Anti PD-L1 (Atezolizumab) as an Immune Primer and Concurrently With Extended Field Chemoradiotherapy for Node Positive Locally Advanced Cervical Cancer
Phase: PHASE1
Conditions: Cervical Adenocarcinoma, Cervical Adenosquamous Carcinoma, Cervical Squamous Cell Carcinoma, Stage IB2 Cervical Cancer AJCC v8, Stage II Cervical Cancer AJCC v8, Stage IIA Cervical Cancer AJCC v8, Stage IIA1 Cervical Cancer AJCC v8, Stage IIA2 Cervical Cancer AJCC v8, Stage IIB Cervical Cancer AJCC v8, Stage IIIB Cervical Cancer AJCC v8, Stage IVA Cervical Cancer AJCC v8
Sponsor: National Cancer Institute (NCI)

Offi ci al  Titl e:   A nti   P  D  -L 1 (  At e z oli z u  m a b)  a s  a n I  m  m u n e   Pri  m er  a n d 
C o n c urr e ntl y   wit h   E xt e n d e d  Fi el d   C h e  m or a di ot h er a p y f or   N o d e 
P o siti v e  L o c all y   A d v a n c e d   C er vi c al   C a n c er  
N  C T   N u  m b er:     N  C T  0 3 7 3 8 2 2 8  
D o c u  m e nt   D at e:     Pr ot o c ol   A  m e n d  m e nt    1: 0 8 -N o v e  m b er  -2 0 1 8  
 
 

 
i 
 
 
 
 
F or pr ot oc ol A m e n d me nt # 1:  
 
N CI Pr ot oc ol # N R G -G Y 0 1 7  
 
N CI Versi o n Dat e: N o ve m ber 8 , 2 0 1 8 
 
Secti o n  
C o m me nts  
Title p a ge  N CI Versi o n date has bee n u p date d.  
Versi o n date f or A me n d me nt # 1 has bee n a d de d.  
Title p a ge  T he i nstit uti o n c o de f or U C S D has bee n a d de d.  
T w o a d diti o nal P hase I sites ha ve bee n a d de d t o t he r oster, U T -S o ut h wester n a n d 
U ni versit y of Ala ba ma.  
N C T 0 3 7 3 8 2 2 8 has bee n a d de d.  
1 3. 9    
T he n u m ber of e x pect e d His pa nic or lati n o fe males o n t he d o mestic pla n ne d 
e nr oll me nt re p ort has b ee n c orrecte d fr o m 8 t o 1 0.  
I C D   
N CI Versi o n date a n d N C T # ha ve  bee n u p date d.  
 

 
3  
 
N R G O nc ol o g y P artici p ati n g I nstit uti o ns  
P A 0 7 5    
A bra ms o n Ca ncer Ce nter at t he U ni versit y of Pe n ns yl va nia  
A Z 1 5 1    
Ariz o na Ca n cer Ce nt er  
O H 0 2 7    
Cle vela n d Cli nic F o u n dati o n  
P A 0 8 6    
F o x C hase Ca n cer Ce nter  
M D 0 1 7    
J o h ns H o p ki ns U ni versit y/ Si d ne y Ki m mel Ca ncer Ce nter 
G A 0 2 0    
Ge or gia Re g e nts U ni versit y  
C T 0 0 9    
Hartf or d H os pital  
T X 0 3 5    
M. D. A n ders o n Ca ncer Ce nter  
N Y 0 1 6    
Me m orial Sl oa n Ketteri n g Ca ncer Ce nter  
WI 0 1 3    
Fr oe dtert a n d t he Me di cal C olle ge of Wisc o nsi n  
O H 0 0 7    
O hi o State U ni versit y  
O K 0 0 3    
O kla h o ma U ni versit y  
N Y 1 5 8    
R os well Par k Ca ncer I nstit ute  
P A 1 2 1    
T h o mas Jeffers o n U ni versit y  
C A 1 8 9    
U C Da vis Me dical Ce nter  
C A 0 8 8  
C A 0 2 4 9  
U ni versit y of Calif or nia Me dical Ce nter at Ir vi ne -Ora n ge Ca m p us  
U ni versit y of Calif or nia Sa n Die g o Me dical Ce nt er  
O H 2 7 4    
U H H S –  C ha gri n Hi g hla n ds Me dical Ce nter  
I L 0 5 7   
U ni versit y of C hica g o  
C O 0 7 0    
U ni versit y of C ol ora d o Ca ncer Ce nter  
O H 0 2 9    
Case Wester n Reser ve U ni versit y  
I A 0 1 8   
U ni versit y of I o wa H os pitals a n d Cli nics  
P A 0 1 5    
U ni versit y of Pitts b ur g h Ca ncer Ce nter  
V A 0 0 9    
U ni versit y of Vir gi nia Healt h S yste ms  
V A 0 1 0    
Vir gi nia C o m m o n wealt h U ni versit y  
M O 0 1 1    
Was hi n gt o n U ni versit y Sc h o ol of Me dici ne  
RI 0 1 2    
W o me n’s a n d I nfa nts H os pital  
T X 0 1 1    
U ni versit y of Te xas –  S o ut h wester n  
A L 0 0 2    
U ni versit y of Ala ba ma  
 
Pr ot oc ol A ge nts  
A ge nt    
S u p pl y    
N S C #    
I N D #   
I N D 
S p o ns or  
Atez oliz u ma b 
( M P D L 3 2 8 0 A) 
C T E P/ P M B  
7 8 3 6 0 8    
 
 
 
D C T D, 
N CI  
Cis plati n    
C o m mercial  
1 1 9 8 7 5  
 
P artici p ati n g Sites  
U. S.  
 Ca na da  
 A p pr o ve d I nter nati o nal Me m ber Sites  

 
4  
 
 
D oc u m e nt Hist or y  
 
Versi o n D ate  
 
M o nt h, D a y, Ye ar  
 
 
 
 
 
 
A me n d me nt 1  
N o ve m ber 8 , 2 0 1 8 
Acti vati o n  
Oct o ber 2 6, 2 0 1 8  
Pre -Acti vati o n    
 
 
T his pr ot oc ol w as desi g ne d a n d de vel o pe d b y N R G O nc ol o g y. It is i nte n de d 
t o be use d o nl y i n c o nj u ncti o n wit h i nstit uti o n-s pecific I R B a p pr o v al f or 
st u d y e ntr y.  N o ot her use or re pr o d ucti o n is a ut h orize d b y N R G O nc ol o g y 
n or d oes N R G  O nc ol o g y  ass u me a n y res p o nsi bilit y f or u n a ut h orize d use of 
t his pr ot oc ol. 

 
N R G -G Y 0 1 7  
5    
Versi o n Date:  N o ve m ber 8 , 2 0 1 8 
N R G O N C O L O G Y  
N R G G Y 0 1 7  
A nti P D -L 1 ( Atez oliz u m a b) as a n I m m u ne Pri mer a n d C o nc urre ntl y wit h E xte n de d Fiel d 
C he m or a di ot her a p y f or N o de P ositi ve L oc all y A d v a nce d Cer vic al C a n cer  
 
C O N T A C T I N F O R M A TI O N  
 
F or re g ul at or y re q uire me nts : 
F or p atie nt e nr oll me nts:   
F or  st u d y d at a s u b missi o n: 
Re g ulat or y d oc u me ntati o n m ust 
be s u b mitte d t o t he C T S U via 
t he Re g ulat or y S u b missi o n 
P ortal:  
 
Re g ulat or y S u b missi o n P ortal 
( Si g n i n at w w w.cts u. or g ,            
a n d select t he Re g ulat or y 
S u b missi o n s u b -ta b u n der t he 
Re g ulat or y ta b.)   
 
I nstit uti o ns wit h patie nts 
waiti n g t hat are u na ble t o use 
t he P ortal s h o ul d alert t he 
C T S U Re g ulat or y Office 
i m me diatel y at 1-8 6 6 -6 5 1 -2 8 7 8 
t o recei ve f urt her i nstr ucti o n 
a n d s u p p ort. 
 
C o ntact t he C T S U Re g ulat or y 
Hel p Des k at 1 -8 6 6 -6 5 1 -2 8 7 8 
f or re g ulat or y assista nce. 
Please refer t o t he patie nt 
e nr oll me nt secti o n of t he pr ot oc ol 
f or i nstr ucti o ns o n usi n g t he 
O nc ol o g y Patie nt E nr oll me nt 
Net w or k ( O P E N) w hic h ca n be 
accesse d at 
htt ps:// w w w.cts u. or g/ O P E N S Y S
T E M/  or htt ps:// O P E N.cts u. or g . 
 
C o ntact t he C T S U Hel p Des k 
wit h a n y O P E N -relate d q uesti o ns 
at cts uc o ntact @ westat.c o m . 
 
 
Data c ollecti o n f or t his st u d y 
will be d o ne e xcl usi vel y t hr o u g h 
Me di data Ra ve.  Please see t he  
data s u b missi o n secti o n of t he 
pr ot oc ol f or f urt her i nstr ucti o ns.  
 
 
T he  m ost c urre nt versi o n of t he st u d y pr ot oc ol a n d all s u p p orti n g d oc u me nts  m ust be d o w nl oa de d 
fr o m t he pr ot oc ol-s pecific We b pa ge of t he C T S U Me m ber We b site l ocate d at htt ps:// w w w.cts u. or g .  
Access t o t he C T S U me m bers’ we b site is ma na ge d t hr o u g h t he Ca ncer T hera p y a n d E val uati o n Pr o gra m 
- I de ntit y a n d Access Ma na ge me nt ( C T E P-I A M) re gistrati o n s yste m a n d re q uires user l o g o n wit h 
C T E P -I A M user na me a n d pass w or d. Per missi o n t o vie w a n d d o w nl oa d t his pr ot oc o l a n d its s u p p orti n g 
d oc u me nts is restricte d a n d is base d o n pers o n a n d site r oster  assi g n me nt h o use d i n t he C T S U R S S.    
F or cli nic al q uesti o ns (i.e. p atie nt eli gi bilit y or tre at me nt -rel ate d) c o ntact t he St u d y PI of t he Lea d 
Pr ot oc ol Or ga nizati o n.  
F or n o n -cli nic al q uesti o ns (i.e. u nrel ate d t o p atie nt eli gi bilit y, tre at me nt, or cli nic al d at a 
s u b missi o n) c o ntact t he C T S U Hel p Des k b y p h o ne or e -mail:   
C T S U Ge neral I nf or mati o n Li ne –  1 -8 8 8 -8 2 3 -5 9 2 3, or cts uc o ntact @ westat.c o m .  All calls a n d 
c orres p o n de nce will be tria ge d t o t he a p pr o priate C T S U re prese ntati ve.  
T he C T S U We b site is l oc ate d at htt ps:// w w w.cts u. or g . 

 
N R G -G Y 0 1 7  
6    
Versi o n Date:  N o ve m ber 8 , 2 0 1 8 
T A B L E O F C O N T E N T S  
1.  
O BJ E C TI V E S  ......................................................................................................................9  
 
Pri mar y O bjecti ve  ....................................................................................................9  
 
Sec o n dar y O bj ecti ves ...............................................................................................9  
 
E x pl orat or y O bjecti ves  ............................................................................................9  
2.  
B A C K G R O U N D  .................................................................................................................9  
 
Cer vical Ca ncer Bac k gr o u n d  ...................................................................................9  
 
I m m u n ol o g y of H P V I nfecti o n a n d Cer vical Ca ncer ............................................1 0  
 
Cli nical Safet y Data  ...............................................................................................1 1  
 
Rati o nale f or E xte n de d Fiel d I nte nsit y M o d ulate d Ra diati o n T hera p y  .................1 1  
 
Rati o nale f or I ma ge G ui de d Brac h yt hera p y (I G B T)  .............................................1 2  
 
Rati o nale f or t he P E T i ma gi n g p ost treat me nt as e x pl orat or y e n d p oi nt  ................1 2  
3.  
P A TI E N T S E L E C TI O N, E LI GI BI LI T Y, A N D I N E LI GI BI LI T Y C RI T E RI A  ................1 2  
 
Patie nt Selecti o n G ui deli nes  ..................................................................................1 2  
 
Eli gi bilit y Criteria  ..................................................................................................1 3  
 
I n eli gi bilit y Criteria ...............................................................................................1 4  
4.  
R E Q UI R E M E N T S F O R S T U D Y E N T R Y, T R E A T M E N T, A N D F O L L O W -U P  ..........1 8  
 
P R E -T R E A T M E N T A S S E S S M E N T S  ..................................................................1 8  
 
A S S E S S M E N T S D U RI N G T R E A T M E N T  ..........................................................1 9  
 
A S S E S S M E N T S I N F O L L O W U P  .......................................................................1 9  
 
St u d y Cale n dar  .......................................................................................................2 0  
5.  
T R E A T M E N T P L A N/ Re gi me n descri pti o n ......................................................................2 1  
5. 1  
C he m ot hera p y  ........................................................................................................2 4  
5. 2  
Ra diati o n T hera p y  ..................................................................................................2 6  
5. 3  
I ma gi n g ..................................................................................................................4 1  
5. 4  
I nte gral Assa y/ Bi o mar ker ......................................................................................4 2  
5. 5  
Ge neral C o nc o mita nt Me dicati o n a n d S u p p orti ve Care G ui deli nes  ......................4 2  
5. 6  
D urati o n of T hera p y  ...............................................................................................4 3  
5. 7  
D ose Li miti n g T o xicit y  ..........................................................................................4 4  
6. T R E A T M E N T M O DI FI C A TI O N S/ ma na g E me nt .....................................................................4 6  
6. 1  
Cis plati n D ose M o dificati o ns  ................................................................................4 6  
6. 2  
Atez oliz u ma b D ose M o dificati o n a n d T o xicit y Ma na ge me nt G ui deli nes  ............4 8  
6. 3  
Ra diati o n T hera p y D ose Deli ver y M o dificati o ns  ..................................................6 3  
7.  
A D V E R S E E V E N T S R E P O R TI N G R E Q UI R E M E N T S  .................................................6 4  
7. 1  
Pr ot oc ol A ge nts  ......................................................................................................6 4  
7. 2  
A d verse E ve nts a n d Seri o us A d verse E ve nts  ........................................................6 4  
7. 3  
C o m pre he nsi ve A d verse E ve nts a n d P ote ntial Ris ks ( C A E P R) List .....................6 5  
7. 4  
A d verse E ve nts f or C o m mercial St u d y A ge nts  .....................................................6 9  
7. 5  
A d verse E ve nt C haracteristics  ...............................................................................6 9  
7. 6  
E x pe dite d Re p orti n g of A d verse E ve nts  ................................................................7 0  

 
N R G -G Y 0 1 7  
7    
Versi o n Date:  N o ve m ber 8 , 2 0 1 8 
8.  
R E GI S T R A TI O N A N D S T U D Y E N T R Y P R O C E D U R E S  .............................................7 3  
8. 1  
C T E P Re gistrati o n Pr oce d ures  ..............................................................................7 3  
8. 2  
C T S U Re gistrati o n Pr oce d ures  ..............................................................................7 4  
8. 3  
Patie nt E nr oll me nt  .................................................................................................7 6  
8. 4  
R T -S pecific Pre -Re gistrati o n Re q uire me nts ..........................................................7 7  
9.  
D R U G I N F O R M A TI O N  ...................................................................................................7 9  
 
Atez oliz u ma b ( N S C 7 8 3 6 0 8)  .................................................................................7 9  
 
Cis plati n ( N S C # 1 1 9 8 7 5)  .......................................................................................8 2  
1 0.  
P A T H O L O G Y/ BI O S P E CI M E N  .......................................................................................8 3  
 
Ce ntral Pat h ol o g y Re vie w G ui deli nes  ...................................................................8 3  
 
Bi o mar ker Selecti o n f or I nte gral Bi o mar ker Testi n g  ............................................8 3  
 
Bi os peci me n Selecti o n f or I nte grat e d Bi o mar ker Testi n g  8 5 Err or! B o o k m ar k n ot 
defi ne d.  
 
Bi os peci me n S u b missi o n Ta bles  ...........................................................................8 5  
1 1.  
M o dalit y Re vie ws  ..............................................................................................................8 7  
1 2.  
D A T A A N D R E C O R D S  ...................................................................................................8 7  
 
Data Ma na g e me nt/ C ollecti o n  ................................................................................8 7  
 
S u m mar y of Data S u b missi o n  ...............................................................................8 8  
 
Gl o bal Re p orti n g/ M o nit ori n g  ................................................................................8 8  
1 3.  
S T A TI S TI C A L C O N SI D E R A TI O N S ...............................................................................8 9  
1 3. 1  
St u d y Desi g n  ..........................................................................................................8 9  
1 3. 2  
St u d y E n d p oi nts  .....................................................................................................8 9  
1 3. 3  
Pri mar y O bjecti ves St u d y Desi g n  ..........................................................................8 9  
1 3. 4  
St u d y M o nit ori n g of Pri mar y O bjecti ves  ...............................................................9 1  
1 3. 5  
Accr ual/ St u d y D urati o n C o nsi derati o ns  ................................................................9 2  
1 3. 6  
D ose Le vel G ui d eli nes  ...........................................................................................9 2  
1 3. 7  
Sec o n dar y or E x pl orat or y E n d p oi nts (i ncl u di n g c orrelati ve sci e nce ai ms)  ...........9 2  
1 3. 8  
E x pl orat or y H y p ot hesis a n d E n d p oi nts  .................................................................9 4  
1 3. 9  
Ge n der/ Et h nicit y/ Race Distri b uti o n .......................................................................9 5  
1 4.  
R E F E R E N C E S  ..................................................................................................................9 5  
A P P E N DI X I –  T R A N S L A TI O N A L S CI E N C E BI O S P E CI M E N P R O C E D U R E S  ..................1 0 3  
A P P E N DI X II –  P E R F O R M A N C E S T A T U S C RI T E RI A  .........................................................1 0 9  
A P P E N DI X III –  R A DI A TI O N T H E R A P Y C O N T O U R S .........................................................1 1 0  
A P P E N DI X I V –  Letter t o pat h ol o gists .......................................................................................1 1 4  
A P P E N DI X V - BI O P S Y P A T H O L O G Y V E RI FI C A TI O N  ......................................................1 1 5  
A P P E N DI X VI –  N CI/ D C T D C olla b orati ve A gree me nts La n g ua ge  ..........................................1 1 6  

 
N R G -G Y 0 1 7  
8    
Versi o n Date:  N o ve m ber 8 , 2 0 1 8 
 
N R G G Y 0 1 7  
S C H E M A  
 
 
 

 
N R G -G Y 0 1 7  
9    
Versi o n Date:  N o ve m ber 8 , 2 0 1 8 
1.  O B J E C TI V E S  
 
1. 1   
Pri m ar y O bjecti ve  
1. 1. 1  T o deter mi ne w het her differe n ces i n se q ue nci n g of atez oliz u ma b a n d c he m ora diati o n 
res ult i n differe ntial i m m u ne acti vati o n, as det er mi ne d b y cl o nal e x pa nsi o n of T cell 
rece pt or beta ( T C R B) re pert oires i n peri p h eral bl o o d o n  da y 2 1 .   
 
 
1. 2   
Sec o n d ar y O bjecti ve s 
1. 2. 1  T o i n vesti gate t he feasi bilit y of a d mi nistrati o n of  t he a nti P D-L 1 a nti b o d y 
(atez oliz u ma b) as a n i m m u ne pri mer a n d c o nc urre nt wit h c he m ora diati o n ( C R T) 
t hera p y i n patie nts wit h l ocall y a d va nce d cer vical ca ncer.   
1. 2. 2  T o deter mi ne t he nat ure a n d de gree of t o xicit y of t he a nti P D -L 1 a nti b o d y 
(atez oliz u ma b) a d mi nistere d as a n i m m u ne pri mer a n d c o nc urre nt wit h c he m ora diati o n 
( C R T) t hera p y i n patie nts wit h l ocall y a d va nce d cer vical ca ncer. 
1. 2. 3  T o e xa mi ne t he c h a n ges i n T C R cl o nalit y, di versit y, a n d fre q ue nc y i n peri p heral bl o o d 
a n d tiss ue a n d c orrelate t his wit h cli nical o utc o mes, s uc h as t he e x pl orat or y res p o nse 
assess me nt o n t he  p ost -treat me nt P E T -C T sca n a n d 2-year disease -free s ur vi val ( D F S).  
1. 2. 4  T o assess t he pre di cti ve val ue of bas eli ne a n d o n -treat me nt P D -L 1 e x pressi o n i n t he 
tiss ue i n eac h treat me nt ar m f or cli nical o utc o mes usi n g p ost -treat me nt P E T-C T sca n 
a n d 2-year D F S as t he o utc o me meas ure s. 
 
1. 3   
E x pl or at or y O bjecti ves  
1. 3. 1  T o e x pl ore bas eli ne a n d o n -treat me nt bl o od a n d tiss ue bi o mar kers  t hat c o ul d pre dict 
res p o nse t o t he c o m bi nati o n t hera p y, as c orrel ate d t o t he e x pl orat or y cli nical e n d p oi nt of 
t he wee k 1 2 ( da y 1 4 0) P E T  – C T sca n  a n d 2 -year D F S.   
1. 3. 2    T o e x pl ore t he res p o nse assess me nt o n t he e x pl orat or y a n d o pti o nal p ost -treat me nt wee k 
1 2 ( da y 1 4 0) P E T -C T sca n a n d t he cli nical 2 -year  disease free s ur vi val ( D F S) .   
 
2.  B A C K G R O U N D  
 
2. 1   
Cer vic al C a ncer B ac k g r o u n d  
  
Cer vical ca ncer affects a n esti mate d 1 2, 9 0 0 w o me n a n d acc o u nts f or a n esti mate d 4, 1 0 0 deat hs 
i n t he U nite d States, a n d 2 6 6, 0 0 0 deat hs gl o ball y eac h year.  L ocall y a d va nce d cer vical ca ncer is 
defi ne d as sta g e I B 2 (t u m or c o nfi ne d t o t he cer vi x meas uri n g > 4c m ), sta ge II (t u m or i n va di n g 
be y o n d t he uter us or u p p er 2/ 3 of va gi na), sta ge III (t u m or e xte n di n g t o pel vic si de wall, l o wer 
1/ 3 of va gi na, or ca usi n g h y dr o n ep hr osis), a n d sta ge I V A (t u m or i n va di n g m uc osa of bla d der or 
rect u m or e xt e n di n g be y o n d t he tr ue pel vis). Patie nts dia g n ose d wit h l ocall y -a d va nce d cer vical 
ca ncer ha v e a hi g her ris k of rec urre n ce a n d w orse s ur vi val t ha n t he earl y sta ge patie nts. After 
u pfr o nt s ur ger y, t he rela pse rate i n all sta ges e xcee ds 3 0 perce nt, wit h 5 -year s ur vi val of 3 0 % i n 
pati e nts wit h sta ge III dis ease 1, 2. Patie nts prese nti n g wit h para-a ortic l y m p h n o de ( P A L N) 
metastases at dia g n osis re prese nt a partic ularl y p o or pr o g n ostic gr o u p wit h 5 year s ur vi val of 
a p pr o xi matel y 4 0 % acr oss t he sta ges 3. T he i nte grati o n of c he m ot h era p y, partic ularl y cis plati n 
wit h ra di ot hera p y, d e m o nstrate d i m pr o ve d s ur vi val rates, res ulti n g i n a para di g m s hift i n care f or 
l ocall y a d va nce d cer vical ca ncer 4, 5.  Des pite t hese a d va nces, patie nts pres e nti n g i n t he u pfr o nt 
c urati ve setti n g wit h P A L N metastasis ha ve a dis mal t hree year o verall a n d pr o gressi o n free 

 
N R G -G Y 0 1 7  
1 0    
Versi o n Date:  N o ve m ber 8 , 2 0 1 8 
i nter val of 3 9 % a n d 3 4 %, res pecti vel y, e ve n wit h t he use of exte n de d fiel d ra diati o n a n d 
c o nc urre nt c he m ot hera p y  6. T he r ole of a dj u va nt c he m ot hera p y i n t his setti n g re mai ns u n k n o w n 
a n d is bei n g i n vesti gate d i n a n i nter nati o nal ra n d o mize d O U T B A C K trial, t he res ults of w hic h 
are still pe n di n g. T heref ore, t here is a n u n met nee d f or t hera pe utic treat me nt o pti o ns f or patie nts 
wit h P A L N, gi ve n t he dis mal s ur vi val wit h c urre nt t hera pe utic o pti o ns a vaila ble .  
 
2. 2   
I m m u n ol o g y of H P V I nfecti o n a n d Cer vic al C a ncer 
 
Cer vical ca ncer has bee n i de ntifie d t o be direct c o nse q ue nce of i nfecti o ns b y s pecific viral 
s u bt y pes, na mel y h u ma n pa pill o ma vir us ( H P V) s u bt y pes 1 6 a n d 1 8 7 -9. Des pite t he h ost i m m u ne 
res p o nse t o t u m ors, ca n cer ofte n de vel o ps m ulti ple resista nce mec ha nis ms s uc h as l ocal i m m u ne 
s u p pressi o n, i m m u ne e vasi o n, i n d uce d ysf uncti o nal T cell mec ha nis ms a n d i m m u ne t olera nce, 
a n d e vasi o n t hr o u g h e n d o ge n o us i m m u n e c hec k p oi nt i n hi bit ors 1 0.   
 
A nti -P D -L 1  
P D -L 1, als o k n o w n as B 7 -H 1, t he li ga n d f or P D -1 is e x presse d a n d has bee n s pecificall y 
de m o nstrate d i n cer vical ca ncer, as well as i n ot her ca ncers  1 1.  I n hi bit ors t o P D-L 1 ma y f urt her 
rest ore T cell f u ncti o n a n d i m m u ne T cell pri mi n g b y bl oc ki n g n ot o nl y its i nteracti o ns wit h P D-
1 b ut als o a n ot her fa mil y me m ber B 7. 1 T cell i nteracti o ns.  T he st u d y dr u g, atez oliz u ma b, 
recei v e d brea kt hr o u g h desi g nati o n stat us b y t he U S F o o d a n d Dr u g A d mi nistrati o n ( F D A) i n 
J u ne 2 0 1 4 f or metastatic bla d der ca ncer, a n d i n Fe br uar y 2 0 1 5 f or t he treat me nt of P D -L 1 
p ositi ve n o n -s mall cell l u n g ca ncer patie nts, w h os e disease has pr o gresse d d uri n g or after 
plati n u m -b ase d c he m ot h era p y (a n d a n a p pr o priat e tar gete d t hera p y f or t h ose wit h a n E G F R 
m utati o n -p ositi ve or A L K -p ositi ve t u m or).  Atez oliz u ma b has p ote ntial pr o mise i n l ocall y 
a d va nce d cer vical ca ncer.  
 
Preli mi nar y Data o n C hec k p oi nt I n hi biti o n a n d C er vical Ca ncer    
G O G -9 9 2 9, a p h ase I tri al of se q ue ntial i pili m u ma b after C R T f or t he treat me nt of patie nts wit h 
l ocall y a d va nce d cer vical ca ncer sta ges I B 2/II A wit h p ositi ve para-a ortic l y m p h n o des a n d sta ge 
II B/III B/I V A wit h pel vic/ para-a ortic l y m p h n o des as a N CI s u p p orte d nati o nal cli nical trial t o 
i n vesti gate t he  ma xi m u m t olerate d d ose ( M T D) a n d d ose-li miti n g t o xicities ( D L T) of a dj u va nt 
i pili m u ma b f oll o wi n g c o nc urre nt w ee kl y cis plati n a n d e xte n de d fiel d ra di ati o n i n w o me n wit h 
ne wl y dia g n ose d l ocall y a d va nce d cer v ical ca ncer.  W he n re vi e wi n g o ur o utc o me data prese nte d 
at A S C O 2 0 1 7 at o ne  year o n G O G -9 9 2 9, o ur o ne  year P F S is 6 9 %, w hic h is i m pressi ve w he n 
c o m pare d t o hist orical t hree year o verall a n d pr o gressi o n free i nter val of 3 9 % a n d 3 4 %, 
res pecti vel y, wit h e xt e n d e d fiel d ra di ati o n a n d c o nc urre nt c he m ot hera p y fr o m pre vi o us G O G 
st u dies 6.   G O G-9 9 2 9 data s h o ws a si g nifica nt i ncrease i n P D -1 e x pressi n g T cells p ost 
c he m ora diati o n.  I n a d diti o n, t he K E Y N O T E 0 2 8 trial, 2 2 patie nts wit h metastatic P D L -1 
p ositi ve c er vical ca ncer were treate d wit h a n a nti -P D -1, pe m br oliz u ma b, wit h a n o verall 
res p o nse rate of 1 7 %, d e m o nstrati n g acce pt a ble t o xicit y pr ofile.  T hese data e nc o ura ge o ur 
selecti o n of a n a nti-P D L -1 st u d y dr u g i n t he pr o p ose d c o nce pt t o use a pri mi n g d ose of a nti- 
P D L -1 t hera p y pri or t o a n d c o nc urre ntl y wit h c he m ora diati o n f or l oc all y a d va nce d cer vical 
ca ncer.  
 
Ra diati o n a n d I m m u ne C hec k p oi nt Bl oc ka de, D ose a n d Ti mi n g  
O pti mal res ults wit h i m m u n ot hera p y ma y occ ur wit h m ulti m o dalit y treat me nt o pti o ns i ncl u di n g 

 
N R G -G Y 0 1 7  
1 1    
Versi o n Date:  N o ve m ber 8 , 2 0 1 8 
d ual c hec k p oi nt bl oc ka d e or ra di ati o n t hera p y.  R esista nce mec ha nis ms of c hec k p oi nt bl oc ka de 
ca n be o v erc o me b y re g ulati o n of c hec k p oi nt i n hi biti o n.  Earl y data s u g gests t hat t he i m m u ne 
s yste m, i n partic ular C D 8 + T cells, ha ve a ke y r ole f or t u m or cell deat h wit hi n a ra diati o n fiel d 
1 2, 1 3.  O pti mal res ults wit h i m m u n ot hera p y ma y occ ur wit h m ulti m o dalit y treat me nt o pti o ns 
incl u di n g c hec k p oi nt bl oc ka de wit h ra diati o n t hera p y.  Ra diati o n t hera p y ca uses mi grati o n of 
de n dritic cells, cr oss -pe n etrati o n of t u m or a nti ge ns w hic h ca n res ult i n T cell acti vati o n a n d 
pr oliferati o n 1 4.  F urt her m ore, ra diati o n t hera p y i ncreas es t he de nsit y of t u m or i nfiltrati n g 
l y m p h oc ytes ( TI L) wit hi n a t u m or li kel y by e xtra vasati o n of TI L wit hi n t he vasc ulat ure of 
t u m ors a n d c he m o ki nes acti vati o n 1 4 , 1 5_ E N R E F _ 4 4 .   It is k n o w n t hat ra diati o n t hera p y alters t he 
T cell re p ert oire of peri p heral T cell cl o nes 1 6.  T here are li mite d data s urr o u n di n g the o pti mal 
d ose a n d fracti o nati o n nee de d t o pr o v o ke a n i deal i m m u ne res p o nse w he n c o m bi ni n g 
i m m u n ot hera p y wit h ra di ati o n.  I m m u n ot hera p y a n d se q ue nci n g data wit h ra diati o n de m o nstrate 
t hat w he n a C T L A-4 is deli vere d pri or t o R T t here is i ncrease d efficac y c o m pare d t o deli ver y 
after R T, or if al o ne a n d n ot i n c o m bi nati o n wit h R T 1 7.   
 
2. 3   
Cli nic al S afet y D at a  
 
O ur res ults fr o m G O G -9 9 2 9 s h o w t hat se q ue ntial a nti-C T L A 4 after C R T is t olera ble.  Gi ve n t hat 
t hese cer vical ca ncer pati e nts are treate d wit h a n e xte n de d fiel d ra diati o n a n d t he e ntire pel vis, 
patie nts were treate d wit h se q ue ntial i pil im u ma b after l y m p h oc yte c o u nt t o xicities res ol ve d t o  a 
gra de 1 wit hi n 2 -6 wee ks p ost C R T.  O ur data s h o w t hat t w o patie nts i n t he ma xi m u m t olerate d 
d ose le vel ( 1 0 m g/ k g) i n t he c o h ort e x p a nsi o n e x perie nce d a re versi ble gra de 3 t o xicit y –  gra de 3 
li pase, a n d s ki n ras h.  Gi ve n t he t o xicit y data usi n g a n a nti PD -1, a n d a nti P D L -1 acr oss vari o us 
disease sites, we e x pect t hat t he use of at ez oliz u m a b a n d C R T will be t olera ble.  T o f urt her 
re d uce b o wel t o xicit y, w e pla n t o use a n i nte nsit y m o d ulate d ra diati o n t hera p y (I M R T) a p pr oach 
as alrea d y e xpl ore d i n N R G -G Y 0 0 6.   T he ra diati o n a n d p h ysics q uali t y ass ura nce pat h wa y us e d 
i n N R G-G Y 0 0 6 will be als o use d i n t he de vel o p me nt of t he pr o p ose d st u d y f or safet y a n d q ualit y 
ra diati o n deli ver y 
 
2. 4   
R ati o n ale f or E xte n de d Fiel d I nte nsit y M o d ul ate d R a di ati o n T her a p y  
 
E xte n de d fiel d  I M R T is a n effecti ve ra di ati o n deli ver y a p pr oac h t o treat P A L N p ositi ve a n d hi g h 
ris k pel vic L N p ositi ve cer vical ca ncer 1 8, 1 9.  M ulti ple p u blis he d st u dies i n dicate t hat I M R T ca n 
re d uce b ot h h e mat ol o gic a n d gastr oi ntesti nal ( GI) t o xicities, a n d ca n pr o vi d e e xcelle nt l o n g-ter m 
o utc o mes 2 0, 2 1.  A pr os pecti ve st u d y of l ocall y a d va nce d cer vical ca ncer patie nts treate d wit h 
E F R T a n d cis plati n base d c he m ot hera p y s h o we d a n i m pr o ve me nt i n t he  3 -year act uari al o verall 
s ur vi val, disease-free s ur vi val, a n d dista nt metastasis-free s ur vi val : 8 7 % vers us 6 2 % ( P = 0. 0 2), 
8 2 % vers us 5 4 % ( P = 0. 0 2), a n d 7 9 % vers us 5 7 % ( P = 0. 0 1), vers us pel vic ra diati o n o nl y 
hist orical c o ntr ols 1 8.  F urt her m ore, a st u d y fr o m t he U ni versit y of Pitts b ur g s h o we d t hat i n 6 1 
patie nts wit h P A L N p ositi ve or hi g h ris k f or micr osc o pic disease, E F R T wit h I M R T was 
t olera ble wit h a late gra d e 3 + a d v erse e ve nt rat e of 4 % 1 9.  F urt her m ore, t h e y f o u n d t hat E F R T 
wit h I M R T res ulte d i n l o w re gi o nal rec urre nce i n n o de -p ositi ve cer v i cal ca ncer 1 9.  I n a l ar ge 
retr os pecti ve re vie w, cer vical ca ncer patie nts wit h p ositi ve P A L N  treate d wit h defi niti ve 
e xte n de d-fiel d ra diati o n t hera p y s h o we d t hat I M R T i m pr o ve d disease s pecific s ur vi val a n d a 
decrease i n treat me nt rel ate d a d verse effects c o m pare d t o patie nts n ot treate d wit h I M R T 2 2.   
 

 
N R G -G Y 0 1 7  
1 2    
Versi o n Date:  N o ve m ber 8 , 2 0 1 8 
2. 5   
R ati o n ale f or I m a ge G ui de d Br ac h yt her a p y (I G B T)  
 
Brac h yt hera p y is a ke y c o m p o ne nt i n t he treat me nt of cer vical ca ncer as it all o ws f or d ose 
escalati o n t o t he t u m or w hile mi ni mizi n g t he d ose t o s urr o u n di n g critical or ga ns at ris k s uc h as 
t he si g m oi d, bla d der, a n d rect u m.  Patter ns of care st u dies esta blis he d t he esse ntial r ole of 
brac h yt hera p y i n t he ma na ge me nt of cer vical ca ncer, a n d li n ke d its use t o i m pr o ve me nts i n 
pel vic c o ntr ol a n d disease free s ur vi val  2 3.  F urt her m ore, wit hi n t he last deca de, t he a d ve nt of 
i ma ge-g ui de d brac h yt hera p y (I G B T) f or b ot h a p plic at or i nserti o n a n d treat me nt pla n ni n g has 
i ncreas e d t he pr oce d ural i m pla ntati o n a n d treat me nt pla n ni n g o pti o ns f or t he treat me nt of 
cer vical ca n cer  2 4.  Wit h t he wi des prea d use of s o p histicate d i ma gi n g m o dalities i n ra diati o n 
o nc ol o g y de part me nts, t h e maj or it y of brac h yt hera p y ce nters use 3 D i ma gi n g f or c o nt o uri n g a n d 
treat me nt pla n ni n g i n brac h yt hera p y 2 5  2 5 -3 2.  T he A merica n Brac h yt hera p y S ociet y rece ntl y 
i n vesti gate d t he use of i ma ge g ui de d brac h yt hera p y s h o wi n g a n i m pr o ve me nt i n pel vic c o ntr ol 
a n d D F S c o m pare d t o st u dies wit h c o n ve nti o nal 2 D base d i ma gi n g tec h n ol o g y i n patie nts treate d 
wit h C R T f or l ocall y a d va nce d cer vical ca ncer 3 3.   
 
2. 6   
R ati o n ale f or t he P E T i m a gi n g p ost tre at me nt as e x pl or at or y e n d p oi nt  
 
I n t he defi niti ve treat me nt of cer vical cancer, 1 2 wee k p ost t hera p y p ositr o n e missi o n t o m o gra p h y ( P E T) 
wit h F -1 8 fl u or o de o x y gl uc ose ( F D G) is pre dicti ve of s ur vi val o utc o me ( Sc h wartz et al. 2 0 0 7).  We 
i n vesti gate d t he r ole of t he p ost i m m u n ot hera p y p ositr o n e missi o n t o m o gra p h y ( P E T) as a 
s urr o gate bi o mar ker f or s ur vi val f or cer vical ca ncer patie nts ( pts) treate d wit h sta n dar d 
c he m ora diati o n ( C R T) f oll o we d b y i pili m u ma b o n G O G -9 9 2 9.  T he P E T was o btai ne d fr o m 4 -
1 2 wee ks.  T hirt y -t w o of 3 4 e nr olle d pts i nitiate d st u d y treat me nt, of w h o m 1 5 pts ha ve c o m plete 
pre a n d p ost t hera p y P E T data, wit h at least o ne  d ose of i pili m u ma b.  Of t he 1 5 pts wit h p ost -
i pili m u ma b P E T sca n data, 9 3 % were s q ua m o us hist ol o g y; all ha d p ositi ve pel vic l y m p h n o des, 
wit h 4 7 % ha vi n g p ositi ve paraa ortic l y m p h n o des i n a d diti o n.  All 1 5 pts c o m plete d C R T, wit h 
i pili m u ma b c o m pleti o n rates of 7 3 % wit h 4 c ycles, 1 3 % wit h 3 c ycles, 7 % wit h 2 c ycles a n d 7 % 
wit h 1 c ycle.   Ele ve n  h a d a meta b olic C R, t w o ha d sta ble disease, a n d t w o ha d a P R.  Wit h a 
me dia n f oll o w u p of 1 2 m o nt hs f or t hese  1 5 pts, o ne  patie nt wit h C R o n P E T ha d a rec urre nce. 
We pla n t o i n vesti gate t h e r ole of p ost t hera p y P E T f or res p o ns e assess me nt.  
 
3.  P A TI E N T S E L E C TI O N, E LI GI BI LI T Y , A N D I N E LI GI BI LIT Y  C RI T E RI A  
 
 
N ote: Per N CI g ui deli nes, e xce pti o ns t o i ncl usi o n a n d e xcl usi o n criteri a are n ot 
per mitte d.  F or q uesti o ns c o ncer ni n g eli gi bilit y, please c o ntact t he Bi ostatistical/ Data 
Ma na ge me nt Ce nter ( see pr ot oc ol c o ver pa ge). F or ra diati o n t hera p y-relate d eli gi bilit y 
q uesti o ns, please c o ntact R T Q A  (see pr ot oc ol c o ver pa ge).  
 
3. 1   
P atie nt Selecti o n G ui deli nes  
Alt h o u g h t h e g ui deli nes pr o vi de d bel o w are n ot i ncl usi o n/e xcl usi o n criteria, i n vesti gat ors 
s h o ul d c o nsi der t hese fact ors w he n selecti n g patie nts f or t his trial. I n vesti gat ors als o 
s h o ul d c o nsi der all ot her rele va nt fact ors ( m e dical a n d n o n-me dical), as well as t he ri s ks 
a n d be nefits of t he st u d y t hera p y, w he n deci di n g if a patie nt is a n a p pr o priat e ca n di date 
f or t his trial. 
 
3 . 1. 1 S u b missi o n of t u m or bi o psies  is re q uire d f or all patie nts. I n vesti gat ors s h o ul d c hec k wit h 

 
N R G -G Y 0 1 7  
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Versi o n Date:  N o ve m ber 8 , 2 0 1 8 
t heir site p at h ol o g y d e part me nt re gar di n g releas e of bi os peci me ns  bef ore a p pr oac hi n g 
patie nts a b o ut partici pati o n i n t he trial . 
 
3. 2   
Eli gi bilit y  Criteri a  
A p atie nt c a n n ot be c o nsi dere d eli gi ble f or t his st u dy u nless A L L of t he f oll o wi n g 
c o n diti o ns are met.  
 
3. 2. 1  Patie nts wit h hist ol o gicall y c o nfir me d ne wl y dia g n ose d a d va nce d cer vical ca ncer 
(s q ua m o us cell carci n o m a, a de n ocarci n o ma, a n d a de n os q ua m o us cell carci n o ma):  
FI G O cli nical sta ges I B 2/II A wit h p ositi ve para -a ortic n o des, or FI G O cli nical sta ges 
II B/III B/I V A wit h p ositi ve pel vic or para-a ortic l y m p h n o des ( P A L N).  Pel vic or 
P A L N n o dal stat us c o nfir me d b y P E T/ C T sca n  or fi ne nee dle bi o ps y or e xtra 
perit o neal bi o ps y  or la par osc o pic bi o ps y.  T he P A L N m ust be i nferi or t o t he T 1 2/ L 1 
i nters pace. 
 
3. 2. 2  E C O G perf or ma nce stat us ≤2 ( Kar n ofs k y ≥6 0 %, see A p pe n di x II). 
 
3. 2. 3  Patie nts m ust ha ve n or mal or ga n a n d marr o w f u ncti o n as defi ne d bel o w:  
 
•  
le u k oc ytes 
≥2, 5 0 0/ mc L  
•  
a bs ol ute ne utr o p hil c o u nt    
≥1, 5 0 0/ mc L  
•  
platelets  
≥1 0 0, 0 0 0/ mc L (> 5 0, 0 0 0 f or patie nts wit h he mat ol o gic 
mali g na ncies)  
•  
he m o gl o bi n  
≥8 g/ d L  (ca n be tra nsf use d wit h re d bl o o d cells pre-
st u d y) 
•  
t otal bilir u bi n 
≤1. 5 × i nstit uti o nal u p per li mit of n or mal ( U L N) 
( h o we ver, patie nts wit h k n o w n Gil bert disease w h o 
ha ve ser u m bilir u bi n le vel  3   U L N ma y be e nr olle d)  
•  
A S T( S G O T)/ A L T( S G P T)  
≤3 × U L N ( A S T a n d/ or A L T 5   U L N f or patie nts 
wit h li ver i n v ol ve me nt)  
•  
al kali ne p h os p hatase     
≤2. 5 × U L N ( 5   U L N f or patie nts wit h d oc u me nte d 
li ver i n v ol ve me nt or b o ne metastases) 
•  
creati ni ne cleara nce     
< 1. 5 m g/ d L t o recei v e wee kl y Cis plati n *  
 
* Patie nts w h ose ser u m creati ni ne is bet wee n 1. 5 a n d 1. 9 m g/ d L are eli gi ble f or cis plati n 
if t here is n o h y dr o ne p hr osis a n d t he esti mate d creati ni ne cleara nce ( C Cr) is > 3 0 ml/ mi n. 
F or t he p ur p os e of esti mati n g t he C Cr, t he f or m ula of C oc kcr oft a n d Ga ult f or  fe males 
s h o ul d be use d: 
 
 
  
 
   
 
 
C Cr = 0. 8 5 x ( 1 4 0 –  a ge) x I B W  
 
  
 
   
 
 
 
   
( Scr x 7 2) 
 
w here a ge is t he patie nt’s a ge i n years (fr o m 2 0 t o 8 0 years), Scr is t he ser u m creati ni ne 
i n m g/ d L, a n d I B W is t he i deal b o d y wei g ht i n k g (acc or di n g t o t he calc ulati o n I B W = 
4 5. 5 k g + 2. 3 k g f or eac h i nc h o ver 5 feet).  
 

 
N R G -G Y 0 1 7  
1 4    
Versi o n Date:  N o ve m ber 8 , 2 0 1 8 
•  
I N R a n d a P T T 
1. 5   U L N ( T his a p plies o nl y t o patie nts w h o d o n ot  
recei v e t hera pe utic a ntic oa g ulati o n; patie nts recei vi n g 
t hera pe utic a ntic oa g ulati o n, s uc h as l o w-m olec ular -
wei g ht he pari n or warfari n, s h o ul d  be o n a sta ble d ose.)  
 
3. 2. 4  A ge is >  1 8 years.  
 
3. 2. 5  Patie nt d oes n ot ha ve a k n o w n aller g y t o cis plati n or c o m p o u n ds of si milar bi ol o gic 
c o m p ositi o n. 
 
3. 2. 6  Patie nt is n ot acti vel y breastfee d i n g ( or has a gree d t o disc o nti n ue breastfee di n g bef ore 
t he i nitiati o n or pr ot oc ol t hera p y). 
 
3. 2. 7  T S H wit hi n n or mal li mits or n or mal free T 4 i n t h ose wit h a b n or mal T S H.  
 
3. 2. 8  A bilit y t o u n dersta n d a n d t he willi n g ness t o si g n a writte n i nf or me d c o ns e nt d oc u me nt.  
 
3. 2. 9  Patie n ts p ositi ve f or h u ma n i m m u n o deficie nc y vir us ( HI V) are all o we d o n st u d y, b ut 
HI V -p ositi ve patie nts m ust ha ve:  
•  
A sta ble re gi me n of hi g hl y acti ve a nti -retr o viral t hera p y ( H A A R T) 
•  
N o re q uire m e nt f or c o n c urre nt a nti bi otics or a ntif u n gal a ge nts f or t he pre ve nti o n of 
o p p ort u nistic i nfecti o ns  
•  
A C D 4 c o u nt a b o ve 2 5 0 cells/ mc L a n d a n u n detecta ble HI V viral l oa d o n sta n dar d 
P C R -base d tests.  
 
