ps or pr o gressi o n. 
7.  Uri ne pre g n a nc y test m ust be perf or m e d f or F C B P wit hi n 7 2 h o urs bef ore st u d y dr u g 
a d mi nistrati o n a n d ne gati ve bef or e st u d y dr u g a d mi nistrati o n, if patie nts are still recei vi n g 
b o oster d oses of G 3 0 5 a n d/ or atez oliz u ma b. 
 
F or patie nts i n t he c o ntr ol ar m, b l o o d sa m ples f or cell ular i m m u nit y ( 5 5 m L) a n d a t u m or bi o ps y 
will occ ur o n Da y 9 8  ( ± 2 wee ks) a n d t he f oll o wi n g pr o ce d ures will occ ur o n Da y 1 0 5: 
•  1 2- lea d E C G 
•  Bl o o d f or safet y la b or at or y e val uati o ns ( 1 0 m L)  
•  Uri ne pre g n a nc y test f or F C B Ps  
•  A d mi nistrati o n of atez oliz u ma b  
All s u bjects will ret ur n t o t he cli nic e ver y 3 wee ks f or t he f oll o wi n g assess me nts:  
1.  A Es a n d S A Es (i ncl u di n g M E OIs; o nl y t h ose p ossi bl y relat e d t o st u d y dr u g will be re p orte d) 
2.  C o nc o mita nt Me dicati o ns ( o nl y t h ose relate d will be re p ort e d) 
3.  Vital Si g ns  
4.  P h ysical E x a mi nati o n (s y m pt o m -s pecific) 
5.  E C O G stat us  
6.  Bl o o d f or safet y la b or at or y e val uati o ns ( 1 0 m L ) 
7.  T h yr oi d f u ncti o n tests s h o ul d be m o nit ore d at least e ver y 3 m o nt hs  
8.  T u m or sta gi n g  b y  C T  e v er y 6 wee ks  f or t he first year, t he n e ver y 1 2 wee ks  
T he f oll o wi n g pr oce d ures will occ ur at select st u d y visits acc or di n g t o t he st u d y visit sc he d ule 
pr o vi de d i n Ta ble  1: 
•  
A t u m or bi o ps y s h o ul d b e perf or me d  at 6 m o nt hs or l o n ger (f or patie nts i n t he c o ntr ol 
ar m wit h  treat me nt r es p o nse) a n d at t he ti me of pr o gressi o n  
•  
F or patie nts i n t he c o ntr ol ar m, a bl o o d sa m ple will be c ollecte d at D a y  1 6 8 f or HI V 
testi n g ( 5 m L). 
•  
Bl o o d sa m ples will be c ollecte d at Da y 1 6 8 (c o ntr olle d ar m), t he n a gai n at 1 2 a n d 
2 4 m o nt hs ( p ost Da y 0) f or L V 3 0 5 persiste n ce testi n g ( 8 m L).  
8. 2. 4  
S ur vi v al F oll o w- u p P h ase ( P ost -M ai nte n a nce P h ase L o n g- Ter m Q u arterl y 
F oll o w- u p )  
F oll o wi n g ra di o gra p hi c disease pr o gr essi o n a n d disc o nti n uati o n of st u d y dr u gs f or m ore t ha n 
3 0 da ys , p atie nts will be f oll o we d- u p b y q uarterl y tele p h o ne calls t o t he atte n di n g p h ysicia n or 
data base s ear c h  u ntil st u d y c o m pleti o n f or s ur vi v al stat us a n d s u bse q ue nt treat me nt. 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 7 8  of 1 2 8  
 
 
9. 0  
A S S E S S M E N T S O F E F FI C A C Y  A N D S A F E T Y  
9. 1  
Ti mi n g of Assess me nts  
T he ti mi n g  of st u d y assess me nts is s u m marize d i n t he Sc he d ules of E ve nts f or eac h treat me nt 
ar m (Ta ble  1 a n d Ta bl e  2) a n d detaile d i n  Secti o n  8. 2  ( St u d y C o n d uct). Aft er fi ve c ycles  of 
atez oliz u ma b  a d mi nistrati o n , o ne of t hree c ycles ma y b e dela ye d b y 1 wee k ( 2 8 da ys i nstea d of 
2 1 da ys f or o ne c ycle) t o all o w f or vacati o ns. 
9. 2  
De m o gr a p hics , Me dic al Hist or y , a n d B aseli ne C h ar acteristics  
Me dical hist or y i n cl u des pre vi o us cli nicall y si g nifi ca nt diseases, s ur geries, ca ncer hist or y a n d 
t hera pies, r es p o nses t o pri or t hera pies a n d m e dicati o ns use d b y t he p atie nt wit hi n 2 8 da ys pri or t o 
scree ni n g. D e m o gra p hic i nf or mati o n will i ncl u de a ge, se x, race, et h nicit y, etc. E C O G 
Perf or ma nce stat us will be assesse d usi n g sta n dar d met h o d ol o gies a n d criteria o utli ne d i n 
A p pe n di x A . 
9. 3  
Effic ac y Assess me nts  
9. 3. 1  
T u m or R es p o nse  B ase d u p o n  R E CI S T a n d ir R C  
T u m or sta gi n g  b y  C T will be perf or m e d e ver y 6 t o 9 wee ks a n d i ma ges/sca ns will be e val uate d 
b y t he sites f or treat me nt decisi o ns a n d later b y BI C R f or t u m or res p o nses. T he R E CI S T v 1. 1 
criteria m o difie d t o use ir R C3 7 will be use d t o deter mi ne disease pr o gressi o n as defi ne d i n  
A p pe n di x C . T he ir R C als o re q uire a c o nfir mati o n of C R/ P R/ P D at least 4 wee ks la ter wit h 
i ma gi n g. O nce c o nfir me d, t he date of pr o gressi o n will be defi ne d as t he first date t hat t he t otal 
t u m or b ur de n was s h o w n t o ha ve i ncrease d b y at least 2 0 % c o m pare d wit h na dir. F or t his st u d y, 
t he m o difie d ir R C usi n g u ni di me nsi o nal meas ure me nts of t he t u m or will be i m ple me nte d (see 
A p pe n di x C a n d A p pe n di x D ). E val uati o ns will be use d f or d eter mi nati o n of P F R, P F S, O R R, 
D O R, a n d ti me t o res p o nse. O S will als o be e val u ate d.  
9. 3. 2  
I m m u ne R es p o nse  
T he f oll o wi n g e x pl orat or y i m m u ne m o nit ori n g will be c o n d ucte d: 
•  
Cell ular i m m u n o ge nicit y as meas ure d b y c ha n ges fr o m baseli ne a n d o v er t h e c o urse of 
t he trial peri o d i n peri p heral bl o o d le vels of T cells, T-cell effect or a n d me m or y 
p o p ulati o ns, a n d T- cell ass ociate d c yt o ki ne pr o d u cti o n. 
•  
H u m oral i m m u n o ge nicit y as meas ure d b y c ha n ges fr o m baseli ne a n d o v er t he c o urse of 
t he trial peri o d wit h a nti-N Y -E S O - 1 a nti b o dies or T A As . 
•  
E val uati o n of d osi n g res p o nse b y R N A pr ofili n g of P B M Cs as meas ure d b y t he c ha n ges 
fro m baseli ne. 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 7 9  of 1 2 8  
 
 
Details f or sa m ple h a n dli n g a n d assa y perf or m a nce will be pr o vi de d i n t he I m m u ne M o nit ori n g 
Ma n ual.  
9. 3. 3  
E x pl or at or y Bi o m ar kers 
Pre -, o n-, a n d p ost-tr eat me nt bl o o d or t u m or sa m ples ma y b e c ollect e d f or e x pl orat or y a n al ys es 
of p ote ntial bi o mar kers o f C M B 3 0 5 or at ez oliz u ma b  i m m u n o ge nicit y a n d cli nical t u m or 
res p o nse. A n u m ber of e x pl orat or y a nal yses are b ei n g i n vesti gate d, b ut t he pre dicti ve val ue of 
s uc h tests is n ot yet k n o w n. T he data c ollecte d fr o m t hese e x pl orat or y tests will hel p t o defi ne a 
set of bi o mar kers t hat mi g ht be us e d i n f ut ure st u dies t o hel p defi ne t he a bilit y of C M B 3 0 5 t o 
sti m ulate a ntit u m or i m m u ne res p o nses, t o hel p stratif y p atie nts w h o mi g ht res p o n d t o t hese 
treat me nts, a n d/ or t o deter mi ne a mi ni m u m t hera pe utic d ose. E x pl orat or y bl o o d tests ma y 
i ncl u de f u ncti o nal assa ys of c yt ol ytic T cells or ot her i m m u ne cells directe d a gai nst a ut ol o g o us 
t u m or cells or s urr o gat e tar get cells, m o dificati o ns of c urre nt assa ys t o detect a ntit u m or cell ular 
i m m u nit y, det ecti o n or a nal yses of cir c ulatin g t u m or cells, a n d/or a n al ys es of ot her (as of yet 
u n defi ne d) t u m or mar kers a n d i m m u ne f u ncti o n.  
Pre - a n d o n-st u d y ca ncer bi o ps y tiss ue will be e x a mi ne d f or e vi de n ce of a ntit u m or cell ular 
i m m u nit y (e. g., C D 8 T cell or N K cell  i nfiltrati o n, t u m or necr osis, etc.) a n d f or e vi de n ce of 
i m m u ne s u p pressi o n wit hi n t he t u m or micr oe n vir o n me nt. Bl o o d or t u m or sa m ples will o nl y be 
use d t o e x a mi ne t he patie nt’s i m m u ne res p o nse, t heir ca n cer, or t o hel p e val uate a n y p ote ntial 
t o xicit y arisi n g i n t he st u d y. T he s a m ples will n ot be e x a mi ne d f or u nrel ate d researc h or diseases. 
9. 4  
S af et y  Assess me nts  
Safet y will be e val uat e d f or all treate d p atie nts usi n g N CI C T C A E  v 4. 0 3.2 9 Safet y assess me nts 
will be base d o n me dical re vie w of b ot h s olicite d a n d s p o nta ne o usl y re p orte d A Es, S A Es, a n d 
M E OIs  i n cl u di n g s y m pt o ms, p h ysical e x a mi nati o n fi n di n gs, vital si g ns, la b orat or y fi n di n gs, 
E C Gs, a n d disc o nti n uati o ns f or A Es. After i nitiati o n of st u d y dr u g, all A E s, re gar dless of 
relati o ns hi p t o st u d y dr u g, will be r e p orte d u ntil 3 0 da ys after t h e last d ose of st u d y dr u g or u ntil 
i nitiati o n of a n ot her a nti-ca ncer t her a p y, w hic h e ver occ urs first.  
9. 4. 1  
Defi niti o ns  
A d verse E ve nt ( A E)  - A n y u nt o war d me dical o cc urre nce i n a patie nt or cli nical i n vesti gati o n 
patie nt a d mi nistere d a p h ar mace utical pr o d uct, me dical treat me nt , or pr oce d ure a n d w hic h d oes 
n ot necessaril y ha v e t o h a ve a ca usal r elati o ns hi p wit h t his re gi me n. A n A E ca n t heref ore be a n y 
u nfa v ora bl e a n d u ni nte n d e d si g n (i n cl u di n g a n a b n or mal la b orat or y fi n di n g, f or e x a m ple), 
s y m pt o m, or disease t e m p orall y ass ociate d wit h t he use of a m e dici nal pr o d uct, me dical 
treat me nt, or pr o ce d ur e w het her or n ot c o nsi dere d p ossi bl y, pr o ba bl y, or d efi nitel y relate d t o t he 
me dici nal pr o d uct.  

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 8 0  of 1 2 8  
 
 
U ne x pecte d A d verse E v e nt  – A n A E is “ u ne x pecte d” w he n its nat ure (s pecificit y), se verit y, or 
fre q ue n c y ar e n ot c o nsiste nt wit h t he k n o w n or f oreseea bl e ris k of A E ass ociate d wit h t he 
researc h pr o ce d ur es descri be d i n t he pr ot oc ol, i nf or me d c o nse nt f or m, or t he I n vesti gat or 
B r oc h ure. 
Seri o us A d verse E ve nt ( S A E)  – A n y a d vers e e v e nt occ urri n g t h at r es ults i n a n y of t h e 
f oll o wi n g o utc o mes: 
•  
Deat h  
•  
A life -t hreate ni n g A E 
•  
I n p atie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n 
N ote : H os pitalizati o ns n ot t o be re p orte d as S A Es i ncl u de a d missi o ns f or a pla n ne d 
me dical/s ur gical pr o ce d ure (s uc h a s sc he d ul e d t u m or e x cisi o n or de b ul ki n g s ur ger y) or 
r o uti ne healt h assess me nt re q uiri n g a d missi o n f or baseli ne/tre n di n g of healt h stat us 
d oc u me ntati o n ( e. g., r o uti ne c ol o n osc o p y) or a d missi o n f or s ocial p ur p oses s uc h as lac k 
of h o usi n g, ec o n o mic i na de q uac y , care-gi ver res pite, or fa mil y circ u msta n ces.  
•  
A persiste nt or si g nifica nt disa bilit y/i nca p acit y  
•  
Res ults i n a c o n ge nital a n o mal y/ birt h defect 
•  
Is a me dicall y i m p orta nt c o n diti o n w hic h is j u d ge d b y a h ealt h care pr ofessi o nal as 
seri o us 
T he ter m “life -t hreate ni n g” ref ers t o a n e ve nt i n w hic h t he patie nt was at ris k of deat h at t he ti me 
of t he e ve nt, a n d it d oes n ot refer t o a n e ve nt t hat h y p ot heticall y mi g ht ha v e ca use d d eat h if it 
were m or e se vere.  
Disa bilit y ref ers t o a s u bsta ntial dis r u pti o n of a pers o n’s a bilit y t o c o n d uct n or mal life f u ncti o n.  
Me dical a n d sci e ntific j u d g me nt will be e x ercis e d i n deci di n g w h et her e x pe dite d re p orti n g is 
a p pr o priate i n ot her sit uati o ns, s uc h as i m p orta nt me dical e ve nts t hat 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 p ar 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 o utc o mes liste d i n t he defi niti o n a b o ve. T hese ma y als o be 
c o nsi dere d seri o us. E x a m ples of s uc h e ve nts are i nte nsi ve treat me n t i n a n e mer ge n c y r o o m or at 
h o me f or aller gi c br o nc h os pas m; or 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.  
W he n t here is d o u bt re gar di n g a n A E meeti n g t he criteria f or a n S A E, t he I n vesti gat or s h o ul d 
defa ult t o re p orti n g t he A E as a n S A E.  
Pre g n a nc y  – Alt h o u g h pre g na nc y is n ot c o nsi dere d a n S A E, a n d is i nstea d a n or mal h u ma n 
e x perie nce, all pr e g na nci es re p orte d i n t he m o nt h bef ore or aft er t he last i n vesti gati o nal i njecti o n 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 8 1  of 1 2 8  
 
 
m ust be re p orte d t o t he S p o ns or usi n g t he Pre g n a n c y Re p ort F or m as o utli ne d i n t he Site Safet y 
Ma n ual.  
O ver d ose – A n o ver d os e is defi ne d as t he acci de nt al or i nte nti o nal a d mi nistrati o n of a n y d ose of 
a pr o d uct t hat is c o nsi der e d b ot h e x cessi ve a n d me dicall y i m p orta nt. I n t his trial, a n o ver d ose 
will be defi ne d as ≥1 0 0 0 m g ( 5 x t he d ose) of atez oliz u ma b . F or re p orti n g p ur p oses, a n o ver d ose 
will be c o nsi dere d, r e gar dless of a d vers e o utc o me, as a n i m p orta nt me dical e ve nt. All cases of 
o ver d ose m ust be r e p orte d i m me diatel y t o t he S p o ns or.  
Me dic al E ve nts of I nterest  – Select n o n -s eri o us A Es a n d S A Es i de ntifie d b y t he S p o ns or will 
be c o nsi der e d M E OIs. All M E OIs o utli ne d i n Secti o n  9. 4. 8  m ust be re p orte d t o t he S p o ns or 
usi n g t he M E OI R e p ort F or m as o ut li ne i n t he Site Safet y M a n ual.  
9. 4. 2  
A d verse E ve nt Se verit y  
All A Es will be e val uate d acc or di n g t o t he N CI C T C A E v 4. 0 3 ( 2 0 1 0). 2 9 
F or A Es n ot liste d i n t his refere nce scale, se verit y will be assesse d b y t he I n vesti gat or acc or di n g 
t o t he criteria i n Ta bl e  4. 
T a ble 4 
A d verse E ve nt Se verit y Assess me nt  
Gr a de 1 ( Mil d)  
Mil d; as y m pt o matic or mil d s y m pt o ms; cli nical or dia g n ostic 
o bser vati o ns o nl y; i nter v e nti o n n ot i n dicate d.  
Gr a de 2 ( M o der ate)  
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 ) *. 
Gr a de 3 ( Se vere)  
Se vere or m e dicall y si g nifica nt b ut n ot i m me diatel y life -
t hreate ni n g; h os pitalizati o n or pr ol o n gati o n of h os pitalizati o n 
i n dicate d; disa bli n g; li miti n g self-care A D L * *.  
Gr a de 4 ( Lif e t hre ate ni n g)  
Lif e -t hreate ni n g c o nse q u e nces; ur ge nt i nter ve nti o n i n dicate d. 
Gr a de 5 ( De at h)  
Deat h rel ate d t o A E.  
* I nstr u me ntal A D L refer t o pre p ari n g me als, s h o p pi n g f or gr o ceries or cl ot h es, usi n g t h e tele p h o n e, ma n a gi n g m o n e y, etc. 
* *  Self -car e A D L refer t o b at hi n g, dressi n g a n d u n dressi n g, fee di n g self, usi n g t h e t oilet, ta ki n g me dicati o ns, a n d n ot b e dri d de n. 
 
C ha n ges i n t he s e verit y of a n A E s h o ul d be d o c u me nte d t o e na ble a n assess me nt of t he d urati o n 
of t he e ve nt at eac h l e vel of i nte nsit y. A Es  c h aract erize d as i nter mitte nt re q uire d oc u me ntati o n of 
o nset a n d d urati o n of eac h e pis o de.  

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 8 2  of 1 2 8  
 
 
9. 4. 3  
Rel ati o ns hi p  t o I n vesti g ati o n al Dr u g 
T he  I n vesti gat or will re p ort his or her i nter pretati o n of t he relati o ns hi p bet wee n a n A E a n d t he 
st u d y treat me nt o n t he basis of t heir cli nical j u d g m e nt a n d t he defi niti o ns i n Ta ble  5. 
T a ble 5 
Assess me nt of Rel ati o ns hi p  
Defi nitel y rel ate d  
A Es clearl y attri b uta ble t o st u d y re gi me n a d mi nistrati o n . 
Pr o b a bl y rel at e d  
A Es f or w hic h t here is a reas o na bl e p ossi bilit y of ca usal ass oci ati o n 
t o st u d y re gi me n. 
P ossi bl y rel ate d  
A Es f or w hic h t here is c o nf o u n di n g b y c o m or bi dities, me dicati o ns or 
ot her c o nsi derati o ns b ut f or w hic h it is n ot u nreas o na ble t hat t he A E 
ma y h a ve bee n ca use d b y st u d y re gi me n. N ote t hat it is n ot 
a p pr o priate t o i n v o ke “ y o u ca n’t r ule it o ut.” 
N ot rel at e d  
A Es t hat are c o nsi dere d clearl y n ot ca us all y relate d t o st u d y 
re gi me n, or f or w hic h t here is a clear alter nati ve e x pla nati o n 
A E = a d verse e ve nt  
 
If t here is a n y q uesti o n w het her or n ot a n A E is p ossi bl y, pr o babl y or d efi nitel y relate d, t he 
I n v esti gat or s h o ul d defa ult t o c o nser vatis m i n cate g orizati o n. Si milarl y, if a n e ve nt meets o ne of 
t he defi niti o ns descri be d a b o ve a n d t here is a n y d o u bt re gar di n g t he seri o us nat ure of a n A E, the 
I n v esti gat or s h o ul d defa ult t o c o nservatis m b y calli n g a n A E a n S A E.  
9. 4. 4  
A d verse E ve nt C ollecti o n Peri o d  
A Es  i ncl u de a n y u nt o war d si g ns (i ncl u di n g a b n or mal la b orat or y fi n di n gs) or s y m pt o ms 
e x perie nce d b y t he p atie nt  a n d will be c ollecte d  fr o m t he ti me of e nr oll me nt u ntil 3 0 da ys after 
t he last d ose of st u d y dr u g. All e nr olle d patie nts will ha ve peri o dic assess m e nt of cli nical a n d 
la b orat or y A Es. All A Es a n d S A Es will be c ollect e d at eac h St u d y Visit f oll o wi n g c o m pleti o n of 
all sc he d ule d pr o ce d ur es. T hereafte r, n e w mali g na ncies a n d S A Es t hat c o m e t o t he atte nti o n of 
t he site staff t hat ar e c o nsi dere d at least p ossi bl y relate d t o C M B 3 0 5 or atez oliz u ma b  will be 
c ollecte d u ntil t he last patie nt c o ntact.   
9. 4. 5  
A d verse  E ve nt R e p orti n g  
At eac h st u d y visit (i ncl u di n g u nsc h e d ule d visits), t he I n v esti gat or, or d esi g nee, will deter mi ne 
w het her a n y A Es ha v e occ urre d. A Es will be re p orte d i n t he patie nt’s me dical rec or d a n d o n t he 
A E C R F pa ge a n d eac h will be classifie d acc or di n g t o t he criteria i n Secti o n  9. 4. 2  a n d 
Secti o n  9. 4. 3 . If k n o w n, t he dia g n osis s h o ul d be rec or de d, i n prefere nce t o t he listi n g of 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 8 3  of 1 2 8  
 
 
i n di vi d ual si g ns a n d s y m pt o ms. A n y pre-e xisti n g c o n diti o ns t hat are detecte d as part of t h e i nitial 
scree ni n g pr o ce d ures will nee d t o be re p orte d i n t he me dical hist or y a n d n ot as a n A E. H o w e ver, 
pre -e xisti n g c o n diti o ns t hat w orse n f oll o wi n g e nr oll ment s h o ul d be re p orte d as a n A E. 
A Es  t hat occ ur d uri n g or wit hi n 2 4 h o urs after st u d y dr u g a d mi nistrati o n s h o ul d be ca pt ure d as 
i n di vi d ual si g ns a n d s y m pt o ms o n t he A E  e C R F rat her t ha n a n o v erall dia g n osis (e. g., rec or d 
d ys p nea a n d h y p ote nsi o n as se par ate e v e nts rat her t ha n a dia g n osis of i nf usi o n- relate d reacti o n). 
F or all patie nts, pr o gressi o n of t he ca n cer u n d er st u d y is n ot c o nsi dere d a n A E u nless it assesse d 
b y t he I n vesti gat or as dr u g- relate d.  
All A Es  a n d S A Es t hat are u ne x pecte d a n d c o nsi d ere d p ossi bl y, pr o ba bl y, or defi nitel y relat e d t o 
st u d y re gi me n will be re p orte d t o t he U S F o o d a n d Dr u g A d mi nistrati o n ( F D A ) b y I M D Z, or 
desi g nee, i n acc or d a nce wit h t he re q uire me nts o utli ne d i n t he C o de of Fe d eral Re g ulati o ns 
( C F R), 2 1 C F R  § 3 1 2. 3 2. Deat hs d ue t o ca ncer pr o gressi o n will n ot be re p orte d as e x pe dite d 
e ve nts b ut m ust be re p ort e d t o t he S p o ns or as S A Es wit hi n t he 2 4 h o ur ti me peri o d. T he 
I n v esti gat or will c o nti n ue t o m o nit or t he patie nt u ntil a n y ne w, c ha n ge d, or w orse ne d A E 
res ol ves, ret ur ns t o baseli ne, or u ntil t he I n vesti gat or a n d I M D Z a gree t hat f oll o w - u p is n o l o n ger 
necessar y. A Es m ust be f oll o we d u ntil res ol uti o n w he ne ver p os si ble. 
T he I n vesti gat or is r es p o nsi ble f or t he a p pr o priate me dical care a n d s afet y of patie nts w h o ha ve 
e ntere d t his st u d y. T he I n vesti gat or m ust n otif y t h e S p o ns or wit hi n 2 4 h o urs if eit her of t he 
f oll o wi n g e v e nts occ urs: 
•  
A n y e ve nt c o nsi dere d a n M E OI (see Secti o n  9. 4. 8 ) 
•  
A n y e ve nt meeti n g t he criteria f or a n S A E  
 
T he nat ure, s e verit y, a n d fre q ue n c y of A Es will be m o nit ore d o n a n o n g oi n g basis f or ris k 
assess me nt a n d t o deter mi ne if ris k ma na ge me nt i nter ve nti o ns are warra nte d (i.e., e x pe dite d 
n otificati o n of safet y fi n di n gs t o i n vesti gat ors, I R Bs, or re g ulat ors; u p d ate of I B a n d I C F ris ks 
a n d re- c o nse nti n g st u d y patie nts; re visi o n of safet y m o nit ori n g pr oce d ures; re visi o n of eli gi bilit y 
criteria or ot h er st u d y pr o ce d ures).  
9. 4. 6  
Seri o us A d verse  E ve nt Re p orti n g  
If a n S A E occ urs, t he I n v esti gat or m ust n otif y I M D Z wit hi n 2 4 h o urs of a ware n ess of t he e v e nt  
(see c o nt act i nf or mati o n bel o w). If t he S A E is fatal or life-t hreate ni n g, I M D Z m ust be n otifie d 
i m me diatel y, irr es pecti ve of t he e xte nt of a vaila ble S A E i nf or mati o n. I n t h e rare e ve nt t hat t he 
I n v esti gat or or desi g nee d oes n ot bec o me a ware of t he occ urre n ce of a S A E i m me diatel y, t he 
I n v esti gat or or desi g nee m ust re p ort t he e ve nt wit hi n 2 4 h o urs of t heir a w are ness a n d d o c u me nt 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 8 4  of 1 2 8  
 
 
t he ti me of w he n his/ her first a war e ness occ urre d. F or all S A Es, t he In v esti gat or or desi g nee is 
o bli gate d t o p urs u e a n d pr o vi de i nf or mati o n t o I M D Z i n acc or da nce wit h t he ti mefra mes f or 
re p orti n g s pecifi e d a b o ve. I n a d diti o n, t he I n vesti gat or ma y be re q ueste d t o o btai n s pecific 
a d diti o nal f oll o w- u p i nf or mati o n i n a n e x pe dite d fas hi o n. T his i nf or mati o n m a y b e m ore det aile d 
t ha n t hat ca pt ure d o n t h e A E case re p ort f or m. I n ge neral, t his will i ncl u de a descri pti o n of t he 
A E i n s ufficie nt detail t o all o w f or a c o m plete me dical assess me nt of t he cas e a n d i n de pe n d e nt 
deter mi nati o n of ca usalit y.  
D uri n g t h e scr ee ni n g peri o d, a n y n e w S A Es e x peri e nce d b y p atie nts ( pre -st u d y treat me nt) will be 
re p orte d t o I M D Z if t he e ve nts are c o nsi dere d relat e d t o st u d y pr o ce d ures. F or t he peri o d after 
si g ni n g t he I C F u ntil Da y 0, a n y n e w S A Es deter mi ne d t o be relate d t o st u d y tests or pr o ce d ures 
( n ot i ncl u di n g ca ncer-r el ate d e ve nts) a n d a n y h os pitalizati o ns t hat are e x perie nce d b y patie nts 
will be re p orte d o n t he S A E f or m a n d i n t he e C R F. Fr o m t he start of st u d y treat me nt ( D a y  0) 
u ntil 3 0 da ys f oll o wi n g cessati o n of st u d y dr u g ( or if t he patie nt  i nitiates ne w a ntica ncer t hera p y, 
w hic he ver is earlier) , S A Es will be re p orte d o n t h e S A E f or m a n d i n t he e C R F. After t hat p oi nt, 
a n y S A E t h at c o mes t o t he atte nti o n of t he site staff t hat ma y b e ca usall y rel ate d t o st u d y dr u g 
(i.e., t here is a reas o na ble p ossi bilit y t hat t he e v e nt ma y h a ve bee n ca use d b y t he dr u g) will be 
re p orte d t o I M D Z. 
S A Es will be m o nit ore d u ntil t he y ha ve res ol ve d, ret ur ne d t o bas eli ne, or u ntil t he y are n o l o n ger 
cli nicall y si g nifica nt, sta ble, or d o n ot re q uire a d d iti o nal f oll o w- u p, as j u d ge d b y t h e I n vesti gat or 
a n d I M D Z. 
S T U D Y C O N T A C T F O R R E P O R TI N G  
S E RI O U S A D V E R S E E V E N T S  
E verest Cli nical Researc h I n c.  
Tele p h o ne:  
 ( office) or 
 ( m o bile) 
Fa x:  
See t he S A E Re p ort C o m pleti o n G ui deli nes  
E mail:  
S A E f or ms t o 
  
S u p ple me ntal i nf or mati o n t o 
  
 
9. 4. 7  
A d verse  E ve nt F oll o w -u p  
Patie nts wit h ra di o gr a p hic disease pr o gressi o n will be f oll o we d e ver y 3 m o nt hs b y tele p h o ne 
u ntil t he st u d y is c o m plet e d (last patie nt, last deat h i n t he st u d y) . F oll o w-u p tele p h o ne calls will 
ascert ai n vital stat us, p ossi ble occ urr e nce of sec o n d mali g na n cies, a n d s u bs e q ue nt treat me nt as 
o utli ne d i n Secti o n  5. 7 . I n t he e ve nt of deat h, atte m pts will be ma de t o esta blis h t he date a n d 
ca use of d eat h , as a p plica ble.  
P P D
P P D
P P D
P P D

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 8 5  of 1 2 8  
 
 
9. 4. 8  
Me dic al E ve nts of I nterest  
Selecte d n o n -seri o us A Es  are cl assifie d  as M E OI s (see bel o w) a n d m ust be rec or d e d as s uc h o n 
t he A E  Case Re p ort F or ms a n d re p orte d t he S p o ns or eit her b y electr o nic m e dia or pa p er o n a 
M E OI Re p ort F or m . S p o ns or C o ntact i nf or mati o n ca n be f o u n d i n Secti o n  9. 4. 6 . 
M E OIs  f or t his trial i ncl u de t he f oll o wi n g: 
•  
D L Ts  
•  
A n o ver d ose of S p o ns or's pr o d uct t hat is n ot ass ociate d wit h cli nical s y m pt o ms or 
a b n or mal la b or at or y res ults.  
•  
A n ele vate d A S T or A L T la b val ue t hat is ≥3 x U L N  a n d a n el e vate d t otal bilir u bi n la b 
val ue ≥2 x U L N  a n d, at t he sa me ti me, a n al k ali ne p h os p hatase la b orat or y v al ue t hat is 
< 2 x U L N , as d eter mi ne d b y w a y of pr ot oc ol-s pecifie d la b orat or y t esti n g or u nsc he d ule d 
la b orat or y testi n g. 
* N ote : T hese criteri a ar e base d u p o n a v aila ble re g ulat or y g ui da n ce d o c u me nts.  T he 
p ur p ose of t he criteria is t o s pecif y a t hres h ol d of a b n or mal he patic t ests t hat ma y re q uire 
a n a d diti o nal e val uati o n f or a n u n derl yi n g eti ol o g y. T he trial site g ui d a nce f or assess me nt 
a n d f oll o w u p of t hese criteria ca n b e f o u n d i n t he I n v esti gat or T rial File Bi n der ( or 
e q ui vale nt). 
•  
T he f oll o wi n g c o nfir me d treat me nt -e mer ge nt a ut oi m m u ne c o n diti o ns: 
•  P ne u m o nitis 
•  H y p o xia or d ys p nea ≥Gr a de 3 
•  C olitis  
•  E n d ocri n o pat hies: dia bet es mellit us, pa ncreatitis, or a dre n al i ns ufficie n c y 
•  Vasc ulitis  
•  He patitis  
•  Tra nsa mi nitis: ≥Gra de  2 ( A S T or A L T > 3 x U L N a n d bilir u bi n > 2 x U L N) O R 
A S T/ A L T  > 1 0 x U L N 
•  S yste mic l u p us er yt he mat os us  
•  G uillai n - Barre s y n dr o m e 
•  S ki n reacti o ns: vitili g o, pe m p hi g oi d  
•  E ve nts s u g gesti ve of h y p erse nsiti vit y, c yt o ki ne rel ease, i nfl ue nza- li ke ill ness, 
s yste mic i nfla m mat or y res p o nse s y n dr o m e ( SI R S), or i nf usi o n reacti o n s y n dr o me. 
S u bjects s h o ul d be assesse d f or p ossi ble M E OIs  pri or t o eac h d ose of st u d y treat me nt . La b 
res ults s h o ul d be e val uat e d a n d s u bjects s h o ul d be as ke d f or si g ns a n d s y m pt o ms s u g gesti ve of 
a n i m m u ne-relate d e ve nt. S u bjects w h o de vel o p a n M E OI  t h o u g ht t o be i m m u ne-relat e d s h o ul d 
ha ve a d diti o nal testi n g t o r ule o ut ot her eti ol o gic ca uses. If la b res ults or s y m pt o ms i n dicate  

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 8 6  of 1 2 8  
 
 
p ossi ble i m m u ne- relate d M E OIs , t h e n a d diti o nal testi n g s h o ul d be perf or m e d t o r ule o ut ot her 
eti ol o gic ca uses.  If n o ot her ca us e is f o u n d, t he n it is ass u me d t o be i m m u ne-rel ate d. 
M E OIs i d e ntifie d fr o m t he date of first d ose t hr o u g h 9 0 da ys f oll o wi n g cessati o n of treat me nt, or 
3 0 da ys after t h e i nitiati o n of a ne w a ntica ncer t hera p y, w hic he v er is earlier, nee d t o be re p orte d 
t o t he S p o ns or wit hi n 2 4 h o urs of t he e v e nt i n t he sa me ma n ner as o utli ne d f or S A Es 
(Secti o n  9. 4. 6 ). 
9. 4. 9  
P re g n a nc y  
S e veral n o ncli nical st u di es ha ve alrea d y d e m o nstrate d t hat t he P D -L 1/ P D - 1 si g nali n g pat h wa y is 
esse ntial i n esta blis hi n g mater nal/fetal t olera nce, w hic h is necess ar y f or e m br y o -fetal s ur vi val 
d uri n g gest ati o n .3 1 As a res ult, n o de vel o p me ntal or re pr o d u cti ve t o xicit y st u dies ha ve bee n 
c o n d ucte d wit h atez oliz u ma b. T he effects of atez oliz u ma b o n h u ma n re pr o d ucti o n or o n t he fet us 
or t he de vel o pi n g i nfa nt are u n k n o w n b ut it is e x pecte d t o ha v e a n a d v erse effect  F urt h er m ore, it 
is n ot k n o w n w het her atez oliz u ma b is e x crete d i n h u ma n mil k; h o we ver, a nti b o dies are k n o w n t o 
cr oss t he place nta a n d ar e e x crete d i n breast mil k d uri n g lactati o n.   
Base d o n t h e crit ical r ole t hat P D-L 1/ P D -1 p at h w a y pl a ys i n t he m ai nte na n ce of mater nal -fetal 
t olera nce a n d t he e x creti o n of a nti b o dies d uri n g l actati o n, atez oliz u ma b s h o ul d n ot be 
a d mi nistere d t o pre g na nt w o me n or n ursi n g m ot hers. T he effects of atez oliz u ma b o n h u ma n 
re pro d ucti o n or o n t he fet us or t he de vel o pi n g i nfa nt are u n k n o w n b ut it is e x pecte d t o ha ve a n 
a d verse eff ect .  
A bse nce of pre g n a nc y m ust be c o nfir me d pri or t o i nitiati o n of atez oliz u ma b . Fe male  p atie nts of 
c hil d beari n g p ote ntial s h o ul d utilize c o ntrace pti o n a n d ta ke acti ve meas ures t o a v oi d pre g na nc y 
w hile u n der g oi n g atez oliz u ma b  treat me nt a n d f or at least 9 0 da ys aft er t he l ast d ose of 
atez oliz u ma b . 
If a f e male patie nt  i na d v erte ntl y bec o mes pre g na nt w hile o n treat me nt wit h C M B 3 0 5 or 
atez oliz u ma b, t he y will be i m me diatel y re m o ve d fr o m t he st u d y. T he site will c o ntact t he patie nt  
at least m o nt hl y t o d oc u me nt t he patie nt ’s stat us u ntil t he pre g n a nc y has b ee n c o m plete d or 
ter mi nate d. T he o utc o me of t he pre g n a nc y will be re p orte d t o t he S p o ns or wit h o ut dela y a n d 
wit hi n 2 4 h o urs if t he o utc o me is a n S A E (e. g., d eat h, a b orti o n, c o n ge nital a n o mal y, or ot her 
disa bli n g or life -t hreat e ni n g c o m plicati o n t o t he m ot her or ne w b or n). T h e st u d y i n vesti gat or 
s h o ul d ma ke e ver y eff ort t o o btai n per missi o n t o f oll o w t he o utc o me of t he pre g na nc y a n d r e p ort 
t he c o n diti o n of t he fet us or ne w b or n t o t he S p o ns or. If a mal e patie nt  i m pre g n ates his fe mal e 
part ner, t he st u d y pers o n nel at t he site m ust be i nf or me d i m me diatel y a n d t he pre g na n c y re p orte d 
t o t he S p o ns or. 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 8 7  of 1 2 8  
 
 
Se x uall y acti ve me n a n d F C B P s m ust use a n effecti ve met h o d of birt h c o ntr ol d uri n g t he c o urse 
of t he st u d y, i n a m a n ner s uc h t hat ris k of fail ure is mi ni mize d. Bef ore e nr olli n g F C B P i n t his 
cli nical trial, all F C B P s m ust be a d vise d of t he i m p orta nce of a v oi di n g pre g n a nc y d uri n g tri al 
partici pati o n a n d t he p ote ntial ris k fact ors f or a n u ni nte nti o nal pre g n a nc y. All patie nts ( me n a n d 
w o me n) m ust si g n a n i nf or me d c o nse nt f or m d oc u me nti n g t his disc ussi o n.  
All F C B P s m ust ha ve a n e gati ve pre g n a nc y test wit hi n 2 wee ks pri o r t o t he st u d y re gi me n 
i nitiati o n. If t he pr e g na nc y test is p ositi ve, t he patie nt  m ust n ot be e nr olle d i n t he st u d y.  
I n a d diti o n, all F C B Ps s h o ul d be i nstr ucte d t o c o nt act t he In vesti gat or i m me diatel y if t he y 
s us pect t he y mi g ht be pre g na nt (e. g., misse d or lat e me nstr ual peri o d) at a n y ti me d uri n g st u d y 
partici pati o n.  
If, f oll o wi n g i nitiati o n of st u d y d osi n g, it is s u bse q ue ntl y disc o vere d t hat a trial patie nt  is 
pre g na nt or ma y h a ve b ee n pre g na nt wit hi n o ne m o nt h bef ore or 4 m o nt hs after st u d y re gi me ns , 
t he patie nt  will be per ma ne ntl y disc o nti n ue d. Th e patie nt will be f oll o we d f or as l o n g as p ossi ble 
b y t he I n vesti gat or or d esi g nate d h ealt h care pr ofessi o nal t o deter mi ne pre g na nc y o utc o mes f or 
b ot h m ot her a n d c hil d. If t he fe male p art ner of a m ale patie nt enr olle d i n t he st u d y bec o mes 
pre g na nt, t he I n v esti gat or ( or desi g nat e d healt h pr ofessi o nal) s h o ul d re q u est per missi o n t o 
a p pr oac h t h e part n er r e gar di n g f oll o w- u p i n or der t o deter mi ne pre g na nc y o utc o mes of t he 
m ot her a n d ba b y. 
9. 4. 1 0  
L a b or at or y S af et y Assess me nts  
Bl o o d will be c ollecte d a s pecific st u d y visits as o utli ne d i n Secti o n  8. 2  a n d t he sc he d ules of 
e ve nts f or eac h tr eat me nt ar m. La b or at or y assess m ents t o be perf or me d  i ncl u de, b ut are n ot 
li mite d t o, t he f oll o wi n g: 
•  
He mat ol o g y: w hite bl o o d cell ( W B C ) c o u nt wit h differe ntial, A N C, re d bl o o d cell (R B C ) 
c o u nt, H b, he mat ocrit, pl atelet c o u nt, P T/ P T T , a n d I N R;  
•  
Cli nical c he mistr y  ( or l ocal pa nel if i ncl usi ve of t he f oll o wi n g): s o di u m, c hl ori de, 
p otassi u m, gl uc ose, bl o o d urea nitr o ge n ( B U N ), creati ni ne, calci u m, A S T, A L T, t otal 
bilir u bi n, al kali ne p h os p hatase, lactic aci d de h y dr o ge n ase, t otal pr otei n, a n d al b u mi n; a n d  
•  
Uri nal ysis  ( at baseli ne): pr otei n, gl uc os e, bl o o d, le u k oc ytes, nitrites, ur o bili n o ge n, 
bilir u bi n, p H, s pecific gr a vit y, a n d k et o nes.  
Scree ni n g saf et y la b or at or y s afet y ass ess me nts s h o ul d be perf or m e d wit hi n 4 da ys of treat me nt 
i nitial. O n d osi n g da ys, h e mat ol o g y a n d cli nical c he mistr y ass ess me nts s h o ul d be perf or m e d a n d 
re vie we d pri or t o st u d y dr u g a d mi nistrati o ns. T hese assess me nts ma y be d o ne u p t o 4 8 h o urs 
pri or t o d osi n g. 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 8 8  of 1 2 8  
 
 
Res ults will be d oc u me nte d i n t he patie nt C R Fs. Cli nicall y si g nifica nt fi n di n gs ma y b e rec or de d 
as A Es.  
9. 4. 1 0. 1  
T h yr oi d F u ncti o n Tests  
Assess me nts f or t h yr oi d f u ncti o n i ncl u di n g trii o d ot h yr o ni ne [ T 3 ], t h yr o xi ne [ T4] , a n d t h yr oi d 
sti m ulati n g h or m o ne [ T S H] will be perf or me d at s cree ni n g a n d at least e ver y 3 m o nt hs w hile 
bei n g tr eate d wit h at ez oliz u ma b . Patie nts will be m o nit ore d f or c ha n ges i n t h yr oi d f u n cti o n 
d uri n g tr eat me nt wit h atez oliz u ma b  f or cli nical si g ns a n d s y m pt o ms of t h yr oi d dis or ders. 
Assess me nts will be perf or me d at t he sta rt of treat me nt, peri o dicall y d uri n g treat me nt, a n d as 
i n dicate d base d o n cli nical e val uati o n. Res ults will be d oc u me nte d i n t he p atie nt C R Fs. 
Cli nicall y si g nifica nt fi n di n gs ma y be rec or de d as A Es.  
9. 4. 1 1  
Ot her L a b or at or y Tests 
Bl o o d sa m ples will als o be o btai ne d f or i m m u n ol o gical testi n g a n d s er ol o g y f or atez oliz u ma b 
c o nce ntr ati o n . Testi n g f or HI V, H e p B, a n d He p C will be perf or me d at scree ni n g a n d m ust be 
ne gati ve f or e ntr y i nt o t he st u d y. Bl o o d f or i m m u n ol o gical testi n g will be dra w n t wice at 
baseli ne t o e ns ure a g o o d yiel d. Res ults will be d oc u me nte d i n t he patie nt C R Fs. Cli nicall y 
si g nifica nt fi n di n gs ma y be rec or de d as A Es. 
L V 3 0 5 was ori gi nall y deri ve d fr o m HI V, b ut m ost of t he ge n o me has b ee n re place d t o e n ha n ce 
safet y a n d s pecificit y. T h e pr o d uct utilizes 3 r d ge n erati o n le nti viral vect or tec h n ol o g y, w hic h 
mea ns t hat it is de v oi d of all HI V -deri ve d access or y ge nes. 7 H o we v er, s o m e pr otei ns are 
i ncl u de d in t he particle t h at ma y ca use s cree ni n g tests f or HI V t o bec o me p ositi ve as a res ult of 
t he treat me nts, alt h o u g h c o nfir mat or y testi n g w o ul d li kel y be c o nsi dere d i n deter mi nate. T he 
c o n ve nti o nal scr ee ni n g test f or HI V i nfecti o n is t he re peate dl y reacti ve i m m u n oassa y (I A), 
f oll o we d b y a c o nfir mat or y test. If a p atie nt is teste d f or HI V a n d scree ne d p ositi ve, t he C D C 
rec o m me n ds f urt her testi n g wit h a n F D A-a p pr o v e d 2 n d ge n erati o n a nti b o d y i m m u n oassa y t o 
detect HI V - 1 a n d/ or HI V- 2 a nti b o dies.3 2 T his test w o ul d us uall y be i nter prete d as p ositi ve if 
ba n ds a p pear at t he site of t w o or m ore of t h e f oll o wi n g HI V a nti ge ns: p 2 4, g p 4 1, or g p 1 2 0/ 1 6 0. 
If o nl y o n e ba n d is p ositi ve, t he test w o ul d be c o nsi dere d i n deter mi nat e. S peci me ns t hat are 
reacti ve o n t h e i nitial assa y a n d ne gati ve or i n deter mi nate o n t he HI V-1/ HI V - 2 a nti b o d y 
differe ntiati o n I A ar e t he n t o be teste d wit h a n F D A- a p pr o v e d n ucleic aci d test ( N A T) f or HI V - 1 
R N A. U n der n or m al circ u msta nces, a reacti ve N A T res ult i n dicates t he prese nce of ac u te HI V- 1 
i nfecti o n a n d a n e gati ve r es ult i n dicates t he a bse n ce of HI V- 1 i nfecti o n. H o we ver, at least o ne 
N A T (t he R oc h e C O B A S A m pli Pre p/ C O B A S Ta q -Ma n HI V - 1 Test, v 2. 0) was re p orte d t o ha ve 
bee n fals el y p ositi ve i n t w o patie nts w h o ha d bee n treate d wit h a d iffere nt le nti vir us.3 3 A n 
e xte nsi ve searc h f aile d t o detect wil d -t y pe i nfecti o us HI V- 1 or v ect or-d eri v e d re plicati o n -
c o m pete nt vir us a n d a P C R assa y f or HI V pr o viral D N A ( R oc h e C O B A S A M P LI C O R HI V- 1 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 8 9  of 1 2 8  
 