3. 3   
I neli gi bilit y Criteri a  
P atie nts wit h a ny  of t he f oll o wi n g c o n diti o ns are N O T eli gi ble f or t his st u dy.  
   
 
3. 3. 1  Patie nts w h o ha ve recei v e d pri or ra di ati o n t hera p y t o t he pel vis or a b d o mi nal ca vit y, 
P A L N ra diati o n, or pre vi o us t hera p y of a n y ki n d f or t his mali g na nc y or pel vic, P A L N, 
or a b d o mi nal ra diati o n f or a n y pri or mali g na nc y.  
 
3. 3. 2  Patie nts wit h P A L N n o dal metastasis a b o ve t he  T 1 2/ L 1  i nters pace. 
 
3. 3. 3  Patie nts w h o ha d a ra di cal h ysterect o m y wit h p ositi ve P A L Ns are n ot eli gi ble.  
 
3. 3. 4  Patie nts wit h pri or all o ge neic b o ne marr o w tra ns pl a ntati o n or pri or s oli d or ga n 
tra ns pla ntati o n. 
 
3. 3. 5  P atie nts pre vi o usl y tre ate d wit h s yste mic a ntic a ncer t her ap y  (e. g., c he m ot hera p y, 
tar gete d t hera p y, i m m u n ot hera p y) wit hi n 3 years pri or t o e nteri n g t he st u d y. 
 
3. 3. 6  Treat me nt wit h s yste mic i m m u n os u p pressi ve me dicati o ns (i ncl u di n g, b ut n ot li mite d 
t o, pre d nis o ne, 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) wit hi n 2 wee ks pri or t o C ycle 1, Da y  1.  
•  Patie nts w h o ha ve recei v e d ac ute, l o w d ose, s yste mic i m m u n os u p pressa nt 

 
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me dicati o ns ( e. g., a o n e-ti me d ose of de xa m et has o ne f or na us ea or ster oi ds as C T 
sca n c o ntrast pre me dicati o n) ma y be e nr olle d. 
•  T he use of 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) 
f or patie nts wit h ort h ostatic h y p ote nsi o n or a dre n oc ortical i ns ufficie nc y is 
all o we d.  
 
3. 3. 7  K n o w n h y perse nsiti vit y t o C hi nese ha mster o var y cell  pr o d ucts or ot her rec o m bi na nt 
h u ma n a nti b o dies.  
 
3. 3. 8  Hist or y of se vere aller gic, a na p h ylactic, or ot her h y perse nsiti vit y reacti o ns t o c hi meric 
or h u ma nize d a nti b o dies or f usi o n pr otei ns.  
 
3. 3. 9  Patie nts re q uiri n g treat m e nt wit h a R A N K L i n hi bit or (e. g., de n os u ma b) w h o ca n n ot 
disc o nti n ue it bef ore treat me nt wit h atez oliz u ma b.  
 
3. 3. 1 0  K n o w n cli nicall y si g nifica nt li ver disease, i ncl u di n g acti ve viral, alc o h olic, or ot her 
he patitis; cirr h osis; fatt y li ver; a n d i n herite d li ver disease  
•  Patie nts wit h past or res ol ve d he patitis B i nfecti o n ( defi ne d as ha vi n g a 
ne gati ve he p atitis B s urface a nti ge n [ H Bs A g] test a n d a p ositi ve a nti -H Bc 
[a nti b o d y t o he patitis B c ore a nti ge n] a nti b o d y test) are eli gi ble. 
•  Patie nts p ositi ve f or he patitis C vir us ( H C V) a nti b o d y  
 
3. 3. 1 1  Hist or y or ris k of a ut oi m m u ne disease, i ncl u di n g b ut n ot li mite d t o s yste mic l u p us 
er yt he mat os us, r he u m at 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, Bell’s pals y, G uillai n-Barré s y n dr o me, m ulti ple scler osis, a ut oi m m u ne 
t h yr oi d disease, vasc ulitis, or gl o mer ul o ne p hritis. 
•  Patie nts wit h a hist or y of a ut oi m m u ne 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 are eli gi ble. 
•  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 
or T y pe 2 dia bet es mellit us are eli gi ble.  
•  Patie nts wit h ecze ma, ps oriasis, lic he n si m ple x c hr o nic us or vitili g o wit h 
der mat ol o gic ma nifestati o ns o nl y (e. g., patie nts wit h ps oriatic art hritis w o ul d 
be e xcl u de d) are per mitte d pr o vi de d t hat t he y meet t he f oll o wi n g c o n diti o ns:  
o  
Patie nts wit h ps oriasis m ust ha ve a bas eli ne o p ht hal m ol o gic e xa m t o r ule 
o ut oc ular ma nifestati o ns  
o  
Ras h m ust c o ver less t ha n 1 0 % of b o d y s urface area ( B S A)  
o  
Disease is well c o ntr olle d at baseli ne a n d o nl y re q uiri n g l o w p ote nc y 
t o pical ster oi ds (e. g., h y dr oc ortis o ne 2. 5 %, h y dr oc ortis o ne b ut yrate 0. 1 %, 
fl uci n ol o ne 0. 0 1 %, des o ni de 0. 0 5 %, alcl o metas o n e di pr o pi o nate 0. 0 5 %) 
o  
N o ac ute e xacer bati o ns of u n derl yi n g c o n diti o n wit hi n t he last 1 2 m o nt hs 
( n ot re q uiri n g ps orale n pl us ultra vi olet A ra diati o n [ P U V A], 
met h otre xate, reti n oi ds, bi ol o gic a ge nts, oral calci ne uri n i n hi bit ors; hi g h 
p ote nc y or ster oi ds)  
 

 
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3. 3. 1 2  Hist or y of i di o pat hic p ul m o nar y fi br osis, p ne u m o nitis (i ncl u di n g dr u g i n d uce d), 
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, etc.), or e vi d e nce of acti ve p ne u m o nitis o n scree ni n g c hest c o m p ute d 
t o m o gra p h y ( 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. 
 
3. 3. 1 3  Patie nts wit h ac ti ve t u berc ul osis ( T B) are e xcl u de d. 
 
3. 3. 1 4  Se vere i nfecti o ns wit hi n 4  wee ks pri or t o C ycle 1, Da y 1, i ncl u di n g b ut n ot li mite d 
t o h os pitalizati o n f or c o m plicati o ns of i nfecti o n, bactere mia, or se vere p ne u m o nia.  
 
3. 3. 1 5  Si g ns or s y m pt o ms of i nfecti o n wit hi n 2 wee ks pri or t o C ycle 1, Da y 1.  
 
3. 3. 1 6  Recei ve d i ntra v e n o us (I V) a nti bi otics wit hi n 2 wee ks pri or t o C ycle 1, Da y 1.  Patie nts 
recei vi n g pr o p h yl actic 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 eli g i ble. 
 
3. 3. 1 7  Maj or s ur gical pr oce d ure wit hi n 2 8 da ys pri or t o C ycle 1, Da y 1 or a ntici pati o n of 
nee d f or a maj or s ur gical pr oce d ure d uri n g t he c o urse of t he st u d y.  
 
3. 3. 1 8  A d mi nistrati o n of a li ve, atte n uate d vacci ne wit hi n 4 wee ks bef ore C ycl e 1, Da y 1 or 
a ntici pati o n  t hat s uc h a li ve, atte n uate d vacci n e will be re q uire d d uri n g t he st u d y a n d 
u p t o 5 m o nt hs after t he last d ose of atez oliz u ma b.  
•  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 recei ve li ve, atte n uat e d 
i nfl ue nza vacci ne wit hi n 4 wee ks pri or t o C ycle 1, Da y 1 or at a n y ti me d uri n g 
t he st u d y. 
 
3. 3. 1 9  U nc o ntr olle d i nterc urre nt ill ness i ncl u di n g, b ut n ot li mite d t o, o n g oi n g or acti ve 
i nfecti o n, s y m pt o matic c o n gesti ve heart fail ure, u nsta ble a n gi na pect oris, car diac 
arr h yt h mia, or ps yc hi atric ill ness/s ocial sit uati o ns t hat w o ul d li mit c o m plia nce wit h 
st u d y re q uire me nts. 
 
3. 3. 2 0  Se vere, acti ve c o -m or bi dit y defi ne d as f oll o ws:  
•  C urre nt ( wit hi n 2 8 da ys of C ycle 1, Da y 1) si g ns a n d/ or s y m pt o ms of b o wel 
o bstr ucti o n  
•  Patie nts w h o re q uire pare ntal h y drati o n a n d/ or n utriti o n  
•  Patie nts w h o re q uire drai na ge gastr ost o m y t u be  
•  E vi de nce of blee di n g diat hesis or cli nicall y si g nifica nt c oa g ul o p at h y  
•  Seri o us, n o n -heali n g or de hisci n g w o u n d, acti ve ul cer or u ntreate d b o ne 
fract ure 
•  Hist or y of he m o pt ysis ( ≥ 1/ 2 teas p o o n of bri g ht re d bl o o d per e pis o de) wit hi n 
1 m o nt h of st u d y e nr oll me nt  
 
3. 3. 2 1  Si g nifica nt car di o vasc ul ar or cere br o vasc ular disease i ncl u di n g:  
•  U nc o ntr olle d h y perte nsi o n ( S B P > 1 5 0; D B P > 9 0)  

 
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•  Hist or y of m y ocar dial i nfarcti o n wit hi n 6 m o nt hs 
•  U nsta ble a n gi na  
•  Ne w Y or k Heart Ass ociati o n f u ncti o nal classificati o n II, III or I V  
•  Baseli ne ejecti o n fracti o n ≤ 5 0 % as assesse d b y ec h ocar di o gra m or M U G A  
•  Cere bral v asc ular acci de nt ( C V A) or tra nsie nt isc he mic attac k ( TI A) wit hi n  6 
m o nt hs  
•  Si g nifica nt vasc ular disease (e. g., a ortic a ne ur ys m, re q uiri n g s ur gical re pair or 
peri p heral arterial t hr o m b osis) wit hi n 6 m o nt hs  
 
3. 3. 2 2  Hist or y of a b d o mi nal/ pel vic or trac he oes o p ha geal fist ula or gastr oi ntesti nal 
perf orati o n a n d/ or a bscess wit hi n 6 m o nt hs pri or t o i nitiati o n of treat me nt.  
 
3. 3. 2 3  If patie nts are of c hil d-b eari n g p ote ntial a n d d o n ot a gree t o use t w o f or ms of birt h 
c o ntr ol t he n t he y are i neli gi ble.  
 
3. 3. 2 4  Patie nts w h o ha ve ha d a h ysterect o m y or are pla n ni n g t o ha ve a n a dj u va nt 
h ysterect o m y f oll o wi n g ra diati o n as part of t heir cer vical ca ncer treat me nt are 
i neli gi ble. 
 
3. 3. 2 5  Patie nts sc he d ule d t o be treate d wit h a dj u v a nt c o ns oli dati o n c he m ot hera p y at t he 
c o ncl usi o n of t heir sta n dar d c he m ora diati o n.  
 
3. 3. 2 6  Pre g na nt w o me n are e x cl u de d fr o m t his st u d y beca use ra di a ti o n t hera p y has t he 
p ote ntial f or terat o g e nic or a b ortifacie nt effects.  Beca use t here is a n u n k n o w n b ut 
p ote ntial ris k f or a d verse e ve nts i n n ursi n g i nfa nts sec o n dar y t o treat me nt of t he 
m ot her wit h Atez oliz u ma b , breastfee di n g s h o ul d be disc o nti n ue d if t he m ot her is 
treate d wit h Atez oliz u ma b. 
 
3. 3. 2 7  W o me n of c hil d -b eari n g p ote ntial a n d me n m ust a gree t o use a de q uat e c o ntrace pti o n 
( h or m o nal or barrier m et h o d of birt h c o ntr ol; a bsti ne nce) pri or t o st u d y e ntr y, f or t he 
d urati o n of st u d y partici p ati o n, a n d f or t he 5 m o nt hs ( 1 5 0 da ys) after t he last d ose of 
t he st u d y a ge nt. S h o ul d a w o ma n bec o me pre g na nt or s us pect s he is pre g na nt w hile 
s he or her part ner is p artici pati n g i n t his st u d y, s he s h o ul d i nf or m her treati n g 
p h ysicia n i m me diatel y.  
 
3. 3. 2 8  Patie nts ta ki n g bis p h os p h o nate t hera p y f or s y m pt o matic h y percalce mia.  Use of 
bis p h os p h o nate t hera p y f or ot her reas o ns ( e. g.ost e o p or osis) is all o we d.  
 
3. 3. 2 9  Patie nts wit h k n o w n pri mar y ce ntral ner v o us s yste m ( C N S) mali g na nc y or C N S 
metastases are e x cl u de d.  
 
3. 3. 3 0  Patie nts wit h a pri or k n o w n hist or y of vesic o va gi nal, e nter o va gi n al or c ol o n va gi nal  
Fist ula.  
 
 
 

 
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4.  R E Q UI R E M E N T S F O R S T U D Y E N T R Y, T R E A T M E N T, A N D F O L L O W -U P  
 
4. 1   
P R E -T R E A T M E N T A S S E S S M E N T S  
 
Assess me nts  
Pri or t o 
Re gistr ati o n  
 (c ale n d ar 
d a ys)  
Pri or t o 
tre at me nt 
st art 
 
Hist or y a n d P h ysical  
≤ 1 4 da ys    
≤ 1 4 da ys  
C o nc o mita nt Me dicati o ns  
≤ 1 4 da ys    
≤ 1 4 da ys  
Vital Si g ns  
≤ 1 4 da ys    
≤ 1 4 da ys  
Perf or ma nce Stat us  
≤ 1 4 da ys    
≤ 1 4 da ys  
T o xicit y Assess me nt  
≤ 1 4 da ys    
≤ 1 4 da ys  
C B C/ Differe ntial/ Platelets  
≤ 1 4 da ys    
≤ 1 4 da ys  
C he mistries ( B U N, Creati ni ne, S o di u m, P otassi u m, 
C hl ori de, C O 2, Calci u m, Gl uc ose, Bilir u bi n, Pr otei n, 
Al b u mi n, Al kali ne P h os p hatase, A S T, A L T)  
≤ 1 4 da ys    
≤ 1 4 da ys  
T S H  
≤ 1 4 da ys    
≤ 2 8 da ys  
He patitis B S urface A nti ge n  
≤ 2 8 da ys    
≤ 2 8 da ys  
He patitis B C ore A nti b o d y  
≤ 2 8 da ys    
≤ 2 8 da ys  
He patitis C A nti b o d y  
≤ 2 8 da ys    
≤ 2 8 da ys  
U P C R  
≤ 1 4 da ys    
≤ 1 4 da ys  
I N R a n d a P T T §  
≤ 2 8 da ys    
≤ 2 8 da ys  
Pre g na nc y Test (if c hil d b eari n g p ote ntial e xists)  
≤ 7 da ys    
≤ 7 da ys  
E K G ( Electr ocar di o gra m)  
≤ 2 8 da ys    
≤ 2 8 da ys  
P E T/ C T sca n  
≤ 2 8 da ys    
≤ 2 8 da ys  
 
 
 
Ra di o gra p hic T u m or Meas ure me nt *  
≤ 2 8 da ys    
≤ 2 8 da ys  
 
 
 
 
§ F or patie nts n ot recei vi n g t hera pe utic a ntic oa g ul ati o n.  
* Ra di o gra p hic t u m or meas ure me nts s h o ul d be o bt ai ne d via i ma gi n g of t he c hest, a b d o me n 
a n d pel vis  t o esta blis h t he l ocati o n a n d e xt e nt of disease. See R E CI S T 1. 1 f or all o wa ble 
i ma gi n g m o dalities used t o assess disease at b aseli ne (a n d s u bse q ue nt assess me nts). C o ntrast 
C T is t he preferre d m o dalit y.  
 

 
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4. 2   
A S S E S S M E N T S D U RI N G T R E A T M E N T  
Assess me nts  
Pri or t o e ac h 
tre at me nt of 
Atez oliz u m a b  
Hist or y a n d P h ysical  
X  
C o nc o mita nt Me dicati o ns *  
X  
C ortic oster oi d Use ( o nl y t o ma na ge a d verse e ve nts)  
X  
Sec o n dar y I m m u n os u p pressi ve A ge nt Use (e. g., i nfli xi ma b)  
X  
Vital Si g ns  
X  
Perf or ma nce Stat us  
X  
T o xicit y Assess me nt  
X  
C B C/ Differe ntial/ Platelets  
≤ 3 da ys  
C he mistries ( B U N, Creati ni ne, S o di u m, P otassi u m, C hl ori de, C O 2, 
Calci u m, Gl uc ose, Bilir u bi n, Pr otei n, Al b u mi n, Al kali ne 
P h os p hatase, A S T, A L T, A m ylase, Li pase)  
≤ 3 da ys  
T S H  
≤ 7 da ys  
*  D ue t o t heir i m m u n os u p pressi ve effect, a d mi nistr ati o n of s yste mic ster oi ds (e. g., 
de x a met h as o ne) as a n a ntie metic a n d/ or pre p ar ati ve re gi me n f or h y perse nsiti vit y 
re acti o ns s h o ul d be a v oi de d if ot her me a ns of tre at me nt are a v ail a ble a n d me dic all y 
a p pr o pri a te. 
 
4. 3   
A S S E S S M E N T S I N F O L L O W U P  
Assess me nts  
E n d of tre at me nt, 1 m o nt h a n d 3 m o nt hs, q 3 
m o nt hs f or 2 ye ars  
Me dical hist or y, p h ysical 
e xa mi nati o n, E C O G  perf or ma nce 
stat us, vital si g ns ( heart rate, bl o o d 
press ure, res pirat or y rate, 
te m perat ure), a n d vital st at us 
(i ncl u di n g a n y rec urre nce) 
1 m o nt h a n d 3 m o nt hs, q 3 m o nt hs f or 2 years  
T o xicit y Assess me nt  
1 m o nt h a n d 3 m o nt hs, q 3 m o nt hs f or 2 years  
Ra di o gra p hic t u m or meas ure me nt  
3 m o nt hs, 1 y ear, 2 yea r 
C B C / Differe ntial / Platelets  
C he mistries (i ncl u di n g s o di u m, 
p otassi u m, c hl ori de, bicar b o nate, 
calci u m, gl uc ose, ma g nesi u m, 
B U N/creati ni ne, t otal bilir u bi n, t otal 
pr otei n, A L T, A S T, al kali ne 
p h os p h atase, al b u mi n), T S H  
 
 
P E T/ C T, pre -sca n gl uc ose-
O P TI O N A L  
 
1 m o nt h a n d 3 m o nt hs  
 
 
 
 
 
 
 
 
3 m o nt hs  ( o pti o nal) 
 

 
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4. 4   
St u d y C ale n d ar  
 
A R M A  
 
 
 
 
A R M B  
 
 

 
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5.  T R E A T M E N T P L A N /R E GI M E N  D E S C RI P TI O N  
 
T his st u d y has t w o st u d y ar ms: 
 
Ar m A: will get o ne d ose of atez oliz u ma b pri or t o cis plati n c he m ot hera p y a n d ra diati o n t hera p y, 
a n d t he n t w o s u bse q ue nt d oses of atez oliz u m a b d uri n g t he c he m ot hera p y a n d ra diati o n t hera p y  
Re gi me n Descri pti o n Ar m A  
 
A ge nt    
Pre -me dic ati o ns; 
Prec a uti o ns  
 
D ose  
 
R o ute  
 
Sc he d ule  
Cycle 
Le n gt h  
Atez oliz u m a b  Pre parati ve 
a nti hista mi ne use 
is all o we d (e. g., 
di p he n h y dra mi ne 
2 5 m g I V)  
 
1 2 0 0 m g    
I V i nf usi o n 
deli vere d o ver 
6 0 ( 1 5) 
mi n utes.  If 
t he 
first i nf usi o n 
is t olerate d 
wit h o ut 
Ar m A: -
2 1 da ys, 
Da ys 0, 
2 1  
 
E ver y 3 
wee ks 
d osi n g  

 
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i nf usi o n 
ass ociate d 
A Es, t he 
sec o n d 
i nf usi o n ma y 
be deli vere d 
o ver 3 0 ( 1 0) 
mi n utes  
Cis pl ati n    
I n crease d oral 
i nta ke of fl ui d 
s h o ul d be 
e nc o ura g e d 2 4 
h o urs pri or t o 
i nf usi o n; 1 0 0 0 ml 
of ½ n or mal sali ne 
i nf use d I V o ne 
h o ur bef ore 
cis plati n. 
A ntie metic 
pr o p h yla xis wit h a 
ser ot o ni n 
a nta g o nist a n d/ or 
de xa met has o ne 1 0 -
2 0 m g I V is 
all o we d as a pre-
me dicati o n.  
4 0 m g/ m 2 ( 7 0 
m g 
ma xi m u m) 
dil ute d i n 
2 5 0 -1 0 0 0 ml 
n or mal sali ne, 
rec o nstit uti o n 
res ults i n a 
c ol orless 
s ol uti o n. 
Mi xi n g a n d 
a d mi nistrati o
n s h o ul d 
f oll o w l ocal 
sta n dar ds 
I V i nf usi o n at 
a rate of 
1 m g/ mi n, 
us uall y 
i nf usi n g o ver 
1 ½ h o urs ( 9 0 
mi n utes), 
usi n g n o n -
al u mi n u m 
a d mi nistrati o n 
sets; after is 
a n a d diti o nal 
1 0 0 0 ml of ½ 
n or mal sali ne 
i nf use d o ver 
o ne h o ur  
Da ys 0 , 
7,  
1 4 , 2 1, 
2 8, 3 5  
O ne ti me 
wee kl y 
(prefer a b
l y bef ore, 
b ut 
all o we d t o 
be  after 
pel vic 
ra diati o n 
treat me nt) 
 
Pelvic a n d 
P A L N 
exter n al  
be a m 
r a di ati o n 
t her a py 
S ki n, a ntie metic, or 
a nti-diarr heal 
me dicati o ns ma y 
be a d mi nistere d as 
nee de d.  
1. 8 G y/ da y  
 
See R T 
secti o n  
Dail y      
(e xcl u des 
wee ke n ds 
a n d 
h oli da ys)  
Dail y  
( Start o n a 
M o n da y is 
preferre d)  
I m a ge 
G ui de d 
Br ac hy -
t her a py 
A ntie metic a n d 
a nti-diarr heal 
me dicati o n ma y be 
a d mi nistere d as 
nee de d.  
Mi ni m u m 8 5 
G y t o C T V 
( E Q D 2) f or 
cer vical  
See R T 
secti o n   
See R T 
secti o n  
See R T 
Secti o n  
 
Ar m B: will get 3 d oses of atez oliz u ma b d uri n g t he cis plati n c he m ot hera p y a n d ra diati o n t hera p y  
Re gi me n Descri pti o n Ar m B  
 
A ge nt    
Pre -me dic ati o ns; 
Prec a uti o ns  
 
D ose  
 
R o ute  
 
Sc he d ule  
Cycle 
Le n gt h  
Atez oliz u m a b  Pre parati ve 
a nti hista mi ne use 
is all o we d (e. g., 
1 2 0 0 m g    
I V i nf usi o n 
deli vere d o ver 
6 0 ( 1 5) 
 
Ar m B: 
Da ys 0, 
E ver y 3 
wee ks 
d osi n g  

 
N R G -G Y 0 1 7  
2 3    
Versi o n Date:  N o ve m ber 8 , 2 0 1 8 
di p he n h y dra mi ne 
2 5 m g I V)  
 
mi n utes.  If 
t he 
first i nf usi o n 
is 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 deli vere d 
o ver 3 0 ( 1 0) 
mi n utes  
2 1, 4 2  
Cis pl ati n    
I n crease d oral 
i nta ke of fl ui d 
s h o ul d be 
e nc o ura g e d 2 4 
h o urs pri or t o 
i nf usi o n; 1 0 0 0 ml 
of ½ n or mal sali ne 
i nf use d I V o ne 
h o ur bef ore 
cis plati n. 
A ntie metic 
pr o p h yla xis wit h a 
ser ot o ni n 
a nta g o nist a n d/ or 
de xa met has o ne 1 0 -
2 0 m g I V is 
all o we d as a pre-
me dicati o n.  
4 0 m g/ m 2 ( 7 0 
m g 
ma xi m u m) 
dil ute d i n 
2 5 0 -1 0 0 0 ml 
n or mal sali ne, 
rec o nstit uti o n 
res ults i n a 
c ol orless 
s ol uti o n. 
Mi xi n g  a n d 
a d mi nistrati o
n s h o ul d 
f oll o w l ocal 
sta n dar ds 
I V i nf usi o n at 
a rate of 
1 m g/ mi n, 
us uall y 
i nf usi n g o ver 
1 ½ h o urs ( 9 0 
mi n utes), 
usi n g n o n -
al u mi n u m 
a d mi nistrati o n 
sets; after is 
a n a d diti o nal 
1 0 0 0 ml of ½ 
n or mal sali ne 
i nf use d o ver 
o ne h o ur  
Da ys 0 , 
7,  
1 4 , 2 1, 
2 8, 3 5  
O ne ti me 
wee kl y 
(prefer a b
l y bef ore, 
b ut 
all o we d t o 
be  after 
pel vic 
ra diati o n 
treat me nt) 
 
Pelvic a n d 
P A L N 
exter n al  
be a m 
r a di ati o n 
t her a py 
S ki n, a ntie metic, or 
a nti-diarr heal 
me dicati o ns ma y 
be a d mi nistere d as 
nee de d.  
1. 8 G y/ da y  
 
See R T 
secti o n  
Dail y      
(e xcl u des 
wee ke n ds 
a n d 
h oli da ys)  
Dail y  
( Start o n a 
M o n da y is 
preferre d)  
I m a ge 
G ui de d 
Br ac hy -
t her a py 
A ntie metic a n d 
a nti-diarr heal 
me dicati o n ma y be 
a d mi nistere d as 
nee de d.  
Mi ni m u m 8 5 
G y t o C T V 
( E Q D 2) f or 
cer vical  
See R T 
secti o n   
See R T 
secti o n  
See R T 
Secti o n  
 
Defi niti o n of Dise ase Assess me nts  
 
Res p o nse a n d pr o gressi o n will be e val uate d i n t his st u d y usi n g t he ne w i nter nati o nal criteria 

 
N R G -G Y 0 1 7  
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pr o p ose d b y t he re vise d Res p o nse E val uati o n Criteria i n S oli d T u m ors ( R E CI S T) g ui deli ne 
( versi o n 1. 1) [E ur J C a  4 5: 2 2 8 -2 4 7, 2 0 0 9].  C ha n ges i n t he lar gest dia meter ( u ni di me nsi o nal 
meas ure me nt) of t he t u m or lesi o ns a n d t he s h ortest dia meter i n t he cas e of mali g na nt l y m p h 
n o des are  us e d i n t he R E CI S T criteria.  
 
5 . 1  
C he m ot her a p y   
 
5. 1. 1  Cis plati n C he m ot hera p y  
All patie nts will recei ve si x  o ne -ti me wee kl y i ntra ve n o us i nf usi o ns of cis plati n 4 0 m g/ m 2 
( 7 0 m g ma xi m u m) dil ute d i n 2 5 0-1 0 0 0  m L n or mal sali ne. T he cis plati n i nf usi o ns  occ ur 
o n da ys 0 , 7, 1 4 , 2 1, 2 8, a n d 3 5. T o acc o m m o date sc he d uli n g iss ues, cis plati n 
a d mi nistrati o n is all o we d t o be after pel vic ra di ati o n treat me nt, b ut is prefera bl y d o ne 
pri or t o P R T . I ncreas e d oral i nta ke of fl ui d s h o ul d be e nc o ura ge d 2 4 h o urs pri or t o 
cis plati n i nf us i o n. It is rec o m me n de d t hat 1 0 0 0 ml of ½ n or mal sali ne be i nf use d 
i ntra ve n o usl y o ne h o ur b ef ore cis plati n i nf usi o n, b ut ot her i nstit uti o nal pr ot oc ols are 
acce pte d. A ntie metic pr o p h yla xis wit h a ser ot o ni n a nta g o nist is all o we d as a pre -
me dicati o n. It is rec o m m e n de d t hat t he cis plati n i ntra ve n o us i nf usi o n pr ocee d at a rate of 
1 m g/ mi n ute, us uall y i nf usi n g o ver 9 0 mi n utes. Ot her i nf usi o n rates are acce pta ble per 
i nstit uti o nal r o uti ne. N o n-al u mi n u m i ntra ve n o us a d mi nistrati o n sets are re q uire d. A n 
a d diti o nal 1 0 0 0  ml of ½ n or mal sali ne s h o ul d be i nf use d i ntra ve n o usl y o ver o ne h o ur 
after cis plati n i nf usi o n, b ut ot her i nstit uti o nal pr ot oc ols are acce pte d.   
 
5. 1. 2  A tezoliz u ma b  
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 me dical 
facilities a nd 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.  
 
All patie nts will recei ve t hree i ntra ve n o us i nf usi o ns of atez oliz u ma b 1 2 0 0 m g e ver y t hree 
wee ks. Ar m A will recei ve atez oliz u ma b treat me nt o n da ys -2 1, 0, a n d 2 1. Ar m B will 
recei ve atez oliz u ma b o n da ys 0, 2 1, 4 2.   T he atez oliz u ma b will be deli vere d d uri n g t he 
p ost -cis plati n h y drati o n o n t he da ys w he n b ot h dr u gs are a d mi nistere d o n Ar m A: da ys 0, 
a n d 2 1; Ar m B: da ys 0, 2 1, 4 2.  
 
T he i nitial d ose of atez oli z u ma b  will be deli vere d o ver 6 0 ( 1 5) mi n utes.  If t he 
first i nf usi on is 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 
deli vere d o ver 3 0 ( 1 0) mi n utes.   
 
F or t he first i nf usi o n, t he patie nt’s vital si g ns ( heart rate, res pirat or y rate, bl o o d press ure, 
a n d te m perat ure) s h o ul d be deter mi ne d wit hi n 6 0 mi n utes bef ore, d uri n g (e ver y 1 5 [ 5] 
mi n utes), a n d 3 0  (1 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 
will be c ollecte d wit hi n 6 0 mi n utes bef ore a n d wit hi n 3 0  mi n utes after t he  i nf usi o n.  Vital 
si g ns s h o ul d be c ollecte d d uri n g t he i nf usi o n o nl y if cli nicall y i n dicate d.  Patie nts will be 
i nf or me d a b o ut t he p ossi bilit y of dela ye d p ost-i nf usi o n s y m pt o ms a n d i nstr ucte d t o 
c o ntact t heir st u d y p h ysicia n if t he y de vel o p s uc h s y m pt o ms.  
 
Pre me dicati o n is n ot per mitte d f or t he first d ose of atez oliz u ma b.  Pre parati ve 
a nti hista mi ne use is all o we d at t he discreti o n of t he treati n g p h ysicia n.  T he ma na ge m e nt 

 
N R G -G Y 0 1 7  
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Versi o n Date:  N o ve m ber 8 , 2 0 1 8 
of I nf usi o n Relate d Reacti o ns will be acc or di n g t o se verit y as f oll o ws:  
 
•  I n t he e ve nt t hat a p atie nt e x perie nces a Gra de 1 I nf usi o n Relate d Reacti o n d uri n g 
t he first treat me nt, t he i nf usi o n rate s h o ul d be re d uce d t o half t he rate bei n g gi ve n 
at t he ti me of e ve nt o nset.  O nce 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 ut es w hile deli veri n g t he i nf usi o n at t he re d uce d rate.  If t ol erate d, 
t he i nf usi o n rate ma y t he n be i ncrease d t o t he ori gi nal rate. 
 
•  I n t he e ve nt t hat a patie nt e x perie nces a Gra de 2 I nf usi o n Relate d Reacti o n, or 
fl us hi n g, fe ver, or t hr oat pai n, t he i nf usi on s h o ul d be i m me diatel y i nterr u pt e d a n d 
t he patie nt s h o ul d recei ve a g gressi ve s y m pt o mati c treat me nt.  T he i nf usi o n s h o ul d 
be restart e d o nl y after t he s y m pt o ms ha ve a de q uat el 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 nf usi o n Relate d Reacti o n.  F or s u bse q ue nt 
i nf usi o ns, a d mi nister oral pre me dicati o n wit h a nti hista mi ne a n d a nti-p yreti c a n d 
m o nit or cl osel y f or I nf usi o n Relate d Reacti o ns.  
 
•  F or Gra de 3 or 4 I nf usi o n Relate d Reacti o ns, 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 (e. g., oral or I V a nti hista mi ne, a nti-p yretic, gl uc oc ortic oi ds, e pi n e p hri ne, 
br o nc h o dilat ors, o x y ge n) .  Atez oliz u ma b s h o ul d b e per ma ne ntl y disc o nti n ue d.  
Res u m pti o n of atez oliz u ma b ma y be c o nsi dere d i n patie nts w h o are deri vi n g 
be nefit a n d ha v e f ull y rec o vere d fr o m t he i m m u ne -relate d e ve nt; retreat me nt 
re q uires c o ns ultati o n wit h, a n d c o nse nt of, t he tri al Pri nci pal I n vesti gat or ( PI). 
 
F or a n a p h yla xis preca uti o ns, use t he f oll o wi n g pr oce d ure:  
 
E q ui p me nt Nee de d  
 
•  T o ur ni q uet  
•  O x y ge n  
•  E pi ne p hri ne f or s u b c uta ne o us, i ntra ve n o us, a n d/ or e n d otrac heal use i n acc or da nce 
wit h sta n dar d practice  
•  A nti hista mi nes  
•  C ortic oster oi ds  
•  I ntra ve n o us i nf usi o n s ol uti o ns, t u bi n g, cat heters, a n d ta pe  
 
Pr oce d ures  
 
I n t he e ve nt of a s us pect e d a na p h ylactic reacti o n d uri n g atez oliz u ma b i nf usi o n, t he 
f oll o wi n g pr oce d ures s h o ul d be perf or me d: 
 
1.  St o p t he st u d y dr u g i nf usi o n.  
2.  A p pl y a t o ur ni q uet pr o xi mal t o t he i njecti o n site t o sl o w s yste mic a bs or pti o n 
of  st u d y dr u g.  D o n ot o bstr uct arteri al fl o w i n t he li m b. 
3.  Mai ntai n a n a de q u ate air wa y.  

 
N R G -G Y 0 1 7  
2 6    
Versi o n Date:  N o ve m ber 8 , 2 0 1 8 
4.  A d mi nister a nti hista mi nes, e pi ne p hri ne, or ot her me dicati o ns as re q uire d b y 
patie nt stat us a n d directe d b y t h e p h ysicia n i n c har ge.  
5.  C o nti n ue t o o bser ve t he patie nt a n d d oc u me nt o bser vati o n.  
 
5 . 2  
R a di ati o n T he ra p y  
 
* * Please n ote t hat all cas es re q uire a pre -treat me nt re vie w. Please s ee secti o n 11 * *  
 
Ge ner al Pri nci p als  
 
T his pr ot oc ol re q uires p h ot o n e xter nal bea m ra diati o n t hera p y ( E B R T), wit h e xte n de d fiel d 
i nte nsit y m o d ulate d ra diati o n t hera p y (I M R T) tec h ni q ues f oll o we d b y l o w d ose rate ( L D R), 
p ulse d d ose rate ( P D R), or hi g h d ose rate ( H D R) brac h yt hera p y. All ra di ati o n t hera p y m ust be 
c o m plete d i deall y wit hi n 5 6 da ys of i nitiati o n (less t ha n or e q ual t o 5 9 da ys f or c o m plia nce).  
 
T he e xter n al bea m ra diati o n is gi ve n via I M R T wit h t he e xce pti o n of t he para metrial b o ost t o be 
3 D c o nf or mal R T or I M R T.  If fiel d size t o c o ver t he tar get meas ures lar ger t ha n i nstit uti o n’s 
li near accelerat or lar gest fiel d size f or cli nical use, a t w o-is oce nter tec h ni q u e is rec o m me n de d t o 
use f or pla n ni n g. T he prescri pti o n d ose is 4 5 G y i n 2 5 fracti o ns at 1. 8 G y/fracti o n, u nless a 
si m ulta ne o us i nte grate d b o ost ( SI B) is re q uire d f or gr oss n o dal disease. F or SI B cas es, t he gr oss 
n o dal P T V b o ost will recei ve 5 0 G y i n 2 G y/fracti o n, a n d t he n recei ve a se q ue ntial b o ost d ose of 
2 G y per fracti o n f or a t otal d ose of 5 4 -5 8 G y de pe n di n g o n t he c o ntri b uti o n of t he brac h yt hera p y 
a n d l ocati o n of t he l y m p h n o de or para metrial b o osts.  
 
I M R T s h o ul d be gi ve n o nce dail y M o nda y -Fri da y, 5 fracti o ns per wee k.  
  
F or brac h yt hera p y, t he prescri pti o n d oses are 2 7. 5 - 3 0 G y f or H D R a n d 3 5 - 4 0 G y f or L D R or 
P D R, f oll o wi n g i nstit uti o nal pr ot oc ol wit h i ma ge g ui de d brac h yt hera p y.  
 
If cli ps are pres e nt fr o m t he l y m p h n o de dissecti o n t o d oc u me nt t he p ositi o n of t he l y m p h n o des, 
t he n t hese s h o ul d be use d as a g ui de w he n a nteri or bl oc ks are desi g ne d t o s hiel d s mall b o wel.  
 
5. 2. 1 Tre at me nt Tec h n ol o g y  
 
T he f oll o wi n g treat me nt m o dalities i ncl u de p h ot o ns wit h I M R T, a n d i ma ge g ui de d 
brac h yt hera p y.   
 
E xter nal Bea m Ra diati o n T hera p y ( E B R T): Pel vic a n d P A L N: E xte n de d fiel d R T ( E F R T)  
 
Pel vis a n d P A L N ra di ot hera p y will be deli vere d vi a I M R T.  Pla ns ma y i ncl u de static fiel d 
arra n g e me nts (e. g. 5 -9 fiel ds) , m o d ulate d arc t hera p y, or T o m o T hera p y. A pse u d o-ste p-we d ge 
i nte nsit y m o d ulati o n ( P S WI M) tec h ni q u e is per mitte d. I M R T s h o ul d use 4-1 8 M V p h ot o ns.  
 
Para metrial a n d/ or N o dal B o ost  
A para metrial b o ost ca n be deli vere d at t he treati n g  p h ysicia n’s discreti o n a n d it ca n be 
acc o m plis he d via 3 D C R T or I M R T.  T he n o dal b o osts will be deter mi ne d b y t he treati n g 

 
N R G -G Y 0 1 7  
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Versi o n Date:  N o ve m ber 8 , 2 0 1 8 
p h ysicia n i n refere n ce t o t he dia g n ostic C T or P E T  sca n.  T he b o ost le vel of 5 4 G y or 5 8G y is 
deter mi ne d relati ve t o t he brac h yt h era p y c o ntri b uti o n i n t he pel v is.   
 
Brac h yt hera p y  
Hi g h d ose rate ( H D R), p ulse d d ose rate ( P D R), or l o w d ose rate ( L D R) brac h yt hera p y is 
per mitte d. Eit her sta n dar d ( p oi nt -directe d usi n g v ol u metric  brac h yt h era p y i ma gi n g or pla n ni n g 
f or or ga ns at ris k) or v ol u me-direct e d brac h yt hera p y te c h ni q ues are per mitte d acc or di n g t o eac h 
i nstit uti o n’s sta n dar d. V ol u me-directe d brac h yt h era p y is e nc o ura ge d. I ntraca vitar y (e. g., t a n de m 
a n d o v oi ds or ta n de m a n d ri n g) a n d/ or i nterstitial (e. g., i nterstitial a p plicat ors) brac h yt hera p y is 
per mitte d.  
 
5. 2. 2 I m m o biliz ati o n a n d Si m ul ati o n   
 
3 D pla n ni n g is re q uire d f or t his pr ot oc ol.  A C T si m ulati o n sca n is re q uire d wit h a slice t hic k ness 
≤ 3. 0 m m f or t he re gi o ns e xte n di n g at least 4c m a b o ve a n d bel o w tar get v ol u mes. Patie nts ca n be 
si m ulate d s u pi ne or pr o n e. It is rec o m me n de d t hat C T sca ns be o btai ne d fr o m t he T 1 0 verte bral 
b o d y t o 5 c m bel o w t he isc hial t u ber osities. All s u bjects will ha ve a c ust o mize d i m m o bilizati o n 
de vice (e. g., Al p ha Cra dl e or Vac -L oc) fa bricat e d at t he ti me of si m ulati o n.  I ntra ve n o us c o ntrast 
is rec o m me n de d t o vis ualize vessels better. Oral or rect al c o ntrast is use d at t he discreti o n of t he 
ra diati o n o nc ol o gist f or treat me nt pla n ni n g p ur p oses.   I ntra ve n o us c o ntrast is rec o m me n de d 
u nless me dicall y c o ntrai n dicate d.  
 
A f ull bla d der is i nte n de d t o be c o mf orta bl y fille d o n  t he treat me nt pla n ni n g C T sca n a n d 
t hr o u g h o ut t he treat me nt. Patie nts are as ke d t o dri n k 3 0 0-5 0 0 ml of li q ui d r o u g hl y 4 5 mi ns pri or 
t o t he C T si m ulati o n a n d treat me nt.  T he rect u m a n d si g m oi d s h o ul d be as e m pt y as p ossi ble. 
T he patie nt s h o ul d be as k e d t o e m pt y t he st o ols bef ore sca n ni n g a n d treat me nt.  If a n i nter nal 
tar get v ol u me (I T V) will be use d, it is rec o m me n de d t hat t he patie nt u n der g o b ot h a f ull a n d 
e m pt y bla d der C T si m ulati o n.  
 
T he i nferi or e xte nt or va gi nal e xte nsi o n of diseas e s h o ul d be mar ke d  s o t hat t he i nferi or b or der of 
disease ca n be d oc u m e nte d. U ni n v ol ve d n or mal tiss ues ma y be bl oc ke d alt h o u g h t he p ositi o n of 
t he uter us s h o ul d be c o nt o ure d t o e ns ure a de q uate c o vera ge.   
 
5. 2. 3 I m a gi n g f or Str uct ure Defi niti o n, I m a ge Re gistr ati o n/ F usi o n  
 
Pel vic M RI or P E T f usi o n wit h t he C T si m ulati o n sca n is rec o m me n de d t o ai d tar get deli neati o n. 
F usi o n s h o ul d be o pti mize d t o matc h t he M RI/ P E T sca ns t o t he treat me nt p ositi o n.  
 
 
5. 2. 4  T ar get V ol u me Defi niti o n a n d N o me ncl at ure  
 
All str uct ures m ust be na me d  f or di gital R T data s u b missi o n as liste d i n t he ta bles bel o w. Ca pital 
letters, s paci n g a n d use of u n dersc ores m ust be a p plie d e xactl y as i n dicat e d. Res u b missi o n of 
data ma y be re q uire d if l a beli n g of str uct ures d oes n ot c o nf or m t o t he sta n dar d DI C O M na m e 
liste d.  T he str uct ures mar ke d as “ Re q uire d” i n t he ta ble m ust be c o nt o ure d a n d s u b mitte d wit h 
t he treat me nt pla n. Str uct ures mar ke d as “ Re q uire d w he n a p plica bl e” m ust be c o nt o ure d a n d 

 
N R G -G Y 0 1 7  
2 8    
Versi o n Date:  N o ve m ber 8 , 2 0 1 8 
s u b mitte d w he n a p plica ble. 
  
T he Gr oss T u m or V ol u m e ( G T V), Cli nical Tar get V ol u me ( C T V) a n d Pla n ni n g Tar get V ol u me 
( P T V) will be c o nt o ure d o n all C T slices i n w hic h t he str uct ures e xist.  
 
T he defi niti o n of all v ol u mes will be i n acc or da nce wit h t he 1 9 9 3 I C R U Re p ort # 5 0: Prescri bi n g, 
Rec or di n g a n d Re p orti n g P h ot o n Bea m T hera p y a n d wit h t he 1 9 9 9 I C R U Re p ort # 6 2: 
Prescri bi n g, Rec or di n g a n d Re p orti n g P h ot o n Bea m T hera p y ( S u p ple me nt t o I C R U Re p ort # 5 0).   
 
Please see t he attac he d A p pe n di x III  Ra diati o n C o nt o urs f or e xa m ples of:  
 
St a n d ar d 
N a me  
 
Descri pti o n  
 
Det aile d S pecific ati o n  
G T V _ 4 5 0 0    
G T V t o recei ve 4 5 G y  
Re q uire d  
 
T he G T V is defi ne d as all k n o w n gr oss 
cer vical disease deter mi ne d fr o m 
ra di o gra p hic st u dies, cli nical 
i nf or mati o n, p h ysical e xa mi nati o n, 
e n d osc o pic e xa mi nati o n, a n d bi o ps y 
res ults. 
C T V _ 4 5 0 0    
C T V t o recei ve 4 5 G y  
Re q uire d  
 
It is rec o m me n de d t o di vi de t he C T V 
i nt o 3 s u b re gi o ns: C T V n ( n o dal), a n d 
C T V p 1 a n d C T V p 2 ( pri mar y).  C T V p 1 
will c o nsist of t he gr oss t u m or, cer vi x, 
a n d uter us, o varies a n d t u bes; C T V p 2 
c o nsists of t he para metria a n d s u peri or 
t hir d of t he va gi na ( or half of t he va gi na, 
if t he va gi na is cli nicall y i n v ol ve d). 
C T V n will i ncl u de t he P A L N re gi o n t o 
t he verte bral le vel of L 1/ L 2 i nters pace or 
3 c m cra nial t o gr oss P A L N disease, 
c o m m o n, e xter nal, a n d i nter nal iliac a n d 
presacral l y m p h n o des. It is acce pta ble t o 
i ncl u de t he mes orectal n o des i n C T V n.   
T he u p per b or der of t he C T V n s h o ul d n ot 
e xte n d a b o ve t h e c o nfl ue nce of t he 
c o m m o n iliac arteries wit h t he a orta (i.e., 
a ortic bif urcati o n), a n d s h o ul d be gi n n o 
l o wer t ha n s u peri or b or der of L 5.  
T he C T V n will be o btai ne d b y e ns uri n g 
a n a p pr o xi matel y 7 m m mar gi n ar o u n d 
t he vessels, pl us e xte nsi o n t o i ncl u de a n y 
a djace nt visi ble l y m p h n o des, 
l y m p h oceles, or perti ne nt s ur gical cli ps. 
T he presacral n o des s h o ul d be c o nt o ure d 
u ntil t he s u peri or b or der of t he S 3 

 
N R G -G Y 0 1 7  
2 9    
Versi o n Date:  N o ve m ber 8 , 2 0 1 8 
verte bral b o d y is reac he d; bel o w t his 
p oi nt t he n o dal v ol u me ca n be se parate d 
i nt o t w o str uct ures. T he e xter nal iliac 
n o des s h o ul d be c o nt o ure d t o t he s u peri or 
as pect of t he fe m oral hea d. C T V n s h o ul d 
be m o difie d t o e xcl u de b o ne, m uscle, a n d 
b o wel.  T he C T V s h o ul d n ot e xt e n d 
i nferi or t o t he isc hial t u ber osities. 
C T V _ 5 0 0 0  
(f or SI B sc he mes 
o nl y)  
C T V t o recei ve 5 0 G y  
Re q uire d  
  
Gr oss pel vic L N or P A L N.  T his c o nsists 
of t he gr oss n o dal area as defi ne d b y P E T 
a n d C T wit h a 7 m m e x pa nsi o n ar o u n d 
t he n o de or i ncl usi ve of cli nical 
e xte nsi o n.  
 
If a patie nt is t o be treate d wit h a 
para metri al b o ost, t his area is i ncl u de d i n 
t he C T V _ 5 0 00  
  
C T V _ 5 4 0 0  
(f or SI B sc he mes 
o nl y)  
 
 
 
C T V _ 5 8 0 0 (f or 
SI B sc he m es 
o nl y)  
 
 
 
C T V t o recei ve 5 4 G y  
Re q uire d  
 
 
 
 
C T V t o recei ve 5 8 G y  
Re q uire d  
Gr oss pel vic l y m p h n o des ( o bt urat or L N, 
i nter nal or e xter nal iliac L N) t hat will 
recei v e B T c o ntri b uti o n.  Para metrial 
b o osts will be i ncl u de d i n t his v ol u me.  
 
 
Gr oss P A L N or pel vic l y m p h n o des 
(c o m m o n iliac hi g h or l o w i nter nal or 
e xter nal iliac L N) t hat will N O T recei ve 
B T c o ntri b uti o n  
 
Para metrial b o ost v ol u mes will N O T be 
i ncl u de d i n t his v ol u me. 
 
 
I T V _ 4 5 0 0   
 I T V t o recei ve 4 5 G y 
C o nt o uri n g is 
re q uire d o nl y w he n 
I T V a p pr o ac h is use d. 
Patie nts s h o ul d be si m ulate d wit h b ot h a 
f ull a n d e m pt y bla d der (i. e., 2 si m ulati o n 
sca ns). C T V p a n d C T V n a n d P T V p a n d 
P T V n s h o ul d be deli neat e d as descri be d 
a b o ve o n t he pla n use d f or treat me nt 
(eit her t he f ull or e m pt y bla d der sca n).  
T he C T V p fr o m b ot h sca ns s h o ul d be 
f use d t o get her t o ge nerate t he I T V _ 4 5 0 0. 
A 7 m m mar gi n s h o ul d be a p plie d t o 
ge nerat e P T Vi.  
P T V _ 4 5 0 0    
P T V t o recei ve 4 5 G y  
Re q uire d  
Ar o u n d C T V p 1, a 1 5 m m u nif or m 
e x pa nsi o n s h o ul d be use d. Ar o u n d 
C T V p 2, a 1 0 m m u nif or m e x pa nsi o n 

 
N R G -G Y 0 1 7  
3 0    
Versi o n Date:  N o ve m ber 8 , 2 0 1 8 
 
s h o ul d be use d.  Ar o u n d C T V n, a 7 m m 
u nif or m e x pa nsi o n s h o ul d be use d. T hes e 
e x pa nsi o ns will ge nerat e P T V p 1, P T V p 2, 
a n d P T V n. P T V n a n d P T V p 1 a n d P T V p 2 
will be f use d t o ge nerate t he P T V _ 4 5 0 0. 
If t he I T V a p pr oac h is us e d, P T Vi s h o ul d 
be f use d wit h P T V n t o g e nerat e 
P T V 4 5 0 0.  
P T V _ 4 5 0 0 -0 3    
P T V - 3 m m fr o m s ki n 
s urface 
Re q uire d w he n 
a p plic a ble  
T he P T V s h o ul d be ma n uall y or 
a ut o maticall y tri m me d u p t o 3 m m fr o m 
t he s ki n s urface, if necessar y, t o s pare 
s ki n. H o we ver, t he C T V still nee ds t o be 
i ncl u de d e ntirel y wit hi n t he P T V. 
P T V _ 5 0 0 0  
(f or SI B sc he mes 
o nl y)  
P T V t o recei ve 5 0 G y  
Re q uire d  
 
Ar o u n d C T V _ 5 0 0 0, a 7 m m e x pa nsi o n is 
use d  
P T V _ 5 0 0 0 -0 3  (f or 
SI B sc he m es 
o nl y)  
P T V - 3 m m fr o m s ki n 
s urface 
Re q uire d w he n 
a p plic a ble   
 
T he P T V s h o ul d be ma n uall y or 
a ut o maticall y tri m me d u p t o 3 m m fr o m 
t he s ki n s urface, if necessar y, t o s pare 
s ki n.. H o we ver, t he C T V still nee ds t o be 
i ncl u de d e ntirel y wit hi n t he P T V. 
P T V _ 5 4 0 0  
(f or SI B sc he mes 
o nl y ) 
 
P T V _ 5 8 0 0  
(f or SI B sc he mes 
o nl y)  
 
 
P T V t o recei ve 5 4. 0 G y  
Re q uire d  
 
 
P T V t o recei ve 5 8. 0 G y  
Re q uire d  
7 m m u nif or m e x pa nsi o n ar o u n d 
C T V _ 5 4 0 0  
 
 
 
7 m m u nif or m e x pa nsi o n ar o u n d 
C T V _ 5 8 0 0  
P T V _ 5 4 0 0 -0 3   
(f or SI B sc he mes 
o nl y)  
 
 
 
 
P T V _ 5 8 0 0 -0 3  
 (f or SI B sc he mes 
o nl y)  
 
 
 
 
 
P T V - 3 m m fr o m s ki n 
s urface 
Re q uire d w he n 
a p plic a ble   
 
 
 
P T V - 3 m m fr o m s ki n 
s urface 
Re q uire d w he n 
a p plic a ble   
 
T he P T V s h o ul d be ma n uall y or 
a ut o maticall y tri m me d u p t o 3 m m fr o m 
t he s ki n s urface, if necessar y, t o s pare 
s ki n. H o we ver, t he C T V still nee ds t o be 
i ncl u de d e ntirel y wit hi n t he P T V. 
 
 
T he P T V s h o ul d be ma n uall y or 
a ut o maticall y tri m me d u p t o 3 m m fr o m 
t he s ki n s urface, if necessar y, t o s pare 
s ki n. H o we ver, t he C T V still nee ds t o be 
i ncl u de d e ntirel y wit hi n t he P T V. 

 
N R G -G Y 0 1 7  
3 1    
Versi o n Date:  N o ve m ber 8 , 2 0 1 8 
5. 2. 5  Critic al Str uct ure a n d A v oi d a nce Str uct ure N o me ncl at ure  
All str uct ures m ust be na me d f or di gital R T data s u b missi o n as liste d i n t he ta bles bel o w. Ca pital 
letters, s paci n g a n d use of u n dersc ores m ust be a p plie d e xactl y as i n dicat e d. Res u b missi o n of 
data ma y be re q uire d if l a beli n g of str uct ures d oes n ot c o nf or m t o t he sta n dar d DI C O M na m e 
liste d.  T he str uct ures mar ke d as “ Re q uire d” i n t he ta ble m ust be c o nt o ure d a n d s u b mitte d wit h 
t he treat me nt pla n.  Str uct ures mar ke d as “ Re q uire d w he n a p plica bl e” m ust be c o nt o ure d a n d 
s u b mitte d w he n a p plica ble. 
 
St a n d ar d 
N a me  
 
Descri pti o n  
 
Det aile d S pecific ati o n  
E xter nal    
E xter nal patie nt 
c o nt o ur e nc o m passi n g 
all patie nt a nat o m y 
wit h a si n gle c o nt o ur 
o n eac h slice  
Re q uire d  
 
N or mal tiss ues will be c o nt o ure d o n t he 
C T si m ulati o n sca n. T he tiss ue wit hi n t he 
s ki n s urface a n d o utsi de all ot her critical 
n or mal str uct ures a n d t h e P T V s h o ul d be 
c o nt o ure d o n e ver y slice a n d desi g nate d 
as “ E xter nal”.  
E -P T V _ 4 5 0 0    
All tiss ue e xcl u di n g t he 
P T V _ 4 5 0 0. Ge nerate d 
b y s u btracti n g t he P T V 
recei vi n g a d os e 4 5 G y 
fr o m E xter nal C o nt o ur 
Re q uire d  
A ll tiss ue e xcl u di n g t he P T V _ 4 5 0 0, a n d 
is ge nerate d b y s u btracti n g t he P T V 
recei vi n g a d os e of 4 5 G y fr o m 
“ E xter nal ”.  
S pc _ B o wel    
T he s pace t hat t he 
b o wel ma y occ u p y  
Re q uire d  
B o wel S pace will be c o nt o ure d 
be gi n ni n g fr o m t he a xial slice sit uate d 1 
c m s u peri or t o t he s u peri or -m ost slice 
c o ntai ni n g P T V (if b o wel is n ot prese nt 
at t his le vel, t he b o wel c o nt o ur will start 
fr o m its m ost s u peri or e xte nt), a n d will 
c o nti n ue t o its m ost i nferi or e xte nt i n t he 
pel vis. T he B o wel S pace will i ncl u de t he 
o uter m ost e xte nt of t he b o wel l o o ps pl us 
a n y s pace wit hi n t he a b d o mi nal ca vit y 
t he b o wel ma y occ u p y. I n di vi d ual l o o ps 
of b o wel s h o ul d n ot be c o nt o ure d 
se parat el y. B o wel S pace will be o utli ne d 
o n eac h a xial C T slice. Rect u m s h o ul d be 
c o nt o ure d se paratel y fr o m b o wel.  
Rect u m  
Rect u m  
Re q uire d  
 
T he o uter rectal wall will be c o nt o ure d 
a n d fille d i n, treati n g t he or ga n as a s oli d 
c o nti n u o us str uct ure, a n d will be d efi ne d 
fr o m t he le vel of t he si g m oi d fle x ure t o 
t he a n us. 

 
N R G -G Y 0 1 7  
3 2    
Versi o n Date:  N o ve m ber 8 , 2 0 1 8 
 
5. 2. 6   D ose Pres cri pti o n  
 
Tar get 
Sta n dar d 
Na me  
D ose 
( G y) 
Fracti o n 
Size ( G y)  
T otal # of 
Fracti o ns  
D ose 
S pecificati o n 
Tec h ni q ue  
P T V _ 4 5 0 0    
4 5    
1. 8  
2 5  
> = 9 5 % of P T V 
recei v es > = 4 5 
G y  
P T V _ 5 0 0 0 
(f or SI B 
sc he mes o nl y) 
5 0    
2  
2 5  
> = 9 5 % of P T V 
recei v es > = 5 0 
G y  
P T V _ 5 4 0 0  
 
 
P T V _ 5 8 0 0  
 (f or SI B 
sc he mes o nl y) 
5 4  
 
 
 
 
5 8  
 
2  
 
 
 
 
2  
 
2 7  
 
 
 
 
2 9  
 
> = 9 5 % of P T V 
recei v es > = 5 4 
G y  
> = 9 5 % of P T V 
recei v es > = 5 8 
G y  
 
Bla d der    
Bla d der  
Re q uire d  
 
T he o uter bla d der wall will be c o nt o ure d 
a n d fille d i n, treati n g t he or ga n as a s oli d 
c o nti n u o us str uct ure.    
Ki d ne y _ R  
 
Ki d ne y _ L  
Ki d ne y s 
Re q uire d  
 
T he o uter b o ne c o nt o ur will be deli neate d 
a n d fille d i n, treati n g t he ri g ht a n d left 
ki d ne y as a s oli d c o n ti n u o us str uct ure.  
S pi nal C or d  
 
 
 
 
D u o de n u m  
 
 
 
Li ver  
S pi nal c or d  
Re q uire d  
 
 
 
D u o de n u m  
Re q uire d  
 
 
Li ver  
Re q uire d  
T he s pi nal c or d will be c o nt o ure d a n d 
fille d i n, fr o m t he le vel of T 1 0/ T 1 1 t o t he 
L 1/ L 2 i nters pace  
 
 
T he d u o de n u m will be c o nt o ure d a n d 
fille d i n fr o m t he distal st o mac h t o t he 
jej u n u m 
 
 
T he li ver will be c o nt o ure d a n d fille d i n  
Fe m ur _ Bas e _ L    
Left fe m ur  
Re q uire d  
 
T he o uter c o nt o urs of t he left fe m oral 
base  will be deli neat e d a n d fille d i n, 
treati n g eac h as a s oli d c o nti n u o us 
str uct ure. D o n ot i ncl u de t he fe m oral 
nec k.   
Fe m ur _ Bas e _ R    
Ri g ht fe m ur  
Re q uire d  
 
T he o uter c o nt o urs of t he ri g ht fe m oral 
base  will be deli neat e d a n d fille d i n, 
treati n g eac h as a s oli d c o nti n u o us 
str uct ure. D o n ot i ncl u de t he fe m oral 
nec k.   

 
N R G -G Y 0 1 7  
3 3    
Versi o n Date:  N o ve m ber 8 , 2 0 1 8 
Pel vic or P A L N n o d al b o ost  
 
P A L N or p el vic n o d al b o ost is at t he discreti o n of t he treati n g ra diati o n o nc ol o gist. N o dal 
i n v ol ve me nt is defi ne d as a n y pel vic or c o m m o n iliac n o des if t he y are eit her P E T p ositi ve or t heir 
s h ort a xis dia meter is > 1 5 m m o n C T a n d/ or M RI or if n o des are f o u n d t o be hist ol o gicall y p ositi ve 
o n s ur gical sa m pli n g.  
 
T he P A L N b o ost will recei ve a SI B t o 5 0 G y i n 2 G y/fracti o n d uri n g t he E F R T.  After, t he L N b o ost 
w ill recei ve a b o ost d ose of 8 G y i n 2G y/fr acti o n f or a t otal d ose of 5 8 G y.  
 
T he pel vic L N b o ost  will recei ve a SI B t o 5 0 G y i n 2 G y/fracti o n d uri n g t he E F R T.  After, t he L N 
b o ost will rec ei ve a b o ost d ose of EI T H E R 4 G y i n 2 G y/fr acti o n f or a t otal d ose of 5 4 G y, or 8 G y 
i n 2G y/fr acti o n f or a t otal d ose of 5 8 G y.  T he l ocati o n of t he pel vic L N a n d brac h yt h era p y d ose 
c o ntri b uti o n will dictate t he decisi o n o n t he n o dal b o ost le vel of 5 4 G y or 5 8 G y.   Pel vic L N 
i ncl u di n g t he c o m m o n iliac, hi g h e xter nal or i nter nal L N will recei v e a d ose of 5 8 G y gi ve n t he 
mi n ute brac h yt hera p y c o ntri b uti o n.  Pel vic L N i n t he o bt u rat or s pace, mi d i nter nal iliac or e xter nal 
iliac L N will recei v e a d ose of 5 4 G y gi ve n t he brac h yt hera p y c o ntri b uti o n.   
 
P ar a metri al B o ost  
 
A para metrial b o ost ca n be deli vere d at t he treati n g p h ysicia n’s discreti o n. T he para metrial b o ost 
ma y be i ncl usi v e or i n cl ose a p pr o xi mati o n wit h a pel vic L N b o ost.  T he para metrial b o ost will 
be i ncl u de d i n t he I M R T v ol u mes, s pecifie d as C T V _ 5 0 0 0 as a SI B.  After war ds, t he para metri al 
b o ost will g o t o a fi nal d ose of 5 4 G y i n 2 G y/fracti o n.  T he v ol u me f or t he se q ue nt ial b o ost will 
be C T V _ 5 4 0 0.  T his b o ost ca n use a n I M R T or 3 D c o nf or mal R T arra n ge me nt.   I n ge neral, t he 
para metri al b o ost will ha ve t he s u peri or b or der s h o ul d be re d uce d t o i ncl u de o nl y t he tr ue pel vis 
a n d t he u p per b or der of t he tr ue pel vis is defi ne d a s 1 c m a b o ve t he i nferi or as pect of t h e 
sacr oiliac j oi nt. T he i nferi or b or der re mai ns t he sa me as i n t he pel vis fiel ds. A para metrial ce ntral 
fiel d bl oc k is a mi ni m u m of 4 c m wi de.  If I M R T pla n ni n g is use d, a mi dli ne str uct ure s h o ul d be 
use d t o mi ni mize d ose w here t here will be brac h yt hera p y c o ntri b uti o n.   
 
5. 2. 7  R a di ati o n C o m pli a nce Criteri a  
 
T ar get V ol u me C o nstr ai nts a n d C o m pli a nce Criteri a  
T he d ose is pres cri be d t o c o ver 9 5 % of t he P T V.  SI B d oses of 4 5 G y a n d 5 0 G y wit h t he b o ost 
d ose t o 5 4 G y a n d 5 8 G y.  T he D ma x per pres cri pti o n str uct ure is s pecifi e d i n t he ta ble bel o w .  
T he P T V _ 4 5 0 0 a n d P T V _ 5 0 0 0 will be e val uate d pri or t o t he c o ntri b uti o n of t he b o ost d oses 
w he n e val u ati n g t he pla n c o m plia nce as t hese P T V will c o ntai n t he b o ost P T V _ 5 4 0 0 a n d 
P T V _ 5 8 0 0.  T he P T V _ 5 4 0 0 a n d P T V _ 5 8 0 0 will be e val uate d fr o m t he c o m p osite pla n.  
   
 
N or malizati o n of D ose: T he pla n is n or malize d s uc h t hat 9 5 % of t he P T V _ v ol u me recei v es 
prescri pti o n d ose.  
 
N ote: De viati o n U nacce pta ble occ urs w he n d ose li mits f or Variati o n Acce pta ble  are n ot met  
 

 
N R G -G Y 0 1 7  
3 4    
Versi o n Date:  N o ve m ber 8 , 2 0 1 8 
N or m al Str uct ure C o ns tr ai nts a n d C o m pli a nce Criteri a 
Na me of Str uct ure  
D osi metric 
para meter  
Per Pr ot oc ol    
Variati o n Acce pta ble   
De viati o n 
U nacce pta ble  
Bla d der  
D 5 0 % ( G y)   
 < = 4 5    
< = 5 5  
> 5 5  
D 0. 0 3cc  ( G y)   
< = 5 2    
< = 5 7. 5  
> 5 7. 5  
Rect u m  
D 5 0 % ( G y)   
< = 4 5    
< =  5 4  
> 5 4  
D 0. 0 3cc  ( G y)   
< = 5 0    
< = 5 5  
> 5 5  
B o wel  
D 3 5 % ( G y)   
< = 3 5    
< = 5 0  
> 5 0  
D 0. 0 3cc  ( G y)   
< =  6 0    
< = 6 6  
> 6 6  
Fe m urs  
D 1 5 % ( G y)   
< = 3 0    
< = 5 0  
> 5 0  
D 0. 0 3cc  ( G y)   
< = 5 0    
< = 5 5  
> 5 5  
B ilateral Ki d ne y   
D 5 0 % ( G y)   
< = 1 8    
< = 2 0  
> 2 0  
Li ver  
D 5 0 % ( G y)   
< = 2 5    
< = 3 0  
> 3 0  
D u o de n u m    
D 5 0 % ( G y)   
< = 4 0    
< =  5 0  
> 5 0  
 
D 0. 0 3cc  ( G y)   
< = 5 6    
< = 6 0  
>  6 0  
S pi nal C or d    
D 0. 0 3cc  ( G y)   
< = 4 5    
< = 4 7. 5  
> 4 7. 5  
 
5. 2. 8    
I m a ge G ui de d Br ac h yt her a p y  
 
Ge ner al Pri nci p als  
All patie nts will be treate d wit h v ol u me -directe d brac h yt hera p y.  Eit her p oi nt -directe d 
v ol u met ric pla n ni n g or v ol u me-directe d brac h yt h era p y tec h ni q ues are per mitte d acc or di n g t o 
eac h i nstit uti o n’s sta n dar d.  C T pla n ni n g is re q uire d wit h or wit h o ut M RI g ui da nce.  
Na me of Str uct ure  
D osi metric 
para meter  
Per Pr ot oc ol    
Variati o n Acce pta ble  
De viati o n 
U nacce pta ble  
P T V _ 4 5 0 0  
D 9 5 % ( G y)   
> = 4 5    
> = 4 3. 6 5  
< 4 3. 6 5  
D 9 7 % ( G y)   
> = 4 3. 6 5    
> = 4 0. 5  
< 4 0. 5  
D 0. 0 3cc ( G y)   
< = 5 1. 7 5    
< = 5 4  
> 5 4  
  
D 9 5 % ( G y)   
> = 5 0    
> = 4 8. 5 0  
< 4 8. 5 0  
P T V _ 5 0 0 0    
D 9 7 % ( G y)   
> = 4 8. 5 0    
> = 4 5  
< 4 5  
  
D 0. 0 3cc ( G y)   
< = 5 7. 5    
< = 6 0  
> 6 0  
P T V _ 5 4 0 0  
D 9 5 % ( G y)   
> = 5 4    
> = 5 2. 4  
< 5 2. 4  
D 9 7 % ( G y)   
> = 5 2. 4    
> = 4 8. 6  
< 4 8. 6  
D 0. 0 3cc ( G y)   
< = 6 2. 1 0    
< = 6 4. 8  
> 6 4. 8  
P T V _ 5 8 0 0    
D 9 5 % ( G y)   
> = 5 8    
> = 5 5. 1  
< 5 5. 1  
  
D 9 7 % ( G y)   
> = 5 6. 2    
> = 5 2. 2  
< 5 2. 2  
  
D 0. 0 3cc ( G y)   
< = 6 6. 7    
< = 6 9. 6  
> 6 9. 6  
 
 
 
 
 

 
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Brac h yt hera p y d ose pres cri pti o ns ma y be t o  a v ol u metric str uct ure or p oi nt A.  If a v ol u me 
directe d tar get v ol u me is use d, t he hi g h ris k C T V ( C T V _ H R ) will be o btai ne d fr o m t he C T 
pla n ni n g sca n, or wit h t h e a d diti o nal i nf or mati o n of a G T V fr o m a n M RI.  A pel vic M RI is 
e nc o ura g e d ( ≤ 3 m m slice t hic k ness) wit h eit her t he first or sec o n d i nserti o n. A C T a n d M RI -
c o m pati ble a p plicat or will be re q uire d t o p erf or m v ol u me -directe d brac h yt hera p y. S u bse q ue nt 
i nserti o ns ma y use C T or M RI ( T 2 s e q ue nce wei g hti n g) f or pla n ni n g.   
 
Use of I M R T or ot her e xter nal be a m tec h ni q ues i n place of brac h yt h era p y t o b o ost gr oss cer vical 
disease is e x pressl y disc o ura ge d. If dee m e d necess ar y or ess e ntial f or t he patie nt’s care (e. g., if a 
patie nt ref uses brac h yt h era p y), reas o ns f or n ot perf or mi n g brac h yt hera p y s h o ul d be d oc u me n te d 
a n d t he st u d y PI (J y oti Ma ya de v) s h o ul d be n otifie d.  
 
Eit her H D R, P D R, or L D R brac h yt hera p y is per mitte d acc or di n g t o eac h i nstit uti o n’s sta n dar d.   
I nstit uti o ns m ust a d here t o t heir declare d brac h yt h era p y re gi me n f or all patie nts treate d o n t his 
pr ot oc ol. It is all o we d t o a d mi nister m ore t ha n o ne B T fracti o n b y use of t he sa me i m pla nt.  
 
Ti mi n g a n d fr acti o n ati o n of Br ac h yt her a p y   
E B R T or c he m ot hera p y s h o ul d n ot be gi ve n o n t he da y of H D R brac h yt hera p y. T he 
brac h yt hera p y ma y start i n wee k 4, 5 or a t t he e n d of e xter nal bea m ra di ot hera p y. T w o i ns erti o ns 
per wee k ma y be d o n e. F or L D R brac h yt h era p y, t he patie nt will recei ve a n i ntraca vitar y i m pla nt 
i n o ne or t w o a p plicati o ns after t he E B R T.  I n L D R p oi nt-directe d brac h yt hera p y, if 2 i nserti o ns 
are use d t h e y s h o ul d be s e parat e d b y a mi ni m u m of 7 da ys a n d ma xi m u m of 2 1 da ys. If 2 
i nserti o ns are use d, t he sec o n d i m pla nt s h o ul d be c o m plete d wit hi n t hree wee ks of t he 
c o m pleti o n of e xter n al bea m irra di ati o n.  P D R brac h yt hera p y ca n be deli vere d usi n g a n Iri di u m -
1 9 2 s o urce wit h t he sa me sc he d ule as L D R. E B R T a n d brac h yt h era p y m a y n ot be a d mi nistere d 
o n t he sa me da y.   
 
Br ac h yt her a p y S o urce  
Iri di u m-1 9 2 is t he preferre d s o urce f or H D R a n d P D R brac h yt hera p y. Cesi u m -1 3 7 is t he 
preferre d s o urce f or L D R brac h yt hera p y.  All brac h yt hera p y s o urces m ust be liste d o n t he j oi nt 
A A P M/I R O C H o ust o n Re gistr y of Brac h yt hera p y S o urces i n or der t o be utilize d o n N C T N 
cli nical trials ( htt p://ir oc h o ust o n. m da n ders o n. or g/ R P C/ Brac h y See ds/ S o urce _ Re gistr y. ht m  ). 
 
A p plic at ors  
Brac h yt hera p y a p plicat or selecti o n is base d o n t he discreti o n of t he ra diati o n o nc ol o gist t o 
a de q uatel y c o ver t he cli nical tar get v ol u me a n d t u m or.  
Brac h yt hera p y a p plicati o ns t hat are acce pta ble i ncl u de:  
I ntraca vitar y a p plicat ors: Ta n de m a n d ri n g or t a n dem a n d o v oi ds  
I ntraca vitar y-I nt erstitial a p plicat ors “ H y bri d”:  Ta n de m a n d ri n g wit h nee dl es; ta n de m a n d o v oi d 
wit h nee dles  
I nterstitial a p plicat ors: T a n de m a n d c yli n ders wit h nee dles  
 
Si m ul ati o n  
F or 3 D brac h yt hera p y pl a n ni n g, all s u bjects will u n der g o a C T ( or P E T/ C T) si m ulati o n sca n 
usi n g a slice t hic k ness ≤ 3. 0 m m wit h brac h yt hera p y a p plicat ors a n d d u m m y s o urces i n. It is 
rec o m me n de d t h at C T sca ns c o ntai n t he e ntire brac h yt hera p y a p plicat ors a n d t he critical 

 
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str uct ures s uc h as bla d der, rect u m, a n d si g m oi d. Mai ntai ni n g a p plicat or p ositi o n is re q uire d fr o m 
t he ti me of a p plicat or i ns erti o n t o si m ulati o n a n d treat me nt.  Bla d der c o ntrast a n d rectal c o n trast 
are per mitte d.  I n H D R brac h yt hera p y, a fi xati o n de vice ca n mi ni mize a p plicat or r otati o ns. 
Peri o dic c he c ks d uri n g P D R/ L D R brac h yt hera p y, a n d i nitial a n d fi nal c hec k i n H D R 
brac h yt hera p y are rec o m me n de d t o m o nit or c ha n ges i n t he a p plicat or p ositi o n.  
 
A p plic at or Rec o nstr ucti o n  
A p plicat or rec o nstr ucti o n will f oll o w i nstit uti o nal pr ot oc ols.  U ncertai nties of a t least half t he 
slice t hic k ness ca n b e prese nt i n a p plicat or rec o nstr ucti o n. De viati o ns of d ose > 1 0 % are c o m m o n 
f or a p plicat or dis place me nt of 3 m m (al o n g i ntra uteri ne a xis) f or C T V _ H R ( D 1 0 0, D 9 0) a n d 
rect u m, bla d der a n d si g m oi d ( D 2cc).  D u m m y wires or C T rec o nstr ucti o ns li brar y pla ns are 
o pti mal f or C T base d pla n ne d.  F or M RI rec o nstr ucti o ns, t he C T pla n ni n g sca n ma y be re gistere d 
t o t he M RI dataset b y usi n g defi ne d mar ker p oi nts or ot her re gistrati o n tec h ni q ues. Direct 
rec o nstr ucti o n ca n be a p plie d i n M RI w he n mar kers are i nserte d i nt o t he a p plicat or c ha n nels.  
 
Br ac h yt her a p y C o nt o urs  
C o nt o uri n g of G T V ( bas e d o n t he M RI o nl y), C T V _ H R , bla d der, rect u m a n d si g m oi d.  N o 
mar gi ns s h o ul d be a d de d t o t he c o nt o urs.  
 
Det aile d S pecific ati o ns  
Brac h yt hera p y ( V ol u me -directe d)  
C T or M R i ma ges s h o ul d be use d t o deli neate t he tar get v ol u me. I deall y M RI bas e d tar get 
deli neati o n s h o ul d be use d t o i de ntif y t he G T V. T he M RI ca n be re us e d b y s u peri m p ositi o n i n 
t he pr ocess of c o nt o uri n g o n C T, if f or s u bse q ue nt fracti o ns of brac h yt hera p y o nl y C T ca n be 
use d wit h t he a p plicat or i n place. N o pla n ni n g mar gi ns will be a d de d t o  C T V _ H R . 
 
Tar get v ol u mes: T he d efi niti o ns of tar get v ol u mes will be i n acc or da nce wit h t he 2 0 1 3 I C R U 
Re p ort # 8 9 a n d G E C -E S T R O/ A B S rec o m me n dati o ns . 
 
G T V : Macr osc o pic t u m or (if pres e nt) at ti me of brac h yt hera p y 
Hi g h Ris k -C T V ( C T V _ H R ): G T V + w h ole cer vi x + e xtra cer vical t u m or e xte nsi o n at ti me of 
brac h yt hera p y  
 
Str uct ure Na me  (f or v ol u me-
directe d brac h yt hera p y)    
Detaile d S pecificati o n  
G T V  Re q uire d  
Macr osc o pic t u m or at ti me of brac h yt hera p y s ee n o n M RI  
C T V
H R Re q uire d    
G T V + cer vi x + macr osc o pic e xte nsi o n or para metrial i n v ol ve me nt  
Bla d der  Re q uire d  
T he o uter bla d der wall is c o nt o ure d as s ee n o n t he 3 D pla n ni n g 
sca n.  T he o uter wall is c o nt o ure d. 
Rect u m  Re q uire d  
T he o uter rectal wall is c o nt o ure d fr o m a b o ve t he a nal s p hi ncter t o 
t he le vel of tra nsiti o n i nt o t he si g m oi d. 

 
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Si g m oi d  Re q uire d  
T he o uter si g m oi d wall is t o be c o nt o ure d fr o m t he rect o -si g m oi d 
fle x ure t o 2 c m s u peri or t o t he para metria a n d t he uter us. 
 
I C R U P oi nt Descri pti o ns a n d Re p orti n g (f or p oi nt-directe d br ac h yt her a p y)  
T he I C R U bla d der, rect u m a n d va gi nal s urface refere nce p oi nt d oses m ust be calc ulate d a n d 
re p orte d. Pleas e f oll o w t he defi niti o ns i n I C R U 3 8. 
F or eit her v ol u me-directe d or  p oi nt -directe d brac h yt hera p y, t he d ose t o p oi nts A f or sta n dar d 
a p plicati o n ( n o n -i nterstitial a n d n o n-h y bri d cases)  m ust t o be d oc u me nte d.  
 
Br ac h yt her a p y D ose O pti miz ati o n  
 
Brac h yt hera p y o pti mizati o n i ncl u des t he use of sta n dar d l oa di n g patter ns f or d ose p oi nt 
o pti mizati o n, ma n ual l oa di n g of d well ti mes or wei g ht, gra p hical o pti mizati o n, or i n verse 
o pti mizati o n.   T he p h ysicia n a n d p h ysicist s h o ul d re vie w t he o p ti mizati o n base d o n d ose v ol u me 
hist o gra ms, pla n re vie w, a n d d ose c o nstrai nts f or f urt her o pti mizati o n of t he brac h yt h era p y pl a n.  
F or t he H D R brac h yt h era p y, t he E Q D 2 d ose (T ot al Bi ol o gical E q ui vale nt D ose i n 2 G y 
Fracti o ns ) usi n g m o del ass u m pti o ns base d o n t he li near q ua dratic m o del will be use d f or t he 
i n di vi d ual treat me nt pla n ni n g.  A n e xa m ple of t he E Q D 2 w or ks heet is pr o vi de d b y t he A merica n 
Brac h yt hera p y S ociet y:  
htt ps:// w w w.a merica n brac h yt hera p y. or g/ g ui deli nes/ g y n _ H D R _ B T _ d oc u _s heets. xls  
 
Br ac h yt her a p y D ose Prescri pti o n  
 
I n p oi nt-directe d a p pr oac h, t he d oses of 2 7. 5 - 3 0 G y a n d 3 5 - 4 0 G y will b e deli vere d t o t he 
p oi nt A f or H D R  a n d L D R  or P D R brac h yt hera p y , res pecti vel y as i n t he ta bles bel o w. T he H D R 
a n d P D R brac h yt hera p y d ose ca n be prescri be d t o a  hi g h -ris k cli nical tar get v ol u me (C T V _ H R ) 
as v ol u me-direct e d a p pr oac h, b ut p oi nt A d ose m ust be d oc u me nte d.  
 
H D R -P oi nt A deter mi ne d i m pla nt or v ol u me directe d a p pr oac h  
T ot al E B R T 
( G y)  
# H D R 
fr acti o ns 
H D R P oi nt A 
d ose/fr acti o n or 
C T V
H R   ( G y) 
T ot al H D R 
p oi nt A d ose or 
C T V
H R  ( G y) 
T ot al P oi nt A  
or C T V _ H R  
E Q D 2 -G y 1 0 
4 5  
4  
7. 0  
2 8. 0  
8 3. 9  
4 5  
5  
5. 5  
2 7. 5  
7 9. 8  
4 5  
5  
6. 0  
3 0. 0  
8 4. 3  
 
P D R a n d L D R -P oi nt A deter mi ne d i m pla nt  
T ot al E B R T 
( G y)  
# L D R 
fr acti o ns 
L D R P oi nt A 
d ose/fr acti o n 
( G y) 
T ot al L D R 
p oi nt A d ose 
( G y) 
T ot al P oi nt A 
d ose ( G y)  
4 5  
1  
3 5 -4 0  
3 5 -4 0    
8 0 -8 5  
4 5  
2  
1 7. 5 -2 0    
3 5 -4 0    
8 0 -8 5  
 
T ar get a n d N or m al Tiss ue C o m pli a nce Criteri a:  E B R T + H D R/ P D R v ol u me -directe d or 
H D R/ P D R/ L D R p oi nt -directe d b r ac h yt her a p y  
 

 
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D ose c o ntri b uti o n fr o m E B R T is ass u me d t o be prescri pti o n d ose ( 4 5 G y) a n d d oses are 
c u m ulati ve E Q D 2 ( α / β = 1 0 f or tar get, α / β = 3 f or n or mal tiss ues)  f or H D R a n d p h ysical d oses f or 
P D R / L D R.  
 
Na me of Str uct ure  D osi metric para m eter  
Per Pr ot oc ol  Variati o n 
Acce pt a ble  
De viati o n 
U nacce pta ble  
P oi nt A ( p oi nt -
directe d)  
 
P oi nt A ( G y)  
 
8 0 -8 5  
 
> 9 0  
 
< 7 5  
C T V _ H R  
(v ol u me -d irect e d) 
D 9 0 % ( G y) 
 
8 0 -9 0    
> 9 0    
 
Bla d der  
Bla d der *  
D 2cc  ( G y) 
I C R U 3 8 pt 
< = 8 0  
< = 8 5  
< = 9 0  
< = 9 0  
> 9 0  
> 9 5  
Rect u m  
Rect u m *  
D 2cc ( G y)  
I C R U 3 8 pt 
< = 6 5  
< = 6 5  
< = 7 5  
< = 8 0  
> 7 5  
Si g m oi d    
D 2cc ( G y) 
< = 7 5    
< = 7 5    
> 7 5  
Va gi nal S urf *    
I C R U 3 8 pt   
< = 1 5 0    
 < = 1 7 5    
 
 
* F or P oi nt -directe d brac h yt hera p y a n d I C R U 3 8 refere nce p oi nt descri pti o n. (Va gi nal _ S urf = 
va gi nal s urface p oi nt ) 
 
It is rec o m me n de d t o kee p t he ma xi m u m b o wel d ose < 2 5 % of t he brac h yt hera p y prescri pti o n 
d ose.  T he P oi nt A d ose will be rec or de d b ut t here is n o s pecificati o n o n t he d ose t o P oi nt A if 
v ol u metric pla n ni n g is use d.  
 
Br ac h yt her a p y V ol u metric D ose Re p orti n g  
 
F or v ol u me -directe d brac h yt hera p y, u nif or m d ose v ol u me re p orti n g acc or di n g t o t he I C R U 
Re p ort # 8 9 a n d G E C -E S T R O rec o m me n dati o ns . F or eac h fracti o n t he f oll o wi n g para meters 
s h o ul d be c ollecte d a ut o maticall y  i n R A V E w he n s u b mitti n g t he C T str uct ure set or M R  
str uct ures set a n d d os e file t o T RI A D:    
 
• T R A K  
• D 1 0 0 a n d D 9 8 f or G T V, C T V _ H R  
• D 9 0 f or G T V a n d C T V _ H R  
• D 5 0 f or C T V _ H R   
• V 1 0 0 f or C T V _ H R   
• D 2cc of t he bla d der, rect u m, si g m oi d a n d s mall b o wel (f or H D R, E Q D 2 per f or m ula E Q D 2 = 
D *[( d + α/ β)/( 2 + α/ β)]  usi n g α/ β = 3)  
 
Deli ver y C o m pli a nce Criteri a  
 
 
Per Pr ot oc ol    
Variati o n 
Acce pt a ble  
De viati o n 
U nacce pta ble  
O verall Treat me nt 
ti me 
≤ 5 6 da ys    
≤ 5 9 da ys    
> 6 0 da ys  

 
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5. 2. 9  R a di ati o n Tre at me nt Pl a n ni n g Pri orities a n d I nstr ucti o ns  
- Critical Str uct ure a n d Tar get pri orities are liste d i n or der of decreasi n g i m p orta nce 
 
E B R T  
1.  P T V  
2.  B o wel  
3.  Rect u m  
4.  Bla d der  
5.  Fe m urs  
 
Brac h yt hera p y  
1. C T V _ H R (if v ol u me -directe d pla n us e d)  
2. Si g m oi d   
3. Rect u m  
4.  Bla d der  
 
If d ose c o nstrai nts of critical str uct ures are e xcee de d, t he f oll o wi n g s ol uti o n is s u g geste d:  
F or v ol u me -directe d brac h yt hera p y, if t he treat me nt pla n ni n g s yste m pr o vi des a ma n ual 
o pti mizati o n o pti o n, t he pla n ca n be m a n uall y o pti mize d t o re d uce d os e t o t he critical str uct ures 
as l o n g as D 9 0 of C T V meets tar get v ol u me c o nstrai nts. T he use of i nterstitial brac h yt hera p y is 
s o meti mes usef ul t o i m pr o ve t he c o vera ge a n d decrease t h e O A R d ose b ut t his tec h ni q ue s h o ul d 
be use d w he n i n dicate d a n d b y trai ne d p h ysic ia ns. 
 
-Re q uire d al g orit h ms  
( C o n v ol uti o n/ S u per p ositi o n, M o nte Carl o, etc. …) 
F or C o n v ol uti o n/ S u per p ositi o n -t y pe al g orit h ms, d ose s h o ul d be re p orte d as c o m p ute d i n here ntl y 
b y t he gi ve n al g orit h m.  F or M o nte Carl o or Gri d Base d B oltz ma n n S ol ver al g orit h ms, 
co n versi o n of D m ( d os e -t o-me di u m) t o D w ( d ose -t o-water) s h o ul d be a v oi de d. D m, c o m p ute d 
i n here ntl y b y t hese al g orit h ms, s h o ul d be re p orte d. 
 
-Pri mar y dataset f or d ose calc ulati o n  
E B R T  
T he pri mar y dat a set f or d ose calc ulati o ns is C T. I n t he case i n w hic h c o ntrast is prese nt d uri n g 
t he treat me nt pla n ni n g C T, t he de nsit y of t he c o ntrast s h o ul d be o verr o de t o a re prese ntati ve 
bac k gr o u n d el ectr o n de nsit y. Heter o ge neit y c orrecti o ns m ust be a p plie d.  
 
Brac h yt hera p y  
Pla n ni n g C T i ma ges are t he pri mar y dat aset f or d os e calc ulati o n. If M R i ma ges are us e d f or d os e 
calc ulati o n, a met h o d of c orrecti n g i ma ge dist orti o n a n d tiss ue de nsit y has t o be a p plie d. 
Heter o ge n eit y c orrecti o ns are n ot ma n dat or y.  
 
-D ose matri x res ol uti o n  
D ose gri d size s h o ul d be ≤ 3 m m ( prefera bl y ≤ 2 m m t o mi ni mize effects of partial v ol u me 
a vera gi n g) i n all directi o ns.  
 

 
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5. 2. 1 0  P atie nt s pecific Q A  
F or I M R T/ V M A T pla ns, patie nt -s pecific Q A is hi g hl y rec o m me n de d. A n y patie nt-s pecific Q A 
perf or me d s h o ul d f oll o w res pecti ve i nstit uti o nal g ui deli nes. T he rec o m me n de d patie nt s pecifi c 
Q A criteri o n  is t hat 9 0 % of t he c o m paris o n p oi nts  pass a ± 3 %/ 3 m m  Ga m ma I n de x a nal ysis as 
rec o m me n de d. 
 
5. 2. 1 1  D ail y Tre at me nt L oc aliz ati o n/I G R T  
 
I ma ge-g ui de d ra diati o n t hera p y (I G R T) is ra di ati o n t hera p y usi n g i ma gi n g t o facilitate acc urac y 
a n d precisi o n t hr o u g h o ut its e ntire pr ocess fr o m tar get a n d n or mal tiss ue deli neati o n, t o ra diati o n 
deli ver y, t o a da ptati o n of t hera p y t o a nat o mic a n d bi ol o gical c ha n ges o ver ti me i n i n di vi d ual 
patie nts. I n t his secti o n we us e t he ter mi n ol o g y I G R T t o f oc us o n i ma ge -g ui da nce at t he ti me of 
ra diati o n deli ver y t o e ns ure its a d here nce t o t he pl a n ne d treat me nt. 
 
E B R T  
Dail y I G R T is re q uire d f or t his pr ot oc ol w he n t he I M R T treat me nt tec h ni q ue is use d. A n y f or m 
of o nli ne i ma gi n g is ac ce pta ble, s uc h as M V or k V pla nar i ma gi n g, M V C T or M V C B C T, k V 
C B C T, C T o n rails, etc. T he A A P M rec o m me n dati o ns f or verif yi n g t he c oi nci de nce of t he 
i ma gi n g a n d treat me nt refere n ce p oi nts m ust be a d here d t o t he dail y use of I G R T. At t he ti me of 
si m ulati o n, it is rec o m me n de d t o place t he is oce nt er al o n g t he patie nt’s mi dli ne 1. 5 c m ca u dal t o 
t he i nferi or b or der of t h e sacr oiliac j oi nt. I n ge neral, t he C T or C B C T will be use d f or s et u p 
verificati o n usi n g b o ne la n d mar ks o nl y a n d n ot f or s oft tiss ue ali g n me nt. S mall s oft tiss ue s hifts 
( ≤ 3 m m) are acce pta ble. Ot her wise, t he treati n g p h ysicia n ma y elect t o p ost p o ne treat me nt or re-
si m ulate. 
 
M a n a ge me nt of R a di ati o n D ose t o t he P atie nt fr o m I G R T  
N R G O nc ol o g y is c o ncer ne d a b o ut t he esti mate d d oses gi ve n fr o m I G R T, a n d is c o m mitte d t o 
li miti n g t he i ma gi n g d ose w he n I G R T is use d i n a n y of its pr ot oc ols. T his ca n be acc o m plis he d 
b y a v oi di n g t he use of t his tec h n ol o g y t o ma ke s mall c ha n ges i n patie nt p ositi o ni n g t hat are 
wit hi n t he state d P T V mar gi ns. T he i ma gi n g d ose t o t he patie nt ma y bec o m e si g nifica nt if 
re peat e d st u dies are perf or me d f or patie nts wit h s e vere s et u p pr o ble ms (e. g. re q uiri n g fre q ue nt 
c orrecti o ns t hat are lar ger t ha n t he P T V mar gi ns) . It is rec o m me n de d t hat patie nts de m o nstrati n g 
se vere s et-u p pr o ble ms  d uri n g t he first wee k of treat me nt be m o ve d t o a treat me nt wit h lar ger 
mar gi ns.  
 
5. 2. 1 2    
Ge ner al C o nc o mit a nt Me dic ati o n a n d S u p p orti ve C are G ui deli nes  
 
R a di ati o n T her a p y S u p p orti ve C are G ui deli nes  
 
Patie nts s h o ul d recei ve f ull s u p p orti ve care, i ncl u di n g tra nsf usi o ns of bl o o d a n d bl o o d 
pr o d ucts, s u p ple me ntal ir o n, a nti bi otics, a nti -e metics, etc., w he n a p pr o priate at t he 
discreti o n of t he treati n g p h ysicia n. Beca use it has bee n o bser ve d t hat he m o gl o bi n  
le vels bel o w 1 0-1 2 g/ d L d uri n g ra di ot hera p y are ass ociate d wit h decreas e d l ocal 
c o ntr ol, bl o o d tra nsf usi o ns s h o ul d be offere d t o a n d use d t o treat patie nts at t he 
discreti o n of treati n g p h ysicia ns pri or t o or d uri n g ra di ot hera p y. T here s h o ul d be n o 
ra di othera p y treat me nt d ela ys d ue t o a l o w he m o gl o bi n le vels. Trials e val u ati n g 

 
N R G -G Y 0 1 7  
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e p oeiti n al p ha ( Pr ocrit, E p o ge n) a n d ra di o -c he m ot hera p y i n cer vical ca ncer ha ve 
i n dicate d t hat e p oeiti n al p ha ma y be ass o ciate d wit h a n i ncreas e d ris k f or 
t hr o m b oe m b olis m, a n d t h us, ma y n ot be use d i n t his st u d y.  
 