 
M O NI T O R Test, v 1. 5), as well as a p 2 4 e nz y m e-li n ke d i m m u n os or be nt assa y ( E LI S A), were 
b ot h ne gati ve. U nf ort u n atel y, t her e is n o si m ple pat h t o a defi niti ve dia g n osis. W hile t here is a 
c ha nce of ser o c o n versi o n, it is pre dicte d t o be l o w beca use t h e le nti viral vect or use d i n t his 
pr o gra m is re plicati o n -i nc o m pete nt a n d i nte grati o n- deficie nt. E v e n if ser o c o n versi o n occ urs i n 
s o me assa ys, it d oes n ot mea n t hat t he patie nt has HI V ( u nless t he y h a d bec o me tr ul y i nf ecte d 
fr o m s o me ot her e x p os ur e); caref ul f oll o w- u p t esti n g nee ds t o be d o ne t o e v al uate t hat p ote ntial. 
Testi n g will be d o ne at st u d y e ntr y a n d o n D a y 1 6 8 t o e val uate t he c ha nce of ser oc o n v ersi o n 
wit h L V 3 0 5; a n y p ositi v es will be f urt her e val uat e d t o deter mi ne t he tr u e stat us of i nfecti o n. 
Patie nts are als o gi ve n a ‘ Dear D oct or’ letter at st u d y e ntr y i n case t h e y ha ve HI V testi n g d o ne at 
a n e xter nal la b.  
9. 4. 1 2  
Vit al Si g ns  
Vital si g n assess me nts perf or me d at s p ecifie d st u d y visits will i ncl u de te m perat ure, H R, a n d  
resti n g B P. T hese assess me nts s h o ul d be perf or m e d pri or t o d osi n g a n d 3 0 mi n utes p ost d ose 
a d mi nistrati o n o n dr u g d osi n g da ys.  F or t he first atez oliz u ma b i nf usi o n, t he patie nt’s vital si g ns 
( H R, res pirat or y rate, B P, a n d te m perat ure) s h o ul d be meas ure d wi t hi n 1 5 mi n ute of t he i nf usi o n, 
d uri n g t he 6 0- mi n ute i nf usi o n (e ver y 1 5 [ ± 5] mi n utes), a n d 3 0 mi n utes after t he i nf usi o n.  F or 
s u bse q ue nt i nf usi o ns, vital si g ns d o n ot nee d t o b e o btai ne d d uri n g t h e i nf usi o n if t he pri or 
i nf usi o n was t olerate d wit h o ut s y m pt o ms. 
9. 4. 1 3  
P h ysic al E x a mi n ati o n 
A c o m plete p h ysical e x a mi nati o n i ncl u di n g hei g ht a n d wei g ht will be perf or me d d uri n g 
scree ni n g. S u bse q u e nt p h ysical e x a mi nati o ns will be si m ple s y m pt o m- directe d e x a mi nati o ns. 
Cli nicall y si g nifica nt det eri orati o ns will be rec or d e d as A Es.  
9. 4. 1 4  
1 2- Le a d Electr oc a r di o gr a m ( E C G)  
A 1 2 -lea d E C G will be d o ne at scr ee ni n g a n d at t he fi nal p ost-treat me nt Visit ( Da y 1 0 5). 
Cli nicall y si g nifica nt fi n di n gs ma y be rec or de d as A Es.  
9. 4. 1 5  
L V 3 0 5 Persiste nce 
F or s u bjects tr eate d wit h C M B 3 0 5, peri p heral bl o o d will be c ollecte d t o assa y f or t he persiste nce 
of L V 3 0 5 at bas eli ne, a n d 6, 1 2, a n d 2 4 m o nt hs b y P C R. De pe n di n g o n t h e res ults t hr o u g h 1 2 
m o nt hs, a n n ual assess me nts ma y c o nti n ue u ntil 2 c o nsec uti ve sa m ples s h o w n o e vi de nce of 
L V 3 0 5 p ersiste nce. 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 9 0  of 1 2 8  
 
 
1 0. 0  
S T A TI S TI C A L  C O N SI D E R A TI O N S  
1 0. 1  
St u d y  E n d p oi nts  
T he st u d y e n d p oi nts ( Secti o n  4. 2 ) i ncl u de b ot h cli nical effi cac y a n d safet y. W here p ossi ble, 
para meters will be q ua ntifie d f or dir ect c o m paris o ns bet wee n t he treat me nt gr o u ps.  
1 0. 2  
D at a  A n al ysis 
T he fi nal a n al ysis will be c o n d uc te d w h e n at least 7 2 deat hs ha ve b ee n o bser ve d, or s o o ner if t he 
S p o ns or s o deci des . Details of all a nal ys es, p o p ulati o ns, a n d data ha n dli n g r ules will be pr o vi de d 
i n a Statistical A nal ysis Pla n ( S A P) a n d fi nalize d pri or t o data base l o c k.  
1 0. 2. 1  
A n al ysis P o p ul ati o ns 
F or t he p ur p os e of statistical a nal ysis, t here are 2 a nal ysis p o p ulati o ns: I nte nt- t o- Treat p o p ulati o n 
(I T T), a n d Safet y p o p ulati o n. 
T he I T T p o p ulati o n c o nsists of all ra n d o mize d s u bjects. All a nal yses of t his p o p ulati o n will be 
base d o n t he treat me nt ar m t o w hic h t he s u bjects are ra n d o mize d. 
T he Safet y P o p ulati o n will c o nsist of all patie nts w h o recei ve d at least o ne i njecti o n / d ose of 
st u d y treat me nt.  T he Saf et y P o p ulati o n is t he pri mar y p o p ulati o n f or safet y a n al ys es i ncl u di n g 
A Es  a n d cli nical la b or at or y d ata. Trial pr o d uct e x p os ure will als o be s u m marize d usi n g t he 
Safet y P o p ulati o n. 
1 0. 2. 2  
A n al yses 
I n ge ner al, cat e g orical v aria bles will be s u m marize d b y n u m b er a n d p erce nta ges a n d c o nti n u o us 
varia bles will be s u m marize d wit h descri pti ve statistics. All st u d y dat a will be pr o vi de d i n 
listi n gs. 
1 0. 2. 2. 1  
P ati e nt  Dis p ositi o n  
S u m maries will i ncl u de patie nts w h o c o m plete d t he st u d y a n d  f or t h ose w h o di d n ot c o m plete 
t he st u d y, r eas o ns f or earl y disc o nti n uati o n. 
1 0. 2. 2. 2  
B aseli ne C h ar acteristics  
Patie nt a ge, r ace, ge n d er, we i g ht, h ei g ht, a n d ot her de m o gra p hic i nf or m ati o n i ncl u di n g me dical 
hist or y, diseas e hist or y, a n d me dicati o n hist or y will be s u m marize d b y treat me nt gr o u p. 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 9 1  of 1 2 8  
 
 
1 0. 2. 2. 3  
Tre at me nt A d mi nistr ati o n/ C o m pli a nce  
Treat me nt a d mi nistrati o n, e x p os ure, a n d c o m plia n ce wit h st u d y trea t me nts/ pr oce d ures will be 
d oc u me nte d a n d s u m marize d. E x p os ure a n d c o m plia nce data will be s u m marize d f or all patie nt s 
i n eac h treat me nt gr o u p/ar m.  
1 0. 2. 2. 4  
Effic ac y  A n al yses 
1 0. 2. 2. 4. 1  
Pri m ar y Effic ac y A n al ysis 
T he pri mar y efficac y a n al ysis will be t he e val u ati o n of O S a n d P F S base d o n t he I T T P o p ulati o n. 
O verall s ur vi val is defi n e d as t he ti me i nter val fr o m ra n d o mizati o n t o deat h of a n y ca us e. 
Patie nts w h o are ali ve will be ce ns ore d at t he last k n o w n date ali ve or d ata a nal ysis c ut off dat e, 
w hic he ver is earlier. P F S is defi ne d as t he ti me i nter val fr o m ra n d o mizati o n t o t u m or pr o gressi o n 
or deat h. Acc or di n gl y, t h e precis e defi niti o n of pr o gressi o n a n d t he ti mi n g of i ma gi n g sca ns t o 
pr o gressi o n ar e ver y i m p orta nt. E ver y eff ort m ust be ma de t o ass ure t hat ti mefra mes f or f oll o w-
u p i ma gi n g sca ns are ac hie ve d, s o t hat b ot h treat m e nt gr o u ps ca n b e usef ull y c o m p are d. 
Assess me nts m ust be a de q uate t o e val uate t ar get l esi o ns, n o n-tar get lesi o ns, a n d t o searc h f or 
ne w lesi o ns.  
P F S will be base d o n R E CI S T 1. 1 res p o ns e g ui deli nes m o difie d t o use ir R C- s pecific 
c o nfir mati o n. P F S will be defi ne d as t he ti me fr o m ra n d o mizati o n t o disease pr o gressi o n or d eat h 
(a n y ca us e), w hic he ver o cc urs first. T h e ir R C m o dificati o n re q uires a c o nfir mati o n of 
pr o gressi ve disease ( P D) at least 4 wee ks l ater wit h i ma gi n g; o nce c o nfir m e d, t he date of 
pr o gressi o n is defi ne d as t he first date t hat t he t otal t u m or b ur de n was s h o w n t o ha ve i ncrease d 
b y at least 2 0 % c o m pare d wit h t he na dir. Patie nts w h o d o n ot ha ve diseas e pr o gressi o n or ha v e 
n ot die d will be ce ns ore d at t he date w h e n t he last t u m or assess me nt deter mi nes a lac k of 
pr o gressi o n.  If a patie nt be gi ns a ne w a nti -ca n cer t hera p y or h as ra di ot hera p y or s ur ger y at a 
lesi o n site pri or t o c o nfir me d pr o gressi o n ( or d eat h), t he patie nt will be ce ns ore d at t he last 
assess me nt w her e t he patie nt was d oc u me nte d as pr o gressi o n free pri or t o t he i nter ve nti o n. 
Patie nts wit h t w o or m ore missi n g res p o ns e assess me nts pri or t o a visit wit h pr o gressi o n ( or 
deat h) will be ce ns ore d at t he last visit w here t he patie nt is d oc u me nte d t o be pr o gressi o n free.  
T he pri mar y efficac y a n al ysis will be t he e val u ati o n of O S a n d P F S usi n g K a pla n- Meier 
met h o d ol o g y a n d will be perf or me d o n t h e I T T P o p ulati o n f or eac h treat me nt ar m. Ka pla n- M eier 
pl ots a n d 9 5 % c o nfi de nce i nter vals ( CIs) f or 7 5 %, 5 0 % a n d 2 5 % s ur vi val, if reac he d, will be 
pr o vi de d f or eac h tr eat m e nt gr o u p. 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 9 2  of 1 2 8  
 
 
1 0. 2. 2. 4. 2  
Sec o n d ar y Effic ac y A n al ysis 
A sec o n dar y efficac y a nal ysis will be base d o n t he pr o p orti o n of patie nts t hat are pr o gressi o n-
free at 6 m o nt hs after start of st u d y dr u g treat me nt ( Day 0). E ac h treat me nt gr o u p will be 
e val uate d wit h a Si m o n 2-sta ge desi g n ( Secti o n 1 0. 3. 1 ).  Ti me -t o-ne xt -treat me nt a n d D M F S will 
be c o m par e d bet wee n treat me nt ar m s base d o n a stratifie d l o g-ra n k t est. T he Ka pla n-M eier c ur ve 
will s u m marize T T N T gr a p hicall y b y treat me nt ar m. Ta b ular s u m maries of t he Ka pla n -M eier 
c ur ves will be pr o vi de d b y treat me nt ar m. 
I m m u ne res p o nse a n d hist ol o gic a n d m olec ular tiss ue c ha n ges i n t u m or tiss ue or peri p h eral 
bl o o d will be s u m marize d b y treat me nt ar m.  
1 0. 2. 2. 5  
S af et y  
D escri pti ve statistics will be perf or me d f or all safet y i nf or mati o n i ncl u di n g A Es, S A Es, 
la b orat or y fi n di n gs a n d disc o nti n uati o ns of patie nts at all data c ollecti o n ti me p oi nts. No f or mal 
statistical h y p ot hesis will be teste d. 
T he hi g h est t o xicit y gr a d es per patie nt will be ta b ulate d f or A Es a n d la b orat or y m eas ure me nts, 
a n d t he n u m ber a n d p er ce nt of patie nts re p orti n g A Es (all, se vere or w orse, seri o us a n d rel ate d) 
will be q ua ntifie d. Listi n gs will be r e q uire d f or all o n -st u d y deat hs, S A Es a n d A Es t hat lea d t o 
wit h dra wal fr o m st u d y. Ne w S A Es e x perie nce d b y patie nts d uri n g t he Scree ni n g Peri o d ( pre-
st u d y treat me nt) will be r e p orte d t o I M D Z if t he e ve nts are c o nsi dere d relat e d t o st u dy 
pr oce d ur es a n d will be ta b ulate d se par atel y.  
1 0. 2. 2. 6  
E x pl or at or y 
1 0. 2. 2. 6. 1  
O ver all S ur vi v al a n d Pr o gressi o n- Free S ur vi v al  
E x pl orat or y c o m paris o ns bet wee n tr eat me nt ar ms of O S a n d P F S will be base d o n stratifie d 
l o g-r a n k tests. Wei g hte d l o g-r a n k tests will be e x pl ore d if dela ye d treat me nt effect i s o bser ve d. 
E x pl orat or y a nal ys es of O S at 6, 1 2, 1 8, a n d 2 4 m o nt hs, a n d P F S at 3 a n d 1 2 m o nt hs will als o be 
assesse d.  
1 0. 2. 2. 6. 2  
O ver all Res p o nse R ate a n d D ur ati o n of Res p o nse  
O verall r es p o nse r ate  is defi ne d as t he n u m b er of p atie nts wit h best o verall res p o nse of C R or P R 
di vi de d b y t he n u m ber of e val ua ble p atie nts.    
D urati o n of res p o ns e is defi ne d as t he ti me fr o m C R or P R t o pr o gressi o n or deat h, a m o n g 
patie nts wit h C R or P R.  T he D O R e ve nt a n d ce ns ori n g r ul es are t he sa me as t hat descri be d 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 9 3  of 1 2 8  
 
 
u n der P F S. E x pl orat or y c o m paris o ns of t he D O R will be base d o n stratifie d l o g- ra n k tests.  O R R 
will be c o m pare d b et wee n treat me nt ar m s usi n g a stratifie d l o gistic re gressi o n m o del . T G R, 
P A R , C B R, a n d q ualit y of life will be e val u ate d f or eac h gr o u p.    
1 0. 2. 2. 6. 3  
I m m u n o ge nicit y 
D escri pti ve statistics will be perf or me d c o m pari n g t he baseli ne a n d treat me nt a d mi nistrati o n 
peri p her al bl o o d N Y- E S O - 1-r es p o nsi ve T cells b et wee n t he 2 treat me nt ar ms. A nal yses will be 
perf or me d t o d eter mi ne if t here are a n y statisticall y si g nifica nt c ha n ges fr o m baseli ne val ues. 
C ha n ges fr o m bas eli ne i n serial a nti -N Y -E S O -1 a nti b o dies will be e x presse d as ge o metric mea n 
titers. 
1 0. 2. 2. 6. 4  
Bi o m ar kers  
Descri pti ve statistics will be pr o vi de d f or bi o mar k ers a n d treat me nts will be c o m pare d usi n g 
a nal ysis of varia n ce  (A N O V A ), or n o n- para metric met h o d w he n a p pr o priat e, of s pecifi c ge nes 
(e. g., T-cell rece pt ors) a n d/ or ge n e- n et w or ks (e. g., si g nali n g of i m m u ne cells) a n d ge ne m o d ules 
(e. g., sets of ge n es [t y picall y 1 0 0- 2 0 0]) t hat are u p- or d o w n-re g ulate d i n c o ncert i n certai n 
c o n diti o ns or disease stat es ( e. g., i nfecti o n, a ut oi m m u nit y, etc.) will be p erf or me d.  Data will be 
use d t o c o m pare t h e baseli ne wit h res p o nses p ost- treat me nt.  A d diti o nall y, j oi nt m o dels of 
o verall s ur vi val a n d l o n git u di nal bi o mar kers ma y b e e x pl ore d.  
1 0. 2. 2. 6. 5  
T u m or Gr o wt h R ate, Pr o gressi o n Arrest R ate, Cli nic al Be nefit R ate, a n d 
Q u alit y of Lif e  
T u m or gr o wt h rate a n d P A R will be e x pl ore d bet wee n treat me nt ar ms. A d diti o nall y, t h e 
relati o ns hi p bet wee n T G R a n d O S, a n d P A R a n d O S , ma y be e x pl ore d.   
Cli nical be nefit rate  will be e x pl ore d usi n g met h o ds si milar t o t hat descri be d f or O R R.  
Q ualit y of lif e as a c o m p osite e n d p oi nt (i ncl u di n g b ut n ot li mite d t o t he f oll o wi n g: w hile o n 
st u d y, t he i nci de n ce of h os pitalizati o n, tra nsf usi o ns, a n d la b orat or y mar kers [ e g. a bs ol ute 
ne utr o p hil c o u nt, he m o gl o bi n, a n d platelets]) will be e x pl ore d. 
1 0. 3  
I nteri m A n al ysis 
A n e x pl orat or y a nal ysis of t he P F R at 6 m o nt hs after treat me nt i nitiati o n will be use d as a n o n -
bi n di n g f utilit y a n al ysis f or eac h treat me nt ar m. U p o n o btai ni n g t he pr o gressi o n stat us after 6 
m o nt hs o n st u d y fr o m t he first 3 6 ( 1 8 per ar m) a n d s u bse q ue ntl y fr o m all e nr olle d patie nts, 
i nteri m a nal ys es will be perf or me d a n d prese nte d t o t he D M C, w hic h will i ncl u de esti mates of 
P F S a n d assess me nt of P F R. Bas e d o n t he ass u m pti o ns i n Secti o n 1 0. 3. 1, f utilit y g ui deli nes at 
Sta ge 1 will be b ase d o n 1 8 patie nts a n d will re q uire at least 6 p atie nts t o be pr o gressi o n free t o 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 9 4  of 1 2 8  
 
 
c o nti n ue o n t o Sta ge 2. Wit h a n a d diti o nal 2 2 patie nts at t he e n d of Sta ge 2, at least 1 4 of t he 
t otal of 4 0 patie nts s h o ul d be pr o gressi o n free at 6 m o nt hs after i nitial d osi n g t o rec o m me n d 
f urt her st u d y i n t his setti n g. N o f or mal i nteri m a n al ysis will be perf or me d f or efficac y. F or t h e 
p ur p oses of saf et y m o nit ori n g, ke y s af et y a nal ysis will als o be p erf or m e d q uarterl y. T he D M C 
will e val uate t he a v aila ble data a n d m a ke necessar y rec o m me n dati o ns t o t h e st u d y. D etails will 
be o utli ne d i n t he D M C c harter.  
A fi nal a nal ysis will be c o n d ucte d w he n at least 7 2  deat hs ha ve b ee n o bser ve d, or s o o ner if t h e 
S p o ns or s o deci des . 
1 0. 3. 1  
S a m ple Size  
T he me dia n P F S f or first -li ne c he m ot hera p y f or p atie nts wit h metastatic s y n o vial sarc o ma h as 
bee n re p orte d t o be 2. 5 t o 8. 3 m o nt hs; 3 4 P F S wit h atez oliz u ma b i n t he p ost- c he m ot hera p y 
setti n g is u n k n o w n. T h us, n o p o wer calc ulati o ns b ase d o n c o m paris o ns of P F S were ma de. 
H o we ver, base d o n a n u n acce pta ble a n d d esira ble me dia n P F S of 3 m o nt hs a n d 5. 2 m o nt hs, 
res pecti vel y, c orr es p o n di n g P F Rs at 6 m o nt hs were deri ve d. Wit h a n u nacce pta ble P F R of 2 5 % 
a n d a n acce pt a ble P F R of 4 5 % at 6 m o nt hs, a Si m o n 2-sta ge desi g n will be use d t o e x a mi ne t he 
P F R i n 4 0 patie nts i n eac h ar m (al p ha = 0. 1, beta = 0. 1 5). F or t his st u d y, t w o gr o u ps of 
a p pr o xi matel y 4 0 patie nts eac h ( a p pr o xi matel y  80 patie nts  t otal) will be d ose d wit h C M B 3 0 5 
wit h atez oliz u ma b or wit h  atez oliz u ma b al o ne t o assess t he q uartiles ( 2 5 %, 5 0 %, a n d 7 5 %) of 
P F S wit h 9 5 % c o nfi de nce i nter vals ( CIs) a n d t he P F R at 6 m o nt hs. If fa v ora ble res ults are 
o bser ve d, t he st u d y ma y be e x pa n de d t o i m pr o ve t he esti mates of P F S. 
1 0. 4  
M ulti plicit y  
T he pri mar y a n al yses f or t his st u d y will be t he e val uati o n of O S a n d P F S usi n g Ka pl a n- Meier 
met h o d ol o g y. Ka pl a n- M eier pl ots a n d 9 5 % c o nfi de nce i nter v als ( CIs) f or 7 5 %, 5 0 % a n d 2 5 % 
s ur vi val, if reac he d, will be pr o vi de d f or eac h treat me nt ar m. T here will be n o a dj ust me nt t o 
m ulti plicit y. All p val ues are c o nsi d ere d n o mi nal.   
  

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 9 5  of 1 2 8  
 
 
1 1. 0  
DI R E C T A C C E S S T O S O U R C E D A T A/ D O C U M E N T A TI O N  
I nf or mati o n o n t he C R Fs will be verifia ble t o s o urce d oc u me nts. Ot her rec or ds t hat will be 
c o nsi dere d s o ur ce d o c u me nts i ncl u de, b ut are n ot li mite d t o, h os pital rec or ds, cli nic c harts, 
ra di o gra p hic d ata, la b or at or y r e p orts a n d p at h ol o g y re p orts. C o pies of s o urce d oc u me nts t hat 
s h o ul d be se nt t o I M D Z or its a ut h orize d re pres e ntati ve, if re q ueste d, i n cl u de h os pital or cli nic 
rec or ds, ra di o gra p hic dat a, la b orat or y re p orts, pat h ol o g y re p orts, o perati ve s u m maries a n d 
disc har ge re p orts . Ot her s o urce d oc u m e ntati o n ma y i ncl u de h os pital disc h ar ge s u m maries , if 
a vaila ble, or i nf or mati o n i n lie u of a disc har ge s u m mar y, s u c h as disc harge or ders or pr o gress 
n otes; a n y rele v a nt n otes pertai ni n g t o A Es, a d diti o nal s ur gical pr oce d ures , or deat hs a n d a ut o ps y 
re p orts. A n y d oc u m e ntati o n se nt fr o m t he site s h o ul d be re dacte d t o e x cl u de patie nt i de ntif yi n g 
i nf or mati o n. 
1 2. 0  
D A T A  Q U A LI T Y C O N T R O L A N D Q U A LI T Y A S S U R A N C E  
I M D Z perf or ms q ualit y ass ura nce c hec ks o n all cli nical st u dies t hat it s p o ns ors. Pri or t o 
e nr oll me nt of a n y patie nts i n t his st u d y, I M D Z or its a ut h orize d re prese nt ati ve a n d t he 
I n v esti gat or will re vie w t he Pr ot oc ol, t he I B, t h e C R Fs a n d c o m pleti o n i nstr ucti o ns, t he 
pr oce d ur e f or o bt ai ni n g i nf or me d c o ns e nt, a n d A E/ S A E re p orti n g pr oce d ures . Site m o nit ori n g 
visits will be perf or me d b y I M D Z or its a ut h orize d re pres e ntati ve o n a re g ular basis p urs ua nt t o 
its M o nit ori n g Pla n. D uri n g t hese visits, i nf or mati o n rec or d e d o n t he C R Fs will be verifie d 
a gai nst s o urce d o c u me nts . After t he C R Fs are recei ve d b y I M D Z or its a ut h orize d re pres e ntati ve, 
t hey will be r e vie w e d f or safet y i nf or mati o n, le gi bilit y, c o m plete ness, acc urac y a n d l o gical 
c o nsiste nc y. T he dat a will be e ntere d i nt o a d ata base. A d diti o nal c o m p uter pr o gra ms t hat i de ntif y 
selecte d pr ot o c ol de viati o ns, o ut- of-ra n ge data, a n d ot her data err ors ma y be use d t o hel p m o nit or 
t he st u d y. As necessar y, r e q uests f or cl arificati o n or c orrecti o n will be se nt t o t he I n v esti gat or.  
I n d e pe n de nt a u dit ors fr o m I M D Z or its a ut h orize d re pres e ntati ve will be all o we d b y t he 
I n v esti gat or t o a u dit pre vi o usl y m o nit ore d data. I n a d diti o n, a u dits ma y be c o n d ucte d b y 
a p pr o priate re g ulat or y a ut h orities.  
Data e ntere d i n t he C R F will be s o urce verifie d f or acc urac y a n d c o m plete ness. I n a d diti o n, 
pr ot oc ol c o m plia nce a n d c o m plia nce wit h F D A re g ulati o ns a n d t he I nter nati o nal C o nfere nce o n 
Har m o nisati o n ( I C H) GC P g ui deli nes will be verifie d.  