I n p artic ular, p atie nts s h o ul d be t ol d t o be a ware of t heir t y pical defecati o n patter n. At 
t he first si g n t hat t heir st o ols bec o me s ofter t h a n us ual or t he y ha ve a n y i n creas e i n 
st o ol fre q ue nc y o v er w h at is n or mal f or t he m, t he y s h o ul d be gi n ta ki n g o ver-t he-
c o u nter l o pera mi de as directe d b y t heir p h ysicia n(s). Patie nt s h o ul d u n dersta n d t hat if 
t he y d o n ot start ta ki n g l o pera mi de at t he st art of diarr hea, t he diarr hea ma y bec o me 
se vere a n d last se veral da ys. Persiste nt diarr hea or a n y e vi de nce of he m at oc hezia 
s h o ul d pr o m pt a st o ol e val uati o n f or fecal le u k oc ytes a n d/ or Cl ostri di u m difficile  t o xi n 
& o va/ parasite e v al uati o n. Di p he n o x ylate/ atr o pi ne prescri pti o ns are per mitte d. 
L o pera mi de will be rec o m me n de d d uri n g t he st u d y i n o r der t o pre ve nt diarr hea t hat 
ma y ulti matel y lea d t o i ntra ve n o us i nf usi o n of fl ui ds or h os pitalizati o ns.  
 
F or t he a d mi nistrati o n of l o pera mi de, it is rec o m m e n de d t hat patie nts ta ke t w o ( 2) 
ca plets ( 4 m g) at t he first si g n of diarr hea. Patie nts s h o ul d c o nt i n ue ta ki n g o ne ( 1) 
ca plet ( 2 m g) e ver y t w o h o urs u ntil t he y ret ur n t o t heir n or mal patter n of b o wel 
m o ve me nts. T he y ma y re peat sa me d oses a n d fre q ue nc y if diarr hea ret ur ns.  D uri n g 
t he ni g ht, patie nts ma y ta ke t w o ( 2) ca plets e ver y f o ur h o urs rat her t ha n o ne ( 1) e ver y 
t w o h o urs. Patie nts s h o ul d call t heir d oct or if t he y ha ve a n y q uesti o ns a b o ut ta ki n g 
l o pera mi de, if t he y b elie ve t he y are n ot ac hie vi n g a de q uate c o ntr ol of diarr hea, or if 
t he y are feeli n g e xtre mel y wea k, li g ht hea de d, or dizz y (s y m pt o ms of deh y drati o n). 
Si de effects of l o pera mi d e i ncl u de tire d ness, dr o wsi ness, or dizzi ness. If t he y 
e x perie n ce t hese si de effects, t he y s h o ul d a v oi d dri vi n g a m ot orize d ve hicle or 
o perati n g mac hi ner y. Bef ore usi n g a n y la xati ve, patie nts s h o ul d c o ns ult t heir 
p h ysic ia n. Patie nts s h o ul d ma ke a n e xtra eff ort t o dri n k l ots of fl ui ds (se veral glasses 
of water, fr uit j uices, s o d a, s o u p, etc.) e ver y da y w hile t he y partici pate i n t his st u d y.  
 
5 . 3  
I m a gi n g  
5 . 3. 1  
- 
P E T/ C T sca n will be perf or me d as a scree ni n g st u d y e ntr y dia g n ostic criteria .  T he 
P E T/ C T ma y be perf or me d wit h a hi g h -q ualit y C T f or C T dia g n ostic p ur p oses.   F or cases 
w he n t he P E T is n ot acc o m pa nie d b y a hi g h -q ualit y C T (f or e xa m ple has a l ac k of or 
i ns ufficie nt I V c o ntrast, lac k of or i ns ufficie nt oral / rectal c o ntrast, or lac k of a f ull y 
dia g n ostic m ulti p hasic C T i ma gi n g ), t he n a se parate dia g n ostic C T of t he c hest, 
a b d o me n, a n d pel vis will be re q uire d f or t he baseli ne sca n.   
•   
- 
 
T he 1 2 -wee k  p ost t hera p y P E T/ C T is o pti o nal ( Da y 1 4 0).    T he P E T/ C T ma y be 
perf or me d wit h a hi g h -q ualit y C T f or dia g n ostic p ur p oses.  F or cas es w he n t he P E T is n ot 
acc o m pa ni e d b y a hi g h -q ualit y C T (f or e xa m ple has a lac k of or i ns ufficie nt I V c o ntrast, 
lac k of or i ns ufficie nt oral / rectal c o ntrast, or lac k of a f ull y dia g n ostic m ulti p hasic C T 
i ma gi n g), t he n a se parate dia g n ostic C T of t he c hest, a b d o me n, a n d pel vis is o pti o nal f or 
t his e x pl orat or y p ost t hera p y 1 2 wee k ( Da y 1 4 0) sca n.   
•   

 
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5 . 4  
I nte gr al Ass a y/ Bi o m ar ker   
5 . 4. 1 See Secti o n 1 0  f or det ails. 
 
5. 5    
Ge ner al C o nc o mit a nt Me dic ati o n a n d S u p p orti ve C are G ui deli nes  
 
5 . 5. 1   
Per mitte d S u p p orti ve/ A ncillar y Care a n d C o nc o mita nt Me dicati o ns  
   
All s u p p orti ve t hera p y f or o pti mal me dical care will be gi ve n d uri n g t he st u d y peri o d at 
t he discreti o n of t he att e n di n g p h ysicia n(s) wit hi n t he para m eters of t he pr ot oc ol a n d 
d oc u me nte d o n eac h site’s s o urce d oc u m e nts as c o nc o mita nt me dicati o n.  
▪ A ntic o n v ulsa nts  
▪ A ntie metics  
▪ A ntic oa g ula nts  
▪ A nti diarr heals  
▪ A nal gesics  
▪ He mat o p oietic Gr o wt h Fact ors  
▪ Her bal pr o d ucts  
▪ N utriti o nal s u p ple me ntati o n  
▪ Hi g hl y acti ve a ntiretr o viral t hera p y ( H A A R T)  
 
C o nc o mita nt t hera p y i ncl u des a n y pres cri pti o n me dicati o ns or o ver t h e c o u nter 
pre parati o ns use d b y a patie nt bet wee n t he 7 da ys prece di n g t he s cree ni n g e val uati o n a n d 
t he treat me nt disc o nti n uati o n visit. 
 
Patie nts w h o e x perie n ce i nf usi o n -ass ociate d s y m pt o ms ma y be treate d s y m pt o maticall y 
wit h aceta mi n o p he n, i b u pr ofe n, di p h e n h y dra mi ne, a n d/ or ci meti di ne or a n ot her H 2 
rece pt or a nta g o nist, as per sta n dar d practice (f or sites o utsi de t he U nite d States, 
e q ui vale nt me dicati o ns ma y be s u bstit ute d per l ocal practice).  Seri o us i nf usi o n 
ass ociate d e v e nts ma nifeste d b y d ys p nea, h y p ot e nsi o n, w heezi n g, br o nc h os pas m, 
tac h ycar dia, re d uce d o x y ge n sat urati o n, or res pirat or y distress s h o ul d be ma na ge d wit h 
s u p p orti ve t hera pies as cli nicall y i n dicate d (e. g., s u p ple me ntal o x y ge n a n d 2-a dre ner gic 
a g o nists; see Secti o n 5. 1. 2 ). 
 
S yste mic c ortic o ster oi ds a n d T N F i n hi bit ors ma y atte n uate p ote ntial be neficial 
i m m u n ol o gic effects of treat me nt wit h atez oliz u m a b b ut ma y be a d mi nistere d at t he 
discreti o n of t he treati n g p h ysicia n.  If feasi ble, alt er nati ves t o c ortic ost er oi ds s h o ul d be 
c o nsi dere d.  Pre me dicati o n ma y be a d mi nistere d f or C ycles ≥2 at t he discreti o n of t he 
treati n g p h ysicia n.  T he use of 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) f or patie nts wit h ort h ostatic h y p ote nsi o n or a dre n oc ortical i ns ufficie nc y 
is all o wed.  Me gestr ol a d mi nistere d as a p petite sti m ula nt is acce pta ble w hile t he patie nt is 
e nr olle d i n t he st u d y.   
 
Patie nts w h o use oral c o ntrace pti ves, h or m o ne -re place me nt t hera p y, pr o p h ylactic or 
t hera pe utic a ntic o a g ulati o n t hera p y (s uc h as l o w-m olec ular -wei g ht he pari n or warfari n at 
a sta ble d ose le vel), or ot her all o we d mai nte na nce t hera p y s h o ul d c o nti n ue t heir use.  Males 
a n d fe males of re pr o d ucti ve p ote ntial s h o ul d use hi g hl y effecti ve mea ns of c o ntrace pti o n , 

 
N R G -G Y 0 1 7  
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defi ne d as a pre vi o us hist or y of fe male sterili zati o n (t u bal li gati o n) or male sterilizati o n 
( vasect o m y), or t he use of birt h c o ntr ol me dicati o ns ( pill, patc h, i njecta ble), dia p hra g m or 
ri n g.  T he use of mal e c o n d o ms is n ot a hi g hl y effecti ve mea ns of c o ntrace pti o n al o ne.  
  
5 . 5. 2   
Pr o hi bite d T hera pies  
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 het 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 u nless it is s pecificall y i ncl u de d i n t he 
treat me nt re gi me n d escri be d i n t his pr ot oc ol.  T his i ncl u des b ut is n ot li mite d t o t he 
f oll o wi n g: 
•  C he m ot hera 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, i n v esti gati o nal 
a ge nts, or her bal t hera p y (e xce pt f or mai nte na nce t hera pies o utli ne d i n Secti o n  Err or! R
efere nce s o urce n ot f o u n d. ). 
o  After C ycle 1, certai n f or ms of ra di ot hera p y m a y be c o nsi dere d f or pai n palliati o n 
if patie nts are d eri vi n g be nefit (e. g., treat me nt of k n o w n b o n y metastases); 
atez oliz u ma b a d mi nistrati o n ma y be s us pe n de d d uri n g ra di ot hera p y.  
 
It is str o n gl y rec o m me n d e d t hat:  
•  Tra diti o nal her bal me di ci nes n ot be a d mi nistere d beca use t h e i n gre die nts of ma n y 
her bal me dici nes are n ot f ull y st u die d a n d t heir use ma y res ult i n u na ntici pate d 
dr u g -d r u g i nteracti o ns t hat ma y ca use, or c o nf o u n d assess me nt of, t o xicit y. 
•  T he use of a R A N K L i n hi bit or ( de n os u ma b) be disc o nti n ue d d uri n g t he st u d y; 
t his a ge nt 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 m a b.  
 
I nitiati o n or i ncreas e d d ose of gra n ul oc yte c ol o n y-sti m ulati n g fact ors (e. g., gra n ul oc yte 
c ol o n y-sti m ulati n g fact or, gra n ul oc yte/ macr o p ha ge c ol o n y-sti m ulati n g fact or, a n d/ or 
pe gfil grasti m) is pr o hi bite d f or patie nts wit h s oli d mali g na ncies.  
 
Patie nts are n ot all o we d t o recei v e i m m u n ost i m ulat or y a ge nts, i ncl u di n g, b ut n ot li mite d 
t o, I F N-, I F N-, or I L-2, d uri n g t he e ntire st u d y.  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 ncrease t he ris k f or a ut oi m m u ne c o n diti o ns.  
 
Patie nts s h o ul d als o n ot be recei vi n g i m m u n os u p pressi 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 xate, a n d t h ali 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 safet y of atez oliz u ma b.  S yste mic 
c ortic oster oi ds a n d a nti -T N F  a ge nts ma y atte n uate p ote ntial be neficial i m m u n ol o gic 
effects of treat me nt wit h atez oliz u ma b b ut ma y be a d mi nistere d at t he discreti o n of t he 
treati n g p h ysicia n.  If feasi ble, alter nati ves t o t hes e a ge nts s h o ul d be c o nsi dere d. 
 
5 . 6  
D ur ati o n of T her a p y  
I n t he a bse n ce of treat me nt dela ys d ue t o a d verse e ve nt (s), treat me nt ma y c o nti n ue as 
s pecifie d i n t he a b o v e treat me nt m o dalit y secti o ns or u ntil o ne of t he f oll o wi n g criteria 
a p plies:  
▪ 
Disease pr o gressi o n,  
▪ 
I nterc urre nt ill ness t hat pre ve nts f urt h er a d mi nistrati o n of treat me nt,  
▪ 
U nacce pta ble a d verse e v e nt(s),  as des cri be d i n Secti o n 6  
▪ 
Patie nt deci des t o wit h dra w c o nse nt f or partici p ati o n i n t he st u d y, or 

 
N R G -G Y 0 1 7  
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▪ 
Ge neral or s pecific c h a n ges i n t he patie nt's c o n diti o n re n der t he patie nt u nacce pta ble 
f or f urt her treat me nt i n t he j u d g me nt of t he i n vesti gat or. 
 
5. 7   
D ose Li miti n g T o xicit y  
D ose -li miti n g t o xicities ( D L Ts) will be defi ne d b y dr u g relate d a d verse effects t hat meet 
t he criteria b el o w as e v al uate d b y N CI C T C A E v.5  u nless clearl y u nrelate d t o st u d y 
t hera p y (e. g., disease pr o gressi o n).  As t his re gi m e n is bei n g de vel o pe d as a fr o nt-li ne 
t hera p y, t he g oal is f or patie nts t o c o m plete all treat me nts.  T h us, all c ycles will be 
c o nsi dere d i n det er mi ni n g D L T.  S pecificall y , t he D L T peri o d f or Ar m A: start of t he 
pri mi n g d ose of atez oliz u ma b u ntil 3 0 da ys after t he c o m pleti o n of C R T; f or Ar m B: start 
of C R T u ntil 3 0 da ys after t he c o m pleti o n of C R T.  
 
A D L T i ncl u des:  
• 
A n y Gra d e 4 i m m u ne rel ate d a d verse e ve nt  
• 
A n y > = gra de 3  i m m u ne relate d c olitis 
• 
A n y Gra d e 3 or 4 n o ni nfecti o us p ne u m o nitis (irres pecti ve of d urati o n)  
• 
A n y Gra d e 2 n o ni nfecti o us p ne u m o nitis t hat d oes n ot res ol ve t o < = gra de 1 wit hi n 7 
da ys of t he i nitiati o n of ma xi mal s u p p orti ve care  
• 
Li ver tra nsa mi nas e ele v ati o n > 8 x U L N or t otal bilir u bi n > 5 x U L N  
• 
A n y > = gra de 3 n o n i m m u ne relate d a d verse e ve nt e xce pt f or t he e xcl usi o n list bel o w  
• 
Dela y of wee kl y cis plati n of great er t ha n 2 wee ks d ue t o fail ure t o rec o ver A E/fail ure 
t o meet pr ot oc ol directe d treat me nt para meters f or restart after ma na ge me nt of A E  
• 
A n y treat me nt relate d deat h.  
 
A D L T d oes n ot i ncl u de:  
• 
Gra de 3 i nf usi o n reacti o n t o atez oliz u ma b or cis plati n t hera p y t hat is me dicall y 
ma na ge d  
• 
Gra de 3 fati g ue, a n ore xia or c o nsti pati o n lasti n g less t ha n o ne wee k  
• 
Gra de 3 e n d ocri ne dis or d ers (t h yr oi d, pit uitar y, a n d/ or a dre nal i ns ufficie nc y) t hat is 
ma na ge d wit h or wit h o ut s yste mic c ortic oster oi d t hera p y a n d/ or h or m o ne re place 
t hera p y a n d t he s u bj ect is as y m pt o matic 
• 
Gra de 3 i nf usi o n relate d reacti o n  
• 
Gr a de 3 or 4 ne utr o pe nia (t hat is n ot ass ociate d wit h fe ver or i nfecti o n) lasti n g < = 7 
da ys  
• 
Gra de 3 or 4 l y m p h o pe nia  
• 
Gra de 3 t hr o m b o c yt o pe nia t hat is n ot ass ociate d wit h cli nicall y si g nifica nt blee di n g  
• 
Is olat e d gra d e 3 electr ol yte a b n or malities t hat are n ot ass ociate d wit h cli nical si g ns or 
s y m pt o ms a n d are re v erse d wit h a p pr o priat e ma xi mal me dical i nter ve nti o n  
• 
Gra de 3 h y p erte nsi o n  
• 
Gra de 3 n a usea a n d/ or v o miti n g ( ma xi mal me dical ma na ge me nt s h o ul d be e m pl o ye d) 
lasti n g < 4 8 h o urs 
• 
Gra de 3 d e h y drati o n as a res ult of na usea or v o miti n g lasti n g < 4 8 h o urs  
• 
Gra de 3 a n d 4 as y m pt o matic a m ylase/li pase el e vati o n.  
 
Ar m  A:  If >  6 p atie nts ( or > 3 0 % of D L T -e val ua ble patie nts of t he 2 0 e nr olle d) de vel o p a 
D L T d uri n g t he start of t hera p y (i.e ., start of t he pri mi n g d ose of atez oliz u ma b u ntil 3 0 

 
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da ys after t he c o m pleti o n of C R T ), t he re gi me n will be place d o n h ol d a n d a disc ussi o n 
wit h t he pri nci pal i n vesti gat ors a n d Ge ne ntec h will be c o ntacte d t o deter mi ne f ut ure pla ns 
f or t he st u d y.   
 
Ar m B:  If > 6 patie nts ( or > 3 0 % of D L T-e val ua ble patie nts of t he 2 0 e nr olle d) de vel o p a 
D L T d uri n g t he start of t hera p y (i.e., start of C R T u ntil 3 0 da ys after t he c o m pleti o n of 
C R T), t he re gi me n will be place d o n h ol d a n d a disc ussi o n wit h t he pri nci pal 
i n vestigat ors a n d Ge ne nt ec h will be c o ntacte d t o deter mi ne f ut ure pla ns f or t he st u d y.   
 
D L T a n d ot her t o xicities are disc usse d a m o n g t he St u d y C hair, C o -C hairs, t he P hase I 
C o m mittee C hair , C T E P m o nit ors  a n d t he St u d y Bi ostatisticia n. T he disc ussi o ns are t he 
ba sis f or t he decisi o ns re gar di n g pr ot oc ol or treat me nt m o dificati o ns acc or di n g t o t he 
r ules of t he pr ot oc ol.   
 
F or o verall e val u ati o n of t o xicit y, all patie nts w h o recei v e a n y st u d y dr u g will be 
e val ua ble.  F or t he pri mar y e n d p oi nt, all eli gi ble patie nt w h o recei ve d o n Ar m A ( d ose at 
da y -2 1 a n d d ose at da y 0) a n d Ar m B ( d ose at da y 0) a n d ha ve T C R B meas ure me nts at 
da y 2 1 will be e val ua bl e.  F or t he e val uati o n of D L T, all eli gi ble patie nts w h o ha ve a 
D L T a n d ha v e at least o n e d ose of Atez oliz u ma b, or c o m ple te pr ot oc ol t hera p y u ntil 3 0 
da ys after t he c o m pleti o n of C R T.  T he D L T t o xicit y 3 0 % t hres h ol d will o nl y i ncl u de 
t h ose patie nts w h o c o m plete pr ot oc ol t hera p y a n d are e val ua ble at t he D L T s pecifie d ti me 
peri o d (t he D L T peri o d f or Ar m A: start of t he pri mi n g  d ose of atez oliz u m a b u ntil 3 0 
da ys after t he c o m pleti o n of C R T; f or Ar m B: start of C R T u ntil 3 0 da ys after t he 
c o m pleti o n of C R T) if a D L T was n ot deter mi ne d pri or t o t his peri o d.  
 
Usi n g a critical val u e det er mi ne d b y m ore t ha n 3 0 % of t he D L T -e val ua ble p atie nts 
ha vi n g at least o ne  D L T, a p o wer c ur ve is dis pla ye d i n Fi g ure 5. 7  w here N is t he t otal 
n u m ber of D L T -e val ua bl e patie nts , X is t he n u m ber of patie nts e x perie nci n g at least o ne 
D L T , a n d π is t he pr o ba bilit y of a patie nt e x perie nci n g at least o ne D L T. I n t his st u d y, t he 
ma xi m u m n u m ber of patie nts f or D L T -e val ua ble is 2 0 f or eac h ar m . Gi ve n a sa m ple size 
of 2 0, if π is tr ul y 2 0 %, t he n pr o ba bilit y t o o bser ve m ore t ha n 6 patie nts wit h D L T is 
8. 7 %; if π is tr ul y 3 0 %, t he n pr o ba bilit y t o o bser ve m ore t h a n 6 patie nts wit h D L T is 
3 9 %; if π is tr ul y 4 0 %, t he n pr o ba bilit y t o o bser ve m ore t ha n 6 patie nts wit h D L T is 7 5 %.  
 
 
 

 
N R G -G Y 0 1 7  
4 6    
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Fi g ure 5. 7  
 
 
6 . T R E A T M E N T M O DI FI C A TI O N S /M A N A G E M E N T  
 
6. 1    
Cis pl ati n  D ose M o dific ati o ns  
Cis plati n d ose m o dificati o ns will be ma de acc or di n g t o o bser ve d s y m pt o ms.  
C he m ot hera p y will n ot be a d mi nistere d d uri n g a ra diati o n t hera p y del a y.  
 
6. 1 . 1 Gastr oi ntesti nal A d verse Effects:  (e. g., na usea a n d v o miti n g) 
Pr o p h ylactic a ntie metics s h o ul d be use d as descri be d a b o ve i n secti o n 5. 1. 1. 
Please f oll o w l ocal i nstit uti o nal sta n dar ds f or pati e nts t hat de vel o p na usea a n d 
v o miti n g i n s pite of t he use of pr o p h ylactic meas ures. F or persiste nt gra de 4 
na usea a n d v o miti n g des pite o pti mal me dical ma na ge me nt, h ol d cis plati n u ntil 
re d uce d t o gra de 1 a n d re d uce cis plati n b y 2 5 %.  F or patie nts wit h rec urre nce 
of t his f oll o wi n g d ose re d ucti o n, cis plati n m ust be disc o nti n ue d.   
 
6. 1 . 2 Re nal A d verse Effects:  If creati ni ne rises t o great er t ha n 2. 0 m g/ d L, 
disc o nti n ue cis plati n t hera p y. Selecti ve re nal t u b ular defects are s o meti mes 
o bser ve d. D oc u me nte d h y p o ma g nese mia will be treate d wit h i ncreas e d 
ma g nesi u m s u p ple me ntati o n per i nstit uti o nal pr ot oc ol.  H y p ocalce mia a n d 
h y p o kale mia are c o m m o n a n d p ote ntiall y se vere. Re place me nt of p ot assi u m 
a n d calci u m are us uall y effecti ve per i nstit uti o nal pr ot oc ol. Se vere t u b ular 
effects ma y re q uire c hr o nic re place me nt t hera p y. Dia g n ostic tests f or ot her 
eti ol o g y of h y p ocalce mia ( GI or meta b olic) s h o ul d be c o nsi dere d per 
i nstit uti o nal pr ot oc ol. 
 
6. 1 . 3 Ne ur ot o xicit y A d verse Effects: F or gra de 2, re d uce cis plati n d ose b y 
2 5 %. F or gra de 3 -4, disc o nti n ue cis plati n t hera p y.  
 

 
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6. 1 . 4 Ti n nit us or heari n g c ha n ges:  F or gra de 2 h ol d cis plati n u ntil 
ne ur o pat h y res ol ves t o gra de 1 a n d d os e re d uce b y 2 5 %. Disc o nti n ue cis plati n 
if ti n nit us or heari n g c ha n ges d o n ot res ol ve wit hi n 2 1 da ys. Disc o nti n ue 
cis plati n f or gra d e 3 or 4 t o xicit y.   
 
6. 1 . 5 He mat ol o gic A d verse Effects: Cis plati n s h o ul d be wit h hel d fr o m 
patie nts wit h a n a bs ol ute ne utr o p hil c o u nt less t ha n 1 5 0 0 / m m 3 or platelet 
c o u nt less t ha n 7 5, 0 0 0 / m m 3. Cis plati n i nf usi o ns s h o ul d be dela ye d wee k-b y -
wee k u ntil t hese le vels are e xcee de d.  Please refer t o t he ta ble bel o w f or 
s pecific he m at ol o gic t o xicities a n d rec o m me n de d m o dificati o ns.   
 
H E M A T O L O GI C 
T O XI CI T Y  
P A R A M E T E R  
D O S E 
M O DI FI C A TI O N  
A ne mia  
N ot a p plica ble f or t his 
pr ot oc ol  
N o d ose m o dificati o ns 
f or a nemia. Please refer 
t o secti o n 5 f or 
a d diti o nal details.  
Fe brile Ne utr o pe nia or A N C    
First occ urre nce of fe brile 
ne utr o pe nia ( gra de 3 or 4) 
- O R –  A N C < 5 0 0 /  µ L  
lasti n g greater t ha n 7 
da ys  
H ol d cis plati n x 1 wee k 
a n d re peat C B C.  If 
A N C has res ol ve d t o 
gra de 1 ( > 1 5 0 0 /  µ L ), 
t he n d ose re d uce b y 2 5 % 
a n d treat. If A N C has 
n ot res ol ve d t o gra de 1 
t he n disc o nti n ue 
cis plat i n. 
Fe brile Ne utr o pe nia or A N C    
Sec o n d occ urre nce    
Disc o nti n ue cis plati n.  
A N C al o ne  
U nc o m plicate d A N C < 
5 0 0 /  µ L  lasti n g greater 
t ha n 7 da ys wit h o ut 
i nfecti o n or fe ver  
D ose re d ucti o n n ot 
i n dicate d, b ut h ol d 
t hera p y u ntil A N C 
res ol ves t o gra de 1  
Platelets wit h o ut blee di n g    
Gra de 3 u nc o m plicate d    
H ol d u ntil platelets > 
7 5, 0 0 0 / µ L  a n d res u me 
at c urre nt d ose le vel 
wit h o ut m o dificati o n  
Platelets wit h blee di n g    
First occ urre nce gra de 4 
t hr o m b oc yt o pe nia – O R –  
gra de 3 
t hr o m b oc yt o pe nia wit h 
blee di n g  
H ol d cis plati n x 1 wee k 
a n d re peat C B C.  If 
platelet c o u nt has 
res ol ve d t o > 7 5, 0 0 0 / 
µ L , t he n d ose re d uce b y 
2 5 % a n d treat. If 
t hr o m b oc yt o pe nia has 
n ot res ol ve d t o gra de 1, 
t he n disc o nti n ue 
cis plati n 
Platelets wit h blee di n g    
 
Disc o nti n ue cis plati n  
 
6. 1 . 6 Ot her n o n -he m at o l o gic t o xicit y:  F or a n y ot her n o n-s pecific gra de 3 or 
4 t o xicit y, ot her  t ha n fati g ue, h ol d cis plati n u ntil t o xicit y res ol ves t o gra de 1 

 
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a n d t he n res u me at sa me d ose.  If t o xicit y d oes n ot res ol ve t o gra de 1 wit hi n 2 1 
da ys, disc o nti n ue cis plati n.   
 
6. 1 . 7 E xter nal -bea m pel vic ra diati o n a n d atez oliz u ma b i nf usi o ns s h o ul d 
c o nti n ue w hile a n y or all c o urses of cis plati n are wit h hel d. F or dela ys i n 
cis plati n i nf usi o n greater t ha n t w o wee ks, cis plati n ma y n ot be c o nti n ue d at t he 
j oi nt discreti o n of t he patie nt’s treati n g p h ysicia ns a n d t he pri nci pal 
i n vesti gat or (face s heet). 
 
6. 2   
Atez oliz u m a b D ose M o dific ati o n a n d T o xicit y M a n a ge me nt G ui deli nes  
 
6. 2 . 1   
Ge neral A E Ma na ge me nt a n d D ose M o dificati o n G ui deli nes  
 
T here will be n o d ose re d ucti o n f or atez oliz u ma b i n t his st u d y.  
 
Patie nts ma y te m p oraril y s us pe n d st u d y treat me nt if st u d y dr u g -relate d t o xi cit y re q uiri n g 
d ose s us pe nsi o n is e x perie nce d.  If atez oliz u ma b is hel d beca us e of A Es be y o n d t he 
sc he d ule d date of i nf usi o n, t he patie nt will be disc o nti n ue d fr o m atez oliz u ma b a n d will 
be f oll o we d f or safet y a n d efficac y as s p ecifie d i n t his  pr ot oc ol .  If t he A E res ol ves a n d 
t he patie nt is recei vi n g c ortic oster oi d t hera p y f or t he e ve nt, atez oliz u ma b ma y be hel d f or 
t he re mai ni n g d oses o n st u d y i n or der t o all o w ta peri n g of t he ster oi d d ose t o ≤1 0 m g oral 
pre d nis o ne or e q ui vale nt.  
 
D ose i nterr u pti o ns f or reas o ns ot her t ha n t o xicit y, s uc h as s ur gical pr oce d ures, ma y be 
all o we d.  T he acce pta ble le n gt h of i nterr u pti o n will be at t he discreti o n of t h e st u d y PI i n 
c o ns ultati o n wit h C T E P.  
 
Atez oliz u ma b m ust be per m a ne ntl y disc o nti n ue d  if t he patie nt e x perie nces a n y of t he 
f oll o wi n g e ve nts, re gar dless of be nefit: 
 
•  Gra de 4 p n e u m o nitis  
•  A S T or A L T > 5 × U L N or t otal bilir u bi n > 3 × U L N  
•  Gra de 4 diarr hea or c olitis  
•  Gra de 4 h y p o p h ysitis  
•  A n y gra de m y ast he nic s y n dr o me/ m yast he nia gra vis, G uillai n -Bar ré or 
me ni n g oe nce p h alitis  
•  Gra de 4 o c ular i nfla m mat or y t o xicit y  
•  Gra de 4 p a ncreatitis or a n y gra de of rec urre nt p a ncreatitis  
•  Gra de 4 ras h  
•  A n y gra de m y o car ditis  
 
Treat me nt ma y, u n d er li mite d a n d c o m pelli n g circ u msta nces, be res u me d i n patie nts w h o 
ha ve rec o ve re d fr o m t he f oll o wi n g e ve nts, b ut o nl y after c o ns ultati o n wit h t he trial 
Pri nci pal I n v esti gat or : 
•  Gra de 3 p n e u m o nitis  
•  Gra de 3 o c ular i nfla m mat or y t o xicit y  

 
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•  Gra de 3 or 4 i nf usi o n -rel ate d reacti o ns 
 
A n y t o xicities ass ociate 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 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.  
Alt h o u g h m ost i m m u ne -relate d a d verse e ve nts (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 ve b ee n mil d a n d self -li miti n g, s uc h e ve nts s h o ul d be 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 ( Di Giac o m o et al., 2 0 1 0).  
Disc o nti n uati o n of at ez oliz u ma b ma y n ot ha ve a n i m me diate t hera pe 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 vere cas es, i m m u ne-rel ate 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 ot her 
i m m u n os u p pressi ve a ge nts.  T he i n vesti gat or s h o ul d c o nsi der t he be nefit-ris k bala nce 
pri or t o f urt her a d mi nistrati o n of atez oliz u ma b . 
 
F or detaile d i nf or mati o n re gar di n g ma na ge me nt of a d verse e ve nts ass ociat e d wit h 
atez oliz u ma b, please refer t o t he m ost c urre nt versi o n of t he Atez oliz u ma b I n vesti gat or’s 
Br oc h ure a n d t h e F D A pr o d uct la bel . 
 
T he pri mar y a p pr oac h t o gra de 1 t o 2 ir A Es is s u p p orti ve a n d s y m pt o matic care wit h 
c o nti n ue d treat me nt wit h atez oliz u ma b; f or hi g her -gra de ir A Es, atez oliz u ma b s h o ul d be 
wit h hel d a n d or al a n d/ or pare nteral ster oi ds a d mi nistere d.  Rec urre nt gra de 2 ir A Es ma y 
als o ma n date wit h h ol di n g atez oliz u ma b or t h e use of ster oi ds.  Assess me nt of t he 
be nefit -ris k bal a nce s h o ul d be ma de b y t he i n vesti gat or, wit h c o nsi derati o n of t he t otalit y 
of i nf or ma ti o n as it pertai ns t o t he nat ure of t he t o xicit y a n d t he de gree of cli nical be nefit 
a gi ve n patie nt ma y be e x perie nci n g pri or t o f urt h er 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 ir AEs.  
 
Patie nts s h o ul d be assesse d cli nicall y (i ncl u di n g re vie w of la b orat or y val u es) f or t o xicit y 
pri or t o, d uri n g, a n d after eac h i nf usi o n.  If u n ma na gea ble t o xicit y d ue t o at ez oliz u ma b 
occ urs at a n y ti me d uri n g t he st u d y, treat me nt wit h atez oliz u ma b s h o ul d be disc o nti n ue d.  
 
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 is a rare c o n diti o n c haract erize d b y a n e xcessi 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, s yste mic i m m u ne acti vati o n 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 neo m o d ulati n g 
a ge nts.  S yste mic i m m u ne acti vati o n 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 nati ve eti ol o g y, de vel 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, a n d t h e i nitial e val uati o n s h o ul d i ncl u de t he 
f oll o wi n g: 
•  C B C wit h peri p heral s mear  
•  P T, P T T, fi bri n o ge n, a n d D -di mer  
•  Ferriti n  
•  Tri gl yceri des  
•  A S T, A L T, a n d t otal bilir u bi n  
•  L D H  

 
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Versi o n Date:  N o ve m ber 8 , 2 0 1 8 
•  C o m plete ne ur ol o gic a n d a b d o mi nal e xa mi nati o n (assess f or 
he pat os ple n o me gal y)  
 
If s yste mic i m m u ne acti v ati o n is still s us pecte d after t he i nitial e val uati o n, c o ntact t he 
Pri nci pal I n v esti gat or f or a d diti o nal rec o m me n dati o ns.  
 
6. 2 . 2   
Ma na ge me nt of S pecific A Es  
 
Ma na ge me nt of certai n A Es of c o ncer n, i ncl u di n g i m m u ne -relate d p ne u m o nitis, he patitis, 
c olitis, e n d ocri n o pat hies, pa ncreatitis, ne ur o pat hies, m e nin g oe nce p halitis, a n d p ote ntial 
oc ular t o xicities are pres e nte d i n t he Atez oliz u ma b I n vesti gat or’s Br oc h ure.  S ee Secti o n 
5. 1 . 2 a n d t he A E M a n a g e me nt a n d D ose I nterr u pti o n G ui deli nes f or S pecific 
T o xicities  ta ble bel o w f or g ui deli nes f or t he ma na ge me nt of I nf usi o n Relate d Reacti o ns 
a n d A na p h yla xis.  
 
F or rec o m me n dati o ns t o h ol d atez oliz u ma b a n d be gi n c ortic oster oi d treat me nt, use t he 
f oll o wi n g g ui da nce f or t a peri n g t he c ortic oster oi d a n d res u mi n g atez oliz u ma b t hera p y 
after res ol uti o n of t h e e v e nt:  
 
•  C ortic oster oi d ta per:  C ortic oster oi ds m ust be ta pere d o ver 1 m o nt h t o 
1 0  m g/ da y oral pre d nis o ne or e q ui vale nt b ef ore atez oliz u ma b ca n be res u me d.  
A s h orter ster oi d ta p er ma y be all o we d if a p pr o priate, after disc ussi o n wit h t he 
me dical o nc ol o g y c o -c hair. 
•  Atez oliz u ma b ma y b e hel d f or a peri o d of ti me be y o n d 1 2 wee ks t o all o w f or 
c ortic oster oi ds t o be re d uce d t o 1 0 m g/ da y oral pre d nis o ne or e q ui vale nt.  
 
P ul m o nar y E ve nts  
D ys p nea, 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 nfiltra tes ha ve bee n 
ass ociate d wit h t he a d mi nistrati o n of atez oliz u ma b.  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.   
 
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 val u ate d f or ot her c o m m o nl y re p orte d 
eti ol o gies s uc h as p ne u m o nia  or ot her 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, c hr o nic o bstr ucti ve p ul m o nar y disease, or p ul m o nar y 
h y perte nsi o n.   Ma na g e me nt g ui deli nes f or p ul m o nar y e ve nts are pr o vi de d i n  t he A E 
M a n a ge m e nt a n d D ose I nterr u pti o n G ui deli nes f or S pecific T o xicities  t a ble bel o w.  
E n d ocri ne Dis or ders  
Patie nts e x perie nci n g o n e or m ore  u ne x plai ne d A Es p ossi bl y i n dicati ve of e n d ocri ne 
d ysf u ncti o n  (i ncl u di n g fati g ue, m yal gias, 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 hies.  T h e p atie nt s h o ul d be referre d t o a n e n d ocri n ol o gist if a n 
e n d ocri n o pat h y is s us pecte d.  T h yr oi d-sti m ulati n g h or m o ne ( T S H) a n d free T 3 a n d T 4 
le vels s h o ul d be meas ure 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 ntiat e 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. 

 
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D ose ma na ge m e nt g ui deli nes f or h y pert h yr oi dis m, h y p ot h yr oi dis m, s y m pt o matic a dre nal 
i ns ufficie nc y, a n d h y per gl yce mia are descri be d i n t he  A E M a n a ge me nt a n d D ose 
I nterr u pti o n G ui deli nes f or S pecific T o xicities  t a ble bel o w. 
 
Me ni n g oe nce p h alitis  
I m m u ne-relat e d me ni n g o e nce p halitis is a n i de ntifie d ris k ass ociate d wit h t he 
a d mi nistrati o n of atez oliz u ma b.  I m m u ne -rel ate d me ni n g oe nce p halitis s h o ul d be 
s us pecte d i n a n y patie nt prese nti n g wit h si g ns or s y m pt o ms s u g gesti ve of me ni n gitis or 
e nce p h alitis, i ncl u di n g, b ut n ot li mite d t o, hea dac he, nec k pai n, c o nf usi o n, s eiz ure, m ot or 
or se ns or y d ysf u ncti o n, a n d altere d or de press e d le vel of c o nsci o us ness.  E n ce p hal o pat h y 
fr o m meta b olic or el ectr ol yte i m bala nces nee ds t o be disti n g uis he d fr o m p ote ntial 
me ni n g o e nce p h alitis res ulti n g fr o m i nfecti o n ( bact erial, viral, or f u n gal) or pr o gressi o n of 
mali g na nc y, or sec o n dar y t o a para ne o plastic pr ocess.   
 
All patie nts bei n g c o nsi dere d f or me ni n g oe nce p halitis s h o ul d be ur ge ntl y e val uate d wit h 
a C T sca n a n d/ or M RI s ca n  of t he brai n t o e val uate f or metastasis, i nfla m m ati o n, or 
e de ma.  If dee m e d safe b y t he treati n g p h ysicia n, a l u m bar p u nct ure s h o ul d be perf or me d 
a n d a ne ur ol o gist s h o ul d be c o ns ulte d.  
 
Patie nts wit h si g ns a n d s y m pt o ms of me ni n g oe nce p halitis, i n t he a bse n ce of a n i de ntifie d 
alter nate eti ol o g y, s h o ul d be treate d  acc or di n g t o t he g ui deli nes i n t he  A E M a n a ge me nt 
a n d D ose I nterr u pti o n G ui deli nes f or S pecific T o xicities  table bel o w.  
 
Ne ur ol o gic dis or ders  
M yast he nia gra vis a n d G uillai n -Barré s y n dr o me ha ve bee n o bser ve 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 haracteri zati o n t o 
differe ntiat e bet wee n alter nati ve eti ol o gies.  Ma na ge me nt g ui deli nes f or ne ur ol o gic 
dis or ders are pr o vi de d i n  t he ta ble bel o w. 
 
F or rec o m me n dati o ns t o h ol d atez oliz u ma b a n d be gi n c ortic oster oi d treat me nt, use t he 
f oll o wi n g g ui da nce f or t a peri n g t he c ortic oster oi d a n d res u mi n g atez oliz u ma b t hera p y 
after res ol uti o n of t he e v e nt:  
•  C ortic oster oi ds m ust be ta pere d o ver 1 m o nt h t o 1 0  m g/ da y oral pre d nis o ne or 
e q ui vale nt bef ore atez oliz u ma b ca n be res u m e d.  
•  Atez oliz u ma b ma y b e hel d f or  a peri o d of ti me be y o n d 1 2 wee ks t o all o w f or 
c ortic oster oi ds t o be re d uce d t o 1 0 m g/ da y oral pre d nis o ne or e q ui vale nt.  
 
Re nal Dis or ders  
It is rec o m me n de d t hat T E C E N T RI Q ®(atez oliz u ma b) s h o ul d be wit h hel d f or m o derat e 
( Gra d e 2) i m m u ne-relate d ne p hritis a nd per ma ne ntl y disc o nti n ue d f or se vere ne p hritis 
( Gra d e 3 a n d 4). Please refer patie nt t o re nal s p eci alist a n d c o nsi der re nal bi o ps y a n d 

 
N R G -G Y 0 1 7  
5 2    
Versi o n Date:  N o ve m ber 8 , 2 0 1 8 
s u p p orti ve meas ures as i n dicate d. C ortic oster oi ds a n d/ or a d diti o nal i m m u n os u p pressi ve 
a ge nts s h o ul d be a d mi nistere d as c li nicall y i n dicate d. 
 
A E M a n a ge me nt a n d D ose I nterr u pti o n G ui deli nes f or S pecific T o xicities  
T o xicit y    
Se verit y/ D ur ati o n    
M a n a ge me nt  
A b d o mi nal pai n  
Ac ute a b d o mi nal pai n  
S y m pt o ms of a b d o mi nal pai n ass ociate d wit h 
ele vati o ns of a m ylase a n d li pase, s u g gesti ve of 
pa ncreatitis, ha ve bee n ass ociate d wit h 
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 u ati o n 
f or o bstr ucti o n, as well as ser u m a m ylase a n d 
li pase tests.  See t he g ui deli nes f or “ A m ylase 
a n d/ or li pase i ncrease” a n d “I m m u ne -relate d 
pa ncreatitis” else w here i n t his ta ble, as nee de d.  
 
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 be 
e val uate d f or p ote ntial he pat ot o xicit y (see t he 
“ He pat ot o xicit y” g ui deli ne else w here i n t his 
ta ble). 
A dre nal 
i ns ufficie nc y 
Gra de 2 + 
(s y m pt o matic) 
H ol d atez oliz u ma b.  
 
Refer patie nt t o e n d ocri n ol o gist.  
 
Perf or m a p pr o priate i ma gi n g.  
 
I nitiate treat me nt wit h 1−2 m g/ k g/ da y 
i ntra ve n o us met h yl pre d nis ol o ne or e q ui vale nt 
a n d c o n vert t o 1 −2  m g/ k g/ da y oral pre d nis o ne or 
e q ui vale nt u p o n i m pr o ve me nt.  
 
If e ve nt res ol ves t o gra de 1 or better a n d patie nt 
is sta ble o n re place me nt t hera p y (if re q uire d) 
wit hi n 1 2 wee ks, ta per c ortic oster oi ds a n d res u m e 
atez oliz u ma b acc or di n g t o t he g ui deli nes a b o ve.  
 
Per ma ne ntl y disc o nti n ue atez oliz u ma b if e ve nt 
d oes n ot res ol ve t o gra de 1 or better or patie nt is 
n ot sta ble o n re place me nt t hera p y wit hi n 1 2 
wee ks.  
A m ylas e a n d/ or 
li pase i ncrease d 
Gra de 1  
C o nti n ue atez oliz u ma b.  
 
M o nit or a m ylase a n d li pase pri or t o d osi n g.  

 
N R G -G Y 0 1 7  
5 3    
Versi o n Date:  N o ve m ber 8 , 2 0 1 8 
A E M a n a ge me nt a n d D ose I nterr u pti o n G ui deli nes f or S pecific T o xicities  
T o xicit y    
Se verit y/ D ur ati o n    
M a n a ge me nt  
Gra de 2  
C o nti n ue atez oliz u ma b.  
 
M o nit or a m ylase a n d li pase wee kl y.  
 
F or pr ol o n ge d ele vati o n ( e. g., 3 wee ks), 
c o nsi der treat me nt wit h 1 0 m g/ da y oral 
pre d nis o ne or e q ui vale nt.  
Gra de 3 or 4    
H ol d atez oliz u ma b.  
 
C o nsi der r eferral t o gastr oi ntesti nal ( GI) 
s pecialist.  
 
M o nit or a m ylase a n d li pase  e ver y ot her da y . 
 
If n o i m pr o ve me nt, c o nsi der treat me nt wit h 
1 −2  m g/ k g/ da y oral pre d nis o ne or e q ui vale nt.  
 
If e ve nt res ol ves t o gra de 1 or better wit hi n 1 2 
wee ks, ta per c ortic ost er oi ds a n d res u me 
atez oliz u ma b acc or di n g t o t he g ui deli nes a b o ve.  
 
Per ma ne ntl y disc o nti n ue atez oliz u ma b if e ve nt 
d oes n ot res ol ve t o gra de 1 or better wit hi n 1 2 
wee ks.  
 
F or  rec urre nt e ve nts, per ma ne ntl y disc o nti n ue 
atez oliz u ma b.   
Der mat ol o gic 
t o xicit y/ras h 
(e. g., 
mac ul o pa p ular or 
p ur p ura)  
Gra de 1  
C o nti n ue atez oliz u ma b. 
 
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). 
Gra 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 c ortic oster oi ds.  
 
C o nsi der hi g her p ote nc y t o pical c ortic oster oi ds if 
e ve nt d oes n ot i m pr o ve.  

 
N R G -G Y 0 1 7  
5 4    
Versi o n Date:  N o ve m ber 8 , 2 0 1 8 
A E M a n a ge me nt a n d D ose I nterr u pti o n G ui deli nes f or S pecific T o xicities  
T o xicit y    
Se verit y/ D ur ati o n    
M a n a ge me nt  
Gra de 3  
H ol d atez oliz u ma b.   
 
Refer patie nt t o 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 t he e ve nt 
d oes n ot i m pr o ve wit hi n 4 8 −7 2 h o urs, i ncreas e 
d ose t o 1 – 2 m g/ k g/ da y or e q ui vale nt.  
Restart atez oliz u ma b if e ve nt res ol ves t o gra de 1 
or better wit hi n 1 2 wee ks.  
 
Per ma ne ntl y disc o nti n ue atez oliz u ma b if e ve nt 
d oes  n ot res ol ve t o gra de 1 or better wit hi n 1 2 
wee ks . 
Gra de 4  
Per ma ne ntl y disc o nti n ue atez oliz u ma b.  Patie nt 
ma y n ot res u me treat me nt, re gar dless of be nefit.  
Ot her wise, ma na ge as a b o ve.  
Persiste nt a n d/ or 
se vere ras h or pr urit us, 
a n y gra de  
A der mat ol o gist s h o ul d e val uate t he e ve nt.  A 
bi o ps y s h o ul d be perf or me d u nless 
c o ntrai n dicate d.  
Diarr hea or 
c olitis 
A n y gra de  
Patie nts s h o ul d be a d vise d t o i nf or m t he 
i n vesti gat or if a n y diarr hea occ urs, e ve n if it is 
mil d.  
 