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 9 6  of 1 2 8  
 
 
1 3. 0  
E T HI C A L C O N SI D E R A TI O N S  
1 3. 1  
I n de pe n de nt Et hics C o m mittee (I E C) o r I nstit uti o n al Re vie w B o ar d (I R B)  
T he Pr ot oc ol a n d t he I C Fs m ust ha ve t he a p pr o val of a pr o perl y c o nstit ute d I R B res p o nsi ble f or 
a p pr o vi n g cli nical st u dies. T he si g n e d I R B a p pr o val letter m ust s pecif y t h e date of Pr ot oc ol a n d 
I C F a p pr o v al, a n d i de ntif y t he a p pr o ve d d o c u me nts i ncl u di n g t he In v esti gat or's n a me a n d t he 
Pr ot oc ol versi o n, date, a n d title. A n y patie nt materials or a d vertise me nts us e d t o recr uit 
v ol u nteers s h o ul d als o be re vie we d a n d a p pr o ve d b y t he I R B. Patie nts  s h o ul d n ot be s olicite d f or 
partici pati o n i n t he st u d y a n d cli nical s u p plies will n ot be s hi p pe d u ntil a si g ne d a p pr o val letter 
fr o m t he I R B h as bee n recei ve d a n d a c o ntract ual a gree m e nt has bee n si g n e d b y I M D Z or its 
a ut h orize d re pres e ntati ve a n d t he cli nical site.  
1 3. 2  
Et hic al C o n d uct of t he St u d y  
All i n vesti gat ors m ust ha ve recei ve d f or mal trai ni n g i n t he et hical c o n d uct of h u ma n researc h. 
T he st u d y will be c o n d uc te d i n acc or d a nce wit h t he et hical pri nci ples t hat h a ve t heir ori gi ns i n 
t he Declarati o n of H elsi n ki. All C R Fs, c o m plia nce wit h t he pr ot oc ol, c o m plia nce wit h G C P, a n d 
c o m plia nce wit h t he F D A’s 2 1 C F R, as a p plica ble, will be m o nit ore d b y a n i n de pe n de nt m o ni t or 
r o uti nel y at eac h i nstit uti o n partici pati n g i n t his tri al. T his pr ocess, as w ell as t he pr ocess f or t he 
d oc u me ntati o n of t he m o nit ori n g, will be d oc u me nte d i n detail i n t he Cli nical M o nit ori n g Pla n 
D oc u me nt. 
1 3. 3  
P ati e nt I nf or m ati o n a n d C o nse nt  
Writte n i nf o r me d c o nse nt m ust be o btai ne d fr o m t he patie nt pri or t o perf or mi n g a n y 
st u d y-r elate d pr o ce d ur es, i ncl u di n g scree ni n g ass ess me nts. T he I n vesti gat or or I n vesti gat or’s 
desi g nee will pr o vi de bac k gr o u n d i nf or mati o n o n t he st u d y, i ncl u di n g t he be nefits a n d ris ks of 
t he i n vesti gati ve re gi me n. T he I n vesti gat or or I n vesti gat or’s d esi g n ee will als o e nc o ura ge t he 
pr os pecti ve patie nt t o as k q uesti o ns a b o ut t he st u d y a n d will pr o vi de t he pr os pecti ve patie nt wit h 
s ufficie nt o p p ort u nit y t o c o nsi der w het h er or n ot t o partici pate.  
Ori gi nal si g ne d I C Fs m ust be file d i n t he patie nt rec or ds at t he site. A c o p y of t he si g n e d c o nse nt 
m ust als o be pr o vi de d t o t he patie nt. 
T he patie nt I C F te m plat e t hat has bee n  pr o vi d e d f or t his st u d y ma y be re vise d b y t h e In vesti gat or 
or a n I R B b ase d o n t he i nstit uti o n’s re q uire me nts. H o we ve r, all c ha n ges re q ueste d b y t h e 
I n v esti gat or or a n I R B, e ve n t h ose t hat are n ot s u bsta ntial a n d/ or d o n ot affect t he ri g hts, saf et y 
or welfare of a patie nt, m ust be a p pr o ve d b y I M D Z. If I M D Z d eter mi nes t hat t he re visi o ns are 
s u bsta ntial a n d/ or aff ect t he ri g hts, s afet y or welfare of a p atie nt, t he I C F m ust be re vie w e d a n d 
a p pr o ve d b y b ot h I M D Z a n d l ocal I R B b ef ore t he I C F ca n b e utilize d.  

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 9 7  of 1 2 8  
 
 
1 3. 4  
P ati e nt C o nfi de nti alit y  
Patie nt na mes s hall n ot be re veale d t o I M D Z or its a ut h orize d re pres e ntati v e. O nl y t h e patie nt 
i de ntifier will be rec or de d i n t he C R F, a n d if t he p atie nt’s na me a p p ears o n a n y ot h er d oc u me nt, 
it m ust be re dacte d a n d r e place d wit h t he patie nt i de ntifier bef ore a c o p y of t he d oc u me nt will be 
s u p plie d t o I M D Z or its a ut h orize d re prese nt ati ves. St u d y fi n di n gs st ore d o n a c o m p uter will be 
st ore d i n acc or da nce wit h l ocal data pr otecti o n la ws. I n t h e e ve nt of acci de ntal c o m m u nicati o n of 
s uc h i nf or mati o n, i m me diate ste ps t o re dact t he i nf or mati o n fr o m all st u d y files will be 
i m ple me nte d, wit h a p pr o priate d oc u me ntati o n i n t he patie nt st u d y file. 
1 4. 0  
D A T A  H A N D LI N G A N D R E C O R D K E E PI N G  
1 4. 1  
C ase Re p ort F or ms  
T he I n vesti gat or is r es p o nsi ble f or mai ntai ni n g a d e q uate a n d acc urate m e dical rec or ds fr o m 
w hic h i nf or mati o n will be tra nsferre d i nt o t he st u d y dat a base. I nf or mati o n o n t he C R F s h o ul d be 
verifia ble t o s o ur ce d oc u me nts. T he C R Fs s h o ul d be c o m plete d b y t he I n v esti gat or or d e le gate d 
pers o n nel. I n t he c o nte xt of t his pr ot oc ol C R F will refer t o electr o nic C R Fs .  
A n e C R F will be cr eate d f or eac h patie nt i n t he electr o nic data ca pt ure s yst e m. I n vesti gat or 
pers o n nel will recei ve tr ai ni n g pertai ni n g t o use of t he data base a n d pr o ce d ures f or e nteri n g 
patie nt data. Trai n e d pers o n nel will t he n c o m plete t he f or ms f or eac h p atie nt acc or di n g t o t he 
pr o vi de d i nstr ucti o ns. Q ueries i n t he electr o nic dat a ca pt ure ( E D C) s yste m will be use d f or 
c orrecti o ns t hat bec o me necessar y aft er data v erifi cati o n pr oce d ures. C o m plete d e C R Fs will be 
re vie we d a n d electr o nicall y si g n e d b y t he I n v esti gat or i n dicati n g his/ her ass ura nce of t he 
acc ur ac y of all rec or de d data. It is e x pecte d t hat t he I n vesti gat or a n d his/ h er staff will c o o perat e 
wit h t he m o nit ori n g t ea m a n d pr o vi de missi n g dat a or res p o n d t o q u eries i n a ti mel y ma n n er.  
O nl y c o m plet e C R Fs, re vie we d a n d si g ne d b y t he I n v esti gat or i n dicati n g his/ her ass ura n ce of t h e 
acc ur ac y of all rec or de d data, will be acce pte d. It is e x pecte d t hat t he I n vesti gat or a n d his/ her 
staff will c o o per ate wit h t he m o nit ori n g tea m a n d pr o vi de a n y missi n g dat a or data clarificati o ns 
i n a ti mel y ma n ner. Data Clarificati o n F or ms ma y  be use d f or c orrecti o ns t hat bec o me n ecess ar y 
after i n-h o us e data v erifi cati o n pr oce d ures.  
1 4. 2  
Rec or d  Rete nti o n  
Esse ntial d oc u me nts s h o ul d be retai ne d u ntil at least 2 years after t he l ast a p pr o val of a 
mar keti n g a p plicati o n i n a n I C H re gi o n a n d u ntil t here are n o p e n di n g or c o nte m plate d mar keti n g 
a p plicati o ns i n a n I C H re gi o n or at least 2 years ha ve ela pse d si nce t he f or mal disc o nti n uati o n of 
cli nical de vel o p me nt of t he i n vesti gati o nal pr o d uct. T hese d oc u me nts s h o ul d be retai ne d f or a 
l o n ger p eri o d, if r e q uire d b y t he a p plica ble re g ulat or y re q uire m e nts or b y a n a gree m e nt wit h 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 9 8  of 1 2 8  
 
 
I M D Z. It is t he res p o nsi bilit y of I M D Z t o i nf or m t he I n vesti gat or/i nstit uti o n as t o w he n t hese 
d oc u me nts n o l o n ger nee d t o be retai ne d. 
Esse ntial d oc u me nts are t h ose d oc u me nts, w hic h i n di vi d uall y a n d c ollecti vel y, p er mit e val uati o n 
of t he c o n d uct of a trial a n d t he q ualit y of t he d ata pr o d uce d. T h ese d oc u me nts ser ve t o 
de m o nstrate t he c o m plia nce of t he I n vesti gat or, S p o ns or, a n d m o nit or wit h t he sta n dar ds of G C P 
a n d wit h all a p plica ble r e g ulat or y re q uire m e nts. 
A n y or all of t he d oc u m e nts s h o ul d be a vaila ble f or a u dit b y t he S p o ns or’s a u dit or a n d i ns pecti o n 
b y t he r e g ulat or y a ut h orities.  
I M D Z or its a ut h orize d r e prese nt ati ve will mai ntai n all rec or ds relate d t o t his i n vesti gati o nal 
st u d y, acc or di n g t o 2 1 C F R § 3 1 2. 3 2 a n d a n y ot her l ocal re g ul at or y re q uire me nts. I n a d diti o n, 
par a gr a p h  4. 9. 5 of t he I C H E 6 g ui d eli nes a p plies.  
1 5. 0  
FI N A N CI N G  AN D C O M P E N S A TI O N  
T he fi na nci al as pects of t he trial ar e d oc u me nte d i n a n a gree me nt bet w ee n t he S p o ns or a n d t he 
In v esti gat or/i nstit uti o n. Details re gar di n g S p o ns or- pr o vi de d i ns ura nce/i n d e m nit y, patie nt 
c o m pe nsati o n a n d c osts t o patie nts are d o c u me nte d i n a n a gree me nt bet wee n t he S p o ns or a n d t he 
In v esti gat or/t he i nstit uti o n. A s u m mar y of t his i nf or mati o n f or t he patie nt  is als o pr o vi de d i n t he 
i nf or me d c o nse nt.  
1 6. 0  
C H A N G E S I N S T U D Y C O N D U C T  
1 6. 1  
P r ot oc ol  Ame n d m e nts  
A n y a me n d me nt t o t he st u d y pr ot o c ol m ust be a p pr o ve d b y I M D Z. A pr ot o c ol a me n d me nt ma y 
n ot be i m ple me nte d u ntil after it has bee n s u b mitte d t o t he F D A a n d a p pr o ve d b y t h e I R B, u nless 
i m me diate i m ple me ntati o n of t he c ha n ge is necessar y f or p atie nt safet y. I n t his case, t he pr ot oc ol 
c ha n ge m ust be d oc u m e nte d i n a n a me n d me nt a n d re p orte d t o t he I R B wit hi n 5 w or ki n g d a ys. 
O nce a pr ot oc ol a me n d m e nt has recei ve d a p pr o val fr o m I M D Z, t he In v esti gat or will s u b mit it t o 
t he I R B f or writte n a p pr o val. T he a p pr o v al letter, si g ne d b y t he I R B C hair, m ust refer 
s pecificall y t o t he In v esti gat or, t h e pr ot oc ol title, t he pr ot oc ol a me n d me nt n u m ber, a n d t he dat e 
of t he pr ot oc ol a me n d m e nt. I M D Z is res p o nsi ble f or s u b mitti n g all pr ot oc ol a me n d me nts t o t he 
F D A.  
1 6. 2  
Pr ot oc ol D e vi a ti o n Re p orti n g 
A pr ot oc ol de viati o n is a n y c h a n ge, di ver ge nce, or de part ure fr o m t he st u d y desi g n or pr oce d ures 
defi ne d i n t he pr ot oc ol, s uc h as t he acci de ntal d estr ucti o n of a tiss ue bi o ps y sa m ple i nte n de d f or 
i m m u ne assess me nt t o c haract erize t he patie nt's t y pe of t u m or i n or der t o d eter mi ne st u d y 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 9 9  of 1 2 8  
 
 
eli gi bilit y, or a n acci de nt al misrea d of a l a b orat or y val u e as bei n g wit hi n t he refere n ce ra n ge 
w he n it act uall y is s uffici e ntl y a b n or mal t o precl u de st u d y p artici pati o n b y t he patie nt . 
I m p ort a nt pr ot oc ol de viati o ns are a s u bset of pr ot o c ol de viati o ns t hat mi g ht si g nifica ntl y affect 
t he c o m plete ness, acc ur ac y, a n d/ or r elia bilit y of t he st u d y d ata or t hat mi g ht si g nifica ntl y affect a 
patie nt ’s ri g hts, safet y or well bei n g s u c h as t he I n v esti gat or prescri bi n g or a d m i nisteri n g t he 
wr o n g d ose, or t he st u d y patie nt  bei n g s c he d ule d t o ret ur n f or f oll o w- u p i nter ve nti o n o utsi de t he 
pr ot oc ol- dictate d wi n d o w as a c o n v e nie nce t o t he patie nt or st u d y staff. W hile i nter pretati o n of 
i ncl usi o n/e x cl usi o n criteria ca n be disc uss e d wit h t he me dical m o nit or, e x ce pti o ns  ge nerall y  will 
n ot be a p pr o ve d wit h o ut I R B a p pr o v al. 
T here will be u nf oresee n circ u msta nces t hat are be y o n d t he I n vesti gat or’s c o ntr ol (e. g. , a patie nt 
n ot atte n di n g a s c he d ule d f oll o w- u p visit). Pri or a p pr o val will n ot be gra nte d i n t hese sit uati o ns, 
b ut t he I n v esti gat or s h o ul d re p ort t hese e ve nts u p o n deter mi ni n g t hat a de vi ati o n has occ urre d. 
T he I n vesti gat or is r es p o nsi ble f or c o m pl yi n g wit h a n d a d heri n g t o I R B pr oce d ures f or re p orti n g 
pr ot oc ol de viati o ns a n d vi olati o ns. All pr ot oc ol de viati o ns s h o ul d be d oc u me nte d a n d f or war d e d 
t o I M D Z or its a ut h orize d re pres e ntati ve.  
Pr ot oc ol de viati o ns will be c ollecte d d uri n g t h e st u d y, a n d re p ort e d b y I M D Z or its a ut h orize d 
re pres e ntati ve t o t he F D A a n d I R Bs yearl y i n t he a n n ual re p ort. Partici pati n g i n vesti gat ors will 
recei v e re g ul ar u p dates r e gar di n g t heir site’s de viati o ns. 
1 7. 0  
P U B LI C A TI O N  P O LI C Y  
It is e x pecte d t hat t he res ults of t his st u d y will be p u blis he d i n a peer-re vie we d j o ur nal. A 
p u blicati o n pla n f or t he pri mar y res ults will be disc usse d wit h t he PIs a n d esta blis he d bef ore t h e 
start of t he trial. A n y ma n uscri pts re p orti n g t he res ults of t his cli nical trial m ust be pr o vi de d t o 
t he S p o ns or b y t he Pri nci pal I n v esti gat or f or re vie w a n d c o m me nt pri or t o s u b missi o n f or 
p u blicati o n. I M D Z will ha ve 3 0 da ys fr o m t he dat e of recei pt f or re vie w, a n d s hall ha ve t he ri g ht 
t o re q uest t hat p u blicati o n be dela ye d f or u p t o a n a d diti o nal 3 0 da ys i n or d er t o e ns ure t h at t he 
S p o ns or’s c o nfi de ntial a n d pr o prietar y d ata, i n a d diti o n t o t he S p o ns or’s i ntellect ual pr o pert y 
ri g hts, ar e pr otecte d. A bstracts, press r eleas es, a n d ot her me dia prese ntati o ns m ust als o be 
f or war de d t o t he S p o ns or pri or t o releas e. N o p u blicati o n, ma n uscri pt, or ot her f or m of p u blic 
discl os ure s hall c o ntai n a n y of t he S p o ns or’s c o nfi de ntial/ pr o prietar y i nf or mati o n. C o-a ut h ors hi p 
of s u bse q ue nt p u blicati o ns wit h I M D Z p ers o n nel will be disc usse d a n d m ut uall y a gree d u p o n 
bef ore s u b missi o n of a m a n uscri pt t o a p u blis her. 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 1 0 0  of 1 2 8  
 
 
1 8. 0  
R E F E R E N C E S  
1.  
G nj atic S, Nis hi ka wa H, J u n g bl ut h A A, G ure A O, Ritter G, J a ger E, et al. N Y -E S O - 1: 
re vie w of a n i m m u n o ge nic t u m or a nti ge n. A d v Ca ncer Res.  2 0 0 6; 9 5: 1- 3 0. 
2.  
C hee ver M A, Allis o n J P, Ferris A S, Fi n n OJ, Hasti n gs B M, Hec ht T T, et al. T he 
pri oritizati o n of ca ncer a nti ge ns: a nati o nal ca ncer i nstit ute pil ot p r oject f or t he 
accelerati o n of tr a nslati o nal researc h. Cli n  Ca ncer Res.  2 0 0 9; 1 5( 1 7): 5 3 2 3- 5 3 3 7. 
3.  
J u n g bl ut h A A, A nt o nesc u C R, B usa m KJ, I vers e n K, K ol b D, C o pla n K, et al. M o n o p hasic 
a n d bi p hasic s y n o vial sar c o mas a b u n da ntl y e x press ca ncer/testis a nti ge n N Y- E S O - 1 b ut 
n ot M A G E - A 1 or C T 7. I nt J Ca ncer. 2 0 0 1; 9 4( 2): 2 5 2- 2 5 6. 
4.  
J u n g bl ut h A A, C he n Y T, St oc kert E, B usa m KJ, K ol b D, I vers e n K, et al. 
I m m u n o hist oc he mical a n al ysis of NY- E S O - 1 a nti ge n e x pressi o n i n n or mal a n d 
mali g na nt h u ma n tiss ues. I nt J Ca ncer. 2 0 0 1; 9 2( 6): 8 5 6- 8 6 0. Errat u m i n: I nt J Ca ncer. 
2 0 2; 9 7( 6): 8 7 8. 
5.  
Nic h ola o u T, E bert L, Da vis I D, R o bs o n N, Kl ei n O, Maras k o vs k y E, et al. Directi o ns i n t he 
i m m u ne tar geti n g of can cer: less o ns lear ne d fr o m t he ca ncer -t estis A g N Y-E S O - 1. 
I m m u n ol Cell Bi ol. 2 0 0 6; 8 4( 3): 3 0 3- 3 1 7. 
6.  
I n v esti gat or’s Br oc h ure f or C M B 3 0 5: L V 3 0 5 a n d G 3 0 5 Se q ue ntial Re gi me n. I m m u ne 
Desi g n C or p. Versi o n 0 1. 2 7 Se pte m ber 2 0 1 4. 
7.  
Taree n S U, Kelle y -Clar k e B, Nic ol ai CJ, Cassia n o L A, Nels o n L T, Sl o u g h M M , et al. 
Desi g n of a n o vel i nte gr ati o n- deficie nt le nti vect or tec h n ol o g y t h at i nc or p orates ge netic 
a n d p osttra nslati o nal ele me nts t o tar get h u ma n de n dritic cells. M ol T her. 2 0 1 4; 
2 2( 3): 5 7 5- 5 8 7. 
8.  
Fratta E, C or al S, C o vre A , Parisi G, C olizzi F, Da nielli R, et al. T he bi ol o g y of ca ncer testis 
a nti ge ns: p utati ve f u ncti o n, re g ulati o n a n d t hera pe utic p ote ntial. M ol O nc ol. 2 0 1 1; 
5( 2): 1 6 4- 1 8 2. 
9.  
Dai B, Y a n g L, Ya n g H, H u B, Balti m ore D, Wa n g P. HI V- 1 Ga g -s pecifi c i m m u nit y 
i n d uce d by a le nti vect or -base d vacci ne directe d t o de n dritic cells. P r oc N atl A ca d S ci 
U S A . 2 0 0 9; 1 0 6( 4 8):2 0 3 8 2- 2 0 3 8 7. 
1 0.  S o maia h N, Bl oc k M S, Ki m J W, S ha pir o G, H w u P, E der J P, et al. P hase  1 First -i n- H u ma n 
Trial of L V 3 0 5 i n Patie nts Wit h A d va nce d or Met astatic Ca nce r E x pressi n g N Y-E S O - 1. 
P oster sessi o n prese nte d at: T he A merica n S ociet y of Cli nical O n c ol o g y ( A S C O) A n n ual 
Meeti n g ; 2 0 1 5 Ma y 2 9 – 2 0 1 5 J u n 0 2; C hica g o, I L. 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 1 0 1  of 1 2 8  
 
 
1 1.  Ma hi pal, A, O d u nsi K, G njatic S, Ki m - Sc h ulze S, Ke n ne y R, Eja di S. A First -i n- H u ma n 
P hase  1 D ose-escalati n g Trial of G 3 0 5 i n Patie nts wit h S oli d T u m ors E x pressi n g N Y -
E S O - 1. P oster sessi o n pr ese nte d at: T he A merica n S ociet y of Cli nical O n c ol o g y ( A S C O) 
A n n ual Meeti n g ; 2 0 1 5 Ma y 2 9 – 2 0 1 5 J u n 0 2; C hica g o, I L. 
1 2.  Pe d oee m A, Az o ula y- Alf a g ut er I, Strazza M, Sil ve r ma n GJ, M or A. Pr o gra m me d deat h- 1 
pat h wa y i n ca n cer a n d a ut oi m m u nit y. Cli n I m m u n ol. 2 0 1 4; 1 5 3 ( 1): 1 4 5- 1 5 2. 
1 3.  Kari m R, J or da n o va E S, Piers ma SJ, Ke nter G G, C he n L, B oer J M, et al. T u m or- e x presse d 
B 7 - H 1 a n d B 7- D C i n rel ati o n t o P D-1 + T -cell i nfiltrati o n a n d s ur vi val of p atie nts wit h 
cer vical carci n o ma. Cli n Ca ncer Res. 2 0 0 9; 1 5 ( 2): 6 3 4 1- 6 3 4 7. 
1 4.  Ta u be J M, A n ders R A, Y o u n g G D, X u  H, S har m a R, Mc Miller T L, et al. C ol ocalizati o n of 
i nfla m mat or y res p o nse wit h B 7- h 1 e x pressi o n i n h u ma n mela n oc ytic lesi o ns s u p p orts a n 
a da pti ve resista n ce mec h a nis m of i m m u ne esca pe. Sci  Tr a nsl M e d. 2 0 1 2; 4( 1 2 7): 1 2 7ra 3 7. 
1 5.  Sa n ma me d M F  a n d C he n L. I n d u ci ble e x pressi o n of B 7-H 1 ( P D -L 1) a n d its selecti ve r ole i n 
t u m or site im m u ne m o d ulati o n. Ca ncer J. 2 0 1 4; 2 0 ( 4): 2 5 6- 2 6 1. 
1 6.  B utte MJ, Keir M E, P ha m d u y T B, S har pe A H, Free ma n GJ. Pr o gra m me d deat h- 1 li ga n d 1 
i nteracts s pecificall y wit h t he B 7-1 c osti m ulat or y m olec ule t o i n hi bit T cell res p o nses.  
I m m u nit y. 2 0 0 7; 2 7( 1): 1 1 1- 1 2 2. 
1 7.  Ya n g J, Riella L V, C h oc k S, Li u T, Z ha o X, Y ua n X, et al. T he n o vel c osti m ul at or y 
pr o gra m me d deat h li ga n d 1/ B 7. 1 pat h wa y is f u n cti o nal i n i n hi biti n g all oi m m u ne 
res p o nses i n vi v o. J I m m u n ol. 2 0 1 1; 1 8 7( 3): 1 1 1 3- 1 1 1 9. 
1 8.  va n de n Eert we g h AJ, Versl uis J, va n de n Ber g H P, et al. C o m bi ne d i m m u n ot hera p y wit h 
gr a n ul oc yte- m acr o p h a ge c ol o n y -stim ulati n g fact or -tra ns d uce d all o ge neic pr ostate ca ncer 
cells a n d i pili m u ma b i n patie nts wit h metastatic castrati o n -resista nt pr ostate ca ncer: a 
p hase 1 d ose- escal ati o n trial. La ncet O nc ol 2 0 1 2; 1 3: 5 0 9- 1 7.   
1 9.  Ma da n R A, M o he btas h M, Arle n P M, Ver gati M, Ra uc k h or st M, Stei n ber g S M, et al. 
( 2 0 1 2). I pili m u ma b a n d a p o x viral vacci ne tar geti n g pr ostat e-s pecific a nti ge n i n 
metastatic castr ati o n -resista nt pr ostate ca n cer: a p hase 1 d ose-escal ati o n trial. La ncet 
O nc ol 1 3( 5): 5 0 1 – 8 1 0. 
2 0.  P ha m N L, Ba d o vi nac V P, a n d Hart y J T. A defa ult pat h wa y of me m or y C D 8 T cell 
differe ntiati o n after d e n dritic cell i m m u nizati o n is deflecte d b y e nc o u nter wit h 
i nfla m mat or y c yt o ki nes d uri n g a nti ge n- dri ve n pr oliferati o n. J I m m u n ol. 2 0 0 9; 
1 8 3( 4): 2 3 3 7- 2 3 4 8. 
2 1.  Mell ma n I, C o u k os G, a n d Dra n off G. Ca ncer i m m u n ot hera p y c o mes of a ge. Nat ure . 2 0 1 1; 
4 8 0( 7 3 7 8): 4 8 0- 4 8 9. 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 1 0 2  of 1 2 8  
 
 
2 2.  I w ai Y, Is hi da M, T a na k a Y, O kaza ki T, H o nj o T, Mi nat o N. I n v ol v e me nt of P D- L 1 o n 
t u m or cells i n t he esca p e fr o m h ost i m m u ne s yste m a n d t u m or i m m u n ot hera p y b y P D-L 1 
bl oc ka de. Pr oc  Nat l Aca d Sci U S A.  2 0 0 2: 9 9( 1 9):1 2 2 9 3- 1 2 2 9 7. 
2 3.  Str o me S E, D o n g H, T a m ura H, V oss S G, Flies D B, Ta m a da K, et al . B 7 - H 1 bl oc ka de 
a u g m e nts a d o pti ve T-cell i m m u n ot hera p y f or s q ua m o us cell carci n o ma. Ca ncer  Res. 
2 0 0 3; 6 3( 1 9) :6 5 0 1- 6 5 0 5. 
2 4.  Her bst R S, G or d o n M S, Fi ne G D, S os ma n J A, S oria J C, Ha mi d O , et al. A st u d y of 
M P D L 3 2 8 0 A , a n e n gi neere d P D- L 1 a nti b o d y i n p atie nts wit h l ocall y a d v a nce d or 
metastatic t u m ors. P rese nte d at: T he A meri ca n S ociet y of Cli nical O nc ol o g y ( A S C O) 
A n n ual Meeti n g 2 0 1 3; A bstract 3 0 0 0. 
2 5.  C oler R N, Bert h olet S, M o utaftsi M, G u deria n J A, Wi n dis h H P, Bal d wi n S L, et al.  
De vel o p me nt a n d c har act erizati o n of s y nt hetic gl u c o p yra n os yl li pi d a dj u va nt s yste m as a 
vacci ne a dj u va nt. P L o S O N E . 2 0 1 1; 6( 1): e 1 6 3 3 3. 
2 6.  U S De part me nt of H ealt h a n d H u ma n Ser vices  F o o d a n d Dr u g A d mi nistrati o n Ce nter f or 
Bi ol o gics E v al uati o n a n d Researc h. G ui da nce f or I n d ustr y. T o xicit y Gra di n g Scal e f or 
Healt h y A d ult a n d A d olesce nt V ol u nteers E nr olle d i n Pre ve ntati ve Vacci n e Cli nical 
Trials. Se pte m ber 2 0 0 7. 
2 7.  W olc h o k J D, H o os A, O' Da y S, We ber J S, Ha mi d O, Le b be C , et al. G ui d eli nes f or t he 
e val uati o n of i m m u ne t hera p y acti vit y i n s oli d t u m ors: i m m u ne -relate d res p o nse criteria. 
Cli n Ca ncer  Res . 2 0 0 9; 1 5( 2 3 ):7 4 1 2- 7 4 2 0. 
2 8.  Ver w eij J. Ot her e n d p oi nts i n scree ni n g st u dies f or s oft tiss ue sarc o mas. O n c ol o gist 2 0 0 8; 1 3 
S u p pl 2: 2 7- 3 1. 
2 9.  U S De part me nt of H ealt h a n d H u ma n Scie nces. Nati o nal I nstit utes of Healt h. 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 vers e E ve nts ( C T C A E). 
Versi o n  4. 0 3. J u ne 1 4, 2 0 1 0. 
3 0.  Sala h S, Yaser S, Sale m A, A l M o usa A, A b u S hei k ha A, S ulta n I. Fact ors i nfl ue nci n g 
s ur vi val i n metastatic s y n o vial sarc o ma: i m p orta nce of patter ns of metastases a n d t he 
first-li ne c he m ot her a p y r e gi me n. M e d O nc ol. 2 0 1 3; 3 0( 3):6 3 9. 
3 1.  Tri pat hi S, G uleria I. R ole of P D 1/ P D L 1 p at h wa y, a n d T H 1 7 a n d tre g cells i n mater nal 
t olera nce t o t he fet us. Bi o me d J 2 0 1 5; 3 8: 2 5- 3 1. 
3 2.  Ce nters f or Disease C o ntr ol a n d Pre ve nti o n a n d Ass ociati o n of P u blic Healt h La b orat ories. 
La b orat or y T esti n g f or t h e Dia g n osis of HI V I nfecti o n: U p date d Rec o m me n dati o ns. 
P u blis he d J u ne 2 7, 2 0 1 4. A vaila ble fr o m htt p://stac ks.c dc. g o v/ vie w/c d c/ 2 3 4 4 7.  

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 1 0 3  of 1 2 8  
 
 
3 3.  De Ra vi n S, Gra y J T, T hr o m R E, et al. False- P ositi ve HI V P C R Test F oll o wi n g E x Vi v o 
Le nti vir al Ge ne Tra nsf er Treat me nt of X -li n ke d Se vere C o m bi ne d I m m u n o deficienc y 
Vect or, M ol T her 2 0 1 4; 2 2: 2 4 4. 
3 4.  Sala h S, Yaser S, Sale m A, Al M o usa A, A b u S hei k ha A, S ulta n I. Fact ors i nfl ue nci n g 
s ur vi val i n metastatic s y n o vial sarc o ma: i m p orta nce of patter ns of metastases a n d t he 
first-li ne c he m ot her a p y r e gi me n. M e dical o nc ol o g y 2 0 1 3; 3 0: 6 3 9. 
3 5.  Si m o n R. O pti mal t w o -sta ge desi g ns f or p h ase II cli nical trials. C o ntr ol Cli n Trials. 1 9 8 9; 
1 0( 1): 1- 1 0. 
3 6.  O ke n M M, Creec h R H, T or me y D C, H ort o n J, Da vis T E, Mc Fa d de n E T , et al. T o xicit y a n d 
res p o nse criteria of t h e E aster n C o o perati ve O nc ol o g y Gr o u p. A m J Cli n O nc ol.  1 9 8 2; 
5( 6):  6 4 9- 6 5 5. 
3 7.  Nis hi n o M, Gi o b bie- H ur der A, G ar ga n o M, S u da M, Ra mai ya N H, H o di F S. De vel o pi n g a 
c o m m o n la n g u a ge f or t u m or res p o nse t o i m m u n ot hera p y: i m m u ne- rel ate d res p o nse 
criteria usi n g u ni di me nsi o nal meas ure m e nts. Cli n Ca ncer Res.  2 0 1 3; 1 9( 1 4): 3 9 3 6- 3 9 4 3. 
3 8.  Nis hi n o M, Gar ga n o M, S u da M, Ra mai ya N H, H o di F S. O pti mizi n g i m m u ne -rel ate d t u m or 
res p o nse ass ess me nt: d oes re d uci n g t he n u m ber of lesi o ns i m pact res p o nse assess me nt i n 
mela n o ma patie nts treat e d wit h i pili m u ma b. J  I m m u n ot her Ca ncer 2 0 1 4; 2: 1 7. 
3 9.  Di Giac o m o A M, Bi a gi oli M, Mai o M. T he e mer gi n g t o xicit y pr ofiles of a nti -C T L A - 4 
a nti b o dies acr oss cli nical i n dicati o ns. Se mi nars i n o nc ol o g y 2 0 1 0; 3 7: 4 9 9- 5 0 7. 
4 0.  Hej bl u m G, La m b otte O, Galicier L, et al. A we b - base d del p hi st u d y f or eli citi n g hel pf ul 
criteria i n t he p ositi ve dia g n osis of he m o p h a g oc ytic s y n dr o me i n a d ult patie nts. Pl o S o ne 
2 0 1 4; 9:e 9 4 0 2 4. 
4 1.  Teac h e y D T, R hei n g ol d S R, Ma u de S L, et al. C yt o ki ne releas e s y n dr o me after 
bli nat u m o ma b treat me nt relate d t o a b n or mal macr o p ha ge acti vati o n a n d a meli orate d wit h 
c yt o ki ne- directe d t her a p y. Bl o o d 2 0 1 3; 1 2 1: 5 1 5 4- 7. 
4 2.  Lee D W, Gar d n er R, P orter D L, et al. C urre nt c o n ce pts i n t he dia g n osis a n d ma na ge me nt of 
c yt o ki ne release s y n dr o m e. Bl o o d 2 0 1 4; 1 2 4: 1 8 8- 9 5. 
4 3.  Ma u de S L, Barr ett D, Teac he y D T, Gr u p p S A. M a na gi n g c yt o ki ne rele as e s y n dr o me 
ass ociate d wit h n o vel T cell -e n ga gi n g t hera pies. C a ncer J 2 0 1 4; 2 0: 1 1 9- 2 2. 
 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 1 0 4  of 1 2 8  
 
 
A P P E N DI C E S  
A p pe n di x  A 
E C O G Perf or m a nce St at us  
E C O G P E R F O R M A N C E S T A T U S  
Gr a de  
Defi niti o n  
0  
F ull y acti ve, a bl e t o carr y o n all pre -diseas e  perf or ma nce wit h o ut restricti o n  
1  
Restricte d i n p h ysicall y stre n u o us acti vit y b ut a m b ulat or y a n d a ble t o carr y o ut w or k of 
a li g ht or se d e ntar y n at ur e, e. g., li g ht h o use w or k, office w or k 
2  
A m b ulat or y a n d ca p a ble of all self -care b ut u n a ble t o carr y o ut  a n y w or k acti vities. U p 
a n d a b o ut m ore t ha n 5 0 % of wa ki n g h o urs 
3  
Ca pa ble of o nl y li mite d self -care, c o nfi ne d t o be d or c hair m ore t ha n 5 0 % of wa ki n g 
h o urs 
4  
C o m pletel y disa ble d. Ca n n ot carr y o n a n y self -care. T otall y c o nfi ne d t o b e d or c hair  
5  
Dea d  
* As p u blis he d i n O ke n et al.3 6 
 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 1 0 5  of 1 2 8  
 
 
A p pe n di x  B 
Me dic al E ve nts of I nterest  
M E OIs, als o k n o w n as A Es of s pecial i nterest ( A E SIs), f or t hera pe utic o nc ol o g y vacci nes are 
lar gel y i nfla m mat or y a n d a ut oi m m u ne s y n dr o mes, i ncl u di n g: 
Ne ur ol o gic  
De m yeli nati n g c o n diti o ns  
O ptic Ne uritis  
M S  
M yelitis  
U veitis  
E nce p halitis  
G uilla n Barre S y n dr o me 
Bell's pals y   
Narc ole ps y  
M yast he ni a Gr a vis  
 
C o n necti ve Tiss ue Dis or ders   
I nfla m mat or y m o n oart hritis or p ol yart hritis 
S yste mic l u p us er yt he mat os us  
P ol y m y ositis or Der mat o m y ositis  
Sj o gre n's s y n dr o me 
 
G astr oi nt esti n al Dis or ders  
Cr o h n’s Disease 
Ulcerati ve c olitis  
Ot her i nfla m mat or y b o w el disease  
 
I m m u ne S yste m Dis or d ers  
I m m u ne T hr o m b oc yt o pe nic P ur p ura 
C o o m b’s p ositi ve he m ol ytic a n e mia 
Ps oriasis  
Er yt h e ma n o d os u m 
Al o pecia  
Ste ve n’s J o h ns o n S y n dr o me 
Vitili g o  
 
T h yr oi d Dis or ders   

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 1 0 6  of 1 2 8  
 
 
Gra ve’s Diseas e  
Has hi m ot o’s t h yr oi ditis  
 
Re n al a n d Uri n ar y Dis or ders   
Ne p hritis  
He mat uria  
 
V asc ul ar   
C uta ne o us vasc ulitis 
Te m p oral art eritis  
A N C A - Ass ociate d gra n ul o mat o us p ol ya n giitis 
C or o nar y art eritis  
 
C ar di ac  
Car ditis  
Pericar ditis  

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 1 0 7  of 1 2 8  
 
 
A p pe n di x  C 
R E CI S T a n d I m m u ne -Rel ate d Res p o nse Criteri a  
F or t his st u d y, b ot h R E CI S T v 1. 1 a n d R E CI S T- b ase d ir R C data will be c ollecte d b ut o nl y ir R C 
will be use d t o deter mi ne disease pr o gr essi o n. F ull R E CI S T defi niti o ns are i ncl u de d i n t he St u d y 
Refere n ce  M a n ual.   
T he ir R C was ori gi nall y de vel o pe d usi n g t he W orl d Healt h Or ga nizati o n ( W H O ) t u m or res p o nse 
meas ure me nt criteria w h ere bi di me nsi o nal meas ure me nts were use d t o defi ne t u m or b ur de n.
2 7 I n 
s oli d ca ncers, R E CI S T is n o w m ore c o m m o nl y us e d. R E CI S T uses t he s u m of t he l o n gest 
u ni di me nsi o nal meas ure me nt of t u m or lesi o ns as t he basis of its criteria. M a n y h a v e n o w 
a d o pte d a m o difie d R E CI S T- b ase d ir R C as t he criteria use d t o meas ure t he effect of 
i m m u n ot hera pe utic a p pr oac hes i n s oli d ca n cers (s ee c o m paris o ns bel o w). Nis hi n o, et al 
pr os pecti vel y e x a mi ne d t he i m pact of usi n g bi di me nsi o nal vs. u ni di me nsi o nal meas ure m e nts. 3 7 
T he y c o ncl u de d t h at ir R C usi n g t he u ni di me nsi o nal meas ure m e nts pr o vi de d hi g hl y c o n c or da nt 
res p o nse ass ess me nt c o m pare d wit h t he bi di me nsi o nal ir R C, wit h less meas ure me nt varia bilit y  
a n d rec o mme n d e d t he us e of u ni di me nsi o nal ir R C t o assess res p o nse t o i m m u n ot hera p y i n s oli d 
t u m ors.  
A p pe n di x T a ble  1 
S u m m ar y of Me as ure me nt a n d Res p o nse Assess me nt A p pr o ac hes 
f or Bi di me nsi o n al a n d U ni di me nsi o n al Assess me nt B ase d o n ir R C 
 
Bi di me nsi o n al assess me nt  
(t he ori gi n al ir R C) 
U ni di me nsi o n al assess me nt  
Me as ur a ble lesi o ns  
≥5 x 5 m m 2 b y bi di me nsi o nal 
meas ure me nts  
≥1 0 m m i n t he l o n gest 
dia meter  
Me as ure me nt of e ac h 
lesi o n 
T he l o n gest dia meter x t he l o n gest 
per pe n dic ular dia meter  (c m2) 
T he l o n gest dia meter (c m)  
T he s u m of t he 
me as ure me nts  
T he s u m of t he bi di me nsi o nal 
meas ure me nts of all tar get lesi o ns a n d 
ne w lesi o ns if a n y  
T he s u m of t he l o n gest 
dia meters of all tar get lesi o ns 
a n d ne w lesi o ns if a n y 
Res p o nse assess me nt  
P D: ≥2 5 % i ncrease fr o m t he na dir 
P R: ≥5 0 % decrease fr o m baseli ne 
C R: Disa p peara nce of all lesi o ns  
P D: ≥2 0 % i ncrease fr o m t he 
na dir 
P R: ≥3 0 % decrease fr o m 
baseli ne  
C R: Disa p peara nce of all 
lesi o ns 
Ne w lesi o ns  
T he prese nce of ne w lesi o n(s) d oes n ot defi ne pr o gressi o n. T he 
meas ure me nts  of t he ne w lesi o n(s) are i ncl u de d i n t he s u m of t he 
meas ure me nts.  

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 1 0 8  of 1 2 8  
 
 
C o nfir m ati o n  
C o nfir mati o n b y 2 c o nsec uti ve o bser vati o ns n ot less t ha n 4 wee ks a part 
was re q uire d f or C R, P R, P D 
As p u blis he d i n Nis hi n o et al. 3 7  
 
Nis hi n o et al. we nt o n t o st u d y t he i m pact of re d uci n g t he n u m ber of tar get lesi o ns t o o pti mize 
t he a p pr oac h a n d f o u n d t his di d n ot si g nifica ntl y affect i m m u ne-relate d res p o nse assess me nt or 
meas ure me nt v aria bilit y .3 8 T heir  res ults s h o w t hat usi n g u p t o 2 tar get lesi o ns per or ga n  a n d u p 
t o 5 tar get lesi o ns i n t otal ma y b e s ufficie nt f or i m m u ne-relat e d res p o nse assess me nt, as l o n g as 
t he i m p orta nt feat ur es of ir R C s uc h as c o nfir mati o n of pr o gressi o n a n d i n cl usi o n of ne w lesi o n 
meas ure me nts  are k e pt. Decr easi n g t he n u m ber of tar get lesi o ns ma y  als o hel p t o i ncreas e t he 
practicalit y of i m m u ne -r elate d res p o nse assess me nt. F or t his trial, t he R E CI S T  v 1. 1-base d i r R C 
will be use d  acc or di n g t o t his o pti mize d strate g y. 
A p pe n di x T a ble  2  
S u m m ar y of me as ure me nt a p pr o ac hes f or t w o assess me nts 
 
ir R C si m ul ati n g R E CI S T 1. 0  
ir R C si m ul ati n g R E CI S T 1. 1  
N u m ber of t ar get 
lesi o ns 
U p t o 5 per or ga n, u p t o 1 0 i n 
t otal 
U p t o 2 per or ga n, u p t o 5 i n t otal 
Me as ur a ble 
lesi o ns 
≥1 0 m m i n t he l o n gest dia meter 
f or all lesi o ns 
≥1 0 m m i n t he l o n gest dia meter f or all 
lesi o ns e xce pt f or l y m p h n o des 
≥1 5 m m i n s h ort a xis f or n o des 
Me as ure me nt of 
e ac h lesi o n 
T he l o n gest dia meter f or all tar get 
lesi o ns 
T he l o n gest dia meter f or n o n - n o dal lesi o ns, 
s h ort a xis f or l y m p h n o des 
Ne w lesi o ns  
T he prese nce of ne w lesi o n d oes 
n ot defi ne pr o gressi o n 
Sa me as ir R C si m ulati n g R E CI S T 1. 0 e xce pt:  
 
T he meas ure me nts of t he ne w 
lesi o n (s) are i ncl u de d i n t he s u m 
of t he meas ure me nts  
A l y m p h n o de has t o be ≥1 5 m m i n t he s h ort 
a xis t o be a meas ura ble ne w lesi o n a n d its 
s h ort a xis meas ure me nt is i ncl u de d i n t he 
s u m 
 
U p t o 5 ne w lesi o ns per or ga n, u p 
t o 1 0 ne w lesi o ns i n t otal ca n be 
a d de d t o meas ure me nts 
U p t o 2 ne w lesi o ns per or ga n, u p t o 5 ne w 
lesi o ns 
As p u blis he d i n Nis hi n o et al.  3 8 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 1 0 9  of 1 2 8  
 
 
A p pe n di x  D  
C o m p aris o n of R E CI S T v 1. 1 vs. R E CI S T-b ase d ir R C  
 
R E CI S T v 1. 1 
R E CI S T -b ase d ir R C  
Ne w, 
Me as ur a ble 
lesi o ns (> 1 0 
m m)  
Rec or de d as P D  
I nc or p orate d i nt o t u m or b ur de n (see 
A p pe n di x C ) 
Ne w, n o n-
me as ur a ble 
lesi o ns ( < 1 0 
m m)  
Rec or de d as P D  
D o n ot defi ne pr o gressi o n ( b ut precl u de 
ir C R) 
N o n - T ar get 
Lesi o ns  
C o ntri b utes t o best o verall res p o nse ( C R, 
P R, S D, P D)  
C o ntri b ute t o i r C R (c o m plete 
disa p peara nce re q uire d)  
C R  
Disa p peara nce of all lesi o n i n 2 
c o nsec uti ve o bser vati o ns ≥4 wee ks a part  
Disa p peara nce of all lesi o ns i n 2 
c o nsec uti ve o bser vati o ns ≥4 wee ks a part  
P R  
≥3 0 % decrease i n s u m of t he l o n gest 
dia meter of all i n de x lesi o ns c o m pare d 
wit h baseli ne i n 2 o bser vati o ns ≥ 4 wee ks 
a part, i n t he a bse nce of ne w lesi o ns or 
u ne q ui v ocal pr o gressi o n of n o n -i n de x 
lesi o ns 
≥3 0 % decrease i n t u m or b ur de n 
c o m pare d wit h baseli ne i n 2 
o bser vati o ns ≥4 wee ks a part  
S D  
Neit her s ufficie nt s hri n ka ge t o q ualif y f or 
P R or i ncrease t o q ualif y f or P D w he n 
c o m pare d t o t he s mallest s u m of dia meters 
w hile o n st u d y  
3 0 % decrease i n t u m or b ur de n c o m pare d 
wit h baseli ne ca n n ot be esta blis he d n or 
2 0 % i ncrease w he n c o m pare d wit h na dir 
P D  
≥2 0 % i ncrease i n  t he s u m of t he dia meters 
of t he tar get lesi o ns w he n c o m pare d t o t he 
s mallest s u m w hile o n st u d y. T he s u m 
m ust als o de m o n strate a n a bs ol ute i ncrease 
of ≥5  m m. T he a p peara nce of ≥1 ne w 
lesi o n is c o nsi dere d P D  
≥2 0 % i ncrease i n t u m or b ur de n 
c o m pare d wit h na dir (at a n y si n gle 
ti me p oi nt) i n 2 c o nsec uti ve 
meas ure me nts ≥4 wee ks a part.  
C R = c o m plete res p o nse; ir R C  = i m m u n e-relate d res p o nse criteria; ir C R = i m m u n e-relate d c o m plete res p o nse; P D  = pr o gressi ve 
disease; P R = p artial res p o nse; R E CI S T  =  res p o nse e val u ati o n criteria i n s oli d t u m ors; S D  =  sta ble disease. 
 