All e ve nts of diarr hea or c olitis s h o ul d be 
t h or o u g hl y e val uate d f or ot her m ore c o m m o n 
eti ol o gies.  F or e ve nts of si g nifica nt d urati o n or 
ma g nit u de or ass ociate d wit h si g ns of s yste mic 
i nfla m mati o n or ac ute-p hase reacta nts 
(e. g., i ncrease d C R P, platelet c ou nt, or 
ba n de mia):  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 t hree t o fi ve s peci me ns f or sta n dar d paraffi 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 nfiltrates t o c o nfir m c olitis dia g n osis. 
Gra de 1  
C o nti n ue atez oliz u ma b.  
 
I nitiate 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 7  da ys.  
 
M o nit or cl osel y.  

 
N R G -G Y 0 1 7  
5 5    
Versi o n Date:  N o ve m ber 8 , 2 0 1 8 
A E M a n a ge me nt a n d D ose I nterr u pti o n G ui deli nes f or S pecific T o xicities  
T o xicit y    
Se verit y/ D ur ati o n    
M a n a ge me nt  
Gra de 2  
H ol d atez oliz u ma b.  
 
I nitiate s y m pt o matic treat me nt. 
 
Patie nt referral t o GI s p ecialist is rec o m me n de d. 
 
F or rec urre nt e ve nts or e ve nts t hat persist > 5 
da ys, i nitiate treat me nt wit h 1 −2 m g/ k g/ da y oral 
pre d nis o ne or e q ui vale nt.  
 
If e ve nt res ol ves t o gra de 1 or better wit hi n 1 2 
wee ks, ta per c ortic ost er oi ds a n d res u me 
atez oliz u ma b acc or di n g t o t he g ui deli nes a b o ve.  
 
Per ma ne ntl y disc o nti n ue atez oliz u ma b if e ve nt 
d oes n ot res ol ve t o gra de 1 or better wit hi n 1 2 
wee ks.  Res u m pti o n of at ez oliz u ma b ma y be 
c o nsi dere d, after c o ns ultati o n wit h t he trial PI, i n 
patie nts w h o are deri vi n g be nef it a n d ha ve f ull y 
rec o vere d fr o m t he i m m u ne-rel ate d e ve nt. 
Gra de 3  
H ol d atez oliz u ma b.  
 
Refer patie nt t o GI s peci alist f or e val uati o n a n d 
c o nfir mat or y bi o ps y.  
 
I nitiate treat me nt wit h 1−2 m g/ k g/ da y 
i ntra ve n o us met h yl pre d nis ol o ne or e q ui vale nt 
a n d c o n vert t o 1−2  m g/ k g/ da y oral pre d nis o ne or 
e q ui vale nt u p o n i m pr o ve me nt.  
 
If e ve nt res ol ves t o gra de 1 or better wit hi n 1 2 
wee ks, ta per c ortic ost er oi ds a n d res u me 
atez oliz u ma b acc or di n g t o t he g ui deli nes a b o ve.  
 
Per ma ne ntl y disc o nti n ue atez oliz u ma b if e ve nt 
d oes n ot res ol ve t o Gra de 1 or better wit hi n 1 2 
wee ks.  Res u m pti o n of at ez oliz u ma b ma y be 
c o nsi dere d, after c o ns ultati o n wit h t he trial PI, i n 
patie nts w h o are deri vi n g be nefit a n d ha ve f ull y 
rec o vere d fr o m t he i m m u ne-rel ate d e ve nt. 

 
N R G -G Y 0 1 7  
5 6    
Versi o n Date:  N o ve m ber 8 , 2 0 1 8 
A E M a n a ge me nt a n d D ose I nterr u pti o n G ui deli nes f or S pecific T o xicities  
T o xicit y    
Se verit y/ D ur ati o n    
M a n a ge me nt  
Gra de 4   
Per ma ne ntl y disc o nti n ue atez oliz u ma b. Patie nt 
ma y n ot res u me treat me nt, re gar dless of be nefit.  
 
Refer patie nt t o GI s peci alist f or e val uati o n a n d 
c o nfir mati o n bi o ps y.  
 
I nitiate treat me nt wit h 1−2 m g/ k g/ da y 
i ntra ve n o us met h yl pre d nis ol o ne or e q ui vale nt 
a n d c o n vert t o 1−2 m g/ k g/ da y oral pre d nis o ne or 
e q ui vale nt u p o n i m pr o ve me nt.  
 
If e ve nt d o es n ot i m pr o ve wit hi n 4 8 h o urs after 
i nitiati n g c ortic oster oi ds, c o nsi der a d di n g a n 
i m m u n os u p pressi ve a ge nt. 
 
If e ve nt res ol ves t o gra de 1 or better, ta per 
c ortic oster oi ds  o ver 1 m o nt h.  Res u m pti o n of 
atez oliz u ma b ma y be c o nsi dere d i n patie nts w h o 
are deri vi n g be nefit a n d ha ve f ull y rec o vere d 
fr o m t he i m m u ne-rel ate d e ve nt. 
He pat ot o xicit y   
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  
Ris k of i m m u ne -me diate d he patitis.  L F Ts s h o ul d 
be perf or me d i m me diatel y, a n d L F Ts s h o ul d be 
re vie we d bef ore a d mi nistrati o n of t he ne xt d ose 
of st u d y dr u g.  F or patie nts wit h ele vate d L F Ts, 
c o nc urre nt me dicati o n, 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 nsi dere d a n d 
a d dresse d, as  a p pr o priate.  
 
S y m pt o ms of a b d o mi nal pai n ass ociate d wit h 
ele vati o ns of a m ylase a n d li pase, 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 atez oliz u ma b.  T he differe ntial 
dia g n osis of ac ute a b d o mi nal pai n s h o ul d als o 
i ncl u de pa ncreatitis, as d escri be d bel o w. 
Gra de 1 h e patic e ve nt  
C o nti n ue atez oliz u ma b.  
 
M o nit or L F Ts u ntil val ues res ol ve t o wit hi n 
n or mal li mits.  
Gra de 2 h e patic e ve nt, 
≤5 da ys  
C o nti n ue atez oliz u ma b.  
 
M o nit or L F Ts m ore fre q ue ntl y u ntil val ues 
res ol ve t o baseli ne val ues. 

 
N R G -G Y 0 1 7  
5 7    
Versi o n Date:  N o ve m ber 8 , 2 0 1 8 
A E M a n a ge me nt a n d D ose I nterr u pti o n G ui deli nes f or S pecific T o xicities  
T o xicit y    
Se verit y/ D ur ati o n    
M a n a ge me nt  
Gra de 2 h e patic e ve nt, 
> 5 da ys  
H ol d atez oliz u ma b.  
 
I nitiate treat me nt wit h 1−2 m g/ k g/ da y oral 
pre d nis o ne or e q ui vale nt.  
 
If e ve nt res ol ves t o gra de 1 or better wit hi n 1 2 
wee ks, ta per c ortic ost er oi ds a n d res u me 
atez oliz u ma b acc or di n g t o t he g ui deli nes a b o ve.  
 
Per ma ne ntl y disc o nti n ue atez oliz u ma b if e ve nt 
d oes n ot res ol ve t o Gra de 1 or better wit hi n 1 2 
wee ks.  
Gra de 3 or 4 he patic 
e ve nt  
Per ma ne ntl y disc o nti n ue atez oliz u ma b.  
 
C o nsi der pa tie nt referral t o GI s p ecialist f or 
e val uati o n a n d li ver bi o ps y t o esta blis h eti ol o g y 
of he patic i nj ur y.  
 
I nitiate treat me nt wit h 1−2 m g/ k g/ da y oral 
pre d nis o ne or e q ui vale nt.  
 
If e ve nt d o es n ot i m pr o ve wit hi n 4 8 h o urs after 
i nitiati n g c ortic oster oi ds, c o nsi der a d di n g a n 
i m m u n os u p pressi ve a ge nt. 
 
If e ve nt res ol ves t o gra de 1 or better, ta per 
c ortic oster oi ds o ver 1 m o nt h.  
H y per gl yce mia    
Gra de 1 or 2    
C o nti n ue atez oliz u ma b.  
 
I nitiate treat me nt wit h i ns uli n if nee de d. 
 
M o nit or f or gl uc ose c o ntr ol.  
Gra de 3 or 4    
H ol d atez oliz u ma b.  
 
I nitiate treat me nt wit h i ns uli n. 
 
M o nit or f or gl uc ose c o ntr ol.  
 
Res u me atez oliz u ma b w he n s y m pt o ms res ol ve 
a n d gl uc ose le vels are sta ble.  

 
N R G -G Y 0 1 7  
5 8    
Versi o n Date:  N o ve m ber 8 , 2 0 1 8 
A E M a n a ge me nt a n d D ose I nterr u pti o n G ui deli nes f or S pecific T o xicities  
T o xicit y    
Se verit y/ D ur ati o n    
M a n a ge me nt  
H y pert h yr oi dis m  Gra de 1 
(as y m pt o matic) 
T S H  0. 1 m U/ L a n d  0. 5 m U/ L:  
C o nti n ue atez oliz u ma b.  M o nit or T S H e ver y 4 
wee ks.  
 
T S H  0. 1 m U/ L:  
F oll o w g ui deli nes f or s y m pt o matic 
h y pert h yr oi dis m.  
Gra de 2 + 
(s y m pt o matic) 
H ol d atez oliz u ma b.  
 
I nitiate treat me nt wit h a nti-t h yr oi d dr u g s uc h as 
met hi maz ole or car bi maz ole as nee de d.  
 
C o nsi der patie nt referral t o e n d ocri n ol o gist.  
 
Res u me atez oliz u ma b w he n s y m pt o ms are 
c o ntr olle d a n d t h yr oi d f u ncti o n is i m pr o vi n g.  
 
Per ma ne ntl y disc o nti n ue atez oliz u ma b f or 
life-t hreat e ni n g i m m u ne-relate d h y pert h yr oi dis m.  
H y p ot h yr oi dis m  
Gra de 1 
(as y m pt o matic) 
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.  
Gra des 2 + 
(s y m pt o matic) 
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.  
 
M o nit or T S H wee kl y.  
 
Restart atez oliz u ma b w he n s y m pt o ms are 
c o ntr olle d a n d t h yr oi d f u ncti o n is i m pr o vi n g.  

 
N R G -G Y 0 1 7  
5 9    
Versi o n Date:  N o ve m ber 8 , 2 0 1 8 
A E M a n a ge me nt a n d D ose I nterr u pti o n G ui deli nes f or S pecific T o xicities  
T o xicit y    
Se verit y/ D ur ati o n    
M a n a ge me nt  
Me ni n g o -
e nce p h alitis, 
i m m u ne-relate d 
 
(si g ns a n d 
s y m pt o ms i n 
a bse nce of a n 
i de ntifie d 
alter nate 
eti ol o g y) 
 
All gra des  
Per ma ne ntl y disc o nti n ue atez oliz u ma b. Patie nt 
ma y n ot res u me treat me nt, re gar dless of be nefit.
 
 
Refer patie nt t o ne ur ol o gist.  
 
I nitiate treat me nt wit h 1−2 m g/ k g/ da y I V 
met h yl pre d nis ol o ne or e q ui vale n t a n d c o n vert t o 
1 −2  m g/ k g/ da y oral pre d nis o ne or e q ui vale nt 
u p o n i m pr o ve me nt.  
 
If e ve nt res ol ves t o gra de 1 or better, ta per 
c ortic oster oi ds o ver 1 m o nt h.  
 
If e ve nt d o es n ot i m pr o ve wit hi n 4 8 h o urs after 
i nitiati n g c ortic oster oi ds, c o nsi der a d di n g a n 
i m m u n os u p pressi ve a ge nt. 
M yast he nia 
gra vis a n d 
G uillai n -Barré 
s y n dr o me 
All gra des  
Per ma ne ntl y disc o nti n ue atez oliz u ma b. Patie nt 
ma y n ot res u me treat me nt, re gar dless of be nefit.
 
 
Refer patie nt t o ne ur ol o gist.  
 
I nitiate treat me nt as per i nstit uti o nal g ui deli nes. 
 
C o nsi der i nitiati o n of 1 −2 m g/ k g/ da y oral or I V 
pre d nis o ne or e q ui vale nt.  
M y ocar ditis    
All gra des  
Please see ta ble 4 8 i n secti o n 6. 7. i n t he 
i n vesti gat or’s br oc h ure. 
Ne ur o pat h y, 
i m m u ne-relate d 
 
(se ns or y a n d/ or 
m ot or)  
Gra de 1  
C o nti n ue atez oliz u ma b.  
 
E val uate f or alter nati ve eti ol o gies.  
Gra de 2  
H ol d atez oliz u ma b.  
 
E val uate f or alter nati ve eti ol o gies.  
 
I nitiate treat me nt as per i nstit uti o nal g ui deli nes. 
 
Res u me atez oliz u ma b if e ve nt res ol ves t o gra de 1 
or better wit hi n 1 2 wee ks.  
 
Per ma ne ntl y disc o nti n ue atez oliz u ma b if e ve nt 
d oes n ot res ol ve t o gra de 1 or better wit hi n 1 2 
wee ks.  

 
N R G -G Y 0 1 7  
6 0    
Versi o n Date:  N o ve m ber 8 , 2 0 1 8 
A E M a n a ge me nt a n d D ose I nterr u pti o n G ui deli nes f or S pecific T o xicities  
T o xicit y    
Se verit y/ D ur ati o n    
M a n a ge me nt  
Gra de 3 or 4    
Per ma ne ntl y disc o nti n ue atez oliz u ma b.  
 
I nitiate treat me nt as per i nstit uti o nal g ui deli nes. 
Oc ular e v e nt 
(e. g., u veitis, 
reti nal e ve nts) 
Gra de 1  
C o nti n ue atez oliz u ma b.  
 
Patie nt referral t o o p ht hal m ol o gist is str o n gl y 
rec o m me n de d. 
 
I nitiate treat me nt wit h t o pical c ortic oster oi d e ye 
dr o ps a n d t o pical i m m u n os u p pressi ve t hera p y.  
 
If s y m pt o ms persist, treat as a gra de 2 e ve nt. 
Gra de 2  
Wit h h ol d atez oliz u ma b.  
 
Patie nt referral t o o p ht hal m ol o gist is str o n gl y 
rec o m me n de d. 
 
I nitiate treat me nt wit h t o pical c ortic oster oi d e ye 
dr o ps a n d t o pical i m m u n os u p pressi ve t hera p y.  
 
If e ve nt res ol ves t o gra de 1 or better wit hi n 1 2 
wee ks, ta per c ortic ost er oi ds a n d res u me 
atez oliz u ma b acc or di n g t o t he g ui deli nes a b o ve.  
 
Per ma ne ntl y disc o nti n ue atez oliz u ma b if e ve nt 
d oes n ot res ol ve t o gra de 1 or better wit hi n 
1 2  wee ks.  
Gra de 3 or 4    
Per ma ne ntl y disc o nti n ue atez oliz u ma b.    
 
Refer patie nt t o o p ht hal m ol o gist.  
 
I nitiate treat me nt wit h 1−2 m g/ k g/ da y oral 
pre d nis o ne or e q ui vale nt.  
 
If e ve nt res ol ves t o gra de 1 or better, ta per 
c ortic oster oi ds o ver 1 m o nt h. F or gra de 3 A Es, 
patie nt ma y o nl y res u me treat me nt after 
c o ns ultati o n wit h t he trial PI; f or gra de 4, patie nt 
ca n n ot res u me treat me nt, re gar dless of be nefit.  

 
N R G -G Y 0 1 7  
6 1    
Versi o n Date:  N o ve m ber 8 , 2 0 1 8 
A E M a n a ge me nt a n d D ose I nterr u pti o n G ui deli nes f or S pecific T o xicities  
T o xicit y    
Se verit y/ D ur ati o n    
M a n a ge me nt  
Pa ncreatitis, 
i m m u ne relate d  
 
See A m ylase 
a n d/ or li pase 
i ncreas e d secti o n 
a b o ve  
Gra de 2 ( wit h 
ra di o gra p hic fi n di n gs) 
or 3   
H ol d atez oliz u ma b.  
 
Refer patie nt t o GI s peci alist.  
 
I nitiate treat me nt wit h 1−2 m g/ k g/ da y 
i ntra ve n o us met h yl pre d nis ol o ne or e q ui vale nt 
a n d c o n vert t o 1 −2  m g/ k g/ da y oral pre d nis o ne or 
e q ui vale nt u p o n i m pr o ve me nt.  
 
If e ve nt res ol ves t o gra de 1 or better wit hi n 1 2 
wee ks, ta per c ortic ost er oi ds a n d res u me 
atez oliz u ma b acc or di n g t o t he g ui deli nes a b o ve.  
 
Per ma ne ntl y disc o nti n ue atez oliz u ma b if e ve nt 
d oes n ot res ol ve t o gra de 1 or better wit hi n 
1 2  wee ks.  P atie nt ma y o nl y res u me treat me nt 
after c o ns ultati o n wit h t he trial PI.  
 
F or r ec urre nt e ve nts, per ma ne ntl y disc o nti n ue 
atez oliz u ma b.  Patie nt m a y n ot res u me treat me nt, 
re gar dless of be nefit. 
Gra de 4  
Per ma ne ntl y disc o nti n ue atez oliz u ma b. Patie nt 
ma y n ot res u me treat me nt, re gar dless of be nefit.
 
 
Refer patie nt t o GI s peci alist. 
 
I nitiate treat me nt wit h 1−2 m g/ k g/ da y 
i ntra ve n o us met h yl pre d nis ol o ne or e q ui vale nt 
a n d c o n vert t o 1 −2  m g/ k g/ da y oral pre d nis o ne or 
e q ui vale nt u p o n i m pr o ve me nt.  
 
If e ve nt d o es n ot i m pr o ve wit hi n 4 8 h o urs after 
i nitiati n g c ortic oster oi ds, c o nsi der a d di n g a n 
i m m u n os u p pressi ve a ge nt. 
 
If e ve nt res ol ves t o gra de 1 or better, ta per 
c ortic oster oi ds o ver 1 m o nt h.  
P ul m o nar y 
t o xicit y 
All p ul m o nar y e ve nts   
E val uate t h or o u g hl y f or ot her c o m m o nl y re p orte 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, c hr o nic o bstr ucti ve 
p ul m o nar y disease ( C O P D), or p ul m o nar y 
h y perte nsi o n.  

 
N R G -G Y 0 1 7  
6 2    
Versi o n Date:  N o ve m ber 8 , 2 0 1 8 
A E M a n a ge me nt a n d D ose I nterr u pti o n G ui deli nes f or S pecific T o xicities  
T o xicit y    
Se verit y/ D ur ati o n    
M a n a ge me nt  
Gra de 1  
C o nti n ue atez oliz u ma b a n d m o nit or cl osel y .   
 
Re -e val uate o n serial i ma gi n g.  
 
C o nsi der patie nt referral t o a p ul m o nar y 
s pecialist. 
 
F or rec urre nt p ne u m o nitis, treat as a gra de 3 or 4 
e ve nt.  
Gra de 2  
H ol d atez oliz u ma b.   
 
Refer patie nt t o p ul m o nar y a n d i nfecti o us disease 
s pecialists a n d c o nsi der br o nc h osc o p y or 
br o nc h osc o pic al ve olar la va ge ( B A L).  
 
I nitiate treat me nt wit h 1−2 m g/ k g/ da y oral 
pre d nis o ne or e q ui vale nt.  
 
If e ve nt res ol ves t o gra de 1 or better wit hi n 1 2 
wee ks, ta per c ortic ost er oi ds a n d res u me 
atez oliz u ma b acc or di n g t o t he g ui deli nes a b o ve.  
 
Per ma ne ntl y disc o nti n ue atez oliz u ma b if e ve nt 
d oes n ot res ol ve t o gra de 1 or better wit hi n 
1 2  wee ks.  
 
F or rec urre nt e ve nts, treat as a Gra de 3 or 4 
e ve nt.  
Gra de 3 or 4    
Per ma ne ntl y disc o nti n ue atez oliz u ma b.  
 
Br o nc h osc o p y or B A L is rec o m me n de d.  
 
I nitiate treat me nt wit h 1−2 m g/ k g/ da y oral 
pre d nis o ne or e q ui vale nt.  
 
If e ve nt d o es n ot i m pr o ve wit hi n 4 8 h o urs after 
i nitiati n g c ortic oster oi ds, c o nsi der a d di n g a n 
i m m u n os u p pressi ve a ge nt. 
 
If e ve nt res ol ves t o gra de 1 or better, ta per 
c ortic oster oi ds o ver 1 m o nt h.  F or gra de 3 A Es, 
patie nt ma y o nl y res u me treat me nt after 
c o ns ultati o n wit h t he trial PI; f or gra de 4, patie nt 
ca n n ot res u me treat me nt, re gar dless of be nefit.  

 
N R G -G Y 0 1 7  
6 3    
Versi o n Date:  N o ve m ber 8 , 2 0 1 8 
 
6. 3    
R a di ati o n T her a p y  D ose Deli ver y M o dific ati o ns  
 
6. 3. 1  Ra diati o n t hera p y ma y o nl y be s us pe n de d sec o n dar y t o a si g nifica nt 
a d verse e ve nt at t he j oi nt discreti o n of t he patie nt’s treati n g p h ysicia ns a n d t he 
st u d y c hair (face s h eet). T he st u d y c hair m ust be n otifie d i n writi n g (e. g., 
e mail) of d ose m o dificati o ns or treat me nt m o dalit y m o dificati o ns f or e xter nal 
bea m ra diati o n t hera p y or f or brac h yt hera p y.  
 
6. 3. 2  Beca use it has bee n o bser ve d t hat he m o gl o bi n le vels bel o w 1 0 -1 2 g/ d L 
d uri n g ra diati o n t her a p y are ass o ciate d wit h decrease d l ocal c o ntr ol, bl o o d 
tra nsf usi o ns s h o ul d be offere d t o p atie nts a n d use d t o treat patie nts at t he 
discreti o n of treati n g p h ysicia ns pri or t o or d uri n g ra di ot hera p y per 
i nstit uti o nal pr ot oc ol. T here s h o ul d be n o ra diati o n thera p y treat me nt dela ys 
d ue t o a l o w he m o gl o bi n le vels. P u blis he d res ults e val uati n g e p oeiti n al p ha 
( Pr ocrit, E p o ge n) a n d ra di oc he m ot hera p y i n cer vical ca ncer ha ve i n dicate d t hat 
e p oeiti n al p ha ma y be ass ociate d wit h a n i ncrease d ris k f or t hr o m b oe m b olis m, 
a n d t heref ore, ma y N O T be use d i n t his st u d y.  
 
6. 3. 3  He mat ol o gic A d verse E ve nts: He mat ol o gic t o xicities are see n 
i nfre q ue ntl y u nless pel vi c ra diati o n occ urs wit h c he m ot hera p y. A c o m plete 
bl o o d c o u nt s h o ul d be o btai ne d wee kl y d uri n g ra di oc he m ot hera p y. If t h e 
a bs ol ute ne utr o p hil c o u nt falls t o less t ha n 5 0 0 / m m 3 or platelet c o u nt falls t o 
less t ha n 2 5, 0 0 0 / m m3, ra diati o n t hera p y ma y be te m p oraril y wit h hel d t o all o w 
rec o ver y a b o v e t hese le vels at t he discreti o n of t h e treati n g p h ysicia n. 
 
6. 3. 4  Gastr oi ntesti nal A d verse E ve nts: Na usea a n d v o miti n g are rat h er 
u n us ual after p el vic ra di ati o n. A ntie metics ma y be gi ve n w he n s y m pt o ms 
occ ur or m a y be gi ve n pr o p h ylacticall y pri or t o treat me nt per i nstit uti o nal 
pr ot oc ol. I ntract a ble na us ea or v o miti n g is rarel y s ee n wi t h pel vic ra diati o n 
al o ne a n d is us uall y t he res ult of a n ot her pr ocess, i.e. b o wel o bstr ucti o n. 
I n crease d b o wel acti vit y wit h diarr hea us u all y ca n be c o ntr olle d wit h l o w fi ber, 
l o w fat, bla n d diets a n d a nti diarr heal me dicati o ns. S h o ul d gastr oi ntesti nal 
t o xicit y bec o me se vere, h os pitalizati o n ma y be re q uire d at w hic h ti me t he 
treat me nt ma y be i nterr u pte d te m p oraril y u ntil t he patie nt’s c o n diti o n 
i m pr o ves. 
 
6. 3. 5  Ge nit o uri nar y A d verse E ve nts: Ac ute t o xicit y of t he uri nar y tract is 
ma nifeste d b y c ystitis. Mai n tai ni n g hi g h fl ui d i nta ke is i m p orta nt. Bla d der 
a ntis pas m o dics, a nal gesi cs a n d a nti bi otics are rec o m me n de d per i nstit uti o nal 
pr ot oc ol. He mat uria is n ot us uall y see n wit h ac ute c ystitis a n d s u g gests bla d der 
i n vasi o n b y t u m or. Ac ute v ul v o va gi nitis is see n w he n t he pel vic fiel ds e xte n d 
i nferi orl y t o i ncl u de t he v ul v o peri neal area. Treat me nt of ac ute v ul v o peri neal 
reacti o n ma y re q uire war m sali ne s oa ks, weari n g l o ose cl ot hi n g a n d kee pi n g 
t he area dr y usi n g a hair dr yer. T o pical ster oi ds, a nti bi otics, crea ms, a nd 
treat me nt i nterr u pti o n ma y be necessar y per i nstit uti o nal pr ot oc ol. 
 

 
N R G -G Y 0 1 7  
6 4    
Versi o n Date:  N o ve m ber 8 , 2 0 1 8 
6. 3. 6  C uta ne o us S ki n T o xicit y A d verse E ve nts:  Wit h t he use of me ga v olta ge 
e xter nal bea m ra diati o n t hera p y, s ki n reacti o ns i n t he treat me nt fiel d are 
i nfre q ue nt b ut are m ore li kel y t o de vel o p if sites s uc h as t he i n g ui nal area, 
v ul va, a n d t he peri ne u m are e xt e nsi vel y wit hi n t he ra diati o n fiel ds. D uri n g 
ra diati o n t hera p y, mil d irritati o n a n d re d ness of t h e s ki n ma y occ ur wit hi n t he 
ra diati o n fiel ds. S o me patie nts ma y e x perie nce m ore i nte nse s ki n reacti o n s uc h 
as dr y or m oist des q ua mati o n de pe n di n g u p o n t he e ner g y of t he me ga v olta ge 
bea m, n u m ber of fiel ds use d per da y, nee d t o c o ver distal va gi na a n d t heref ore 
flas hi n g peri ne u m a n d use of c he m ot hera p y. Hair l oss i n t he p u bic area ma y 
occ ur w hic h ca n b e per ma ne nt. Late s u bc uta ne o us fi br osis, tela n giectasia, a n d 
s ki n atr o p h y are u n c o m m o n se q uelae. Al m ost all patie nts wit h v ul var/ peri neal 
s ki n i n t he treat me nt fiel ds ma y e x pect t o de vel o p ac ute m oist des q ua mati o n 
d uri n g t he c o urse of e xter nal b ea m ra diati o n t hera p y.  
 
Ac ute s ki n reacti o ns ma y be treate d acc or di n g t o i nstit uti o nal prefere nces. 
A q ua p h or or ster oi d crea ms ma y be use d f or C T C A E v 4 gra de 1 -2 reacti o ns 
a n d it is n ot necessar y t o i nterr u pt t he ra diati o n t hera p y. F or C T C A E v 4 gra de 
3 -4 s ki n reacti o ns w he n ge neralize d mac ul ar, pa p ular or vesic ular er u pti o ns 
ha ve de v el o pe d, or t here is ge neralize d e xf oliati ve or ulcerati ve der matitis i n 
t he treat me nt fiel ds, r a diati o n t hera p y ma y be i nterr u pte d, b ut t his s h o ul d be 
a v oi de d. Treat me nt ma y re q uire s y m pt o matic ma na ge me nt of pai n, us e of 
war m sali ne s oa ks, vita mi n A & D oi nt me nt, weari n g l o ose cl ot hi n g, a n d 
kee pi n g t he area dr y acc or di n g t o i nstit uti o nal pr ot oc ol. Ra diati o n t hera p y 
s h o ul d be res u me d as s o o n as t he s ki n reacti o ns ha ve i m pr o ve d. T he pri nci pal 
i n vesti gat or s h o ul d be n otifie d wit hi n 9 6 h o urs of a n y gra de 4 t o xicit y. 
 
7 . A D V E R S E E V E N T S R E P O R TI N G  R E Q UI R E M E N T S  
 
7 .1   
Pr ot oc ol A g e nts  
   
I n v esti gati o nal A ge nts 
T he i n vesti gati o nal a ge nt a d mi nistere d i n N R G -G Y 0 1 7,  is Atez oliz u m a b , w hic h is 
bei n g ma de a v aila ble u n der a n I N D s p o ns ore d b y C T E P , D C T D , N CI.  F or patie nts 
recei vi n g atez oliz u m a b , deter mi nati o n of w het h er a n a d verse e ve nt meets e x pe dite d 
re p orti n g criteria, see t h e re p orti n g ta ble i n secti on 7. 6  of t he pr ot oc ol.  
   
C o m mercial A ge nts  
T he c o m mercial a ge nt i n N R G -G Y 0 1 7  is Cis pl ati n.    I n t his st u d y t he c o m mercial a ge nt is 
use d i n c o m bi nati o n wit h i n vesti gati o nal a ge nt; t heref ore, after recei vi n g cis plati n, t he 
e x pe dite d a d v erse e ve nt re p orti n g criteria f or a n i n vesti gati o nal a ge nt/t hera p y a p pl y; 
see re p orti n g ta ble i n secti o n 7. 6 of t he pr ot oc ol.  
7. 2   
A d verse E ve nts a n d Seri o us A d verse E ve nts  
7 .2 .1   
 
T his st u d y will utilize t he N CI C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts 
( C T C A E) versi o n 5. 0 f or re p orti n g of a d verse e ve nts ( A Es), l ocate d o n t he C T E P we b 
site, htt p://cte p.ca ncer. g o v/ pr ot oc ol De vel o p me nt/electr o nic _a p plicati o ns/ctc. ht m .  All 
a p pr o priate treat me nt areas s h o ul d ha ve access t o a c o p y of t he C T C A E versi o n 5. 0  

 
N R G -G Y 0 1 7  
6 9    
Versi o n Date:  N o ve m ber 8 , 2 0 1 8 
 
2Atez oliz u ma b, bei n g a me m ber of a class of a ge nts i n v ol ve d i n t he i n hi biti o n of “i m m u ne 
c hec k p oi nts,” ma y res ult i n se vere a n d p ossi bl y fatal i m m u ne -me diate d a d verse e ve nts pr o ba bl y 
d ue t o T -cell acti vati o n a n d pr oliferati o n.  I m m u ne -me diate d a d verse reacti o ns ha ve bee n 
re p orted i n patie nts recei vi n g atez oliz u ma b.  A d verse e ve nts p ote ntiall y relate d t o atez oliz u ma b 
ma y be ma nifestati o ns of i m m u ne -me diate d a d verse e ve nts.  I n cli nical trials, m ost i m m u ne -
me diate d a d verse reacti o ns were re versi ble a n d m a na ge d wit h i nterr u pti o ns of  atez oliz u ma b, 
a d mi nistrati o n of c ortic oster oi ds a n d s u p p orti ve care.  
 
3I nf usi o n reacti o ns, i ncl u di n g hi g h-gra de h y perse nsiti vit y reacti o ns, a na p h yla xis, a n d c yt o ki ne 
releas e s y n dr o me, w hic h ha ve bee n o bser ve d f oll o wi n g a d mi nistrati o n of atez oliz u ma b, ma y 
ma nifest as fe v er, c hills, s ha kes, itc hi n g, ras h, h y p erte nsi o n or h y p ote nsi o n, or diffic ult y 
breat hi n g d uri n g a n d i m me diatel y after a d mi nistrati o n of atez oliz u ma b.  
 
A d verse e v e nts re p orte d o n atez oliz u m a b ( M P D L 3 2 8 0 A) tri als, b ut f or w hic h t here is 
i ns ufficie nt e vi de nce t o s u g gest t h at t here w as a re as o n a ble p ossi bilit y t h at atez oliz u m a b 
( M P D L 3 2 8 0 A) c a use d t he a d verse e ve nt: 
 
C A R DI A C DI S O R D E R S  - Car diac arrest  
G A S T R OI N T E S TI N A L DI S O R D E R S  - C o nsti pati o n; Ile us  
G E N E R A L DI S O R D E R S A N D A D MI NI S T R A TI O N SI T E  c o n diti o ns  - C hills; E de ma 
li m bs; Malaise; Pai n 
I N F E C TI O N S A N D I N F E S T A TI O N S - L u n g i nfecti o n; Se psis; Uri nar y tract i nfecti o n  
I N V E S TI G A TI O N S - Wei g ht l oss; W hite bl o o d cell decreas e d  
M E T A B O LI S M A N D N U T RI TI O N DI S O R D E R S  - H y p o p h os p hate mia ; T u m or l ysis 
s y n dr o me 
M U S C U L O S K E L E T A L A N D C O N N E C TI V E TI S S U E DI S O R D E R S  - Bac k pai n; B o ne 
pai n  
N E R V O U S S Y S T E M DI S O R D E R S  - Hea dac he  
P S Y C HI A T RI C DI S O R D E R S  - C o nf usi o n; I ns o m nia; S uici de atte m pt  
R E P R O D U C TI V E S Y S T E M A N D B R E A S T DI S O R D E R S  - Breast pai n  
R E S PI R A T O R Y, T H O R A CI C A N D M E DI A S TI N A L DI S O R D E R S  - Br o nc h o p ul m o nar y 
he m orr ha g e; P ul m o nar y h y perte nsi o n  
S KI N A N D S U B C U T A N E O U S TI S S U E  DI S O R D E R S  - Al o pecia; Dr y s ki n 3 5; H y per hi dr osis 
V A S C U L A R DI S O R D E R S  - H y perte nsi o n; H y p ote nsi o n; T hr o m b oe m b olic e ve nt  
 
N ote : Atez oliz u m a b ( M P D L 3 2 8 0 A) i n c o m bi nati o n wit h ot her a ge nts c o ul d ca use a n 
e xacer bati o n of a n y a d verse e ve nt c urr e ntl y k n o w n t o be ca use d b y t he ot her a ge nt, or t he 
c o m bi nati o n ma y res ult i n e ve nts ne ver pre vi o usl y ass ociate d wit h eit her a ge nt.  
 
7 .4   
A d verse E ve nts f o r C o m merci al St u d y A ge nts  
 Refer t o t he p ac k a ge i nsert f o r det aile d p h ar m ac ol o gic a n d s afet y i nf or m at i o n 
 
7. 5   
A d verse E ve nt C h ar acteristics  
 
•  C T C A E ter m ( A E descri pti o n) a n d gr a de:  T he descri pti o ns a n d gra di n g scales f o u n d 

 
N R G -G Y 0 1 7  
7 0    
Versi o n Date:  N o ve m ber 8 , 2 0 1 8 
i n t he re vise d N CI C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts ( C T C A E) versi o n 
5 . 0 will be utilize d f or A E re p orti n g.  All a p pr o priate treat me nt areas s h o ul d ha ve access 
t o a c o p y of t he C T C A E versi o n 5 . 0.  A c op y of t h e C T C A E versi o n 5 . 0 ca n be 
d o w nl oa de d fr o m t he C T E P we b site 
htt p://cte p.ca ncer. g o v/ pr ot oc ol De vel o p me nt/electr o nic a p plicati o ns/ctc. ht m . 
 
•  F or e x pe dite d re p orti n g p ur p oses o nl y:   
- 
A Es f or t he a g e nt  t hat are b ol d a n d it alicize d  i n t he C A E P R (i.e., t h ose liste d i n t he 
S P E E R c ol u m n, Secti o n 7. 3 ) s h o ul d be re p orte d t hr o u g h C T E P-A E R S o nl y if t he 
gra de is a b o ve t he gra d e pr o vi de d i n t he S P E E R.  
 
•  Attri b uti o n  of t he A E:  
•  Defi nite –  T he A E is cle arly rel ate d t o t he st u d y treat me nt. 
•  Pr o ba ble –  T he A E is likely rel ate d t o t he st u d y treat me nt. 
•  P ossi ble –  T he A E m ay b e rel ate d  t o t he st u d y treat me nt. 
•  U nli kel y –  T he A E is d o u btf ully rel ate d t o t he st u d y treat me nt.  
•  U nrelate d –  T he A E is cl e arly N O T rel ate d t o t he st u d y treat me nt 
 
7 .6   
E x pe dite d Re p orti n g of A d verse E ve nts  
All seri o us a d verse e ve nts t hat meet e x pe dite d re p orti n g criteria de fi ne d i n t he re p orti n g 
ta ble bel o w will be re p orte d via t he C T E P A d vers e E ve nt Re p orti n g S yste m, C T E P -
A E R S , accesse d vi a t he C T E P we b site,  
htt ps://ea p ps -cte p. nci. ni h. g o v/cte paers/ pa ges/tas k?ra n d = 1 3 9 0 8 5 3 4 8 9 6 1 3  
 
S u b mitti n g a re p ort via C T E P -A E R S  ser ves as n otificati o n t o N R G a n d satisfies N R G 
re q uire me nts f or e x pe dit e d a d verse e ve nt re p orti n g. 
 
I n t he r are e v e nt w he n I nter net c o n necti vit y is disr u pte d, a 2 4 -h o ur n otific ati o n 
m ust be m a de t o C T E P f or t his st u d y b y tele p h o ne at 3 0 1 -8 9 7 -7 4 9 7 a n d t o t he N R G 
Re g ul at or y Aff airs  b y p h o ne at 2 1 5 -8 5 4 -0 7 7 0.   A n electr o nic re p ort m ust be 
s u b mitte d i m me di atel y u p o n re-est a blis h me nt of t he I nter net c o n necti o n.  
 
7. 6 .1  E x pe dite d Re p orti n g Met h o ds  
•  Per C T E P N CI G ui deli nes f or A d verse E ve nts Re p orti n g Re q uire me n ts, a C T E P-
A E R S 2 4 -h o ur n otificati o n m ust be s u b mitte d wit hi n 2 4 h o urs of lear ni n g of t he 
a d verse e ve nt .  Eac h C T E P -A E R S  2 4 -h o ur n otificati o n m ust be f oll o we d b y a 
c o m plete re p ort wit hi n 5  da ys .  
•  S u p p orti n g s o urce d oc u me nt ati o n is re q ueste d b y t he I N D S p o ns or f or t his st u d y 
( C T E P/ D C T D) a n d N R G as nee de d t o c o m plete a d verse e ve nt re vie w .  S u p p orti n g 
s o urce d oc u m e ntati o n s h o ul d i ncl u de t he pr ot oc ol n u m ber, patie nt I D n u m ber, a n d 
C T E P -A E R S  tic ket n u m ber o n eac h pa ge, a n d fa x s u p p orti n g d oc u me ntati o n t o C T E P 
at 3 0 1 -2 3 0 -0 1 5 9 a n d t o  N R G Re g ulat or y Affairs  at 2 1 5 -8 5 4 -0 7 1 6   
•  A seri o us a d verse e v e nt t hat meets e x pe dite d re p orti n g criteria o utli ne d i n t he A E  
Re p orti n g Ta bles  b ut is assesse d b y t he C T E P -A E R S  as “a n acti o n n ot  
rec o m me n de d” m ust still be re p orte d t o f ulfill N R G safet y re p orti n g o bli gati o ns. Sites 
m ust b y pass t he “ N O T rec o m me n de d” assess me nt; t he C T E P -A E R S  all o ws 

 
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•  Cases of p ote ntial dr u g -i n d uce d li ver i nj ur y t hat i ncl u de a n el e vate d A L T or A S T i n 
c o m bi nati o n wit h eit her a n ele vat e d bilir u bi n or cli nical ja u n dice, as defi ne d b y H y's La w 
a n d base d o n t he f oll o wi n g o bser vati o ns:  
o  Treat me nt -e mer ge nt A L T or A S T > 3 x U L N ( or > 3 x baseli ne val u e i n disease states 
w h ere L F Ts ma y be ele vate d at baseli ne) i n c o m bi nati o n wit h t otal bilir u bi n > 2 x U L N 
( of w hic h ≥ 3 5 % is direct bilir u bi n) 
o  Treat me nt -e mer ge nt A L T or A S T > 3 x U L N ( or > 3 x baseli ne val u e i n disease states 
w here L F Ts ma y be ele vate d at baseli ne) i n c o m bi nati o n wit h cli nical ja u n dice  
•  S us pecte d tra ns missi o n of a n i nfecti o us a ge nt b y t he st u d y treat me nt, as defi ne d bel o w:  
o  A n y or ga nis m, vir us, or i nfecti o us particle (e. g., pri o n pr otei n tra ns mitti n g tra ns missi ble 
s p o n gif or m e nce p h al o pat h y), pat h o ge nic or n o n-pat h o ge nic, is c o nsi dere d a n i nfecti o us 
a ge nt. A tra ns missi o n of a n i nfecti o us a ge nt ma y be s us pecte d fr o m cli nical s y m pt o ms or 
la b orat or y fi n di n gs t hat i n dicate a n i nfecti o n i n a patie nt e x p ose d t o a me di ci nal pr o d uct. 
T his ter m a p plies o nl y w he n a c o nta mi nat i o n of st u d y treat me nt is s us pecte d. 
•  P ne u m o nitis  
•  C olitis  
•   E n d ocri n o pat hies: dia bet es mellit us, pa ncreatitis, a dre nal i ns ufficie nc y, h y pert h yr oi dis m, 
a n d h y p o p h ysitis  
•  He patitis, i ncl u di n g A S T or A L T > 1 0 x U L N  
•  S yste mic l u p us er yt he mat os us  
•  Ne ur ol o gical dis or ders: G uillai n -Barré s y n dr o me, m yast he nic s y n dr o me or m y ast he nia 
gra vis, a n d me ni n g oe nce p halitis  
•  E ve nts s u g gesti ve of h y p erse nsiti vit y, i nf usi o n -relate d reacti o ns, c yt o ki ne release 
s y n dr o me, 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 me, a n d 
s yste mic i m m u ne acti vati o n  
•  Ne p hritis  
•   Oc ular t o xic ities (e. g., u veitis, reti nitis, o ptic ne uritis)  
•  M y ositis  
•  M y o pat hies, i ncl u di n g r ha b d o m y ol ysis  
•  Gra de > 2 car diac dis or d ers (e. g., atrial fi brillati o n, m y ocar ditis, pericar ditis)  
•  Vasc ulitis  
•  A ut oi m m u ne he m ol ytic a ne mia  
•  Se vere c ut a ne o us reacti o ns (e. g.,  Ste ve ns -J o h ns o n s y n dr o me, der matitis b ull o us, t o xic 
e pi der mal necr ol ysis)  
7. 6. 4  Re p orti n g t o t he Site I R B/ R E B  
I n v esti gat ors will re p ort seri o us a d verse e ve nts t o t he l ocal I nstit uti o nal Re vie w B oar d 

 
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Sites partici pati n g o n t he N CI CI R B i nitiati ve t hat are a p pr o ve d b y t he CI R B f or t his 
st u d y are n ot re q uire d t o s u b mit I R B a p pr o val d oc u me ntati o n t o t he C T S U Re g ulat or y 
Office. F or sites usi n g t h e CI R B, I R B a p pr o val i nf or mati o n is recei ve d fr o m t he CI R B 
a n d a p plie d t o t he R S S i n a n a ut o mate d pr ocess. Si g nat or y I nstit uti o ns m ust s u b mit a 
St u d y S pecific W or ks heet f or L ocal C o nte xt ( S S W) t o t he CI R B via I R B Ma na ger t o 
i n dicate t heir i nte nt t o o pe n t he st u d y l ocally.  T he CI R B’s a p pr o val of t he S S W is t he n 
c o m m u nicate d t o t he C T S U Re g ulat or y Office.  I n or der f or t he S S W a p pr o val t o be 
pr ocesse d, t he Si g nat or y I nstit uti o n m ust i nf or m t he C T S U w hic h CI R B -a p pr o ve d 
i nstit uti o ns ali g ne d wit h t he Si g nat or y I nstit uti o n are partici p ati n g i n t he st u d y.  
 
D o w nl o a di n g Site Re gistr ati o n D oc u me nts:   
 
Site re gistrati o n f or ms ma y be d o w nl oa de d fr o m t he N R G -G Y 0 1 7  pr ot oc ol pa ge l ocat e d 
o n t he C T S U me m bers’ we bsite . Per missi o n t o vie w a n d d o w nl oa d t his pr ot oc ol a n d its 
s u p p orti n g d ocu me nts is restricte d a n d is base d o n pers o n a n d site r oster assi g n me nt 
h o use d i n t he C T S U R S S.  
▪ G o t o htt ps:// w w w.cts u. or g  a n d l o g i n t o t he me m bers’ area usi n g y o ur C T E P-I A M 
user na me a n d pass w or d  
▪ Clic k o n t he Pr ot oc ols ta b i n t he u p per left of y o ur scree n  
▪ Eit her e nter t he pr ot oc ol #  N R G -G Y 0 1 7  i n t he searc h fiel d at t he t o p of t h e pr ot oc ol 
tree, or 
▪ Clic k o n t he B y Lea d Or ga nizati o n f ol der t o e x pa n d  
▪ Clic k o n t he  N R G O nc ol o g y  li n k t o e x pa n d, t he n select trial pr ot oc ol # N R G -
G Y 0 1 7 . 
▪ Clic k o n L P O D oc u me nts, select t he Site Re gistrati o n d oc u me nts li n k, a n d 
d o w nl oa d a n d c o m plete t he f or ms pr o vi de d.   
 
Re q uire me nts F or N R G -G Y 0 1 7  Site Re gistr ati o n:  
 
• I R B a p pr o val ( F or sites n ot partici pati n g via t he N CI CI R B; l ocal I R B 
d oc u me ntati o n, a n I R B -si g ne d C T S U I R B Certificati o n F or m, Pr ot oc ol of H u ma n 
S u bjects Ass ura nce I de ntificati o n/I R B Certificati o n/ Declarati o n of E xe m pti o n 
F or m, or c o m bi nati o n is acce pte d ) 
 
S u b mitti n g Re g ul at or y D oc u me nts:  
 
S u b mit re q uire d f or ms a n d d oc u me nts  t o t he C T S U Re g ulat or y Office via t he Re g ulat or y 
S u b missi o n P ortal, w here t he y will be e ntere d a n d trac ke d i n t he C T S U R S S.  
 
Re g ulat or y S u b missi o n P ortal: w w w.cts u. or g   ( me m bers’ area) → R e g ulat or y Ta b 

 
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→Re g ulat or y S u b missi o n  
W he n a p plica ble, ori gi nal d oc u me nts s h o ul d be maile d t o:  
C T S U Re g ulat or y Office  
      1 8 1 8 Mar ket Street, S uite 3 0 0 0  
      P hila del p hia, P A 1 9 1 0 3  
I nstit uti o ns wit h patie nts waiti n g t hat are u na bl e t o use t he P ortal s h o ul d alert t he C T S U 
Re g ulat or y Office i m me diatel y at 1 -8 6 6 -6 5 1 -2 8 7 8 i n or der t o recei ve f urt her i nstr ucti o n 
a n d s u p p ort.  
 
C he c ki n g Y o ur Site’s Re gistr ati o n St at us:  
 
Y o u ca n verif y y o ur site re gistrati o n stat us o n t he me m bers’ secti o n of t he C T S U 
we bsite.   
 
•  G o t o htt ps:// w w w.cts u. or g  a n d l o g i n t o t he me m bers’ area usi n g y o ur C T E P -I A M 
user na me a n d pass w or d  
•  Clic k o n t he Re g ulat or y ta b  
•  Clic k o n t he Site Re gistrati o n ta b  
•  E nter y o ur 5 -c haracter C T E P I nstit uti o n C o de a n d clic k o n G o  
 
N ote: T he stat us gi ve n o nl y reflects c o m plia nce wit h I R B d oc u me ntati o n a n d i nstit uti o nal 
c o m plia nce wit h pr ot oc ol -s pecific re q uire m e nts o utli ne d b y t he Lea d Net w or k. It d oes 
n ot reflect c o m plia nce wit h pr ot oc ol re q uire m e nts f or i n di vi d uals partici pati n g o n t he 
pr ot oc ol or t he e nr olli n g i n vesti gat or’s stat us wit h t he N CI or t heir affiliate d net w or ks.  
 
8. 3   
P atie nt E nr oll me nt  
 
Patie nt e nr oll me nt will be facilitate d usi n g t he O nc ol o g y Patie nt E nr oll me nt Net w or k 
( O P E N).  O P E N is a we b-base d re gistrati o n s yste m a vaila ble o n a 2 4/ 7 basis.  T o access 
O P E N, t he site user m ust ha ve a n acti ve C T E P -I A M acc o u nt (c hec k at < 
htt ps:// cte pc ore. nci. ni h. g o v/ia m  >) a n d a ‘Re gistrar ’ r ole o n eit her t he L P O or 
partici pati n g or ga nizati o n r oster.  Re gistrars m ust h ol d a mi ni m u m of a n A P re gistrati o n 
t y pe.  If a D T L is re q uire d f or t he st u d y, t he re gistrar(s) m ust als o be assi g ne d t he O P E N 
Re gistrar tas k o n t he D T L.    
 
All site staff will use O P E N t o e nr oll patie nts t o t his st u d y.  It is i nte grate d wit h t he 
C T S U E nter prise S yste m f or re g ulat or y a n d r oster data  a n d, u p o n e nr oll me nt, i nitializes 
t he patie nt i n t he Ra ve data base.  O P E N ca n be accesse d at htt ps:// o pe n.cts u. or g  or fr o m 
t he O P E N ta b o n t he C T S U me m bers’ si de of t he we bsite at htt ps:// w w w.cts u. or g .  T o 
assi g n a n I V R or N PI V R as t he treati n g, cre diti n g, c o nse nti n g, dr u g s hi p me nt (I V R o nl y), 
or i n vesti gat or recei vi n g a tra nsfer i n O P E N, t he I V R or N PI V R m ust l ist o n t heir F or m 
F D A 1 5 7 2 i n R C R t he I R B n u m ber use d o n t he site’s I R B a p pr o val.  If a D T L is re q uire d 
f or t he st u d y, t he I V R or N PI V R m ust als o be assi g ne d t he a p pr o priate O P E N-relate d 
tas ks o n t he D T L. 
 
Pri or t o accessi n g O P E N, site staff s h o ul d verif y t he f oll o wi n g:  

 
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•  All eli gi bilit y criteria ha ve bee n met  wit hi n t he pr ot oc ol state d ti mefra mes.  
•  All patie nts ha ve si g ne d a n a p pr o priate c o nse nt f or m a n d HI P A A 
a ut h orizati o n  f or m (if a p plica ble). 
 
N ote:   T he O P E N  s yste m will pr o vi de t he site wit h a pri nta ble c o nfir mati o n of 
re gistrati o n a n d treat me nt i nf or mati o n.   Please pri nt t his c o nfir mati o n f or y o ur rec or ds.   
 
F urt her i nstr ucti o nal i nf or mati o n is pr o vi de d o n t he O P E N ta b of t he C T S U me m bers’ 
si de of t he C T S U we bsite at htt ps:// w w w.cts u. or g  or at htt ps:// o pe n.cts u. or g .  F or a n y 
a d diti o nal q uesti o ns c o ntact t he C T S U Hel p Des k at 1 -8 8 8 -8 2 3 -5 9 2 3 or 
cts uc o ntact @ westat.c o m . 
 
8. 4   
R T -S pecific Pre -Re gist r ati o n Re q uire me nts  
F or detaile d i nf or mati o n o n t he s pecific tec h n ol o g y re q uire me nt re q uire d f or t his 
st u d y, please refer t o t he ta ble bel o w a n d utilize t h e we b li n k pr o vi de d f or detaile d 
i nstr ucti o ns. T he c hec k mar ks u n der t he treat me nt m o dalit y c ol u m ns i n dicate w het her 
t hat s pecific cre de ntiali n g re q uire me nt is re q uire d f or t his st u d y. I R O C-H o ust o n will 
be t he e ntit y t o n otif y y o ur i nstit uti o n w he n all cre de ntiali n g re q uire me nts ha ve bee n 
met a n d t he i nstit uti o n is R T cre de ntiale d t o e nter patie nts o nt o t his st u d y.  
S ee t he ta ble a b o v e  f or t h e cre de ntiali n g re q uire me nts of t his st u d y. 

 
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8 .4 . 1 Di gital R T Data S u b missi o n t o N R G  Usi n g T RI A D  
T RI A D is t he i ma ge e x c ha n ge a p plicati o n use d b y t he N R G.  T RI A D pr o vi des 
sites partici pati n g i n N R G cli nical trials a sec ure met h o d t o tra ns mit DI C O M R T 
a n d ot her o bjects.  T RI A D a n o n y mizes a n d vali dates t he i ma ges as t he y are 
tra nsferre d. 
 
T RI A D Access Re q uire me nts:  
•  Site p h ysics staff w h o will s u b mit i ma ges t hr o u g h T RI A D will nee d t o be re gistere d 
wit h T he Ca ncer T hera p y E val uati o n Pr o gra m ( C T E P) a n d ha ve a vali d a n d acti ve 
C T E P I d e ntit y a n d Access 
Ma na ge me nt (I A M)  acc o u nt. Please refer t o t he 
be gi n ni n g of Secti o n 4  f or i nstr ucti o ns o n h o w t o re q uest a C T E P-I A M acc o u nt. 
•  T o s u b mit i ma ges, t he site  p h ysics user m ust ha ve bee n assi g ne d t he ‘T RI A D site 
user ’ r ole o n t he rele va nt Gr o u p or C T S U r oster. N R G  users s h o ul d c o ntact y o ur 
site Lea d R A t o b e a d d e d t o y o ur site r oster.  Users fr o m ot her c o o perati ve gr o u ps 
s h o uld f oll o w t heir pr oce d ures f or assi g n me nt of r oster r oles.  
R T Cre de ntiali n g 
Re q uire me nts  
 
We b Li n k f or Pr oce d ures a n d I nstr ucti o ns: htt p://ir oc h o ust o n. m da n ders o n. or g  
 
Treat me nt 
M o dalit y  
 
IM R T  
Ke y I nf or m ati o n  
 
Facilit y 
Q uesti o n naire  
X  
T he I R O C H o ust o n electr o nic facilit y q uesti o n naire ( F Q) 
s h o ul d be c o m plete d or u p date d wit h t he m ost rece nt 
i nf or mati o n a b o ut y o ur i nstit uti o n. T o access t his F Q, e mail 
ir oc h o ust o n @ m da n ders o n. or g t o recei ve y o ur F Q li n k. 
Cre de ntiali n g 
Stat us I n q uir y 
F or m  
X  
T o deter mi ne w het her y o ur i nstit uti o n nee ds t o c o m plete a n y 
f urt her cre de ntiali n g re q uire me nts, please c o m plete t he 
“ Cre de ntiali n g Stat us I n q uir y F or m” f o u n d u n der cre de ntiali n g 
o n t he I R O C H o ust o n Q A Ce nter we bsite 
(htt p://ir oc h o ust o n. m da n ders o n. or g ) 
P ha nt o m 
Irra diati o n 
X  
A n I M R T p ha nt o m st u d y pr o vi de d b y t he I R O C Q A Ce nter 
H o ust o n m ust be s uccessf ull y c o m plete d. I nstr ucti o ns f or 
re q uesti n g a n d irra diati n g t he p ha nt o m are f o u n d o n t he I R O C 
H o ust o n we b site ( htt p://ir oc h o ust o n. m da n ders o n. or g ). 
T o m ot hera p y treat me nt deli ver y m o dalit y m ust be cre de ntiale d 
i n di vi d uall y.   
Cre de ntiali n g N otificati o n Iss ue d t o:  
I nstit uti o n 
 
I R O C H o ust o n Q A Ce nter will n otif y t he i nstit uti o n a n d N R G 
Hea d q uarters t hat all desire d cre de ntiali n g re q uire me nts ha ve 
bee n met.  T he site will nee d t o u pl oa d a P D F of t he a p pr o val 
e mail fr o m I R O C H o ust o n t o t he C T S U Re g ulat or y P ortal f or 
R S S t o be u p date d.  

 
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•  R A s are a ble t o s u b mit sta n dar d of care i ma gi n g t hr o u g h t he sa me met h o d.  
 
T RI A D I nst all ati o ns : 
W he n  a user a p plies f or a C T E P -I A M acc o u nt wit h pr o per user r ole, h e/ s he 
will nee d t o h a ve t he T RI A D a p plic ati o n i nst alle d o n his/ her w or kst ati o n t o 
be a ble t o s u b mit i m a ges. T RI A D i nst all ati o n d oc u me nt ati o n c a n be f o u n d b y 
f oll o wi n g t his li n k: htt p://tri a di nst all. acr. or g/tri a dclie nt/ 
 
T his pr ocess ca n be d o ne i n parallel t o o btai ni n g y o ur C T E P -I A M acc o u nt 
user na me a n d pass w or d.  
 
If y o u ha ve a n y q uesti o ns re gar di n g t his i nf or mati o n, please se n d a n e -mail t o t he 
T RI A D S u p p ort mail b o x at T RI A D -S u p p ort @acr. or g . 
 
9.  D R U G I N F O R M A TI O N  
 
9. 1   
Atez oliz u m a b ( N S C 7 8 3 6 0 8)  
 
Ot her N a mes:   Tece ntri q T M , M P D L 3 2 8 0 A 
 
Cl assific ati o n:  m o n ocl o nal a nti b o d y  
 
M. W.:   1 5 0 K D  
 
M o de of Acti o n:   a nti-P D -L 1  
 
Descri pti o n:  
Atez oliz u ma b is a h u ma nize d I g G 1 m o n ocl o nal a nti b o d y c o nsisti n g of t w o hea v y c hai ns 
( 4 4 8 a mi n o aci ds) a n d t w o li g ht c hai ns ( 2 1 4 a mi n o aci ds). Atez oliz u ma b tar gets h u ma n 
P D -L 1 a n d i n hi bits its i nteracti o n wit h its rece pt or P D -1. Atez oliz u ma b al s o bl oc ks t he 
bi n di n g of P D -L 1 t o B 7. 1, a n i nteracti o n t hat is re p orte d t o pr o vi de a d diti o nal i n hi bit or y 
si g nals t o T cells ( B utte et al. 2 0 0 7).  
 
H o w S u p plie d:  
Atez oliz u ma b is pr o vi de d b y Ge ne ntec h/ F. H off m a n n -La R oc he L T D a n d distri b ute d b y 
t he P har mace utical Ma na ge me nt Bra nc h, C T E P , N CI.  T he a ge nt is s u p plie d i n a si n gle-
use, 2 0 -m L glass vial as a c ol orless -t o-sli g htl y-yell o w, sterile, preser vati 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. Atez oliz u ma b 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 bate 2 0, at a 
p H of 5. 8.  T he vial is desi g ne d t o deli ver 2 0 m L ( 1 2 0 0 m g) of atez oliz u m a b s ol uti o n b ut 
ma y c o ntai n m ore t ha n t h e 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.  
 
Pre p ar ati o n:   
T he prescri be d d ose of at ez oliz u ma b s h o ul d be dil ute d i n 2 5 0 m L 0. 9 % Na Cl a n d i nf use d 
t hr o u g h a 0. 2 micr o meter i n-li ne filter. T he I V ba g ma y be c o nstr uct e d of P V C or P O; t he 
I V i nf usi o n li ne ma y be c o nstr ucte d of P V C or P E; a n d t he 0.2 micr o meter i n -li ne filter 

 
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ma y be c o nstr uct e d of P E S.  T he pre pare d s ol uti o n ma y be st ore d at 2° C -8° C or r o o m 
te m perat ure f or u p t o 8 h o urs. 
 
St or a ge:   2° C – 8° C ( 3 6° F – 4 6° F). 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 su nli g ht.  
 
If a st ora g e te m perat ure e xc ursi o n is i de ntifie d, pr o m ptl y ret ur n atez oliz u m a b t o 2° C-8° C 
( 3 6° F-4 6° F) a n d q uara nti ne t he s u p plies.  Pr o vi de a detaile d re p ort of t he e xc ursi o n 
(i ncl u di n g d oc u me ntati o n of te m perat ure m o nit ori n g a n d d urati o n of t he e xc ursi o n) t o 
P M B After H o urs @ mail. ni h. g o v  f or deter mi nati o n of s uita bilit y. 
 
St a bilit y:  Sta bilit y st u d ies are o n g oi n g. 
 
C A U TI O N:  N o preser vati ve is use d i n atez oliz u ma b; 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 re mai ni n g i n a vial.  
 
R o ute of A d mi nistr ati o n:  I V i nf usi o n 
 
Met h o d of A d mi nistr ati o n:  
Atez oliz u m a b is a d mi nistere d as a n i ntra ve n o us i nf usi o n o ver 6 0 mi n utes. If t he first 
i nf usi o n is t olerate d, all s u bse q ue nt i nf usi o ns ma y be deli vere d o ver 3 0 mi n utes. D o n ot 
a d mi nister atez oliz u ma b as a n i ntra ve n o us p us h or b ol us.  N o pre me dicati o n is i n dicate d 
f or a d mi nistrati o n of C ycle 1 of atez oliz u m a b. Patie nts w h o e x perie nce a n i nf usi o n 
relate d reacti o n wit h C ycle 1 of atez oliz u m a b ma y recei v e pre m e dicati o n wit h 
a nti hista mi nes or a nti p yretics/a nal gesics (e. g. acet a mi n o p he n) f or s u bse q ue nt i nf usi o ns.  
 
P ote nti al  Dr u g I nter a cti o ns:  
C yt oc hr o me P 4 5 0 e nz y m es as well as c o nj u gati o n/ gl uc ur o ni dati o n reacti o ns are n ot 
i n v ol ve d i n t he meta b olis m of atez oliz u ma b. 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 uct e d or are pla n ne d. T here are n o k n o w n i nteracti o ns wit h ot her 
me dici nal pr o d ucts or ot her f or m of i nteracti o ns.  
 
P atie nt C are I m plic ati o ns:  
Male patie nts a n d fe male patie 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 m a b t reat me nt 
a n d f or at least 5 m o nt hs ( 1 5 0 da ys) after t he last d ose of atez oliz u ma b.  
 
A v ail a bilit y  
 
Atez oliz u m a b  is a n i n vesti gati o nal a ge nt s u p plie d t o i n vesti gat ors b y t he Di visi o n of 
Ca ncer Treat me nt a n d Di a g n osis ( D C T D), N CI.  
 
Atez oliz u m a b  is pr o vi de d t o t he N CI u n der a C olla b orati ve A gree me nt bet wee n t he 
P har mace utical C olla b orat or a n d t he D C T D, N CI (see A p pe n di x VI ). 
 

 
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9. 1. 1  A ge nt Or deri n g a n d A ge nt Acc o u nta bilit y  
 
9. 1. 1. 1  N CI -s u p plie d a ge nts ma y be re q uest e d b y t he Pri nci pal I n vesti gat or ( or t heir a ut h orize d 
desi g nee) at eac h partici p ati n g i nstit uti o n.  P har mace utical Ma na ge me nt Bra nc h ( P M B) 
p olic y re q uires t hat a g e nt be s hi p pe d directl y t o t he i nstit uti o n w here  t he patie nt is t o be 
treate d.  P M B d oes n ot per mit t he tra nsfer of a ge nts bet wee n i nstit uti o ns ( u nl ess pri or 
a p pr o val fr o m P M B is o btai ne d).  T he C T E P -assi g ne d pr ot oc ol n u m ber m ust be use d f or 
or deri n g all C T E P -s u p plie d i n vesti gati o nal a ge nts.  T he res p o nsi ble i n vesti gat or at eac h 
partici pati n g i nstit uti o n m ust be re gistere d wit h C T E P, D C T D t hr o u g h a n a n n ual 
s u b missi o n of F D A F or m 1 5 7 2 ( State me nt of I n vesti gat or), Bi os ketc h/ C urric ul u m Vitae, 
S u p ple me ntal I n v esti gat or Data F or m (I D F), a n d Fi na ncial Discl os ure F or m ( F D F).  If 
t here are se v eral p artici p ati n g i n vesti gat ors at o ne i nstit uti o n, C T E P-s u p plie d 
in vesti gati o nal a ge nts f or t he st u d y s h o ul d be or dere d u n der t he na me of o ne lea d 
i n vesti gat or at t hat i nstit uti o n. 
Sites ma y or der atez oliz u ma b after a patie nt has bee n e nr olle d i nt o t he st u d y.  
 
Acti ve C T E P -re gistere d i n vesti gat ors a n d i n vesti gat or-desi g na te d s hi p pi n g desi g nees a n d 
or deri n g desi g nees ca n s u b mit a ge nt re q uests t hr o u g h t he P M B O nli ne A ge nt Or der 
Pr ocessi n g ( O A O P) a p plicati o n.  Access t o O A O P re q uires t he esta blis h me nt of a C T E P 
I d e ntit y a n d Access Ma na ge me nt (I A M) acc o u nt a n d t he mai nte na nce of a n “acti ve” 
acc o u nt stat us a n d a “c urre nt” pass w or d.  F or q uesti o ns a b o ut dr u g or ders, tra nsfers, 
ret ur ns, or acc o u nta bilit y, call or e mail P M B a n y ti me.  Refer t o t he P M B’s we bsite f or 
s pecific p olicies a n d g ui d eli nes relate d t o a ge nt ma na ge me nt.   
 
9. 1. 1. 2  A ge nt I n ve nt or y Rec or ds –  T he i n vesti gat or, or a res p o nsi ble part y desi g nat e d b y t he 
i n vesti gat or, m ust mai ntai n a caref ul rec or d of t he recei pt, dis pe nsi n g a n d fi nal 
dis p ositi o n of all a ge nts recei ve d fr o m t he P M B usi n g t he a p pr o priate N CI 
I n v estigati o nal A ge nt ( Dr u g) Acc o u nta bilit y Rec or d ( D A R F) a vaila bl e o n t he C T E P 
f or ms pa ge.  St ore a n d mai ntai n se parate N CI I n vesti gati o nal A ge nt Acc o u nta bilit y 
Rec or ds f or eac h a ge nt, stre n gt h, f or m ulati o n a n d or deri n g i n vesti gat or o n t his pr ot oc ol.  
 
9. 1. 2  I n v esti gator Br oc h ure A vaila bilit y  
T he c urre nt versi o ns of t he I Bs f or t he a ge nts will be accessi ble t o site i n vesti gat ors a n d 
researc h staff t hr o u g h t he P M B O A O P a p plicati o n.  Access t o O A O P re q uires t he 
esta blis h me nt of a C T E P I A M acc o u nt a n d t he mai nte na nce of a n  “acti ve” acc o u nt stat us 
a n d a “c urre nt” pass w or d.  Q uesti o ns a b o ut I B access ma y be directe d t o t h e P M B I B 
C o or di nat or via e mail.  
 
9. 1. 3  Usef ul Li n ks a n d C o ntacts  
•  C T E P F or ms, Te m plates, D oc u me nts:  htt p://cte p.c a ncer. g o v/f or ms/  
•  N CI C T E P I n vesti gat or Re gistrati o n:  R C R Hel p Des k @ ni h. g o v  
•  P M B p olicies a n d g ui deli nes: 
htt p://cte p.ca ncer. g o v/ bra nc hes/ p m b/a ge nt
ma na ge me nt. ht m   
•  P M B O nli ne A ge nt Or der Pr ocessi n g ( O A O P) a p plicati o n:  

 
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htt ps ://cte pc ore. nci. ni h. g o v/ O A O P  
•  C T E P I de ntit y a n d Access Ma na ge me nt (I A M) acc o u nt: 
htt ps://cte pc ore. nci. ni h. g o v/ia m/   
•  C T E P I A M acc o u nt hel p:  cte pre g hel p @ cte p. nci. ni h. g o v   
•  I B C o or di nat or:  I B C o or di nat or @ mail. ni h. g o v  
•  P M B e mail:  P M B After H o urs @ mail. ni h. g o v  
•  P M B p h o ne a n d h o urs of ser vic e: ( 2 4 0) 2 7 6-6 5 7 5 M o n da y t hr o u g h Fri da y 
bet wee n 8: 3 0 a m a n d 4: 3 0 p m ( E T)  
 
9. 2   
Cis pl ati n ( N S C # 1 1 9 8 7 5)  
 
F or m ul ati o n:  P L A TI N O L ® -A Q (cis plati n i njecti o n) i nf usi o n c o nce ntrate is a 
clear, c ol orless, sterile a q ue o us s ol uti o n a vaila ble i n a m ber vials. 
Eac h 5 0 m L or 1 0 0 m L a m ber vial of i nf usi o n c o nce ntrate 
c o ntai ns: 1 m g/ m L cis plati n, 9 m g/ m L s o di u m c hl ori de, 
h y dr oc hl oric aci d a n d s o di u m h y dr o xi de t o a p pr o xi mate p H of 4. 0, 
a n d water f or i njecti o n t o a fi nal v ol u me of 5 0 m L or 1 0 0 m L, 
res pecti vel y. 
 
S u p plier:    
C o m me rciall y a vaila ble. Refer t o i n di vi d ual 
F D A -a p pr o ve d 
pac ka g e i nsert.  
 
Pre p ar ati o n:  P L A TI N O L ® -A Q (cis plati n i njecti o n) i nf usi o n c o nce ntrate ( 1 
m g/ m L) m ust be f urt her dil ute d pri or t o a d mi nistrati o n.  Cis plati n 
( 4 0 m g/ m2, 7 0 m g ma xi m u m) will be dil ute d i n 2 5 0-1 0 0 0 m L of 
n or mal sali ne.  
 
N O T E: Al u mi n u m reacts wit h cis plati n ca usi n g preci pitati o n 
f or mati o n a n d l oss of p ote nc y, t heref ore, nee dl es or i ntra ve n o us 
sets c o ntai ni n g al u mi n u m parts t hat ma y c o me i n c o ntact wit h t he 
dr u g m ust n ot be use d f or t he pre parati o n or a d mi nistrati o n of 
cis plati n. 
 
St or a ge:    
St ore at 1 5° t o 2 5° C ( 5 9° t o 7 7° F). D o n ot refri gerate. Pr otect 
u n o pe ne d c o ntai ner fr o m li g ht.  
 
St a bilit y:    
T he cis plati n re mai ni n g i n t he a m ber vial f oll o wi n g i nitial e ntr y is 
sta ble f or 2 8 da ys pr otecte d fr o m li g ht or f or 7 da ys u n der 
fl u oresce nt r o o m li g ht. 
 
A d mi nistr ati o n:  O nce wee kl y cis plati n ( 4 0 m g/ m 2, 7 0 m g ma xi m u m) is 
a d ministere d i ntra ve n o usl y o n Da ys 0 , 7, 1 4 , 2 1, 2 8, a n d 3 5. A n 
i nf usi o n of 1 0 0 0 ml of ½ n or mal sali ne s h o ul d be gi ve n 
i ntra ve n o usl y o ne h o ur bef ore cis plati n. I ncrease d oral i nta ke 
s h o ul d be e nc o ura ge d starti n g t he da y bef ore. A d diti o nal fl ui d ma y 
be gi ve n as nee de d f or s y m pt o matic s u p p ort. Cis plati n s h o ul d be 

 
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i nf use d at a rate of 1 m g/ mi n, us uall y o ver a t otal of 9 0 mi n utes or 
as per i nstit uti o nal pr ot oc ol. I m me diatel y after c o m pleti o n of t he 
cis plati n i nf usi o n, a n a d diti o nal 1 0 0 0 ml of ½ n or mal sali ne s h o ul d 
be gi ve n or as p er i nstit uti o nal pr ot oc ol.  
 
A d verse effects:    
 
I nfre q u e nt: Car diac a b n or malities, a n ore xia, ele vate d S G O T, ras h, al o p ecia, a n d ac ute m yel oi d 
le u ke mia. 
 
N O T E:  A mi n o gl yc osi de a nti bi otics gi ve n bef ore, wit h, or after cis plati n ma y p ote ntiate re nal 
t o xicit y a n d s h o ul d be a v oi de d w he ne ver p ossi ble. 
 
9. 2. 1  A d verse E ve nts  
   
Please refer t o t he p ac ka ge i nsert  f or c o m plete disc ussi o n of a d verse e ve nts. 
Le u k o pe nia, t hr o m b oc yt o pe nia, a ne mia, na usea, v o miti n g, ne p hr ot o xicit y, ot ot o xicit y, 
peri p heral ne ur o pat h y, electr ol yte i m bala nce, h y p ocalce mia, h y p o m a g nese mia, 
a mi n o gl yc osi de ot ot o xicit y, oc ular t o xicit y, a n d aller gic reac ti o ns.  
 
Refer t o t he p ac k a ge i nsert f o r det aile d p h ar m ac ol o gic a n d s afet y i nf or m ati o n  
 
9 . 2.2  A vaila bilit y/ S u p pl y   
   
Please see Secti o n 9. 2  f or a d mi nistrati o n i nstr ucti o ns. Please refer t o t he c urre nt F D A-
a p pr o ve d pac ka g e i nsert pr o vi de d wit h eac h dr u g a n d t he site -s pecific p har mac y f or 
t o xicit y i nf or mati o n a n d i nstr ucti o ns f or dr u g pre parati o n, ha n dli n g, a n d st ora ge. 
 
[If off-la bel, t he f oll o wi n g state me nt m ust be i ncl u de d f or eac h I N D e xe m pt dr u g]: T he 
use of dr u g(s) or c o m bi n ati o n of dr u gs i n t his pr ot oc ol meet t he criteria des cri be d u n der 
Title 2 1 C F R 3 1 2. 2( b) f or I N D e xe m pti o n.)  
 
1 0.  P A T H O L O G Y /BI O S P E CI M E N  
 
1 0. 1  
Ce ntr al P at h ol o g y Re vi e w G ui deli nes  
N ot a p plica ble  
 
1 0. 2  
Bi o m ar ker Selecti o n f or I nte gr al Bi o m ar ker Testi n g  
1 0. 2. 1  Bi o m ar ker t o be  Teste d  
T o satisf y t he pri mar y o bjecti ve of t he st u d y, t he f oll o wi n g will be assesse d i n res p o nse 
t o se q ue ntial vers us c o nc urre nt atez oliz u ma b a n d ra diati o n: ( 1) peri p heral bl o o d T Cell 
Rece pt or ( T C R) cl o n alit y, a n d ( 2) peri p heral bl o o d e x pa nsi o n of T C R cl o nes, i ncl u di n g 
T C R cl o nes i de ntifie d i n t u m or sa m ples.  
 
1 0. 2. 2  Testi n g Re q uire me nts a n d Re p orti n g  
F or ass ess me nt of t he pri mar y e n d p oi nt, pre -treatme nt F F P E t u m or bi o psies (t o deter mi ne 
w hic h T C R cl o nes are prese nt wit hi n t he t u m or), as well as pre -treat me nt an d o n -
treat me nt bl o o ds will be re q uire d.  

 
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1 0. 2. 3  Met h o d of Testi n g  
T he N R G O nc ol o g y Bi os peci me n Ba n k ( N R G B B) -C ol u m b us will batc h s hi p, e ver y si x 
m o nt hs, u nstai ne d secti o ns of pre -treat me nt F F P E t u m or bi o psies t o t he la b orat or y of Dr. 
 Q ualit y of F F P E tiss ue ( de gree of t u m or c o nte nt a n d necr osis) will be 
deter mi ne d b y a b o ar d -certifie d pat h ol o gist w or ki n g wit h Dr.
base d o n 
H & E testi n g of a re prese ntati ve secti o n fr o m eac h t u m or. T u m or areas a p pr o priate f or 
a nal ysis will be macr o dis secte d a n d D N A will be e xtracte d usi n g Qi a ge n kit i n Dr.  
la b orat or y. D N A q ualit y a n d q ua ntit y will be ass ure d b y O D 2 6 0/ 2 8 0 a n d O D 
2 6 0/ 2 3 0 rati os. D N A e xtracte d fr o m baseli ne t u m or tiss ue will be s hi p pe d t o A da pti ve 
Bi otec h n ol o gies f or T C R se q ue nci n g.  
 
T he N R G B B -C ol u m b us will batc h s hi p, e ver y si x m o nt hs, pre -treat me nt a n d da y 2 1 
fr oze n w h ole bl o o d t o A da pti ve Bi otec h n ol o gies f or D N A e xtracti o n a n d q ualit y 
c o nfir mati o n usi n g O D 2 6 0/ 2 8 0 a n d O D 2 6 0/ 2 3 0 rati os. T his will be f oll o we d b y  dee p 
se q ue nci n g of C D R 3 re gi o ns . Rearra n ge d T C R beta C D R 3 se q ue nces will be a m plifie d 
a n d se q ue nce d usi n g t he A da pti ve Bi otec h n ol o gies i m m u n o S E Q platf or m. A bs ol ute 
c o u nts a n d fre q ue ncies of i n di vi d ual cl o ne te m plates will be deter mi ne d o n a per sa m ple 
basis usi n g a s p i ke-i n c o ntr ol re pert oire. Ad diti o nal i nter nal c o ntr ols als o re p ort t he 
q ua ntificati o n of sa m ple d T cells a n d t otal n ucleat e d cells. Pr ocessi n g will be  per t he 
A da pti ve Bi otec h n ol o gies sta n dar d O perati n g Pr oce d ure (S O P) f or t he O ne -Reacti o n 
pr ot oc ol.  
 
1 0. 2. 4  L oc a ti o n of Testi n g 
D N A e xtracti o n fr o m pre -treat me nt t u m or tiss ue will be perf or me d i n t he l a b orat or y of 
Dr.
(
). D N A 
e xtracti o n fr o m pre -treat me nt a n d da y 2 1 w h ole bl o o d will be d o ne at A da pti ve 
Bi o tec h n ol o gies. T C R se q ue nci n g of D N A fr o m b ot h t u m or tiss ue a n d w h ole bl o o d will 
be d o ne at A d a pti ve Bi otec h n ol o gies  
 
1 0. 2. 5  Bi os peci me n S u b missi o n f or Testi n g  
See  Ma n dat or y Bi os peci me n S u b missi o n Ta ble ( secti o n 1 0. 4. 1) f or details. 
 
1 0. 3  
Bi os peci me n Selecti o n f or I nte gr ate d Bi o m ar ker Testi n g  
N ote: Ex pl or at ory bi o m arker testi n g of b a nke d s p eci me ns will n ot occ ur u ntil a n a me n d me nt t o 
t his tre at me nt pr ot oc ol ( or se p ar ate c orrel ative s cie nce pr ot oc ol at a l ater d ate) is revie we d a n d 
a p pr ove d i n acc or d a n ce wit h N ati o n al Cli nic al Tri als Net w ork ( N C T N) p olicies . 
 
1 0. 3. 1  Bi o m ar ker t o be Teste d  
P D -L 1  
 
1 0. 3. 2  Testi n g Re q uire me nts a n d Re p orti n g  
F F P E t u m or bi o psies will be use d f or retr os pecti v e P D-L 1 testi n g. See Ma n dat or y 
Bi os peci me n S u b missi o n Ta ble ( secti o n 1 0. 4. 1) f or details. 
 

 
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site user m ust ha ve a n acti ve C T E P-I A M acc o u nt a n d t he a p pr o priate Ra ve r ole ( Ra ve 
C R A, Rea d -O nl y, Site I n vesti gat or) o n eit her t he L P O or partici pati n g or ga nizati o n 
r osters at t he e nr olli n g site. 
 
U p o n i nitial site re gistrati o n a p pr o val f or t he st u d y i n R S S, all pers o ns wit h Ra ve r oles 
assi g ne d o n t he a p pr o priate r oster will be s e nt a st u d y i n vitati o n e -mail fr o m i Me di data  
(i Me di data-N otificati o n @ m ds ol.c o m) t o acti vate t heir acc o u nt. T o acce pt t he i n vitati o n, 
site users m ust l o g i nt o t he Select L o gi n ( htt ps://l o gi n.i me di data.c o m/selectl o gi n) usi n g 
t heir C T E P-I A M user n a me a n d pass w or d, a n d cli c k o n t he “acce pt” li n k i n t he u p per 
ri g ht-c or ner of t he i Me di data pa ge. Please n ote, site users will n ot be  a ble t o access t he 
st u d y i n Ra ve u ntil all re q uire d Me di data a n d st u d y s pecific trai ni n gs are c o m plete d. 
Trai ni n gs will be i n t he f or m of electr o ni c lear ni n gs (e Lear ni n gs) a n d will be liste d i n t he 
u p per ri g ht pa ne of t he i Me di data scree n.  
  
Users t hat ha v e n ot pre vi o usl y acti vate d t heir i Me di data/ Ra ve acc o u nts als o will recei ve a 
se parat e i n vitati o n fr o m i Me di data t o acti vate t heir acc o u nt. Acc o u nt acti vati o n 
i nstr ucti o ns are l ocat e d o n t he C T S U we bsite, Ra ve ta b u n der t he R a ve res o urce materials 
( Me di data Acc o u nt Acti v ati o n a n d St u d y I n vitati o n Acce pt a nce). A d diti o nal i nf or mati o n 
o n i Me di data/ Ra ve is a vaila ble o n t he C T S U we bsite u n der t he Ra ve t a b at 
w w w.cts u. or g/ R A V E/ or b y c o ntacti n g t he C T S U Hel p Des k at 1 -8 8 8 -8 2 3 -5 9 2 3 or b y e -
mail at cts uc o ntact @ westat.c o m . 
 
1 2. 2  
S u m m ar y of D at a S u b missi o n  
A d verse e ve nt data c ollecti o n a n d re p orti n g, w hic h are re q uire d as part of e ver y cli nical 
trial, are d o n e t o e ns ure t he safet y of patie nts e nr olle d i n t he st u dies as well as t h ose w h o 
will e nr oll i n f ut ure st u dies usi n g si milar a ge nts. A d verse e ve nts are re p orte d i n a r o uti ne 
ma n ner at sc he d ule d ti mes d uri n g t he trial usi n g Me di da ta Ra ve ®. A d diti o nall y, certai n 
a d verse e ve nts m ust be re p orte d i n a n e x pe dite d ma n ner f or ti melier m o nit ori n g of patie nt 
safet y a n d care. S ee Secti o ns 7  a n d 7. 6  f or i nf or m ati o n a b o ut e x pe dite d a n d r o uti ne 
re p orti n g.  
  
S u m mar y of Data S u b missi o n : Refer t o t he N R G/ C T S U we bsite.  
 
See Secti o n 8. 4  f or T RI AD  acc o u nt access a n d i nstallati o n i nstr ucti o ns.  
 
1 2. 3  
Gl o b al Re p orti n g/ M o nit ori n g  
T his st u d y will be m o nit ore d b y t he Cli nical Data U p date S yste m ( C D U S) versi o n 3. 0. 
C u m ulati ve C D U S data will be s u b mitte d q uarterl y t o C T E P b y electr o nic mea ns. 
Re p orts are d u e Ja n uar y 3 1, A pril 3 0, J ul y 3 1, a n d Oct o ber 3 1.  
 
N ote :  If y o ur st u d y has bee n assi g ne d t o C D U S-C o m plete re p orti n g, a ll a d verse e ve nts  
( b ot h r o uti ne a n d e x p e dite d) t hat ha ve occ urre d o n t he st u d y a n d meet t he ma n dat or y 
C D U S re p orti n g g ui deli nes  m ust be re p orte d vi a t he m o nit ori n g met h o d i de ntifie d a b o ve.   
If y o ur st u d y has bee n assi g ne d t o C D U S-A b bre vi ate d re p orti n g, n o a d verse e ve nt 
re p orti n g (r o uti ne or e x p e dite d) is re q uire d t o be re p orte d via C D U S, b ut e x pe dite d 
a d verse e ve nts are still re q uire d t o be s u b mitte d via C T E P -A E R S.  

 
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1 3.  S T A TI S TI C A L C O N SI D E R A TI O N S  
 
1 3 . 1 
St u d y Desi g n  
T he pri mar y o bjecti ve of t his st u d y is t o assess w het her t here is a differe nce of i m m u ne 
e x pressi o n bet w ee n t he t w o treat me n t ar ms t hr o u g h T cell rece pt or bet a ( T C R B) cl o nal 
e x pa nsi o n i n peri p heral bl o o d. T his st u d y is desi g ne d as a t w o -ar m, o pe n l a bel, 
ra n d o mize d pil ot trial wit h t w o e x peri me ntal ar ms, w here ar m A will get o n e d ose of 
Atez oliz u ma b pri or t o cis plati n c he m ot hera p y a n d ra diati o n t hera p y, a n d t he n t w o 
s u bse q ue nt d oses of Atez oliz u ma b d uri n g t he c he m ot hera p y a n d ra diati o n t hera p y, a n d 
ar m B will get 3 d oses d uri n g t he cis plati n c he m ot hera p y a n d ra diati o n t hera p y.  
 
Pri or t o patie nt re gistrati o n, eli gi bilit y will be re vie we d b y E ntr y F or m verificati o n. T he 
se q ue nce of treat me nt assi g n me nts will be c o nceale d fr o m i nstit uti o ns a n d patie nts u ntil 
re gistrati o n wit h verificati o n of eli gi bilit y. Patie nts will be re gistere d b y t he partici pati n g 
site t hr o u g h O P E N a n d ra n d o mizati o n will be carrie d o ut ce ntrall y b y t he N R G Statistics 
a n d Data Ma n a ge me nt C e nter. Treat me nt gr o u p assi g n me nt will be deter mi ne d usi n g a 
pr oce d ure t hat te n ds t o ra n d o ml y all ocate st u d y treat me nt s at a 1 t o 1 rati o.  
 
1 3 . 2 
St u d y E n d p oi nts  
Pri mar y E n d p oi n t 
1)  Meas ure me nts of T C R B cl o nal e x pa nsi o n i n peri p heral bl o o d at da y 2 1.  
 
Sec o n dar y E n d p oi nts  
1)  D L Ts occ urri n g d uri n g t he peri o d ti me fr o m t he start of first d ose of atez oliz u ma b 
(ar m A) or t he start of C R T treat me nt (ar m B) u ntil 3 0 da ys after t he c o m pleti o n of 
C R T.  
2)  Fre q u e nc y a n d se verit y of a d verse e ve nts as assesse d b y C T C A E v 5 . 
            3)   Meas ure me nts of T C R cl o nalit y, di versit y a n d fre q ue nc y i n peri p heral bl o o d /-tiss ue 
at eac h pr ot oc ol -s pecifie d c ollecti n g ti me p oi nt a n d meas ures of P E T -C T  sca n at p ost-
t hera p y 1 2 wee ks (e x pl orat or y a n d o pti o nal), a n d 2-year cli nical D F S . 
             
            4 )  Meas ure me nts of P D -L 1 e x pressi o n i n tiss ue at eac h pr ot oc ol -s p ecifie d c ollecti n g 
ti me p oi nt, meas ureme nt s of p ost -treat me nt wee k 1 2 P E T -C T sca n  (e x pl orat or y a n d 
o p ti o nal), a n d 2 -year cli nical D F S.  
 
E x pl orat or y Scie nce E n d p oi nts  
1)  Meas ure me nts of bi o mar kers fr o m bl o o d/ tiss ue at baseli ne a n d o n -treat me nt, 
meas ures of P E T -C T  sca n at p ost-t hera p y 1 2 wee ks ( da y 1 4 0), a n d 2 -year  D F S.  
2)  Res p o nse assess me nt o n t he p ost -treat me nt wee k 1 2 P E T-C T sca n (e x pl orat or y a n d 
o pti o nal) a n d 2-year cli ni cal D F S.  
 
1 3 . 3   
Pri m ar y O bjecti ves St u d y Desi g n  
 
1 3 . 3. 1 Pri mar y H y p ot hesis a n d E n d p oi nts  
T he pri mar y o bjecti ve of t his st u d y is t o deter mi ne w het her t here is a differe nce of 

 
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i m m u ne e x pressi o n bet w ee n t he t w o treat me nt ar ms t hr o u g h T cell rece pt or beta ( T C R B) 
cl o nal e x pa nsi o n i n peri p heral bl o o d  at da y 2 1. It is h y p ot hesize d t hat a treat me nt wit h 
i ncreas e d cli nical be nefit will ge nerate m ore cl o nal e x pa nsi o n i n peri p heral bl o o d or m ore 
e x pa nsi o n of t u m or -ass o ciate d cl o nes i n peri p heral bl o o d. T heref ore, t he e val uati o n of 
t he differe nce of i m m u ne e x pressi o n bet wee n t he t w o treat me nt ar ms meas ure d b y T C R B 
cl o nal e x pa nsi o n i n peri p heral bl o o d will be f or m ulate d t hr o u g h h y p ot hesis testi n g via t he 
differe n ce of t he mea ns. T he pri mar y h y p ot heses f or t his st u d y are 
H 0: μ A  = μ B,  
 H 1: μ A  ≠ μ B , 
w here μ A  a n d μ B are t he mea ns of t he T C R B i n peri p heral bl o o d f or ar m A a n d ar m B, 
res pecti vel y. 
 
Ass u me t hat t he T C R B is n or mall y distri b ute d i n ar m A a n d ar m B wit h a n e q ual 
sta n dar d de viati o n ( σ). A t w o-si de d t-test will be use d f or testi n g t he pri mar y h y p ot heses 
at 1 0 % si g nifica nce le vel. T he cli nicall y i ntereste d effect size ( δ) is 0. 9 5, i.e., t he 
differe n ce of mea ns is 0. 9 5 ti mes of t he sta n dar d de viati o n. A sa m ple size of  4 0  patie nts 
( 2 0 i n eac h treat me nt ar m) will gi ve t his st u d y a 9 0 % p o wer t o det ect a n effect size of 
0. 9 5 b y a t w o -si de d t-test at si g nifica nce le vel of 0. 1.  Fi g ure 1 s h o ws t he esti mate d 
p o wer of t his st u d y vers us t he effect size b y t he n u m ber of patie nts e nr olle d o n eac h ar m.  
 

 
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                                                                   Fi g ure 1  
 
Base d o n pri or e x p erie nce i n G O G -9 9 2 9, it is e x pecte d t hat at least 5 0 % of t he e nr olle d 
patie nts are e val ua ble f or D L T, t h us, a sa m ple size of 4 0 patie nts ( 2 0 i n eac h treat me nt 
ar m) will e ns ure at  least 1 0 D L T-e val u a ble patie nts f or eac h re gi me n.  
 
1 3 . 3. 2 H o w  Pri mar y E n d p oi nts Will Be A nal yze d  
All eli gi ble patie nts w h o recei v e d  Ar m A ( d ose at da y -2 1 a n d d ose at da y 0) a n d Ar m B 
( d ose at da y 0) an d ha v e T C R B meas ure me nts will be e val ua ble.  F or t he pri mar y 
o bjecti ve, t here will be a c o m paris o n of t he ar ms at da y 2 1 c ollecti o n  b y 2 -si de d t-test at 
1 0 % si g nifica nce l e vel .  Base d o n t he mec ha nis m of acti o n of P D -L 1 i n hi bit ors, it is 
u nli kel y t hat t hera pe utic d ose w o ul d ha ve a n i m me diate effect o n t he tr a nsl ati o nal 
efficac y para meters  ( d ose gi ve n at da y 2 1). H o we ver, t o e ns ure t h at t his d oes n ot 
c o nf o u n d t he fi n di n gs, all la bs f or effi cac y assess me nt will be c ollecte d pri or t o treat me nt 
a d mi nistrati o n.    
 
1 3 . 3. 3 Sa m ple Size a n d P o wer Calc ulati o ns:   
T he sa m ple size a n d p o wer cal c ulati o n is base d o n 2 -si de d t-test u n der t he ass u m pti o ns 
t hat t he T C R B is n or mall y distri b ute d i n ar m A a n d ar m B wit h a n e q ual sta n dar d 
de viati o n ( σ).  T he tar get accr ual of t his st u d y is 4 0 patie nts ( 2 0 i n eac h  treat me nt ar m). 
 
            A sa m ple size of 4 0 patie nts ( 2 0 i n eac h treat me nt ar m) will gi ve t his st u d y a 9 0 % p o wer 
t o detect a n effect size of 0. 9 5 b y a t w o-si de d t-test at si g nifica nce le vel of 0. 1. 
 
D ue t o p ote ntial attriti o n, a feasi bilit y  assess me nt of t he pr o p orti o n of patie nts w h o are 
eit her i neli gi ble or d o n ot ha ve t heir bi o -s peci me n f or e val u ati o n of t he pri mar y e n d p oi nts 
s u b mitte d will be e val uate d at t he st u d y accr ual of 2 0 patie nts. T he pr o p orti o n of patie nts 
e x perie n ci n g at least o ne D L T i n D L T -eval ua ble patie nts will be esti mate d b y treat me nt 
ar m at t his ti me, a n d t he fre q ue nc y a n d se verit y of all t o xicities will be ta b ulate d b y 
treat me nt ar m f or all pati e nts w h o recei ve a n y st u d y treat me nt. If eit her t he pr o p orti o n of 
attriti o n is hi g her t ha n 2 5 % or t he pr o p orti o n of patie nts wit h D L T is hi g her t ha n 3 0 %, 
t he n t he pri nci pal i n vesti gat ors will be c o ntact e d, a n d c o nfere nce calls will be sc he d ule d 
a m o n g t he pri nci pal i n vesti gat ors a n d st u d y tea m.       
 