O ver all Res p o nse Usi n g t he ir R C  
T he o ver all res p o nse acc or di n g t o t he ir R C is deri ve d fr o m ti me p oi nt res p o nse assess me nts 
( base d o n t u m or b ur d e n) as f oll o ws: 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 1 1 0  of 1 2 8  
 
 
•  
I m m u ne-relat e d c o m plet e res p o nse (ir C R): c o m plete disa p peara n ce of all lesi o ns ( w het her 
meas ura ble or n ot, a n d n o ne w lesi o ns) a n d c o nfir mati o n b y a re peat, c o nsec uti ve assess me nt 
n o less t ha n 4 wee ks  fr o m t he date first d oc u me nt e d 
•  
I m m u ne-relat e d partial r es p o nse (ir P R): decrease i n t u m or b ur de n ≥3 0 % rel ati ve t o baseli ne 
a n d c o nfir me d b y a c o ns ec uti ve assess me nt at least 4 wee ks aft er first d oc u me ntati o n  
•  
I m m u ne-relat e d Sta ble Disease (ir S D): n ot meeti n g criteria f or ir C R or ir P R, i n a bse nce of 
ir P D 
•  
I m m u ne-relat e d Pr o gressi ve Disease (ir P D): i ncrease i n t u m or b ur de n ≥2 0 % relati ve t o na dir 
( mi ni m u m rec or de d t u m or b ur de n) a n d c o nfir mati o n b y a re peat, c o nsec uti ve assess me nt n o 
less t ha n 4 wee ks fr o m t he date first d oc u m e nte d 
 
 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 1 1 1  of 1 2 8  
 
 
A p pe n di x  E 
Pree xisti n g A ut oi m m u ne Dise ases  
S u bjects s h o ul d be caref ull y q uesti o ne d re gar di n g t heir hist or y of ac q uire d or c o n ge nital i m m u ne 
deficie nci es or a ut oi m m u ne disease.  S u bjects wit h a n y hist or y of i m m u ne deficie nci es or 
a ut oi m m u ne disease liste d i n t he ta ble bel o w are e x cl u de d fr o m partici pati n g i n t he st u d y.  
P ossi ble e x ce pti o ns t o t his e x cl usi o n c o ul d be s u bjects wit h a me dical hist or y of s u c h e ntities as 
at o pic disease or c hil d h o o d art hral gias w h ere t h e cli nical s us pici o n of a ut oi m m u ne disease is 
l o w. Patie nts wit h a hist or y of a ut oi m m u ne -relate d h y p ot h yr oi dis m o n a sta ble d ose of t h yr oi d 
re place me nt h or m o ne ma y be eli gi ble f or t his st u d y. I n a d diti o n, tra nsie nt a ut oi m m u ne 
ma nifestati o ns of a n ac ut e i nfecti o us diseas e t hat res ol ve d u p o n treat me nt of t he i nfecti o us a ge nt 
are n ot e x cl u de d ( e. g., ac ute L y me art hritis).  C o ntact t he Me dical M o nit or re gar di n g a n y 
u ncertai nt y o ver a ut oi m m u ne e x cl usi o ns.  
Ac ute disse mi nate d  
e nce p hal o m yelitis 
A d dis o n’s disease  
A n k yl osi n g s p o n d ylitis 
A nti p h os p h oli pi d a nti b o d y  
s y n dr o me 
A plastic a ne mia  
A ut oi m m u ne he m ol ytic a ne mia  
A ut oi m m u ne he patitis 
A ut oi m m u ne 
h y p o parat h yr oi dis m 
A ut oi m m u ne h y p o p h ysitis 
A ut oi m m u ne m y ocar ditis  
A ut oi m m u ne o o p h oritis 
A ut oi m m u ne orc hitis 
A ut oi m m u ne t hr o m b oc yt o pe nic 
p ur p ura 
Be hcet’s disease  
B ull o us pe m p hi g ol d 
C hr o nic i nfla m mat or y 
de m yeli nati n g  
p ol y ne ur o pat h y 
C h u n g- Stra uss s y n dr o me  
Cr o h n’s disease  
Der mat o m y ositis  
D ysa ut o n o mia 
E pi der m ol ysis b ull osa ac q uista 
Gestati o nal pe m p hi g oi d 
Gia nt cell arteritis  
G o o d past ure’s s y n dr o me  
Gra ves’ disease  
G uillai n - Barré s y n dr o me 
Has hi m ot o’s disease  
I g A ne p hr o pat h y 
I nfla m mat or y b o wel disease 
I nterstitial c ystitis 
Ka wasa ki’s disease  
La m bert - Eat o n m yast he nia 
s y n dr o me 
L u p us er yt he mat os us 
L y me disease - c hr o nic 
Me niere’s s y n dr o me  
M o ore n’s ulcer  
M or p hea 
M ulti ple scler osis  
M yast he nia gra vis  
Ne ur o m y ot o nia  
O ps ocl o n us m y ocl o n us 
s y n dr o me 
O ptic ne uritis  
Or d’s t h yr oi ditis  
Pe m p hi g us 
Per nici o us a ne mia  
P ol yarteritis n o d usa 
P ol yart hritis  
P ol y gla n d ular a ut oi m m u ne 
s y n dr o me 
Pri mar y biliar y cirr h osis  
Ps oriasis  
Reiter’s s y n dr o me  
R he u mat oi d art hritis 
Sarc oi d osis 
Scler o der ma  
Sj ö gre n’s s y n dr o me 
Stiff - Pers o n s y n dr o me 
T a ka yas u’s arteritis  
Ulcerati ve c olitis  
V o gt -K o va na gi -Hara da disease  
We ge ner’s gra n ul o mat osis  

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 1 1 2  of 1 2 8  
 
A p pe n di x  F 
D ose  M o dific ati o n a n d S u p p orti ve C are G ui deli nes f or A tez oliz u m a b 
As of Ma y 2 0 1 5, atez oliz u ma b has bee n a d mi nistere d t o a p pr o xi matel y 3 2 0 0 patie nts wit h s oli d 
t u m ors a n d he mat ol o gi c mali g na n cies. I n a d diti o n t o st u dies prese nte d i n t he pre vi o us secti o ns, 
safet y i nf or mati o n f or atez oliz u ma b is als o glea ne d fr o m st u dies i n t he e ntire de vel o p me nt 
pr o gra m, i ncl u di n g t h ose w here atez oliz u ma b is i n vesti gate d i n c o m bi nati o n wit h ot her 
u na p pr o ve d a ge nts.   
St u d y P C D 4 9 8 9 g, i n w hi c h atez oliz u ma b is bei n g use d as a si n gle a ge nt i n patie nts wit h l ocall y 
a d va nce d or metastatic s oli d t u m ors or he mat ol o gic mali g na n cies, pr o vi des t he maj orit y of d ata 
( wit h 5 5 8 safet y e v al ua bl e patie nts as of t he d ata e xtracti o n date of 1 1 Ma y 2 0 1 5) f or t he safet y 
pr ofile of atez oliz u ma b as m o n ot hera p y. C urre ntl y, n o ma xi m u m t olerate d d ose, n o d ose- li miti ng 
t o xicities a n d n o clear d ose-relat e d tre n ds i n t he i n ci de nce of A Es ha v e bee n deter mi ne d. 
I n tri als i n vesti gati n g t he c o m bi nati o ns of atez oliz u ma b wit h be vaciz u ma b a n d/ or 
c he m ot hera pi es, c o bi meti ni b, or ve m urafe ni b, t he i nci de nce of A Es i n t he treat me nt ar ms wit h 
c o m bi ne d use was c o nsiste nt wit h t he k n o w n safet y pr ofiles of t he i n di vi d ual st u d y dr u gs.  
Fati g ue, decrease d a p petite, na usea a n d c o u g h w ere c o m m o nl y re p orte d a d verse e v e nts i n si n gle 
a n d c o m bi nati o n t hera p y. T he o ver all i m m u ne me diate d a d vers e e v e nts re p orte d f or 
atez oliz u ma b were c o nsi dere d m o derate i n se v erit y a n d m aj orit y of patie nts were a ble t o 
c o nti n ue o n atez oliz u ma b t hera p y.  
Alt h o u g h m ost i m m u ne- me diate d a d verse e v e nts o bser ve d wit h i m m u n o m o d ulat or y a ge nts ha v e 
bee n mil d a n d self- li mitin g, s uc h e ve nts s h o ul d b e rec o g nize d earl y a n d treate d pr o m ptl y t o 
a v oi d p ote ntial maj or c o m plicati o ns. 3 9 A s u m mar y of i de ntifi e d ris ks f or at ez oliz u ma b  is 
prese nte d i n A p p e n di x Ta ble 3 . 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 1 1 3  of 1 2 8  
 
A p pe n di x T a ble  3 
S u m m ar y of I de ntifie d Ris ks of A tez oliz u m a b 
I de ntifie d Ris k 
Descri pti o n of Ris k  
C olitis  
Seri o us re p orts of bi o ps y c o nfir me d c olitis ha ve bee n re p orte d i n less t ha n 0. 5 % 
of patie nts w h o recei ve d si n gle a ge nt atez oliz u ma b. T he e ve nts were of Gra de 2 
or 3 i n se verit y a n d t he maj orit y of re p orte d c olitis res ol ve d f oll o wi n g treat me nt. 
Patie nts c o nti n ue d t o recei ve atez oliz u ma b des pite t he e ve nt. Diarr hea ( 1 9. 7 %) 
has bee n re p orte d wit h si n gle a ge nt atez oliz u ma b. T hese e ve nts were c o nsi dere d 
mil d t o m o derate a n d res ol ve d wit h o ut treat me nt.  
Der m at ol o gic 
re acti o ns 
Der mat ol o gic reacti o ns ha ve bee n re p orte d i n 4 2 % of patie nts recei vi n g si n gle 
a ge nt atez oliz u ma b.  Reacti o ns ha ve bee n mil d t o m o derate ( < 1 % re p orte d as 
se vere). C o m m o nl y re p orte d e ve nts i n P C D 4 9 8 9 g i ncl u de ras h ( 1 5 %), pr urit us 
( 1 3 %), dr y s ki n ( 7 %), mac ul o pa p ular ras h (6 %), ni g ht s weats ( 6 %) a n d er yt he ma 
( 3 %). Al o pecia, der matitis ac neif or m, der matitis ps oriaif or m, vitili g o, se b orr heic 
der matitis, lic he n pla n us, b ull o us der matitis a n d s ki n pi g me ntati o n c ha n ges ha ve 
als o bee n re p orte d less c o m m o nl y.  
E n d ocri ne 
dis or ders  
A dre nal i ns ufficie nc y has bee n o bser ve d i n 0. 2 % of patie nts recei vi n g si n gle 
a ge nt atez oliz u ma b, a n d i n < 2 % of patie nts recei vi n g atez oliz u ma b i n 
c o m bi nati o n wit h ot her c he m ot hera p y. Ass ociate d la b orat or y para meters s uc h as 
h y p o natre mia a n d h y p o kale mia were o bser ve d i n < 1 % of patie nts recei vi n g 
si n gle a ge nt atez oliz u ma b, a n d h y p o natre mia was o bser ve d i n 1. 6 % of patie nts 
recei vi n g atez oliz u ma b i n c o m bi nati o n wit h c he m ot hera p y.  
H y p ot h yr oi dis m e ve nts ha ve bee n re p orte d i n u p t o 6 % of patie nts recei vi n g 
atez oliz u ma b acr oss t he cli nical pr o gra m.  T he maj orit y of e ve nts were re p orte d i n 
patie nts recei vi n g si n gle a ge nt atez oliz u ma b.  E ve nts ha ve ge nerall y bee n mil d 
a n d patie nts w h o recei ve d treat me nt wit h t h yr oi d re place me nt were a ble t o 
c o nti n ue o n st u d y treat me nt.  
H y pert h yr oi dis m e ve nts ha ve occ urre d i n 0. 7 % of patie nts recei vi n g si n gle a ge nt 
atez oliz u ma b. T he maj orit y of patie nts wit h h y pert h yr oi dis m a p pear t o be 
as y m pt o matic.  Patie nts recei ve d treat me nt wit h a nti -t h yr oi d a ge nts a n d were 
c o nti n ue d o n st u d y treat me nt. 
He p atitis  
I n patie nts recei vi n g atez oliz u ma b as a si n gle a ge nt, he patitis a n d ele vati o ns of 
al kali ne p h os p hatase, A S T a n d A L T ha ve bee n re p orte d i n 0. 5 %, 4. 1 %, 6. 1 % a n d 
5. 6 % of patie nts, res pecti vel y. I n t he cli nical pr o gra m, < 1 % of patie nts 
e x perie nce d seri o us a d verse e ve nts of he pat o biliar y dis or ders i ncl u di n g 
a ut oi m m u ne he patitis ( 5), he patitis ( 3), a n d t he f oll o wi n g ( 1 patie nt eac h): dr u g 
i n d uce d li ver i nj ur y, he patic fail ure, a b n or mal he patic f u ncti o n, he pat ocell ular 
i nj ur y, a n d li ver disor der.  
H y perse nsiti vit y  
H y perse nsiti vit y reacti o ns i ncl u di n g aller gic a n d a na p h ylactic reacti o ns ha ve 
bee n re p orte d i n < 1 % of patie nts recei vi n g si n gle a ge nt.  O utc o mes f or t hese 
e ve nts were c o nsi dere d res ol ve d.  Patie nts ma y prese nt wit h c o m plai nts s uc h as  
fl us hi n g, fe ver, c hills, bl o o d press ure c ha n ge, tac h ycar dia or s h ort ness of breat h 
I nfl ue nz a-li ke 
ill ness 
I nfl ue nza li ke ill ness has bee n re p orte d i n patie nts recei vi n g atez oliz u ma b as a 
si n gle a ge nt i n P C D 4 9 8 9 g ( 7. 3 %). E ve nts ass ociate d wit h i nfl ue nza l i ke ill ness 
were pri maril y o bser ve d o ne t o t w o wee ks after recei vi n g t he first c ycle.  
Reacti o ns ha ve i ncl u de d fe ver, fati g ue, ast he nia, c hills, m yal gia, art hral gia a n d 
hea dac he.  T he e ve nts ha ve bee n mil d t o m o derate i n se verit y.   

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 1 1 4  of 1 2 8  
 
I de ntifie d Ris k 
Descri pti o n of Ris k  
I nf usi o n-rel ate d 
re acti o ns 
S y m pt o ms ma y prese nt wit hi n 3 0 mi n utes t o 2 4 h o urs after i nf usi o n, are 
ge nerall y mil d a n d ma na gea ble, a n d wa ne wit h s u bse q ue nt i nf usi o ns.  Wit h si n gle 
a ge nt atez oliz u ma b, I R Rs ha ve bee n re p orte d i n 0. 4 % of patie nts. T he m ost 
c o m m o n s y m pt o ms re p orte d wit h si n gle a ge nt use wit hi n 2 4 h o urs of t he first 
c ycle were p yre xia, fati g ue, na usea, h y perte nsi o n, hea dac he a n d diarr hea.   
Ne ur ol o gic 
dis or ders  
M yast he nia gra vis a n d G uillai n -Barr é s y n dr o me ha ve bee n o bser ve d i n less t ha n 
1 % of patie nts ta ki n g atez oliz u ma b. Patie nts ma y prese nt wit h si g ns a n d 
s y m pt o ms of se ns or y a n d/ or m ot or ne ur o pat h y. Me ni n gitis ( n o n -i nfecti o us) has 
als o bee n re p orte d i n < 1 % of patie nts.  Patie nts wit h me ni n gitis ma y prese nt wit h 
altere d me ntal stat us, c o nf usi o n, hea dac he, or fe ver.  Dia g n ostic w or k- u p is 
esse ntial f or a n acc urate c haracterizati o n t o differe ntiate bet wee n alter nate 
eti ol o gies. 
P ne u m o nitis  
P ne u m o nitis has bee n re p orte d i n 1. 4 % of patie nts recei vi n g si n gle a ge nt 
atez oliz u ma b. T hese e ve nts ha ve bee n pri maril y o bser ve d i n patie n ts wit h l u n g 
ca ncer. F o ur fatal re p orts of p ne u m o nitis ha ve bee n re p orte d. Patie nts ma y 
prese nt wit h d ys p nea, h y p o xia or ot her res pirat or y c o m plicati o n. Dia g n ostic 
w or k -u p is esse ntial f or a n acc urate c haracterizati o n t o differe ntiate bet wee n 
alter nate eti ol o gies s uc h as i nfecti o n, p ul m o nar y e m b olis m or u n derl yi n g disease.  
A L T =al a ni ne tra nsa mi n ase; A S T =as p artate tra nsa mi n ase; I R R = i nf usi o n-relate d reacti o ns. 
N ote: T his ta ble is b ase d o n si n gle a ge nt d ata fr o m St u d y P C D 4 9 8 9 g as of t h e d ata e xtracti o n d ate of 1 1 Ma y 2 0 1 5 i n 5 5 8 treate d 
patie nts.  T he i nf or mati o n is als o b ase d o n a re vie w of safet y i nf or mati o n acr oss t h e atez oliz u ma b d e vel o p me nt pr o gra m as of t he 
c ut off date f or t his versi o n of t h e I B.  Si n gle -a ge nt st u dies i n cl u d e G O 2 8 7 5 3, G O 2 8 7 5 4, G O 2 8 6 2 5, G O 2 8 9 1 5 a n d G O 2 9 2 9 3.  
C o m bi nati o n st u dies i n cl u d e W O 2 9 0 7 4, G O 2 9 3 2 2, a n d G P 2 8 3 2 8.  
 
W he n t he I B is use d as t h e Refer e nce Safet y I nf or mati o n, t he A p pe n di x Ta ble 4  pr o vi des a list of 
t he a d vers e dr u g r eacti o ns ( A D Rs), w hic h are c o nsi dere d “e x pecte d” f or re g ulat or y re p orti n g 
p ur p oses b y t he S p o ns or. Descri pti o ns of t he ris ks ass ociate d wit h eac h of t he l iste d A D Rs are 
s u m marize d i n A p pe n di x Ta ble 3 , i ncl u di n g p o p ul ati o n e x p ose d t o t he I M P, a n d i nte nsit y a n d 
fre q ue n c y of t he ris k ( w h ere a v aila ble). 
T he classificati o n o f a n A E as a n A D R is bas e d o n data a vaila ble at t he ti me of assess me nt. D ata 
o btai ne d at later d ates ma y r ef ute t he c o n necti o n bet wee n a n A E a n d atez oliz u ma b, a n d lea d t o 
a n A D R bei n g s u bse q ue ntl y reclassifie d as a n A E.  G ui deli nes f or ma na ge m e nt of t hese e v e nts 
are pr o vi d e d  a b o ve. 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 1 1 5  of 1 2 8  
 
A p pe n di x T a ble  4 
E x pecte d A d verse Dr u g Re acti o ns f or A tez oliz u m a b i n All I n dic ati o ns 
f or Re g ul at or y Re p orti n g P ur p oses O nl y 
Ris k  
N otes/ E xcl usi o ns 
G astr oi ntesti n al Dis or ders  
I ncl u des c olitis, diarr hea, d ys p ha gia, na usea, v o miti n g, a b d o mi nal 
pai n a n d decrease d a p petite  
Der m at ol o gic re acti o ns  
I ncl u des ras h a n d pr urit us 
E n d ocri ne dis or ders  
I ncl u des h y pert h yr oi dis m, h y p ot h yr oi dis m a n d a dre nal i ns ufficie nc y 
He p atitis a 
I ncl u des A L T i ncrease d, A S T i ncrease d, a n d he patic e nz y mes 
a b n or mal 
H y perse nsiti vit y re acti o ns/ 
I nf usi o n-rel ate d Re acti o ns  
 
I nfl ue nz a-li ke ill ness 
I ncl u des art hral gia, m usc ul os keletal pai n, ast he nia, c hills, fe ver, 
fati g ue, a n d nasal c o n gesti o n 
Ner v o us s yste m dis or ders  
I ncl u des me ni n gitis, G uillai n -Barr é s y n dr o me, m yast he nic s y n dr o me  
P ne u m o nitis a 
I ncl u des d ys p nea a n d h y p o xia 
Ge ner al a n d Met a b olic 
dis or ders  
I ncl u des h y p o natre mia , h y p o kale mia, a n d i ns o m nia 
V asc ul ar dis or ders  
I ncl u des h y perte nsi o n a n d h y p ote nsi o n 
a I ncl u des fatal e v e nts. 
N ote: A n y ter m c o vere d b y t h e me dical c o n ce pts prese nte d i n t his list is c o nsi d ere d “e x p ecte d ” f or b ot h n o n -seri o us a n d seri o us 
re p orts of s us p ecte d u n e x p ecte d A D Rs t o Healt h A ut h orities, e xcl u di n g e ve nts wit h fatal o utc o me u nless d etaile d ot h er wise i n 
t he ta ble. 
 