If t he pr o p orti o n of patie nts wit h attriti o n is 2 5 % or less, a sa m ple size of 4 0 ( 2 0 i n eac h 
ar m) will res ults i n at least 3 0 eli gi ble a n d e val ua ble patie nts ( 1 5 i n eac h ar m) w hic h 
w o ul d gi ve t he st u d y at least 8 1 % p o wer t o det ect t he effect size of 0. 9 5 at si g nifica nce 
le vel of 0. 1 usi n g a t w o-si de d t-test. 
 
1 3 . 4 
St u d y M o nit ori n g of Pri m ar y O bjecti ves  
(I nteri m A nal ysis) 
I nteri m A nal ysis f or t he D M C 
T here is n o f or mal i nteri m a nal ysis pla n ne d. T he N R G O nc ol o g y Data M o nit ori n g 
C o m mittee ( D M C) will re vie w t he st u d y t wice a year wit h res pect t o patie nt accr ual a n d 
m or bi dit y. T he D M C als o will re vie w t he st u d y o n a n “as nee de d” basis.  
 

 
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1 3 . 5 
Accr u al / St u d y D ur ati o n  C o nsi der ati o ns  
T he accr ual rate f or  t his st u d y is pr ojecte d t o be a p pr o xi matel y 3 patie nts per m o nt h 
base d o n G O G -9 9 2 9 wit h a dj ust me nt of h ol di n g ti me.  
 
T his st u d y will ta ke a p pr o xi matel y 1 6 m o nt hs t o accr ue t h e tar gete d sa m ple size of 4 0 
patie nts i ncl u di n g a 2 t o 3 m o nt hs of start -u p ti me wit h little t o n o accr ual. T he d urati o n 
of st u d y treat me nt is a b o ut 2 0 wee ks , i ncl u di n g F D G P ET/ C T at p ost -treat me nt 1 2 
wee ks.  Fi nal a nal ysis will re q uire distri b uti o n of s peci me ns, res ol uti o n of q ueries, 
c o m pleti o n of all la b orat or y tests, a n d c ollati o n o f la b orat or y dat a wit h cli nical data. 
T hese ca n be acc o m plis he d wit hi n 1 2 -1 8  m o nt hs of fi nal patie nt e ntr y.  
 
1 3 . 6 
D ose Le vel G ui deli nes  
            T here are n o d os e le vel c ha n g es defi ne d i n t his st u d y.  
 
1 3 . 7 
Sec o n d ar y or E x pl or at or y E n d p oi nts  (i ncl u di n g c orrel ati ve scie nce ai ms) 
 
1 3 . 7. 1 Sec o n dar y H y p ot h eses a n d E n d p oi nts:   
            T he sec o n d ar y o bje cti ves f oc us  o n esti mati o n a n d des cri pti o n; t here are n o s pecific  
h y p ot heses.  
             
            Se c o n dar y e n d p oi nts see Secti o n 1 3 . 2. 
 
1 3 . 7. 2 Defi niti o ns of Sec o n dar y E n d p oi nts a n d H o w T hese Will Be A nal yze d  
D L T is defi ne d i n Se cti o n 5. 7. T he n u m ber of patie nts w h o e x perie nce D L Ts will be 
s u m marize d i n t he D L T-e val ua ble patie nts b y treat me nt ar m, t he c orres p o n di n g 
pr o p orti o n of patie nts wit h D L Ts a n d 9 0 % c o nfi de nce i nter val will be esti mate d.  
 
A d verse e ve nts are assesse d b y N CI C T C A E v 5 . T he fre q ue nc y a n d ma xi m u m se verit y 
of ac ute a d verse e ve nts will be ta b ulate d b y treat me nt ar m gra de d b y C T C A E v 5 .  
 
All patie nts w h o recei ve a n y st u d y dr u g will be e val ua ble f or t o xicit y. T he D L T -
e val ua ble p atie nts will o nl y i ncl u de t h ose eli gi ble patie nts w h o ha ve a D L T a n d ha ve 
recei v e d at least o ne d ose of Atez oliz uma b , or c o m plete assi g ne d pr ot oc ol t hera p y a n d 
are e v al ua ble at t he D L T s pecifie d ti me peri o d , w here t he D L T peri o d f or Ar m A: start of 
t he pri mi n g d ose of atez oliz u ma b u ntil 3 0 da ys after t he c o m pleti o n of C R T; f or Ar m B: 
start of C R T u ntil 3 0 da ys after t he c o m pleti o n of C R T. 
 
Disease -free s ur vi val ( D F S) is defi ne d as t he d urati o n of ti me fr o m st u d y e ntr y t o date of 
first d oc u me nte d rec urre nce or pr o gressi o n of dis ease or deat h, w hic he ver occ urs first. 
D F S is ce ns ore d i n patie nts w h o are ali ve a n d disease ha ve n ot rec urre d or pr o gresse d.  
 
S u m mar y statistics (a n d gra p h w here it is a p pr o priate) f or t he m eas ure me nts of T C R 
cl o nalit y, di versit y a n d fre q ue nc y i n peri p heral bl o o d /tiss ue at eac h pr ot oc ol -s pecifie d 
c ollecti n g ti me p oi nt , meas ures of P E T -C T  sca n at p ost-t hera p y 1 2 wee ks, a n d t he 
pr o p orti o n of patie nts w h o are ali ve a n d diseas e -free f or at least 2 years will be pr o vi de d 
b y treat me nt ar m. If feasi ble, re peate d meas ure tec h ni q ues will be a p plie d t o i n vesti gate 

 
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t he c ha n ges a n d t he traj ect ories of T C R cl o nalit y, di versit y, a n d fre q ue nc y i n peri p heral 
bl o o d b y treat me nt ar m, a n d mi xe d m o deli n g ma y be use d t o e x pl ore t h e c orres p o n di n g 
ass ociati o ns wit h meas ure me nt f or P E T -C T  sca n at p ost -t hera p y 1 2 wee ks a n d 2-year 
D F S . 
 
P D -L 1 e x pressi o n i n t he tiss ue b y treat me nt ar m will be s u m marize d  f or eac h pr ot oc ol-
s pecifie d c ollecti n g ti me p oi nt. S pear ma n’s c orrel ati o n c oe ffi cie nt will be use d t o assess 
t he c orrelati o n of P D-L 1 e x pressi o n i n t he tiss ue at eac h pr ot oc ol-s pecifi e d c ollecti n g 
ti me p oi nt b y ar m wit h D F S at 2 years  a n d meas ure me nt f or p ost -treat me nt P E T-C T , 
res pecti vel y. T he ma xi m u m n u m ber of patie nts wit h t u m or tis s ues at eac h c ollecti n g ti me 
is 2 0 f or eac h ar m.  
 
T here are n o f or mal s pecific h y p ot heses re gar di n g P D -L 1 e x pressi o n i n t u m or tiss ue, b ut 
it is h y p ot hesize d t hat a patie nt wit h hi g her pre-treat me nt P D-L 1 e x pressi o n i n t u m or 
tiss ue will ha ve better cli nical res p o nses t hat are meas ure d b y disease -free s ur vi val at 2 
years a n d p ost -treat me nt P E T-C T  i n t he treat me nt wit h Pe m br oliz u ma b. Fi g ure 2  s h o ws 
t he p o wer t o detect a series of S pear ma n’s ra n k c orrelati o n c oefficie nts fr o m t he 
S pear ma n’s ra n k c orrelati o n c oefficie nt ( ρ) of 0 b y differe nt  s a m ple size usi n g a n 
as y m pt otic o ne-si de d test at 1 0 % si g nifica nce le vel. A sa m ple size of 2 0 will pr o vi de 
a p pr o xi matel y at least 8 0 % p o wer t o det ect a S pear ma n’s ra n k c orrelati o n c oefficie nt of 
0. 5 or hi g her  fr o m ρ = 0  usi n g a o ne -si de d test at 1 0 % si g nifica nce l e vel.   
 
 
Fi g ure 2  
 
T he p ur p ose of sec o n d ar y o bjecti ves is t o esti mate a n d ge nerate h y p ot heses f or f ut ure 
st u d y. T heref ore, t here will be n o a dj ust me nt f or m ulti ple tests. D ue t o s mall sa m ple size 
of t his st u d y, e xact testi n g pr oce d ure (i.e., e xa ct S pear ma n c orrelati o n test) ma y be use d 
w here it is a p pr o priate . 
 
1 3 . 7. 3 I nteri m A nal ysis f or All Ot her E n d p oi nts ( G oals):  
            N o i nteri m a nal ys es are pl a n ne d f or sec o n dar y e n d p oi nts.  

 
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1 3 . 7. 4 P o wer Calc ulati o ns:   
            As t here are n o s p ecific h y p ot heses f or t he sec o n dar y e n d p oi nts, n o p o wer calc ulati o ns 
are d o ne.  
 
1 3 . 7. 5 Data a n d Safet y M o nit ori n g:   
              Cli nical data c ollecte d o n t his pr ot oc ol will be re vie we d b y t he st u d y data ma na ger a n d 
will als o be re vie we d b y t he St u d y C hair pers o n i n c o nj u ncti o n wit h t he Statistics a n d Data 
Ma na ge me nt Ce nter ( S D M C) o n a n o n g oi n g basis. I n s o me i nsta nces, beca use of 
u ne x pecte dl y se v ere t o xicit y, earl y cl os ure of a st u d y ma y be electe d.  
 
          T he fre q ue nc y a n d se verit y of all t o xicities are ta b ulat e d fr o m s u b mitte d case re p ort f or ms 
a n d s u m marize d f or re vi e w b y t he st u d y c hair pers o n, disease site c o m mittee a n d t he  
c o m mittee c har ge d wit h m o nit ori n g safet y i n c o nj u ncti o n wit h eac h se mi -a n n ual meeti n g.  
 
          All seri o us a d verse e ve nts ( S A Es) are re p orte d t o t he St u d y C hair, S p o ns or, a n d re g ul at or y 
a ge ncies as ma n date d i n t he pr ot oc ol. S A E re p orts are re vie we d b y  t he St u d y C hair ( or 
desi g nate d c o -c hair) i m me diatel y f or c o nsi derati o n of i n vesti gat or n otificati o n of a 
s us pecte d u ne x p ecte d seri o us a d verse reacti o n ( S U S A R), pr ot oc ol a me n d me nt, a n d/ or 
i m me diate st u d y s us pe nsi o n. All partici pati n g i nstit uti o ns will recei ve n otificati o n of t he 
S U S A R fr o m N R G as well as t he reas o n f or st u d y s us pe nsi o n (if a p plica ble). U n der t hese 
circ u msta nces, accr ual ca n n ot be re -acti vate d u ntil t he st u d y is re vie we d b y t he c o m mittee 
c har ge d wit h m o nit ori n g safet y. H o we ver, patie nts c urr e ntl y recei vi n g treat me nt ma y 
c o nti n ue t o recei ve treat me nt i n acc or da nce wit h pr ot oc ol g ui deli nes at t he discreti o n of 
t heir p h ysicia ns, u nless directe d ot her wise. 
 
1 3 . 8 
E x pl or at or y H y p ot hesis a n d E n d p oi nts  
             
E x pl orat or y e n d p oi nts see Secti o n 1 3. 2 . 
 
S u m mar y statistics (a n d gra p hs  w here it is a p pr o priate ) of e x pl orat or y e n d p oi nts will be 
d o ne b y treat m e nt ar m.  
 
S pear ma n’s c orrel ati o n c oefficie nt will be i m ple m e nte d t o e x pl ore t he ass o ciati o ns of  
bi o mar kers meas ure d at baseli ne or o n -treat me nt fr o m bl o o d a n d tiss ue wit h 2 -year D F S 
a n d P E T sca n  at p ost -t hera p y 1 2 wee ks ( da y 1 4 0), res pecti vel y, b y treat ment ar m .  
 
L o g -ra n k test or C o x P H m o del will be use d t o e x pl ore t he ass ociati o ns of bi o mar kers 
meas ure d at baseli ne or o n -treat me nt fr o m bl o o d a n d tiss ue wit h D F S  b y treat me nt ar m.  
 
T he ass ociati o n of 2 -y ear D F S wit h t he res p o nse assess me nt o n t he p ost -treat me nt wee k-
1 2 P E T -C T sca n i n eac h treat me nt ar m will be e xa mi ne d wit h C hi -s q uare d tests. T he 
res p o nse ass ess me nt o n t he p ost -treat me nt wee k-1 2 P E T -C T s ca n is e val uate d base d o n 
t he rati o of p ost-treat me nt wee k-1 2 P E T -C T S U V ma x t o base -li ne P E T-C T sca n S U V 
ma x: t he res p o nse will be classifie d as c o m plet e meta b olic res p o nse f or t he rati o < 0. 3 4, 
or classifie d as p artial meta b olic res p o nse f or 0. 3 4 < = t he rati o < 0. 7 6, or cl assifie d as 

 
N R G -G Y 0 1 7  
9 6    
Versi o n Date:  N o ve m ber 8 , 2 0 1 8 
( 2 0 1 4). "Irra diati o n a n d a nti-P D -L 1 treat me nt s y ner gis ticall y pr o m ote a ntit u m or i m m u nit y i n 
mice." J Cli n I n vest 1 2 4 ( 2): 6 8 7-6 9 5.  
 
Di Giac o m o, A. M., M. Bia gi oli, M. Mai o. ( 2 0 1 0). 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 n O nc ol.  3 7: 4 9 9 -5 0 7.  
 
D o ve di, S. J., A. L. A dlar d, G. Li p o ws ka -B halla, C. Mc Ke n na, S. J o nes, E. J. C hea dle, I. J. 
Stratf or d, E. P o o n, M. M orr o w, R. Ste wart, H. J o n es, R. W. Wil ki ns o n, J. H o ne yc h urc h a n d T. 
M. Illi d ge ( 2 0 1 4). " Ac q uire d resista nce t o fracti o nate d ra di ot hera p y ca n  be o verc o me b y 
c o nc urre nt P D -L 1 bl oc ka de." Ca ncer Res  7 4 ( 1 9): 5 4 5 8-5 4 6 8.  
 
Eise n ha uer, E. A., P. T herasse, J. B o gaerts, et al. ( 2 0 0 9). Ne w res p o nse e val uati o n criteria i n 
s oli d t u m o urs: re vise d R E CI S T g ui deli ne ( versi o n 1. 1). E ur J C a ncer.  4 5: 2 2 8 -2 4 7.  
 
Ga o,  M., K. Al b u q uer q u e, A. C hi a n d I. R us u ( 2 0 1 0). " 3 D C T -base d v ol u metric d ose assess me nt 
of 2 D pla ns usi n g G E C -E S T R O g ui deli nes f or cer vical ca ncer brac h yt hera p y." Brac h yt hera p y  
9 ( 1): 5 5-6 0.  
 
Gr o ver, S., M. M. Har ke nri der, L. P. C h o, B. Eric ks o n, C. S mall, W. S mall, Jr. a n d A. N. 
Vis wa nat ha n ( 2 0 1 6). "I m a ge G ui de d Cer vical Brac h yt hera p y: 2 0 1 4 S ur ve y of t he A merica n 
Brac h yt hera p y S ociet y." I nt J Ra diat O nc ol Bi ol P h ys 9 4 ( 3): 5 9 8-6 0 4.  
 
Haie -Me d er, C., R. P otter, E. Va n Li m ber ge n, E. Bri ot, M. De Bra ba n dere, J. Di m o p o ul os, I. 
D u mas, T. P. Helle b ust, C. Kirisits, S. La n g, S. M usc hitz, J. Ne vi ns o n, A. N ule ns, P. Petr o w, N. 
Wac hter -Gerst ner a n d G. E. C. E. W. G. G y naec ol o gical ( 2 0 0 5). " Rec o m m e n dati o ns fr o m 
G y naec ol o gical ( G Y N) G E C -E S T R O W or ki n g Gr o u p (I): c o nce pts a n d ter ms i n 3 D i ma ge base d 
3 D treat me nt pla n ni n g i n cer vi x ca ncer brac h yt hera p y wit h e m p hasis o n M RI ass ess me nt of 
G T V a n d C T V." Ra di ot her O nc ol  7 4 ( 3): 2 3 5-2 4 5.  
 
Halla ha n, D., J. K u c hi b h otla a n d C. W y ble ( 1 9 9 6). " Cell a d hesi o n m olec ules me diate ra diati o n -
i n d uce d le u k oc yte a d hesi o n t o t he vasc ular e n d ot heli u m." Ca ncer Res  5 6 ( 2 2): 5 1 5 0-5 1 5 5.  
 
Ha ma nis hi, J., M. Ma n dai, M. I wasa ki, et al. ( 2 0 0 7). Pr o gra m me d cell deat h 1 li ga n d 1 a n d 
t u m or-i nfiltrati n g C D 8 + T l y m p h oc ytes are pr o g n ostic fact ors of h u ma n o varia n ca ncer. Pr oc 
N atl Ac a d Sci U S A . 1 0 4: 3 3 6 0-3 3 6 5.  
 
Ha n ks, G. E., D. F. Herri n g a n d S. Kra mer ( 1 9 8 3). " Patter ns of care o utc o me st u dies. Res ults of 
t he nati o nal practice i n ca ncer of t he cer vi x." Ca ncer  5 1 ( 5): 9 5 9-9 6 7.  
 
Her bst, R. S., J -C. S oria, M. K o wa netz, et al. ( 2 0 1 4). Pre dicti ve c orrelates of res p o nse t o t he a nti-
P D -L 1 a nti b o d y M P D L 3 2 8 0 A i n ca ncer patie nts. N at ure.  5 1 5: 5 6 3 -5 6 7.  
 
Hi n o, R., K. Ka bas hi ma, Y. Kat o, et al. ( 2 0 1 0). T u m or cell e x pressi o n of pr o gra m me d cell 
deat h -1 li ga n d 1 is a pr o g n ostic fact or f or mali g na nt mela n o ma. C a ncer.  1 1 6: 1 7 5 7 -1 7 6 6.  
 
I n v esti gat or’s Br oc h ure, Atez oliz u ma b ( M P D L 3 2 8 0 A). Versi o n 9, A u g ust 2 0 1 6. 

 
N R G -G Y 0 1 7  
9 7    
Versi o n Date:  N o ve m ber 8 , 2 0 1 8 
 
Keir, M. E ., M.J. B utte, G.J. Free ma n, et al. ( 2 0 0 8). P D-1 a n d its li ga n ds i n t olera nce a n d 
i m m u nit y. A n n u al Rev I m m u n ol . 2 6: 6 7 7-7 0 4.  
 
Ke ys, H. M., B. N. B u n d y, F. B. Ste h ma n, L. I. M u ders pac h, W. E. C hafe, C. L. S u g gs, 3r d, J. L. 
Wal ker a n d D. Gersell ( 1 9 9 9). " Cis p lati n, ra diati o n, a n d a dj u va nt h ysterect o m y c o m pare d wit h 
ra diati o n a n d a dj u va nt h ysterect o m y f or b ul k y sta ge I B cer vical carci n o ma." N E n gl J Me d  
3 4 0 ( 1 5): 1 1 5 4-1 1 6 1.  
 
Ki d d, E., B. Sie gel, F. De h das hti a n d e. al ( 2 0 1 0). " Cli nical o utc o mes of defi niti ve i nt e nsit y-
m o d ulate d ra diati o n t hera p y wit h fl u or o de o x y gl u c ose -p ositr o n e missi o n t o m o gra p h y si m ulati o n 
i n patie nts wit h l ocall y a d va nce d cer vical ca ncer." I nt J Ra diat O nc ol Bi ol P h ys 7 7 : 1 0 8 5-1 0 9 1.  
 
Kl o p p, A., J. M o u g ha n, L. P ortela nce, B. Miller, M. Sale h p o u r, D. D' S o uza, L. S o u ha mi, W. 
S mall, R. Ga ur a n d A. J hi n gra n ( 2 0 1 0). " He mat ol o gic t o xicit y o n R T O G 0 4 1 8: A p hase II st u d y 
of p ost -o perati ve I M R T f or g y nec ol o gic ca ncer." I nt J Ra diat O nc ol Bi ol P h ys: S 1 2 1: 2 5 8. 
 
Lee, Y., S. L. A u h, Y. Wa n g, B. B ur nette, Y.  Wa n g, Y. Me n g, M. Bec kett, R. S har ma, R. C hi n, 
T. T u, R. R. Weic hsel ba u m a n d Y. X. F u ( 2 0 0 9). " T hera pe utic effects of a blati ve ra diati o n o n 
l ocal t u m or re q uire C D 8 + T cells: c ha n gi n g strate gies f or ca ncer treat me nt." Bl o o d  1 1 4 ( 3): 5 8 9-
5 9 5.  
 
Lia n g, J. A., S. W. C he n, Y. C. H u n g, L. S. Ye h, W. C. C ha n g, W. C. Li n a n d Y. Y. C ha n g 
( 2 0 1 4). " L o w-d ose, pr o p h ylactic, e xte n de d -fiel d, i nte nsit y-m o d ulate d ra di ot hera p y pl us 
c o nc urre nt wee kl y cis plati n f or patie nts wit h sta ge I B 2 -III B cer vical ca ncer, p ositi ve pel vic 
ly m p h n o des, a n d ne gati ve para -a ortic l y m p h n o des." I nt J G y n ec ol Ca ncer 2 4 ( 5): 9 0 1-9 0 7.  
 
Ma ya de v, J., A. Vis w a nat ha n, Y. Li u, C. S. Li, K. Al b u q uer q ue, A. L. Da m at o, S. Beri wal a n d 
B. Eric ks o n ( 2 0 1 7). " A m erica n Brac h yt hera p y Tas k Gr o u p Re p ort: A p o ole d a na l ysis of cli nical 
o utc o mes f or hi g h -d ose -rate brac h yt hera p y f or cer vical ca ncer." Brac h yt hera p y  1 6 ( 1): 2 2-4 3.  
 
M u n oz, N., F. X. B osc h, S. de Sa nj ose, R. Herrer o, X. Castellsa g ue, K. V. S ha h, P. J. S nij ders, 
C. J. Meijer a n d G. I nter nati o nal A ge nc y f or Rese arc h o n Ca ncer M ultice nt er Cer vical Ca ncer 
St u d y ( 2 0 0 3). " E pi de mi ol o gic classificati o n of h u ma n pa pill o ma vir us t y pes ass ociate d wit h 
cer vical ca n cer." N E n gl J Me d  3 4 8 ( 6): 5 1 8-5 2 7.  
 
O kaza ki, T., T. H o nj o. ( 2 0 0 7). P D -1 a n d P D -1 li ga n ds: fr o m disc o ver y t o cli nical a p plicati o n. I nt 
I m m u n ol. 9: 8 1 3-8 2 4.  
 
Os b or ne, E. M., A. H. Kl o p p, A. J hi n gra n, L. A. Me yer a n d P. J. Eifel ( 2 0 1 7). "I m p act of 
treat me nt year o n s ur vi val a n d a d verse effects i n patie nts wit h cer vical ca ncer a n d para ortic 
l y m p h n o de metastases tr eate d wit h defi niti ve e xt e n de d-fiel d ra diati o n t hera p y." Pract Ra diat 
O nc ol  7 ( 3): e 1 6 5-e 1 7 3.  
 
Pa va ma ni, S., D. P. D' S o uza, L. P ortela nce, P. S. Crai g hea d, A. G. Pearce, L. L. Tra pt o w a n d C. 
M. D oll ( 2 0 1 1). "I m a ge -g ui de d brac h yt hera p y f or cer vical ca ncer: a C a na dia n Brac h yt hera p y 

 
N R G -G Y 0 1 7  
9 8    
Versi o n Date:  N o ve m ber 8 , 2 0 1 8 
Gr o u p s ur ve y." Brac h yt h er a p y 1 0 ( 5): 3 4 5-3 5 1.  
 
P otter, R., P. Ge or g, J. C. Di m o p o ul os, M. Gri m m, D. Ber ger, N. Nes vacil, D. Ge or g, M. P. 
Sc h mi d, A. Rei nt haller, A. St ur dza a n d C. Kirisits ( 2 0 1 1). " Cli nical o utc o me of pr ot oc ol base d 
i ma ge ( M RI) g ui de d a d a pti ve brac h yt hera p y c o m bi ne d wit h 3 D c o nf or mal ra di ot hera p y wit h or 
wit h o ut c he m ot hera p y i n patie nts wit h l ocall y a d va nce d cer vical ca ncer." R a di ot her O nc ol  
1 0 0 ( 1): 1 1 6-1 2 3.  
 
P otter, R., C. Hai e-Me der a n d E. Li m ber ge nc ( 2 0 0 6 ). " Rec o m me n dati o ns fr o m g y naec ol o gical 
( G Y N) G E C E S T R O w or ki n ggr o u p (II): C o nce pts a n d ter ms i n 3 D  i ma ge-base d treat me nt 
pla n ni n g i n cer vi x ca n cer brac h yt hera py — 3 D d ose v ol u me para m eters a n d as pects of 3 D i ma ge -
base d a nat o m y, ra diati o n p h ysics, ra di o bi ol o g y." Ra di ot hera p y a n d O nc ol o g y  7 8 6 7 – 7 7.  
 
P o tter, R., C. Kirisits, E. F. Fi dar o va, J. C. A. Di m o p o ul os, D. Ber ger, K. Ta n der u p a n d J. C. 
Li n de gaar d ( 2 0 0 8). " Pres e nt stat us a n d f ut ure of hi g h -precisi o n i ma ge g ui de d a da pti ve 
brac h yt hera p y f or cer vi x carci n o ma." Acta O nc ol o gica  4 7 ( 7): 1 3 2 5-1 3 3 6.  
 
P o wles, T., J. P. E der , G. D. Fi ne, et al. ( 2 0 1 4). M P D L 3 2 8 0 A (a nti-P D -L 1) treat me nt lea ds t o 
cli nical acti vit y i n metastatic bla d der ca ncer. N at ure.  5 1 5: 5 5 8 -5 6 2.  
 
R ose, P. G., B. N. B u n d y, E. B. Wat ki ns, J. T. T hi g pe n, G. De p pe, M. A. Mai ma n, D. L. Clar ke -
Pears o n a n d S. I nsalac o  ( 1 9 9 9). " C o nc urre nt cis pl ati n-base d ra di ot hera p y a n d c he m ot hera p y f or 
l ocall y a d va nce d cer vical ca ncer." N E n gl J Me d  3 4 0 ( 1 5): 1 1 4 4-1 1 5 3.  
 
S hara bi, A. B., M. Li m, T. L. De Weese a n d C. G. Dra ke ( 2 0 1 5). " Ra diati o n a n d c hec k p oi nt 
bl oc ka de i m m u n ot hera p y: ra di ose nsitisati o n a n d p ote ntial mec ha nis ms of s y ner g y." La ncet 
O nc ol  1 6 ( 1 3): e 4 9 8-5 0 9.  
 
S har o n, E., H. Streic her, P. G o ncal ves a n d H. X. C he n ( 2 0 1 4). "I m m u ne c hec k p oi nt i n hi bit ors i n 
cli nical trials." C hi n J Ca ncer  3 3 ( 9): 4 3 4-4 4 4.  
 
S n y der, A., T. Nat ha ns o n, S . A. F u nt, A. A h uja, J. B ur os N o vi k, M. D. Hell ma n n, E. C ha n g, B. 
A. A ks o y, H. Al -A h ma di e, E. Y us k o, M. Vi g nali, S. Be nze n o, M. B o y d, M. M ora n, G. I yer, H. 
S. R o bi ns, E. R. Mar dis, T. Mer g h o u b, J. Ha m mer bac her, J. E. R os e n ber g a n d D. F. Baj ori n 
( 2 0 1 7). " C ontri b uti o n of s yste mic a n d s o matic fact ors t o cli nical res p o nse a n d resista nce t o P D -
L 1 bl oc ka de i n ur ot helial ca ncer: A n e x pl orat or y m ulti -o mic a nal ysis." P L o S Me d  1 4 ( 5): 
e 1 0 0 2 3 0 9. 
 
St o ne, H. B., L. J. Peters a n d L. Milas ( 1 9 7 9). " Effect of h ost i m m u ne ca pa bilit y o n 
ra di oc ura bilit y a n d s u bse q ue nt tra ns pla nta bilit y of a m uri ne fi br osarc o ma." J Natl Ca ncer I nst 
6 3 ( 5): 1 2 2 9-1 2 3 5.  
 
T h o m ps o n, R. H., S. M. K u ntz, B. C. Lei b o vic h, et al. ( 2 0 0 6). T u m or B 7-H 1 is ass ociate d wit h 
p o or pr o g n osis i n re nal cell carci n o ma p atie nts wit h l o n g -ter m f oll o w-u p. C a ncer Res.  6 6: 3 3 8 1 -
3 3 8 5.  
 

 
N R G -G Y 0 1 7  
9 9    
Versi o n Date:  N o ve m ber 8 , 2 0 1 8 
T o palia n, S. L., F. S. H o di, J. R. Bra h mer, S. N. Getti n ger, D. C. S mit h, D. F. Mc Der m ott, J. D. 
P o w derl y, R. D. Car vajal, J. A. S os ma n, M. B. At ki ns, P. D. Le mi n g, D. R. S pi gel, S. J. A nt o nia, 
L. H or n, C. G. Dra k e, D. M. Par d oll, L. C he n, W. H. S harf ma n, R. A. A n ders, J. M. Ta u be, T. L. 
Mc Miller, H. X u, A. J. K or ma n, M. J ure -K u n kel, S. A gra wal, D. Mc D o nal d, G. D. K ollia, A. 
G u pta, J. M. Wi g gi nt o n a n d M. Sz n ol ( 2 0 1 2). " Safet y, acti vit y, a n d i m m u ne c orrel ates of a nti -
P D -1 a nti b o d y i n ca ncer." N E n gl J Me d  3 6 6 ( 2 6): 2 4 4 3-2 4 5 4.  
 
Tsai, K. K., I. Zarz os o a n d A. I. Da u d ( 2 0 1 4). " P D -1 a n d P D -L 1 a nti b o dies f or mela n o ma." H u m 
Vacci n I m m u n ot her  1 0 ( 1 1): 3 1 1 1-3 1 1 6.  
 
T w y ma n -Sai nt Vict or, C., A. J. Rec h, A. Mait y, R. Re n ga n, K. E. Pa u ke n, E. Stele kati, J. L. 
Be nci, B. X u, H. Da da, P. M. O d orizzi, R. S. Herati, K. D. Ma nsfiel d, D. Patsc h, R. K. 
A mara va di, L. M. Sc h u c hter, H. Is h wara n, R. Mic k, D. A. Pr y ma, X. X u, M. D. F el d ma n, T. C. 
Ga n ga d har, S. M. Ha h n, E. J. W herr y, R. H. V o n der hei de a n d A. J. Mi n n ( 2 0 1 5). " Ra diati o n a n d 
d ual c hec k p oi nt bl oc ka de acti vate n o n -re d u n da nt i m m u ne mec ha nis ms i n ca ncer." Nat ure  
5 2 0 ( 7 5 4 7): 3 7 3-3 7 7.  
 
va n D y k, S., D. B yra m a n d D. Ber ns ha w ( 2 0 1 0 ). " Use of 3 D i ma gi n g a n d a ware ness of G E C-
E S T R O rec o m me n dati o ns f or cer vi x ca ncer brac h yt hera p y t hr o u g h o ut A ustralia a n d Ne w 
Zeala n d." J Me d I m a gi n g Ra diat O nc ol 5 4 ( 4): 3 8 3-3 8 7.  
 
Var g o, J. A., H. Ki m, S. C h oi, P. S u k u m va nic h, A. B. Ola wai ye, J. L. Kelle y,  R. P. E d war ds, J. 
T. C o merci a n d S. Beri wal ( 2 0 1 4). " E xte n de d fiel d i nte nsit y m o d ulate d ra diati o n t hera p y wit h 
c o nc o mita nt b o ost f or l y m p h n o de -p ositi ve cer vical ca ncer: a nal ysis of re gi o nal c o ntr ol a n d 
rec urre nce patter ns i n t he p ositr o n e missi o n t o m o grap h y/c o m p ute d t o m o gra p h y era." I nt J Ra diat 
O nc ol Bi ol P h ys  9 0 ( 5): 1 0 9 1-1 0 9 8.  
 
Varia, M. A., B. N. B u n d y, G. De p pe, R. Ma n nel, H. E. A verette, P. G. R ose a n d P. C o n nell y 
( 1 9 9 8). " Cer vical carci n o ma metastatic t o para-a ortic n o des: e xte n de d fiel d ra diati o n t hera p y 
wit h c o nc o mita nt 5 -fl u or o uracil a n d cis plati n c he m ot hera p y: a G y nec ol o gic O nc ol o g y Gr o u p 
st u d y." I nt J Ra diat O nc ol Bi ol P h ys 4 2 ( 5): 1 0 1 5-1 0 2 3.  
 
W olc h o k, J. D., A. H o os, S. O’ Da y, et al. ( 2 0 0 9). G ui deli nes f or t he e val uati o n of i m m u ne 
t hera p y acti vity i n s oli d t u m ors: i m m u ne -relate d res p o nse criteria. Cli n C a n Res . 1 5: 7 4 1 2-7 4 2 0.   
 
1.    
Del ga d o G, B u n d y B, Zai n o R, Se vi n B U, Creas ma n W T, Maj or F. Pr os pecti ve s ur gical -
pat h ol o gical st u d y of disease -free i nter val i n patie nts wit h sta ge I B s q ua m o us cell 
carci n o ma of t he cer vi x: a G y nec ol o gic O nc ol o g y Gr o u p st u d y. Gy nec ol o gic o nc ol o gy. 
1 9 9 0; 3 8( 3): 3 5 2 -3 5 7.  
2.    
R ot ma n M, Se dlis A, Pie d m o nte M R, et al. A p hase III ra n d o mize d tri al of p ost o perati ve 
pel vic irra diati o n i n Sta ge I B cer vical carci n o ma  wit h p o or pr o g n ostic feat ures: f oll o w -u p 
of a g y nec ol o gic o n c ol o g y gr o u p st u d y. I nt J R a di at O nc ol Bi ol P hys. 2 0 0 6; 6 5( 1): 1 6 9 -
1 7 6.  
3.    
Mac d o nal d O K, C he n J, D o ds o n M, Lee C M, Gaff ne y D K. Pr o g n ostic si g nifica nce of 
hist ol o g y a n d p ositi ve l y m p h n o de i n v ol ve me nt f oll o wi n g ra dical h ysterect o m y i n 
carci n o ma of t he cer vi x. A meric a n j o ur n al of cli nic al o nc ol o gy. 2 0 0 9; 3 2( 4): 4 1 1 -4 1 6.  

 
N R G -G Y 0 1 7  
1 0 0    
Versi o n Date:  N o ve m ber 8 , 2 0 1 8 
4.    
R ose P G, B u n d y B N, Wat ki ns E B, et al. C o nc urre nt cis plati n -base d ra di ot hera p y a n d 
c he m ot hera p y f or l ocall y a d va nce d cer vical ca ncer. N E n gl J Me d. 1 9 9 9; 3 4 0( 1 5): 1 1 4 4 -
1 1 5 3.  
5.    
Ke ys H M, B u n d y B N, Ste h ma n F B, et al. Cis plati n, ra diati o n, a n d a dj u va nt h ysterect o m y 
c o m pare d wit h ra diati o n a n d a dj u va nt h ysterect o m y f or b ul k y sta ge I B cer vical 
carci n o ma. N E n gl J Me d. 1 9 9 9; 3 4 0( 1 5): 1 1 5 4 -1 1 6 1.  
6.    
Varia M A, B u n d y B N, De p pe G, et al. Cer vical carci n o ma metastatic t o para -a ortic 
n o des: e xte n de d fiel d ra diati o n t hera p y w it h c o nc o mita nt 5-fl u or o uracil a n d cis plati n 
c he m ot hera p y: a G y nec ol o gic O nc ol o g y Gr o u p st u d y. I nter n ati o n al j o ur n al of r a di ati o n 
o nc ol o gy, bi ol o gy, p hysics. 1 9 9 8; 4 2( 5): 1 0 1 5 -1 0 2 3.  
7.    
Cliff or d G M, S mit h J S, Pl u m mer M, M u n oz N, Fra ncesc hi S. H u ma n pa pill o ma v ir us 
t y pes i n i n vasi ve cer vical ca ncer w orl d wi d e: a met a-a nal ysis. Br J C a ncer. 
2 0 0 3; 8 8( 1): 6 3 -7 3.  
8.    
M u n oz N, B osc h F X, de Sa nj ose S, et al. E pi de mi ol o gic classificati o n of h u ma n 
pa pill o ma vir us t y pes ass ociate d wit h cer vical ca ncer. N E n gl J Me d. 2 0 0 3; 3 4 8( 6): 5 1 8 -
5 2 7.  
9.    
C o glia n o V, Baa n R, Straif K, et al. Carci n o g e nicit y of h u ma n pa pill o ma vir uses. L a ncet 
O nc ol. 2 0 0 5; 6( 4): 2 0 4.  
1 0.   
T o palia n S L, H o di F S, Bra h mer J R, et al. Safet y, acti vit y, a n d i m m u ne c orrelates of a nti -
P D -1 a nti b o d y i n ca ncer. N E n gl J Me d. 2 0 1 2; 3 6 6( 2 6): 2 4 4 3 -2 4 5 4.  
1 1.   
Ya n g W, S o n g Y, L u Y L, S u n J Z, Wa n g H W. I ncrease d e x pressi o n of pr o gra m me d deat h 
( P D)-1 a n d its li ga n d P D -L 1 c orrelates wit h i m paire d cell -m e diate d i m m u nit y i n hi g h -
ris k h u ma n pa pill o ma vir us-relate d cer vical i ntrae pit helial ne o plasia. I m m u n ol o gy. 
2 0 1 3; 1 3 9( 4): 5 1 3 -5 2 2.  
1 2.   
St o ne H B, Peters LJ, Milas L. Effect of h ost i m m u ne ca pa bilit y o n ra di oc ura bilit y a n d 
s u bse q ue nt tra ns pla nta bilit y of a m uri ne fi br osarc o ma. J o ur n al of t he N ati o n al C a ncer 
I nstit ute. 1 9 7 9; 6 3( 5): 1 2 2 9 -1 2 3 5.  
1 3.   
Lee  Y, A u h S L, Wa n g Y, et al. T hera pe utic effects of a blati ve ra diati o n o n l ocal t u m or 
re q uire C D 8 + T cells: c ha n gi n g strate gies f or ca ncer treat me nt. Bl o o d. 2 0 0 9; 1 1 4( 3): 5 8 9 -
5 9 5.  
1 4.   
S hara bi A B, Li m M, De Weese T L, Dra ke C G. R a diati o n a n d c hec k p oi nt bl oc ka de 
i m m u n ot hera p y: ra di ose nsitisati o n a n d p ote ntial mec ha nis ms of s y ner g y. L a ncet O nc ol. 
2 0 1 5; 1 6( 1 3):e 4 9 8 -5 0 9.  
1 5.   
Halla ha n D, K u c hi b h otla J, W y ble C. Cell a d hesi o n m olec ules me diate ra diati o n -i n d uce d 
le u k oc yte a d h esi o n t o t he vasc ular e n d ot heli u m. C a ncer rese ar c h. 1 9 9 6; 5 6( 2 2): 5 1 5 0 -
5 1 5 5.  
1 6.   
T w y ma n -Sai nt Vict or C, Rec h AJ, Mait y A, et al. Ra diati o n a n d d ual c hec k p oi nt 
bl oc ka de acti vate n o n -re d u n da nt i m m u ne mec ha nis ms i n ca ncer. N at ure. 
2 0 1 5; 5 2 0( 7 5 4 7): 3 7 3 -3 7 7.  
1 7.   
Y o u n g K H, Bair d J R, Sa va ge T, et al. O pti mizi n g Ti mi n g of I m m u n ot hera p y I m pr o ves 
C o ntr ol of T u m ors b y H y p ofracti o nat e d Ra diati o n T hera p y. P L o S O ne. 
2 0 1 6; 1 1( 6):e 0 1 5 7 1 6 4.  
1 8.   
Lia n g J A, C he n S W, H u n g Y C, et al. L o w -d ose, pr o p h ylacti c, e xte n de d -fiel d, i nte nsit y-
m o d ulate d ra di ot hera p y pl us c o nc urre nt wee kl y cis plati n f or patie nts wit h sta ge I B 2 -III B 
cer vical ca n cer, p ositi ve pel vic l y m p h n o des, a n d ne gati ve para -a ortic l y m p h n o des. I nt J 
Gy nec ol C a ncer. 2 0 1 4; 2 4( 5): 9 0 1 -9 0 7.  

 
N R G -G Y 0 1 7  
1 0 1    
Versi o n Date:  N o ve m ber 8 , 2 0 1 8 
1 9.   
Var g o J A , Ki m H, C h oi S, et al. E xte n de d fiel d i nte nsit y m o d ulate d ra diati o n t hera p y 
wit h c o nc o mita nt b o ost f or l y m p h n o de -p ositi ve cer vical ca ncer: a nal ysis of re gi o nal 
c o ntr ol a n d rec urre nce patter ns i n t he p ositr o n e missi o n t o m o gra p h y/c o m p ute d 
t o m o gra p h y era. Int J R a di at O nc ol Bi ol P hys. 2 0 1 4; 9 0( 5): 1 0 9 1 -1 0 9 8.  
2 0.   
Kl o p p A, M o u g ha n J, P ortela nce L, et al. He m at ol o gic t o xicit y o n R T O G 0 4 1 8: A p hase 
II st u d y of p ost-o perati ve I M R T f or g y nec ol o gic ca ncer. I nt J R a di at O nc ol Bi ol P hys. 
2 0 1 0: S 1 2 1: 2 5 8.  
2 1.   
Ki d d E, Sie gel B, De h das hti F, al e. Cli nical o utc o mes of defi niti ve i nte nsit y -m o d ulate d 
ra diati o n t hera p y wit h fl u or o de o x y gl uc ose-p ositr o n e missi o n t o m o gra p h y si m ulati o n i n 
patie nts wit h l ocall y a d va nce d cer vical ca ncer. I nt J R a di at O nc ol Bi ol P hys. 
2 0 1 0; 7 7: 1 0 8 5 -1 0 9 1.  
2 2.   
Os b or ne E M, Kl o p p A H, J hi n gra n A, Me yer L A, Eifel PJ. I m pact of treat me nt year o n 
s ur vi val a n d a d verse effects i n patie nts wit h cer vical ca ncer a n d para ortic l y m p h n o de 
metastases treate d wit h d efi niti ve e xte n de d -fiel d ra diati o n t hera p y. Pr act R a di at O nc ol. 
2 0 1 7; 7( 3):e 1 6 5 -e 1 7 3.  
2 3.   
Ha n ks G E, Herri n g D F, Kra mer S. Patter ns of care o utc o me st u dies. Res ults of t he 
nati o nal practice i n ca n cer of t he cer vi x. C a ncer. 1 9 8 3; 5 1( 5): 9 5 9 -9 6 7.  
2 4.   
P otter R, Ge or g P, Di m o p o ul os J C, et al. Cli nical o utc o me of pr ot oc ol base d i ma ge 
( M RI) g ui de d a d a pti ve brac h yt hera p y c o m bi ne d wit h 3 D c o nf or mal ra di ot hera p y wit h or 
wit h o ut c he m ot hera p y i n patie nts wit h l ocall y a d va nce d cer vical ca ncer. R a di ot her a py 
a n d o nc ol o gy : j o ur n al of t he E ur o pe a n S ociety f or T her a pe utic R a di ol o gy a n d 
O nc ol o gy. 2 0 1 1; 1 0 0( 1): 1 1 6 -1 2 3.  
2 5.   
Gr o ver S, Har ke nri der M M, C h o L P, et al. I ma ge G ui de d Cer vical Brac h yt hera p y: 2 0 1 4 
S ur ve y of t he A merica n Brac h yt hera p y S ociet y. I nt J R a di at O nc ol Bi ol P hys. 
2 0 1 6; 9 4( 3): 5 9 8 -6 0 4.  
2 6.   
Da vi ds o n M T, Y ue n J, D' S o uza D,  Batc helar D L. I ma ge -g ui de d cer vi x hi g h -d ose -rate 
brac h yt hera p y treat me nt pla n ni n g:  
D oes c ust o m c o m p ute d t o m o gra p h y pla n ni n g f or eac h i nserti o n pr o vi de  
better c o nf or mal a v oi da n ce of or g a ns at ris k? Br ac hyt her a py. 2 0 0 8; 7: 3 7 -4 2.  
2 7.   
Ga o M, Al b u q uer q ue K, C hi  A, R us u I. 3 D C T -base d v ol u metric d ose assess me nt of 2 D 
pla ns usi n g G E C -E S T R O g ui deli nes f or cer vical ca ncer brac h yt hera p y. Br ac hyt her a py. 
2 0 1 0; 9( 1): 5 5 -6 0.  
2 8.   
Haie -Me d er C, P otter R, Va n Li m ber ge n E, et al. Rec o m me n dati o ns fr o m 
G y naec ol o gical ( G Y N) G E C -E S T R O W or ki n g Gr o u p (I): c o nce pts a n d ter ms i n 3 D 
i ma ge base d 3 D treat me nt pla n ni n g i n cer vi x ca ncer brac h yt hera p y wit h e m p hasis o n 
M RI ass ess me nt of G T V a n d C T V. R a di ot her a py a n d o nc ol o gy : j o ur n al of t he E ur o pe a n 
S ociety f or T her a pe utic R a di ol o gy a n d O nc o l o gy. 2 0 0 5; 7 4( 3): 2 3 5 -2 4 5.  
2 9.   
P otter R, Haie -Me der C, Li m ber ge nc E. Rec o m me n dati o ns fr o m g y naec ol o gical ( G Y N) 
G E C E S T R O w or ki n g  
gr o u p (II): C o nce pts a n d ter ms i n 3 D i ma ge -bas e d treat me nt pla n ni n g  
i n cer vi x ca n cer brac h yt hera p y— 3 D d ose v ol u me para meters a n d  
as pects of 3 D i ma ge -bas e d a nat o m y, ra di ati o n p h ysics, ra di o bi ol o g y. R a di ot her a py a n d 
O nc ol o gy. 2 0 0 6  
 7 8 6 7 – 7 7.  
3 0.   
P ötter R, Kirisits C, Fi dar o va E F, et al. Prese nt stat us a n d f ut ure of hi g h -precisi o n i ma ge 
g ui de d a da pti ve brac h yt h era p y f or cer vi x carci n o ma. Act a O nc ol o gic a. 2 0 0 8; 4 7( 7): 1 3 2 5 -

 
N R G -G Y 0 1 7  
1 0 2    
Versi o n Date:  N o ve m ber 8 , 2 0 1 8 
1 3 3 6.  
3 1.   
va n D y k S, B yra m D, Ber ns ha w D. Use of 3 D i ma gi n g a n d a ware ness of G E C -E S T R O 
rec o m me n dati o ns f or cer vi x ca ncer brac h yt hera p y t hr o u g h o ut A ustralia a n d Ne w 
Zeala n d. J Me d I m a gi n g R a di at O nc ol. 2 0 1 0; 5 4( 4): 3 8 3 -3 8 7 . 
3 2.   
Pa va ma ni S, D' S o uza D P, P ortela nce L, et al. I ma ge -g ui de d brac h yt hera p y f or cer vical 
ca ncer: a Ca n a dia n Brac h yt hera p y Gr o u p s ur ve y. Br ac hyt her a py. 2 0 1 1; 1 0( 5): 3 4 5 -3 5 1.  
3 3.   
Ma ya de v J, Vis w a nat ha n A, Li u Y, et al. A merica n Brac h yt hera p y Tas k Gr o u p Re p or t: A 
p o ole d a nal ysis of cli nical o utc o mes f or hi g h -d ose -rate brac h yt hera p y f or cer vical ca ncer. 
Br ac hyt her a py. 2 0 1 7; 1 6( 1): 2 2 -4 3.  
3 4.   
G y or ki D E, Calla ha n M, W olc h o k J D, Ari ya n C E. T he delicate bala nce of mela n o ma 
i m m u n ot hera p y. Cli n Tr a nsl I m m u n ol o gy. 2 0 1 3; 2( 8):e 5.  
3 5.   
Atez oliz u ma b, bei n g a me m ber of class of a ge nts i n v ol ve d i n t he i n hi biti o n of “i m m u ne 
c hec k p oi nts,” ma y res ult i n se vere a n d p ossi bl y fatal i m m u ne -me diate d a d verse e ve nts 
pr o ba bl y d ue t o T -cell acti vati o n a n d pr oliferati o n.  I m m u ne -me diate d a d verse reacti o ns 
ha ve bee n re p orte d i n patie nts recei vi n g atez oliz u ma b.  A d verse e ve nts p ot e ntiall y relate d 
t o atez oliz u ma b ma y be ma nifestati o ns of i m m u ne-me diate d a d verse e ve nts.  I n cli nical 
trials, m ost i m m u ne-me diate d a d verse reacti o ns were re versi ble a n d ma na ge d wit h 
i nterr u pti o ns of atez oliz u ma b, a d mi nistrati o n of c ortic oster oi ds a n d s u p p orti ve care. 
3 6.   
K u n os C, Ra di v o ye vitc h T, A b d ul -Kari m F W, Fa ul ha ber P. 1 8 F -fl u or o-2 -de o x y -D -
gl uc ose p ositr o n e missi o n t o m o gra p h y sta n dar d u pta ke val ue rati o as a n i n dicat or of 
cer vical ca n cer c he m ora diati o n t hera pe utic res p o nse. I nter n ati o n al j o ur n al of 
gy nec ol o gic al c a nc er : offici al j o ur n al of t he I nter n ati o n al Gy nec ol o gic al C a ncer 
S ociety. 2 0 1 1; 2 1( 6): 1 1 1 7 -1 1 2 3.  
 