T he classificati o n of a n A E  as a p ote ntial ris k is base d o n t he mec h a nis m of acti o n of 
atez oliz u ma b , pre-cli nical fi n di n gs, as w ell as ot her a ge nts wit h si milar mec ha nis m s of acti o n . 
As of t he c ut off d ate f or t h e data i ncl u de d b el o w , t he safet y pr ofile re m ai ns c o nsiste nt base d o n 
t he k n o w n mec ha nis m of acti o n of atez oliz u ma b. T he p ote ntial ris ks ass oci ate d wit h 
atez oliz u ma b  are s u m marize d i n A p pe n di x Ta ble 5 , f oll o we d b y g ui deli nes f or t he ma na ge me nt 
of t hese atez oliz u ma b -s pecific A Es. 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 1 1 6  of 1 2 8  
 
A p pe n di x T a ble  5  
S u m m ar y of I m p ort a nt P ote nti al Ris ks of Atez oliz u m a b 
P ote nti al Ris k  
Descri pti o n of Ris k  
A nti -t hera pe utic 
A nti b o dies  
A T As ha ve bee n o bser ve d i n patie nts i n t he o n g oi n g cli nical pr o gra m i n 
m ulti ple t u m or t y pes. T he n u m ber of patie nts i n t he si n gle ar m st u d y, 
P C D 4 9 8 9 g, wit h a sa m ple t hat s h o we d p ositi ve A T A at baseli ne was 
c o nsiste nt acr oss d os e gr o u ps wit h a pre vale nce rate ra n gi n g fr o m 2. 2 -
3. 4 %. T he p ost - baseli ne A T A i nci de nce ra n ge d fr o m 9. 1- 3 9. 5 % acr oss 
differe nt d osi n g gr o u ps, eac h wit h varie d sa m ple size. N o c o nsiste nt 
relati o ns hi p has bee n o bser ve d bet wee n t he A T A res p o nses a n d P K, 
a d verse e ve nts, or t hera pe utic acti vit y. M o nit ori n g a n d c haracterizati o n of 
A T As is o n g oi n g f or all cli nical st u dies of atez oliz u ma b. 
M y o pat hies  
M y ositis ( 1 patie nt), m y o pat h y ( 1 patie nt), a n d r ha b d o m y ol ysis ( 2 
patie nts) ha ve bee n re p orte d acr oss t he cli nical de vel o p me nt pr o gra m of 
atez oliz u ma b. Patie nts w h o prese nt wit h si g ns or s y m pt o ms of m usc ular 
pai n s h o ul d be assesse d f or i nfla m mat or y ca uses f or m uscle pai ns. 
Ma na ge me nt of t hese patie nts s h o ul d be al o n g i nstit uti o nal g ui deli nes. 
Ne p hritis  
Ne p hritis is a c o ncer n gi ve n t he mec ha nis m of acti o n of atez oliz u ma b a n d 
fi n di n gs fr o m ot her i m m u n e m o d ulati n g a ge nts. A si n gle re p ort of Gra de 2 
ne p hritis was o bser ve d i n a patie nt treate d wit h ve m urafe ni b a n d 
atez oliz u ma b, w hic h was treate d wit h pre d nis o ne wit h res ol ut i o n. T he 
patie nt ha d a hist or y of h y perte nsi o n, a n d c o nc o mita nt me dicati o n 
i ncl u de d h y dr oc hl or ot hiazi de/l osarta n.  
Ot her E n d ocri n o pat hies 
Dia betes a n d pa ncreatitis are c o ncer ns gi ve n t he mec ha nis m of acti o n of 
atez oliz u ma b. Dia betes mellit us or h y per gl yce mia has bee n o bser ve d i n 
0. 7 % of patie nts i n t he P C D 4 9 8 9 g st u d y. I n s o me cases, dia betes mellit us 
was a pre -e xisti n g c o n diti o n. Pa ncreatitis has bee n o bser ve d i n less t ha n 
1 % of patie nts recei vi n g atez oliz u ma b i n t he P C D 4 9 8 9 g st u d y.  
S yste mic I m m u ne 
Acti v ati o n 
E xcessi ve acti vati o n of t he i m m u ne s yste m is a p ote ntial ris k ass ociate d 
wit h atez oliz u ma b, a n d has bee n o bser ve d w he n atez oliz u ma b is use d i n 
c o m bi nati o n wit h ot her i m m u ne m o d ulati n g a ge nts. O ne patie nt 
partici pati n g i n St u d y B P 2 9 3 9 2 (atez oliz u ma b i n c o m bi nati o n wit h 
R O 7 0 0 9 7 8 9 [ C D 4 0 a g o nist]) de vel o pe d SI A after t he first c ycle. I n t his 
st u d y, C D 4 0 a g o nist was a d mi nistere d first, f oll o we d b y atez oliz u ma b 6 
wee ks later. T he patie nt de vel o pe d a ut oi m m u ne he m ol ytic a ne mia a n d 
p ne u m o nitis 1 2 da ys after t he first d ose of atez oliz u ma b wit h s u bse q ue nt 
de vel o p me nt of ac ute re nal fail ure d uri n g h os pitalizati o n. Treat me nt wit h 
hi g h d ose ster oi ds a n d s u p p orti ve care was a d mi nistere d wit h res ol uti o n of 
e ve nts. 
A T A = a nti-t hera p e utic a nti b o dies; SI A= s yste mic i m m u ne acti v ati o n.   
N ote: T his ta ble is b ase d o n si n gle a ge nt d ata fr o m St u d y P C D 4 9 8 9 g as of 1 0 Ma y 2 0 1 5 i n 5 5 8 treate d p atie nts.  T h e 
i nf or mati o n is als o b ase d o n a re vie w of seri o us a d verse e ve nts a n d n o n-seri o us a d verse e ve nts of s p ecial i nterest acr oss t he 
atez oliz u ma b d e vel o p me nt pr o gra m as of 1 0 Ma y 2 0 1 5.  Si n gle -a ge nt st u dies i n cl u d e G O 2 8 7 5 3, G O 2 8 7 5 4, G O 2 8 6 2 5, 
G O 2 8 9 1 5 a n d G O 2 9 2 9 3.  C o m bi nati o n st u dies i n cl u d e W O 2 9 0 7 4, G O 2 9 3 2 2, a n d G P 2 8 3 2 8.  
 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 1 1 7  of 1 2 8  
 
M a n a ge me nt of A tez oliz u m a b-S pecific A d verse E ve nts  
T o xicities ass o ciate d or p ossi bl y ass ociate d wit h atez oliz u ma b  treat me nt s h o ul d be ma na ge d 
acc or di n g t o sta n d ar d me dical practice. A d diti o nal tests, s uc h as a ut oi m m u ne ser ol o g y or 
bi o psies, s h o ul d be use d t o deter mi ne a p ossi ble i m m u n o ge nic eti ol o g y. 
Alt h o u g h m ost i m m u ne- me diate d  a d verse e v e nts o bser ve d wit h i m m u n o m o d ulat or y a ge nts ha v e 
bee n mil d a n d self-li miti n g, s uc h e ve nts s h o ul d b e rec o g nize d earl y a n d treate d pr o m ptl y t o 
a v oi d p ote ntial maj or c o m plicati o ns. Disc o nti n uati o n of atez oliz u ma b  ma y n ot ha ve a n 
i m me diate thera pe utic effect a n d i n se v ere cas es, i m m u ne -relate d t o xicities ma y re q uire ac ute 
ma na ge me nt wit h t o pical c ortic oster oi ds, s yste mic c ortic oster oi ds, m yc o p h e n olate, or T N F −α  
i n hi bit ors. 
T he i n vesti gat or s h o ul d c o nsi der t he be nefit-ris k b ala nce a gi ve n patie nt ma y be e x perie nci n g 
pri or t o  f urt her a d mi nistrati o n of atez oliz u ma b . Atez oliz u ma b s h o ul d be per ma ne ntl y 
disc o nti n ue d i n patie nts wit h life -t hreate ni n g i m m u ne-me diate d  a d v erse e ve nts.  F or t he 
ma na ge me nt of ot her a d v erse e v e nts ass ociate d wit h atez oliz u ma b n ot pr o vi de d i n t he f oll o wi n g 
disc ussi o n , refer t o t he Atez oliz u ma b I B. 
P ul m o n ar y T o xicit y  
D ys p n ea, c o u g h, fati g ue, h y p o xia, p ne u m o nitis a n d p ul m o nar y i nfiltrat es h a ve bee n ass ociat e d 
wit h t he a d mi nistrati o n of atez oliz u ma b  a n d ha ve pri maril y b ee n o bser ve d i n patie nts wit h 
u n derl yi n g N S C L C.  
Mil d t o m o derate e ve nts of p ne u m o nitis ha ve bee n re p orte d wit h at ez oliz u ma b . All p ul m o nar y 
e ve nts s h o ul d be t h or o u g hl y e v al uate d f or ot her c o m m o nl y re p ort e d eti ol o gies s uc h as 
p ne u m o nia/i nfecti o n, l y m p ha n gitic carci n o mat osis, p ul m o nar y e m b olis m, heart fail ure, or 
c hr o nic o bstr ucti ve p ul m o nar y disease, or p ul m o nar y h y pert e nsi o n: 
•  
Meas ure me nt of o x y ge n sat urati o n (i.e., arterial bl o o d gas) 
•  
Hi g h -res ol uti o n C T sca n of t he c hest 
•  
Br o nc h os c o p y wit h br o n c h oal ve olar l a va ge a n d bi o ps y 
•  
P ul m o nar y f u n cti o n tests ( diff usi o n ca p acit y of t h e l u n g f or car b o n m o n o xi de [ D L C O ]) 
•  
P ul m o nar y f u n cti o n testi n g wit h a p ul m o nar y e m b olis m pr ot oc ol 
Patie nts will be assesse d f or p ul m o nar y si g ns a n d s y m pt o ms t hr o u g h o ut t he st u d y. Patie nts will 
als o ha ve C T sca ns of t he c hest at e v er y t u m or assess me nt.  

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 1 1 8  of 1 2 8  
 
A p pe n di x T a ble  6 
G ui deli nes f or M a n a ge me nt of A tez oliz u m a b-Ass oci ate d P ul m o n ar y 
T o xicit y 
P ul m o n ar y 
E ve nts/ 
P ne u m o nitis  
Se verit y  
M a n a ge me nt 
Gr a de 1  
•  
Ma y c o nti n ue atez oliz u ma b wit h cl ose m o nit ori n g 
•  
Re -e val uate o n serial i ma gi n g  
•  
C o nsi der p ul m o nar y c o ns ultati o n  
Gr a de 2  
•  
Wit h h ol d atez oliz u ma b 
•  
P ul m o nar y a n d I D c o ns ultati o n wit h c o nsi derati o n f or 
br o nc h osc o p y/ B A L 
•  
Start 6 0  m g pre d nis o ne or e q ui vale nt per da y 
•  
W he n i m pr o ves t o Gra de 0 or Gra de 1, t he n ta per ster oi ds 
o ver ≥1 m o nt h 
•  
Atez oliz u ma b ma y be res u me d if t he e ve nt i m pr o ves t o 
Gra de 0 or 1 wit hi n 1 2 wee ks a n d c ortic oster oi ds ha ve 
bee n re d uce d t o t he e q ui vale nt of oral pre d nis o ne 1 0 m g 
dail y or less.  
•  
Treat as Gra des 3 - 4 if rec urre nt e pis o de of p ne u m o nitis 
Gr a de 3 a n d 4  
•  
Per ma ne ntl y disc o nti n ue atez oliz u ma b  
•  
Br o nc h osc o p y/ B A L is rec o m me n de d 
•  
Start 6 0  m g pre d nis o ne or e q ui vale nt per da y.  
•  
T a per ster oi ds o ver ≥1 m o nt h o nce s y m pt o ms i m pr o ve t o 
Gra de 0 or 1. 
•  
If n ot i m pr o vi n g after 4 8 h o urs or w orse ni n g: a d d 
a d diti o nal i m m u n os u p pressi o n (e. g., i nfli xi ma b, 
c ycl o p h os p ha mi de, I VI G, or m yc o p he n olate m ofetil)  
•  
C o ntact Me dical M o nit or if atez oliz u ma b is di sc o nti n ue d 
B A L = b r o nc h osc o pic al ve olar la va ge; I D= i nfecti o us diseases; I VI G= i ntra ve n o us i m m u n o gl o b uli n 
 
He p atic E ve nts  
I m m u ne-me diate d  h e patitis has bee n ass ociat e d wit h t he a d mi nistrati o n of atez oliz u ma b . Eli gi ble 
patie nts m ust ha ve a de q u ate li ver f u n cti o n, as ma nifeste d b y meas ure me nts of t otal bilir u bi n a n d 
he patic tra ns a mi nase s, a n d li ver f u ncti o n will be m o nit ore d t hr o u g h o ut st u d y treat me nt.  
W hile i n t his st u d y, p atie nts w h o prese nt wit h ri g ht u p per- q ua dra nt a b d o mi nal pai n a n d/ or 
u ne x plai ne d na usea or v o miti n g s h o ul d ha ve li ver f u ncti o n tests ( L F Ts) p erf or me d i m me diatel y 
a n d re vie w e d bef ore a d mi nistrati o n of t he ne xt d ose of st u d y dr u g.  
If L F Ts i n crease, c o n c urr e nt me dicati o ns, viral he patitis, a n d t o xic or ne o plastic eti ol o gies 
s h o ul d be c o nsidere d a n d a d dresse d, as  a p pr o priat e.  I m a gi n g of t he li ver, gall bla d der, a n d biliar y 
tree s h o ul d be perf or me d t o r ule o ut ne o plastic or ot her ca us es f or i ncreas e d L F Ts. A nti -n uclear 
a nti b o d y, peri n uclear a nti- ne utr o p hil c yt o pl as mic a nti b o d y, a nti- li ver ki dne y micr os o mal  

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 1 1 9  of 1 2 8  
 
a nti b o dies, a n d a nti −s m o ot h m uscle a nti b o d y tests s h o ul d be perf or m e d if a n a ut oi m m u ne 
eti ol o g y is c o nsi der e d.  
A p pe n di x T a ble 7 
M a n a ge me nt G ui deli nes f or He p atic E ve nts  
He p atic e ve nts  Se verit y  
M a n a ge me nt 
Gr a de 1  
•  C o nti n ue t hera p y  
•  C o nti n ue L F T m o nit ori n g  
Gr a de 2  
•  M o nit or L F Ts m ore fre q ue ntl y u ntil ret ur n t o bas eli ne 
val ues  
•  If persists ≥5- 7 da ys: wit h h ol d t hera p y a n d start 6 0 
m g pre d nis o n e or e q ui val e nt per da y; w h e n L F Ts are 
≤ G ra de 1, ta p er ster oi ds o ver ≥1 m o nt h, res u me 
t hera p y if t he e ve nt i m pr o ves t o Gra de 0 or Gra de 1 
wit hi n 1 2 wee ks a n d s yst e mic ster oi d d ose is ≤1 0 m g 
oral pre d nis o ne e q ui vale nt per da y 
Gr a de 3 a n d 4  
•  Disc o nti n ue t hera p y  
•  C o nsi der GI c o ns ult a n d li ver bi o ps y t o es ta blis h 
eti ol o g y of he p atic i nj ur y if necessar y  
•  Start 6 0 m g pre d nis o ne or e q ui vale nt per da y 
•  If L F T res ults d o n ot decrease wit hi n 4 8 h o urs aft er 
i nitiati o n of s yste mic ster oi ds, a d diti o n of a n 
alter nati ve i m m u n os u p pressi ve a ge nt (e. g., 
m yc o p h e n olate or T N F - α a nta g o nist) ma y be 
c o nsi dere d. 
•  Ta per ster oi ds o ver ≥ 1 m o nt h, w he n s y m pt o ms 
i m pr o ve t o Gra de 0 or 1  
•  C o ntact Me dical M o nit or if atez oliz u ma b is 
disc o nti n ue d 
GI = gastr oi ntesti n al; L F T = li ver f u n cti o n test; T N F-α = t u m or n ecr osis fa ct or al p h a. 
 
G a str oi nt e sti n al E v e nt s  
I m m u ne-me diate d  c olitis has bee n ass o ciate d wit h t he a d mi nistrati o n of atez oliz u ma b .  
If t he e v e nt is of si g nifica nt d urati o n or ma g nit u d e or is ass ociate d wit h si g ns of s yste mic 
i nfla m mati o n or ac ute p h ase reacta nts (e. g., i ncreased C-reacti ve pr otei n, pl atelet c o u nt , or 
ba n de mia), t he f oll o wi n g are r ec o m me n d e d : 
•  
Perf or m si g m oi d osc o p y ( or c ol o n osc o p y, if a p pr o priate) wit h c ol o nic bi o ps y wit h 3 t o 5 
s peci me ns f or sta n d ar d p araffi n bl oc k t o c hec k f or i nfla m mati o n a n d l y m p h oc ytic i nfiltrat es 
f or c o nfir m ati o n of t he dia g n osis of c olitis. If p ossi ble, o ne or t w o bi o ps y s peci me ns s h o ul d 
be s na p -fr oze n a n d st ore d.  
•  
Perf or m la b or at or y tests t o r ule o ut alter nat e eti ol o g y (i.e ., W B Cs a n d st o ol cal pr otecti n). 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 1 2 0  of 1 2 8  
 
A p pe n di x T a ble 8 
M a n a ge me nt G ui deli nes f or GI E ve nts ( Di arr h e a/ C olitis)  
GI E ve nts 
( Di arr he a/ C olitis) 
Se verit y  
M a n a ge me nt 
Gr a de 1 
di arr he a or 
c olitis 
•  
C o nti n ue t hera p y 
•  
S y m pt o matic treat me nt  
•  
E n d osc o p y is rec o m me n de d if s y m pt o ms persist f or 
greater t ha n 7 da ys.  
•  
Cl ose m o nit ori n g  
Gr a de 2 
di arr he a or 
Gr a de 2 c olitis  
•  
Wit h h ol d atez oliz u ma b  
•  
S y m pt o matic t hera p y  
•  
GI c o ns ultati o n rec o m me n de d  
•  
If persists  5 da ys or rec urs:  Pre d nis o ne 6 0 m g/ da y or 
e q ui vale nt 
•  
T a per  ster oi ds o ver  1 m o nth w he n s y m pt o ms 
i m pr o ve t o Gra de 0 or 1  
•  
Trea t me nt ma y be res u me d if t he e ve nt i m pr o ves t o 
Gra de 0 or 1 wit hi n 1 2 wee ks a n d c ortic oster oi ds ha ve 
bee n re d uce d t o t he e q ui vale nt of pre d nis o ne 1 0 m g P O 
dail y or less.  
Gr a de 3 
di arr he a or 
c olitis 
•  
Wit h h ol d atez oliz u ma b  
•  
GI referral a n d c o nfir mati o n bi o ps y  
•  
Treat wit h I V ster oi ds ( 1- 2 m g/ k g/ da y 
met h yl pre d nis ol o ne or e q ui vale nt) a n d c o n vert t o oral 
ster oi ds ( pre d nis o ne 6 0 m g/ da y or e q ui vale nt) after  
i m pr o ve me nt 
•  
W he n i m pr o ves t o Gra de 0 or 1 , t he n ta per ster oi ds 
o ver ≥ 1 m o nt h 
•  
Treat me nt ma y be  res u me d if t he e ve nt i m pr o ves t o 
G ra de 0 or 1 wit hi n 1 2 wee ks a n d c ortic oster oi ds ha ve 
bee n re d uce d t o t he e q ui vale nt of oral pre d nis o ne 1 0 
m g dail y or less.  
Gr a de 4 
di arr he a or 
c olitis 
•  
Disc o nti n ue atez oliz u ma b 
•  
GI referral a n d c o nfir mati o n bi o ps y 
•  
Treat wit h I V ster oi ds ( 1- 2 m g/ k g/ da y 
met h yl pre d nis ol o ne or e q ui vale nt) a n d c o n vert t o oral 
ster oi ds ( pre d nis o ne 6 0 m g/ da y or e q ui vale nt) o nce 
i m pr o ve me nt 
•  
W he n patie nt’s diarr hea or c olitis  i m pr o ves t o Gra de 0 
or 1, t he n ta per ster oi ds o ver ≥ 1 m o nt h 
•  
If n ot i m pr o vi n g after 4 8 h of i nitiati n g ster oi ds or 
w orse ni n g, a d diti o n of a n alter nati ve 
i m m u n os u p pressi ve a ge nt (e. g., m yc o p he n olate or 
T N F - α a nta g o nist) ma y be c o nsi dere d. 
•  
C o ntact me dical m o nit or if atez oliz u ma b is 
disc o nti n ue d. 
GI = gastr oi ntesti n al; P O = p er oral; T N F -α = t u m or n ecr osis fact or al p h a. 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 1 2 1  of 1 2 8  
 
E n d ocri ne E ve nts  
T h yr oi d dis or d ers or a dre nal i ns ufficie nc y h as bee n ass ociate d wit h t he a d mi nistrati o n of 
atez oliz u ma b .  
Patie nts wit h u ne x plai ne d s y m pt o ms s uc h as fati g ue, m yal gi as, i m p ote nce, me ntal stat us 
c ha n ges, or c o nsti pati o n s h o ul d be i n vesti gate d f or t he prese n ce of t h yr oi d, pit uitar y, or a dre n al 
e n d ocri n o pat hies, as well as f or h y p o natre mia or h y p er kale mia. A n  e n d ocri n ol o gist s h o ul d be 
c o ns ulte d if a n e n d o cri n o pat h y is s us pecte d. T S H  a n d free t h yr o xi ne ( T 4) l e vels s h o ul d be 
o btai ne d t o deter mi ne w h et her t h yr oi d a b n or m alities are prese nt.  T S H, pr ol acti n, a n d a m or ni n g 
c ortis ol le vel will hel p t o differe ntiat e pri mar y a dre nal i ns ufficie n c y fr o m pri mar y pit uitar y 
i ns ufficie nc y. 
A p pe n di x T a ble 9 
M a n a ge me nt G ui deli nes f or E n d ocri ne E ve nts  
E n d ocri ne 
E ve nts  
Se verit y  
M a n a ge me nt  
As y m pt o m atic 
h y p ot h yr oi dis m 
•  
C o nti n ue atez oliz u ma b  
•  
Start t h yr oi d re place me nt h or m o ne 
•  
M o nit or T S H wee kl y  
S y m pt o m atic 
h y p ot h yr oi dis m 
•  
Wit h h ol d atez oliz u ma b  
•  
Start t h yr oi d re place me nt h or m o ne 
•  
C o nsi der referral t o a n e n d ocri n ol o gist  
•  
Restart atez oliz u ma b w he n s y m pt o ms are c o ntr olle d b y 
t h yr oi d re place me nt a n d T S H le vels are decreasi n g 
As y m pt o m atic 
h y pert h yr oi dis m  
•  
If ser u m T S H  0. 5 m U/ L, re peat wit h free T 4 a n d T 3 t o 
dia g n ose as y m pt o matic h y pert h yr oi dis m  
•  
If c o nfir me d, a n d i n t he a bse nce of s y m pt o ms, c o nti n ue 
atez oliz u ma b a n d re peat tests i n 4 wee ks  
•  
If t h yr oi d val ues re mai n sta ble a n d patie nt is 
as y m pt o matic, f oll o w la b res ults m o nt hl y 
•  
H ol d a tez oliz u ma b if T S H ≤0. 1 m U/ L or if patie nt 
de vel o ps s y m pt o matic h y pert h yr oi dis m  
•  
C o nsi der referral t o a n e n d ocri n ol o gist a n d treat acc or di n g 
t o s y m pt o matic h y pert h yr oi dis m g ui deli nes 
S y m pt o m atic 
h y pert h yr oi dis m  
•  
Wit h h ol d atez oliz u ma b  
•  
Start met hi maz ole as nee de d  
•  
C o nsi der referral t o a n e n d ocri n ol o gist 
•  
Restart atez oliz u ma b w he n s y m pt o ms are c o ntr olle d b y 
t h yr oi d re place me nt  
•  
Per ma ne ntl y disc o nti n ue atez oliz u ma b f or life t hreate ni n g 
i m m u ne-me diate d  h y pert h yr oi dis m. 
 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 1 2 2  of 1 2 8  
 