 

 
N R G -G Y 0 1 7  
1 0 3    
Versi o n Date:  N o ve m ber 8 , 2 0 1 8 
A P P E N DI X I –  T R A N S L A TI O N A L S CI E N C E BI O S P E CI M E N P R O C E D U R E S  
 
1.  O bt ai ni n g a B a n k I D f or Tr a nsl ati o n al Scie nce Bi os peci me ns  
O nl y o ne Ba n k I D ( # # # # - # # - G # # #) is assi g ne d per patie nt. All tra nslati o nal scie nce 
bi os peci me ns a n d acc o m pa n yi n g pa per w or k m ust be la bele d wit h t his c o de d patie nt n u m ber.  
 
A Ba n k I D is a ut o maticall y assi g ne d o nce t he S peci me n C o nse nt is c o m plet e d a n d i n dicates t hat 
a patie nt has a gree d t o p artici pate i n t he tra nslati o nal scie nce c o m p o ne nt. If a patie nt has 
pre vi o usl y bee n assi g ne d a Ba n k I D, please e ns ure t he Ba n k I D a p peari n g i n Ra ve is t he sa me as 
t he pre vi o usl y assi g ne d Ba n k I D. 
 
Please c o nta ct Us er S u p p ort if y o u nee d assista nce or ha ve assi g ne d m ore t ha n o ne Ba n k I D t o a 
patie nt ( E mail: s u p p ort @ nr g o nc ol o g y. or g; P h o ne: 7 1 6-8 4 5 -7 7 6 7).  
 
2.  Re q uesti n g Tr a nsl ati o n al Scie nce Bi os peci me n Kits  
T hree si n gle c h a m ber kits will be pr o vi de d per patie nt f or t he c ollecti o n a n d s hi p me nt of fr oze n 
plas ma, b uff y c o at, a n d w h ole bl o o d bi os peci me ns. O ne kit will be pr o vi de d f or eac h of t he 
f oll o wi n g ti me p oi nts: 
1.  da ys -2 1  (re gi me n A o nl y), 0, a n d 2 1; 
2.  da ys  4 2 , a n d 6 3; a n d  
3.  da y 1 4 0.  
 
Sites ca n or der kits o nli ne via t he Kit Ma na ge me nt s yste m 
(htt ps://rica p ps . nati o n wi dec hil dre ns. or g/ Kit Ma na ge me nt/). Eac h site ma y or der t w o kit t y pes per 
pr ot oc ol per da y ( dail y ma x = 6 kits).  
 
  
Please c o ntact t he N R G B B -C ol u m b us if y o u nee d assista nce ( E mail: 
B P C Ba n k @ nati o n wi dec hil dre ns. or g ; P h o ne: 8 6 6-4 6 4 -2 2 6 2).  
 
Be s ure t o pla n a hea d a n d all o w ti me f or kits t o be s hi p pe d b y gr o u n d tra ns p ortati o n. Kits s h o ul d 
arri ve wit hi n 3 -5 b usi ness da ys.  
 
N ote: U n use d s u p plies a n d kits s h o ul d be ret ur ne d t o t he N R G B B -C ol u m b us. A pre -pai d 
s hi p pi n g label f or t he ret ur n of u n use d s u p plies a n d kits ma y be o btai ne d via t he Kit 
Ma na ge me nt s yste m. Sel ect “ E m pt y Kit” f or pac ka ge c o nte nts w he n ret ur ni n g u n use d kits.  
 
3.   F F P E T u m or Bi os peci me ns S hi p pe d t o t he N R G B B -C ol u m b us  
O nl y o ne bl oc k ma y be s u b mitte d per t iss ue t y pe. All F F P E tiss ue s h o ul d be s u b mitte d wit h t he 
c orres p o n di n g p at h ol o g y re p ort.  If a p at h ol o g y re p ort if n ot a v ail a ble f or t he bi o ps y, a c o p y 
of t he r a di ol o g y re p ort or o per ati ve re p ort fr o m t he bi o ps y pr oce d ure m ust  be se nt t o t he 
N R G B B -C ol u m b us , al o n g wit h a c o m plete d c o p y of t he Bi o ps y P at h ol o g y Verific ati o n 
( A p pe n di x V ). 
 
3. 1    
F F P E Bi os peci me n Re q uire me nt  
3. 1. 1   
T u m or Tiss ue T y pe  
F or mali n -fi xe d, p araffi n e m be d de d ( F F P E) tiss ue s h o ul d be t he m ost re pres e ntati ve of t he 

 
N R G -G Y 0 1 7  
1 0 4    
Versi o n Date:  N o ve m ber 8 , 2 0 1 8 
re q uire d t y pe: 
 
Re gi me n A O nl y  
•  D -2 1 F F P E pri m ar y ( F P 0 1) or met ast atic ( F M 0 1) t u m or bi o ps y  s h o ul d be c ollecte d f or 
after ra n d o mizati o n, pri or t o t he patie nt recei vi n g a n y st u d y treat me nt ( da y -2 1 ± 3 da ys) . 
 
Re gi me ns A a n d B  
•  D 0 F F P E p ri m ar y ( F P 0 2)  or met ast atic ( F M 0 2)  t u m or c he m or a di ati o n bi o ps y  s h o ul d be 
c ollecte d at t he start of c he m ora diati o n ( da y 0 ± 3 da ys) . 
•  D 2 8  F F P E p ri m ar y ( F P 0 3)  or  met ast atic ( F M 0 3)  t u m or br ac h yt her a p y bi o ps y  s h o ul d be 
c ollecte d at t he first brac h yt hera p y ( da y 2 8 ± 7 da ys) . 
 
3. 1. 2   
F F P E T y pe  
O nl y  bl oc k s will be acce pte d. Ple ase pr o vi de A p pe n di x I V t o y o ur p at h ol o gist. 
 
3. 1. 3   
L a beli n g F F P E Bi os peci me ns  
A water pr o of per ma ne nt mar ker or pri nte d la bel s h o ul d be use d t o la bel eac h tra nslati o nal 
scie nce F F P E bi os peci me n wit h: 
 
Ba n k I D ( # # # # - # # - G # # #)  
pr ot oc ol n u m ber ( N R G -G Y 0 1 7)  
s peci me n c o de (see s ecti o n 3. 1. 1 a b o ve) 
c ollecti o n date ( m m/ d d/ y y y y)  
s ur gical pat h ol o g y accessi o n n u m ber 
bl oc k n u m ber  
 
N ote: If la beli n g sli des, o nl y la bel o n t he t o p, fr o nt p orti o n of t he sli de. D o n ot place a la bel o n 
t he bac k of t he sli de or o ver t he tiss ue. T he la bel m ust fit o n t he sli de a n d s h o ul d n ot be wra p pe d 
ar o u n d t he sli de or ha n g o ver t he e d g e.  
 
3. 1. 4   
C o m pleti n g F or m T R f or F F P E Bi os peci me ns  
T he t y pe  of bi os peci me n ( bl oc k ) sh o ul d be s pecifie d o n F or m T R.  
 
T he ti me t he tiss ue was i n f or mali n (i.e., fi xati o n ti me) s h o ul d be e ntere d as Esti mate d 
Pr ocessi n g Ti me.  
 
4.  Pl as m a a n d B uff y C o at Bi os peci me ns S hi p pe d t o t he N R G B B -C ol u m b us  
4. 1    
Pl as m a a n d B uff y C o at Bi os peci me n Re q uire me nt  
Plas ma a n d b uff y c o at bi os peci me ns s h o ul d be c ollecte d at t he f oll o wi n g ti me p oi nts:  
 
Re gi me n A O nl y  
1.  da y -2 1, pri or t o atez oliz u ma b ( P B 0 1 f or plas ma; L B 0 1 f or b uff y c oat) ; 
 
Re gi me ns A a n d B  
2.  da y 0 ± 3 da ys ( P B 0 2 or plas ma; L B 0 2 f or b uff y c oat);  
3.  da y 2 1  ± 1 da y ( P B 0 3 f or plas ma; L B 0 3 f or b uff y c oat);  

 
N R G -G Y 0 1 7  
1 0 5    
Versi o n Date:  N o ve m ber 8 , 2 0 1 8 
4.  da y 4 2  ± 7 da ys , at start of brac h yt h era p y ( P B 0 4 for plas ma; L B 0 4 f or b uff y c oat);  
5.  da y 6 3  ± 3 da ys ( P B 0 5 f or plas ma; L B 0 5 f or b uff y c oat) ; a n d 
6.  da y 1 4 0 ± 7 da ys , at ti me of dia g n ostic P E T/ C T ( P B 0 6 f or plas ma; L B 0 6 f or b uff y c oat). 
 
4. 2   
Pr ocessi n g Pl as m a a n d B uff y C o at Bi os peci me ns  
1.  La bel  si x cr y o vials (fi ve f or plas ma a n d o ne f or b uff y c oat) a n d a 1 5 m L c o nical t u be as 
descri be d b el o w. Use 2 m L cr y o vials as plas ma a n d b uff y c oat will be s hi p pe d t o t he N R G 
B B -C ol u m b us.  
2.  Dra w 7 -1 0 m L of bl o o d i nt o  la ve n der/ p ur ple t o p ( K 2 E D T A) t u be(s).  
3.  I m me diat el y after c ollecti o n, ge ntl y i n vert t he bl o o d c ollecti o n t u be 5-1 0 ti mes t o mi x t he 
bl o o d a n d K 2 E D T A.  
4.  Ce ntrif u ge t he bl o o d  at 1 0 0 0 g f or 1 5 mi n utes at 4º C ( preferre d) or r o o m te m perat ure t o 
se parat e t he plas ma (t o p, stra w -c ol ore d la yer) fr o m t he b uff y c oat ( mi d dle, w hite la yer) a n d 
t he re d bl o o d cells ( b ott o m, re d la yer).  
5.  Tra nsfer t he plas ma i nt o a pre -l a bele d 1 5 m L c o ni cal t u be a n d ge ntl y mi x. 
6.  Q uic kl y, e ve nl y dis pe nse (ali q u ot) t he plas ma i nt o f i ve pre-l a bele d cr y o vials a n d ca p 
t he t u bes sec urel y. Place at least 0. 2 5 m L i nt o eac h cr y o vial. 
7.  Tra nsfer t he b uff y c oat t o t he pre -la bele d cr y o vial. 
8.  I m me diat el y freeze t he plas ma a n d b uff y c oat i n a n u pri g ht p ositi o n i n a -7 0 oC t o -8 0 oC 
freezer or by direct e x p os ure wit h dr y ice u ntil rea d y t o s hi p. If a -7 0 oC t o -8 0 oC freezer is 
n ot a vaila ble f or st ora ge, st ore a n d s hi p o n dr y ice wit hi n 2 4 h o urs of c ollecti o n.  
 
4. 3   
L a beli n g Pl as m a a n d B uff y C o at  
A water pr o of per ma ne nt mar ker or pri nte d la bel m ust be use d t o la bel eac h tra nslati o nal scie nce 
plas ma a n d b uff y c oat bi os peci me n wit h:  
 
Ba n k I D ( # # # # - # # - G # # #)  
pr ot oc ol n u m ber ( N R G -G Y 0 1 7)  
s peci me n c o de ( W B # #; s ee secti o n 4. 1 a b o ve) 
c ollecti o n date ( m m/ d d/ y y y y)  
 
5.  W h ole Bl o o d S hi p pe d t o t he N R G B B -C ol u m b us  
5. 1   
W h ole Bl o o d Bi os peci me n Re q uire me nts  
W h ole bl o o d s h o ul d be c ollecte d at t he f oll o wi n g ti me p oi nts:  
 
Re gi me n A O nl y  
1.  da y -2 1, pri or t o atez oliz u ma b ( W B 0 1 ); 
 
Re gi me ns A a n d B  
2.  da y 0 ± 3 da ys ( W B 0 2);  
3.  da y 2 1  ± 1 da y ( W B 0 3);  
4.  da y 4 2  ± 7 da ys , at start of brac h yt h era p y (W B 0 4);  
5.  da y 6 3  ± 3 da ys ( W B 0 5 ); a n d 
6.  da y 1 4 0 ± 7 da ys , at ti me of dia g n ostic P E T/ C T (W B 0 6 ). 
 
5. 2   
Pr ocessi n g W h ole Bl o o d Bi os peci me ns  

 
N R G -G Y 0 1 7  
1 0 6    
Versi o n Date:  N o ve m ber 8 , 2 0 1 8 
1.  La bel t he la ve n d er/ p ur pl e t o p ( E D T A) c ollecti o n t u be(s) as des cri be d bel o w. M ulti pl e t u bes 
ma y be use d t o c ollect t h e re q uire d a m o u nt. D o n ot  use gl ass bl o o d c ollecti o n t u bes.  
2.  Dra w 7 -1 0 m L of bl o o d i nt o t he la bele d la ve n der/ p ur ple t o p t u be(s). A mi ni m u m of 3 m L is 
nee de d f or pr ocessi n g.  
3.  I m me diat el y after c ollecti o n, ge ntl y i n vert t h e t u be 5-1 0 ti mes t o mi x t he bl o o d a n d E D T A.  
4.   
 
I m me diat el y freeze t he bl o o d i n a n u pri g ht p ositi o n i n a -7 0 oC t o -8 0 oC freezer or b y direct 
e x p os ure wit h dr y ice u ntil rea d y t o s hi p. If a -7 0 oC t o -8 0 oC freezer is n ot a vaila ble f or 
st ora ge, st ore a n d s hi p o n dr y ice wit hi n 2 4 h o urs of c ollecti o n. 
 
5. 3   
L a beli n g W h ole Bl o o d  
A water pr o of per ma ne nt mar ker or pri nte d la bel m ust be use d t o la bel eac h tra nslati o nal scie nce 
w h ole bl o o d bi os peci me n wit h:  
 
Ba n k I D ( # # # # - # # - G # # #)  
pr ot oc ol n u m ber ( N R G -G Y 0 1 7)  
s peci me n c o de ( W B # #; s ee secti o n 5. 1 a b o ve) 
c ollecti o n date ( m m/ d d/ y y y y)  
 
6.  S u b mitti n g F or m T R  
A s peci me n tra ns mittal f or m (i.e., F or m T R) f or eac h bi os peci me n will be a vaila ble i n t he 
Tr a nsl ati o n al Rese arc h F ol der i n R a ve , o nce t he S peci me n C o nse nt (locate d i n t he Baseli ne 
F ol der) has bee n c o m plet e d.  
 
A n electr o nicall y (i.e., R a ve) c o m plet e d c o p y of F or m T R m ust acc o m pa n y eac h bi os peci me n 
s hi p pe d t o t he N R G B B-C ol u m b us. Ha n d writte n f or ms will n ot be acce pt e d.  
 
N ote: A c o p y d oes n ot nee d t o be se nt t o t he N R G B B -C ol u m b us if bi os peci me ns are n ot 
c ollecte d.  
 
F or m T R m ust  be pri nte d fr o m t he Tra nslati o nal Researc h F or m scree n i n Ra ve usi n g t he “ P D F 
File ” li n k at t he t o p of t he f or m . Clic ki n g t his li n k will ge nerate a si n gle pa ge P D F. D o n ot us e 
t he “ Pri nta ble Versi o n” or “ Vie w P D F” li n ks at t he b ott o m of t he f or m or a n y ot her met h o d t o 
pri nt t he f or m, as t hese f or mats will n ot be acce pte d.  
 
N ote: Bi os peci me ns will n ot be mar ke d as recei ve d i n Ra ve wit h o ut recei pt of a c orres p o n di n g 
electr o nicall y c o m plete d F or m T R. I nc o m plete f or ms or t h ose c o nt ai ni n g i nc orrect 
i nf or m ati o n will n ot be pr ocesse d a n d m a y res ult i n a d at a q uer y . 
  
Retai n a pri nt o ut of t he c o m plete d f or m f or y o ur rec or ds.  
  
Please c o ntact Us er S u p p ort if y o u nee d assista nce ( E mail: s u p p ort @ nr g o nc ol o g y. or g; P h o ne: 
7 1 6 -8 4 5 -7 7 6 7).  
 
7.  S h i p pi n g Tr a nsl ati o n al Scie nce Bi os peci me ns 
7. 1   
Ge ner al I nf or m ati o n f or S hi p pi n g Bi os peci me ns t o t he N R G B B -C ol u m b us  

 
N R G -G Y 0 1 7  
1 0 7    
Versi o n Date:  N o ve m ber 8 , 2 0 1 8 
•  Tra nslati o nal scie n ce bi os peci me ns s h o ul d n ot be s hi p pe d u ntil after patie nt re gistrati o n a n d 
Ba n k I D assi g n me nt.  
•  A n electr o nicall y c o m plete d  c o p y of F or m T R m ust be i ncl u de d f or eac h tra nslati o nal 
scie nce bi os peci me n. 
•  All tra nslati o nal scie nce bi os peci me ns s h o ul d be s hi p pe d t o:  
 
N R G B B -C ol u m b us / Pr ot oc ol N R G -G Y 0 1 7  
Nati o n wi de C hil dre n’s H os pital  
7 0 0 C hil dre n’s Dr, W A 1 3 4 0  
C ol u m b us, O H 4 3 2 0 5  
P h o ne: 6 1 4 -7 2 2 -2 8 6 5  
F A X: 6 1 4 -7 2 2 -2 8 9 7  
E mail: B P C Ba n k @ nati o n wi dec hil dre ns. or g  
 
7. 2   
F F P E Tiss ue S hi p pe d t o t he N R G B B -C ol u m b us  
F F P E tiss ue a n d a c o p y of t he c orres p o n di n g pat h ol o g y re p ort  ( or Bi o ps y Pat h ol o g y 
Verificati o n)  s h o ul d be s hi p pe d usi n g y o ur o w n c o ntai ner at y o ur o w n e x pe nse t o t he N R G B B-
C ol u m b us (a d dress i n secti o n 7. 1).  
 
D o n ot s hi p F F P E tiss ue f or S at ur d a y deli ver y.  
 
7. 3   
Fr oze n Bi os peci me ns S hi p pe d t o t he N R G B B -C ol u m b us  
Fr oze n plas ma, b uff y c oat, a n d w h ole bl o o d s h o ul d be s hi p pe d usi n g t he bi os peci me n kits 
pr o vi de d t o t he N R G B B -C ol u m b us (a d dress i n secti o n 9. 1).  
 
Fr oze n bi os peci me ns s h o ul d be s hi p pe d M o n d a y t hr o u g h T h urs d a y f or T ues d a y t hr o u g h 
Fri d a y deli ver y . D o n ot s hi p fr oze n bi os peci me ns o n Fri da y or t he da y bef ore a h oli da y. N ote: 
Sat ur da y deli ver y is n ot a vaila ble f or  fr oze n bi os peci me ns.  
 
Fr oze n bi os peci me ns s h o ul d be st ore d i n a n ultra -c ol d freezi n g/st ora ge s p ace (i.e., ultra -c ol d ≤-
7 0 oC freezer, li q ui d nitr o ge n, or direct e x p os ure wit h dr y ice) u ntil t he bi os peci me ns ca n be 
s hi p pe d. 
 
7. 3. 1  S hi p pi n g Fr oze n Tr a nsl ati o n al Scie nce Bi os peci me ns i n a Si n gle C h a m ber Kit  
 
 
1.  Pre -fill t he kit c ha m ber a b o ut 1/ 3 f ull wit h dr y ice. 
2.  Place t he fr oze n bi os peci me ns fr o m eac h ti me p oi nt i n a se parat e zi p -l oc k ba g. 
3.  Place t he zi p -l oc k ba gs i n t he bi o hazar d e n vel o pe c o ntai ni n g a bs or be nt material. D o n ot p ut 
m ore t ha n 2 5 cr y o vials i n a si n gle c ha m ber kit. P ut t he sec o n dar y e n vel o pe i nt o a T y ve k 
e n vel o pe. E x pel as m uc h air as p ossi ble bef ore seali n g b ot h e n vel o pes . 
4.  Place t he T y ve k e n vel o pe c o ntai ni n g t he fr oze n bi os peci me ns i nt o t he kit a n d  fill t he c ha m ber 
t o t he t o p wit h dr y ice. 
5.  I ns ert a c o p y of F or m T R f or eac h bi os peci me n.  
6.  P lace t he c o ver o n t o p of t he kit. Ta pe t he o uter b o x of t he kit cl ose d wit h fila me nt or ot her 
d ura ble seali n g ta pe. Please d o n ot ta pe t he i n ner c ha m ber.  

 
N R G -G Y 0 1 7  
1 0 8    
Versi o n Date:  N o ve m ber 8 , 2 0 1 8 
7.  Pri nt a pre -pai d Fe d E x air bill usi n g t he Kit Ma na ge me nt li n k 
(htt ps://rica p ps. nati o n wi dec hil dre ns. or g/ Kit Ma na ge me nt/ ). Attac h t he air bill. 
8.  Attac h t he dr y ice la bel ( U N 1 8 4 5) a n d t he E xe m pt H u ma n S peci me n stic ker.  
9.  Arra n g e f or Fe d E x pi c k -u p t hr o u g h y o ur site’s us ual pr oce d ure or b y calli n g 8 0 0 -2 3 8 -5 3 5 5.  
 
8.  B a n ki n g Tr a ns l ati o n al Scie nce Bi os peci me ns f or F ut ure Res e arc h 
Bi os peci me ns will re mai n i n t he N R G B B -C ol u m b us a n d ma de a vaila ble f or a p pr o ve d researc h 
pr ojects if t he patie nt has pr o vi de d per missi o n f or t he use of her bi os peci me ns f or f ut ure healt h 
researc h. 
 
N ote: Te sti n g of b a nke d bi os peci me ns will n ot occ ur u ntil a n a me n d me nt t o t his tre at me nt 
pr ot oc ol ( or se p ar ate c orrel ative scie nce pr ot oc ol) is revie we d a n d a p pr ove d i n acc or d a nce wit h 
N ati o n al Cli nic al Tri als Net w ork ( N C T N) p olicies.  
 
T he patie nt’s bi os peci me n c o nse nt c h oices will be rec or de d o n t he si g ne d i nf or me d c o ns e nt 
d oc u me nt a n d electr o nicall y via t he S peci me n C o nse nt f or m. At t he ti me of bi os peci me n 
selecti o n f or pr oj ect distri b uti o n, t he m ost rece nt c o nse nt i nf or mati o n will be use d.  
 
Sites c a n a me n d a p at ie nt’s c h oices re g ar di n g t he f ut ure use of her bi os peci me ns at a n y 
ti me if t he p atie nt c h a n ges her mi n d. 
 
If t he patie nt re v o kes per missi o n t o use her bi os peci me ns, t he N R G B B-C ol u m b us will destr o y 
or ret ur n a n y re mai ni n g bi os peci me ns. T he patie nt’s bi os pe ci me ns will n ot be use d f or a n y 
f urt her researc h; h o w e ver, a n y bi os peci me ns distri b ute d f or res earc h pri or t o re v o ki n g c o nse nt 
ca n n ot be ret ur ne d or destr o ye d. I n a d diti o n, t he patie nt ca n n ot be re m o ve d fr o m a n y res earc h 
t hat has bee n d o ne wit h her bi os peci me ns distri b ute d pri or t o re v o ki n g c o nse nt. 
 
N ote: If ret ur n of bi os peci me ns is re q ueste d, s hi p pi n g will be at t he site’s e x pe nse.  
 
 

 
N R G -G Y 0 1 7  
1 0 9    
Versi o n Date:  N o ve m ber 8 , 2 0 1 8 
A P P E N DI X II –  P E R F O R M A N C E S T A T U S C RI T E RI A  
 
E C O G Perf or m a nce St at us Sc ale  
K ar n ofs k y Perf or m a nce Sc ale  
Gra de  
Descri pti o ns  
Perce nt  
Descri pti o n  
0  
N or mal acti vit y.  F ull y acti ve, a ble 
t o carr y o n all pre-diseas e 
perf or ma n ce wit h o ut restricti o n.  
1 0 0  
N or mal, n o c o m plai nts, n o e vi de nce 
of disease.  
9 0  
A ble t o carr y o n n or mal acti vit y; 
mi n or si g ns or s y m pt o ms of disease.  
1  
S y m pt o ms, b ut a m b ulat or y.  
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 de ntar y n at ure (e. g., li g ht 
h o use w or k, offi ce w or k).  
8 0  
N or mal acti vit y wit h eff ort; s o me 
si g ns or s y m pt o ms of disease. 
7 0  
Cares f or s elf, u na ble t o carr y o n 
n or mal acti vit y or t o d o acti ve w or k.  
2  
I n b e d < 5 0 % of t he ti me.  
A m b ulat or y a n d ca p a ble of all 
self-care, b ut u na bl e 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.  
6 0  
Re q uires occasi o nal assista nce, b ut 
is a ble t o care f or m ost of his/ her 
nee ds.  
5 0  
Re q uires c o nsi dera ble assista nce a n d 
fre q ue nt me di cal care. 
3  
I n b e d > 5 0 % of t he ti me.  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 0  
Disa ble d, re q uires s pecial care a n d 
assista nce.  
3 0  
Se verel y disa ble d, h os pit alizati o n 
i n dicate d.  Deat h n ot i m mi ne nt. 
4  
1 0 0 % be dri d de n.  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 be d 
or c hair.  
2 0  
Ver y sic k, h os pitalizati o n i n dicate d. 
Deat h n ot i m mi ne nt.  
1 0  
M ori b u n d, fatal pr ocesses 
pr o gressi n g ra pi dl y.  
5    
Dea d.  
0    
Dea d.  
 
 

 
N R G -G Y 0 1 7  
1 1 0    
Versi o n Date:  N o ve m ber 8 , 2 0 1 8 
A P P E N DI X III –  R A DI A TI O N T H E R A P Y C O N T O U R S  
 
E xa m ple c o nt o urs f or t h e C T V pri mar y, n o dal v ol u mes, P T V b o ost v ol u mes.  
 
C T V i nt o 3 s u b re gi o ns: C T V n ( n o dal), a n d C T V p 1 a n d C T V p 2 ( pri mar y).  C T V p 1 will c o nsist 
of t he gr oss t u m or, cer vi x, a n d uter us as s h o w n i n Fi g ure 1; C T V p 2 c o nsists of t he para m etria 
a n d s u peri or t hir d of t he va gi na ( or half of t he va gi na, if t he  va gi na is cli nicall y i n v ol ve d), as 
s h o w n i n fi g ure 2.  
 
C T V n will i ncl u de t he P A L N re gi o n t o t he verte bral le vel of L 1/ L 2 i nters pace or 3 c m cra nial t o 
gr oss P A L N disease, c o m m o n, e xter nal, a n d i nter nal iliac a n d presacral l y m p h n o des. It is 
acce pta ble t o  i ncl u de t he mes orectal n o des i n C T V n.  T he u p per b or der of t he C T V n s h o ul d n ot 
e xte n d a b o ve t h e c o nfl ue nce of t he c o m m o n iliac arteries wit h t he a orta (i.e., a ortic bif urcati o n), 
a n d s h o ul d be gi n n o l o wer t ha n s u peri or b or der of L 5.  T he pel vic  
 
T he C T V n  will be o btai ne d b y e ns uri n g a n a p pr o xi matel y 7 m m mar gi n ar o u n d t he vessels, pl us 
e xte nsi o n t o i ncl u de a n y a djace nt visi ble l y m p h n o des, l y m p h oceles, or perti ne nt s ur gical cli ps. 
T he presacral n o des s h o ul d be c o nt o ure d u ntil t he s u peri or b or der of t he S 3  verte bral b o d y is 
reac h e d; bel o w t his p oi nt t he n o dal v ol u me ca n be se parat e d i nt o t w o str uct ures. T he e xt er nal 
iliac n o des s h o ul d be c o nt o ure d t o t he s u peri or as pect of t he fe m oral hea d. C T V n s h o ul d be 
m o difie d t o e xcl u de b o ne, m uscle, a n d b o wel.  T h e C T V s h o ul d n ot e xte n d i nferi or t o t he isc hial 
t u ber osities. 
 
Fi g ure 1: C T V p 1  
 
 

 
N R G -G Y 0 1 7  
1 1 1    
Versi o n Date:  N o ve m ber 8 , 2 0 1 8 
 
Fi g ure 2:  C T V p 2  
 
 
Fi g ure 3: C T V n f or pel vic L N l ocati o ns  
 

 
N R G -G Y 0 1 7  
1 1 2    
Versi o n Date:  N o ve m ber 8 , 2 0 1 8 
 
Fi g ure 4: C T V n f or P A L N l ocati o ns  
 
C T V _ 5 4 0 0: Gr oss pel vic l y m p h n o des ( o bt urat or L N, i nter nal or e xt er nal iliac L N) t hat will 
recei v e B T c o ntri b uti o n.  Para metrial b o osts will be i ncl u de d i n t his v ol u me.  T he P T V _ 5 4 0 0 is a 
7 m m u nif or m e x pa nsi o n ar o u n d C T V _ 5 4 0 0.  C T V _ 5 8 0 0: Gr oss P A L N or pel vic l y m p h n o des 
(c o m m o n iliac hi g h or l o w i nter nal or e xt er nal iliac L N) t hat will N O T recei ve B T c o ntri b uti o n.  
P T V _ 5 8 0 0 is a 7 m m u nif or m e x pa nsi o n ar o u n d C T V _ 5 8 0 0.  
 

 
N R G -G Y 0 1 7  
1 1 3    
Versi o n Date:  N o ve m ber 8 , 2 0 1 8 
 
Fi g ure 5: C T V _ 5 4 0 0 a n d P T V _ 5 4 0 0 f or a pel vic L N b o ost  
 
 
Fi g ure 6: C T V _ 5 8 0 0 a n d P T V _ 5 8 0 0 f or a P A L N b o ost  
 
 

 
N R G -G Y 0 1 7  
1 1 4    
Versi o n Date:  N o ve m ber 8 , 2 0 1 8 
A P P E N DI X I V –  L E T T E R T O P A T H O L O GI S T S  
 
Dear Pat h ol o g ist, 
 
Y o ur site is a partici pa nt i n N R G G Y 0 1 7 , “ A nti P D-L 1 ( Atez oliz u ma b) as a n I m m u ne Pri mer 
a n d C o nc urre ntl y wit h E xte n de d Fiel d C he m ora di ot hera p y f or N o de P ositi ve L ocall y A d va nce d 
Cer vical Ca ncer.”  
 
T his st u d y i ncl u des i nte gr al a n d i nte gr ate d bi o m ar ker testi n g.  
 
•  T he i nte gral testi n g re q uire d t o c o m plete t he pri m ar y o bjecti ve of t he st u d y will use 
D N A  is olate d fr o m f or mali n-fi xe d, paraffi n-e m be d de d ( F F P E) t u m or bi o psies t o 
e xa mi ne T cell  re pert oires. 
•  T he i nte grate d testi n g re q uire d t o c o m plete a  s ec o n d ar y o bjecti ve will use F F P E t u m or  
bi o psies t o stai n f or P D -L 1 at a s p o ns or -desi g nate d la b orat or y. T he P D -L 1 testi n g  
re q uire me nts ma n d ate t h at sli des use d f or testi n g m ust be fres h c ut. 
 
Gi ve n t he bi os peci me n re q uire me nts f or t his bi o mar ker testi n g, N R G G Y 0 1 7 re q uires all sites 
s u b mit F F P E bl oc ks o nl y (i.e., u nst ai ne d sli des will n ot be acce pte d). Bl oc ks ma y be 
s u b mitte d o n a per ma ne nt or te m p orar y basis.  
 
If s u b mitte d o n a te m p orar y basis, bl oc ks will be ret ur ne d after t he c o m pleti o n of t he i nte gral a n d 
i nte grate d bi o mar k er testi n g. T he N R G Bi os peci me n Ba n k ( B B)-C ol u m b us will secti o n bl oc ks 
e ver y si x m o nt hs . At t he ti me of secti o ni n g , t he N R G B B-C ol u m b us wi ll fres h c ut te n 
c o nsec uti ve u nstai ne d secti o ns ( 5 μ m eac h) f or s hi p me nt t o t he desi g nate d la b orat ories.  
 
If ret ur n of t he bl oc k is re q ueste d, t he N R G B B-C ol u m b us will c o nt act y o ur i nstit uti o n f or 
a Fe d E x Acc o u nt n u m ber a n d s hi p pi n g a d dress after  c o m pleti o n of t he i nte gr al a n d 
i nte gr ate d bi o m ar ker testi n g. 
 
If y o u s h o ul d ha ve a n y q uesti o ns, please d o n ot hesitate t o c o ntact Drs. J y oti Ma ya de v ( PI) a n d 
( Tra nslati o nal Researc h Sci e ntist). 
 
We t ha n k y o u i n a d v a nce f or y o ur partici pati o n i n t his trial a n d y o ur c o m mit me nt t o t he 
s uccessf ul c o m pleti o n of t his st u d y’s o bjecti ves. 
 
Si ncerel y,  
 
J y oti Ma ya de v, M D 
 P h D, M P H 
 
 

 
N R G -G Y 0 1 7  
1 1 5    
Versi o n Date:  N o ve m ber 8 , 2 0 1 8 
A P P E N DI X V  - BI O P S Y P A T H O L O G Y V E RI FI C A TI O N  
 
A c o p y of t he c orres p o n di n g pat h ol o g y re p ort m ust be s hi p pe d wit h all  tiss ue bi o s peci me ns se nt 
t o t he N R G B B -C ol u m b us.  
 
If a p at h ol o g y re p ort is n ot a v ail a ble f or t he bi o ps y, a c o p y of t he r a di ol o g y re p ort or 
o per ati ve re p ort fr o m t he bi o ps y pr oce d ure  m ust  be se nt t o t he N R G B B -C ol u m b us . A 
c o m plete d c o p y of t his a p pe n di x  (i.e., Bi o ps y P at h ol o g y Verific ati o n ) m ust  als o be 
s u b mitte d t o t he N R G B B -C ol u m b us . 
 
N ote: If t his i nf or m ati o n is n ot pr o vi de d wit h t he bi o ps y bi os peci me n, it will n ot be 
acce pte d b y t he N R G B B -C ol u m b us.  
 
 
Please ha ve t he pat h ol o gist res p o nsi ble f or si g ni n g o ut t his patie nt’s case c o m plete t he f oll o wi n g: 
 
B a n k I D: _ _ _ _ _ _ _ _ - _ _ _ _ - G _ _ _ _ _ _  
 
St u d y I D: _ _ _ _ _ _ _ _ _ _ - G Y 0 1 7 - _ _ _ _ _ _ _ _ _ _  
 
D ate of Pr oce d ure ( m m/ d d/ y y y y): _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
Tiss ue T y pe (c ircle o ne):   
Rec urre nt  Pri m ar y     
Rec urre nt Met ast atic  
 
Site Tiss ue T a ke n Fr o m: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
Di a g n osis: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
Rec urre nt dise ase d oc u me nte d b y: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
I a gree t hat t his tiss ue ma y be release d f or res earc h p ur p oses o nl y a n d t hat t he release of t his 
tiss ue will n ot ha ve a n y i m pact o n t he patie nt’s care. 
 
 
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Pat h ol o gist’s Si g nat ure    
   
   
   
   
Date  
 
 
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Pat h ol o gist’s Pri nte d Na me  
 
 

 
N R G -G Y 0 1 7  
1 1 6    
Versi o n Date:  N o ve m ber 8 , 2 0 1 8 
A P P E N DI X VI –  N CI/ D C T D C O L L A B O R A TI V E A G R E E M E N T S L A N G U A G E  
 
C oll a b or ati ve A gree me nts L a n g u a ge  
 
Pr ot oc ols t hat i n v ol ve a ge nt(s) c o vere d b y a c olla b orati ve a gree me nt wit h a bi otec h/ p har ma 
c o m pa n y(ies) m ust i nc or p orate t he N CI/ D C T D C olla b orati ve A gree me nt La n g ua ge s h o w n 
bel o w.  
 
T he a ge nt(s) s u p plie d b y C T E P, D C T D, N CI use d i n t his pr ot oc ol is/are pr o vi de d t o t he N CI 
u n der a C olla b orati ve A gree me nt ( C R A D A, C T A, C S A) bet wee n t he P har mace utica l 
C o m pa n y(ies) ( herei naft er referre d t o as “ C olla b orat or(s)”) a n d t h e N CI Di visi o n of Ca ncer 
Treat me nt a n d Dia g n osis.  T heref ore, t he f oll o wi n g o bli gati o ns/ g ui deli nes, i n a d diti o n t o t he 
pr o visi o ns i n t he “I nt ellect ual Pr o pert y O pti o n t o C olla b orat or” 
( http://cte p.ca ncer. g o v/i n d ustr y C olla b orati o ns 2/i ntellect ual _ pr o pert y. ht m) c o ntai ne d wit hi n t he 
ter ms of a war d, a p pl y t o t he use of t he A ge nt(s) i n t his st u d y: 
 
1.   A ge nt(s) ma y n ot be use d f or a n y p ur p ose o utsi de t he sc o pe of t his pr ot oc ol, n or ca n 
A ge nt(s) be tra nsferre d or lice nse d t o a n y part y n ot partici pati n g i n t he cli nical st u d y.  
C olla b orat or(s) dat a f or A ge nt(s) are c o nfi de ntial a n d pr o prietar y t o C olla b orat or(s) a n d s hall be 
mai ntai ne d as s uc h b y t h e i n vesti gat ors. T he pr ot oc ol d oc u me nts f or st u dies  utilizi n g A ge nts 
c o ntai n c o nfi de ntial i nf or mati o n a n d s h o ul d n ot be s hare d or distri b ute d wit h o ut t he per missi o n 
of t he N CI.  If a c o p y of t his pr ot oc ol is re q ueste d b y a patie nt or patie nt’s fa mil y me m ber 
partici pati n g o n t he st u d y, t he i n di vi d ual s h o ul d  si g n a c o nfi de ntialit y a gree me nt. A s uita ble 
m o del a gree m e nt ca n b e d o w nl oa de d fr o m: htt p://cte p.ca ncer. g o v.  
 
2.   F or a cli nical pr ot oc ol w here t here is a n i n vesti gati o nal A ge nt use d i n c o m bi nati o n wit h 
(a n) ot her A ge nt(s), eac h t he s u bject of differe nt Colla b orati ve A gree me nts, t he access t o a n d use 
of data b y eac h C olla b orat or s hall be as f oll o ws ( data pertai ni n g t o s uc h c o m bi nati o n use s hall 
herei nafter be referre d t o as “ M ulti -Part y Data”):  
 
a.   N CI will pr o vi de all C olla b orat ors wit h pri or writte n n o tice re gar di n g t he e xiste nce a n d 
nat ure of a n y a gree me nts g o ver ni n g t heir c olla b orati o n wit h N CI, t he desi g n of t he pr o p ose d 
c o m bi nati o n pr ot oc ol, a n d t he e xiste nce of a n y o bli gati o ns t hat w o ul d te n d t o restrict N CI's 
partici pati o n i n t he pr o p ose d c o m bi nat i o n pr ot oc ol. 
 
b.   Eac h C olla b orat or s h all a gree t o p er mit use of t he M ulti -Part y Data fr o m t he cli nical trial b y 
a n y ot her C olla b orat or s olel y t o t he e xte nt necess ar y t o all o w sai d ot her C olla b orat or t o de vel o p, 
o btai n re g ulat or y a p pr o val or c o m mercializ e its o w n A ge nt.  
 
c.   A n y C olla b orat or ha vi n g t he ri g ht t o use t he M ulti -Part y Data fr o m t hese trials m ust a gree i n 
writi n g pri or t o t he c o m me nce me nt of t he trials t hat it will use t he M ulti -Part y Data s olel y f or 
de vel o p me nt, re g ulat or y a p pr o val, a n d c o m m erci alizati o n of its o w n A ge nt.  
 
3.   Cli nical Trial Data a n d Res ults a n d Ra w Data de vel o pe d u n der a C olla b orati ve A gree me nt 
will be ma de a vaila ble t o C olla b orat or(s), t he N CI, a n d t he F D A, as a p pr o priate a n d u nless 
a d diti o nal discl os ure is re q uire d b y la w  or c o urt or der as d escri be d i n t he I P O pti o n t o 

 
N R G -G Y 0 1 7  
1 1 7    
Versi o n Date:  N o ve m ber 8 , 2 0 1 8 
C olla b orat or ( htt p://cte p.ca ncer. g o v/i n d ustr y C olla b orati o ns 2/i ntellect ual _ pr o pert y. ht m). 
A d diti o nall y, all Cli nical Data a n d Res ults a n d Ra w Data will be c ollecte d, use d a n d discl ose d 
c o nsiste nt wit h all a p p lica ble fe d eral stat utes a n d re g ulati o ns f or t he pr otecti o n of h u ma n 
s u bjects, i ncl u di n g, if a p plica ble, t he St a n d ar ds f or Priv acy of I n divi d u ally I de ntifi a ble He alt h 
I nf or m ati o n set f ort h i n 4 5 C. F. R. Part 1 6 4. 
 
4.   W he n a C olla b orat or wis hes t o i nitiate a data re q uest, t he re q uest s h o ul d first be se nt t o t he 
N CI, w h o will t he n n otif y t he a p pr o priat e i n vesti gat ors ( Gr o u p C hair f or C o o perati ve Gr o u p 
st u dies, or PI f or ot her st u dies) of C olla b orat or's wis h t o c o ntact t he m. 
 
5.   A n y data pr o vi de d t o  C olla b orat or(s) f or P hase 3 st u dies m ust be i n acc or da nce wit h t he 
g ui deli nes a n d p olicies of t he res p o nsi ble Data M o nit ori n g C o m mittee ( D M C), if t here is a D M C 
f or t his cli nical trial. 
 
6.   A n y ma n uscri pts re p orti n g t he res ults of t his cli nical trial m u st be pr o vi de d t o C T E P b y t he 
Gr o u p office f or C o o perati ve Gr o u p st u dies or b y t he pri nci pal i n vesti gat or f or n o n -C o o perati ve 
Gr o u p st u dies f or i m me diate deli ver y t o C olla b orat or(s) f or a d vis or y re vi e 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.  C olla b orat or(s) will ha ve 3 0 da ys fr o m t he date of recei pt f or 
re vie w.  C olla b orat or 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 der t o e ns ure t h at C olla b orat or’s c o nfi de ntial a n d pr o prietar y dat a, i n 
a d ditio n t o C olla b orat or(s)’s i ntellect ual pr o pert y ri g hts, are pr otecte d.  C o pies of a bstracts m ust 
be pr o vi de d t o C T E P f or f or war di n g t o C olla b orat or(s) f or c o urtes y re vie w as s o o n as p ossi ble 
a n d prefera bl y at least t hree ( 3) d a ys pri or t o s u b missi o n, b ut i n a n y case, pri or t o prese ntati o n at 
t he meeti n g or p u blicati o n i n t he pr ocee di n gs. Press releases a n d ot her me dia prese ntati o ns m ust 
als o be f or war de d t o C T E P pri or t o release. C o pi es of a n y ma n uscri pt, a bstract a n d/ or press 
releas e/ me dia pres e ntati o n s h o ul d be se nt t o: 
 
E mail: ncicte p p u bs @ mail. ni h. g o v   
 
T he Re g ulat or y Affairs Bra nc h will t he n distri b ute t he m t o C olla b orat or(s).  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 C olla b orat or’s c o nfi de ntial/ 
pr o prietar y i nf or mati o n.