E n d ocri ne 
E ve nts  (c o nt.) 
Se verit y  
M a n a ge me nt  
S y m pt o m atic  
p a n -
h y p o pit uit aris m 
a n d a n y Gr a de 
3- 4 e ve nts  
•  
Disc o nti n ue atez oliz u ma b. 
•  
E n d ocri n ol o gist c o ns ultati o n  
•  
Perf or m a p pr o priate i ma gi n g.  
•  
Treat wit h a n i nitial d ose of met h yl pre d nis ol o ne 1 −2 m g/ k g 
per da y I V f oll o we d b y oral pre d nis o ne 1 −2 m g/ k g per da y. 
•  
Start ster oi d ta per w he n s y m pt o ms i m pr o ve t o Gra de 0 or 
Gra de 1. Ta per o ver >  1 m o nt h. 
•  
Patie nts wit h u ne x plai ne d s y m pt o ms s uc h as fati g ue, 
m yal gia, i m p ote nce, me ntal stat us c ha n ges, or c o nsti pati o n 
s h o ul d be i n vesti gate d f or t he prese nce of t h yr oi d, pit uitar y, 
or a dre nal e n d ocri n o pat h y as well as f or h y p o natre mia or 
h y per kale mia. A n e n d ocri n ol o gist s h o ul d be c o ns ulte d if a 
s y m pt o matic e n d ocri n o pat h y is s us pecte d. T S H a n d free T 4 
le vels s h o ul d be o btai ne d t o deter mi ne w het her t h yr oi d 
a b n or malities are prese nt. T S H , pr olacti n, a n d a m or ni n g 
c ortis ol le vel will hel p t o differe ntiate pri mar y a dre nal 
i ns ufficie nc y fr o m pri mar y pit uitar y i ns ufficie nc y. 
•  
C o ntact t he Me dical M o nit or if atez oliz u ma b is 
disc o nti n ue d.  
T 4 = t h yr o xi n e; T S H= t h yr oi d sti m ul ati n g h or m o n e. 
Oc ul ar E ve nts  
A n o p ht hal m ol o gist s h o ul d e val uate vis ual c o m plai nts. U veitis or e piscleritis ma y be treat e d wit h 
t o pical c ortic oster oi d e ye dr o ps. Atez oliz u ma b  s h o ul d be per ma ne ntl y disc o nti n ue d f or i m m u ne-
me diate d oc ular dis ease t hat is u nres p o nsi ve t o l ocal i m m u n os u p pressi ve t hera p y. 
A p pe n di x T a ble 1 0 
M a n a ge me nt G ui deli nes f or Oc ul ar  E ve nts  
E ye E ve nts  
Se verit y  
M a n a ge me nt 
Gr a de s 1 -2  
•  
E val uati o n b y a n o p ht hal m ol o gist is str o n gl y rec o m me n de d 
•  
Treat wit h t o pical c ortic oster oi d e ye dr o ps 
•  
Disc o nti n ue atez oliz u ma b if s y m pt o ms persist des pite 
treat me nt wit h t o pical i m m u n os u p pressi ve t hera p y 
•  
T o pical i m m u n os u p pressi ve t hera p y.  
•  
C o ntact t he Me dical M o nit or if atez oliz u ma b is 
disc o nti n ue d 
Gr a de 3 - 4 
•  
Disc o nti n ue treat me nt  
•  
Start 6 0 m g pre d nis o ne or e q ui vale nt per da y.  
•  
T a per  ster oi ds o ver  1 m o nth o nce s y m pt o ms i m pr o ve t o 
Gra de 0 or 1 
•  
C o nta ct t he Me dical M o nit or if atez oliz u ma b is 
disc o nti n ue d  
 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 1 2 3  of 1 2 8  
 
I nf usi o n-Rel ate d Re acti o ns  
N o pre me dicati o n is i n dicate d f or t he a d mi nistrati o n of atez oliz u ma b  i n C ycle 1 . Patie nts w h o 
e x perie nce a n i nf usi o n-relate d reacti o n (I R R) wit h C ycle 1 of atez oliz u ma b ma y recei ve 
pre me dicati o n wit h a nti hista mi nes or a nti p yretics/a nal gesics (e. g. aceta mi n o p he n) f or s u bs e q ue nt 
i nf usi o ns. 
A p pe n di x T a ble 1 1 
M a n a ge me nt G ui deli nes f or I nf usi o n-Rel ate d Re acti o ns  
I nf usi o n 
Re acti o ns 
Se verit y  
M a n a ge me nt 
Gr a de 1  
•  
Re d uce i nf usi o n rate t o half t he rate bei n g gi ve n at t he ti me 
of e ve nt o nset. 
•  
After  t he e ve nt has res ol ve d, t he i n vesti gat or s h o ul d wait 
f or 3 0 mi n utes w hile deli veri n g t he i nf usi o n at t he re d uce d 
rate 
•  
If t olerate d, t he i nf usi o n rate ma y t he n be i ncrease d t o 
ori gi nal rate  
Gr a de 2  
•  
I nterr u pt atez oliz u ma b i nf usi o n 
•  
A d mi nister a g gressi ve s y m pt o matic treat me nt.  
•  
Restart o nl y after t he s y m pt o ms ha ve a de q uatel y res ol ve d 
t o baseli ne gra de 
•  
T he i nf usi o n rate at restart s h o ul d be half of t he i nf usi o n 
rate t hat was i n pr o gress at t he ti me of t he o nset of t he I R R 
•  
At ne xt c ycle, a d mi nister oral pre me dicati o n wit h 
a nti hista mi ne a n d a nti- p yretic a n d m o nit or cl osel y f or 
i nf usi o n reacti o n  
Gr a de s 3 - 4 
•  
St o p i nf usi o n 
•  
Pr o per me dical ma na ge me nt w hic h ma y i ncl u de oral or I V 
a nti hista mi ne, a nti -p yretic, gl uc oc ortic oi ds, e pi ne p hri ne, 
br o nc h o dilat ors, a n d o x y ge n 
•  
Disc o nti n ue atez oliz u ma b 
•  
C o ntact t he Me dical M o nit or, if atez oliz u ma b is 
disc o nti n ue d.  
I R R =  i nf usi o n-relate d reacti o ns. 
 
P a ncre atic E ve nts 
S y m pt o ms of a b d o mi nal pai n ass ociate d wit h el e v ati o ns of a m yl ase a n d li p ase, s u g gesti ve of 
pa ncreatitis, ha ve bee n ass ociate d wit h t he a d mi nistrati o n of ot her i m m u n o- m o d ulat or y a ge nts. 
T he differe ntial dia g n osis of ac ute a b d o mi nal pai n s h o ul d i ncl u de pa ncreatitis.  A p pr o priate 
w or k - u p s h o ul d i ncl u de a n e val uati o n f or o bstr u cti o n, as well as ser u m a m ylase a n d li pase tests. 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 1 2 4  of 1 2 8  
 
A p pe n di x T a ble 1 2 
M a n a ge me nt G ui deli nes f or P a ncre atitis  
P a ncre atic 
e ve nts 
Se verit y  
M a n a ge me nt 
Gr a de 1 
a m yl ase/li p ase 
ele v ati o n 
•  C o nti n ue atez oliz u ma b 
•  M o nit or a m ylase/li pase le vels pri or t o d osi n g  
Gr a de 2 
a m yl ase/li p ase 
ele v ati o n 
•  C o nti n ue atez oliz u ma b 
•  M o nit or a m ylase/li pase wee kl y  
•  C o nsi der pre d nis o ne 1 0 m g P O dail y or e q ui vale nt f or 
pr ol o n ge d ele vati o n (e. g., m ore t ha n 3 wee ks) 
Gr a de 3 a n d 4 
a m yl ase/li p ase 
ele v ati o n 
•  Wit h h ol d atez oliz u ma b 
•  C o ns ult a gastr oe nter ol o gist 
•  M o nit or a m ylase/li pase e ver y ot her da y a n d c o nsi der oral 
pre d nis o ne 6 0 m g dail y or e q ui vale nt if n o i m pr o ve me nt 
•  W he n la b a b n or malities ret ur n t o Gra de 0 or 1 , t he n ta per 
ster oi ds o ver ≥ 1 m o nt h 
•  Atez oliz u ma b ma y be res u me d if t he e ve nt res ol ves t o 
Gra de 0 or 1 wit hi n 1 2 wee ks a n d c ortic oster oi ds ha ve bee n 
re d uce d t o t he e q ui vale nt of oral pre d nis o ne 1 0 m g dail y or 
less 
•  Per ma ne ntl y disc o nti n ue atez oliz u ma b f or rec urre nt Gra de 
3 or 4 a m ylase/li pase ele vati o ns  
A ut oi m m u ne 
p a ncre atitis 
( a b d o mi n al 
p ai n a n d r aise d 
a m yl ase/li p ase 
le vels) 
 
•  Wit h h ol d atez oliz u ma b 
•  C o ns ult a gastr oe nter ol o gist. 
•  A d mi nister I V ster oi ds ( pre d nis o ne e q ui vale nt of 6 0 
m g/ da y) a n d c o n vert t o oral ster oi ds w he n s y m pt o ms 
i m pr o ve 
•  W he n s y m pt o ms a n d la b a b n or malities i m pr o ve t o Gra de 0 
or 1 , t he n ta per ster oi ds o ver 
 1 m o nt h 
•  Atez oliz u ma b ma y be res u me d if t he e ve nt i m pr o ves t o 
Gra de 0 or 1 wit hi n 1 2 wee ks a n d c ortic oster oi ds ha ve bee n 
re d uce d t o t he e q ui vale nt of pre d nis o ne 1 0 m g P O  dail y or 
less 
•  Per ma ne ntl y disc o nti n ue atez oliz u ma b f or life t hreate ni n g 
i m m u ne-me diate d  pa ncreatitis or rec urre nt pa ncreatitis  
 
Der m at ol o gic E ve nts  
Treat me nt -e mer ge nt ras h has bee n ass o ciate d wit h atez oliz u ma b . T he maj orit y of cases of ras h 
were mil d i n se verit y a n d self -li mite d, wit h or wit h o ut pr urit us. A der mat ol o gist s h o ul d e val uate 
persiste nt a n d/ or se vere r as h or pr urit us. A bi o ps y s h o ul d be c o nsi dere d u nl ess c o ntrai n dicat e d.  

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 1 2 5  of 1 2 8  
 
A p pe n di x T a ble 1 3 
M a n a ge me nt G ui deli nes f or Der m at ol o gic E ve nts 
Der m at ol o gic 
e ve nts 
Se verit y  
M a n a ge me nt 
Gr a de 1  
•  
C o nti n ue atez oliz u ma b 
•  
S y m pt o matic t hera p y wit h a nti hista mi ne as nee de d. 
•  
C o nsi der t o pical ster oi ds a n d/ or ot her s y m pt o matic 
t hera p y (e. g., a nti hista mi nes) 
Gr a de 2  
•  
C o nti n ue atez oliz u ma b 
•  
C o nsi der der mat ol o gist referral.  
•  
A d mi nister t o pical ster oi ds.  
•  
C o nsi der hi g her p ote nc y t o pical ster oi ds if ras h 
u nres ol ve d.  
Gr a de 3  
•  
Wit h h ol d atez oliz u ma b 
•  
C o ns ult a der mat ol o gist 
•  
A d mi nister oral pre d nis o ne 1 0 m g or e q ui vale nt. If ras h 
u nres ol ve d after 4 8- 7 2 h o urs, a d mi nister oral pre d nis o ne 
6 0 m g or e q ui vale nt. 
•  
Restart atez oliz u ma b if ras h res ol ve d a n d s yste mic d ose 
is ≤ 1 0 m g oral pre d nis o ne or e q ui vale nt per da y 
Gr a de 4  
•  
Per ma ne ntl y disc o nti n ue atez oliz u ma b f or life-
t hreate ni n g i m m u ne-me di ate d der mat ol o gic t o xicities 
•  
C o ntact t he Me dical M o nit or if atez oliz u ma b is 
disc o nti n ue d 
 
Ne ur ol o gic Dis or ders  
M yast he ni a gra vis a n d G uillai n -Barr é s y n dr o me h a ve bee n o bser v e d wit h si n gle a ge nt 
atez oliz u ma b.  Patie nts ma y prese nt wit h si g ns a n d s y m pt o ms of se ns or y a n d/ or m ot or 
ne ur o pat h y. Dia g n ostic w or k- u p is esse ntial f or a n acc urate c h aracterizati o n t o differe ntiate 
bet wee n alter nate eti ol o gies.  

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 1 2 6  of 1 2 8  
 
A p pe n di x T a ble 1 4 
M a n a ge me nt G ui deli nes f or Ne ur ol o gic Dis or ders  
A ut oi m m u ne 
Ne ur o p at h y  
Se verit y  
M a n a ge me nt 
Gr a de 1  
•  
C o nti n ue atez oliz u ma b 
•  
E val uate f or alter nate ca uses  
Gr a de 2  
•  
Wit h h ol d atez oliz u ma b 
•  
E val uate f or alter nate ca uses  
•  
Treat me nt s h o ul d be as per i nstit uti o nal g ui deli nes 
Gr a de 3 -4  
•  
Per ma ne ntl y disc o nti n ue atez oliz u ma b f or life-
t hreate ni n g i m m u ne-me di ate d ne ur o pat h y 
•  
Per ma ne ntl y disc o nti n ue atez oliz u ma b f or m yast he nia 
g ra vis or G uillai n-Barr é (all gra des) 
•  
Treat me nt s h o ul d be as per i nstit uti o nal g ui deli nes 
•  
C o ntact t he Me dical M o nit or if atez oliz u ma b is 
disc o nti n ue d. 
M y ast he ni a g r a vis 
a n d G uill ai n -
B arr é 
All Gr a des  
•  
Per ma ne ntl y disc o nti n ue atez oliz u ma b f or m yast he nia 
gra vis or G uillai n -Barré  (all gra des) 
•  
Treat me nt s h o ul d be as per i nstit uti o nal g ui deli nes 
 
S yste mic I m m u ne Acti v ati o n  
S yste mic i m m u ne acti vati o n ( SI A) is a rare c o n diti o n c haracterize d b y  a n e x cessi ve i m m u ne 
res p o nse. Gi ve n t h e mec ha nis m of acti o n of atez oliz u ma b, SI A is c o nsi dere d a p ote ntial ris k 
w he n gi ve n i n c o m bi nati o n wit h ot her i m m u n o m o d ulati n g a ge nts. SI A s h o ul d be i ncl u de d i n t he 
differe ntial dia g n osis f or patie nts w h o, i n t he a bse nce of a n alter n ate eti ol o g y, de v el o p a se psis-
li ke s y n dr o me after a d mi nistrati o n of atez oliz u ma b. 
Rec o m me n dati o ns re gar di n g earl y i de ntificati o n a n d ma na ge m e nt of SI A are pr o vi d e d bel o w.  I n 
t he e ve nt of s us pecte d SI A, t he Me dical M o nit or s h o ul d be c o ntacte d i m me diatel y f or a d diti o nal 
g ui da n ce.  
Earl y disease rec o g niti o n is critical, a n d t he cli nici a n  s h o ul d c o nsi der SI A if, i n t he a bse nce of 
alter nate eti ol o gies, t he prese nce of ≥ 2 of t he f oll o wi n g are prese nt: 
•  
H y p ote nsi o n r efr act or y t o a g gressi ve I V fl ui d c halle n ge 
Ma y/ca n r e q uire vas o press or s u p p ort 
•  
Res pirat or y distress re q uiri n g a g gressi ve s u p p ort i v e care 
S u p ple me ntal o x y ge n, p ossi ble i nt u bati o n 
•  
Fe ver greater t ha n 3 8. 5 °C 
•  
Ac ute re n al or he p atic fail ure  
•  
Blee di n g fr o m c oa g ul o pat h y 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 1 2 7  of 1 2 8  
 
•  
U ne x plai ne d la b orat or y a b n or malities (c ha n ge fr o m baseli ne):  
C yt o pe nias ( ≥ Gr a de 2 i n t w o or m ore li nea ges), si g nifica nt tra nsa mi nitis, c oa g ul o p at h y, 
ele vate d creati ni ne  
 
I nitial e v al uati o n s h o ul d i ncl u de C B C wit h peri p h eral s mear, P T, P T T, fi bri n o ge n, D- di mer, 
ferriti n, tri gl yceri d e, A S T/ A L T, t otal bilir u bi n, L D H, a n d a c o m plete ne ur ol o gic a n d a b d o mi nal 
e x a mi nati o n (assess f or h e pat os ple n o me gal y). 
If c yt o pe nias (≥ 2 li nea ges a n d c ha n ge fr o m bas eli ne) are pres e nt or ferriti n is  ≥ 3 0 0 0 n g/ m L, t he 
f oll o wi n g e v al uati o ns s h o ul d als o be perf or me d: 
•  
B o ne marr o w bi o ps y/as pirate (ass ess f or e vi d e nce of he m o p ha g oc yt osis) 
•  
s C D 2 5 (s ol u ble I L- 2 rece pt or) 
•  
Nat ural killer cell acti vit y  
•  
C yt o m e gal o vir us, E pstei n- Barr vir us a n d h er p es -si m ple x vir us e val uati o n (e val uate f or 
reacti vat e d or acti ve disease) 
 
SI A is a cli nical s y n dr o m e c har acterize d b y t he f oll o wi n g:  
•  
O nset great er t ha n 2 4 h o urs after e x p os ure t o dr u g A N D  
•  
Pr o gr essi ve cli nical det eri orati o n i n a n ac utel y ill patie nt (i n t he a bse n ce of a n alter nat e 
eti ol o g y) A N D  
•  
I n v ol vi n g m ulti ple or ga ns (≥ 2) A N D  
•  
De m o nstrati n g s p ecific l a b a b n or malities  
 
Dia g n osis of SI A s h o ul d o nl y be ma d e i n patie nts w h o prese nt wit h a c o nstellati o n of cli nical 
fi n di n gs as o utli ne d a b o v e a n d w h o f ulfill t he f oll o wi n g est a blis he d dia g n ostic criteria i n t he 
a bse nce of a n alter nate eti ol o g y.  T he dia g n ostic criteria a n d rec o m me n de d ma na ge me nt f o r 
s yste mic i mm u ne acti vati o n are pr o vi d e d i n  A p pe n di x Ta ble 1 5. 

I m m u ne Desi g n 
C M B 3 0 5 ( L V 3 0 5 a n d G 3 0 5) a n d Atez oliz u m a b  
Pr ot oc ol I M D Z -C 2 3 2; Versi o n 0 3 , Rele ase D ate 0 8 M ar 2 0 1 7  
 
C L O -5 1. 0 0 2 V 0 3  
P a ge 1 2 8  of 1 2 8  
 
A p pe n di x T a ble 1 5  Di a g n ostic Criteri a a n d M a n a ge me nt f or S yste mic I m m u ne 
Acti v ati o n 
SI A Criteri a a p pl y o nl y w he n alter n ate eti ol o gies h a ve bee n e xcl u de d  
M aj or criteri a  
Mi n or criteri a  
•  Fe ver ≥3 8. 5 °C ( o n m ore t ha n o ne occasi o n) 
•  Ferriti n > 3 0 0 0 n g/ m L 
•  C yt o pe nias ≥Gra de 2 i n t w o or m ore li nea ges 
•  ≥2 a ge -a dj uste d S D ele vati o n s ol u ble I L - 2 
rece pt or 
•  Se vere m ulti - or ga n d ysf u ncti o n 
•  Decrease d  fi bri n o ge n 
•  S ple n o me gal y  
•  He m o p ha g oc yt osis 
 
B M, s plee n or L N  
•  Ele vate d G G T or L F Ts ( A S T/ A L T/t Bili)  
•  Ele vate d tri gl yceri des  
•  Ele vate d L D H  
•  Decrease d nat ural killer -cell acti vit y 
St at us  
# of Criteri a  
M a n a ge me nt 
C o nsiste nt 
wit h  SI A  
 
4 maj or criteria  
 
C o nsi der t ociliz u ma b ( 4 m g/ k g I V) a n d S ol u me dr ol  ( 1 g I V Q D).  
C o ntact t he Me dical M o nit or f or a d diti o nal rec o m me n dati o ns.  
C o nsi der H L H- 9 4 pr ot oc ol if n o cli nical i m pr o ve me nt. 
P r o b a ble 
SI A  
 
3 maj or criteria  
O R  
2 maj or criteria  
A N D  
3 mi n or criteria 
De pe n di n g o n cli nical se verit y, patie nt ca n be treate d as per 
“ C o nsiste nt wit h SI A” or “ P ossi ble SI A” case defi niti o n.  
C o ntact me dical m o nit or f or a d diti o nal rec o m me n dati o ns 
P ossi ble SI A  
 
1 maj or criteria  
A N D  
4 mi n or criteria 
C o nsi der S ol u me dr ol  ( 1 g I V Q D) 
C o ntact t he Me dical M o nit or f or a d diti o nal rec o m me n dati o ns. 
As per “ C o nsiste nt wit h SI A” rec o m me n dati o ns if n o i m pr o ve me nt 
or cli nicall y w orse ni n g  
B M = b o ne marr o w; G G T = ga m ma -gl uta m yl tra ns p e pti d ase; I L -2 = i nterle u ki n-2; L F T = li ver f u n cti o n test; L N= l y m p h n o d e; 
SI A = s yste mi c i m m u n e acti vati on; I V = i ntra ve n o us; Q D= o n ce a d a y.  t Bili =  t otal bilir u bi n. 
T he criteria w here a d a pte d fr o m a Del p hi S ur ve y of 2 6 e x p erts re gar di n g h el pf ul criteria i n t h e p ositi ve dia g n osis of 
He m o p ha g oc ytic S y n dr o me i n a d ult p atie nts. 4 0 Sta n d ar d of care f or  SI A h as n ot b ee n esta blis h e d. Case re p orts a n d 
rec o m me n dati o ns h a ve b ee n p u blis h e d f or c yt o ki n e release s y n dr o me 4 1 , 4 2 , 4 3 b ase d o n eti ol o gic si milarities , t h ese practices 
ha ve bee n i nc or p orate d i nt o t h e  a b o ve treat me nt rec o m me n d ati o ns. H o we v er, t h ese rec o m me n d ati o ns d o n ot re place cli nical 
j u d g me nt a n d are i nte n d e d as s u g geste d g ui d a n ce o nl y.